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September 2016


Original Article

Evaluation of Platelet Indices in Young Male Patients with Hepatitis C

Murat Afyon 1, Cumhur Artuk 2, Ercan Yenilmez 3, Berksan Şimşek 4, Ayper Kaya 4

1 Primary Care Inspection, Clinic of Family Health Center and the Naval Academy, Gülhane Military Medical Academy Haydarpaşa Teaching Hospital, Istanbul, 2 Department of Infectious Diseases, Gülhane Military Medical Academy Training and Research Hospital, Ankara, 3 Department of Infectious Diseases, Gülhane Military Medical Academy Haydarpaşa Teaching Hospital, Istanbul, 4 Kasımpasa Military Hospital, Istanbul, Turkey

DOI: 10.4328/JCAM.4537 Received: 05.04.2016 Accepted: 25.04.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 706-10

Corresponding Author: Murat Afyon, Gülhane Military Medical Academy Haydarpaşa Teaching Hospital, Primary Care Inspection, Clinic of Family Health Center and the Naval Academy, Tuzla, Istanbul, Turkey. GSM: +905056528032, +905377653082 E-Mail: muratafyon2002@yahoo.com, muratafyon79@gmail.com

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Abstract

Aim: In light of the fact that platelet counts and sizes or lymphocyte counts may be altered in patients with hepatitis C virus (HCV) depending upon the severity of inflammation or fibrosis, we aimed to investigate the values and the roles of platelet indices and platelet-to-lymphocyte ratio (PLR) in male patients with HCV infection compared with healthy controls. Material and Method: Patients with HCV infection who applied to an Infectious Diseases clinic between 01 January 2012 and 01 June 2015 were evaluated retro-spectively. Overall, 21 male HCV patients who underwent percutaneous liver biopsy and 22 gender-and age- matched healthy controls were included in the study. Statistical analyses were performed by SPSS 15.0. Results: There was no significant difference in age variable between the patients group with an age range of 21-41 years [22 (Iq=4), 24.62±5.84 years] and the con-trol group with an age range of 21-41 years [22,5 (Iq=5), 24.59±5.21 years]. The distribution of fibrosis scores among HCV patients was 23.8% fibrosis score 1, 61.9% fibrosis score 2, and only 14.3% fibrosis score 3. Lymphocyte counts, platelet counts, PLR, platelet volume, distribution width, and platelet-crit values were lower, and mean platelet volume (MPV) values were higher, in the patients group compared with controls, but there was no statistical dif-ference between the two groups. There was also no significant difference in platelet counts, platelet indices, or PLR values between groups according to the fibrosis scores or according to the histological activity index (HAI) score. Discussion: In our study, there were minimally but not significantly affected platelet counts, platelet indices, and PLR values in young adult male patients with minimal or moderate fibrosis induced by HCV infection. However, in pa-tients with advanced liver fibrosis or cirrhosis whose platelet counts may be lower, platelet indices may increase in importance.

Keywords: Hepatitis C Virus; Fibrosis; Platelet Indices; Mean Platelet Volume; Platelet-To-Lymphocyte Ratio

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Introduction

Chronic hepatitis C virus (HCV), a leading cause of cirrhosis and hepatocellular carcinoma, is a global health problem with 80-185 million infected individuals worldwide, although the treatment of HCV has shown significant progress with the development of direct-acting antivirals [1]. Percutaneous liver biopsy is the gold standard for detection of liver fibrosis, which is important in predicting prognosis and selecting treatment options in patients with viral hepatitis [2]. However, because liver biopsy is an invasive method and may cause severe complications, there are attempts to find non-invasive predictive models to substitute for liver biopsy; these include elastography, Forns’ index, FIB-4 index (fibrosis index based on four factors), non-invasive hepatitis C related cirrhosis early detection (NIHCED) score, aspartate aminotransferase-to-platelet ratio index (APRI), and platelet indices [3-7].

Platelets also have an important role in the inflammatory response, apart from their function in haemostasis. Their counts or sizes may change in parallel with the severity of infections, including primary viral hepatitis [3-11]. Furthermore, fibrosis severity in patients with hepatitis is another factor influencing platelet counts and indices [3-7].

Aside from total platelet count, indices of platelets such as mean platelet volume (MPV), platelet volume distribution width (PDW), and plateletcrit (PCT) can easily be calculated from routine complete blood count (CBC). MPV measures the average size of the platelets and indicates platelet activation. MPV levels have been described as a diagnostic or prognostic predictor not only for patients with prothrombotic conditions including obesity, hypercholesterolemia, diabetes, hypertension, smoking, and arterial stiffness, but also for those with proinflammatory conditions including rheumatic diseases or infectious disorders such as sepsis, infective endocarditis, pneumonia, or viral hepatitis [3-11]. Also, decreased MPV levels in human immunodeficiency virus (HIV) patients compared with controls have been shown to be correlated with PCT, PDW, and viral load [12]. PDW, an indicator of the variation in platelet size, has also been found significantly higher in non-survivor sepsis patients and has been defined as an independent variable determining the severity of fibrosis [5, 8, 9]. PCT, a reliable parameter of platelet biomass but also the most neglected CBC parameter in clinical practice, is influenced by platelet numbers as well as platelet sizes [8, 12, 13]. PCT has been reported to be negatively correlated with parasitema in patients with malaria caused by Plasmodium vivax [13]. Abnormal platelet indices have also been found to be associated with more severe illness and higher risk of death in intensive care unit patients [14].

Not only platelet counts, but also lymphocyte counts can be affected by chronic inflammatory diseases, infectious diseases, malignancies and myeloproliferative disorders [15-17]. Therefore, the platelet-to-lymphocyte ratio (PLR) may be altered by these disorders. PLR has been shown to be associated with inflammation and inflammation severity and is also described as an independent predictor of some infectious diseases such as infective endocarditis [15-17].

In this study, in light of the fact that platelet counts and sizes or lymphocyte counts may be altered in patients with HCV infection depending upon the severity of inflammation or fibrosis, we aimed to investigate the values and the roles of platelet indices and PLR in male patients with HCV infection compared with healthy controls.

Material and Method

For this study, ethics committee approval was obtained from the Gülhane Military Medical Academy Haydarpaşa Teaching Hospital Non-invasive Clinical Research Ethics Committee. Patients with HCV infection who applied to the Kasımpasa Military Hospital Infectious Diseases clinic between 01 January 2012 and 01 June 2015 were evaluated retrospectively. Male HCV patients who underwent percutaneous liver biopsy were included in the study. Patients with hepatitis B (HBV) or HIV coinfection or with comorbidities such as chronic inflammatory diseases, malignancies, corticosteroid use, myeloproliferative disorders, and other any infectious diseases were excluded. Gender- and age-matched healthy individuals with no known disease and normal physical examination from whom blood samples had been obtained between the same dates were enrolled in the control group.

In the patients group, the data including patients’ age, platelet counts, lymphocyte counts, values of MPV, PDW, PCT, and PLR, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, HCV ribonucleic acid (RNA) levels, fibrosis score, and histological activity index (HAI) score were recorded. Also age, platelet counts, lymphocyte counts, and values of MPV, PDW, PCT, and PLR of healthy controls were noted. In the patients group, CBC was performed with samples that had been taken about one week before liver biopsy. Fibrosis score and HAI score were evaluated by means of modified histological activity index.

Statistical analyses were performed by SPSS 15.0 (SPSS Inc., Chicago, IL, USA). For determining the distribution of continuous variables, the Shapiro-Wilk test was used. All continuous variables were summarized as mean±standard deviation and median [interquartile range (Iq)]. The Mann-Whitney U test or Student’s t-test were applied to compare continuous variables. Correlations between the variables were examined using Pearson’s test or Spearman’s correlation test, depending on the normality of the data distribution. Also, the differences in the variables were analyzed using analysis of variance (ANOVA) or the Kruskal–Wallis tests. p values <0.05 were considered to be statistically significant for all analyses.

Results

Overall, 21 male patients who underwent liver biopsy due to HCV infection without any comorbidities were enrolled in the patients group and 22 gender- and age-matched healthy individuals were included as the control group. All HCV patients were treatment naive. The age variable was not distributed normally. There was no significant difference (p=0.800) in the age variable between the patients group, with an age range of 21-41 years [22 (Iq=4), 24.62±5.84 years], and the control group with an age range of 21-41 years [22.5 (Iq=5), 24.59±5.21 years].

While platelet count, PLR, and MPV variables were distributed normally, lymphocyte count, PCT, and PDW variables were not distributed normally. Results of these parameters are summarized in Table 1. Lymphocyte counts, platelet counts, PLR, PCT, and PDW values were lower, and MPV values were higher in the patients group compared with controls, but there was no statistical difference between the two groups (respectively, p=0.551, p=0.562, p=0.656, p=0.117, p=0.362 and p=0.433).

Patients were divided into 3 groups according to their fibrosis score. There were 5 patients with fibrosis score 1 (23.8%), 13 patients with fibrosis score 2 (61.9%), and only 3 patients with fibrosis score 3 (14.3%). The results of platelet counts, MPV, PDW, PCT, and PLR according to the fibrosis score in the patients group are summarized in Table 2. There was no significant difference in platelet counts, MPV, PDW, PCT, and PLR variables between the groups according to the fibrosis scores, whereas there were declining trends in platelet counts, MPV, and PLR levels when the fibrosis score increased.

Patients were divided into two groups according to their HAI score. Patients whose HAI score was equal or lower than 6 (n=14, 66.7%) were in the first group and patients whose HAI score were higher than 6 (n=7, 33.3%) were in the second. Results of platelet counts, MPV, PDW, PCT, and PLR according to the HAI score in the patients group are summarized in Table 3. All parameters were lower in patients with higher HAI score, but there was not any significant difference between groups.

The mean AST value was 57.57±28.71 U/l with a range of 23-124 U/l. There was no correlation between AST-platelet counts (r=0.226, p=0.324), AST-PLR (r=0.056, p=0.811), AST-MPV (r=0.155, p=0.502), AST-PCT (r=0.341, p=0.130), and AST-PDW (r=-0.050, p=0.829).

The mean ALT value was 97.14±71.70 U/l with a range of 23-285 U/l and median (Iq) of 66 (118). Also, we found no correlation between ALT and platelet counts, PLR, MPV, PCT, or PDW (respectively, r=0.274 and p=0.229, r=0.232 and p=0.311, r=-0.105 and p=0.652, r=0.236 and p=0.303, r=0.017 and p=0.942).

The mean HCV RNA level was 6.12±0.26 log10 IU/ml with a range of 2.76-7.28 log10 IU/ml and median (Iq) of 6.56 (1.57) log10 IU/ml. There was also no correlation between HCV RNA-platelet counts (r=0.144, p=0.533), HCV RNA-PLR (r=-0.065, p=0.780), HCV RNA-MPV (r=-0.101, p=0.664), HCV RNA-PCT (r=0.091, p=0.695), and HCV RNA-PDW (r=-0.246, p=0.283).

Discussion

Platelets have an important role in the inflammatory response in addition to their function in haemostasis. Platelet numbers and sizes may be affected depending upon the severity of inflammation in patients with infection and also the severity of fibrosis in patients with viral hepatitis such as HBV or HCV [3-7]. Accordingly, we investigated the values and the roles of platelet numbers, platelet indices, and PLR in young adult male patients with HCV infection compared with healthy controls.

The median age was 22 (Iq=4) years and the mean age was 24.62±5.84 years in the patients group with an age range of 21-41 years. The distribution of fibrosis scores was 23.8% fibrosis score 1, 61.9% fibrosis score 2, and only 14.3% fibrosis score 3. Also, 14 patients (66.7%) had an HAI score equal to or lower than six and 7 patients (33.3%) had an HAI score higher than six. We think that these low scores, particularly fibrosis scores, may result from the fact that the patients were young adults and so their exposure to the virus has been of short duration.

In our study, platelet counts and also PLR values were lower in the patients group compared with in controls, but there was no statistical difference between the two groups. Due to immune mechanisms including platelet-specific antibodies or auto-immunity, HCV-mediated bone marrow suppression, hypersplenism, inadequate production of trombopoietin, endothelial dysfunction, and drugs used in therapy or fibrosis, thrombocytopenia can be seen with 24% prevalence in patients with HCV infection [18]. Indeed, hypersplenism, inadequate production of trombopoietin, and endothelial dysfunction are associated with advanced fibrosis [18]. So, it may be that because our patients had minimal or moderate fibrosis, there was no significant difference in platelet counts between patients and controls. Furthermore, there are trials suggesting different results regarding platelet numbers in patients with HBV or HCV infection [3-7, 19-23].

We found lower PCT and PDW values and higher MPV values in the patients group compared with the controls. However, there was no statistical difference between the two groups. Under normal circumstances, high MPV levels in destructive thrombocytopenia and low MPV levels in hypoproliferative thrombocytopenia, high PDW values due to swelling, destruction, and immaturity, and PCT values are expected to be non-linearly correlated with platelet counts [8, 9, 24]. PDW has been considered to be a more reliable marker for distinguishing hyperdestructive thrombocytopenia from hypoproductive thrombocytopenia [24]. In the literature, there are studies showing higher MPV values in patients with HCV or HBV infection, no significant difference in MPV values in acute HBV patients or inactive HBV carriers, decreased MPV levels in HIV patients, and lower PCT values and higher PDW values in patients with HBV infection compared with those in controls [6, 7, 12, 20-23]. We consider that platelet indices in our patients may not be significantly affected, in parallel with minimal thrombocytopenia.

Among HCV patients in this study, there was no significant difference in platelet counts, MPV, PDW, PCT, and PLR variables between groups according to the fibrosis scores or according to the HAI score, whereas there were declining trends in platelet counts, MPV, and PLR levels when the fibrosis score increased, and all parameters were lower in patients with a higher HAI score. There are also debates about the predictive value of platelet indices. Although MPV has been shown to be positively correlated with the model for end-stage liver disease (MELD) score, not only high MPV values but also low MPV values have been reported to be independent predictors for cirrhosis or in determining the severity of fibrosis in different trials [3-7]. Also, in a study investigating MPV levels in patients with HBV or HCV infection, no reliable results in HBV patients have been reported [3]. In contrast, in patients with HCV infection, MPV has been described as a useful marker in predicting advanced liver damage [3]. In one study, PDW was determined to be an independent variable determining the severity of fibrosis in HBV patients, while another study including HBV patients showed that there was no significant difference in PDW levels between the groups according to the fibrosis scores [4, 5].

In our study, no correlation between serum AST, ALT, or HCV RNA levels and platelet indices was found in young adult male patients with HCV infection. In the literature, decreased MPV levels in HIV patients have been shown to be correlated with PCT, PDW, and viral load [12]. Also, platelet counts and PCT have been reported to be inversely correlated with HBV deoxyribonucleic acid (DNA) levels [25]. In another study, there was no difference in MPV values between patients with normal ALT levels and patients with high ALT levels or between patients with HCV RNA negativity and patients with HCV RNA positivity [23].

There are several limitations in the present study, the most important of which is the retrospective design. In addition, the number of study patients was limited. One of the reasons for this limitation was the difficulty in finding HCV patients who underwent liver biopsy. The fact that the study was a single-center study may be another drawback and another cause of the limited number of study patients. Furthermore, the patients included in the study were young adults and male because our hospital is a military hospital and our patients are usually young adult males. This may result in short exposure duration to the virus and therefore resulting in low fibrosis scores.

Consequently, it is a fact that thrombocytopenia can be seen in patients with HCV infection, there is a relation between severity of fibrosis and platelet counts, and platelet indices may be altered due to thrombocytopenia [18, 24]. The question remains whether platelet counts, platelet indices, or PLR in patients with minimal or moderate fibrosis may differ significantly from those in healthy individuals. In our study, there were minimally but not significantly affected platelet counts, platelet indices, and PLR values in young adult male patients with minimal or moderate fibrosis induced by HCV infection. However, in patients with advanced liver fibrosis or cirrhosis whose platelet counts may be lower, platelet indices may increase in importance. There are several attempts to find non-invasive predictive models to substitute for liver biopsy. Although there are debates about the value of platelet indices in predicting or determining the severity of fibrosis and there are several disorders affecting platelet indices as a confounding factor, platelet indices, especially in a scoring system, may be a cost-effective and useful marker for evaluating the fibrosis degree in patients with viral hepatitis. However, in order to highlight the role and importance of platelet indices in patients with viral hepatitis, randomized large-scale studies are required. We are planning to investigate different scoring systems containing platelet indices and evaluating the fibrosis degree in patients with viral hepatitis in a large-scale, multi-center study.

Competing interests

The authors declare that they have no competing interests.

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Murat Afyon, Cumhur Artuk, Ercan Yenilmez, Berksan Simsek, Ayper Kaya. Evaluation of Platelet Indices in Young Male Patients with Hepatitis C. J Clin Anal Med. 2016;7(5):706-710

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VEGF, sVEGFR-1 and Endostatin Serum Levels and VEGF Polymorphisms in Recurrent Aphthous Stomatitis

Salim Yüce 1, Binnur Bağcı 2, Gökhan Bağcı 3, Mansur Doğan 1, Sema Koç 4, İlhan Sezgin 3, Ferhan Candan 5, İsmail Önder Uysal 1

1 Department of Otorhinolaryngology, Faculty of Medicine, Cumhuriyet University, Sivas, 2 Department of Nutrition and Dietetics, Faculty of Health Sciences, Cumhuriyet University Sivas, 3 Department of Medical Genetics, Faculty of Medicine, Cumhuriyet University, Sivas, 4 Department of Otorhinolaryngology, Antalya Training and Research Hospital, Antalya, 5 Department of Internal Medicine, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey

DOI: 10.4328/JCAM.4523 Received: 31.03.2016 Accepted: 18.04.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 701-5

Corresponding Author: Binnur Bağcı, Department of Nutrition and Dietetics, Faculty of Health Sciences, Cumhuriyet University, 58140 Sivas, Turkey. T.: +90 3462192523 F.: +90 3462191261 E-Mail: binnur.koksal@hotmail.com

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Aim: Recurrent aphthous stomatitis (RAS) is one of the most frequent dis-eases of the oral mucosa, characterized by chronic, painful, recurrent, and necrotizing ulcerations. The precise etiology and pathogenesis of RAS have not been clarified. Therefore, we aimed to investigate serum levels of VEGF, sVEGFR-1, and endostatin as well as the frequencies of VEGF +936 C/T and -1154 G/A single nucleotide polymorphisms (SNPs) in Turkish patients with recurrent aphthous stomatitis. Material and Method: Forty-two patients with RAS (24 minor RAS and 18 major RAS) and 37 healthy subjects were included in the study. Serum levels of VEGF, sVEGFR-1, and endostatin were measured using the ELISA method. VEGF +936 C/T and -1154 G/A SNPs were deter-mined by the PCR-RFLP method. Results: The mean serum level of VEGF was found higher in bearing CC genotype of +936 C/T SNP compared with CT genotype (639.5 ± 309.1 vs 442.1 ± 197.8; p = 0.032). VEGF -1154 GA genotype was found to be more frequent in patients with minor RAS and GG genotype was more frequent in patients with major RAS (p = 0.022). There was a significant difference between minor RAS and major RAS with regard to mean VEGF serum levels (677.1 ± 316.7 vs 492.9 ± 242.7; p = 0.032).Discussion: The T allele of +936 C/T SNP is associated with decreased se-rum VEGF level, and this decrease may have a contributory role in impaired neovascularization and re-epithelialization in the etiology and pathogenesis of RAS. Further studies are needed to determine the role of VEGF in RAS susceptibility and its clinical manifestations.

Keywords: Recurrent Aphthous Stomatitis; VEGF; VEGFR-1; Endostatin; Polymorphism

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Introduction

Recurrent aphthous stomatitis (RAS) is one of the most frequent diseases of the oral mucosa, characterized by chronic, painful, recurrent, and necrotizing ulcerations. These superficial and rounded ulcers can be basically defined as an inflammation containing non-keratinized mucosa. RAS lesions have been classified as minor, major, and herpetiform ulcerations [1]. The precise etiology and pathogenesis of RAS have not been clarified. Several factors including nutrition, food hypersensitivity, drugs, infection, tobacco, hormones, trauma, and psychological stress are generally considered important etiologic factors for the development of RAS [2]. RAS must be distinguished from other diseases which cause recurrent oral ulcers, such as Behcet’s disease (BD), celiac disease, Crohn’s disease, and systemic lupus erythematosus [3].

Vascular endothelial growth factor (VEGF), a member of a multifunctional growth factor family, has an important role including migration, proliferation, and differentiation of endothelial cells [4, 5]. VEGF is important and necessary both during development and vasculogenesis. VEGF is also considered a pivotal mediator of angiogenesis during wound healing [6, 7]. VEGF has a pleiotropic role in tissue repair via neovascularization, re-epithelialization, and the regulation of extracellular matrix [8].

The gene encoding human VEGF is located on chromosome 6p21.3 and the gene consists of 8 exons [9]. Several single nucleotide polymorphisms (SNPs) have been identified in the VEGF gene [10]. It has been found that the serum VEGF level is increased in patients with BD [11]. The +936 C/T (rs3025039) SNP is located in the 3’ UTR of the VEGF gene. Several researchers found that carriers of a +936 T allele had significantly lower VEGF plasma levels than non-carriers [12-14]. The −1154 G/A (rs1570360) SNP is in the promoter region of the VEGF gene. It has been reported that VEGF −1154 A/A and G/A genotypes were linked with low VEGF expression [15-16].

To date, five VEGF ligands have been identified. These ligands bind to three VEGF receptors (VEGFR-1, VEGFR-2, VEGFR-3) as well as to co-receptors, such as neuropilins and heparan sulphate proteoglycans. The VEGFRs induce cellular processes including cell migration, proliferation, and survival. VEGFR-1 acts as a positive regulator for monocyte and macrophage migration, and a positive and negative regulator of VEGFR-2 signaling capacity [17].

Under normal conditions, there is a balance between endogenous angiogenic inducers and endogenous angiogenic inhibitors that keep the angiogenic process in check and prevent inappropriate vascularization of tissues. Angiogenesis inhibitors are often derived from circulating extracellular matrix proteins. Endostatin is a cleaved product of the carboxyl-terminal domain of collagen XVIII [18] and is an endogenous inhibitor of angiogenesis; it may interfere with the pro-angiogenic action of growth factors including VEGF. In in vivo and in vitro, endostatin inhibits the migration of endothelial cells and induces apoptosis of endothelial cells [19].

To the best of our knowledge, there is no research investigating the association of VEGF +936 C/T and -1154 G/A SNPs with RAS in the literature. Therefore, in this study, we aimed to investigate serum levels of VEGF, sVEGFR-1, and endostatin as well as the frequencies of VEGF +936 C/T and -1154 G/A SNPs in Turkish patients with RAS.

Material and Method

Subjects

A total of 42 patients with RAS (18 males, 24 females; mean age: 40.26 ±14.75 years, range: 15-82 years) and 37 healthy control subjects (19 females, 18 males; mean age: 35.43± 18.97 years; range: 17-82 years) were included in the study. All subjects were Caucasian Turkish. Both the patient and control groups were from the same geographical region. The diagnosis of RAS had been made based on accepted clinical criteria [20]. The study was approved by the local ethics committee. All participants were given a written, informed consent.

Measurement of Serum levels of VEGF, sVEGFR-1, and Endostatin

Blood samples of 5 cc were collected from patient and control groups. The samples were centrifuged at 3000 rpm for 10 min and obtained serums were portioned and kept at -80 °C until the analysis time. Then these samples were cooled to room temperature at the same time and serum VEGF (AviBion Human VEGF ELISA Kit, Vantaa, Finland), sVEGFR-1 (Human sVEGFR1/sFLT1 PicoKine ELISA Kit, Boster Biological Technology, Pleasanton, CA, USA), and endostatin (Human Endostatin ELISA Kit, Assay Biotech, Sunnyvale, CA, USA) levels were measured using the enzyme-linked immunosorbent assay (ELISA) method.

Genotyping

Blood samples of 2-3 cc obtained from both RAS patients and control subjects were collected in tubes containing K3EDTA and were stored at -20 C° until the study time. Total genomic DNA was isolated using a commercial DNA isolation kit (QIAamp DNA Mini Kit, Qiagen, Hilden, Germany). For genotyping of the VEGF SNPs, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used.

VEGF gene +936 C/T and -1154 G/A SNPs were amplified by PCR. The primers for +936 C/T and -1154 G/A were as following: forward: 5’-TCCTGCTCCCTCCTCGCCAATG-3’ and reverse 5’-GGCGGGGACAGGCGAGCCTC-3’; and forward: 5’-AGGGTTTCGGGAACCAGATC-3’ and reverse: 5’-CTCGGTGATTTAGCAGCAAG-3’ respectively. PCR was performed in a final volume of 25 µl using 12, 5 µl 2X PCR master mix (Thermo Fisher Scientific, Massachusetts, USA), 1 µl of each primer and 150-200 ng genomic DNA. After the initial denaturation step at 95oC for 5 min, 35 cycles consisted of denaturation at 95oC for 45 sec, annealing at 62oC for 45 sec, elongation at 72oC for 30 sec, and final elongation at 72oC for 10 min. Genotypes were identified by RFLP. Fast digest restriction enzymes, MnlI and NlaIII (Thermo Fisher Scientific, Massachusetts, USA) were used to detect +936 C/T and -1154 G/A SNPs, respectively. PCR products were digested with 1 U of restriction enzymes at 37oC for 5 to 15 min, and then electrophoresis was performed using a 3% agarose gel.

Statistical Analysis

SPSS version 22.0 (SPSS IBM, Armonk, NY, USA) was used for all statistical analyses. For the comparison of independent samples, Student’s T-test or Mann-Whitney U test were used. According to power and sample size analysis, approximately 40 subjects were included in each group to have statistical power of 80%, for a Student’s t-test comparing means between the patient and control groups. Chi-square test or Fisher’s exact test was used for the comparison of categorical data between RAS patients and controls. One-way ANOVA with Tukey test were used to compare mean serum VEGF levels with regard to genotypes of VEGF -1154 G/A SNP. A p value of less than 0.05 was accepted as significant and all results were given with a 95% confidence interval.

Results

The mean age was 40.26±14.75 years in the patient group and was 35.43±18.97 years in the control group. In terms of age, the difference between the two groups was not significant (p > 0.05). Of those in the patient group, 18 were males (42.9%) and 24 were females (57.1%) while the control group was composed of 18 females (48.6%) and 19 males (51.4%). The difference was not significant when the groups were compared in terms of gender (p > 0.05). In the study group, there were 24 (57.1%) minor aphthous ulcers and 18 (42.9%) major aphthous ulcers. Recurrence frequencies of oral aphthous ulcer were 30 days in 19 individuals (45.2%), 30-90 days in 17 individuals (40.5%), and 90+ days in 6 individuals (14.3%). Of those in the patient group, 7 (16.7%) had a comorbidity (heart disease, diabetes mellitus, hypertension, etc.).

The number of smokers was 3 and ex-smokers 7 in the patient group: there were no smokers or ex-smokers in the control group. While there was a triggering factor (chocolate, spice, stress, dust mites) in 16 (38.1%) of those in the patient group, there was no triggering factor in the control group. In the patient group, septal deviation was observed in 12 (28.6%) patients while none of the patients in the control group had septal deviation. When the groups were compared for oral hygiene, the difference was not significant (p>0.05). Ten (23.8%) of those in the patient group and 5 (13.5%) of those in the control group were receiving medication (for disease treatment). In the patient group, 30 (71.4%) patients recovered over the short term while 12 (28.6%) patients recovered over the long term.

Table 1 shows the comparison of serum levels of VEGF, sVEGFR-1 and endostatin among RAS, minor RAS, major RAS, and control groups. Compared to controls, mean serum levels of VEGF, sVEGFR-1, and endostatin were not significantly different in patients (p > 0.05 for all comparisons). On the other hand, when we compared minor RAS with major RAS, statistically significant difference was found between these two groups with regard to mean VEGF serum levels (p = 0.032). Contrary to this, no significant difference was found with regard to sVEGFR-1 and endostatin serum levels (p > 0.05).

When the VEGF +936 C/T and VEGF -1154 G/A gene SNP of the patients and control groups were compared with regard to genotype and allele frequencies, the difference was not found statistically significant (Table 2).

We also examined VEGF genotypes according to size of aphthous ulcer, recurrence frequency, comorbidity, recovery time, triggering factor, and septum deviation. VEGF -1154 GA genotype was found to be more prevalent in patients with aphthous ulcers smaller than 5 mm (minor RAS) and the GG genotype was found to be more prevalent in patients with aphthous ulcers greater than 5 mm (major RAS) (p = 0.022). Moreover, +936 CC genotype was observed more frequently in those having no triggering factor (88.5% vs. 62.5%) while the CT genotype was found in those having a triggering factor (37.5% vs. 11.5%). However, this difference was not statistically significant (p>0.05). We did not find any significant association with the other clinical characteristics of patients with RAS (Table 3).

Table 4 demonstrates VEGF serum levels with regard to genotypes of VEGF SNPs in RAS, minor RAS, and major RAS. Mean serum level of VEGF was found higher in CC genotype of +936 C/T SNP compared with CT genotype (639.5 ± 309.1 vs 442.1 ± 197.8; p = 0.032). However, it was not statistically significant in minor and major RAS (p > 0.05 for both comparisons). No significant difference was found in terms of mean serum VEGF levels among genotypes of VEGF -1154 G/A SNP (p > 0.05 for all comparisons).

Discussion

In the present study, we demonstrated that VEGF +936 C/T and -1154 G/A SNPs and VEGF, sVEGFR-1, and endostatin serum levels were not significantly different in RAS patients compared with controls. In spite of this finding, VEGF -1154 GA genotype was found more prevalent in patients with minor RAS and GG genotype was found more prevalent in patients with major RAS. Moreover, the mean serum level of VEGF was found higher in CC genotype of +936 C/T SNP compared with CT genotype in RAS patients. When we compared minor RAS and major RAS, significant difference was found between the two groups with regard to mean VEGF serum levels.

Although the etiology of RAS is not fully understood, it is believed to be caused by hereditary factors and changes in the immune reaction against the oral mucosa. A genetic predisposition for the development of aphthous ulcers is strongly suggested to be about 40% for patients with a family history [21,22]. To date, several studies have been reported regarding genetic polymorphisms and RAS susceptibility [23-25].

Saliva has a contributory role in both oral and extra-oral wound healing. It has been known that VEGF is found in human saliva as a part of the major and minor salivary gland secretions. Salivary-derived VEGF also has important roles in mucosal homeostasis [26-28]. However, the role of VEGF in this process is not elucidated. There is a growing body of evidence that vascular endothelium could play a crucial role in recruiting inflammatory infiltrates in RAS [27]. In normal salivary glands, VEGF mRNA and protein are constantly expressed [28]. A stage-dependent fall in salivary levels of VEGF was found in patients with major (but not minor) RAS by Brozovic et al. [29]. Furthermore, decreased salivary VEGF-R3 level was observed in patients with minor RAS [30].

Yalcin et al. [31] showed an increased VEGF expression in correlation with CD34 positivity in oral aphthous of BD. Kamoun et al. [32] have not found any relationship between the VEGF +936 C/T SNP and Behçet’s disease susceptibility. However, they found that serum VEGF levels were considerably higher in BD patients. Bozoglu et al. [33] investigated whether VEGF level may be important in the pathogenesis of thrombosis seen in BD. They found that the levels of VEGF were significantly higher in BD patients with acute thrombosis.

In the current study, we did not find any significant difference between RAS patients and controls with regard to VEGF SNPs and VEGF serum levels. On the other hand, when we compared minor RAS with major RAS, statistically significant difference was found between the two groups with regard to VEGF serum levels. In addition, VEGF -1154 GA genotype was found to be higher in patients with minor RAS and the frequency of GG genotype was higher in patients with major RAS.

Aphthous ulcers are highly angiogenic. Therefore, excess angiogenesis may inhibit re-epithelialization in certain types of ulcers [34]. In a study, lower salivary VEGF levels were found to correlate with impaired neovascularization and re-epithelialization [8]. In the current study, patients bearing CT genotype have been found to have lower VEGF serum levels compared to CC genotype of +936 C/T SNP. We think that the T allele of this SNP may have a contributory role in impaired neovascularization and re-epithelialization.

Hypersensitivity to foods has also been noted as a triggering factor (chocolate, cheese, citrus, tomatoes, seafood, etc.) for RAS development [35]. Allergy or food intolerance is often associated with atopy; a significant association with a history of atopy has been seen in patients with a family history of RAS [36]. The association between RAS and psychological factors including stress and anxiety has been suggested in a growing number of studies [2, 37]. In the current study, while there were not any triggering factor such as chocolate, spice, stress, dust mites in the control group, 16 (38.1%) of those in the RAS group had a triggering factor. Moreover, the CT genotype of +936 C/T SNP was found higher in those having a triggering factor.

The major limitation of the current study was the relatively small number of patients for polymorphism analysis. Thus, in the current study, results of VEGF polymorphisms had low statistical power. Even though polymorphism analysis had a low statistical power, it is the first study of VEGF polymorphisms in RAS patients. We believe that the study has importance because it demonstrates the frequency of VEGF SNPs in RAS patients.

In conclusion, VEGF -1154 GA genotype is more prevalent in patients with minor RAS and GG genotype is more prevalent in patients with major RAS. Moreover, the T allele of +936 C/T SNP decreases serum VEGF level and that decrease may have a contributory role on impaired neovascularization and re-epithelialization in RAS. Further studies are required to determine the role of VEGF in RAS susceptibility and its clinical manifestations.

Acknowledgments This work was supported by the Scientific Research Project Fund of Cumhuriyet University (CUBAP) under the project number T-513.

Competing interests

The authors declare that they have no competing interests.

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Salim Yuce, Binnur Bagci, Gokhan Bagci, Mansur Dogan, Sema Koc, Ilhan Sezgin, Ferhan Candan, İsmail Önder Uysal. VEGF, sVEGFR-1 and Endostatin Serum Levels and VEGF Polymorphisms in Recurrent Aphthous Stomatitis. J Clin Anal Med. 2016;7(5):701-705

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Evaluation of 61 Secondary Amyloidosis Patients: A Single-Center Experience from Turkey

Can Huzmeli 1, Ferhan Candan 1, Gokhan Bagci 2, Demet Alaygut 3, Binnur Bagci 4, Esin Yildiz 5, Ayse Seker Kockara 1, Mansur Kayatas 1

1 Department of Nephrology, Faculty of Medicine, 2 Department of Medical Genetics, Faculty of Medicine, 3 Department of Pediatric Nephrology, Faculty of Medicine, 4 Department of Nutrition and Dietetics, Faculty of Health Sciences, 5 Department of Pathology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey

DOI: 10.4328/JCAM.4481 Received: 12.03.2016 Accepted: 29.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 695-700

Corresponding Author: Binnur Bağcı, Department of Nutrition and Dietetics, Faculty of Health Sciences, Cumhuriyet University, Sivas, Turkey. T.: +90 3462192523 F.: +90 3462191261 E-Mail: binnur.koksal@hotmail.com

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Abstract

Aim: To evaluate demographic,clinical and laboratory characteristics, causes, MEFV gene mutations, and mortality rates of patients with secondary amy-loidosis. Material and Method: 61 patients who had been diagnosed with secondary amyloidosis by renal and rectal biopsy between 2007 and 2013 in the nephrology clinic of Cumhuriyet University, Faculty of Medicine, were included in the study. Demographic characteristics, causes of secondary amyloidosis, MEFV gene mutations, end-stage renal failure (ESRF), renal transplantation, and mortality rates were examined retrospectively. Results: In etiological terms, Familial Mediterranean Fever (FMF) occurrence was 62.2% (38), bronchiectasis and emphysema 9.8% (6), tuberculosis 4.9% (3), coexistence of FMF and ankylosing spondylitis 3.2% (2), coexistence of FMF and rheumatoid arthritis 1.6% (1), coexistence of FMF and systemic lupus erythematosus (SLE) 1.6% (1), osteomyelitis 1.6% (1), septic arthritis 1.6% (1), Crohn’s disease 1.6% (1), colon cancer 1.6% (1), coexistence of bronchiec-tasis and tuberculosis 1.6% (1), rheumatoid arthritis 1.6% (1), and idiopathic cases 6.5% (4). Proteinuria was determined at nephrotic level among 68% (32) of 47 patients who had secondary amyloidosis. MEFV gene mutation of 45 patients with secondary amyloidosis was assessed. Most patients had M694V gene mutation. Surprisingly, we detected heterozygous E148Q muta-tion in 3 cases. 12 cases died; of these, 9 had ESRF. Five cases with ESRF underwent renal transplantation. Discussion: We found FMF as the most common cause for secondary AA amyloidosis in this study. Further studies should be done with larger or multicenter cohorts.

Keywords: AA Amyloidosis; Familial Mediterranean Fever; MEFV

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Introduction

Amyloidosis is a large group of diseases caused by extracellular and/or intracellular accumulation of amyloid fibril proteins due to different etiologies [1]. Accumulations are regarded as localized if seen in one organ or as systemic if seen in multiple organs. Accumulations are mostly seen in the brain, heart, kidney, liver, and digestive systems. Amyloid accumulations in organs other than the brain are generally observed as systemic. In time, the increase of amyloid accumulation causes pressure on the cells. Then atrophic changes in cells and tissue destruction occur. Also, organ dysfunctions occur due to the direct toxic effects of accumulated fibril proteins. Different clinical findings may be observed depending on the amyloid accumulation areas (localized and systemic forms) [1, 2].

Systemic amyloidosis types are mainly classified as primary (immunoglobulin light chain or AL) amyloidosis, secondary (AA) amyloidosis, and familial (hereditary) amyloidosis. To date, approximately 31 different proteins have been identified as causing amyloidosis. These proteins are structurally different from each other [3, 4].

The cause of secondary amyloidosis is an acute phase reactant known as serum amyloid A (SAA) which is the precursor protein of AA amyloidosis. The most common causes of secondary AA amyloidosis are rheumatic diseases, chronic infections, chronic arthritis, auto-inflammatory diseases, and malignancies and rheumatoid arthritis (RA) in particular [5]. The common feature of secondary amyloidosis is chronic inflammation, which is seen in all cases. SAA is synthesized in the liver through the effect of cytokines such as interleukin 1 (IL-1), (IL-6), and tumor necrosis factor (TNF)-alpha and circulates in the bloodstream as a part of high-density lipoprotein 3 fractions (HDL3) [6]. Although the main source of SAA protein is the liver, it is also synthesized in endothelial cells, macrophages, atherosclerotic smooth muscle cells, the brain, and synovium. A high SAA level alone does not cause amyloid accumulation, however it leads to macrophage activation and increased secretion of cytokines such as IL-1, IL-6, and TNF-alpha. This, in turn, is followed by amyloid accumulation. Amyloid accumulation is primarily seen in the spleen, liver and kidneys, and AA amyloidosis can lead to nephrotic syndrome and ESRD [6, 7].

Clinical findings of amyloidosis vary based on the organ involved. Proteinuria develops in renal involvement as a result of accumulation of amyloid fibrils. Proteinuria is more commonly encountered at nephrotic level. Occasionally, renal dysfunction may be observed without proteinuria. Hematuria is observed in some cases. Renal involvement eventually leads to ESRF. Systolic or diastolic dysfunction, heart failure, cardiomyopathy, various arrhythmia, and heart blocks are observed in cardiac involvement. Constrictive pericarditis and restrictive cardiomyopathy may cause accumulation in coronary arteries as well as ischemic cardiac disease. Accumulation of amyloid in the gastrointestinal system and autonomic nerves may cause complaints. In particular, macroglossia is observed [8-10].

The MEFV gene, located on chromosome 16p13.3 and encoding a protein called pyrin, is responsible for Familial Mediterranean Fever (FMF) disease. Mutations in the MEFV gene have been found in the majority of FMF patients [11-14]. The vast majority of MEFV mutations identified in FMF patients include mutations (M680I, M694V, M694I, and V726A) clustered in exon 10 and a mutation in exon 2 (E148Q) [15]. The main concern in FMF is the development of renal amyloidosis. The severe disease phenotypes of amyloidosis were found to be associated with M694V mutation and the compound E148Q-V726A mutation [16]. Furthermore, renal amyloidosis has been reported in asymptomatic individuals who do not experience attacks of serositis (phenotype II) [17]. Colchicine is the drug of choice for the treatment of FMF and can prevent amyloidosis [11, 16].

In this study, demographic, clinical and laboratory characteristics of patients, causes of secondary amyloidosis, MEFV gene mutations, end-stage renal failure (ESRF), renal transplantation, and mortality rates were examined retrospectively.

Material and Method

Sixty-one patients diagnosed as biopsy-proven AA amyloidosis at the nephrology clinic of Cumhuriyet University, Faculty of Medicine between 2007 and 2013 were assessed retrospectively. In the process of studying patient proteinuria or renal dysfunctions in our clinic, AA amyloidosis was determined by renal and rectal biopsy. By screening patient files, we analyzed their laboratory examinations including blood urea nitrogen (BUN), serum creatinine, serum albumin, total protein, alanine aminotransferase enzyme (ALT), aspartate aminotransferase enzyme (AST), low density lipoprotein (LDL), cholesterol, high density lipoprotein (HDL), triglyceride, C-reactive protein (CRP), sedimentation, hemoglobin (Hb), hematocrit (HCT), complete urinalysis, microalbuminuria and proteinuria levels, as well as hepatomegaly and splenomegaly results through abdominal ultrasonography, and we recorded information related to their diagnoses and clinical courses. Among these patients, those diagnosed with FMF were classified as phenotype I or phenotype II.

MEFV gene mutations of 45 patients with secondary amyloidosis were examined. The common mutations of MEFV gene (exon 2, 3, 5 and 10) were detected using Sanger sequencing or Strip assay methods. Patients were categorized according to their proteinuria values as < 1 gr/day, 1-3.5 gr/ day and > 3.5 gr/ day (nephrotic proteinuria).

Biopsy samples were primarily examined in a light microscope, then stained with Congo red and evaluated in a polarized microscope. An additional chemical process was conducted in cases who were observed to have amyloid in tissue, and cases were diagnosed with AA amyloidosis when the tissue with amyloid was exposed to potassium permanganate and amyloid dissolved from the tissue.

Statistical Analysis

All statistical analyses were performed by SPSS version 22.0 (SPSS IBM, Armonk, NY, USA). All demographic data and clinical findings were expressed as mean ± standard deviation (and range) with a 95% confidence interval.

Results

A total of 61 patients diagnosed with secondary amyloidosis were included in the current study. Their mean age was 49.81±17.93. 41 (67.2%) of these patients were male and 20 (32.7%) were female. While the mean age of men was 47.60±16.60 the mean age of women was 54.35±20.07. Table 1 shows demographic and laboratory findings of patients.

Forty-two of the patients included in the study were diagnosed with FMF. Of those, 2 cases were diagnosed with ankylosing spondylitis (AS), one case was diagnosed with RA and one case was diagnosed with (SLE) (Table 2).

MEFV mutation analysis was performed in 45 cases with secondary amyloidosis. Table 3 illustrates MEFV gene mutations of patients. Homozygous or heterozygous M694V gene mutations were determined in most of the cases. There was also coexistence of several gene mutations. R202Q mutation, rarely analyzed, was identified in 4 cases and only one case had RA in addition to FMF. We identified 3 patients with E148Q mutation. Fourteen patients had one heterozygous mutation. In mutation analysis of 9 phenotype II patients, it was found as homozygous M694V and homozygous R202Q (1), heterozygous M694V (3), heterozygous E148Q (1), heterozygous R202Q (1), heterozygous M694V and heterozygous R761H (1), heterozygous M680I (G/C), and heterozygous V726A (1).

Of 61 amyloid patients, hemodialysis was started for a total of 35 patients (57.4%) with the diagnosis of end-stage renal failure (ESRF). 27 of them were diagnosed with FMF, 2 were diagnosed idiopathic, one was diagnosed with emphysema, 2 were diagnosed with bronchiectasis, one was diagnosed with septic arthritis, and one was diagnosed with RA. Twenty two of the FMF patients were determined to bephenotype I and 5 were determined to be phenotype II. Five of the 9 patients with phenotype II were diagnosed with ESRF.

Twelve patients were diagnosed with amyloidosis after their exitus. Seven of these exitus patients died during diagnostic evaluations, 4 patients died approximately within 6 months to one year after diagnosis, and one patient died approximately 5 years after diagnosis. Four of the exitus patients had FMF, one had FMF plus RA, 3 had idiopathic and 4 had bronchiectasis plus emphysema. Seven of the exitus patients had proteinuria at a nephrotic level, one had 1-3.5 gr/day and 1 had < 1 gr/day proteinuria. Proteinuria could not be examined for the other 3 exitus patients. Nine of the exitus patients had anemia. 9 of the 12 exitus patients were undergoing hemodialysis.

Thirty-nine patients included in the study had anemia; of these, 26 were undergoing hemodialysis. Of the 39 anemic patients, 23 had FMF (18 had phenotype I, 5 had phenotype II), one had RA plus FMF, 6 had bronchiectasis plus emphysema, 2 had tuberculosis, one had osteomyelitis, one had septic arthritis, one had colon cancer and one patient was diagnosed with RA.

Of 61 amyloidosis patients, 11 patients had hypothyroid. Seven of them were diagnosed with proteinuria at nephrotic level and 2 were diagnosed with proteinuria at non-nephrotic level. The proteinuria level of one patient could not be examined. Six of the cases with hypothyroid were undergoing hemodialysis.

CRP test was conducted for 56 patients. The results of 43 of these patients were considered as high. Sedimentation was examined for 54 patients. The results of 49 of these patients were found to be high because of the level exceeded 25 mm/h. All patients except for 2 had low serum albumin levels (serum albumin < 4 gr/dl).

Lipid levels of patients with secondary amyloidosis were found to be generally normal; however, the HDL levels were found to be low in 73.6% (39) of patients. Twenty-eight of 38 cases with FMF had low HDL levels, 3 patients had high HDL levels, and 7 had normal HDL levels. Eight of the exitus cases had low HDL levels, 2 had normal HDL levels and one had high HDL level. Two of 10 cases whose LDL levels were above 160 mg/dl had proteinuria above 1-3.5 gr and 8 had proteinuria above 3.5 gr. All of the 8 patients whose triglyceride level was above 200 mg/dl had proteinuria at nephrotic level. Ten of 16 patients whose cholesterol level was above 200 mg/dl had proteinuria at nephrotic level and 5 had 1-3.5 gr proteinuria. The cholesterol level of one patient was not measured.

In the current study, of 61 amyloidosis patients, 56 patients had complete urine analyses, 39 of these patients had proteinuria, 16 had hematuria in addition to proteinuria, and one patient had only hematuria. Proteinuria was determined at nephrotic level among 68% (32) of 47 patients who had secondary amyloidosis. All patients except for 2 had hypoalbuminemia (serum albumin < 4 gr/dl). While hepatomegaly was found in 5 (8.3%) cases, splenomegaly was found in 9 (15%) cases.

In the current study, of 61 amyloidosis patients, 5 patients had renal transplants and also all of the cases who had renal transplants were diagnosed with FMF phenotype I. MEFV mutation results of cases who underwent transplantations were identified as: homozygous M694V (1), heterozygous M694V and heterozygous E148Q (2), heterozygous V726A and heterozygous F479L (1). Mutation analysis of one patient was not performed. Three patients had proteinuria at nephrotic level, one patient had proteinuria between 1-3 gr/day, and proteinuria of one patient was not examined. None of these patients had repeated proteinuria in renal allograft.

Discussion

Secondary amyloidosis is defined as the accumulation of amyloid on tissues and organs as a result of increasing SAA protein, which is an acute phase reactant developing in conjunction with inflammation. SAA production increases in inflammatory conditions [6]. In the current study, we evaluated demographic characteristics, etiology and mortality rates, and MEFV gene mutations of 61 secondary amyloidosis patients who were admitted to our clinic.

Although in Europe the most common cause of amyloidosis is RA, in Turkey the most common cause of amyloidosis is FMF [18]. Amyloid may develop in a period between 2 months and 14 years after FMF episodes. The period leading to ESRF after proteinuria may be 2-13 years [19].Secondary AA amyloidosis remains the most serious manifestation of FMF. The incidence rate of secondary AA amyloidosis among FMF patients is 37% in sephardic Jews, 24% in Armenians, 8% in Ashkenazi Jews, 12% in Turks and 10% in Arabs [20, 21]. Amyloidosis development rates among FMF patients were found as 25.7% in homozygous M694V mutation, 15.4% in M694V compound heterozygous and 12.3% in other mutations. Amyloidosis did not develop in E148Q mutations [22].

Although heterozygous E148Q mutation was found in non-amyloid glomerular diseases [23, 24], there is still no data about whether heterozygous E148Q mutation is an amyloidosis-causing mutation. Topaloglu et al. analyzed 26 patients homozygous for E148Q, 10 compound heterozygous for E148Q, and 8 complex cases. They found that none of their patients had amyloidosis except that 2 cases with E148Q/E148Q mutation had a family history of amyloidosis and one had rapidly progressive glomerulonephritis [25]. Balci et al. investigated AA amyloidosis patients (25 phenotype II) in terms of 4 MEFV mutations (M694V, M680I (G/C), V726A and E148Q), and they observed M694V mutation as the most frequent mutation in homozygous, heterozygous and compound heterozygous states. In their study, E148Q was found as compound heterozygous with M694V mutation in 2 cases [26]. In a study conducted with 507 children with FMF in the southeast of Turkey, renal amyloidosis developed in 1.4% (n=7) of patients. Five of the patients with renal amyloidosis had homozygous M694V mutation and two of them were compound heterozygous with M694V/V726A and M694V/M680I (G/C) mutations. Two of these patients with amyloidosis were phenotype II FMF patients [27]. In a study evaluating frequency of MEFV mutations in FMF patients, it was found that 16 patients had a history of amyloidosis (3.55%). Among the cases with amyloidosis, 12 cases had M694V homozygous, one case had compound heterozygous for M694V and M680I (G/C) mutations, and one case had a complex allele for E148Q/E148Q/M694V mutations. No mutation could be detected in 2 cases with amyloidosis [28]. In Jewish renal amyloidosis patients, M694V/M694V genotype was found as the most frequent mutation. However, E148Q mutation was found as compound heterozygous state together with exon 10 mutation of MEFV gene [16, 17].

In this study, in terms of MEFV gene mutation, M694V mutation was 19.6% (homozygous 7 and heterozygous 5), M694V compound heterozygous frequency was 11.4%, M680I (G/C) mutation was 6.5% (homozygous 2 and heterozygous 2), heterozygous E148Q was 4.9% (3), and heterozygous R202Q was 6.5% (4). The number of patients with at least one exon 10 of MEFV gene mutation was 30. At least one M694V mutation was detected in 23 patients (Table 3). Our MEFV gene mutation results, especially for M694V, were in accordance with the literature. However, we identified 3 patients with E148Q mutation, which is not reported in European publications to cause amyloid accumulations. We think that this is an interesting finding, and this information can bring a new perspective to the literature about E148Q mutation and development of amyloidosis.

Because amyloid accumulation leads to renal failure, it is the most important complication in FMF patients. However, it is not related to the severity of the disease. It can also appear among FMF patients who have rare and mild attacks. Additionally, phenotype II FMF can be observed among patients with no clinical symptom experience [29]. Long-term plasma SAA level should be high for AA amyloidosis development [2]. In a study, SAA levels were determined to be high in 40% of clinical phenotype III cases [30]. Clinical findings of mild FMF were observed in heterozygous persons. Acute phase responses were higher among heterozygous persons than in the healthy control group [30, 31]. Similarly, amyloid accumulation was determined in non-compound heterozygous cases in our study. In addition, 9 cases with FMF phenotype II were determined. During diagnosis, ESRF was observed in 5 of these patients.

The frequency of amyloidosis in autopsies in Western countries has varied between 0.50% and 0.86%. According to the reported series in England and USA, more than half of the cases have juvenile and adult RA. Ankylosing spondylitis is the second most frequent cause with rates up to 12%. It is followed by psoriatic arthritis with the rate of 4-5% [32-34]. AA amyloidosis is a rare complication of RA. However, there have been significant differences among publications. AA amyloid prevalence in RA ranges between 4% and 26% in literature [35]. AA amyloid was higher (14-61%) in RA patients in the post-mortem period [36]. Similarly, one patient had RA and one patient had coexistence of FMF and RA in our study. The most common cause of secondary amyloidosis in Turkey is reported as FMF [18]. Furthermore, the RA-related secondary amyloidosis frequency has been found to be low. In 2 studies conducted in ankylosing spondylitis patients who lived in Europe, amyloidosis rates were 7% and 9% respectively, as determined by rectal and fat biopsy screenings [37, 38]. In the current study, we found 2 (3.2%) cases who had coexistence of ankylosing spondylitis and FMF.

In the current study, there was 3 occurrences of tuberculosis, one of osteomyelitis, one of septic arthritis, and one coexistence of bronchiectasis and tuberculosis among patients with infectious diseases. As in other studies, the most common cause of infectious diseases was found to be tuberculosis in our study. Tuberculosis is the most commonly seen of the chronic infections that cause secondary AA amyloidosis; it is followed by osteomyelitis, chronic bronchitis, chronic mucocutaneous ulcer, leprosy, Q fever, and subacute bacterial endocarditis [1].

In a study that included 287 secondary amyloidosis patients from 11 centers in Turkey, the etiological causes were determined as FMF in 64% of patients, tuberculosis in 10%, bronchiectasis and chronic obstructive pulmonary disease in 6%, RA in 4%, spondyloarthritis in 3%, chronic osteomyelitis in 2%, other causes in 4%, and idiopathic in 7%. While hepatomegaly was 17%, splenomegaly was 11% [18]. In another study that evaluated 59 renal amyloidosis cases, 18 patients (30.5%) were found to have FMF, 12 (20.3%) had pulmonary tuberculosis, 8 (13.5%) had chronic osteomyelitis, 9 (15.2%) had bronchiectasis, 4 (11.8%) had RA, one (1.6%) had Castleman disease, and 7 (11.8%) were idiopathic [39]. In a study including 40 amyloidosis patients between 2003 and 2009 in Egypt, secondary amyloidosis was determined in 32 of patients and primary amyloidosis was determined in 8 patients. 30% of secondary amyloidosis cases (12) were FMF, 20% (8) were pulmonary tuberculosis, 10% (4) were chronic osteomyelitis, 10% (4) were bronchiectasis, 7% (3) were RA, and 2% (1) were rheumatic heart disease [40]. In another study, the most common cause of secondary amyloidosis was RA, which was followed by recurrent pulmonary infections at the rate of 11%, Crohn’s disease at 5%, ankylosing spondylitis at 5%, tuberculosis at 3%, osteomyelitis at 2%, FMF at 2%, Hodgkin’s lymphoma at 2%, and idiopathic cases at 5% [41].

In a multicenter study conducted in Australia and New Zealand, 58,422 patients who underwent renal replacement treatments between 1963 and 2010 were examined; 490 (0.8%) of these patients had problems related to secondary amyloidosis. Survival rates of patients with dialysis-induced secondary amyloidosis were found to be worse and renal allograft survival and renal allograft recurrence were worse compared to those related to other diseases. A significant number of deaths were observed due to amyloidosis complications in amyloidosis-related ESRF. When amyloidosis-related ESRF and ESRF related to other causes were compared, cardiac death rates were 37% and 41%, respectively. However, death from heart failure was more common in the amyloidosis-related group (8.6% vs. 2.2%). No difference was found between the 2 groups in the 10-year follow-up in terms of dialysis interruption, infection, cancer, and other causes of death [42]. One, 2 and 6-year survival rates in the retrospective analysis of 48 ESRF patients with systemic amyloidosis (72%, 62%, and 44% respectively) were significantly lower compared to non-diabetic controls (95%, 91%, and 81%) [43]. In our study, 35 patients were diagnosed with ESRF and transferred to hemodialysis. In a retrospective study performed with 23 amyloidosis patients who underwent renal transplant operations, 10-year patient and graft survival rates were found as 66% and 68% respectively, and no significant difference was found between them and 47 non-amyloidosis control patients (57% and 87%). Recurrent amyloid rates in renal allograft were 4.3% [44]. In a study comparing 45 amyloidosis transplant receivers and 45 control patients, 3-year patient survival rates were 51%, compared to 79% in the control group. Graft survival was 45% as opposed to 38% in the control group. Recurrent amyloidosis rate in renal allograft was 9% [45]. In this study, 5 patients underwent renal transplant. No amyloid developed in renal allograft cases.

It is important to form a clinical picture of FMF in Turkey, especially in the province of Sivas where FMF is most frequently observed [12-14]. Screening of individuals who have FMF in their family histories and evaluating the treatments of phenotype III cases that have mutations but do not show clinical symptoms are prominent issues to be examined. Although studies have been conducted on phenotype II cases, when we consider that secondary amyloidosis can also develop in non-compound heterozygous mutations, it should be clarified through future studies whether phenotype III cases should be detected in early stages and treated through the evaluation of acute phase reactants.

As stated in other studies conducted in Turkey, we found FMF to be the most common cause of secondary amyloidosis. Surprisingly, we detected heterozygous E148Q mutation in 3 cases with amyloidosis. This finding can bring a new perspective to the literature about E148Q mutation and the development of amyloidosis. We suggest that further studies should be done with larger or multicenter cohorts.

Compliance with Ethical Standards

Ethical approval: The Ethics Committee of Cumhuriyet University, Faculty of Medicine approved the present study. The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Competing interests

The authors declare that they have no competing interests.

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Can Huzmeli, Ferhan Candan, Gokhan Bagci, Demet Alaygut, Binnur Bagci, Esin Yildiz, Ayse Seker Kockara, Mansur Kayatas. Evaluation of 61 Secondary Amyloidosis Patients: A Single-Center Experience from Turkey. J Clin Anal Med. 2016;7(5):695-700

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Diagnostic Utility of Ischemic Modified Albumin in Young Adult Patients with Acute Coronary Syndrome

Ramazan Güven 1, K. Can Akyol 2, Nermin Bayar 3, Güzin Aykal 4, Faruk Güngör 2, Mustafa Keşaplı 2, Hamit Yaşar Ellidağ 4, Ahmet Çelik 2

1 Department of Emergency Medicine, Bitlis State Hospital, Bitlis, 2 Department of Emergency Medicine, Antalya Training And Research Hospital, Antalya, 3 Department of Cardiology, Antalya Training And Research Hospital, Antalya, 4 Department of Biochemistry, Antalya Training And Research Hospital, Antalya, Turkey

DOI: 10.4328/JCAM.4482 Received: 13.03.2016 Accepted: 29.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 690-4

Corresponding Author: Ramazan Güven, Department of Emergency Medicine, Bitlis State Hospital, Bitlis, Turkey. GSM: +905323341721 E-Mail: ramon.ra.dr@gmail.com

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Abstract

Aim: In this study, we investigated the diagnostic value of IMA in the positive and negative predictive value of ACS, alone and in combination with TnI. The study population was divided into 3 groups. The first group included those patients with normal coronary arteries (n=40), the second group included the ACS patients with ST segment elevation myocardial infarction (STEMI) (n=49), and the third group included the ACS patients with Non ST-segment elevation myocardial infarction-Unstable Angina (NSTEMI-UA) (n=47). Al-though its use for diagnostic purposes did not provide an additional benefit for ACS patients, we found that the combination of TnI and IMA could better rule out ACS compared to TnI alone.

Keywords: Ischemia Modified Albumin; Cardiac Troponin; Acute Coronary Syndrome

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Introduction

Coronary artery disease (CAD) is the leading cause of morbidity and mortality. Early diagnosis and treatment can reduce mortality and mortality [1]. To date, several markers have been identified for the early diagnosis of ACS. Recently, one of these markers, Ischemia Modified Albumin (IMA), has been increasingly used. Formed as a result of the modification of albumin due to the reactive oxygen species (ROS) that is released due to muscular damage of the hypoxic cardiac tissue, IMA was first discovered in the 1990s [2]. The FDA (Food and Drug Administration of the USA) approved the IMA test in 2003 to rule out acute myocardial infarction in patients who present to the emergency department with chest pain [3]. The IMA level in the blood starts elevating within 10 minutes following ischemia and continues elevating as ischemia persists [4]. This time is much shorter than the time required for other cardiac markers to appear in the blood.

The markers for ischemia are useful to assess ischemia at an earlier stage, to prevent its progression into infarction, and to avoid further complications. The aim of this study was to investigate the diagnostic value for ACS of the other cardiac markers and of IMA alone and in combination with TnI in ACS patients younger than 50 years of age who present to emergency departments with acute cardiac ischemia symptoms.

Material and Method

Study Group

136 patients aged 21 to 50 were included in the study. All patients were selected from among those who underwent angiography. According to the results of clinical examination, ECG, test for cardiac markers, and angiography, the study population was divided into three groups: group 1 (n=40), group 2 (n=49), and group 3 (n=47). Group 1 included patients who did not have significant stenosis (coronary stenosis lower than 50%) according to the angiography results; group 2 included ACS patients who were considered to have STEMI; group 3 included ACS patients considered to have NSTEMI-UA. Troponin I, CK-MB, and myoglobin were analyzed by the chemiluminescence method on the Siemens ADVIA Centaur CP (Siemens Healthcare, Erlangen, Germany) device.

Study Design

This prospective study was conducted at the Central Biochemical Laboratory of Antalya Training and Research Hospital from May 2013 to January 2015. It was conducted in collaboration with the Emergency Department, where an average of 185,000 patients present annually due to non-traumatic reasons, and with the Cardiology Department, where an average of 5,000 percutaneous coronary procedures (of which an of average 1,500 are urgent) are performed annually. Patients who had other cardiac problems such as acute pericarditis and cardiac failure, diseases such as liver failure that affect the albumin level, renal failure, malignancies, and cerebrovascular diseases were excluded from the study. ECG with 12 derivations was performed for all patients who presented to the emergency department within 3 hours following the onset of the symptoms and who conformed to the inclusion criteria at admission. Their troponin I (TnI), myoglobin, creatinine kinase MB (CK-MB), and IMA and albumin levels were analyzed.

Biochemical Analysis

IMA was measured by the albumin cobalt-binding test that was defined by Bar-Or et al. (2). This test is based on the colorimetric measurement of the colorful complex formed by cobalt that is attached to the sample and does not bind to albumin with dithiothreitol (DDT). For the measurement, cobalt chloride solution of 0.1%, 1.5 mg/ml DTT solution, 0.9% NaCl solution, glass tube, vortex, adjustable automatic ependorff pipette, disposable plastic micro cuvette, and Shimadzu UV-120V model spectrophotometer were used. CoCl26H2O (Sigma-Aldrich Lot: S38901-248), DTT solution, and DTT (Sigma-Aldrich Lot: D5545-1G) chemicals were dissolved in the distilled water to prepare the cobalt chloride solution. After 50 µl 0.1% cobalt chloride solution was added to each patient’s blood serum of 200 µl, the mixture was vortexed and incubated for 10 minutes for albumin-cobalt binding. In order to create the color reaction for the cobalt that was not bound by the albumin by the end of incubation, 50 µl 1.5 mg/ml DTT solution was added to the mixture and kept for 2 minutes. After 2 minutes, 1 ml 0.9% NaCl was added to the mixture to complete the reaction. The same steps were taken simultaneously for the samples that were prepared, using distilled water instead of DTT. By the end of the reactions, the differences between the absorbance values of the samples and sample blinds read at 470 nm were recorded as İMA values. The results were recorded as absorbance units (ABSU). All procedures were performed simultaneously by two practitioners. All reactions were realized in glass tubes. All measurements were completed within 3 days. Intra-assay CV (coefficient of variation) and inter-assay CV were found to be lower than 3% in the precision assay performed with the serum pool.

Statistical Analysis

The data obtained from this study were recorded in the SPSS 21.0 (Armonk, NY: IBM Corp.) software. Data were expressed as numbers and percentage for categorical variables and as mean ± standard deviation for continuous variables. Shapiro Wilk test was performed to analyze the concordance of the continuous variables with the normal distribution. The significance of the difference between the ACS patients and the control group with respect to the IMA, TnI, myoglobin, and CK-MB levels was analyzed with Kruskal Wallis test. The significance of the sub-group comparisons was calculated through the Bonferroni correction. In bilateral comparisons between the groups, Student-t test was used for the normally distributed parameters while Mann-Whitney U test was used for the parameters that were not normally distributed. Chi-Square test or Fisher test was used for the analysis of the categorical variables. The effectiveness of the IMA measurement to distinguish the ACS patients from the control group was analyzed by calculating the sensitivity and specificity of the area below the ROC curve. P <0.05 was considered as statistically significant.

Results

14.0% (n=19) of 136 patients included in the study were female while 86.0% (n=117) were male. The mean age of the patients was 43.3±6.3. The comparison between the patients with regard to age, sex, and the traditional risk factors for CAD—hypertension (HT), diabetes mellitus (DM), hyperlipidemia, family history, and smoking—revealed a significant difference between the patient groups in sex, smoking, and hyperlipidemia (Table 1).

The significant differences between the patient groups in the mean values of TnI, CK-MB, myoglobin, and IMA are presented in Table 2. The IMA levels of the patients in groups 2 and 3 who were considered to have ACS were significantly higher than those in group 1 (0.454±0.08, 0.414±0.08 vs 0.404±0.04, p=0.006; Figure 1). The bilateral sub-group comparisons between the groups with respect to IMA levels revealed a significant difference between group 1 (control) and group 2 (STEMI), and between group 1 (control) and group 3 (NSTEMI-UA), whereas there was no significant difference between group 2 (STEMI) and group 3 (NSTEMI-UA) in that regard (0.404±0.04 vs 0.454±0.08, p=0.002; 0.404±0.04 vs 0.414±0.08, p=0.015; 0.454±0.08 vs 0.414±0.08, p=0.416, respectively).

When the cut-off value of IMA level was considered as 0.443 ABSU on the ROC curve to distinguish the acute STEMI patients from the control group, the sensitivity and specificity were found to be 61.2% and 87.5%, respectively, while the negative predictive value was 64.8% and the positive predictive value was 85.7% (AUC:0.692, 95% CI: 0.580-0.804) (Figure 2).

When the cut-off value of IMA level was considered as 0.455 ABSU on the ROC curve to distinguish the patients in Group 3 (NSTEMI-UA) from those in group 1 who were the control patients, the sensitivity and specificity were found to be 36.2% and 90.0%, respectively, while the negative predictive value was 54.5%, and the positive predictive value was 81.0% (AUC:0.644, 95% CI: 0.528-0.761).

When the reference range for TnI was considered as 0.01-0.06 ng/ml, 38.8% (n=19) of the patients in Group 2 and 25.5% (n=12) of the patients in Group 3 had a normal TnI range at admission. TnI that was used to distinguish the acute STEMI patients from the control group was found to have a sensitivity of 61.2%, specificity of 95.0%, negative predictive value of 66.7%, and positive predictive value of 93.8% (p<0.001). When used in combination with IMA (when the reference range was 0.0-0.443), the sensitivity and specificity of TnI for acute STEMI were found to be 63.2% and 97.1%, respectively, while the negative predictive value was 82.9% and positive predictive value was 92.3% (Table 3; Figure 3).

The sensitivity, specificity, negative predictive value, and positive predictive value of TnI when used to distinguish the NSTEMI-UA patients from the control group were found to be 76.6%, 95.0%, 77.6%, and 94.7%, respectively (p<0.001). The sensitivity, specificity, negative predictive value, and positive predictive value of TnI when used in combination with IMA (when reference range was 0.0-0.455) to distinguish NSTEMI-UA were found to be 80.0%, 94.4%, 85.0%, and 92.3%, respectively.

Discussion

Biomarkers play a pivotal role in the diagnosis and management of patients with ACS [5]. However, several markers used for the diagnosis of ACS do not provide the desired level of diagnostic support in the presence of myocardial ischemia without necrosis. Even Troponin, which is the most widely used and most reliable marker, can only be detected in the blood 3-6 hours following myocardial necrosis [6].

IMA, which is one of the markers that have been studied to detect early ischemia, is also recommended in the ACS guidelines [7]. Measurement of the serum IMA level seems to be more advantageous in the diagnosis of cardiac ischemia compared to the other biochemical markers. IMA yields a positive result within a few minutes to a few hours following ischemia before myocardial necrosis develops [8].

Studies of the use of IMA for the diagnosis of ACS report conflicting results. Some researchers have argued that IMA was helpful to diagnose ACS when used alone, while some others claim it had no benefit.

In the study conducted by Roy et al. in which they investigated the patients who presented with chest pain but had normal or non-diagnostic ECG findings and negative TnT values, they found that IMA values were significantly higher in patients with myocardial ischemia compared to those who did not have myocardial ischemia. When used alone to detect myocardial ischemia, IMA’s sensitivity was found to be 75.0%, whereas it rose up to 82.8% when used in combination with TnT [9]. In another study comprising 675 cases, it was found that IMA could be especially helpful in detecting early ACS patients for whom TnI failed [10].

Reddy et al. investigated 3 groups of patients (non ischemic chest pain (NICP), unstable angına (UA), and myocardial infarction (MI)) and reported a similar finding, stating that IMA had a high sensitivity (92.0%) and specificity (88.0%) in detecting ischemia. In that study, they also concluded that IMA could be used as a rule-out criterion due to its high negative predictive value (94.0%) to detect early ACS [11].

Contrary to the results of the abovementioned studies, Çevik et al. evaluated the diagnostic performance of copeptin, TnI, and IMA to detect STEMI patients in a series of 26 cases and concluded that IMA did not have an additional diagnostic value when used either alone or in combination with TnI [12]. Soren et al. evaluated 107 cases and similarly reported that IMA was not superior to the other biomarkers and it would not be useful in diagnosing ACS in ERs [13]. Given that the guidelines specify that treatment should be started for patients diagnosed with STEMI through ECG without waiting for the TnI results, these findings are not surprising. Similar to the abovementioned studies, we also observed that IMA values did not provide any additional diagnostic value for the patients diagnosed with STEMI.

Several studies have reported that IMA can be used as a marker to rule out ACS due to its high negative predictive value [14,15]. Takhshid et al. reported that IMA had a negative predictive value of 88% to rule out ACS when used alone, while it was 96.0% when used in combination with TnI and ECG [16]. Lee et al. also reported a high negative predictive value for IMA. In that study, the sensitivity of IMA was found to increase markedly when combined with TnI and CK-MB as the other cardiac markers [17]. In a meta-analysis performed on 1,800 patients, the combination of IMA, ECG, and troponin was found to rule out myocardial ischemia by 97.1% [18].

Limitations

Our study was conducted in a single center, which may limit the generalizability of our results. The majority of the studies investigating IMA levels have used U/ml as the unit of measure. We used ABSU in our study; therefore, we could not make a comparison with the cut-off values of the other studies. Furthermore, we used a standard troponin I test because our institution did not have a high-sensitivity troponin I test.

Conclusion

Although troponin is considered a gold standard for the diagnosis of ACS, the troponin values of a significant number of ACS patients at admission were below the level required to take a clinical decision. IMA, which was supposed to be an alternative to troponin and other cardiac markers, was not observed to have the expected benefit for the diagnosis of ACS in our study. Contrary to the studies proposing that IMA could be used to rule out ACS, we found that it could only have a significant negative predictive value when used in combination with TnI for ACS patients.

Competing interests

The authors declare that they have no competing interests.

References

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2. Bar-Or D, Lau E, Winkler JV. Novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia–a preliminary report. J Emerg Med 2000;19:311-5.

3. Chawla R, Goyal N. Ischemia Modified Albumin: A Novel Marker For Acute Coronary Syndrome. Indian Journal of Clinical Biochemistry 2006;21(1):77-82.

4. Sinha MK, Gaze DC, Tippins JR, Collinson PO, Kaski JC. Ischemia modified albumin is a sensitive marker of myocardial ischemia after percutaneous coronary intervention. Circulation 2003;107:2403-5.

5. Panteghini M. Role of importance of biochemical markers in clinical cardiology. Eur Heart J 2004;25:1187–96.

6. Lindahl B. Detection of myocardial damage: are the troponins the ultimate solution? Scand Cardiovasc J 2001;35:229–32.

7. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal 2011;32:2999–3054.

8. Worster A, Devereaux PJ, Heels-Ansdell D, Guyatt GH, Opie J, Mookadam F, et al. Capability of ischemia-modified albumin to predictserious cardiac outcomes in the short term among patients with potential acute coronary syndrome. CMAJ 2005;172:1685-90.

9. Roy D, Quiles J, Aldama G, Sinha M, Avanzas P, Arroyo-Espliguero R et al. Ischemia Modified Albumin for the assessment of patients presenting to the emergency department with acute chest pain but normal or non-diagnostic 12 derivations and negative cardiac troponin T. Int J Cardiol 2004;97(2):297-301.

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12. Çevik E, Yılmaz BK , Acar YA, Haklıgör A, Çınar O. Bazı erken kardiyak belirteçlerin (Miyoglobin, IMA ve Copeptin) tanısal performansının STEMI hastalarında değerlendirilmesi. Türk Acil Tıp Derg 2013;13(3):127-32.

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14. Christenson RH, Duh SH, Sanhai WR, Wu AH, Holtman V, Painter P, et al. Characteristics of an albümin cobalt binding test for assessment of acute coronary syndrome patients: a multicenter study. Clin Chem 2001;47:464-70.

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16. Takhshid MA, Kojuri J, Tabei SMB, Tavasouli AR, Heidary S, Tabandeh M. Early Diagnosis of Acute Coronary Syndrome with Sensitive Troponin I and Ischemia Modified Albumin. Iranian Cardiovascular Research Journal 2010;4(4):144-51.

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18. Peacock F, Morris DL, Anwaruddin S, Christenson RH, Collinson PO, Goodacre SW, et al. Meta-analysis of ischemia-modified albumin to rule out acute coronary syndromes in the emergency department. Am Heart J. 2006; 152:253-62.

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Ramazan Guven, Kamil Can Akyol, Nermin Bayar, Güzin Aykal, Faruk Gungor, Mustafa Keşaplı, Hamit Yaşar Ellidağ, Ahmet Çelik. Diagnostic Utility of Ischemic Modified Albumin in Young Adult Patients with Acute Coronary Syndrome. J Clin Anal Med. 2016;7(5):690-694

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Association Between Postoperative Hypoalbuminemia and Complications in Ovarian Carcinoma

Murat Öz 1, Emin Levent Aksoy 2, Nilüfer Çetinkaya 1, Eyüp Gökhan Durmuş 2, Burak Ersak 2, Mehmet Mutlu Meydanlı 1

1 Department of Gynecologic Oncology, 2 Department of Obstetrics and Gynecology, Zekai Tahir Burak Women’s Health Education and Training Hospital, Ankara, Turkey

DOI: 10.4328/JCAM.4478 Received: 11.03.2016 Accepted: 27.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 686-9

Corresponding Author: Murat Öz, Ugur Mumcu Mh. 1649 St. P2K Yenimahalle, Ankara, Turkey. T.: +90 3123065374 E-Mail: ozmurat@gmail.com

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Aim: Several factors have been described as risk factors for increased post-operative complications, such as age, performance status, surgical aggres-siveness, nutritional status, and serum albumin levels. The aim of the present study is to evaluate the predictive role of postoperative serum albumin levels on postoperative complications. Material and Method: Data of patients with the diagnosis of borderline ovarian tumors or invasive ovarian cancer and who had undergone debulking surgery were retrieved retrospectively. We de-fined the cut-off value of 3.5 g/dl for mild hypoalbuminemia and 2.5 g/dl for severe hypoalbuminemia. Results: A total of 200 patients were identified, all of whom had undergone debulking surgery at our hospital in the time period from January 2008 to December 2015. Patients with severe postoperative hypoalbuminemia had higher incidences of severe postoperative compli-cations (CDC grade ≥2) (p<0.05, OR 2.6; 95% CI: 0.7-9.1). Mean dissected lymph node counts for patients with severe hypoalbuminemia, mild hypoal-buminemia, and normal albumin levels were 57.2, 49.4, and 45.5, respectively (P<0.05). Patients with severe hypoalbuminemia had longer hospital stays (mean 10.26 days) and ICU stays (mean 1.5 days) compared to patients with mild hypoalbuminemia (9.3 and 1.3 days, respectively) and those with normal albumin levels (8.2 and 1.2 days, respectively) (p<0.05). Sixty percent of the patients with severe hypoalbuminemia, 42.4% of the patients with mild hy-poalbuminemia, and 20% of the patients with normal albumin levels needed at least one unit of packed RBC transfusion in the per-operative period. Dis-cussion: Patients with postoperative hypoalbuminemia have an increased risk of serious postoperative complications and they should be more closely fol-lowed during the early postoperative course.

Keywords: Hypoalbuminemia; Debulking; Complication; Transfusion

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Introduction

Primary cytoreductive surgery followed by adjuvant chemotherapy, if indicated, is the standard treatment for patients with ovarian carcinoma (OC) [1]. The key point of the surgical approach is to achieve maximal cytoreductive surgery with no gross residual tumor [2]. However, aggressive surgery is often associated with increased intraoperative and postoperative major complications and morbidity [3]. In addition, postoperative major complications may cause a delay in adjuvant chemotherapy following the cytoreductive surgery. Several factors have been described as risk factors for increased postoperative complications: age, performance status, surgical aggressiveness, nutritional status, and serum albumin levels [4,5]. Most of these factors cannot be measured with standardized quantitative methods.

Albumin is the major plasma protein in humans and has the major role in maintaining serum colloid pressure as well as acting as a transport vehicle for intrinsic metabolites, drugs, and anti-oxidative agents; it acts as a free-radical scavenger [6]. Preoperative low serum albumin level has been associated with increased postoperative major complications and morbidity for various types of oncological surgery [7-9]. Albumin level is also an indicator of malnutrition in patients. A significant percentage of patients with gynecological malignancy have malnutrition (20%), but ovarian cancer patients have the highest prevalence of malnutrition (67%) [10]. Previous studies have been focused on preoperative serum albumin status as a predictor. However, the aim of the present study is to evaluate the predictive role of postoperative serum albumin levels on postoperative complications, as categorized by Clavien-Dindo Classification (CDC).

Material and Method

The present study is designed as a retrospective cohort study. Data of the patients who had been operated on at our tertiary-care referral hospital from January 2008 to December 2015 were retrieved from computerized databases and patient files. Diagnoses of the patients were either OC or borderline ovarian tumors (BOT). Both groups of patients underwent cytoreductive surgery of staging including removal of at least one adnexa, infragastric or infracolic omentectomy, and retroperitoneal lymph node dissection up to the renal veins. Those patients without complete surgical staging were excluded from the study. The standard surgical approach for epithelial ovarian carcinoma (EOC) was maximal cytoreductive surgery, whereas BOTs and other OC subtypes were managed according to the patients’ ages and fertility desire. The surgeries were performed by a surgical team specialized in gynecological oncology. Patients who received neo-adjuvant chemotherapy were excluded. Serum albumin levels were measured on postoperative day 1 as a routine postoperative follow-up.

Serum albumin was assayed with bromocresol green, using routine clinical chemical photometric analyzers. We defined the cut-off value of 3.5 g/dl for mild hypoalbuminemia and 2.5 g/dl for severe hypoalbuminemia. Postoperative complications were classified according to CDC [11] including the hospital stay period. According to these criteria, the complications were further stratified as mild (CDC 0-1) or severe (CDC 2-4). Higher CDC scores were noted in those patients with multiple complications or more severe complications.

Descriptive statistics were presented as mean, median, and percentages. Fisher-exact and Pearson correlation tests were used to assess the relationship between continuous variables such as complications and serum albumin levels. Albumin levels were labeled as severe hypoalbuminemia, mild hypoalbuminemia, and normal serum albumin levels, to create categorical variables for univariate and multivariate analyses. Cox logistic regression model was used for univariate analyses. P values <0.05 were considered statistically significant. Statistical software SPSS 21 for Macintosh (SPSS 21, SPSS Inc., Chicago, IL) was used for statistical analysis.

We have obtained the Institutional Review Board approval for the present study. [Date and number: 31.07.2015#14]

Results

A total of 200 patients were identified as having undergone debulking surgery or staging surgery for ovarian tumors in the time period from January 2008 to December 2015. Patient characteristics are shown in Table 1. The median age of the patients was 53 (ranging between 18-81). One hundred twenty-four patients (62%) had epithelial OC, 25 patients (12.5%) had sex-cord stromal tumors, 10 patients (5%) had germ cell tumors, and 41 patients (20.5%) had BOTs. Twenty-eight patients (14%) had fertility sparing staging surgery, whereas remaining 172 patients (86%) had complete debulking surgery. Seventy patients (35%) had advanced stage disease (FIGO 3A-4). According to the inclusion criteria, all patients had bilateral pelvic and para-aortic lymph node dissection. Median dissected lymph node count was 52 (range 5-200). Sixty patients (30%) had serum albumin levels lower than 2.5 g/dl representing severe hypoalbuminemia, while 125 (62.5%) patients had serum albumin levels between 2.5-3.5 g/dl representing mild hypoalbuminemia, and the other 15 (7.5%) patients had normal serum albumin levels, >3.5 g/dl on postoperative day 1. Mean hospitalization duration was 9.9 days (range 5-35 days) and the median ICU stay was 1 day (range 1-33 days). One patient had 33 days of ICU stay, and we excluded this patient from descriptive analysis of ICU and hospital stay. A total of 104 patients had serious postoperative complications of CDC grade 2 or higher.

The patients with severe postoperative hypoalbuminemia (serum albumin level <2.5 g/dl), had a higher incidence of severe postoperative complications (CDC grade ≥2) (p<0.05, OR 2.6; 95% CI: 0.7-9.1) compared to patients with normal albumin levels. Among 60 patients with severe hypoalbuminemia, 40 (66%) of them experienced severe postoperative complications. Also, patients with mild hypoalbuminemia (serum albumin level 2.5-3.5 g/dl) had a higher incidence of CDC grade ≥2 complications compared to patients with normal serum albumin on postoperative day 1 (p<0.05, OR 1.7; 95% CI: 0.6-5.1). Among 125 patients with mild hypoalbuminemia, 60 (48%) of them experienced CDC grade ≥2 complications compared to 4 of 15 (26.6%) patients with albumin levels ≥3.5 g/dl.

Mean dissected lymph node counts were inversely related with serum albumin status. Mean dissected lymph node counts were 57.2, 49.4, and 45.5 for patients with severe hypoalbuminemia, mild hypoalbuminemia, and normal albumin levels, respectively (P<0.05).

The patients with postoperative severe hypoalbuminemia had longer hospital stays (mean 10.26 days) and ICU stays (mean 1.5 days) compared to patients with mild hypoalbuminemia (9.3 and 1.3 days, respectively) and when compared to patients with normal albumin levels (8.2 and 1.2 days, respectively) (p<0.05).

One hundred-eight patients had red blood cell (RBC) transfusion, while the remaining 92 patients did not need RBC transfusion; postoperative hypoalbuminemia was significantly related with the need for RBC transfusion. Thirty-six of 60 patients (60%) with severe hypoalbuminemia, 53 of 125 patients (42.4%) with mild hypoalbuminemia, and only three of 15 patients (20%) with normal albumin levels needed at least one unit of packed RBC transfusion in the per-operative period (P<0.05, OR 2.8; 95% CI: 0.8-4.9 and 2.2; 95% CI: 0.7-4.1 for patients with severe and mild hypoalbuminemia, respectively, compared to patients with normal serum albumin levels). The postoperative complications were further categorized as pulmonary complications, renal failure and electrolyte imbalance, thromboembolic complications, wound complications, sepsis, gastrointestinal complications, surgical complications and cardiac complications. Postoperative hypoalbuminemia was not associated with any specific organ system complications (Table 2).

Discussion

Hypoalbuminemia is a well-known indicator of malnutrition, and an association between hypoalbuminemia, inflammation, and malignancy has been recently suggested [12]. Preoperative low serum albumin level was shown to have a major impact on surgical outcome, length of hospital stay and postoperative complications, especially in radical gastrointestinal surgeries [13,14]. Uppal et al. showed a six times elevated risk of major postoperative complications and ten times more likelihood of death in the first 30 postoperative days for patients with preoperative hypoalbuminemia in their patient cohort, which consisted of 2110 gynecologic oncology patients [7].

Seebacher et al. investigated the impact of preoperative hypoalbuminemia on survival in their retrospective cohort of 465 endometrial cancer patients [9]. The authors found that preoperative low albumin levels were strongly associated with advanced stage disease, a higher histologic grade, and poor survival. However, the authors could not determine a clear prognostic cut-off value for serum albumin.

For advanced stage epithelial ovarian cancer patients, Aletti et al. showed ASA score, tumor grade, surgical complexity, and preoperative low albumin levels were independent risk factors for postoperative complications [15]. Similarly, Obermair et al. demonstrated a significant increase in anastomose failure and septic complications in patients with hypoalbuminemia who underwent bowel resection as part of cytoreduction in advanced stage ovarian cancer [16].

In a recent study, Ataseven et al. investigated the association between preoperative hypoalbuminemia and postoperative complications in 604 EOC patients [17]. The authors concluded that patients with hypoalbuminemia were five times more likely to develop serious postoperative complications than patients with normal serum albumin levels. Moreover, median survival of patients with low albumin levels and normal albumin levels were 24 and 83 months, respectively.

The possible explanation of the relationship between hypoalbuminemia and severe postoperative complications could be that low serum albumin is a strong predictor of malnutrition [18], cachexia, and chronic inflammatory process [19]. Moreover, cancer related cachexia is associated with immunosuppression [20], which has been reported as a predictor for severe postoperative complications [4] and poor survival [8].

It is not well understood whether hypoalbuminemia causes a worse prognosis because it only reflects malnutrition or if it directly and independently influences the patient’s prognosis [17].

Improving the nutritional status of ovarian cancer patients with low serum prealbumin levels through total parenteral nutrition prior to surgery is associated with fewer postoperative complications [4]. However, subsequent randomized trials failed to show the benefit of preoperative nutritional therapy on complication rates [21,22].

Most studies in the literature investigate the association between preoperative low albumin levels and postoperative morbidity. However, our study attempts to demonstrate the additional importance of early postoperative low albumin levels. In our study population, serum albumin levels on postoperative day 1 were ≤3.5 g/dL in a majority of patients and this was associated with more severe complications (≥CDC grade 2), longer ICU administration, and longer hospital stays.

Albumin level is a predictor of malnutrition, as well as a well-known negative acute phase reactant. Serum albumin levels decrease rapidly in response to acute inflammatory cytokines [23]. The association between postoperative hypoalbuminemia and postoperative morbidity is probably due to the negative acute phase reactant nature of the albumin, rather than its being a predictor for malnutrition. Also, a minority of the patients in our study had advanced stage and bulky disease (stage 3C and 4), thus indicating cancer cachexia.

The main limitation of our study is the retrospective design of the study that leads to selection bias and heterogeneity of patients and procedures. In addition, there is no cut-off value for early postoperative serum albumin level in the literature.

In our patient cohort, postoperative albumin levels were inversely related with postoperative complication rates, blood transfusion rates, and the duration of hospital and ICU stays of the patients. Postoperative low albumin levels seem to be related with surgical complexity rather than nutritional status. This is due to the negative acute phase reactant nature of the albumin. The patients with postoperative hypoalbuminemia should be more closely followed-up during the early postoperative course.

Competing interests

The authors declare that they have no competing interests.

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Murat Oz, Emin Levent Aksoy, Nilufer Cetinkaya, Eyüp Gökhan Durmus, Burak Ersak, Mehmet Mutlu Meydanli. Association Between Postoperative Hypoalbuminemia and Complications in Ovarian Carcinoma. J Clin Anal Med. 2016;7(5):686-689

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Evaluation of Children with Recurrent Fever

Soner Sertan Kara 1, Yasemin Ozsurekci 2, Mehmet Ceyhan 2

1 Department of Pediatrics, 2 Department of Pediatric Infectious Diseases, Hacettepe University Medical Faculty, Ankara, Turkey

DOI: 10.4328/JCAM.4475 Received: 10.03.2016 Accepted: 27.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 681-5

Corresponding Author: Soner Sertan Kara, Department of Pediatrics, Hacettepe University Medical Faculty, Sihhiye, Ankara, 06280, Turkey. GSM: +905352577885 F.: +90 3123050143 E-Mail: drsoner@yahoo.com

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Abstract

Aim: Data on recurrent fever in children is limited. The aim of this study is to evaluate the children with this common symptom. Material and Method: We enrolled 138 patients with frequent fever. Twelve febrile episodes/year was determined as the cut-off for “recurrent fever”. Children with ≤12 and >12 febrile episodes/year were included in Group I and Group II, respectively. Their demographic data, symptoms, and clinical and laboratory findings were compared. All children were followed for two years for definitive diagnosis.Results: Fifty-four (39.1%) children experienced recurrent fever according to our criteria. Group I children experienced more frequent sneezing, whereas Group II children experienced more frequent vomiting compared to the other group (p=0.05 and p=0.02, respectively). Febrile episodes were seen more frequently in the winter season in Group I compared to Group II (p=0.03). Age, sex, other clinical symptoms, physical examination findings, and attendance at day care center/school in two groups were not different. Group II chil-dren had higher C-reactive protein levels (p=0.001). There was no difference in other laboratory parameters between the two groups. After two years, two patients in Group II were diagnosed with Familial Mediterranean Fever syndrome and immunoglobulin-G2 subgroup deficiency, while one patient in Group I was diagnosed with periodic fever, aphtous stomatitis, pharyngitis, and adenitis syndrome. Discussion: To investigate only those children pre-senting with fever episodes of at least once a month may not be discrimi-native. To construct an algorithm for diagnosis and treatment, it would be better to follow recurrent fever patients for a longer duration rather than initially categorizing them according to the number of episodes.

Keywords: Children; C-Reactive Protein; Infection; Frequent Fever; Recurrent Fever

Full Text

Introduction

Fever is a beneficial physiological response to many infectious and noninfectious illnesses. It is a very useful sign of illness, but it also evokes inordinate fear and anxiety, especially when it recurs [1]. Recurrent or periodic fever is a fairly common complaint in children, but the literature on this topic is sparse and largely confined to case reports or small case series [2]. Either with regular or irregular intervals, fever may recur as a result of one or more factors, particularly fluctuations in the clinical course of a disease or recurrent diseases of the same organ system at different times or in different recurrent diseases that may involve different organ systems [2-4]. Recurrent fever results most often from infectious diseases, but may also result from congenital immune defects, multifactorial inflammatory diseases, autoinflammatory disorders, and neoplastic diseases [5]. However, there are a number of misconceptions and inaccurate approaches to treatment management regarding fever and recurrent fever in children [6]. For example, the protocol for differential diagnosis and workup of children with recurrent fever is often similar to that used for children with prolonged fever of unknown origin [2].

However, the approach to workup of children with recurrent fever needs to be evaluated thoughtfully and in a more focused way, rather than being based solely on batteries of tests [1]. Patients with recurrent fever present with a history of multiple episodes of fever, so they usually have many visits to primary care providers or emergency rooms where nonspecific diagnoses have been made and antimicrobial therapy may have been prescribed [7].

It is important to generate a differential diagnosis specifically for the child with recurrent fever and to outline a rational approach to workup of these children. Therefore we investigated the difference of some parameters between the children who had 12 or fewer fever episodes per year and those with more than 12. In this way, this study aimed to (a) detect the frequency of fever episodes of patients who present to outpatient clinics complaining of frequent fever and the accompanying symptoms of those febrile episodes, and (b) assess the utility and efficacy of laboratory tests in identifying the cause(s) of fever.

Material and Method

Patient selection and definitions

We conducted a prospective study with patients younger than 18 years old who had a complaint of recurrent fever. The medical records of each patient were reviewed. The children with concurrent history of trauma or known diagnosis of immunodeficiency, chronic pulmonary disease, collagen vascular disease, or any other systemic disorders were excluded. The included patients were seen in outpatient clinics.

After informed consent from the legal guardians, data including age, sex, number of febrile episodes in the previous year, mean duration of febrile episodes, frequency of symptoms accompanying febrile episodes (i.e., oral ulcers, cough, sore throat, rhinorrhea, sneezing, postnasal discharge, skin eruptions, lymphadenopathy, diarrhea, vomiting, abdominal pain, chest pain, genital ulcers, and complaints about joints and the neurological system), attendance at school or day care centers, and seasonal occurrence of febrile episodes was prospectively collected. All febrile participants underwent physical examinations as advised in the literature [2, 4]. The local ethics committee approved the study.

All patients included in the study were followed and checked for two years in order to reach a definitive diagnosis.

Laboratory analysis

Laboratory tests including white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen levels, liver and kidney function tests ([LFT] and [KFT]), and quantitative immunoglobulins (IgA, IgG, and IgM) were performed. Urinary culture was done for all patients. Throat culture was done in patients older than three years with any positive findings related to bacterial tonsillitis/pharyngitis. Blood cultures were planned for patients who experienced febrile episodes of ≥7 days or patients who appeared sick, but no blood culture was performed. Laboratory tests for rheumatological etiology were carried out if the patient had compatible clinical indications. The need for treatment options was also recorded. The same pediatrician reviewed all patients’ charts.

Fever was defined as a temperature of ≥ 37.8°C [8]. We arbitrarily defined recurrent fever as 12 or more episodes of fever in the last 12-month period, and with an interval of at least seven days between febrile episodes. The children were divided into two groups according to the number of febrile attacks per year in order to compare demographic features, symptoms, clinical, and laboratory findings. Patients who had experienced ≤12 febrile episodes were included in Group I while those who had experienced >12 febrile episodes were included in Group II.

Statistical Analysis

Data were analyzed using the SPSS version 19.0 (SPSS, Inc., Chicago, IL, USA). Descriptive statistics were used to summarize the participants’ baseline characteristics, including means, standard deviations (SDs), and medians (ranges) for continuous variables, and frequency distributions for categorical variables. The chi-squared and Fischer exact tests were used for comparisons of categorical variables. The normality of quantitative variables was tested by Kolmogorov–Smirnov test. For continuous variables, we used the independent-groups t test for normally distributed variables or the nonparametric Mann–Whitney U test if the normality assumption was violated. In all analyses, 2-tailed p-values ≤ 0.05 were regarded as statistically significant.

Results

During the study period, a total of 186 children were admitted to outpatient clinics with the complaint of recurrent fever. Of these 186 pediatric patients, 138 were enrolled in the study. Forty eight children with recurrent fever with any underlying diseases or chronic conditions (known immunodeficiency, rheumatological, pulmonary, and cardiovascular diseases) were excluded from the study. None of the patients were hospitalized. According to our cut-off point of 12 febrile episodes in a year, 84 (60.9%) and 54 (39.1%) of the patients were included in Group I and Group II, respectively. The most frequently encountered ranges of fever episodes per year were 5-8 episodes (n=35, 25.3%) and 9-12 episodes (n=35, 25.3%) (Figure 1). The median age of the 138 patients was 37.5 (range 9 to 129) months and the male-to-female ratio was 1.9 (91 boys and 47 girls). Statistically significant differences were not found in terms of patients’ age (p=0.91) and gender (p=0.85).

By the end of the two year follow-up, one patient had been diagnosed with FMF (Familial Mediterranean Fever) and one patient had been diagnosed with IgG2 (immunoglobulin G2 subgroup) deficiency in Group II, while PFAPA (periodic fever, aphtous stomatitis, pharyngitis, and adenitis) was diagnosed in one patient in Group I.

At a statistically significant level, children in Group I experienced sneezing more frequently compared to Group II, whereas children in Group II experienced vomiting more frequently compared to Group I (p=0.05 and p=0.02, respectively) (Figure 2). Febrile episodes were shown to be significantly more frequent in winter season in Group I compared to Group II (p=0.03) (Figure 3). Statistically significant difference was not found regarding attendance at day care/school between Groups I and II (p=0.79).

There were no statistically significant differences between the groups regarding any physical examination findings (Table 1). CRP level was significantly higher in children in Group II compared to the children in Group I (p=0.001) (Table 1). Although blood culture was not performed for any patient, throat culture was performed for 14 patients who presented with tonsillopharyngitis. One throat culture in each group was positive for group A beta hemolytic streptococcus. Among all the patients, 4 had positive urine cultures, three cultures revealed E. Coli and one culture revealed Candida albicans; two had abnormal LFT results and none had abnormal KFT results.

Discussion

To our knowledge, this study is one of the very few to focus on evaluation of recurrent fever in childhood. A major challenge in investigating recurrent fever is that the literature did not provide a definitive cut-off point regarding the frequency of febrile episodes that can be used as a threshold in diagnosing recurrent fever. For example, whereas one of the reports defined recurrent fever as the occurrence of three to four febrile episodes within a 6-month period [2], another defined it as the occurrence of 10 episodes/year during the first two to three years of life [4]. Therefore, we defined “recurrent” fever as at least one febrile episode/month or 12 febrile episodes in a year; this was used as the cut-off point in this study.

After a long period of follow-up, it was realized that a total of three patients with recurrent fever had an underlying disease associated with fever frequency; these diseases were diagnosed with further tests. There are many disorders causing fever to recur. The autoinflammatory diseases, which are rare diseases characterized by the presence of chronic or recurrent systemic inflammation, may result in recurrent fever [5]. FMF is one of the most frequently seen. Furthermore, a large proportion of all the FMF patients in the world live in Turkey. It has a prevalence in the general Turkish population of about 0.093% [9] and mostly presents with peritonitis, fever, and arthritis [10]. In this study, one patient in Group II was diagnosed as FMF. Similarly PFAPA, which represents one of the most common type of recurrent fever in childhood, was diagnosed in one patient in ‘the normal frequency fever group,’ Group I. Also, congenital immune defects are one of the causes of recurrent fever in childhood, and one child had immunodeficiency in Group II in our study.

The patients who experienced 13 or more febrile episodes per year were shown to have significantly higher CRP levels. Although the factors responsible for elevation in CRP levels are unclear in the present study, it may be concluded that these children had a tendency towards infection/inflammation or towards more frequent bacterial infections, despite the fact that only six patients in our study had laboratory-confirmed bacterial infections (four urinary tract infection and two tonsillopharyngitis). In the case of infection, inflammatory disease, and trauma, acute-phase proteins like CRP, ESH, fibrinogen, and procalcitonin are involved with strong negative predictive value for inflammation [11, 12]. Rather than using these measures alone, combining them with WBC will likely yield more information with higher specificity and sensitivity [13-15].

Even healthy children may experience upper-respiratory tract system infection (URTI) three to eight times/year, particularly those who attend a day care center or school, a factor that has been associated with increased URTI [4, 16, 17]. In contrast to those reports, we did not find a significant difference in attendance at day care/school between the groups. The patients with frequent fever experienced more vomiting than the others. The patients who experienced ≤12 febrile episodes tended to experience more sneezing episodes. All of these symptoms are nonspecific and may be caused by any organ systems, although they are most commonly observed with cases of recurrent gastroenteritis, inflammatory bowel disease, meningitis, UTI, URTI, and autoinflammatory syndromes [18, 19]. As a result, careful physical examination is necessary for patients presenting with these symptoms. There was no difference between the groups according to physical examination findings, including skin eruptions, dental caries, and oral and genital ulcers. Since symptoms such as skin eruptions, oral/genital ulcers, and joint complaints may be the signs of Behçet’s disease, inflammatory bowel disease, immunodeficiency, HIV infection, or periodic fever syndrome [19-21], those diseases should be considered in the differential diagnosis of patients with frequent fever.

Although several studies have reported linear growth retardation after recurrent fever and infection [22, 23], only four children in the current study had growth retardation. This can be attributed to the inadequate sample size of this study or characteristics of the patients examined, specifically having self-limiting mild episodes, absence of severe appetite loss, or experience of febrile episodes as part of periodic fever syndrome. Both infectious and non-infectious factors that induce recurrent fever may also affect liver and kidney functioning [24-26]. But, few patients in the present study had these organs involved.

Urinary tract infections have an incidence reported as up to 8.4% in studies [27, 28], as well as a high rate of asymptomatic presentation [29]. Even though there was no significant association between UTI and fever frequency in this study, recurrent fever may be caused by UTI infections that were not confirmed by laboratory tests. Hence, investigation of UTI in pediatric patients with recurrent fever is recommended. Other factors that may affect the incidence of recurrent infection are immunoglobulin levels [30]. Although none of the patients in either group had abnormal (high or low) immunoglobulin levels when compared to normal values for the same age group, one patient was diagnosed with immunodeficiency. This disorder has normal immunoglobulin levels and cannot be diagnosed unless subgroup analysis is performed. Still, testing of quantitative immunoglobulin levels remains part of the routine algorithm of recurrent fever; the decision to do further immunological tests can be made on a case-by-case basis.

Another important finding of the study was that the patients with ≤12 febrile episodes tended to experience febrile episodes more frequently in the winter season compared to other patients. This may be due to those patients having spent more time within crowded indoor places during the cold months and their increased frequency of URTI. Although several types of infections, including diarrhea-related infections, malaria, and upper- and lower-respiratory system infections have been shown to have seasonal fluctuations [31-33], to our knowledge, it is new to describe an association with recurrent fever.

Some limitations of our study should also be noted. The sample population was relatively small and only patients in outpatient clinics were enrolled. So, this may prevent further generalization of the findings. The results need to be confirmed in a larger pool. Also, patients were categorized based on reported symptoms only and not on evident illness. Additionally, the sequential analysis of infectious biomarkers to understand longitudinal changes and optimal timing for prognostic value could not be performed because of financial considerations.

In conclusion, it is known that managing patients with recurrent fever needs careful history taking, repeated physical examinations, and targeted laboratory investigations to provide potential diagnostic clues for further specified tests to reach a correct diagnosis. This study indicates that rather than determining the fever frequency (at least once a month) at admission or trying to demonstrate an algorithm for diagnosis and treatment, it would be better to execute a long term and careful follow-up to discover the etiology.

Competing interests

The authors declare that they have no competing interests.

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Soner Sertan Kara, Yasemin Ozsurekci, Mehmet Ceyhan. Evaluation of Children with Recurrent Fever. J Clin Anal Med. 2016;7(5):681-685

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The Incidence of Concomitant Precancerous Lesions in Cases Who Underwent Hysterectomy for Prolapse

Serdar Aydın, Rabia Zehra Bakar, Aygün Mammadzade, Ramazan Dansuk

Department of Obstetric and Gynecology, Bezmialem Vakif University, Istanbul, Turkey

DOI: 10.4328/JCAM.4385 Received: 09.02.2016 Accepted: 02.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 676-80

Corresponding Author: Serdar Aydın, Obstetric and Gynecology Department, Bezmialem Vakif University, Adnan Menderes Bulvarı, Fatih, İstanbul, Turkey. GSM: +905327097179 F.: +90 2126217580 E-Mail:serdariks@yahoo.com

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Abstract

Aim: The aim of the study was is to assess the incidence of unexpected gynecological cancers and pre-cancerous lesions following hysterectomy for pelvic organ prolapse to better understand the risks of uterine sparing sur-gery. Material and Method: This was a retrospective analysis of histopathol-ogy findings after hysterectomy for uterine prolapse surgery who underwent preoperative diagnostic work including cervical cytology, transvaginal ultra-sonography and endometrial histopathological examination for a high risk group (Postmenopausal women with an endometrial thickness of ≥5 mm and premenopausal women with abnormal bleeding). Patients with a history of endometrial, cervical and/or adnexal precancerous or cancerous pathologi-cal conditions and with incomplete medical records were excluded.Results: Results were taken from 106 women who underwent hysterectomy. The ab-dominal route was used in 22 cases (21.7 %), the vaginal route in 82 patients (77.4 %) and laparoscopic-assisted vaginal route in two (1.9 %) women. Oo-phorectomy was performed in 35 (33 %) cases. None of the patients had malignant histopathology specimens from hysterectomy. Total premalignant pathology incidence was 7.5 % (8/106). Six (5.7%) patients had simple endo-metrial hyperplasia and 2 patients (1.9 %) had cervical intraepithelial neopla-sia. Discussion: The incidence of unexpected endometrial, cervical or ovarian malignancy among women who underwent hysterectomy after preoperative diagnostic workup including transvaginal ultrasonograhy, endometrial patho-logical examination to high risk cases was negligible. The inclusion of low risk endometrial and cervical precancerous lesions increased the incidences. Our results could provide precious data to extrapolate to similar populations with uterine prolapse who desire surgical correction sparing uterus.

Keywords: Hysterectomy; Histopathology; Precancerous; Prolapse

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Introduction

The most common gynecological operation performed worldwide is the hysterectomy [1]. Leiomyomas, abnormal heavy menstrual loss, uterine prolapse, cancer and precancerous lesions in reproductive organs, chronic pelvic pain, endometriosis and pelvic inflammatory disease are frequent indications for hysterectomy. In most cases, hysterectomy is performed to relieve symptoms and improve quality of life. There is an ongoing debate about hysterectomy in the axis of need for hysterectomy, route (robotic, laparoscopic or vaginally), usage of morcellation and total or subtotal. There are many suggestions from the media to avoid hysterectomy, which is the number one surgery women may not need, like episiotomy and heartburn surgery [2]. The decision to perform hysterectomy or not depends on several factors: age, completion of child-bearing, race, cultural beliefs, and whether one is the patient or the surgeon. The anticipated benefits of removing the uterus with or without adnexes must be carefully weighed against the possible risks of surgery and other alternative treatments [3].

Uterovaginal prolapse (UVP) is defined as the descent of the uterus or apex of the vagina into the anterior or posterior vaginal wall. It is particularly common among parous women, with an estimated prevalence ranging from 37 to 50 % [4, 5]. It leads to impaired quality of life (QoL), with a substantial impact on bladder, bowel and sexual function [6]. The estimated prevalence of pelvic organ prolapse (POP) is between 37% to 50%.. Hysterectomy, most commonly vaginal hysterectomy is a frequently carried out operation for POP and is usually combined with other reconstructive or anti-incontinence procedures even when uterine diseases or precancerous lesions are not present [7]. During the last decade there is a renewed interest among surgeons and patients in uterine conservation at the time of UVP surgery. Prolapse of the uterus is the result and not the cause of the apical prolapse and uterus conservative surgery is related with fewer complications, fast postoperative recovery and fewer bladder symptoms [8]. Another concern is to reduce the risk of gynecologic cancers by removing the uterus with or without the ovaries.

In the literature there are only a few reports of missing gynecological cancer in cases of hysterectomy for POP [9-12]. This study aims to assess the incidence of a malignant and/or premalignant, cervical and ovarian pathological condition in women undergoing hysterectomy for POP, who were otherwise asymptomatic, with normal cervical screening and who had undergone a normal transvaginal ultrasound (TVU) scan.

Material and Method

This is a retrospective study of patients who underwent hysterectomy for uterine prolapse between July 2011 and December 2015, in Bezmialem Vakif University, Istanbul, Turkey. As this is a non-interventional observational study, formal ethical approval was not obtained. The demographic data including age at surgery, parity, a history of previous miscarriage, smoking, menopausal status, the preoperative cli¬nical diagnosis, the histopatho¬logy of the endometrium obtained by dilatation and curettage (D&C) when available, the final histopathology results of the hysterectomy specimens and cervical cytology results were all retrieved from the medical records and/or the centra-lized computer system by the authors.

Clinical details, such as medical tests, postmenopausal or abnormal vaginal bleeding and the gynecological examination were recorded. Postmenopausal status was defined as amenorrhea for more than one year since the last menstrual period. TVU is routinely performed in all women and endometrial thickness was measured using TVU before the surgery. A history of medical conditions, including hypertension, diabetes mellitus, hypercholesterolemia and thyroid disease, were recorded if the hospital records confirmed the diagnosis. Body mass index (BMI) was calculated as weight divided by the square of height. Postmenopausal women who were found to have an endometrial thickness of ≥ 5 mm on TVU and premenopausal women with abnormal uterine bleeding, irrespective of the endometrial thickness, underwent D&C. The diagnosis of an abnormal cervical cytology test was based on the documentation of pathology results. In all cases a hysterectomy was performed via transvaginally, abdominally or laparoscopy assisted vaginal route. The vaginal vault was suspended either abdominally (sacrocolpopexy) or transvaginally (uterosacral ligament suspension). Bilateral salpingo-oophorectomy was performed when ovaries were accessible in women wishing to have their ovaries removed. Colposuspension or midurethral sling (MUS) procedures were performed in cases of coexisting stress urinary incontinence, which was confirmed with cough stress test. All specimens underwent microscopic histopathological examination. Patients with a history of endometrial, cervical and/or ovarian precancerous or cancerous pathological conditions and with incomplete medical records were excluded.

Statistical analyses were performed using the statistical package for the Social Sciences,

version 21 (SPSS, Chicago, IL). Descriptive statistics of data were reported as mean ± SD, range, percentage and 95 % confidence intervals (CIs).

Results

During the study period, a total of 111 women with UVP underwent hysterectomy. Three patients with a history of recent cervical dysplasia (2 patients with low-grade squamous intraepithelial lesion and one patient with high-grade squamous intraepithelial lesion), and two patients with a history of an adnexal mass were excluded. There were 106 women remaining who underwent hysterectomy via abdominal or vaginal route and had no known premalignant or malignant gynecologic pathology preoperatively for analysis. Mean age was 61.7±8.3 years (range 43–77, 95 % CI=60–63.3), with a mean BMI of 29.7±3.7 (range 24.3–37.3, 95 % CI=28.2–31.4). The majority of patients were postmenopausal (85 out of 106; 87.6 %).

For all the women, the demographic and gynecologic characteristics are shown in Table 1.

The abdominal route was used in 22 cases (21.7 %), the vaginal one in 82 patients (77.4 %) and laparoscopic-assisted vaginal route in two (1.9 %) women. A detailed description of the procedures performed is presented in Table 2. A total of 17 (16 %) patients underwent a sacrocolpopexy, whereas 29 (27.4%) patients had an anterior or posterior colporrhaphy, and 11 (10.4 %) women had an additional anti-incontinence operation. Oophorectomy either via abdominally or vaginally was performed in 35 (33 %) of the women. Most of the abdominal hysterectomies were accompanied with salpingo-oopherectomy (20 out of 22) cases. A total of 14 bilateral salpingo-oophrecetomies were performed concomitant to vaginal hysterectomy.

None of the patients had malignant histopathology from the specimens of the hysterectomy (Table 3). Total premalignant pathology incidence was 7.5 % (8/106; 95% CI, 2.8– 13.2). Six (5.7%; 95% CI, 1.9– 11.3) patients had unanticipated premalignant endometrial pathology, with simple hyperplasia. From cervical pathology, 2 patients (1.9 %; 95% CI, 0– 4.7) had cervical intraepithelial neoplasia (CIN1). Neither patient had a history of cervical dysplasia. No patients had CIN2-3 or cervical carcinoma.

The histopathology of the endometrium prior to hysterectomy was reported in the case notes of 35 cases (33%) due to postmenopausal endometrial thickness over 5mm, postmenopausal or menorrhagia. The most common finding was an unspecific endometrium change which was reported in 17 cases (48.6 %). Other findings include proliferative endometrium in 7 cases (20%), atrophic endometrium in 2 cases (5.7%), endometrial polyp in two cases (5.7%) and insufficient tissue in 5 cases (14,3%). Most of the women underwent cervical cytological examination. In smear, 50 women (61%) had normal cytology, one (1.2 %) had atypical squamous cells of undetermined significance, 14 (17.1 %) had atrophy and 17 (20.7 %) had inflammatory changes.

With regard to benign disease, fibroid was the most common finding in uterine specimens reported in 29 cases (27.4%). Adenomyosis finding was reported in 19 (17.9 %) of the cases and adenomyosis and leimyoma coexistence were found in 8 cases (7.5%). The most common finding in the endometrium of the uterine specimens was endometrial atrophy (38.7%, 41 out of 106 cases). Other findings include proliferative endometrium in 23 cases (21.7%), endometrial polip in 9 cases (8.5%) and atrophic endometritis in 1 case (0.9 %), endometrial polip in 2 cases (5.7%) and insufficient tissue in 5 cases (14,3%). There was no agreement between the preoperative endometrial pathology and final histopathological evaluation of hysterectomy specimens (Kappa = 0.29).

Discussion

In our study population the incidence of pre cancerous lesions of the endomerium and cervix found at the time of hysterectomy due to UVP was 7.5%. The incidence of cervical, endometrial and ovarian cancer was 0 %. All patients were asymptomatic with a negative diagnostic workup, including a preoperative TVS showing no gynecological abnormalities. Grigordiadis et al. and Frick et. al. reported the incidence of abnormal histopathological finding of the uterus as 4.2% and 2.6% , respectively among women who underwent vaginal hysterectomy for POP [10, 12].

In the literature the incidence of unanticipated cervical cancer among asymptomatic women who undergo a hysterectomy for UVP was 0.3 %. Among 333 women Grigordiasis et al. reported 1 case of cervical cancer in a 71-year-old women and another 1 (0.3 %) with CIN3 in a 66-year-old patient with a normal smear. They reported 3 cases (0.9%) of CIN1 who also had had negative smear tests 6 months to 3 years before the operation [12]. Our 1.9% incidence of unanticipated CIN is compatible with the total 1.2 % rate of this study. In another retrospective study Frick et al. reported no cervical cancer or CIN2/3 among 644 hysterectomy specimens; two patients had (0.3%) CIN1. The risk of cervical carcinoma has not been reported in uterus conserving prolapse surgery, but the rate of cervical carcinoma was low (below 0.3%) from studies evaluating supracervical hysterectomy of which can be extrapolated to uterine-sparing surgery [10]. Even in studies that predated modern cytological and viral screening techniques, the rate of cervical carcinoma was low (below 0.3%) [13]. With HPV vaccine and improved cytological and viral screening, this incidence rate is likely to be even lower.

The incidence of unexpected endometrial cancer among asymptomatic women who undergo a hysterectomy for POP varies between 0 and 0.8 % [9-12]. Renganathan et al. studied pathological specimens from 517 women who underwent vaginal hysterectomy for prolapse and found the rate of endometrial cancer to be 0.8% [9]. There was no information regarding the incidence of endometrial hyperplasia. They noted that whole cases of endometrial malignancy were in postmenopausal women and if premenopausal women are excluded the risk of endometrial cancer rises to 1.1%. They also emphasized the importance of preoperative TVU that they did not perform routinely.

Studies evaluating uterine pathology also demonstrate low risks for endometrial hyperplasia and cancer. In a retrospective study, Renganathan et al. studied pathological specimens from 517 asymptomatic women without abnormal uterine bleeding who underwent vaginal hysterectomy for prolapse and found the rate of endometrial cancer to be 0.8% [9]. Another retrospective trial evaluated the risk of unanticipated pathology at the time of hysterectomy for UVP among 681 pathological specimens. Frick et al. reported 0.8% simple hyperplasia, 0.5% complex hyperplasia, 1.1% complex hyperplasia with atypia, and 0.3% endometrial carcinoma [10]. Also in this study, none of the premenopausal women had premalignant or malignant pathology. The highest rate (13.3%) of missing endometrial pathology was seen in postmenopausal women with abnormal bleeding despite negative preoperative diagnostic evaluations. In a recent retrospective study evaluating the incidence of malignant and premalignant endometrial pathologies 2.7% of cases had endometrial hyperplasia [12]. They reported no cases of endometrial cancer. Three out of four cases of complex endometrial hyperplasia without atypia (1.2%) were found in postmenopausal women. Three out of four cases of simple endometrial hyperplasia (1.2%) and one case of complex endometrial hyperplasia with atypia (0.3%) were found in premenopausal women with endometrial thickness ranging from 6 to 7 mm. In our study we found 6 cases of simple hyperplasia, all of these cases were found in the postmenopausal period, with endometrial thickness ranging from 2.3 to 14 mm. Five out of six cases underwent dilation and curettage before surgery and in all cases endometrial histopathology was negative for premalignant endometrial hyperplasia. This is particularly important when counseling women regarding uterus sparing procedures as simple endometrial hyperplasia without atypical symptoms, have a known risk of 1% to progress to endometrial carcinoma [14].

Currently, a noninvasive, cost-effective screening strategy does not exist for asymptomatic women desiring uterine-sparing surgery. Rengenathan et al. suggested the usage of preoperative transvaginal ultrasonography in all cases to avoid the risk of missing an endometrial cancer, followed by endometrial sampling in women with increased endometrial thickness [9]. Using ultrasound as an isolated screening test may yield high false positive results. Ultrasound has been shown to have a sensitivity of 97% and specificity of 55% for the detection of endometrial cancer with an endometrial stripe of ≥5mm [15]. This would yield a positive predictive value of 57% and a negative predictive value of 99.8%.

In contrast to women with postmenopausal bleeding, women without postmenopausal bleeding, using an endometrial thickness of ≥ 5 mm has a lower sensitivity and specificity for detecting endometrial cancer [16]. Also the absence of ovarian cancer in our series is consistent with previous reports underlining the usefulness of transvaginal ultrasonography as an investigation prior to prolapse surgery [2, 17]. In a study that evaluates the usefulness of transvaginal ultrasonography prior to vaginal hysterectomy Srikrishna et al. found gynecological pathology in 46.6% of patients and changed the planned management in 2.9% of cases due to large fibroids and ovarian cysts [18].

The strengths of our study come from the single institution data with all cases evaluated with transvaginal ultrasoud, cervical cytology and endometrial sampling in cases of necessity. The major limitation is the retrospective design of the study could create selection bias and reliability of data regarding gynecological history. Another limitation was the relatively small size of the study population when assessment of the primary outcome of abnormal gynecologic histopathology was relatively rare. Limited numbers of cases with concomitant oophorectomy, given that ovaries were not systematically removed, must be considered when interpreting the data presented. Lastly, absence of consensus about the definition of abnormal endometrial thickness in asymptomatic postmenopausal women and the exclusion of cases with preoperative malignant or premalignant pathology limits the true incidence of precancerous or cancerous pathologies of patients who will undergo pelvic organ prolapse surgery.

In the present study, we evaluated the risk of unancipated gynecological cancerous or precancerous pathology among women with a defined preoperative diagnostic workup including transvaginal ultrasonograhy, D&C according to increased endometrial thickness, and postmenopausal or pre-menopausal abnormal uterine bleeding. With this examination we did not find any cases of endometrial, cervical or ovarian malignancy. However, the inclusion of low risk endometrial and cervical precancerous lesions (simple endometrial hyperplasia and CIN1) increased the incidence to 7.5% ( 8 out of 106). Our results could be to ensure precious data is extrapolated to similar populations with utero-vaginal prolapse who desire surgical correction. When uterus sparing procedures or procedures involving the conservation of part of the uterus, such as subtotal hysterectomy or ovaries are considered,this information is important during the consulting period. Currently, a cost effective screening strategy or diagnostic work up does not exist for a woman desiring uterine-sparing surgery. Future studies including a larger number of patients, larger number of specimens concomitant oophorectomies and studies that evaluate the incidence of malignancy after uterus sparing surgery are needed to provide more robust evidence.

Competing interests

The authors declare that they have no competing interests.

References

1. Lowensteina L, Yarnitskyb D, Gruenwaldc I, Deutscha M, Sprecherb E, Gedaliac U et al. Does hysterectomy affect genital sensation? Europ J Obstet Gynecol Reprod Biol 2005;119:242–5.

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3. Lefebvre G, Jeffrey J, Vilos G, Arneja J, Birch C, Fortier M. SOGC clinical guidelines hysterectomy. J Obstet GynecolCan 2002;24(1):37–61.

4. Thakar R, Stanton S. Management of genital prolapse. BMJ 2002;324(7348):1258–62.

5. Nygaard I, Barber MD, Burgio KL, Kenton K, Meikle S, Schaffer J, et al. Prevalence of symptomatic pelvic floor disorders in US women. JAMA 2008;300(11):1311–6.

6. Milsom I AD, Herbison P, Lapitan MC, Nelson R, Sillé NU, Thom D. Epidemiology of urinary (UI) and faecal (FI) incontinence and pelvic organ prolapse (POP). In: Abrams P CL, Khoury S, Wein A, (ed.) Incontinence: Paris: Health Publications Ltd; 2009.p.35–111.

7. Ateş S, Özcan P, Aydın S, Yardımcı AS, Karaca N, Kılıç G, et al. Histopathologi¬cal Analysis of 422 Nononcological Hysterectomies in a University Hospital. J Clin Anal Med 2015; DOI: 10.4328/JCAM.3505.

8. Van Brummen HJ, van de Pol G, Aalders CI, Heintz AP, van der Vaart CH. Sacrospinous hysteropexy compared to vaginal hysterectomy as a primary treatment for a descensus uteri: effects on urinary symptoms. Int Urogynecol J 2003;14(3):50–5.

9. Renganathan A, Edwards R, Duckett JR. Uterus conserving prolapse surgery–what is the chance of missing a malignancy? Int Urogynecol J 2010; 21:819–21.

10. Frick AC, Walters MD, Larkin KS, Barber MD. Risk of unanticipated abnormal gynecologic pathology at the time of hysterectomy for uterovaginal prolapse. Am J Obstet Gynecol 2010; 202:507.

11. Wan OY, Cheung RY, Chan SS, Chung TK. Risk of malignancy in women who underwent hysterectomy for uterine prolapse. Aust N Z J Obstet Gynaecol 2013; 53:190–6.

12. Grigoriadis T, Valla A, Zacharakis D, Protopapas A, Athanasiou S. Vaginal hysterectomy for uterovaginal prolapse: what is the incidence of concurrent gynecological malignancy? Int Urogynecol J 2015;26(3):421-5.

13. Storm HH, Clemmensen IH, Manders T, Brinton LA. Supravaginal uterine amputation inDenmark 1978e1988 and risk of cancer. Gynecol Oncol 1992;45:198-201.

14. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985; 56:403–12.

15. Havrilesky LJ, Maxwell GL, Myers ER. Costeffectiveness analysis of annual screening strategies for endometrial cancer. Am J Obstet Gynecol 2009;200:640.e1-8.

16. Breijer MC, Peeters JA, Opmeer BC, Clark TJ, Verheijen RH, Mol BW, et al. Capacity of endometrial thickness measurement to diagnose endometrial carcinoma in asymptomatic postmenopausal women: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2012;40:621-9.

17. Van den Bosch T, Van Schoubroeck D, Domali E, Vergote I, Moerman P, Amant F et al. A thin and regular endometrium on ultrasound is very unlikely in patients with endometrial malignancy. Ultrasound Obstet Gynecol 2007;29(6):674–9.

18. Srikrishna S, Robinson D, Cardozo L, Yazbek J, Jurkovic D (2008) Is transvaginal ultrasound a worthwhile investigation for women undergoing vaginal hysterectomy? J Obstet Gynaecol 2008;28(4):418–20.

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Serdar Aydin, Rabia Zehra Bakar, Aygun Mammadzade, Ramazan Dansuk. The Incidence of Concomitant Precancerous Lesions in Cases Who Underwent Hysterectomy for Prolapse. J Clin Anal Med. 2016;7(5):676-680

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Views of Turkish Men Regarding the use of Drugs and Products for Increasing Sexual Performance

Sadi Turkan 1, Selahittin Çayan 2, Ateş Kadıoğlu 3

1 Private Anadolu Hospital, Kastamonu, 2 Department of Urology, Mersin University, Faculty of Medicine, Mersin, 3 Department of Urology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey

DOI: 10.4328/JCAM.4351 Received: 29.01.2016 Accepted: 02.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 672-5

Corresponding Author: Sadi Turkan, Özel Anadolu Hastanesi, Beyçelebi Mh. Atatürk Cd. No:36/1 Kastamonu, Türkiye. GSM: +905324822876 F.: +90 3662140131 E-Mail saditurkan@hotmail.com

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Aim: This study aims to evaluate the views of the adult male population in Turkey concerning the use of drugs (Phosphodiesterase type 5 inhibitors) and herbal products to increase sexual performance, and to assess the use and outcomes of these medications within the study site. Material and Method: This non-interventional, observational, sectional site study was conducted in 2012. Participants were randomly selected from 19 provinces of Turkey according to Eurostat and Nomenclature of territorial units for statistics (NUTS) Level-2 by a proportional sampling method according to postal code lists. Men aged 18 years or older were included in this study as representa-tives of the male Turkish population. Of these, 410 men using at least one erectile dysfunction (ED) product within the last year were interviewed face-to-face. Results: 98% of participants did not have ED. The rate of drug use for “increasing sexual performance” by those not reporting erection problems was 63%. Among this group of drugs, moderate to high satisfaction rates were observed for sildenafil and herbal products of 85% and 63% respective-ly. Women’s awareness of their partners’ drugs use was low at 25%. Satisfac-tion among women aware of their partners’ drug use was 63%. Discussion: The prevalence of drug use, including PDE-5 inhibitors or herbal products, is high among Turkish men, who often do not inform their partners about their drug use. Given the high rate of satisfaction in cases where partners are informed, we believe that the positive psychosocial effects of these medica-tions on partners could contribute to treatment planning.

Keywords: Erectile Dysfunction; Sexual Performance; Drugs; Herbal Products

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Introduction

Erectile dysfunction (ED) is the most common sexual problem experienced in men [1]. Since the introduction of sildenafil in 1998, phosphodiesterase type 5 inhibitors (PDE5 inhibitors) have been used as a safe and effective drug group in the first-line treatment of ED [2]. These drugs are reportedly also used by men who do not have sexual problems but who wish to increase their sexual pleasure and performance [3]. In addition to these medications, many herbal products are used by men worldwide to increase their sexual performance [4]. In Turkey, many drugs and herbal products are used by men to increase their sexual performance regardless of whether they have ED. However, there has been no research regarding this issue that has evaluated the reasons and results behind men’s use of these drugs and the perceptions of their partners.

In this study, we aim to evaluate the views of the adult male population in Turkey concerning the use of drugs and herbal products to increase sexual performance and also to assess the use and outcomes of these medications within the study site.

Material and Method

This non-interventional, observational, sectional site study was conducted in 2012. Participating males were randomly selected from 19 provinces of Turkey according to Eurostat and Nomenclature of territorial units for statistics (NUTS) Level-2 by a proportional sampling method according to postal code lists. Based on the population distribution between urban and rural geographic regions and age groups, men 18 years of age or older were included in this study as representatives of the male Turkish population. Individuals with cognitive disorders, individuals with limited Turkish language abilities, and individuals who we determined to have poor levels of insight and understanding were excluded from the study.

All participants were visited at home by health care staff who understood the questionnaire and were trained to perform the interviews. Participants were asked to fill out questionnaire forms regarding their sexual habits, existing medications, sexual and medical histories, and their demographic, socioeconomic, and sociocultural status.

Sample Size:

Of this group of men, 410 men who used at least one ED product within the last year were interviewed face-to-face. This sample size allowed the study to be completed with a confidence interval of 95% and ± 4.9% margin of error.

Before registering for the study, participants were informed about the study and their written consent was received. This study was approved by the ethical committee of the Turkish Ministry of Health.

Results

The survey results from the 410 men concerning their reasons and motivations for using PDE-5 inhibitors or herbal products are shown in Table 1. The rate of drug use for “increasing sexual performance” by those not reporting erection problems was 63%. The most common form was PDE-5 inhibitor at 78%. Among this group of drugs, the moderate to high satisfaction rate observed for sildenafil was 85%. The moderate to high satisfaction rate for herbal products was 63%. Interestingly, the average number of instances of intercourse was 2 times in one night and the average duration of intercourse was 26.7 minutes.

The International Index of Erectile Function (IIEF) scores of the men are shown in Table 2. Of the men, 98% included in the study were found not to have ED.

The frequency and distribution of the side effects are given in Table 3. The side effect ratio was 22%. The most common side effect was headaches with a rate of 42%.

The views of the men who preferred this drug and their partners’ views are presented in Table 4. Women’s awareness of their partners’ drugs use was low at 25%. Satisfaction among women who were aware of their partners’ drug use was 63%.

Discussion

Today, PDE-5 inhibitors are a rather safe and effective drug group that is used in the first-line treatment of ED. In Turkey, the use of PDE-5 does not require the recommendation of a physician. Despite insufficient medical evidence concerning their efficacy, many herbal products are also used by men worldwide to increase sexual performance and are within the scope of traditional medical understanding [5]. These products are believed to function by increasing the levels of testosterone in the blood and by providing vasodilatation in the vascular structure of the penis [4]. Additionally, ED in men also has a direct effect on the sexual functions of women. Therefore, the effects of the medication used to treat ED should be taken into account on behalf of both men and women [6]. Pleasure plays a primary role in motivating sexual activity in people [7]. Thus, some men may prefer performance-enhancing products because of their own sexual satisfaction and that of their partners. In our study, according to IIEF scores, 98% of men had high rates of drug use although they did not experience ED, which supports this speculation. Studies have reported rates of moderate to severe ED in 36% of men over 40 years of age [8]. In this study, the rate of repeated drug use within the last 6 months was very high (77%) in men who used these drugs within the last year. These products are reportedly used by a high rate of individuals (63%) to increase sexual performance despite the fact that these individuals do not have ED. This demonstrates that they are seeking out increased quality in sexual intercourse.

Some studies conducted a biochemical analysis of alternative products that are used in the treatment of ED and in increasing sexual performance; several PDE-5 inhibitors, especially sildenafil, were identified [9,10]. Similar to our study’s findings, the satisfaction rate of sexual performance was 48% for men who used PDE-5 inhibitors and 43% for men who used herbal products; these herbal products presented similar effects and side effects. However, 13% of the men included in our study preferred to use only herbal products to increase their sexual performance. This rate was significantly lower than for PDE-5 inhibitors. This may be because sufficient reliability has not yet been established for these herbal products.

The most common side effects of PDE-5 inhibitors include flushing, headache, congestion, blurred vision, muscle pain, and dyspeptic complaints; these effects are usually mild and temporary [11]. The drug-induced side effects experienced by the men in this study were consistent with results found in the literature. The most common side effects were flushing and backaches.

PDE-5 inhibitors are known to significantly increase erection duration. In a study by Padma-Nathan et al. in 2003, erection time was 36 minutes in men who used sildenafil. This result was reported to be significantly higher than in men who consumed placebos [12]. In the men in our study who used performance-enhancing medication, the average number of instances of intercourse was 2 times in one night and the average duration of intercourse was 26.7 minutes.

In a study investigating the perceptions of women regarding ED medications, 46.4% of women had negative perceptions of ED medications and 43.2% of women had negative perceptions toward men who used ED medications [13]. In our study, 54% of the men had not informed their partners about their drug use. This may be due to their desire to be perceived as having natural sexual intercourse and their belief that revealing this information would provoke negative responses in their partners. Satisfaction among women who were aware of their partners’ drug use was 63%.

The limitations of our study include the parameters affecting drug use and ED including age, lifestyle, exercise habits, psychogenic status, intellectual status, and body mass index. These could not be regulated in a more standardized way. Further studies are needed with a larger number of subjects and sub-parameters.

The prevalence of drug use, including PDE-5 inhibitors or herbal products, is high among Turkish men. However, these products are being used by the men to enhance sexual performance more often than as ED treatment. Also, PDE-5 inhibitors are used considerably more than herbal drugs. These men often do not inform their partners about their drug use. Given the high rate of satisfaction in cases where partners are informed, we believe that the positive psychosocial effects of these medications on both men and women could contribute to treatment planning.

Competing interests

The authors declare that they have no competing interests.

References

1. Heidelbaugh JJ. Management of erectile dysfunction. Am Fam Physician 2010;81:305-12.

2. Lewis RW1, Sadovsky R, Eardley I, O’Leary M, Seftel A et al. The efficacy of tadalafil in clinical populations. J Sex Med 2005;2:517-31.

3. Carvalheira A, Forjaz V, Pereira NM. Adherence to phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction in long-term users: how do men use the inhibitors? Sex Med 2014;2:96-102.

4. Chauhan NS, Sharma V, Dixit VK, Thakur M. A review on plants used for improvement of sexual performance and virility. Biomed Res Int 2014;2014:868062. doi: 10.1155/2014/868062

5. Bella AJ, Shamloul R. Traditional plant aphrodisiacs and male sexual dysfunction. Phytother Res 2014;28:831-5.

6. Montorsi F, Althof SE. Partner responses to sildenafil citrate (Viagra) treatment of erectile dysfunction. Urology 2004;63:762-7.

7. Randolph ME, Pinkerton SD, Bogart LM, Cecil H, Abramson PR. Sexual pleasure and condom use. Arch Sex Behav 2007;36:844-8.

8. Gülpinar O, Haliloğlu AH, Abdulmajed MI, Bogga MS, Yaman O. Help-seeking interval in erectile dysfunction: analysis of attitudes, beliefs, and factors affecting treatment-seeking interval in Turkish men with previously untreated erectile dysfunction. J Androl 2012;33:624-8.

9. Low MY, Zeng Y, Li L, Ge XW, Lee R et al. Safety and quality assessment of 175 illegal sexual enhancement products seized in red-light districts in Singapore. Drug Saf 2009;32:1141-6. 10. Campbell N, Clark JP, Stecher VJ, Thomas JW et al. Adulteration of purported herbal and natural sexual performance enhancement dietary supplements with synthetic phosphodiesterase type 5 inhibitors. J Sex Med 2013;10(7):1842-9.

11. Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010;57:804-14.

12. Padma-Nathan H, Stecher VJ, Sweeney M, Orazem J, Tseng LJ et al. Minimal time to successful intercourse after sildenafil citrate: results of a randomized, double-blind, placebo-controlled trial. Urology 2003;62:400-3.

13. Mita K, Shigeta M, Kakehashi M, Matsubara A, Teishima J et al. Women’s perception of male erectile dysfunction drugs in the general population. Maturitas 2007;56:216-22.

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Sadi Turkan, Selahittin Cayan, Ates Kadioglu. Views of Turkish Men Regarding the use of Drugs and Products for Increasing Sexual Performance. J Clin Anal Med. 2016;7(5):672-675

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Trauma and Intentional Injury Characteristics of Pediatric Forensic Cases Applying to Emergency Room

Esin Akgül Kalkan 1, Ahmet Yıldırım 2, Okhan Akdur 2

1 Department of Forensic Medicine, Çanakkale Onsekiz Mart University, Faculty of Medicine, 2 Department of Emergency Medicine, Çanakkale Onsekiz Mart University, Faculty of Medicine, Çanakkale, Turkey

DOI: 10.4328/JCAM.4302 Received: 15.01.2016 Accepted: 03.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 668-71

Corresponding Author: Ahmet Yıldırım, Department of Emergency Medicine, Çanakkale Onsekiz Mart University, Faculty of Medicine, 17000, Çanakkale, Turkey. GSM: +905059063338 F.: +90 2862635956 E-Mail: ahmetyildirim@comu.edu.tr

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Aim: In this study, we aim to reveal the characteristics of intentional inju-ries and the trauma profiles in order to prevent injuries in pediatric forensic cases. Material and Method: Forensic cases of patients aged 18 or younger who were admitted into emergency service were analyzed retrospectively in terms of age, gender, type of injury, and etiology of trauma between January 1, 2014 and December 31, 2014. Results: Of the 148 cases, 62(41.9%) were female and 86(58.1%) male; the mean age was 11.2±0.4. The most com-mon cause of injury was traffic accident (46.6%). The second most common type of injury was intentional injuries (21.6%). The distribution of intentional injury is: beating in 20 cases (13.5%), stab wounds in 7 cases (4.7%), gun-shot wounds in 1 case (0.7%), sexual abuse in 1 case (0.7%), and attempted suicide in 3 cases (2%). Eleven (7.4%) cases had life-threatening injuries. Discussion: Most injuries are preventable because they are due to traffic ac-cidents. Intentional injuries were more frequent during school age and ado-lescence. Understanding these findings is very important in developing child safety programs to reduce injuries.

Keywords: Emergency Service; Pediatric Forensic Cases; Intentional Injury; Child Security

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Introduction

Intentional and unintentional injuries are the leading cause of disability, morbidity, and mortality in children all over the world [1]. As a result of developments in the area of pediatric health and improvements in data collection methods, it appears that in low and middle income countries the leading cause of child mortality and disability is injury. Research and experience suggest that the majority of these injuries are preventable in all countries [2-4]. In the 0-18 year age group, the leading cause of non-mortal traumatic injuries is unintentional injury [5-7].

This study aims to determine the trauma profile and intentional injury characteristics of forensic cases aged 18 years and below applying to a third-stage emergency service.

Material and Method

Pediatric forensic cases aged 18 years and below admitted to Çanakkale Onsekiz Mart University Application and Research Hospital Emergency Service from January 1, 2014 to December 31, 2014 were retrospectively screened using police records and digital patient records. Cases included in the study were investigated in terms of age, sex, cause of trauma, type of injury and the effects of injury on the body. Data were analyzed using the SPSS 15.0 program. Quantitative variables were indicated as mean ± SD (standard deviation) and categorical variables were summarized as numbers and percentages. Categorical data were analyzed by Pearson chi-square or Fisher’s exact test. Values of p<0.05 were considered as statistically significant.

Results

During the time period of the study, 148 pediatric cases applied to the emergency service due to trauma and had a forensic report prepared. Of these cases, 62 were female (41.9%) and 86 were male (58.1%). The distribution of cases according to sex and age is shown in Table 1. The mean age of cases was 11.2±0.4 years. The injury rate of males (58.1%) was greater than for females (41.9%). The intentional injury rate of investigated male cases was observed to be higher than for female cases (p=0.001). When all injuries in both sexes are evaluated together, the unintentional injury cases were observed to be significantly high (p=0.03) (Table 2). It appears that more forensic cases were encountered in the summer months compared to other months (Figure 1).

Fifty-one (34.4%) of the investigated cases were observed to have been exposed to trauma in one body area, while 16 cases (10.8%) had trauma in two regions and 22 cases (14.8%) had trauma in three or more regions. The most frequently injured regions were head-neck and lower extremities (Figure 2). In 29 cases (19.5%), there was no region affected by trauma. In 10 cases (6.7%) there was no available data. The number of cases with systemic effects due to external factors was 20 (13.5%). This systemic effect was observed in poisoning and suicide-attempt cases.

When cases are investigated according to etiology, the most common was traffic accidents (TA) with 69 cases (46.6%). Intentional injury cases, including interpersonal violence and suicide attempts, were second most common totaling 32 cases (21.6%). The distribution of the injuries in the violence-linked and intentional injury category were 20 cases of beating (13.5%), 7 cases of sharp object injuries (SOI) (4.7%), 1 case of firearm injury (FI) (0.7%), 1 case of sexual abuse (0.7%), and 3 suicide-attempt cases (2%). The sexual abuse case concurrently was involved in substance abuse. There were a total of 22 cases (14.8%) with falls from the same level or from a height and 17 cases of poisoning (11.4%). The distribution of cases according to etiology and gender is shown in Table 3. When the admissions to the emergency service were examined, 10 cases (6.7%) admitted themselves, 33 cases (22.2%) came in an ambulance, and 11 cases (7.4%) were transferred from external centers.

The results of forensic traumatology reports were 33 cases (26.4%) with no external traumatic change, 40 (27%) cases in which the situation was resolved with basic medical intervention (BMI), 11 cases (7.4%) that were life-threatening, and 21 cases (14.3%) with bone fractures (Table 4).

In ten (47.6%) cases there were multiple bone fractures. In the head and neck region the most common fracture was nasal bone fracture 5 olgu (23.8%). In one case (4.7%) there were multiple fractures in face bones. In three cases (14.2%) there was frontal bone fracture and in one case (4.7%) there was occipital bone fracture. In all cases the most common bone fractures were lower extremity fractures, of which there were four femur (19.0%), three tibia (14.2%), three fibula (14.2%), and three metatarsal (14.2%). In upper extremities, there were three ulnar (14.2%) and one phalanx fracture (4.7%).

Discussion

Trauma in the childhood period is a significant public health problem as many cases with injuries (either fatal or non-fatal) require hospital care. A significant portion of these patients experience life-long health problems and disabilities. Though trauma in the pediatric period is a significant cause of morbidity and mortality, the majority of traumas are preventable [1, 8]. In pediatric trauma epidemiology studies in our country, usually traffic accidents (TA) appear in first place [9-11]. This fact is of separate importance in terms of preventability of injury in the pediatric period and in ensuring child safety against injury. Additionally, in our study of pediatric forensic cases, the rate of intentional injury linked to violence was very high; it was the most frequent forensic report after TA.

Within the one-year period of the study, the majority of forensic cases under 18 years of age admitted to our emergency service were male (58.1%). Across all cases the majority of forensic reports were in the 15-18 year age interval, whereas the age interval for female cases was 7-14 years. Seasonal distribution of cases showed that the majority (45.5%) admitted in the summer, with 38.8% in the month of August. A recent national study stated that pediatric forensic cases were higher for males, with the most frequent age range being 7-10 years [9].

In a regional study by Erhan et al. [12] the male/female rates were similar; they attributed this to the similarly active lifestyles of male and female children. However, in our study, the male forensic case numbers were significantly higher (p=0.001). In the literature, generally, higher rates for male cases are reported [9, 12, 13]. One reason for TA coming to the fore in our study may be the increased motorcycle and bicycle use in our region, especially during the summer months.

When all trauma cases in our study are evaluated together, TA was the leading cause of emergency application with a rate of 46.6%. There are many studies stating that TA is the most frequent cause of pediatric forensic cases. A study by Çınar et al. reported a rate of 52% while Cooper et al. reported a rate of 59%. These are similar to the results of our study [10, 14]. However, there are some studies that do not align with our results, stating that TA is more rarely observed [12, 15]. It is thought that regional differences are an important factor in these variable epidemiological results.

Intentional injuries were determined to be the second most common trauma with an incidence of 21.6%. Among these injuries, battery was the most frequently encountered cause (62.5%). Of all forensic cases, battery had a rate of 13.5%, with the majority of cases (70.0%) exposed to this trauma being male patients. When examined generally, the percentages of forensic case reports after battery in our study were compatible with other studies [10, 15]. SOI cases were the second most common cause among intentional injuries (4.7%) and fourth place for all traumatic injuries. The majority of these cases (71.4%) were male children. Demir et al. found that SOI was the third most common (6.8%) form of injury in traumatic injury cases [11]. Additionally, three of our cases were suicide attempts, with two of these female. One patient had a firearm injury and one patient applied as a result of sexual abuse. In the adolescent period an individual is greatly affected by friends and environment. Led by feelings of independence, they may act without thinking. It is reported that this situation can increase the tendency for violent behavior, especially in male children [16, 17]. In the pediatric age group, among injuries linked to violence, intentional injury is a serious health problem related to violence, with striking and preventable effects [8, 9]. After intentional injury, fall cases with a 14.8% rate were the third most common forensic case report. Similarly Buken et al. [12] stated that injury linked to falls was the third most common cause with a rate of 11.96%. However Çetinel et al. [18] reported a rate of 23.38%, higher than that generally stated in the literature. In our study poisoning cases (11.4%) were fourth in emergency services applications. The majority of these cases (64.7%) were male patients. In international studies the poisoning rate is approximately 12%, while national studies generally show wide variations in poisoning rates, ranging from 5% to 30% [9, 10, 13, 18].

Many studies state that head-neck and upper extremity regions are the most frequently injured body areas. In single area trauma, again head-neck injuries are the most frequently injured region [10, 13, 16]. In our study, compatible with general findings, nearly half of patients (49.3%) had trauma in the head-neck region, followed by 23.6% with lower extremity trauma. Upper extremity was the third most common region and abdominal the fourth. Additionally, the head-neck region was most frequently affected in single-region injury (34.4%).

During our study, 19.5% of patients with forensic case reports were treated after admission to hospital. The majority of hospitalized patients (82.7%) were unintentional trauma cases and the most common cause was TA. Though 7.4% of hospitalized patients had life-threatening injuries, no forensic case died. Nearly 2/3 of patients had mild injuries requiring basic medical intervention and they were discharged after outpatient treatment. Çetinel et al. [18] reported that half of pediatric forensic applications required hospitalization. The death rate of these cases was 9.0%. Sever et al. [13] had a similar hospital stay rate (40.1%) and reported the death rate as 9.0%. In a study only monitoring in-patients, Akay et al. reported the most common forms of trauma were abdominal trauma and head trauma; the mortality rate was given as 6.7% [11]. In the literature, similar to our study, studies with lower hospitalization rates are found. In these studies, the mortality rate is very low (0.4%) or no case ended in death [9, 10]. In our study, when the cases are evaluated in terms of severity of trauma, in the majority of cases the injury was not life threatening. Basic medical intervention was sufficient and bone fractures did not occur. We did not have any case resulting in death. In conclusion, the majority of our cases were assessed as having a mild or moderate degree of injury. This situation is interpreted clinically as the most important factor in explaining our low hospitalization rates and 0.0% mortality.

According to the results of our research, TA, injury due to falls, and poisoning were identified as the most important etiologic factors in unintentional injury of children. Female children are observed to have more injuries in the early childhood period, whereas male children are observed to have more injuries in the school and adolescent periods. This was identified in the type and frequency of regional differences in forensic cases. Regarding both intentional and unintentional injuries, preventive measures can be taken. To ensure child protection, it is important to determine the characteristics and trauma profile of forensic cases in the pediatric period. In conclusion, in taking preventive precautions for injuries and developing injury control programs, the epidemiological data obtained in these types of studies should be considered.

Competing interests

The authors declare that they have no competing interests.

References

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6. Brook U, Boaz M. Children hospitalized for accidental injuries: Israeli experiences. Patient Education and Counseling 2003;51:177-82.

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12. Büken E, Yaşar ZF. Başkent Üniversitesi Ankara Hastanesi Acil Servisine Başvuran Adli Nitelikli Olguların Değerlendirilmesi. Adli Tıp Bülteni 2015;20(2):93-8.

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Esin Akgul Kalkan, Ahmet Yildirim, Okhan Akdur. Trauma and Intentional Injury Characteristics of Pediatric Forensic Cases Applying to Emergency Room. J Clin Anal Med. 2016;7(5):668-671

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Insulin Like Growth Factor System: How Does it Affect Neonatal Anthropometry?

Emine Kaçar 1, Alev Özer 2, Salih Serin 3, Yakup Gümüşalan 4, Fatma İnanç Tolun 5, Mine Kanat-Pektas 6

1 Department of Anatomy, Sütçü İmam University, Kahramanmaraş, 2 Department of Obstetrics and Gynecology, Sütçü İmam University, Kahramanmaraş, 3 Department of Obstetrics and Gynecology, Tatvan Woman Hospital, Bitlis, 4 Department of Anatomy, Fatih University, İstanbul, 5 Department of Biochemistry, Sütçü İmam University, Kahramanmaraş, 6 Department of Obstetrics and Gynecology, Kocatepe University, Afyonkarahisar, Turkey

DOI: 10.4328/JCAM.4329 Received: 22.01.2016 Accepted: 02.03.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 664-7

Corresponding Author: Alev Özer, Kahramanmaraş Sütçü İmam Üniversite Hastanesi, Kahramanmaraş, Türkiye. T.: +90 3442803434 F.: +90 3443113005 E-Mail: serdarztb78@gmail.com

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Aim: The present study aims to clarify the role of insulin like growth factor-1 (IGF-1), insulin like growth factor binding protein-3 (IGFBP-3), ghrelin, and insulin in fetal growth. Material and Method: Based on Turkish standards, 14 newborns were defined as small for gestational age (SGA), 33 newborns were described as appropriate for gestational age (AGA), and 13 newborns were identified as large for gestational age (LGA). IGF-1, IGFBP-3, ghrelin, and insulin levels were measured in umbilical cord and maternal serum. Results: The LGA group had significantly higher levels of IGF-1, IGFBP-3, ghrelin, and insulin in umbilical cord and maternal serum than the SGA group. Umbilical cord and maternal serum levels of IGF-1 and IGFBP-3 correlated significantly and positively with body weight, body length, head circumference, and ab-dominal circumference of the neonates. Discussion: Based on the findings of the present study, it may be postulated that insulin like growth factor system has a role in fetal growth.

Keywords: Anthropometry; Ghrelin; Insulin; Insulin Like Growth Factors; Insulin Like Growth Factor Binding Proteins; Newborn

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Introduction

Insulin, insulin like growth factors (IGFs), and insulin like growth factor binding proteins (IGFBPs) have been established as the main endocrine regulators of fetal growth. The IGFs in maternal circulation regulate fetal tissue growth and metabolism by means of controlling the availability of nutrients to the mother and fetus. Maternal IGFs also play significant roles in placental development, substrate transport, and hormone secretion [1-6].

Ghrelin is a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract. This “hunger hormone” acts as a signal which points out the status of nutrition and energy storage to the feeding center located within the hypothalamus. Ghrelin has also been addressed as an essential element of the endocrine system that controls fetal growth. Ghrelin acts as a signal which points out the status of nutrition and energy storage to the feeding center located within the hypothalamus. Circulating concentrations of ghrelin have been determined in healthy individuals but there are still limited data about the relative role of maternal and fetal ghrelin in the growth process within the uterus [7, 8].

Fetal growth restriction is associated with increased perinatal morbidity and mortality. Moreover, former infants with a history of fetal growth restriction have a greater risk of developing degenerative diseases in adult life. That is why understanding the role of insulin, ghrelin, and the IGF system in fetal growth is essential for the identification of the mechanisms underlying fetal growth restriction [9, 10].

The present study aims to clarify the role of IGF-1, IGFBP-3, ghrelin, and insulin in fetal growth by investigating how anthropometric measurements of the newborns are related with the levels of these endocrinological markers in both maternal serum and the umbilical cord.

Material and Method

This observational study was approved by the Institutional Review Board and Ethical Committee of Kahramanmaras Sutcu Imam University Hospital where it was conducted between September 2012 and December 2012. Written informed consent was obtained from each participant.

The study population consisted of 102 women with term pregnancies who were enrolled over a 3-month-long period at the Perinatology Unit of the study center. Ten mothers who did not want to participate in this study and four mothers who did not have a history of antenatal care in the last trimester of pregnancy were excluded from the study. Five women with multiple gestation, five women with chronic and gestational diseases, and one woman with clinically evident intraamniotic infection were also excluded. Since oral and intravenous glucose administration can decrease serum ghrelin levels, five women who received dextrose solutions during labor were excluded from this study.

Three mothers who delivered newborns with chromosomal abnormalities, two mothers who gave birth to newborns with congenital anomalies, two mothers who delivered newborns with perinatal infections, three mothers who gave birth to newborns that required intensive care treatment in the immediate postnatal period, and two mothers whose newborns had conflicting anthropometric measurements and fetal biometry were excluded from the study. Therefore, 60 mothers and their newborns were found eligible for final analysis. The Turkish standards for sex, gestational age, and birth weight were used to categorize the newborns of the study cohort. Accordingly, 14 newborns were described as small for gestational age (SGA), 33 newborns were identified as appropriate for gestational age (AGA), and 13 newborns were defined as large for gestational age (LGA) at birth [11].

Venous blood samples were obtained from the antecubital area of each participant by phlebotomy between the hours of 08:00 and 09:00 following 10-12 hours of fasting. Blood samples from the umbilical cord were acquired as soon as the participants delivered their newborns. After procurement, these samples were allowed to clot and were exposed to centrifugation for 10 minutes at 3000 g. Then the sera were separated and stored at –70°C until laboratory studies would be performed.

Immunoradiometric assay was used to determine the serum concentrations of IGF-1 (Immunotech, Beckman-Coulter Inc., CA, USA), and serum levels of IGFBP-3 (DRG Diagnostica, Marburg, Germany). Radioimmunassay was used to measure serum concentrations of ghrelin (DRG Diagnostica, Marburg, Germany) and serum levels of insulin (CIS Bio International, Schering AG, Berlin, Germany). The intra-assay coefficients of variation (CVs) were 5.3%, 3.8%, 7.8%, and 6.2% whereas the inter-assay CVs were 1.8%, 1.5%, 10.0%, and 5.7% for IGF-1, IGFBP-3, ghrelin, and insulin respectively.

Collected data were analyzed by Statistical Package for Social Sciences version 18.0 (SPSS IBM Software, Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (range: minimum-maximum) and categorical variables were denoted as numbers or percentages where appropriate. The Smirnov-Kolmogorov test was used to test the distribution of variables. One-way analysis of variance, Mann Whitney U test, and Kruskal-Wallis test were used for the comparisons. A post hoc analysis was carried out to make a retrospective power analysis and it was determined that a cohort size of 60 newborns (14 SGA newborns, 33 AGA newborns, and 13 LGA newborns) had 57.6% power to detect a difference at the 0.05 significance level. Pearson correlation test was used to detect the correlations among the variables. Two-tailed p values less than 0.05 were accepted to be statistically significant.

Results

Table 1 displays the demographic and clinical characteristics of the reviewed infants. When compared with the SGA group, the LGA group had significantly higher body weight (p=0.001), longer body length (p=0.045), larger abdominal circumference (p=0.001), and more male newborns (p=0.001).

Table 2 shows the biochemical characteristics of the reviewed infants. When compared with the SGA group, the LGA group had significantly higher maternal serum IGF-1 (p=0.033), IGFBP-3 (p=0.040), ghrelin (p=0.020), insulin (p=0.018) and significantly higher umbilical cord IGF-1 (p=0.001), IGFBP-3 (p=0.001), ghrelin (p=0.024), and insulin (p=0.028).

Maternal serum concentrations of IGF-1 correlated significantly and positively with body weight (r=0.124, p=0.001), body length (r=0.338, p=0.001), head circumference (r=0.225, p=0.001), and abdominal circumference (r=0.188, p=0.001). Maternal serum concentrations of IGFBP-3 correlated significantly and positively with body weight (r=0.134, p=0.001), body length (r=0.354, p=0.001), head circumference (r=0.276, p=0.001), and abdominal circumference (r=0.192, p=0.001). Maternal serum concentrations of insulin and ghrelin did not correlate with the anthropometric measurements of the reviewed newborns.

Umbilical cord concentrations of IGF1-1 correlated significantly and positively with body weight (r=0.119, p=0.001), body length (r=0.455, p=0.001), head circumference (r=0.249, p=0.001), and abdominal circumference (r=0.214, p=0.001). Umbilical cord concentrations of IGFBP-3 correlated significantly and positively with body weight (r=0.298, p=0.001), body length (r=0.364, p=0.001), head circumference (r=0.236, p=0.001) and abdominal circumference (r=0.477, p=0.001). Umbilical cord concentrations of insulin and ghrelin did not correlate with the anthropometric measurements of the reviewed newborns.

Discussion

When a fetus is bound to live in an environment with relative deprivation, adaptive mechanisms begin to work. Poor growth may be regarded as one such adaptation, which occurs as a result of certain endocrinological alterations. In other words, an altered growth hormone-IGF system, with relatively low glucose and relatively high ghrelin concentrations, indicate an adaptation for the relative scarcity of nutrients [12, 13].

It has been reported that diminished fetal growth is associated with alterations in the IGF system. Although reduced maternal IGF-1 has been described in some cases of intrauterine growth restriction (IUGR), other studies failed to demonstrate such an association [13]. Similarly, Chiesa et al. [14] were unable to find a relationship between maternal IGF-1 and birth weight within the entire study population of 153 delivering mothers. When the analysis was confined to preterm newborns however, they noticed that maternal IGF-1 was significantly lower in those who gave birth to neonates with IUGR. This finding was attributed to the secondary consequence of placental dysfunction or the adaptation for restricting glucose supply to a hypoxic fetus [14].

IGFBP-3 is the principal carrier of the IGFs existing in maternal and fetal circulation. Being regulated by insulin, IGFBP-3 acts as a positive modulator of fetal growth and even neonatal growth. A Turkish study demonstrated that the effects of accelerated early infant growth on IGF-1/IGFBP-3 axis in SGA-born infants [15]. Another study indicated a significant rise in serum IGFBP-3 concentrations of the mothers who put on excessive weight gain or became obese during pregnancy. This significant increase was found to contribute to the risk of delivering a LGA fetus [16]. In the study of Chiesa et al., the asymmetric LGA newborns had higher insulin and IGFBP-3 concentrations than AGA and symmetric LGA newborns [14].

Mild maternal hyperinsulinemia may also result in the binding of circulating insulin to the IGF-1 receptors due to the structural similarity between the insulin and IGF-1 receptors. Thus, insulin itself may exert direct effects on fetal growth by means of this interaction. On the other hand, insulin can regulate the IGF system by controlling the IGFBP expression. Insulin may also reduce the expression of IGFBPs, regulate IGF bioavailability to high-affinity receptors, and, thus, trigger fetal growth [17, 18].

Maternal IGF-1 correlates negatively but fetal IGF-1 correlates positively with the length of gestation. This may imply a feedback mechanism or physiological process of maternal restriction. Maternal restriction refers to the limitation of fetal overgrowth by maternal size, uterine size, and nutrient availability [13, 14].

As for the present study, insulin, IGF-1 and IGFBP-3 levels in maternal serum and umbilical cord were significantly higher in the LGA newborns than in the SGA newborns. In addition, both maternal serum and umbilical cord concentrations of IGF-1 and IGFBP-3 correlate with weight, length, head circumference, and abdominal circumference of the newborn. However, insulin concentrations did not significantly correlate with neonatal anthropometry. Such discrepancy may be attributed to the small cohort size and the inconsistencies in the measurement of serum insulin levels. Another possible explanation is the existence of mild hyperglycemia in mothers who are known to be without gestational diabetes or impaired glucose intolerance.

The Pedersen hypothesis proposes that maternal hyperglycemia induces an excessive supply of nutrients which causes fetal hyperinsulinemia and subsequent fetal macrosomia in diabetic pregnancies [19]. Therefore, it would be prudent to assume that fetal weight might be affected by even a limited degree of maternal hyperglycemia, which is still considered to be within the normal range [20]. Unfortunately, data related with maternal serum and umbilical cord glucose concentrations are absent. This absence can be considered as a power limiting factor for the present study. Another factor that limits the power of the present study is the lack of data related with maternal and fetal levels of growth hormone and subgroup analysis in the LGA group (e.g. symmetric vs asymmetric).

Serum concentrations of ghrelin are higher in patients with anorexia nervosa than in healthy controls. This finding indicates anorexia nervosa is also associated with high concentrations of growth hormone and low concentrations of IGF-1, suggesting nutritionally acquired growth hormone resistance [12]. It has been reported that maternal ghrelin is easily transferred to the fetal circulation and then prompts fetal growth through direct stimulation of cell proliferation in the second half of pregnancy [21].

Recently gathered evidence showing that ghrelin directly stimulates bone formation also supports the anabolic effects of ghrelin on the fetus [22]. Chiesa et al. also declared that maternal ghrelin concentrations were positively associated with neonatal head circumference (and therefore brain development) [14]. This study also claimed that ghrelin concentrations in maternal serum and umbilical cord increased significantly in LGA newborns when compared to the SGA newborns. However, this study was unable to achieve a significant correlation between ghrelin values and neonatal anthropometry. This failure may be due to the small cohort size and the variances in the measurement of serum ghrelin levels. Another reason may be the fact that modes of delivery that elicit stressful stimuli and prolonged active labor can decrease maternal ghrelin concentrations. Much alike, intrapartum fetal distress may lead to a decrease in the ghrelin levels of the newborns [14, 23].

In conclusion, the present study has detected significant relationships between neonatal anthropometry and metabolic and endocrine factors. Fetal macrosomia is found to be associated with increased insulin, IGF-1, IGFBP-3, and ghrelin concentrations in both maternal serum and umbilical cord. However, the power of the present study is limited by the relatively small cohort size, the lack of data related with maternal body weight and height, the absence of data indicating maternal serum and umbilical cord glucose levels, and the lack of subgroup analysis with respect to symmetric and asymmetric LGA.

Further research is needed to optimize the understanding of the mechanisms by which endocrine and metabolic factors may regulate fetal growth.

Competing interests

The authors declare that they have no competing interests.

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Emine Kacar, Alev Ozer, Salih Serin, Yakup Gumusalan, Fatma Inanc Tolun, Mine Kanat Pektas. Insulin Like Growth Factor System: How Does it Affect Neonatal Anthropometry?. J Clin Anal Med. 2016;7(5):664-667

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What is the Optimal Treatment of Atrophic Scaphoid Non-Union?

Alper Çıraklı 1, Kerim Öner 2, Ahmet Pişkin 3, Mehmet Yıldız 2, Erdal Uzun 1, Hasan Göçer 3

1 Department of Orthopaedic Surgery, Kayseri Research and Training Hospital, Kayseri, 2 Department of Orthopaedic Surgery, Trabzon Karadeniz Technic University Hospital, Trabzon, 3 Department of Orthopaedic Surgery, Samsun Ondokuz Mayıs University Hospital, Samsun, Turkey

DOI: 10.4328/JCAM.4345 Received: 27.01.2016 Accepted: 25.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 660-3

Corresponding Author: Erdal Uzun, Ortopedi ve Travmatoloji Bölümü, Kayseri Eğitim ve Araştirma Hastanesi, Kayseri, Turkey. T.: +90 3523368884 E-Mail: nuzuladre@gmail.com

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Aim: To evaluate the efficacy of the treatment method of autogenous iliac wing or radius bone graft and fixation with screw applied to cases of scaph-oid non-union. Material and Method: A retrospective evaluation was made of 89 cases between 2000 and 2014. Postoperative measurements were taken of both wrists’ movement with a goniometer and muscle strength was assessed with a dynamometer. Fractures were evaluated radiologically ac-cording to the Herbert-Fisher System and the functional results according to the Herbert-Fisher Classification System and the Mayo Clinic Modified Wrist Scoring System. The data were input to the SPSS system and evaluated with the Shapiro-Wilk test. Results: Non-union were on the right side in 47 and the left side in 42 cases. The fracture was seen to be in the waist in 60 cases (67.5%), in the proximal third in 27 cases (30.3%) and in the distal third in two cases (2.2%). The mean follow-up period was 16.4 months (range, 5-72 months). Definitive findings of union were observed in 71 cases. The mean time to union was 14.9 weeks (range, 8-40 weeks). Discussion: The grafting procedure applied is an invasive technique but if it is considered that there are negative effects of open surgery on the feeding of the scaphoid bone, then in the treatment of scaphoid non-union which is atrophic non-union, ultimately autogenous bone grafting and screw fixation is a safe and suc-cessful method and because of the pain created by an iliac wing graft, radius distal bone graft can be considered more appropriate.

Keywords: Scaphoid; Non-Union; Surgical Treatment; Autografting

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Introduction

Scaphoid bone fractures are the second most common wrist trauma after distal radius fractures. Of the carpal bone fractures, they are the most frequently seen fractures [1,2]. Due to biological, mechanical and blood suppply properties, the healing of scaphoid bone fractures is difficult [3]. When there are no signs of union despite 3 and 6 months of treatment in scaphoid bone fractures, it is classified respectively as delayed union and non-union [4].

Many different surgical techniques have been described in the treatment of scaphoid non-unions [5]. Bone grafting, internal fixation with various fixation materials, and vascularised bone grafts with combinations of bone grafting and internal fixation methods are applied in surgical treatment [6]. The aim of all these methods is to achieve a pain-free, functional wrist by removing the problem in the scaphoid bone, which plays a significant role in the stabilisation of the wrist and all wrist movements, and to prevent potential loss of working days [7].

In this paper an evaluation is made of cases of scaphoid non-union treated with autogenous iliac wing or radius bone graft and screw fixation.

Material and Method

The study included 89 cases who were diagnosed with scaphoid non-union and treated with autogenous iliac wing or radius distal bone grafting and screw fixation and had sufficient follow-up at two different clinics between January 2000 and January 2014. Approval for the study was granted by the Local Ethics Committee.

Postoperatively, both wrists were measured with a goniometer for flexion, extension and the degree of radial and ulnar deviation. With the patient in a sitting position, the elbow in 90º flexion and the forearm in a neutral position, the muscle strength of both wrists was measured with a hand dynamometer (Hydraulic Hand Dynamometer, Model SH5001, Saehan Corporation, Masan, Korea). The mean value of 3 measurements was used in the evaluation. Radiological evaluation was made using standard anteroposterior and lateral wrist radiographs. Computed tomography (CT), magnetic resonance imaging (MRI) and scintigraphy were not routinely used.

The fractures were classified radiologically according to the Herbert-Fisher system and the results were evaluated according to the Herbert-Fisher Classification System and the Mayo Clinic Modified Wrist Scoring System. The reason for using two systems in the evaluation of the results was that radiological evaluation cannot be made with the Mayo Clinic Modified Wrist Scoring System.

Statistical analysis

Statistical analysis were made using SPSS v. 15.0 (SPSS Inc., Chicago, IL, USA) software and conformity to normal distribution was evaluated with the Shapiro-Wilk test.

 Results

The 89 cases of non-union comprised 81 males and seven females with a mean age of 30.2 years (range, 15-61 years). The non-union was on the right side in 47 and the left side in 42 cases and the dominant hand in 52 cases. The mechanism of the fracture was a sports injury in 43 cases (48.3%), a fall in 38 (42.6%), and a traffic accident in eight (9.1%).

The fracture was seen to be in the waist of the scaphoid in 60 cases (67.5%), in the proximal third in 27 cases (30.3%), and in the distal third in two cases (2.2%). All the cases were consistent with Herbert-Fisher Type D2 (sclerotic non-union pseudarthrosis) (Fig. 1). The fixation material was Acutrak screw in 60 cases (67.4%) and Herbert screw in 29 cases (32.6%). In 54 cases (60.6%) iliac wing graft was taken and in 35 cases (39.4%) radius distal graft was taken. The form of graft used was spongeous in 46 cases (51.6%) and corticospongeous in 43 cases (48.4%). The mean time from fracture to surgery was 17.8 months (range, 3-300 months).

Clinical and radiological follow-up examinations were made every 3-4 weeks until union was achieved. The time to union was accepted as the period until the first radiograph was obtained on which the fracture line was seen to have disappeared and a trabecular appearance was observed in the location of the fracture line. Definitive findings of union were observed in 71 cases. The mean time to union was 14.9 weeks (range, 8-40 weeks). The mean period of fixation was 6.4 weeks (range, 4-12 weeks), and the mean follow-up period was 16.4 months (range, 5-72 months) (Fig. 2).

Postoperatively compared to the contralateral healthy hand, >10% function loss was observed in the wrist movements. The scapholunate angle was mean 74.3º (range, 62º – 87º) preoperatively and 43.8º (range, 31º-72º) postoperatively. Grip strength postoperatively was mean 35.7 kg (range, 15-63 kg).

According to the Herbert-Fisher classification, the results were found to be excellent or good in 79% and poor in 21%; the Mayo Score was determined as mean 78.1 (range, 40-100).

No vascular or nerve complications developed during surgery. No scar tissue that limited joint movement developed in any patient. No major or minor complication was encountered in the graft donor site. In three patients, the screw was determined to be in an inappropriate position on the postoperative radiographs and in one patient, wound site infection was observed on postoperative day three. These patients were informed and second surgery was necessary. No problems developed in the follow-up period of any of these four patients.

Of the 18 cases where union was not observed, the fracture was in the proximal in 12 cases, in the scaphoid bone waist in five, and in the distal in one. Screw loosening was observed in one of the 18 cases and the screw was seen not to have passed the non-union line in two cases. Avascular necrosis was observed in the proximal fragment in two cases during follow-up and in both cases the screw was removed and the proximal fragment was excised. In three patients with persistent pain, a radical styloidectomy was applied.

Apart from these 18 cases, union was achieved in all other cases and outcomes were evaluated as successful. In one case where union was achieved, the screw was observed to have advanced to the lunatum. Non-union in the distal region is not frequently observed and two cases were operated on for distal region non-union.

Discussion

Scaphoid fractures are seen in the young, active population at a mean age of approximately 25 years at the rate of 13-43 per 100,000 per year [1,2]. Difficulty in determining the fracture line on direct radiographs taken early, fractures that remain untreated, or delay of treatment may result in non-union because of the biological, mechanical and vascular properties of the bone. These situations can cause post-traumatic arthritis and the development of carpal instability in patients [4].

For success in cases of scaphoid non-union, even if treatment is applied later in cases of non-treatment or delayed treatment, effective treatment must be applied before the permanent complication develops of a wrist with painful and limited movement because of the delay. Union in the scaphoid bone only is not sufficient; restoring bone anatomy and obtaining functional recovery must be considered essential [7].

Scaphoid non-unions display the general features of atrophic (avascular) non-union. The treatment principles of atrophic non-unions are cleaning the scar tissue, decortication and bone graft, and stable fixation for fracture healing [8]. These treatment principles are equally valid for scaphoid non-union as for atrophic non-union.

In scaphoid non-unions there are advantages to placing grafts in the spaces between fragments after cleaning and smoothing the surfaces. When autogenous bone grafts are successfully applied, fracture stability is increased, fracture healing is accelerated, and the period of immobilisation is shortened [9,10]. Spongeous graft provides a larger contact surface and more rapid union due to cellularity and vascularity. Cortical graft provides protection and restoration of the scaphoid bone length because of the dense structure and prevents carpal instability from a united but smaller scaphoid bone. Berris et al. [11] reported that corticospongeous grafts were more effective than spongeous grafts in reducing deformity and obtaining initial stabilisation. Rates of union with bone graft were reported as 61-93% by Russe and as 75-100% by Fernandez [12,13]. Even though filling bone defects with autogenous bone grafts is seen as the gold standard, there are risks. The development of fracture, vascular and nerve damage, infection, haematoma, and chronic pain have been reported in 6-25% of cases [14,15]. In the current series, bone restoration was achieved using corticospongeous graft in cases that had lost scaphoid height and spongeous grafts in those that had not, and no complications developed in any patient in the donor site.

Various studies have been made on the subject of graft donor site. Many studies have compared the sites that were used in this study as donor sites–the iliac wing and the distal radus. A study based on postoperative pain reported that the clinical scores were better when the distal radius was used as the donor site rather than the iliac wing [16]. Aguilella and Garcia [17] stated that the anterolateral corner of the distal radius metaphysis could be used as a donor site and provided some advantages compared to other methods. These advantages include providing good quality bone graft, reaching the donor site with the same incision used for scaphoid surgery, no requirement for general anaesthesia, and less morbidity compared to the use of the iliac wing. In the current series, negative effects were observed in patient satisfaction and mobilisation due to pain in cases where iliac graft was used. Complaints of much greater postoperative pain in the wrist have been reported with the use of iliac wing.

The most important of the factors affecting the rate of union in scaphoid fractures is the fracture location; studies have shown lower rates of union in proximal fractures [18]. In the current study, of the 18 cases that were not successful, 12 were non-union with a proximal location. Inoue et al. [19] described avascular necrosis criteria in the proximal fragment as loss of trabeculation, advanced sclerosis, and deformation in the proximal fragment. Surgery is contra-indicated in these kinds of cases. In the current study, of the 27 cases with proximal location of the fracture, avascular necrosis was observed postoperatively in the proximal fragment in two. In one case, the screw was removed and the proximal fragment was excised and the other case refused surgery.

The development of non-union in scaphoid fractures is more evident in proximal pole fractures in particular, due to less blood supply of proximal scaphoid [20]. In uncomplicated stable non-unions, success rates of bone graft and screw fixation have been reported as 70-90% [21]. With bone graft and screw fixation in proximal scaphoid non-union, Megerle et al. [22] obtained union rates of 61%, Inoue et al. [19] 81% and DeMaagd and Engber [23] 92%. In contrast, again in cases of scaphoid non-union that developed avascular necrosis in the proximal pole, success rates with bone graft and internal fixation have been reported to have only reached 50% [12]. On the other hand, Matsuki et al. [24] obtained 100% union with Herbert screw and grafting in 11 cases of proximal pole non-union and this result was reported to be independent of the vascularity of the proximal fragment. In addition, Gereli et al. [25] reported union in 15 of 17 cases where non-vascularised grafting and Acutrak screw were applied for proximal non-union and in 11 of 12 cases where fixation was made with Herbert screw. Thus it can be seen that with rates varying between 50 and 100% for non-vascularised grafting and screw fixation for scaphoid proximal pole fractures, it is possible to talk of both success and failure. The most important factor affecting this result is whether or not there is avascular necrosis. It is thought that in some of the current series cases there could have been proximal region avascular necrosis which could not be determined on direct radiograph. In addition, the open surgery method can be considered as contributing to the unsuccessful results with the effect of impairing the vascularity in the scaphoid bone proximal region in particular [26,27].

Limitations of this study can be said to be that because it was retrospective, there was no evaluation of differences in the types of cannulated screw applied and no MRI of the proximal fragment in proximal region non-unions.

In conclusion, generally rapid union is obtained with autogenous iliac wing or radius bone graft and screw fixation in the treatment of scaphoid atrophic non-union. This method with the appropriate surgical technique and under scopy guidance is safe and successful. Due to the pain caused in iliac wing grafting, distal radius bone graft can be considered more suitable. Thus, by providing rigid internal fixation, early active movement is possible, the immobilisation period is shortened, and workdays lost are reduced.

Competing interests

The authors declare that they have no competing interests.

References

1. Gürbüz Y, Kayalar M, Bal E, Toros T, Küçük L, Sügün TS. Comparison of dorsal and volar percutaneous screw fixation methods in acute Type B scaphoid fractures. Acta Orthop Traumatol Turc 2012;46(5):339-45.

2. Hove LM. Epidemiology of scaphoid fractures in Bergen, Norway. Scand J Plast Reconstr Surg Hand Surg 1999;33:423-6.

3. Tuncay İ, Doğan A, Alpaslan S. Comparison between fixation with Herbert screws and Kirschner wires in the treatment of scaphoid pseudoarthrosis. Acta Orthop Traumatol Turc 2002;36:17-21.

4. Kılıç A, Sökücü S, Parmaksızoğlu AS, Gül M, Kabukçuoğlu YS. Comparative evaluation of radiographic and functional outcomes in the surgical treatment of scaphoid non-unions. Acta Orthop Traumatol Turc 2011;45(6):399-405.

5. Amadio PC, Talesnik J. Fractures of the carpal bones. In: Green DP, Hotchkiss RN, Pederson WC, editors. Green’ s operative surgery. Philadelphia: Churchill-Livingstone; 1999:809-36.

6. Kabak Ş, Baktır A, Türk Y, Şahin V, Karakaş ES. Treatment Result of Scaphoid Fractures. Turkısh J Hand Surg and Microsurg 1995;2-3:59-65.

7. Tomak Y, Karaismailoğlu N, Tilki K, Diri B, Dabak N, Andaç A. Skafoid nonunionlarının iliak kemik grefti ve Herbert vida fiksasyonu ile tedavisi. O.M.Ü. Tıp Dergisi 1999;16(1):7-18.

8. Taylor JC. Delayed Union and Nonunion of Fractures. In: Crenshaw AH, editor. Campbell’ s Operative Orthopaedics. Toronto: Mosby Year-Book Inc; 1991:1287-345.

9. Leung KS, Shen WY, Tsang HK, Chiu KH, Leung PC, Hung LK. An effective treatment of comminuted fractures of the distal radius. J Hand Surg 1990;15:11-7.

10. Cooney WP, Berger RA. Treatment of complex fractures of the distal radius: Combined use of internal fixation and external fixation and arthroscopic reduction. Hand Clin 1993;9:603-12.

11. Berris AE, Soucacos PN, Xenakis T. Scaphoid Nonunion Treated with Bone Graft and Herbert Screw. Acta Orthop Scand 1997;68:60-4.

12. Merrell GA, Wolfe SW, Slade JF. Treatment of scaphoid nonunions: qualitative metanalysis of the literature. J Hand Surg 2002;27:685-91.

13. Steinmann SP, Bishop AT, Berger RA. Use of the 1,2 intercompartmental supraretinacular artery as a vascularized pedicle bone graft for difficult scaphoid nonunion. J Hand Surg 2002;27:391-401.

14. Summers BN, Eisentein SM. Donor site pain from the ileum: A complication of lumbar spine fusion. J Bone Joint Surg 1989;71:677-80.

15. Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma 1989;3:192-5.

16. Garg B, Goyal T, Kotwal PP, Sankineai SR, Tripathy SK. Local distal radius bone graft versus iliac crest bone graft for scaphoid nonunion: a comparative study. Musculoskelet Surg 2013;97:109-14.

17. Aguilella L, Garcia-Elias M. The Anterolateral Corner of the Radial Metaphysis as a Source of Bone Graft for the Treatment of Scaphoid Nonunion. J Hand Surg 2012;37A:1258-62.

18. Ritter K, Giachino AA. The treatment of pseudoarthrosis of the scaphoid by bone grafting and three methods of internal fixation. Can J Surg 2000;43:118-24.

19. Inoue G, Shionoya K, Kuwahata Y. Ununited proximal pole scaphoid fractures. Treatment with a Herbert screw in 16 cases followed for 0.5-8 years. Acta Orthop Scand 1997;68:124-7.

20. Slade JF, Dodds SD. Minimally invasive management of scaphoid nonunions. Clin Orthop Relat Res 2006;445:108-19.

21. Cooney WP, Dobyns JH, Linscheid RL. Nonunion of the scaphoid. analysis of the results from bone grafting. J Hand Surg 1980;5:343-54.

22. Megerle K, Keutgen X, Müller M, Germannn G, Sauerbier M. Treatment of scaphoid nonunions of the proximal third with conventional bone grafting and mini-Herbert screw: an analysisof clinical and radiological results. J Hand Surg 2008;33E:179-85.

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Alper Cirakli, Kerim Oner, Ahmet Piskin, Mehmet Yildiz, Erdal Uzun, Hasan Gocer. What is the Optimal Treatment of Atrophic Scaphoid Non-Union?. J Clin Anal Med. 2016;7(5):660-663

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Post-Endoscopic Retrograde Cholangio-Pancreatography (ERCP) Complications: Our Experience and Comparison with the Literature

Sedat Gözel 1, İhsan Yıldız 2, Yavuz Savaş Koca 2

1 Department of İnternal Medicine, Başkent University Medical School, Adana, 2 Department of General Surgery, Suleyman Demirel University Medical School, Isparta, Türkiye

DOI: 10.4328/JCAM.4344 Received: 27.01.2016 Accepted: 25.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 656-9

Corresponding Author: İhsan Yıldız, Department of General Surgery, Suleyman Demirel University School of Medicine, 32260 Isparta, Turkey. T.: +90 2462119248 F.: +90 2462112830 E-Mail: drihsanyildiz@gmail.com

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Abstract

Aim: Endoscopic retrograde cholangio-pancreatography (ERCP) is a minimal-ly invasive method used in the diagnosis and treatment of pancreatobiliary disorders. Endoscopic retrograde cholangio-pancreatography (ERCP) may lead to serious complications including pancreatitis, bleeding, cholangitis, and perforation. In this study, we compare our experience with post-ERCP complications with the literature. Material and Method: A total of 339 pa-tients who underwent ERCP, including 176 (51.9%) female and 163 (48.1%) male patients, were retrospectively evaluated. Hemogram, sedimentation, C-reactive protein, alkaline phosphatase, gama-glutamil-tranferase, total direct bilirubin, and amylase and lipase activities were recorded both be-fore and 24-72 h after ERCP. The rates of post-ERCP complications of pan-creatitis, bleeding, and cholangitis rates were evaluated. Results: A total of 339 patients who underwent ERCP, including 176 (51.9%) female and 163 (48.1%) male patients, were retrospectively evaluated. Of the 339 patients, pancreatitis occurred in 26 (7.6%), bleeding in 15 (4.4%), and cholangitis in 11 (3.2%). The patients with pancreatitis had a mean age of 56±17 years and the patients without pancreatitis had a mean age of 60±14 years; how-ever, no significant difference was found (p>0.05). The patients with bleeding had a mean age of 67±13 years and the patients without bleeding had a mean age of 59±15 years; a significant difference was found. Discussion: The study shows that the incidence of post-ERCP bleeding increases with age. The most effective way of reducing ERCP complications in elderly patients is to avoid unnecessary ERCP.

Keywords: ERCP Complication; Pancreatitis; Bleeding; Perforation

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Introduction

Endoscopic retrograde cholangio-pancreatography (ERCP) is a minimally invasive method used in the diagnosis and treatment of benign and malignant pancreatobiliary disorders. In particular, ERCP became a commonplace method for the diagnosis and treatment of benign and malignant pancreatobiliary disorders following the visualization of the bile duct and pancreatic duct by McCune et al. in 1968 and following the introduction of endoscopic sphincterotomy by Koch et al. in 1973 [1,2].

Risk factors for post-ERCP complications include the characteristics of the patient, the experience of the endoscopist, the methods employed, and the number of procedures undertaken. Elmuzer and Bor et al. shows that the rates of post-ERCP complications are higher in interventional procedures compared to diagnostic procedures [3,4].

In this study, we present the complications detected in the patients who underwent ERCP due to pancreatobiliary disorders at Akdeniz University Medical School Department of Gastroenterology between January 2009 and February 2012.

Material and Method

The retrospective study included a total of 339 patients who underwent ERCP at Akdeniz University Medical School Department of Gastroenterology between 2009 and 2012. The patients included 176 female and 163 male patients with a mean age of 47 (18-79). For the follow-up of the complications, hemogram, sedimentation, C-reactive protein (C-rp), alkaline phosphatase(Alp), gama-glutamil-tranferase (Ggt), total/direct bilirubin, and amylase and lipase activities were recorded both before and 24-72 h after ERCP. The diagnoses made by ERCP and the number of ERCP procedures performed for each patient were also recorded (Tables 1, 2).

ERCP was performed using a Fujinon ED-450XT5 duodenoscope (Tokyo, Japan) under the guidance of fluoroscopy. Propofol was intravenously administered for sedation. Prior to ERCP, 1 gr intravenous ceftriaxone was administered for prophylaxis and intravenous Hyoscine N-methyl bromide was administered to reduce intestinal contractions.

Laboratory tests and serum amylase and lipase activities were spectrophotometrically evaluated using an automated analyzer (Olympus AU 2700, Mishima Olympus Co. Ltd, Japan). The complications were defined based on the Cotton’s classification [5].

Multivariate analysis and Mann-Whitney U test were used for the statistical evaluations and a p value of <0.05 was considered significant.

Results

Post-ERCP complications occurred in 52 (15.3%) of the patients, including 26 (7.6%) patients with pancreatitis, 15 (4.4 %) with bleeding, and 11 (3.2%) with cholangitis. Pancreatitis was found to be mild in 12, moderate in 13, and severe in 1 patient. Cholangitis was found to be mild in 5, moderate in 5, and severe in 1 patient. Total mortality occurred in 2 (0.58%) patients (Table 3).

The correlation between gender and pancreatitis, cholangitis, and bleeding was investigated but no significant difference was found.

In the 26 patients with pancreatitis, ERCP was performed once in 20, twice in 5, and five times in 1 patient. No correlation was found between the number of ERCP procedures undertaken and pancreatitis development (Table 3).

In the 15 patients with bleeding, ERCP was performed once in 7, twice in 3, three times in 3, and four times in 2 patients. No significant difference was found between the patients who underwent ERCP once and the patients who underwent multiple ERCP procedures (Table 3).

The patients with and without bleeding were compared in terms of mean age. The mean age was 67±12 years in the patients with bleeding as compared to 59±15 years in the patients without bleeding, suggesting that the patients with bleeding had a higher mean age compared to the patients without bleeding (Table 3) (p<0.05).

The 26 patients with pancreatitis had a mean age of 56±17 years and the patients without pancreatitis had a mean age of 60±14 years; however, no significant difference was found. Pancreatitis occurred in 23 (8.4%) out of the 274 patients who underwent sphincterotomy and in 3 (7.5%) out of 40 patients who did not undergo sphincterotomy; however, no significant difference was found (p<0.05). Bleeding occurred in 14 (5.1%) out of 274 patients who underwent sphincterotomy and in 3 (7.5%) out of 40 patients who did not undergo sphincterotomy; however, no significant difference was found (p<0.05).

Between the patients who did and did not undergo liver transplantation, no significant difference was found in terms of post-ERCP complications including pancreatitis and bleeding. The comparison revealed that liver transplantation did not increase complication rates (Tables 4, 5).

The association between stent insertion and pancreatitis and bleeding development was investigated but no significant correlation was found.

Magnetic resonance cholangio-pancreatography (MRCP) was performed in 52 out of 339 patients. The comparison of MRCP and ERCP diagnoses reveal that the diagnoses were the same in 35 (67.3%) patients and different from each other in 17 (32.7%) patients. Of the patients with different diagnoses, 10 had a normal ERCP, 7 had choledocholithiasis on MRCP, 1 patient had choledochal dilatation, 1 patient had pancreatic duct disruption, and 1 patient had a space-occupying lesion in the choledochus.

Discussion

In the literature, post-ERCP complications and their rates have been reported as follows: pancreatitis 1.6-15.7%; bleeding 1.2-4.5%; cholangitis 1-5.6%; and perforation 0.1-0.3%. The mortality rate has been reported to be 0.06% [6-11]. The rates in our study are as follows: pancreatitis 7.6%; bleeding 4.4 %; and cholangitis 3.2%. These results indicate that the rates for bleeding and cholangitis in our study were higher than the rates reported in the literature. We believe this can be attributed to the fact that our hospital is a new reference hospital where patients who have had prior failed surgeries are admitted.

In multivariate studies, biliary sphincter balloon dilatation, pancreatic sphincterotomy, and access (precut) sphincterotomy have been shown to be risk factors for post-ERCP pancreatitis [12-14]. In our study, the patients who did and did not undergo sphincterotomy were compared in terms of pancreatitis development; no significant difference was found. This finding may be attributed to the small number of patients in our study as compared to the studies reported in the literature.

In several studies, female gender has been shown to be an independent risk factor for post-ERCP pancreatitis [15], but a number of other studies have reported that gender is not a risk factor for post-ERCP pancreatitis [12,13]. In our study, we also found no difference between male and female patients in terms of pancreatitis development.

Young age has been commonly shown to be a risk factor for post-ERCP pancreatitis [13]. In our study, although the mean age of the patients with pancreatitis was lower than the mean age of the patients without pancreatitis, no significant difference was found between the two patient groups.

Performing multiple ERCP procedures has been reported in some studies to be a risk factor for post-ERCP pancreatitis [16], whereas some other studies have suggested that the development of post-ERCP complications is dependent on the experience of the endoscopist rather than the number of procedures undertaken [15]. In our study, it was revealed that performing multiple ERCP procedures led to a significant increase in the rates of post-ERCP pancreatitis and other complications. However, it was found that performing multiple ERCP procedures for a single patient is not an independent risk factor for post-ERCP complications.

Bile duct intervention has been shown in several studies not to be a risk factor for an increase in the incidence of post-ERCP pancreatitis, but in other studies it has been shown to be a risk factor [11,13,14]. The studies reporting the bile duct intervention as a risk factor for post-ERCP pancreatitis have identified this risk in multivariate analyses and, unlike other studies, have reported that bile duct stent insertion is an independent risk factor [11,15,16]. In our study, there was no significant difference between the patients who did and did not undergo bile duct stent insertion in terms of post-ERCP pancreatitis. In the studies mentioned above, a metallic stent had been inserted in the patients with malignant biliary obstruction. In our study, since no classification was performed based on the features of the stents and the severity of the malignancies of the patients, we consider that our findings are likely to be different from those reported in the literature.

Post-liver transplantation biliary complications (biliary stricture, choledocolitiasis, biloma, hemobilia, Oddi sphincter dysfunction, and bile duct leak) have been reported to occur in 5-25% of the patients. ERCP is a minimally invasive method used in the patients presenting with these complications, particularly the patients undergoing choledoco-choledochostomy [5, 9]. In our study, the complication rates in the patients who did and did not undergo liver transplantation were similar to each other.

Post-ERCP bleeding has been reported to have an incidence of 1.2% [4,11,16]. In our study, the rate of post-ERCP bleeding (4.4%) was slightly higher than the rate reported in the literature. In numerous multivariate analyses, sphincterotomy, cholangitis, papillary stenosis, access (precut) sphincterotomy, and low endoscopic volume by the endoscopist (which is defined as 1 sphincterotomy per week or less) have been reported as the risk factors for post-ERCP bleeding [13,16].

In the studies reporting the risk factors for post-ERCP bleeding, age is shown to not be a risk factor [11, 13, 14]. In our study, the patients with bleeding had a mean age of 67.29±13.45 years and the patients without bleeding had a mean age of 59.3±15.13 years; a significant difference was found between the two groups (p<0.05). Nevertheless, further large-scale studies are needed to substantiate this finding.

The number of ERCP procedures undertaken per patient has not been reported as a risk factor for post-ERCP bleeding. Similarly, we found no correlation between the number of ERCP procedures and post-ERCP bleeding.

Studies have shown that the incidence of post-ERCP bleeding in patients undergoing liver transplantation is similar to that of the general population [9]. We also found no significant difference between the patients who underwent liver transplantation and the general population in terms of post-ERCP bleeding.

Literature shows that the avoidance of unnecessary ERCP in the cases where MRCP is sufficient is of prime importance for the prevention of pancreatitis [4]. In our study, we compared the MRCP and ERCP outcomes of the 52 patients and found that the ERCP and MRCP diagnoses were the same in 32 patients and different from each other in 20 patients. Of the patients with different diagnoses, 10 had a normal ERCP, whereas 7 patients had choledocholithiasis on MRCP, 1 had choledochal dilatation, 1 had pancreatic duct disruption, and 1 had a space-occupying lesion in the choledochus.

Our study was limited because patient diagnoses were not exhaustively analyzed. In particular, in patients where ERCP and RCP resulted in different diagnoses, the diagnostic value of ERCP was not compared to that of MRCP.

Conclusion

Age was found to be a risk factor for post-ERCP bleeding. The rate of complications in our patients was higher than rates reported in the literature; this can be attributed to the fact that our hospital is a relatively new center, a prominent reference center in the region, and an important center for kidney and liver transplantation. In conclusion, the most effective way of reducing post-ERCP complications in elderly patients is to avoid unnecessary ERCP and to make accurate diagnoses.

Declaration of conflict of interest: The authors declare that there is no conflict of interest.

Competing interests

The authors declare that they have no competing interests.

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Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol 2007;102(8):1781-8.

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Sedat Gozel, Ihsan Yildiz, Yavuz Savas Koca. Post-Endoscopic Retrograde Cholangio-Pancreatography (ERCP) Complications: Our Experience and Comparison with the Literature. J Clin Anal Med. 2016;7(5):656-659

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 Postinfectious Acute Cerebellar Ataxia in Childhood

Olcay Ünver, Büşra Kutlubay, Gülten Thomas, Nilüfer Eldeş Hacifazlioğlu, Güneş Sağer, Dilşad Türkdoğan

Çocuk Nöroloji BD, Çocuk Sağlığı ve Hastalıkları ABD, Marmara Üniversitesi, İstanbul, Türkiye

DOI: 10.4328/JCAM.4337 Received: 24.01.2016 Accepted: 24.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 652-5

Corresponding Author: Olcay Ünver, Fevzi Çakmak Mah. Muhsin Yazıcıoğlu Cad. No: 10 Üst Kaynarca, Pendik, İstanbul, Türkiye. T.: +90 2166254545 F.: +90 2166254580 E-Mail: olcaymd@hotmail.com

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Aim: Postinfectious acute cerebellar ataxia is the most common cause of childhood ataxia. Cases present with acute onset of ataxia to pediatric emer-gency and pediatric neurology clinics. Varicella zoster is the most commonly associated virus. The aim of this study is to assess the clinical features, eti-ology, and prognosis of children with postinfectious acute cerebellar ataxia and to propose a diagnostic approach to acute cerebellar ataxia in children.Material and Method: Files of 16 children admitted between January 2011 and June 2015 were retrospectively evaluated. Results: Nine patients were male (56.2%). The majority of the cases were in the 2-5 years age group (62.5%). A history of a preceding febrile infection was noted in 87.5% of the cases: Two children had varicella infection, one Epstein Barr infection, and the rest nonspecific febrile illness. The mean time interval between the prodromal febrile illness and the onset of the symptoms was 7.4 (±5) days. The mean time of hospitalization was 4.37 (± 1.4) days. The median time for recovery was 7 days. The longest time for recovery was 4 months. Discus-sion: Postinfectious acute cerebellar ataxia in childhood is the most common cause of childhood ataxia, which presents abruptly and requires recovery over weeks. However, it should be kept in mind that it is a diagnosis of exclusion. Appropriate utilization of laboratory tests and imaging studies is necessary for the differential diagnosis from other serious causes of acute cerebellar ataxia including central nervous system infections and mass lesions.

Keywords: Postinfectious Acute Cerebellar Ataxia; Children; Cerebellitis; Varicella Infec-tion; Cerebellar Ataxia

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Introduction

Acute ataxia is a relatively common presentation to pediatric emergency departments or pediatric neurology clinics. It is characterized by motor incoordination of fewer than 72-hours duration in a previously healthy child and is usually most prominently seen in the child’s movements, such as walking and picking up objects. [1]. Acute cerebellar ataxia is the most common cause of acute ataxia in childhood, accounting for 30-50% of all cases [2]. It is characterized by the sudden onset of ataxia following a viral infection, usually varicella [2,3]. However, other infectious agents including Epstein Barr virus (EBV), mumps, Legionella pneumophila, hepatitis A, influenza, herpes simplex, enterovirus, parvovirus B19, rubeola, and mycoplasma pneumoniae are also associated with acute cerebellar ataxia [1,4]. Acute cerebellar ataxia usually results from postinfectious cerebellar demyelination; it less commonly occurs as a result of direct infection of the cerebellum. Postinfectious cerebellar demyelination is thought to be an autoimmune phenomenon incited by infection or immunization [5]. The differential diagnosis of acute cerebellar ataxia is broad. It is a diagnosis of exclusion after other serious conditions including posterior fossa tumors, neuroblastoma (opsoclonus-myoclonus syndrome), acute hemorrhage, drug intoxications, acute labyrinthitis, and metabolic diseases (Hartnup disease, Maple syrup urine disease) have been ruled out [2]. In this study, we aim to analyze all cases of acute cerebellar ataxia presented to our pediatric neurology clinic in order to characterize the clinical features, etiology, and prognosis of the disease and to propose a diagnostic approach to acute ataxia in children.

Material and Method

In this descriptive study, the files of the children diagnosed with acute cerebellar ataxia admitted between January 2011 and June 2015 to our pediatric neurology clinic were examined for age, sex, etiology, accompanying neurological findings, laboratory and imaging findings, hospitalization time, healing time and follow-up time after hospital discharge. A total of 16 patients were included in the study. The diagnosis of acute cerebellar ataxia was based on the following criteria: acute-onset loss of coordination or gait difficulties with or without nystagmus, lasting fewer than 72 hours in a previously healthy child, and the absence of known genetic disorders presenting with ataxia, drug intoxication, bacterial meningitis, episodic ataxia syndromes, and metabolic disorders. The local ethics committee approved the study.

Results

The study included 9 males (56.25%). Mean age at presentation was 4.5 years (±3.06). The youngest patient was 1 year of age and the oldest patient was 13. The demographic and clinical characteristics of the patients are presented in Table 1. Ten of the included cases were in the 2-5 year age group (Figure 1). A febrile illness preceded the onset of symptoms in 14 of the cases. This illness was a nonspecific febrile illness in 11 of the cases. Two patients had a preceding varicella infection whereas one patient had a preceding EBV infection. The mean time interval between the prodromal febrile illness and the onset of the symptoms was 7.4 (±5) days. Dysmetria and dysarthria were the most common accompanying neurological symptoms. The median time for recovery was 7 days. Eight patients healed during the 6-10 day interval (Figure 2). The longest time for recovery was 4 months in a 4½-year-old girl. Lumbar puncture was performed in 7 of the cases. Cerebrospinal fluid protein levels were normal in all of the cases, with a mean of 20,8 mg/dl (±4,9). All patients underwent a cranial imaging, 15 underwent brain magnetic resonance imaging (MRI), and one underwent brain computerized tomography (CT). The results were normal in all of the cases. Electromyography (EMG) was performed in 4 of the cases to exclude Guillain Barre Syndrome (GBS). The results did not reveal any pathology. Two patients were treated with intravenous immunoglobulin (IVIG) and one patient was treated with intravenous methylprednisolon because of the severity of the symptoms and the lack of clinical improvement during the hospitalization period. The mean time for hospitalization was 4.4 (±1.4) days. Three patients were lost to follow-up; the mean follow-up time for the rest of the cases was 2.2 (±1,4) months. Full recovery was observed in all of the cases. One case still had minor degrees of gait ataxia and abnormal cerebellar examination in the 2-month follow-up visit; however, these signs had subsided by the 4-month follow-up visit.

Discussion

There is a small number of case series involving acute cerebellar ataxia in the published literature. In 1959, Weiss and Carter [6] described 18 patients with acute cerebellar ataxia. Six of these children had permanent neurological sequelae including gait disturbances and delayed speech development.

Connolly et al [7] reported the evaluation of 73 patients in 1994. Thirty-six of the cases were related to nonspecific viral infections. Varicella infection was responsible for 19 of the cases, EBV for 2. Fourteen cases were found to be idiopathic and 2 secondary to immunization. Cerebrospinal fluid examination revealed pleocytosis and CSF protein levels ranged between 7-99 mg/dl. Nine patients underwent cranial MRI, of which only 1 examination revealed pathology. Ataxia resolved in 91% of the cases after 4 months of follow-up; however 20% of the cases exhibited behavioral problems and learning difficulties, which subsided during follow-up. Recurrence of symptoms was observed in 4 patients.

Nussinovich et al [2] reported a prodromal illness in 29 of the 39 cases in 2003. About one-third of these cases had varicella infection. Mumps, EBV, mycoplasma, and nonspecific infections were noted in the remainder of the cases. Full recovery without any neurological sequelae was achieved within 24 days in all of the cases. A lumbar puncture was performed in all cases. Pleocytosis was present in 48% of the cases and abnormal CSF protein levels (>40 mg/dl) were observed in 23.5%. Twelve patients underwent CT imaging that revealed normal results. The most commonly-associated neurological findings were dysmetria and dysarthria; nystagmus was noted in only 3 of the cases. Electroencephalography (EEG) was performed in 12 cases. Background slowing was observed in 4 of the cases and epileptic discharges without clinical seizures were observed in 2 cases. The authors stated that acute cerebellar ataxia is a self-limiting disease.

In 2006, Martinez-Gonzalez et al. [8] reported a favorable prognosis in 20 cases with acute cerebellar ataxia attributed to varicella, mycoplasma, enterovirus, EBV, and nonspecific viral infections.

Acute cerebellar ataxia is common in children between 2 and 4 years of age, but also may be seen in older children and adolescents (3,7). Boys are more commonly affected [7]. A history of a febrile illness 5-21 days before the first appearance of the symptoms is evident in about 70% of patients. In our study group, there was a slight male preponderance, the incidence of acute cerebellar ataxia was higher in the 2-5 years age group, and a preceding illness accompanied most of the cases. All of these findings were consistent with the literature.

Varicella may be responsible in as many as 26% of the cases; rarely does ataxia occur before the eruptions [1]. Compared with the literature, in our study group, the rate of acute cerebellar ataxia following varicella infection is lower, which may be attributed to the routine use of varicella vaccine after 2012 in our country.

In our series, all of the cases recovered without any neurological sequelae. Only one case had slight gait ataxia and abnormal cerebellar examination after 2 months of discharge; they eventually subsided completely. This case was a 4 1/2 year-old-girl with a severe gait ataxia at onset causing an inability to walk. She was treated with IVIG.

Acute postinfectious cerebellar ataxia is a diagnosis of exclusion. Detailed evaluation with history and physical examination is more valuable than laboratory tests and imaging techniques in the differential diagnosis. An altered state of consciousness, presence of hallucinations, behavioral changes, and a sleepy state should raise the suspicion of drug intoxication. Acute disseminated encephalitis (ADEM) and meningoencephalitis should be on the differential diagnosis list when fever is added to these symptoms [9]. Drug intoxication constitutes about 32.5% of all childhood acute ataxia cases; therefore children and parents should be questioned about drug intake [3]. Anticonvulsant drugs, benzodiazepines, alcohol, and antihistaminic drug intoxication may cause ataxia. Motor examination should be carefully performed because ataxia may be the first sign of hemiparesis or paraparesis in younger children. Posterior circulation infarcts are relatively rare in young children but should be considered after neck trauma (causing vertebral artery dissection) or in those predisposed to thromboembolic disease [10,11]. Focal cerebral (usually parietal or frontal) and pyramidal tract lesions manifest with a positive Babinski sign and increased deep tendon reflexes [12]. Vomiting and nystagmus should raise the suspicion of labyrinthitis and in the presence of chaotic eye movements, opsoclonus myoclonus syndrome should be considered. Guillain Barre Syndrome should be on the differential diagnosis list when weakness and absence of deep tendon reflexes predominate [9].

Posterior fossa tumors usually present with slowly progressive ataxia and symptoms of increased intracranial pressure such as papilledema and sixth nerve palsy [13]. Brain imaging should be performed in suspected cases. In our study group, all children underwent brain imaging. The results were normal. Although cranial imaging was performed in selected cases in the literature [2,6,7], in countries where patient follow-up is a major problem, it might be more appropriate to evaluate all acute-onset ataxia cases with brain imaging upon admission for the early diagnosis and intervention of brain tumors.

Cerebrospinal fluid examination usually reveals normal results or mild pleocytosis and slight elevation of protein levels. Lumbar puncture should only be performed when central nervous system (CNS) infection is suspected [3]. Rarely, an LP may be helpful in differential diagnosis from GBS, when EMG is not available. However it should always be kept in mind that the CSF protein levels may be normal during the first week of GBS [14]. Therefore an LP is generally not indicated at the initial presentation of acute ataxia [1].

Electromyography is indicated when GBS is considered in the differential diagnosis. We performed EMG on only 4 patients. None of the patients underwent EEG because an altered state of consciousness was not observed in any of them.

Opsoclonus-myoclonus syndrome is a rare autoimmune condition mostly associated with neuroblastoma in childhood [15]. Thorax and abdomen CT or MRI or I123 metaiodobenzilguanidin (MIBG) scanning might be helpful for diagnosis of neuroblastoma in these patients because the levels of cathecolamines in the urine are increased in only 47-60% of the cases [16,17,18]. The treatment of acute cerebellar ataxia is usually watchful waiting; physiotherapy may be helpful in selected cases [15]. Since an autoimmune process has been suggested in the etiology, high dose corticosteroids and IVIG has been used in treatment with favorable results [19,20]. However, the results are mostly limited to case reports and the yield of corticosteroid and IVIG therapy is uncertain (1). We tried IVIG in 2 patients and high dose corticosteroids in 1 patient because of a severe and resistant course without an evident clinical response. Recovery usually begins within the first week after the onset of symptoms [1]. The average duration of symptoms is about 2 months; ataxia remains persistent in a small group of patients [7].

In conclusion, postinfectious acute cerebellar ataxia is the most common cause of acute ataxia in childhood. The prognosis is excellent; however, it causes great anxiety to the parents. After the exclusion of more serious medical conditions presenting with acute ataxia, informing the parents about the course of the disease and close follow-up during recovery is necessary.

Competing interests

The authors declare that they have no competing interests.

References

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2. Nussinovich M, Prais D, Volowitz B, Shapiro R, Amir J. Postinfectious acute cerebellar ataxia in children. Clin Pediatr (Phila) 2003;42:581-4.

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18. Laug WE, Siegel SE, Shaw KN, Landing B, Baptista J, Gutenstein M. Initial urinary catecholamine metabolite concentrations and prognosis in neuroblastoma. Pediatrics 1978;62:77–83.

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20. Go T. Intravenous immunoglobulin therapy for acute cerebellar ataxia. Acta Paediatrica 2003;92(4):504-6.

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Olcay Unver, Busra Kutlubay, Gulten Thomas, Nilüfer Eldes Hacifazlioglu, Gunes Sager, Dilsad Turkdogan. Postinfectious Acute Cerebellar Ataxia in Childhood. J Clin Anal Med. 2016;7(5):652-655

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The Evaluation of Uncertainty for the Measurement of Blood Ethanol

F. Demet Ince 1, Banu Arslan 2, Y. Cem Kaplan 3, Hamit Ellidağ 2

1 Department of Medical Biochemistry, Tepecik Education and Research Hospital, İzmir, 2 Department of Medical Biochemistry, Ataturk Education and Research Hospital, Ankara, 3 Department of Medical Pharmacology, Katip Celebi University, İzmir, Türkiye

DOI: 10.4328/JCAM.4316 Received: 19.01.2016 Accepted: 17.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 648-51

Corresponding Author: Fatma Demet Arslan Ince, Department of Medical Biochemistry, Tepecik Education and Research Hospital, Yenişehir, İzmir, Turkey. GSM: +905056468214 F.: +90 2324330756 E-Mail: fatmademet.arslan@gmail.com

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Aim: In forensic medicine, measurement of ethanol levels is important in law-suits filed against individuals. Each measurement result has a certain amount of uncertainty. The objective of this study is to determine uncertainty of ethanol measurement using the alcohol dehydrogenase method, and also to evaluate sources of variability and their contributions to uncertainty. Ma-terial and Method: Repeatability, calibrator uncertainty, and stability un-certainty were determined for ethanol measurement. After their standard uncertainties were calculated, the squares of each value were summed and the combined standard uncertainty value was found with the square roots of that value. The expanded uncertainty value was obtained by multiplying the combined standard uncertainty value by a coverage factor (k=2; confidence interval, 95%). Results: The uncertainty of measurement for ethanol was found to be ±8.5% (confidence interval, 95%). The result at threshold level (50 mg/dL) was reported as 50±4.3 mg/dL (confidence interval, 95%). Dis-cussion: Measurement uncertainty should be estimated to ensure accuracy and reliability of the results in an accredited laboratory performing alcohol measurement. Sources of error that might affect the results during the pre-analytical, analytical, and post-analytical phases should be identified and the uncertainty value should be calculated.

Keywords: Ethanol; Uncertainty; Alcohol Dehydrogenase

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Introduction

Although alcohol, after coffee, is the second most commonly consumed addictive substance affecting mental and physical activity; it is also the most frequently tolerated drink after coffee [1]. Therefore, in many countries the determination of permissible blood alcohol levels as part of traffic regulations has been affected not just by scientific justifications but also by societal tendencies. In many regions of the world there are legal blood alcohol limits for drivers of motor vehicles. In compliance with the Road Traffic Act in Turkey, drivers of private taxis, taxicabs, minibuses, buses, lorries, and trailers are not allowed to drive while drunk. Private car drivers are not permitted to drive with a blood alcohol concentration greater than 50 mg/dL (according to Road Traffic Act # 2918 dated 6.16.1985 in Turkey). Governments of Austria, Denmark, France, Australia, Canada and The Netherlands have legal limits of 50 mg/dL for blood alcohol concentration for motor vehicle drivers. Limits of permissible alcohol intake vary by country (US, 50-80 mg/dL; UK, 80 mg/dL; Japan, 30 mg/dL; Sweden, 20 mg/dL; Norway, 20 mg/dL; Russia, 20 mg/dL; Poland, 30 mg/dL; Hungary and Romania, 0 mg/dL) [1].

The most practical tool for the breath test is the alcoholometer. It is the prevalent tool used for traffic control. Although this method, which has a margin of error, is not sensitive enough, it is still considered a satisfactory method to determine a driver’s blood alcohol concentration. Certainly, if alcohol consumption is close to the legal limit, a blood analysis should also be performed. The main concern is that erroneous results of blood alcohol measurements mislead legal authorities. Therefore, laboratory test results should be accurate and reliable.

Measurement uncertainty is a parameter characterizing the dispersion of the values attributed to a reasonably measured quantity according to Eurachem/CITAC Guide CG 4 “Quantifying Uncertainty in Analytical Measurement” (QUAM). In other words, it demonstrates the extent to which the result represents the true value. Relevant international standards (as “Guidelines for Evaluating and Expressing the Uncertainty of NIST Measurement Results” prepared by National Institute of Standards and Technology and “EP29-A: Expression of Measurement Uncertainty in Laboratory Medicine” prepared by Clinical and Laboratory Standards Institute) have been included in the working procedures of many disciplines engaged in calibration and testing procedures. Measurement uncertainty is one of the general requirements demonstrating adequacy of a laboratory in compliance with ISO/IEC 17025 and ISO 15189 (prepared by International Organization for Standardization). Because of this requirement, measurement uncertainty is being used by accredited laboratories. However, to date only a few studies have been published on measurement uncertainty focused on the needs of forensic medical matters [2-6].

For threshold blood alcohol levels, calculation and reporting of measurement uncertainty by the laboratory will increase the reliability of the results, which might ease the relatively important decision-making process of legal authorities. The objective of this study is to evaluate sources of variability and to investigate their contribution to uncertainty of measurement of blood alcohol levels.

Material and Method

Blood alcohol levels were measured using the alcohol dehydrogenase method (3L36-20, MULTIGENT Ethanol Reagent, Abbott Diagnostic, GmbH & Co. KG, Germany) on Architect c8000 analysers (Abbott Diagnostic, GmbH & Co. KG, Germany).

Measurement uncertainty is classified as Type A or B according to Eurachem/CITAC Guide CG 4 “Quantifying Uncertainty in Analytical Measurement” (QUAM). Type A is an uncertainty value calculated using statistical methods, while Type B is estimated based on non-statistical methods based on values provided by the manufacturers. The uncertainty related to stability and of repeatability are considered as Type A. The uncertainty related to the calibrator is considered as Type B.

Repeatability (urep): The control samples of 50 mg/dL (3L36-10, MULTIGENT Ethanol 50 Control, Abbott Diagnostic, GmbH & Co. KG, Germany) were analyzed repetitively for 20 times (n = 20) within run, and then the coefficient of variation (CV) was estimated. To comply with the normal distribution of data, the standard uncertainty (urep) was calculated as CV of the result of 20 measurements divided by the square root of n (√n) (Type A).

urep = CV / √n

Calibrator uncertainty (ucal): The uncertainty values related to the calibrator (3L3602, MULTIGENT Ethanol 100 Cal, Abbott Diagnostic, GmbH & Co. KG, Germany) provided by the manufacturer were used. The uncertainty value of the ethanol calibrator (Cal) at a concentration of 100 mg/dL was estimated as 6.7 mg/dL.

Ccal, concentration of the calibrator; and ucer, uncertainty of the calibrator, are recorded in the certificate. Coverage factor (k) is given as k = 2, since a 95% confidence level is used (Type B).

Relative standard uncertainty (ucal) = 100 × ucer / k × Ccal

Stability uncertainty (ustab): The study group consisted of 20 drivers who drink alcohol. Written informed consent was obtained from each participant before inclusion in the study. The procedures were in accordance with the guidelines of the Helsinki Declaration on human experimentation. Blood samples collected into gel-barrier sampling vacuum tubes (Vacutainer®) were centrifuged at 3000 rpm at 25oC for 5 minutes without opening tube caps. Time interval from opening of sample tube caps to the pipetting the sample into the device is thought to be at most 30 minutes. Blood samples (n=20) with certain serum ethanol levels (50-100 mg/dL) were analyzed at baseline and again 30 minutes later. For each concentration, mean of differences% (diff%) was calculated. Assuming compatibility with rectangular distribution, the standard uncertainty was calculated dividing mean of differences by a square root of 3 (√3) (Type A).

ustab = diff% / √3

Combined standard uncertainty (uc): After all standard uncertainties were determined, the squares of each value were summed up and the combined standard uncertainty was found by taking the sum’s square root.

(uc)2 = (urep)2 + (ucal)2 + (ustab)2

Expanded uncertainty (U): The value of the combined standard uncertainty was obtained by multiplying by a coverage factor (k = 2) within the 95% confidence level.

U = k × uc

Results

In our study, repeatability, calibrator, stability and expanded uncertainty values of ethanol were estimated. Standard uncertainty values and ratios are given in Table 1. In our study, the measurement uncertainty of ethanol within 95% confidence level was found as ±8.5%. The result at threshold level (50 mg/dL) was reported as x±U mg/dL, ie. 50±4.3 mg/dL.

Discussion

In forensic medicine, measurement of ethanol levels is important in lawsuits filed against individuals. In these cases, the method of measurement should be validated and, preferably, it should be constantly audited with quality assurance programs including internal and external quality control systems. However, uncertainty of the measurement results cannot be avoided. Therefore, when evaluating the results, uncertainty value should be taken into consideration.

One of the advantages of calculating measurement uncertainty is that it enables us to learn whether the method used has met the known performance criteria of that method. In other words, since measurement uncertainty corresponds to a total error, measurement uncertainty allows us to make evaluations based on acceptable error, which in turn provides information about the performance status of our method. Our uncertainty value (8.5%) was lower than acceptable error values (±15% and ±25%, respectively) of The College of Physicians and Surgeons of Saskatchewan and New York State Department of Health [7].

Another advantage of calculating measurement uncertainty is that the source of measurement uncertainty can be determined during the calculation process. Indeed, identification of the sources of uncertainty will lead the way to eliminate or to minimize the impact of these sources on measurement accuracy. Kristiansen et al. measured ethanol levels using the gas chromatographic method and estimated maximal measurement uncertainty as 4.95% for different blood ethanol concentrations. They suggested that mostly the analytical component (90%) and then to a lesser extent, traceability (<4%), matrix effect (<0.5%), and blood water content (<0.39%) contributed to the measurement uncertainty. They suggested that the ratio of the analytical component can be reduced by increasing the number of repeats [2]. However, Gullberg et al. indicated that a single measurement can only estimate ±20% of the actual blood alcohol concentration [6].

Fung et al. calculated total uncertainty (random and systematic error) value for measurement of blood alcohol as 4% using certified ethanol reference standards [5]. Generally, in a laboratory operating under good quality control system management, random error caused by the devices used is negligibly small in importance. Rather, errors stemming from improper use of the devices are thought to have an important impact on uncertainty. However, in a study performed by Fung et al., the authors demonstrated that deviation from the average values originating from improper use of the devices was only 0.3% without any practical significance as for uncertainty. Our results also support their studies. When we analyzed our sources of uncertainty, the greatest contribution to uncertainty is from calibrators. The second most contributing factor was impaired stability of ethanol in an open tube. This finding indicates the importance of processing ethanol in blood samples as soon as possible after opening the caps of sampling tubes to ensure reliability of the analytical result. Shorter-term studies performed at different time points may prove that the contribution of stability to uncertainty is relatively lesser and variable.

When legal consequences of the reported serum ethanol measurement results are taken into account, laboratory results should be accurate, reliable, and precise. Based on the consensus decision of the College of American Pathologists (CAP), allowable error for AxSym (Abbott Diagnostic, GmbH & Co. KG, Germany) analysers is ±80% [7]. Even the accuracy among the results of gas chromatography has been debated. Therefore, when starting to use “a standard and well-established test method” for ethanol measurement in the laboratory, measurement uncertainty should be estimated. This value will ensure comparability and reliability of the test results reported by different laboratories. Besides, during calculation of uncertainty, laboratory specialists will identify all sources of error effective on the results of the measurement and determine their impact on the results obtained.

The uncertainty value determined for ethanol tests gains special importance in the evaluation of borderline values. For example, our result reported as 50 mg/dL is above the cut-off value and seems to exceed the permissible limit, when estimated uncertainty value (8.5%) in this study is taken into consideration. In reality, it might correspond to a value between 45.7 and 54.3 mg/dL. In this case, this estimated blood alcohol level (50 mg/dL) may not definitively signify alcohol consumption of the individual above permissible legal limits. Conversely, a blood ethanol level of 48 mg/dL may not absolutely indicate that this individual has consumed alcohol below permissible legal limits.

Measurement uncertainty should be estimated to ensure accuracy and reliability of the results in an accredited laboratory performing alcohol measurement. Accordingly, legal authorities making interpretations based on these results should be informed about the subject matter, which is important for the proper progression of the legal procedure.

Competing interests

The authors declare that they have no competing interests.

References

1. Hancı İH, Aşıcıoğlu F, Arslan Ç, Coşkunol H, Şirin H, Dener Y, et al. “Türk Ceza Yasasına Göre Alkollü Araç Kullanmanın Güvenli Sürüş Yeteneğine Etkileri” Çalıştay Sonuç Bildirgesi. Adli Bilimler Dergisi 2009;8(4):3-10.

2. Kristiansen J, Petersen HW. An Uncertainty Budget for the Measurement of Ethanol in Blood by Headspace Gas Chromatography. J Anal Toxicol 2004;28(6):456-63.

3. Sklerov JH, Couper FJ. Calculation and verification of blood ethanol measurement uncertainty for headspace gas chromatography. J Anal Toxicol 2011;35(7):402-10.

4. Wiergowski M, Galer K, Szpiech B, Regula K. Uncertainty of measurement as an integral part of the result and a tool of quality of work improvement for the chemical-toxicology laboratory. Arch Med Sadowej Kryminol 2005;55(1):74-9.

5. Fung WK, Chan KL, Mok VK, Lee CW. The statistical variability of blood alcohol concentration measurements in drink-driving cases. Forensic Sci Int 2000;110(3):207-14.

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7. Harr KE, Flatland B, Nabity M, Freeman KP. ASVCP guidelines: allowable total error guidelines for biochemistry. Vet Clin Pathol 2013;42(4):424-36.

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Fatma Demet Ince, Banu Arslan, Yusuf Cem Kaplan, Hamit Ellidag. The Evaluation of Uncertainty for the Measurement of Blood Ethanol. J Clin Anal Med. 2016;7(5):648-651

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Evaluation of Subclinical Inflammation withNeutrophil Lymphocyte Ratio In Heavy Metal Exposure

Ceylan Bal 1, Uğur Karakulak 2, Meşide Gündüzöz 3, Müjgan Ercan 4, Engin Tutkun 5, Ömer Hınç Yılmaz 5

1 Department of Biochemistry, Yıldırım Beyazıt University, Ankara, 2 Department of Cardiology, Occupational Diseases Hospital, Ankara, 3 Department of Family Medicine, Occupational Diseases Hospital, Ankara, 4 Department of Biochemistry, Public Health Laboratory, Aydın, 5 Department of Toxicology, Occupational Diseases Hospital, Ankara, Turkey

DOI: 10.4328/JCAM.4393 Received: 12.02.2016 Accepted: 16.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 643-7

Corresponding Author: Ceylan Demir Bal, Department of Biochemistry, Yıldırım Beyazıt University, Ankara, 06800, Turkey. GSM: +905057458438 F.: +90 3125808404 E-Mail: ceylandemirbal@gmail.com

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Aim: Neutrophil lymphocyte ratio (NLR) is being used frequently as a marker of subclinical inflammation. The objective of this study is to investigate the association between NLR levels and heavy metal levels in workers with lead exposure. Material and Method: Demographic and laboratory data of 1820 individuals with lead exposure were evaluated retrospectively. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and complete blood count (CBC) were evaluated as inflammatory markers. Participants were cat-egorized into 3 groups according to blood lead levels as < 10 μg/dL (Group 1), 10-30 μg/dL (Group 2), and > 30 μg/dL(Group 3). The association between NLR and lead was evaluated by inter-group and correlation analysis. Results: Median NLR values of Group 1, Group 2 and Group 3 were 1.45 (1.57), 1.90 (6.44), and 1.96 (6.36) respectively (p<0.001). NLR correlated positively with blood lead levels (r=0.412; p<0.001). A positive correlation was also detected with CRP, ESR, white blood cell (WBC), neutrophil, and mean platelet vol-ume (MPV) levels (r=0.140; p<0.001, r=0.075; p=0.002, r=0.237; p<0.001, r=0.585; p<0.001, r=0.060; p<0.012, respectively). There was a negative cor-relation with lymphocyte (r= -0.536; p<0.001). Discussion: To our best knowl-edge, this study is the first one which shows a strong and dose-dependent association between NLR and lead levels.

Keywords: Lead; Neutrophil; Lymphocyte; Inflammation

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Introduction

As the toxicity of heavy metals to human health has become more evident, preventive measures against their exposure have been increasing over time. Risk thresholds are determined by measuring the levels of toxic and heavy metals in the air, underground and drinking water, and food. Then, preventive and/or therapeutic approaches are applied to reducelevels that may affect human health [1-2]. Although the effects of exposure to heavy metals and toxic chemicals have been effectively diminished in daily life, occupational exposure of workers in production and chemical industries continues to be an important health problem [3].

Lead is the most frequently encountered occupational and environmental heavy metal exposure in most countries. Studies have demonstrated nephrotoxic, hepatotoxic, neurotoxic, and genotoxic effects of heavy metals such as mercury, arsenic, cadmium, and especially lead [4-5]. Lead exposure is known to increase inflammatory response by causing oxidative stress through the production of reactive oxygen species (ROS) [6]. Exposure to an especially low dose of heavy metal for a long period is important because of inflammation formation, follow-up, and likely problems.

In routine practice, white blood cell (WBC) count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) are the most commonly used inflammatory markers. Neutrophil lymphocyte ratio (NLR), which has been used in recent years, is a cheap and practical marker that can easily be calculated from complete blood count (CBC). NLR, used as a subclinical inflammatory marker, has been associated with the prognosis and mortality of many diseases [7-8]. In the context of this information, the objective of this study is to evaluate the association between NLR and levels of lead in workers with exposure to lead.

Material and Method

Study population

In this study, a retrospective evaluation of 4946 patients presenting to Ankara Occupational Diseases Hospital with lead exposure from January 2011 to March 2015 was done. In order to minimize possible effects, patients with the following diseases or conditions were excluded from the study: coronary artery disease (defined by patient history, physical examination, electrocardiogram, and laboratory results), diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, acute or chronic inflammatory/infectious condition such as ankylosing spondylitis, rheumatoid arthritis, hepatitis, history of anti-inflammatory drug use (acetylsalycylic acid, corticosteroids, non-steroid anti-inflammatory drugs), smokers, patients with leukocytosis (>12000/µl) or leukopenia (<3500/µl) and abnormal renal, liver, or thyroid function tests. After taking into account these exclusion criteria, 3126 patients were not included in the study, and the study was carried out with a total of 1820 individuals.The greatest number ofindividuals were excluded because they were active smokers.

Of the 1820 participants, 527 (28.9%) were involved in battery production, 732 (40.2%) were involved in metal recycling, 173 (9.5%) were welders, 198 (10.9%) were smelters, and 190 (10.5%) were involved in metal production. All of the participants were workers with a 5 day-a-week and 8 hour-a-day schedule. Most of the participants’ workplaces were small and medium-sized enterprises. Therefore, in most of these workplaces, measurements of environmental exposure/toxic substances were not done. In the small number of workplaces where measurements were done, accurate values could not be obtained because of incorrect measurements and inadequate data. This study was approved by the local ethics committee.

Collection of biological samples

Blood samples were taken from the participants at ‘end of workshift.’ Blood samples were drawn in 10 mm tubes with red caps not containing gel (BD Vacutainer) for serum CRP, AST, ALT, creatinine, and blood urea nitrogen analyses; in 10 mm EDTA-containing trace elements tubes (BD Vacutainer) for whole blood lead analysis, and in 5 mm EDTA-containing tubes (BD Vacutainer) for CBC and ESR analyses. For serum analyses, the specimens were centrifuged at 1500g for ten minutes after at least 30 minutes of incubation. All samples were analyzed on the same day.

Analysis methods

Serum creatinine levels were studied by Jaffe reaction, blood urea nitrogen levels were studied by enzymatic method, CRP levels were studied by latex-enhanced turbidimetric immunoassay method, and AST and ALT levels were studied by kinetic method with Konelab Prime 60 device (Thermo Scientific, Helsinki, Finland). CBC was analyzed on Beckman Coulter GenS instrument (Brea, CA, USA) and ESR analysis was performed by Alifax Test 1 (Padova, Italy). Whole blood lead levels were determined using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) (Agilent 7700 series, Tokyo, Japan). Blood samples were digested by the microwave induced acid digestion method. Standard solution of lead was prepared by dilution of certified standard solutions (High-PurityStandards, Charleston, SC, USA). Two levels of quality control materials were used (Seronorm, Billingstad, Norway).The calibration curve of lead ranged from 0 to 100 μg/dL. Limit of detection and limit of quantification were 0.02 and 0.1 μg/dL, respectively. % Relative Standard Deviation of measurements was 4.2. Participants with lead exposure were categorized into three groups according to blood lead levels as < 10 μg/dL, 10-30 μg/dL and > 30 μg/dL [9].

Statistical Analysis

Statistical analysis of data was made by using the SPSS (Version 18.0) (SPSS Inc, Chicago, IL, USA) package program. Coherence to normal distribution analysis was made by using Kolmogorov-Smirnov test. Values were presented as mean ± SD or median (range). The presence of a statistically significant difference between the groups in terms of continuous variables was examined with ANOVA for parametric and Kruskal Wallis test for non-parametric variables. For the significant (p<0.05) analytes, Student’s T test for parametric and Mann–Whitney U test for non-parametric variables were performed; Spearman’s correlation analysis was also performed.

Results

The demographic and laboratory characteristics of 1820 male patients with lead exposure who participated in the study are demonstrated in Table 1 .No significant difference was observed between the groups in terms of age or working duration.

Median NLR values of Group 1, Group 2, and Group 3 were 1.45 (1.57), 1.90(6.44), and 1.96 (6.36) respectively (p<0.001) (figure 1). Analysis using Spearman’s correlation coefficient showed that NLR correlated positively with blood lead levels (r=0.399; p<0.001; figure 2). A positive correlation was also detected with CRP, ESR, WBC, neutrophil, and MPV levels (r=0.140, p=0.000; r=0.075, p=0.002; r=0.237, p=0.000; r=0.585, p=0.000; r=0.06, p=0.012).There was a negative correlation between NLR and levels of lymphocyte (r=-0.536, p<0.001). There was no correlation between ALT, AST, blood urea nitrogen, creatinine, RBC, HGB, HCT, and PLT (r= -0.021, p=0.372; r=0.040, p=0.372; r= -0.037 p=0.149; r= -0,045, p=0.057; r=0,045, p=0.059; r=0,044, p=0.064; r=0.00, p=0.984; r= -0.046, p=0.055).

Discussion

Follow-up of inflammation is most frequently detected by analysis of CRP, sedimentation, and WBC count. In recent years, NLR, a marker showing the inflammatory status of the body and calculated from blood neutrophil and lymphocyte counts, has been investigated as an alternative and promising marker. To the best of our knowledge, this is the first time that there is a significant association between lead exposure and NLR which has been found to be higher in patients with high levels of blood lead. Moreover, a positive and strong correlation has also been demonstrated between levels of blood lead and NLR.

Like many other toxic metals, lead also causes cellular changes through oxidative stress. Besides, the pathogenesis of lead intoxication is multifactorial and in addition to oxidative stress, inflammation also plays a role. There is a very strong relationship between oxidative stress and inflammation. Oxidative stress stimulates apoptosis and inflammation by increasing the production of nuclear factor (NF-KB) [10]. On the other hand, reactive oxygen species (ROS) secreted from immune cells activated by inflammation stimulates oxidative stress. Therefore, oxidative stress and inflammation continuously stimulate each other resulting in a vicious circle [11].

In many studies, it has been demonstrated that lead stimulates oxidative stress by increasing the production of ROS [12].The ROS thus formed initiates an inflammatory process by causing damage to cell membranes through lipid peroxidation [13].On the one hand, lead causes tissue damage and inflammation by increasing ROS through various pathways. On the other hand, the precipitated inflammation increases oxidative damage by positive feedback and potentiates the negative effects of lead. As a result, it is thought that inflammation and oxidative stress are responsible for the negative effects of lead [14].

Another important effect of lead on the human body is seen through glutathione metabolism. Many heavy metals, particularly lead, show high affinity with sulfhydryl complex bound to glutathione. Glutathione reductase, glutathione peroxidase, and glutathione S transferase, enzymes that are important in glutathione metabolism and that also exhibit antioxidant properties, are deactivated by lead and an oxidative environment is formed [15].Glutathione is a protein rich in cysteine andmost of it is produced in lymphocytes (>90%) [16].Therefore, after exposure to lead, counts of lymphocyte decrease and so does the production of an important antioxidant, glutathione. Along with direct effects of lead on glutathione metabolism, this lymphocyte-mediated decrease further nullifies antioxidant property.

In a study performed by Kim et al., TNF-alpha and WBC counts were found to be higher in individuals with lead exposure when compared to those of the control group [18].Again, in the same study, a significant correlation was found between blood lead levels and these inflammatory markers. Also, in other studies, a similarlysignificant correlation has been demonstrated between levels of blood lead and another important inflammatory marker, hs-CRP [15-18].This study also demonstrated similar results with a significant correlation found between blood lead levels and ESR, CRP, and WBC counts.

In this study, NLR was found to increase with a rise in lead levels with absolute WBC and neutrophil counts rising and absolute lymphocyte counts falling. Results similar to the present study have been demonstrated in experimental studies performed on guinea pigs. Guinea pigs were randomized as controls and lead-exposed and they were evaluated in terms of different inflammatory markers. In the lead-exposed group, total protein, WBC count, and phospholipase A2 levels were found to be significantly higher when compared with the control group. When WBC subgroups were evaluated, neutrophil, basophil, and eosonophil ratio (WBC%) were found to be significantly higher while lymphocyte ratio (WBC%) was found to be significantly lower in the lead-exposed group when compared to the control group [19].

Leukocytes and especially neutrophils are key cellular components in inflammation and they each play a role by secreting different cytokines that govern the production of ROS and toxic mediators. During inflammation, increased glucocorticoid levels and increased apoptosis in response to stress cause lymphocyte counts to decrease [20].However, information on glucocorticoid levels during lead exposure is very limited. Lead has been demonstrated to increase glucocorticoid levels in animal experiments [21-22]. On the other hand, studies performed in humans have demonstrated contradictory results [23-24]. The effect of glucocorticoid on decrease of the lymphocyte count during lead exposure is controversial. Therefore, the effect of lead on the hypothalamus-hypophysis-adrenal axis needs to be investigated further. In addition to inflammatory, stress, and hormonal factors, direct toxicity of lead on the immune system also plays a role in the pathophysiology of lymphocytopenia. Lead not only affects proliferation, but also differentiation of lymphocytes through receptors, intracellular pathways, and DNA [25].

Lead exerts its toxicity through oxidative stress, cytotoxicity, and genotoxicity; however, chronic and systemic inflammation also play a pivotal role. This study has for the first time demonstrated that there is a strong and dose-dependent association between NLR, which is a simple, cheap, easily available, and reproducible marker of inflammation, and lead. Larger experimental and mechanistic studies are needed to understand the pathogenesis of lead toxicity and to develop specific therapeutic pathways.

Competing interests

The authors declare that they have no competing interests.

References

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2. Chiu WA, Caldwell JC, Keshava N, Scott CS. Key scientific issues in the health risk assessment of trichloroethylene. Environ Health Perspect2006;114(9):1445-9.

3. Wu C, Schaum J. Exposure assessment of trichloroethylene. Environ Health Perspect 2006;114(9):1445-9.

4. Ekong EB, Jaar BG, Weaver VM. Lead-related nephrotoxicity. A review of the epidemiologic evidence. Kidney Int 2006;70(12):2074-84.

5. Palus J, Rydzynski K, Dziubaltowska E, Wyszynska K, Natarajan AT, Nilsson R. Genotoxic effects of occupational exposure to lead and cadmium. Mutat Res 2003;540(1):19-28.

6. Flora SJ, Mittal M, Mehta A. Heavy metal induced oxidative stress & its possible reversal by chelation therapy. Indian J Med Res 2008;128(4):501-23.

7. Gomez D, Farid S, Malik HZ, Young AL, Lodge JP, Prasad KR. Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J Surg 2008;32(8):1757-62.

8. Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Widmann WD. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 2012;19(1):217-24.

9. Alan H. B. Wu.Tietz Clinical Guide to Laboratory Tests, 4th Edition, San Francisco, California, USA; 2005 pp. 658

10. Ramesh GT, Manna SK, Aggarwal BB, Jadhav AL. Lead exposure activates nuclear factor kappa b, activator protein-1, c-jun n-terminal kinase and caspases in the rat brain. Toxicol Lett 2001;123(2-3):195-207.

11. Vaziri ND, Khan M. Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. Clin Exp Pharmacol Physiol 2007;34(9):920-5.

12. Gurer-Orhan H, Sabir HU, Ozgunes H. Correlation between clinical indicators of lead poisoning and oxidative stress parameters in controls and lead-exposed workers. Toxicology 2004;195(2-3):147-54.

13. Sirivarasai J, Wananukul W, Kaojarern S, Chanprasertyothin S, Thongmung N, Ratanachaiwong W et al. Association between inflammatory marker, environmental lead exposure, and glutathione s-transferase gene. Biomed Res Int 2013;2013:474963.

14. Iavicoli I, Carelli G, Stanek EJ, Castellino N, Calabrese EJ. Below background levels of blood lead impact cytokine levels in male and female mice. Toxicol Appl Pharmacol 2006;210(1-2):94-9.

15. Hunaiti A, Soud M, Khalil A. Lead concentration and the level of glutathione, glutathiones-transferase, reductase and peroxidase in the blood of some occupational workers from Irbid city, Jordan. Sci Total Environ 1995;170(1-2):95-100.

16. Patrick L. Lead toxicity part ii. The role of free radical damage and the use of antioxidants in the pathology and treatment of lead toxicity. Altern Med Rev 2006;11(2):114-27.

17. Kim JH, Lee KH, Yoo DH, Kang D, Cho SH, Hong YC. Gstm1 and TNF-alpha gene polymorphisms and relations between blood lead and inflammatory markers in a non-occupational population. Mutation Research 2007;629(1):32-9.

18. Khan DA, Qayyum S, Saleem S, Khan FA. Lead-induced oxidative stress adversely affects health of the occupational workers. Toxicol Ind Health. 2008;24(9):611-8.

19. Farkhondeh T, Boskabady MH, Koohi MK, Sadeghi-Hashjin G, Moin M. The effect of lead exposure on selected blood inflammatory biomarkers in guinea pigs. Cardiovasc Hematol Disord Drug Targets 2013;13(1):45-9.

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23. Fortin MC, Cory-Slechta DA, Ohman-Strickland P, Nwankwo C, Yanger TS, Todd AC, et al. Increased lead biomarker levels are associated with changes in hormonal response to stress in occupationally exposed male participants. Environ Health Perspect 2012;120(2):278-83.

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25. Lawrence DA: In vivo and in vitro effects of lead on humoral and cell-mediated immunity. Infection and immunity 1981;31(1):136-143.

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Ceylan Bal, Ugur Karakulak, Meside Gunduzoz, Müjgan Ercan, Engin Tutkun, Ömer Hinç Yilmaz. Evaluation of Subclinical Inflammation with Neutrophil Lymphocyte Ratio In Heavy Metal Exposure. J Clin Anal Med. 2016;7(5):643-647

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Correlation of Liver Enzymes and Liver Histology in Chronic Hepatitis B Virus Infection

Makbule Eren 1, Serap Reyhanioglu 2, Evrim Ciftci 3, Emine Dundar 3, Tercan Us 4, Cagrı Ener Dinleyici 2, Ozcan Bor 5

1 Department of Pediatric Gastroenterology and Hepatology, 2 Department of Pediatrics, 3 Department of Pathology, 4 Department of Microbiology, 5 Deparment of Pediatric Hematology, Eskisehir Osmangazi University Faculty of Medicine, Eskişehir, Türkiye

DOI: 10.4328/JCAM.4340 Received: 27.01.2016 Accepted: 14.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 639-42

Corresponding Author: Makbule Eren, Department of Pediatric Gastroenterology and Hepatology, Eskisehir Osmangazi University, Faculty of Medicine, Eskisehir, Turkey. T.: +90 2222392979-2734, 2700, 2703 F.: +90 2222393774 E-Mail: makbule99@yahoo.com

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Aim: To evaluate the accuracy of current ALT levels in predicting histologi-cally significant liver disease in chronic HBV infected children. Material and Method: Liver biopsies, demographic findings, HBV DNA and ALT levels of HBsAg (+) chronic hepatitis B patients were evaluated retrospectively. Pa-tients were enrolled into group A (ALT<40) or group B (ALT≥40) and further subdivided into males with ALT <25.8 IU/L (A1) and ALT≥25.8 IU/L (A2) and females with ALT <22.1 IU/L (A3) and ALT ≥22.1 IU/L (A4). Significant histol-ogy was defined as a fibrosis score ≥ 2 and/or histological activity index (HAI) ≥4. Results: 34 patients with a mean age of 10.09±3.59 were included. There were 18 patients in group A and 16 patients in group B. Mean HBV DNA levels were 3.21±4.41 vs. 1. 77±2.61 109 copies/ml (p= 0.083). 38.9% of group A patients and 75% of group B patients had histological significant disease (p=0.045). There were no correlations between HBV DNA level and HAI and fibrosis score (respectively (r= -0.133, p=0.45) and (r= -0.259, p=0.14)). Mean histological activity index and fibrosis score were 2.78±2.31 vs. 4.88±2.33 (p=0.013) and 0.5±0.514 vs. 1.31±1.078 (p=0.007) respectively in group A and B. Five out of 9 group A2 patients (p=0.045) and 2 out of 4 group A4 patients had HAI ≥ 4. Discussion: ALT level is a good predictor for liver injury. But a cut-off value of 40 IU/L is not the accurate threshold in predicting liver disease probability in children.

Keywords: Alanine Aminotransferase; Liver; Child; Hepatitis

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Introduction

In spite of decline in its incidence, chronic hepatitis B virus (HBV) infection is still a global problem [1,2]. Ninety-five percent of vertically infected neonates, 25-50% of children aged between 1-5 years, and 6-10 % of acutely infected children unfortunately progress to chronic hepatitis B [3,4].

In the natural course of chronic HBV infection, three phases have been recognized: (I) Immune-tolerant phase, (II) Immune-active (Immune-clearance/seroconversion) phase and (III) inactive phase (Postseroconversion) [5]. In the immune-tolerant phase, the immune system does not react against the virus despite the presence of high viral replication. It is characterized by positive HBsAg, HBeAg, high HBV DNA copies, and normal aminotransferases. Most of the perinatal infected children are in this phase and may stay asymptomatic for years. However, some patients progress to the immune-active phase where they have elevated aminotransferases with positive HBsAg, HBeAg, high HBV DNA copies, and negative anti HBs and anti HBe. Since there is a general knowledge that most of the liver injury occurs in the immune-active state, treatment strategies in adult-patient guidelines attempt to shorten the duration of this phase. In these guidelines, the presence or absence of disease activity is assessed by serum ALT (Alanine aminotransferase) and HBV DNA levels. Treatment is offered to those patients with HBV DNA above 2000 IU/ml (>104 copies/ml), elevated ALT levels and any degree of fibrosis, regardless of their HBeAg status [6-8]. Recently the treatment probability of patients with HBV DNA >2000 IU/mL and elevated alanine aminotransferase level, but no evidence of fibrosis, has been emphasized. However, to date none of these reports suggests treatment for patients in the immune-tolerant phase. The rationale of this consensus depends on the fact that patients in the immune-tolerant phase have only minimal hepatic inflammation, limited fibrosis, and poor treatment response. Due to the lack of predicting parameters for associated histological disease in children, these statements are also applied to children.

Traditionally, the upper normal limit of ALT has been 40IU/ml for both men and women. But recently a few studies in adults have pointed out that chronic hepatitis B infected patients with levels of transaminases currently accepted as normal but with high serum hepatitis B virus (HBV) DNA may have significant histological disease [9]. Furthermore, the normal limits of ALT have been revised both for patients and healthy subjects; the upper normal limit of ALT was determined to be far lower than currently accepted limits [10,11]. New recommendations based on these supporting data are 30 IU/L for adult men and 19 IU/L for adult women and 25.8 IU/L in boys and 22.1 IU/L in girls [12-14]. In this context the primary aim of this study is to evaluate the impact of ALT on liver histology and to determine whether there is a significant histological disease even in children with traditionally normal defined ALT levels. Our secondary aim is to evaluate the correlation of liver histology with newly-defined upper normal limits of ALT levels for children.

Material and Method

Medical records, demographic findings, pretreatment ALT, and HBV DNA levels of children diagnosed with chronic hepatitis B infection between January 1999 and June 2009 were evaluated retrospectively. Children with at least two serum ALT examinations were included. Alanine aminotransferase levels at biopsy day and HBV DNA levels at liver biopsy week were taken into assessment. Patients were subdivided into two groups according to their serum ALT levels: Group A consisted of children with serum ALT levels <40 IU/L and group B consisted of children with serum ALT levels ≥40 IU/L. Based on the new upper normal limits of ALT in children, group A was further subdivided into four groups as males with ALT levels below and over 25.8 IU/L (A1 and A2 respectively) and females with ALT levels below and over 22.1 IU/L (A3 and A4 respectively). Their pretreatment liver biopsies were reevaluated by two pathologists who were blinded to ALT and HBV DNA levels. Hematoxylin and eosin stained specimens were scored for necroinflammation and liver fibrosis according to the Knodell scoring system [15]. Trichrome and reticulin stains were used for histopathological assessment of fibrosis. Significant liver histology was defined as fibrosis score ≥2 and/or Knodell histological activity index (HAI) ≥4. Exclusion criteria were obesity (>BMI levels according to age), abnormal lipid profile, co-infection with hepatitis C infection or other viral agents, and liver biopsies performed under or after Hepatitis B treatment. Routine laboratory tests including liver function tests (ALT) were measured with BM Hitachi. HBsAg, HBeAg, Anti HBs, Anti HBe, Anti HBc Ig G and M were analysed with the AxSym system (Abbott) by microparticle enzyme immunoassay. Quantitative HBV DNA analyses were evaluated with the real time polymerase chain reaction (rt PCR) method using the Rotor-Gene 6000 instrument (Corbett Research, Australia) and the Qiagen Artus RG PCR kit (Qiagen, Hamburg, Germany). Liver biopsies were performed percutaneously using 16/18 gauge tru-cut biopsy needles. The study was approved by the local institutional ethic committee and informed consents were obtained from the patients’ parents.

Statistical analysis was performed with SPPS for Windows 16.0. Normality distributions of the data were checked with Shapiro-Wilks and Lilliefors test. The chi square test was used to compare the two groups. Before comparing the means, the groups’ normality was checked and equality variance was calculated with Levene’s test. In case of equal variance the Student-t test was used and the 95% CI interval was calculated. When the variance analysis was not equal and data were not normally distributed, the Mann Whitney U test was used. We performed bivariate correlation analysis and calculated the Spearman coefficient correlation to assess the association between ALT level and histological disease activity. P values of <0.05 were considered statistically significant.

Results

Thirty-four naive (27 boys and 7 girls), HBeAg positive chronic hepatitis B patients aged between 3-18 years (10.9 ±3.5 years) were eligible for the study. All of the patients were vertically infected. Demographic and baseline characteristics of the study group according to serum ALT levels are shown in Table 1. All of the patients except one had HBV DNA level higher than 105 copies/ml. This patient had HBV DNA level of 104 copies/ml and ALT level more than 2 times UNL, which was defined as 40 IU/L in our laboratory.

Nineteen patients had histologically significant disease. Serum ALT levels were positively correlated with HAI (r=0.653, p<0.001) and fibrosis score (r= 0.595, p<0.001). There were no correlations between HBV DNA level and HAI (r= -0.133, p=0-.45) and fibrosis score (r= -0.259, p=0.14).

Group A consisted of 18 and group B consisted of 16 children. There were no statistical differences in terms of demographic findings and HBV DNA levels between groups A and B (Table 1). Seven out of 18 (38.9%) group A patients and 12 out of 16 (75.0%) group B patients had histological significant disease (p=0.045).

There were significant differences between two groups in terms of HAI and fibrosis score, with higher scores in group B (Tables 1, 2).

Subgroup analysis was performed in group A. There were 14 males and 4 females. Among males, 5 had ALT levels below 25.8 IU/L (A1) and 9 had ALT levels above 25.8 IU/l (A2). Children in group A2 had significantly higher mean HAI than in A1 (1.0 ±0.0 vs. 1, 56 ±0.52 (%95 CI -1, 08—0,032), p=0.039). None of the patients in group A1 but 5 out of 9 children in group A2 had HAI ≥4 (p= 0.045). None of the male patients in this subgroup had fibrosis in their liver biopsy.

All of the 4 females in the subgroup analysis had ALT levels over 22.1 IU/L (group 4). Two of them had HAI ≥4 and 2 had HAI <4. Their mean HAI was 3.25 ±2.36. Their fibrosis level ranged between 0 and 1 (mean: 0.75 ± 0.5).

Discussion

Although treatment guidelines have not been as clearly defined for children as for adults, reviewers recommend treatment for children over 2 years of age with documented active chronic HBV infection—that is, the presence of HBsAg for 3-6 months, evidence of replication (positive HBeAg and HBV DNA above 20.000 IU/ml or 105 copies/ml), and consistently elevated ALT at least 1.5-2 times the upper normal limit [5,4,16]. To date, several studies have reported some conflicting data about the relationship of viral load and the histological severity of HBV infection. Both adult and child studies demonstrated a positive correlation between HAI, fibrosis, and HBV DNA load [17,18]. In contrast, Shao et al. could not find any relationship between histological grade, stage, and DNA levels in HBeAg positive adults [19]. In the present study, we did not find any correlation between ALT and serum HBV DNA levels, reinforcing the fact that viral load doesn’t have any impact on disease severity.

Another marker used to indicate liver injury is ALT. Most of the guidelines take the upper normal limit of ALT as the initial point of treatment indication criterion for antiviral treatment. In Turkey, the criteria currently used for antiviral treatment in children, according to the Ministry of Health reimbursement policy, include a two-fold increase in ALT above the upper normal limit and/or HAI ≥4 and/or fibrosis score ≥2 in a liver biopsy. Liver biopsy is only indicated for those patients with elevated ALT. Despite the high viral load, children with normal ALT levels are assumed to be immune-tolerant and not requiring treatment [9,19].

However, recently concerns have arisen about the absence of histological disease in ALT normal patients. It has become increasingly apparent that previously-defined levels of ALT may underestimate chronic liver disease both in adult and children [9,12,19]. Schwimmer et al. [12] reported new upper normal limits of serum ALT levels as 25.8 IU/L in boys and 22.1 IU/L in girls in the pediatric population.

There is no doubt that high ALT levels have a high prevalence of significant histology [9,19]. In our study, not only the entire group but even the subgroup analysis proved the direct correlation of ALT levels with histological severity. However, 38.8% of patients with normal ALT who were formerly considered to be immune-tolerant and assumed to have mild liver disease also had histologically significant disease. Similarly, in a study evaluating 71 HBV infected children, besides a significant correlation between ALT level and inflammation, 5% of ALT normal patients were found to have HAI≥9 [17]. Also, recent adult studies demonstrated 18-37% significant inflammation and 24-34% significant fibrosis (≥2) even in patients with normal ALT levels [9,20]. Therefore, traditionally defined ALT levels can underestimate chronic liver disease. Based on these emerging data, some authors recommended liver biopsy over age 40 even in normal ALT levels [20]. We also may suggest considering liver biopsy in chronic HBV infected children with currently normal defined ALT levels. However, liver biopsy has some undesirable procedural risks such as bleeding. To avoid over-biopsying we advise using the newly-defined upper limits for liver biopsy decision. There may also be value in some non-invasive tests reflecting liver injury such as transient elastography [21]. But these test needs to be further validated.

Recently, ULN of ALT for children has been reported as 22.1 IU/L for females and 25.8 IU/L for males. None of our patients had histologically significant disease below these thresholds. Although these new cut-off values seem accurate for demonstrating significant histological disease, our study population was very small and insufficient for making an exact recommendation.

Our study is limited by being a single-center, retrospective, small sample size study and by missing genotype analyses. Although it is not exactly defined, there may be an effect of genotype, given that there are controversial results on this issue [18,22]. In conclusion, in contrast to HBV DNA levels, ALT levels seem to be accurate surrogate markers of liver injury. However, a significant proportion of children with currently normal defined ALT seem to have histologically significant disease. Conventional ALT-dependent treatment indication criteria need to be revised. Also, new cut-off values of ALT that satisfactorily reflect liver damage need to be defined for children.

Competing interests

The authors declare that they have no competing interests.

References

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19. Shao J, Wei L, Wang H, Sun Y, Zhang LF, Li J et al. Relationship between hepatitis B virus DNA levels and liver histology in patients with chronic hepatitis B. World J Gastroenterol 2007;13(14):2104-7.

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22. Park JY, Park YN, Kim DY, Paik YH, Lee KS, Moon BS et al. High prevalence of significant histology in asymptomatic chronic hepatitis patients with genotype C and high serum HBV DNA levels. J Viral Hepat 2008;15(8):615-21.

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Makbule Eren, Serap Reyhanioglu, Evrim Ciftci, Emine Dundar, Tercan Us, Cagri Ener Dinleyici, Ozcan Bor. Correlation of Liver Enzymes and Liver Histology in Chronic Hepatitis B Virus Infection. J Clin Anal Med. 2016;7(5):639-642

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Subclinical Inflammation and Simple Blood Parameters in Pregnant with Familial Mediterranean Fever

Korkut Daglar 1, Ayse Kirbas 1, Hakan Timur 1, Hasan Ali Inal 2, Gulenay Gencosmanoglu 1, Zehra Yilmaz 1, Nuri Danisman 1

1 Department of Perinatology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, 2 Department of Obstetrics and Gynecology, Konya Education and Research Hospital, Konya, Turkey

DOI: 10.4328/JCAM.4158 Received: 28.11.2015 Accepted: 12.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 634-8

Corresponding Author: Ayse Kirbas, Department of Perinatology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey. GSM: +905336423162 F.: +90 3123124931 E-Mail: drayse1982@yahoo.com, ayseozdemirkirbas@hotmail.com

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Aim: Familial Mediterranean Fever (FMF) is the most common hereditary monogenic auto-inflammatory disease. Studies suggest that inflammation persists even in attack-free periods in FMF patients. In this study, we aim to investigate the potential of simple blood parameters including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), mean platelet volume (MPV), and platelet distributed width (PDW) as emerging inflammatory markers to identify chronic inflam-mations during symptom-free periods in a group of pregnant patients with FMF. Material and Method: A total of consecutive 65 singleton pregnancies, 33 with FMF and the other 32 healthy women, were followed from the first trimester to the end of the pregnancies. Blood samples for biochemical anal-yses (C-reactive protein, fibrinogen) and a complete blood count were ob-tained at 11-13 weeks and at 16-19 weeks following a detailed examination. Results: While the mean, NLR, PLR, PDW, fibrinogen, and LMR values were comparable between the groups, the mean hs-CRP levels were significantly higher and MPV values were significantly lower in the FMF group compared with the control group at both the first and second trimester. There was a significant negative correlation between hs-CRP levels with MPV at second trimester (r= -0.375 p=0.003). Discussion: Since all of our FMF patients had already been on regular colchicine therapy on admission, we admit, at least theoretically, that the anti-inflammatory and potential effects of colchicine on platelets could have altered our results. Otherwise, MPV may be used as a negative acute-phase reactant in pregnant patients with FMF.

Keywords: Inflammation; Lymphocyte To Monocyte Ratio; Neutrophil To Lymphocyte Ratio; Pregnancy; Platelet

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Introduction

Familial Mediterranean Fever (FMF) is the most common hereditary monogenic auto-inflammatory disease, characterized by recurrent, self-limited episodes of fever and sterile inflammation of serous membranes. FMF is caused by mutations in the Mediterranean fever gene that encodes pyrin (also known as Marenostrin), which is essentially responsible for the regulation of apoptosis, cytokines, and inflammation [1].

The diagnosis of FMF is still based on clinical criteria since there is no specific diagnostic test. Tel Hashomer criteria are widely used for diagnosis of FMF [2].

The treatment of patients with FMF is aimed at suppressing the inflammation. Colchicine, an anti-inflammatory drug, is the first-line therapy to treat pain and to prevent amyloidosis in FMF; it can be used safely in pregnancy [3].

Studies suggest that inflammation persists even in attack-free, asymptomatic periods in FMF patients as shown by high levels of acute-phase proteins, cytokines, and inflammation-induced proteins [4].

Systemic inflammation can be measured by using a variety of biochemical and hematological markers. Recent findings indicate that measuring blood cell subtype ratios, such as the neutrophil to lymphocyte ratio (NLR), the platelet to lymphocyte ratio (PLR), and the lymphocyte/monocyte ratio (LMR), might provide prognostic and diagnostic clues to diseases related to chronic low-grade inflammation [5, 6]. Mean platelet volume (MPV) and platelet distributed width (PDW) are other examples of noninvasive biomarkers that can be easily tested [7,8].

In this study, we aim to investigate the potential of simple blood parameters including NLR, PLR, LMR, PDW, and MPV as emerging inflammatory markers to identify chronic inflammations during symptom-free periods in a group of pregnant patients with FMF. We also aim to investigate whether pregnant patients with FMF have an increased risk for perinatal complications.

Material and Method

This prospective case–control study was conducted between December 2014 and August 2015. Local Institutional Review Board approved the study and the universal principles of the Helsinki Declaration were applied. All patients provided written informed consent.

The diagnosis of FMF was made according to the Tel Hashomer criteria. The definitive diagnosis of FMF was made when two major criteria or one major and two minor criteria were present. The major criteria are: 1- recurrent febrile episodes accompanied by serositis, 2- AA type amyloidosis without apparent predisposing disease, and 3- favorable response to colchicine test. Minor criteria are: 1- recurrent febrile episodes, 2- erysipelas-like skin lesions, and 3- diagnosis of FMF in a first-degree relative [2].

All of the patients had Turkish ethnicity determined by country of origin. Of these, the women with FMF were already on colchicine treatment in appropriate doses to prevent attacks (1-2 mg daily). Proteinuria, suggestive of renal amyloidosis, was excluded on the basis of repetitive urine testing. Patients with any of the following criteria were not eligible to participate in the study: multiple pregnancy, detection of fetal anomalies by USG, and the history of any other systemic diseases.

The pregnancies of sixty patients diagnosed with FMF were followed during the study period at our hospital. A total of 27 patients with FMF were excluded from the study:2 had concomitant connective tissue diseases, 1 had diabetes mellitus, 2 had multiple pregnancies, 2 had IVF pregnancy, and 20 were late (after 14th weeks of gestation) registration (Figure 1). Two of the patients were later excluded from the study due to noncompliance and missing data.

A total of 65 consecutive singleton pregnancies who conceived spontaneously, 33 with FMF and 32 healthy women, were followed from the first trimester to the end of the pregnancies.

All of the patients were examined for infection, routine urine cultures were obtained, and body temperatures were measured. Patient with any signs and symptoms of active infection, (pain, fever, or vaginal discharge), were excluded from the study. None of the patients or controls had a multiple pregnancy, active labor, or pre-existing chronic systemic disease.

The diagnosis of preeclampsia was based on a systolic blood pressure of ≥140 mmHg or diastolic blood pressure ≥90 mmHg, measured twice in four-hour intervals while resting, after the 20th gestational week, as well as 300 mg/dL proteinuria detected in a 24-hour urine sample [9]. Preterm birth was defined as delivery before 37 weeks of pregnancy were completed. The diagnosis of fetal growth restriction was made when estimated fetal weight was below the tenth percentile and was associated with abnormal fetal Doppler parameters, with low birth weight defined as <2500 gram and very low birth weight as <1500 gram [10].

Blood samples for biochemical analyses (high-sensitivity C-reactive protein (hs-CRP), fibrinogen) and a complete blood count (CBC) were obtained at 11-13 weeks and at 16-19 weeks after detailed examination.

All CBC analyses were conducted in the central hematology laboratory of the hospital using a Gen-S automated analyzer (Beckman Coulter, High Wycombe, UK). NLR and PLR values were calculated by dividing the absolute neutrophil and platelet counts, respectively, by the absolute lymphocyte counts. LMR value was calculated by dividing the absolute lymphocyte by the absolute monocyte count. Blood samples were taken in standardized, EDTA containing tubes. Measurements were completed within one hour of blood sampling in order to avoid the EDTA-induced platelet swelling with time. Plasma concentrations of hs-CRP were determined with a Tinaquant CRP (Latex) high-sensitive particle-enhanced immuno turbidimetric assay on a Roche Modular P analyzer (Roche kit; Roche Diagnostics) according to manufacturer instructions. Minimum detectable concentration of hs-CRP was 1×10−5 mg/L. All samples were assessed in duplicate.

Maternal characteristics and levels of each participant, such as age, parity, body mass index (BMI), hs-CRP, fibrinogen, and CBC results, were recorded at first and second trimester. The perinatal outcome parameters, including gestational age at delivery, mean birth weight, mode of delivery, preterm delivery, preeclampsia, fetal loss, 5-minute Apgar score, and neonatal intensive care unit admission, were also assessed.

The statistical analyses were performed using IBM SPSS Statistics version 15 (IBM Corp., Armonk, NY). Normal distribution of data was assessed using the Kolmogorov–Smirnov test. Continuous and normally distributed variables were presented as mean ± standard deviation (SD) and intragroup differences were investigated using one-way analysis of variance. The data were summarized as mean ± standard deviation and median (minimum–maximum). Continuous variables were examined using Kruskal–Wallis tests if the data were not normally distributed. Categorical variables were expressed as number (percentage). Proportions were compared with Fisher’s exact test or the chi-square test where appropriate. Pearson’s correlation analysis was used to study the correlations between measurements. A two-sided p value <0.05 was considered statistically significant.

Results

Of the 60 patients diagnosed with FMF who were followed during the study period, 33 (55%) were enrolled in the study. The demographic characteristics of the groups are presented in Table 1. Maternal age, parity, and BMI were comparable between the groups. The duration of FMF during pregnancy was 7.1 ± 2.5 years in the study group and all of them were under treatment with colchicine 1.5-2 g daily.

Some inflammation related markers (obtained when all participants were asymptomatic) in both the FMF and control groups are shown in Table 2. While the mean WBC, NLR, PLR, PDW, fibrinogen, and LMR values were comparable between the groups, the mean hs-CRP levels were significantly higher and MPV values were significantly lower in the FMF group when compared with the control group at both the first and second trimesters.

There were no significant differences in mode of delivery (p=0.65). No differences in preterm delivery (p=0.73), preeclampsia (p=1), low Apgar scores (p=1), and NICU admission (p=1) were found between the groups. There were no cases of fetal chromosomal anomaly or perinatal mortality in either of the groups. The comparison of the perinatal outcomes of the FMF and control groups is presented in Table 3.

In correlation analysis, there was a significant negative correlation between hs-CRP levels with MPV at second trimester (r= -0.375 p=0.003).

Discussion

The main observation of this study is the identification of the potential role of novel inflammatory markers including NLR, PLR, LMR, and MPV. We found significantly higher serum hs-CRP and lower MPV levels in patients with FMF during the asymptomatic and attack-free period when compared to the controls at both first and second trimester. Indeed, in this study, we showed a negative correlation between MPV and m-CRP.

The attacks of FMF that are caused by neutrophil activation are typically accompanied by leukocytosis and elevation of CRP, fibrinogen, and other inflammatory parameters [4]. Colchicine is one of the oldest known drugs used for prophylaxis of FMF attacks and the prevention of the development of amyloidosis. Its anti-inflammatory mechanism differs from the other anti-inflammatory agents like nonsteroidal anti-inflammatory drugs and glucocorticoids. Instead of being involved in the arachidonic acid pathway, colchicine promotes microtubule depolymerization leading to cytoskeletal changes through cell mitosis, exocytosis, and neutrophil motility. Colchicine not only inhibits neutrophil chemotaxis and the production of interleukin-1, but also down-regulates the tumor necrosis factor alpha-receptors [1-3]. Moreover it has been shown that subclinical inflammation characterized by overproduction of hs-CRP and the other acute-phase reactants persists during remission period in FMF patients. Growing data suggests that colchicine decreases the levels of subclinical inflammation markers in FMF [4]. Indeed previous studies suggested that colchicine use suppresses platelet activation [11,12].

MPV, that universally available routine blood count by automated hemogram, is suggested as an indicator of platelet activation and reactivity that have also been associated with inflammation. Compared to lower platelets, higher platelets have larger granules; they aggregate more rapidly with collagen and increased thromboxane A2synthesis, and they show increased expression of P-selectin, glycoprotein IIb/IIIa and fibrinogen receptors [7].

In previous studies, the MPV levels were measured in patients with FMF. There were contradictory results in the literature. Coban et al. showed significantly higher MPV levels in attack-free periods of FMF patients when compared the healthy participants. They also found a negative correlation between MPV levels and the duration of colchicine treatment, and a positive correlation with delay of diagnosis. They suggested that patients with FMF tend to have increased platelet activation. Therefore, MPV level has been suggested as an index of the comprehensive inflammatory status of the body [13]. However Abanonu et al. reported no statistically significant difference between the FMF patients and the control groups in terms of MPV. They hypothesized that this result may be an effect of the colchicine on platelet function [14]. In another well-designated study, Sahin et al. reported decreased values of MPV in FMF patients during attack and attack-free periods than in healthy subjects [15]. This finding supported our study. We showed lower MPV levels in pregnant patients with FMF during attack-free periods compared to the healthy patients. Since all of our FMF patients had already been on regular colchicine therapy on admission, we admit, at least theoretically, that the anti-inflammatory and potential effects of colchicine on platelets could have altered our results.

Although the cause is not clear, some studies in the literature have shown that the prevalence of preterm births is higher in FMF [16,17]. It has been suggested that FMF is an independent risk factor for preterm delivery [16]. But others reported favorable pregnancy outcomes in patients with FMF treated with colchicine before and after pregnancy [18].

It is difficult to determine an actual cause because preterm birth is a multifactorial pregnancy complication. It has been difficult to determine the risk factors involved in a preterm birth due to various triggers that lead to spontaneous or indicated preterm birth such as idiopathic preterm labor, PPROM, and medical or care-related indications and complications having different etiologies but similar manifestations; these may include severe preeclampsia, placental abruption, and chorioamnionitis [19].

In our current study we documented pregnancy outcomes of pregnant patients with FMF. We showed that their perinatal results were comparable with healthy pregnant women. In this cohort, all participants with FMF continued their colchicine treatment during pregnancy from first trimester safely, and no significant differences were noted regarding congenital malformations.

The strengths of our study are the homogeneity of the characteristics of the women in the study groups and its prospective design. All of the participants were examined for infection and body temperatures were measured before obtaining blood samples. Patients with any signs and symptoms of active infection (pain, fever, or vaginal discharge) were excluded from the study. Moreover, in the present study, since the BMI, the maternal age, and the ethnicity were comparable between the groups, possible confounding effects were also eliminated.

In conclusion, the main findings of our study were that serum hs-CRP levels were still higher and MPV values were lower in pregnant patients with FMF who had already been put on colchicine treatment during the asymptomatic period. On the basis of this observation, it is hypothesized that MPV not only indicates platelet function and activation but also is inversely associated with systemic inflammation. Furthermore, perinatal outcome of patients with FMF was comparable to the patients without FMF.

Acknowledgements: The authors would like to thank Dr. Ozgur Kirbas for his secretarial help.

Competing interests

The authors declare that they have no competing interests.

References

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Korkut Daglar, Ayse Kirbas, Hakan Timur, Hasan Ali Inal, Gulenay Gencosmanoglu, Zehra Yılmaz, Nuri Danisman. Subclinical Inflammation and Simple Blood Parameters in Pregnant with Familial Mediterranean Fever. J Clin Anal Med. 2016;7(5):634-638

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Cytogenetic Analysis of 65 Women with Premature Ovarian Insufficiency

Seda Ateş 1, Pınar Özcan 1, Gözde Yeşil 2

1 Kadın Hastalıkları ve Doğum ABD, 2 Tıbbi Genetik ABD, Bezmiâlem Vakıf Üniversitesi Tıp Fakültesi, İstanbul, Türkiye

DOI: 10.4328/JCAM.4282 Received: 11.01.2016 Accepted: 10.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 630-3

Corresponding Author: Seda Ateş, Kadın Hastalıkları ve Doğum ABD, Bezmialem Vakıf Üniversitesi Tıp Fakültesi Hastanesi, Fatih, İstanbul, Türkiye. GSM: +905053929274 F.: +90 2126217580 E-Mail: drsedaates@yahoo.com

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Aim: Premature ovarian insufficiency (POI) is characterized as amenorrhea for more than 6 months, occurring before the age of 40, with an increased follicle-stimulating hormone and low estrogen concentrations. The aim of our study is to determine the types and distribution of cytogenetic abnormal-ities among women with POI. Material and Method: The study is based on the retrospective karyotype analysis of 65 women with idiopathic POI referred to the Medical Genetics Department at the Bezmialem Vakif University Hos-pital. Results: Chromosomal abnormalities were present in 12 of 65 cases (18.4%). All of them had numerical abnormalities of the X chromosome. The most frequently detected abnormalities were X chromosome mosaicisms. Two cases had fragile X premutation carriers. Eight (12.3%) women were considered as familial POI. Discussion: Our results underline the essential role of the X chromosome in the etiology of POI. Therefore, regardless of clinical features and woman’s age, cytogenetic investigations should be rou-tinely performed in cases with POI.

Keywords: Premature Ovarian Insufficiency; X Chromosome Abnormalities; Karyotype; Mosaicism

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Introduction

Premature ovarian insufficiency (POI) is characterized by amenorrhea, the presence of high levels of gonadotropins [follicle-stimulating hormone (FSH) > 40 mIU/ml], and low levels of estradiol (E2) for at least 6 months duration in women before the age of 40 [1]. POI occurs in ~1% of the general female population before 40 years of age, as its incidence according to age is approximately 10/100,000 in women aged 15 to 29 years and 79/100,000 in women aged 30 to 39 years [2]. The prevalence of familial POI has been reported as 12.5% to 50% with widely varying percentages in series [2-4].

While the etiological causes of (POI) are highly heterogeneous, most cases of isolated POI still appear sporadically. The demonstrated etiological causes of POI include chromosomal or genetic (premutation of the FMR1, either numerical or structural abnormalities of an X chromosome such as monosomy, trisomy, deletions, translocations or autosomes), autoimmune, metabolic (such as galactose-1-phosphate uridyltransferase), infectious (e.g. viral), and iatrogenic factors (e.g. extensive pelvic surgery or oophorectomy, radiation, and chemotherapy) [5]. The importance of genetics in the etiology of POI is supported by the observation that POI occurs in approximately 10%-30% of idiopathic cases [6]. The prevalence of the FMR1 premutation carrier state in the general population of women is 1 in 100 and approximately 16-26% of the female premutation carriers will develop POI [7]. Autoimmunity is responsible for approximately 4-30% of POI cases [8].

The aim of this study is to investigate the prevalence and type of cytogenetic anomalies in 65 Turkish women with POI in order to assess the efficacy of cytogenetic screening.

Material and Method

This study was based on a review of medical records of the karyotype analysis of 65 women with POI who were referred by clinicians to the Medical Genetics Department of the Bezmialem Vakif University Hospital from November 2011 to December 2013. All medical and family histories of the women were taken by gynecology and genetic clinics. Inclusion criteria included secondary amenorrhea for at least 4 months prior to the age of 40 years and two serum FSH measures higher than 40 mIU/ml obtained at least 1 month apart. Exclusion criteria were conditions that can induce POI, such as ovarian surgery, chemo- or radiotherapy, or autoimmune diseases. This study was approved by the Ethics Committee of our hospital and informed consent was obtained from all participants.

Collected data included medical history, menstrual cycle irregularities, menopause age, obstetric history (gravidity, parity, a history of previous miscarriage, and curettage), and measurement of height and weight. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m2). Positive family history was considered if another first- or second-degree relative had POI. POI was defined as familial when the index woman had at least two family members also affected by POI.

Serum samples were collected in a fasting state for the measurement of serum FSH and E2 level. Serum FSH concentrations were measured by a direct chemiluminescence immunoassay and E2 was determined by a competitive chemiluminescent immunoassay (ADVIA Centaur, Siemens Healthcare Diagnostics, NY, USA). Metaphase chromosomes prepared by standard cytogenetic methods were analysed from the collected peripheral blood samples. Twenty metaphase spreads per patient were routinely banded using the trypsin Giemsa technique at resolutions of 500 to 650 bands per haploid set. After evaluation, 100 spreads were additionally banded in cases with mosaic mutations. DNA testing for fragile X premutation was also done.

DNA samples were collected from peripheral blood samples. The number of CGG repeats in the FMR1 gene located on XQ27.3 was analysed with direct fluorescent PCR and capillary electrophoresis fragment analysis. NM_002024.3 was considered as the reference point. The number of CGG repeats 5-40, 41-58, 59-20, and >200 were respectively defined as normal, intermediate allel with risk of mutation, premutant allel, and complete expansion.

Analyses were done using the Statistical Package for the Social Sciences, version 21 (SPSS, Chicago, IL). Data were expressed as mean ± standard deviation or number and percentage, as appropriate.

Results

The results of karyotype analyses of four patients were not found. The remaining 65 patients admitted with secondary amenorrhea were included in the present study. Demographic characteristics and hormone profiles of patients are summarized in Table 1. The average age was 36.38 ± 4.63 at the time of cytogenetic exploration. Of 24 cases (36.9%), at least one first- or second-degree relative had POI and in 8 cases (12.3%) familial POI was identified.

The karyotype was detected as normal in 51 cases (78.4%) and the frequency of genetic abnormalities was 21.5% (14 cases) in patients with POI. Numerical X chromosome abnormalities (12 cases; 18.4%) were the most common abnormalities detected in women with POI in our study. Two cases were fragile X premutation carriers. We also detected 1 case of 46,XX,15p+. The distribution of abnormalities in patients with POI is detailed in Table 2.

All patients had a complete physical examination at the first visit. There was no patient with abnormal secondary sexual characteristics or with characteristic features of Turner syndrome such as short stature, webbed neck, hypoplastic uterus, or other dysmorphic features. The anti-thyroid peroxidase antibody was detected in only a case with 45,X[5] /47,XXX[1] /46,XX[94] . The patient with fragile X premutation carrier was mentally normal but she had a mentally impaired son diagnosed with fragile X syndrome. We did not detect any kinds of structural X chromosome abnormalities and autosomal anomalies in patients with POI.

Discussion

The etiological causes of POI are clearly heterogeneous, with a wide spectrum of causes, and in most cases its underlying mechanisms remain unknown. Structural and numerical abnormalities of the X chromosome were the most common genetic causes of POI because two intact X chromosomes are necessary for normal development of the ovary and of ovarian function. Cytogenetic analysis is the tool currently available for the detection of cytogenetic abnormalities leading to POI.

POI is defined as familial when an index woman with POI has at least two relatives with POI [9]. Several studies reported an incidence of familial POI of between 4% and 33% [3,10]. On the other hand, a study that included 200 cases having at least ≥1 relative with POI found that the incidence of familial POI was 29% [4]. According to a study from Turkey, the incidence of familial POI was reported as 24% [9].

In a recent study including 175 cases, Geckinli et al. [11] detected chromosomal abnormalities in 35 of 94 (37%) cases with primary amenorrhea and in 9 of 81(11.1%) cases with POI. Furthermore, X-aneuploidy or X-structural abnormalities or 46,XY karyotype were the most frequently detected abnormalities in this study. When compared to our results, some studies reported higher frequency while others reported lower frequency of chromosomal abnormalities. The prevalence of chromosomal abnormalities reported in previous studies is presented in Table 3 [1,4,12-18]. The different prevalence in these studies probably results from selection biases because women with primary amenorrhea were included for analysis in some of the studies from different countries.

The strong relationship between X chromosome and ovarian function and the etiology of POI is commonly highlighted in the literature [5,13]. A Dutch study also indicated the relationship between X chromosome and the broader spectrum of menopausal age and POI [19]. However, the present study found that the most frequently detected abnormalities were numerical abnormalities of the X chromosome involving X chromosome mosaicisms. A study reported that the numerical chromosomal abnormalities were 8% of the patients with POI consisting of 4 X chromosome mosaicisms and 2 X chromosome trisomies [9]. Wu et al. [20] found X chromosome mosaicism in 5 (8.2%) of the 65 women with POI in their study. Our results are in accordance with those reported by Ayed et al. [21]. They reported mosaicism with a 45,X line as the most frequently detected anomaly in women with POI and also reported that the prevalence of 47,XXX in 100 POI cases was 3%, including two mosaic and one non-mosaic. There is no clear evidence to indicate the effect of an X trisomy on human fertility, as the strong relationship between an X trisomy and POI is clearly revealed [22]. In fact, our data may support that women with X chromosome mosaicism may experience premature menopause [13,20]. The prevalence of 47,XXX in cases with mosaic pattern was 10.7 %, which is higher than the prevalence reported by Goswami et al. [5] (3.8%) and Jiao et al. [12] (1.5%), respectively.

Autosomal chromosomal abnormalities are uncommon in women presenting with amenorrhea. We detected only 1 case of 46,XX,15p+ which is phenotypically normal. In a more recent study, Demirhan et al. [23] analysed chromosome abnormalities in 393 women presenting with primary and secondary amenorrhea and 46,XX,15p+ was found in 1 case. As the p arm of acrocentric chromosomes has no gene, it is expected that the increasing heterochromatin material in the p arm of acrocentric chromosomes considered as a polymorphic feature does not influence phenotype.

Varying data have been published regarding the incidence of FMR1 premutation carrier in women with POI. Murray et al. [24] showed that the ratio of FMR1 premutation carrier was 1.6% in sporadic cases and 16% in familial POI cases and they suggest that patients with idiopathic POI should be routinely screened for fragile X. Bachelot et al. [25] reported the incidence of FMR1 premutation carrier was 7% in the familial cases and 8% in sporadic groups, which was higher than our result.

The development of new information related to etiology and the molecular basis of POI could contribute to understanding ovarian physiology, genetic counseling, and fertility guidance.

In conclusion, we found that the prevalence of genetic abnormalities in POI is 21.5%. Our study clearly demonstrates the association between chromosomal abnormalities and POI and underlines the essential role of the X chromosome in the etiology of POI. In light of our results, it could be recommended that cytogenetic investigation should routinely become a part of the management of women diagnosed with POI regardless of the patient’s age and even when there are no other clinical features suggesting any chromosomal abnormality.

Conflict of interest

The authors declare no conflict of interest related to this work.

References

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Seda Ates, Pinar Ozcan, Gozde Yesil. Cytogenetic Analysis of 65 Women with Premature Ovarian Insufficiency. J Clin Anal Med. 2016;7(5):630-633

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Bloodstream Infections in a Neonatal Intensive Care Unit

Mehmet Şah İpek 1, Erdal Özbek 2

1 Department of Neonatology, 2 Department of Microbiology, Maternity and Children Hospital, Diyarbakir, Turkey

DOI: 10.4328/JCAM.4276 Received: 08.01.2016 Accepted: 10.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 625-9

Corresponding Author: Mehmet Şah İpek, Maternity and Children Hospital, Urfa Road 7th km, Baglar, Diyarbakir, Turkey. T.: +90 4122519125-1215 F.: +90 4123156611 E-Mail: md.msipek@yahoo.com

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Abstract

Aim: To determine the pattern of bloodstream infections (BSIs) and antimi-crobial susceptibility of pathogens in a neonatal intensive care unit (NICU).Material and Method: Positive hemoculture of neonates diagnosed with nos-ocomial sepsis from March 2011 to March 2014 in the NICU of Diyarbakir Maternity and Children’s Hospital, in the southeastern region of Anatolia, Turkey, were retrospectively reviewed. Results: A total of 148 pathogens were isolated in 142 neonates. The most common microorganisms isolated were Klebsiella pneumoniae (40.5%) and Acinetobacter baumannii (29.7%) which was a result of a hospital outbreak. Multi-drug resistant (MDR) strains accounted for 20.0% of K. pneumoniae isolates and 93.2% of A. baumannii isolates. The sepsis-attributable mortality rate was higher in cases infected with MDR strains than in cases infected without MDR strains or Candida spp (24% vs. 9.7%, p=0.032). Discussion: In our unit, BSIs were more often caused by Gram negative bacteria. BSIs caused by MDR strains were associated with a higher rate of sepsis-attributable mortality.

Keywords: Nosocomial Infection; Neonatal Intensive Care; Multi-drug Resistance; Turkey

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Introduction

Nosocomial infection is a common complication in hospitalized patients, and is an important cause of morbidity and mortality in neonatal intensive care units (NICUs) [1,2]. The incidence of nosocomial infection varies between 18% and 50% [3-7] and accounts for as much as 40% of neonatal deaths in developing countries [2,5,6]. In a survey of 16 centers, conducted by the Turkish Neonatal Society, it was reported that the incidence of nosocomial sepsis varied from 2.1% to 17%, and sepsis-related mortality was approximately 24% [8].

Bloodstream infections (BSIs) were the single most important type of infection because of their high frequency and potentially life-threatening consequences [3,5,7]. The variety and the antimicrobial sensitivity of the microorganism causing sepsis can vary among NICUs and it can also change over time for the same unit [7-9]. The identification of the microorganisms and their antibiotic susceptibility is essential for determining an empirical antibiotic treatment and the appropriate antibiotic. In this study we have evaluated the distribution rate and antibiotic sensitivity of the pathogenic microorganisms growing in blood cultures in our NICU.

Material and Method

Setting: The NICU at Diyarbakir Maternity and Children’s Hospital, at which 20,000 deliveries occur yearly, is one of the largest hospitals in the southeastern region of Anatolia in Turkey. It is supplied with 25 tertiary level, 35 secondary level, and 10 primary level beds. The unit usually receives newborns from the obstetric department. Two neonatologists work during the day (unfortunately there was no sustained neonatologist during the first year of the study period) and one pediatrist works at night. A trained infection control nurse is available on the unit at all times with an average of 1 nurse for 6-7 neonates. Automatic preparation of total parenteral nutrition has also been available as of the year 2012.

Study Design: This retrospective study was performed on data gathered between March 2011 and March 2014. All blood culture positive cases were selected and their records evaluated in terms of sepsis criteria, gestational age, age at onset, gender, birth weight, and microorganism and antimicrobial susceptibilities. Clinical data were analyzed by episodes, which were defined as distinct periods of clinical illness in association with positive blood cultures. Patients who had no infection and/or were not in the incubation period at presentation and who developed blood stream infection 72 hours after hospitalization were eligible for inclusion. Patients who died or were discharged from the NICU within the first 48 hours or who had perinatal or community-acquired infections or recurrent admissions were excluded from the study.

Definitions: BSI was defined as isolation of at least one positive peripheral-blood culture, except for coagulase-negative staphylococcus, for which isolation of two positive blood cultures was required [10]. Sepsis was determined by previous described criteria [9-11]. A C-reactive protein (CRP) value of >1 mg/dl was considered to be significant [10]. Multi-drug resistant (MDR) strains were defined as those resistant to at least 1 agent in ≥3 of the following antimicrobial categories: carbapenems (imipenem and meropenem), penicillins (piperacillin, ticarcillin, and piperacillin/tazobactam), third-generation cephalosporins (ceftazidime and cefotaxime), aminoglycosides (amikacin), and fluorquinolones [12]. Sepsis attributable mortality (SAM) was defined as a patient who expired within 7 days after onset of sepsis, those who died of infectious complications, or clinically progressive deterioration following BSI [12].

Microbiological Methods: Hemoculture is taken under sterile conditions using sterile gloves and cloths. The blood culture system is Bactec 9240 (Becton Disckinson, USA), and the volume of blood taken for each culture is at least 0.5 mL but usually 1.0 mL. When Bacillus, Coryneobacterium, and coagulase negative staphylococcus (CNS) are cultured without clinical findings, contamination is considered to be present [4]. Bacteria identification and antimicrobial susceptibility testing were performed using a BD Phoenix Automated Microbiology System (BD Diagnostic Systems, Sparks, MD) according to the manufacturer’s recommendations. The extended-spectrum β-lactamase (ESBL) production was confirmed by the Double-Disc Synergy Test according to Clinical Laboratory Standards Institute (CLSI) 2010 guidelines. Carbapenem resistance was confirmed with a modified Hodge test.

Statistical Analysis: Statistical Package for the Social Sciences (SPSS) for Windows 17.0 program was used for statistical analysis of the results obtained in the study. Demographic properties in the study were assessed by “descriptive” statistical analysis. Chi-square and Fisher’s exact chi-square test were used for categorical variables. Mann-Whitney U test was used for continous variables. P <0.05 was considered statistically significant.

Results

Of 5166 patients admitted to NICU during this study period, 982 were excluded for the reasons described above. Given the overall cohort of 4184 neonates, 246 (5.9%) infants developed clinical signs of sepsis. Sepsis was confirmed by blood culture as BSI in only 142 (67.6%) neonates with a total of 148 episodes. Total length of hospital stay in the NICU was 45.080 days, and the incidence rate of BSI in our NICU was 3.28 case episodes per 1000 hospital days. The distribution of episodes according to year is shown in Figure 1.

Demographic characteristics of the patients with positive hemoculture are shown in Table 1. BSI rate distribution did not differ among cases with birth weight < 1500 g and higher (p = 0.18). According to day of infection onset, there was not a significant difference between the two groups of cases with birth weight < 1500 g or higher (p =0.32). At the beginning of infection, CRP was negative in 51 (34.5%) patients.

Of 148 blood cultures, 126 (85%) isolates were Gram negative bacteria (GNB), 18 (12.2%) isolates were Candida, and only 4 (2.7%) isolates were Gram positive bacteria (GPB). The microorganisms that were identified from the blood cultures are shown in Table 2.

Meropenem and amikacin resistance for Klebsiella pneumoniae were found in 30% and 22.2% of the cultures, respectively. K. pneumoniae was found to be highly resistant to ampicillin, piperacillin, and third-generation cephalosporins. ESBL production of K. Pneumoniae was found as 37.2%. The majority of Acinetobacter baumannii isolates (93.2%) were MDR. Antibiotic resistance of GNB is shown in Table 3. CNS were found to be sensitive to vancomycin. Because of technical limitations, susceptibility tests were not performed for Candida isolates. An outbreak of A. baumannii was identifed in the second half of 2012. Despite all the measures taken, elimination of A. Baumannii required six months, probably due to the fact that the unit is large and crowded.

Of 142 neonates, 44 (31%) died. The SAM rate was 17.6%. The SAM rate was marginally nondifferent among cases with birth weight < 1500 g compared to those higher (21.9% vs. 10.6%, p =0.052). But, the SAM rate was higher in cases infected with MDR strains (n=58) than in cases infected without MDR strains or Candida spp (24% vs. 9.7%, p=0.032).

Discussion

As in most previous reports, BSI was the most commonly observed form of nosocomial infection [4-8,13]. In other national studies, the incidence of nosocomial sepsis ranges from 2.1% to 17% [8-10]. In this study, sepsis frequency was 5.9%, and BSI occurred at a rate of 3.28 case episode per 1000 hospital days. However, the frequency of sepsis with positive hemoculture was lower (3.5%). It is reported that at least 25% of clinically diagnosed septic episodes are culture-negative [14]. This may be due to many factors such as concurrent use of antibiotics and suboptimal sample volumes [6]. Our findings did not include overall nosocomial infections. Most cases of BSIs in the NICU are associated with indwelling central vascular catheters [4,6,10,13]. In some studies, nosocomial infection was observed 2-3 fold more frequently when catheterization was used [7,10,15]. In our NICU, catheterization is usually not used except in very low birth weight infants, and this may be a reason for the low incidence observed in sepsis. The median onset of infection from day of admission was 23 days, which is comparable with other studies [16,17]. It is well known that in addition to gestation age, prolonged hospital stay with a number of therapeutic interventions is associated with nosocomial infection.

In developed countries GPB is the most common cause of nosocomial sepsis in the NICU [18]. However, nosocomial sepsis caused by GNB is more frequent in developing countries [4,6]. Some authors have reported that K. pneumoniae account for most infections in developing countries [4,6]. In technologically advanced NICUs, following the adoption of tertiary neonatal care with a high rate of invasive device use, CNS stands out as the main agent of neonatal nosocomial sepsis [7,18]. In national studies, some authors [9-11,15] have reported that the most commonly isolated pathogen from blood cultures of neonates diagnosed with nosocomial sepsis was CNS, followed by K. pneumoniae, whereas others [19,20] have reported K. pneumoniae as the most common pathogen. In our study, K.pneumoniae and A. Baumannii were responsible for 40.5% and 29.7% of nosocomial sepsis, respectively. The high rate of A. Baumannii was due to an outbreak that occurred during the study period. It is a ubiquitous microorganism implicated in a number of outbreaks in NICUs [21,22].

Gram negative bacteria have a high degree of resistance to commonly used antibiotics [22-24]. This is not just a problem for developing countries [21,22], but also is a growing threat in developed countries [24]. Couto et al. [4] reported a high resistance of K. pneumoniae to third-generation cephalosporins (64.1%), whereas Bolat et al. [10] reported lower rates (18.7%-37.5%) from Turkey. Shehab El-Din et al. [23] reported that GNB including K. pneumoniae, Serratia marcescens, and A. baumannii have a higher resistance to third-generation cephalosporins (>85%), amikacin (68.5%), imipenem (29.6%) and ciprofloxacin (38.9%). In a study conducted by Mutlu et al. [11] from Turkey, it was reported that GNB were highly resistant to third-generation cephalosporins (31.5%-37.8%) but had low resistance to amikacin (5.2%) and meropenem (2.9%). In our study, 20% of K. Pneumoniae isolates was MDR. The majority of Acinetobacter isolates were resistant to all antimicrobial agents (>90%) except for colistin (2.7%). Tsai et al. [12] reported that bacteremia caused by MDR GNB accounted for nearly one-fifth of all episodes of GNB bacteremia.

Like distribution of etiological pathogens, their antimicrobial susceptibilities were also different from other studies reported in our country. These differences may be related to heavily contaminated environmental sources, high rates of cross-transmission [2], overcrowding, understaffing, inappropriate or insufficient clinical practices (e.g. absence of permanent intensive care physicians like neonatologists), or the later adoption of appropriate and sophisticated tertiary neonatal care practices [7] in our region, which is the least developed region of Turkey [25]. However, the SAM rate in the present study (17.6%) is in accordance with the national average [8,9,11].

According to the findings outlined above, the empirical antibiotic treatment administered may not always be effective for all microorganisms. Therefore, blood cultures and their results should be obtained at an early time and appropriate antibiotics applied. Because outbreaks are often caused by MDR organisms, complete identification and susceptibilities need to be available as soon as possible. It should be noted that additional infection control measures and antimicrobial stewardship programs providing instructions urgently need to be developed for our NICU.

There are some limitations of our study. Although our data came from one of the largest NICU centers in the region, the small study size was unable to detect a difference in outcomes and potential risk factors. Molecular epidemiologic analysis of MDR microorganism types could not be performed due to facilities limitations. Given the retrospective nature of this study, data collection may not have included some needed variables, and consequently this may have led to the difficulty in evaluating temporal relationships between events. Finally, the fact that the data was from a single NICU center limits its representativeness for other geographical areas or institutions.

In conclusion, GNB, especially K. Pneumoniae, were the leading causative agents of nosocomial sepsis in our NICU, and they were resistant to commonly used antibiotics. In view of our findings, it seems mandatory to begin empirical broad-spectrum antibiotics in a neonate suspected with nosocomial sepsis. In response to blood culture results obtained as soon as possible, appropriate and adequate antibiotics should be applied. In the meantime, the strict application of infection control measures, antibiotic stewardship, decreased antibiotic overconsumption, and avoidance of antibiotic under-dosing are valuable in decreasing the resistance rates of MDR GNB.

Funding: The authors have no support or funding to report.

Competing interests

The authors declare that they have no competing interests.

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Mehmet Sah Ipek, Erdal Ozbek. Bloodstream Infections in a Neonatal Intensive Care Unit. J Clin Anal Med. 2016;7(5):625-629

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Discordance Rates Between AMH and FSH in Different Age Groups

Selçuk Selçuk 1, Mehmet Küçükbaş 1, Belgin Devranoglu 1, Melda Kuyucu 1, Seracettin Günaydın 2, Enis Özkaya 3, Hüseyin Tayfun Kutlu 1

1 Department of Obstetrics and Gynecology, Zeynep Kamil Training and Research Hospital, 2 Biochemistry, Istanbul Anatolian Western Public Hospitals, 3 Department of Obstetrics and Gynecology, Zeynep Kamil Training and Research Hospital, Istanbul, Turkey

DOI: 10.4328/JCAM.4324 Received: 20.01.2016 Accepted: 10.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 621-4

Corresponding Author: Selcuk Selcuk, Zeynep Kamil Hastanesi, Üsküdar, İstanbul, Türkiye. GSM: +905321630488 E-Mail: md_sel@hotmail.com

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Aim: To evaluate the discordance rates between anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH) levels according to different age groups in a cohort of Turkish women. Material and Method: This retro-spective study was conducted at infertility clinics of Zeynep Kamil Training and Research Hospital. Patients were divided into 4 groups as ≤ 30 years, 31-35 years, 36-39 years, and ≥ 40 years to evaluate the discordance between AMH and FSH in terms of age. Discordance rates, and median level of AMH and of FSH were determined for each age group. Results: 467 patients who met the inclusion criteria were enrolled in the study. 35.1% (n=164), 28.3% (n=132), 22.7%(n=106), and 13.9% (n=65) of patients were ≤ 30 years, 31-35 years, 36-39 years, and ≥ 40 years, respectively. The discordance rates in terms of normal AMH but abnormal FSH level were 4.2%, 6.7%, 11.0%, 17.9% in the ≤ 30, 31-35, 36-39, ≥40 years age groups, respectively, whereas the discordance rates in terms of normal FSH but abnormal AMH levels were 6.2%, 8.5%, 16.7%, 17.9% in the same age groups, respectively. Discussion: Discordance rates steadily increased with advancing age both for concerning AMH-reassuring FSH and concerning FSH-reassuring AMH. Data from our study and the literature lead us to conclude that age-based AMH and FSH levels and also that discordance between these parameters may vary among different ethnic groups.

Keywords: Anti-Müllerian Hormone; Follicle Stimulating Hormone; Discordance; Age

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Introduction

Ovarian reserve tests have a significant role in predicting ovarian response to gonadotropin stimulation and to the outcome of assisted reproduction treatment (ART). Follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) are the most commonly used ovarian reserve tests [1-3].

Early antral follicles secrete inhibin B and estradiol by stimulation of FSH. Inhibin B and estradiol result in FSH suppression through the feedback mechanism of the pituitary-gonadal axis. Levels of inhibin B and estradiol decrease after diminishing the ovarian follicle reserve and these changes cause the FSH levels to increase [4]. AMH is a member of the transforming growth factor-b (TGF-b) superfamily of growth and differentiation factors. It is produced by granulosa cells of preantral and small antral follicles [5]. AMH and FSH levels reflect the ovarian reserve at different stages of the follicular process; the antral and postantral follicular developments are reflected by FSH whereas postprimordial preantral and early antral follicular developments are reflected by AMH [6,7].

Recently, conflicting results were reported in different studies evaluating the association between AMH and FSH. Some studies demonstrated consistency between AMH and FSH while others found significant discordance between these two ovarian reserve tests [6-10]. The discordance can complicate the prediction of ovarian response to gonadotropin stimulation and ART outcomes.

On the other hand, the different studies emphasize that the characteristics of the female reproductive system have significant variability depending on ethnicity. The variabilities of ovarian reserve tests (AMH, FSH) regarding ethnicity were demonstrated and the normograms of ovarian reserve tests were evaluated based on ethnicity [11,12]. Based on this evidence, we can conclude that the relationship between AMH and FSH might be affected by ethnicity.

Therefore, we aim to evaluate the relationship between AMH and FSH levels in a cohort of Turkish women.

Material and Method

This retrospective study was conducted at infertility clinics of our hospital. The study protocol was approved by the Local Research and Ethics Committee of our hospital. Data on patient age, basal serum estradiol, FSH, and AMH levels were collected from a hospital database. Patient diagnoses were obtained from their medical records according to International Classification of Disease (ICD) codes. Exclusion criteria were: > 45 and < 18 years of age, presence of endocrinologic abnormality, and menstrual irregularity. The cut-off value for estradiol level was accepted as 75 pg/ml to verify that the serum was taken in early follicular phase, thus decreasing the possibility of FSH suppression that could cause a mistake in the assessment of discordance rate. AMH level ≥ 0.8 ng/mL was accepted as normal according to the AMH assay manufacturer’s instructions. The cut-off value for FSH level was accepted as 10 IU/L and basal FSH level > 10 IU/L was defined as abnormal.

The serum FSH was measured on the Architect 16000, with flexible assay protocol, competitive chemiluminescent immunometric enzyme immunoassay system. The FSH intra-assay coefficient of variation was approximately < 5%, and the inter-assay coefficient of variation was approximately 4%. AMH enzyme immunoassay (Beckman-Coulter) was used for the measurement of serum AMH levels (ng/mL). The intra-assay coefficient of variation was <10%.

Statistical analyses

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 11.5 software. Pearson’s correlation analysis was used for the assessment of the correlation between parametric variables (age, AMH, FSH). Data were given as median (minimum-maximum) or percentage. A p-value ≤ 0.05 was considered statistically significant.

Result

In the present study, there were serum FSH and AMH results of 623 patients. The estradiol level of 123 patients was higher than 75 pg/ml and these patients were excluded because it was accepted that the serum was taken in the early follicular phase. 467 patients who met the inclusion criteria were enrolled in the study. Patients were divided into 4 groups as ≤ 30 years, 31-35 years, 36-39 years, and ≥ 40 years to evaluate the discordance between AMH and FSH in terms of age. 35.1% (n=164), 28.3% (n=132), 22.7%(n=106) and 13.9% (n=65) of patients were ≤ 30 years, 31-35 years, 36-39 years, and ≥ 40 years, respectively. The median values of the basal FSH and AMH levels of the age groups are given in Table 1.

The rate of abnormal FSH level among patients with normal AMH level was 7.5% while the rate of abnormal AMH level among patients with normal FSH level was 10.1%. There was a steady increase in discordance with advancing age both for concerning AMH-reassuring FSH and concerning FSH-reassuring AMH (Figs. 1 and 2). The discordance rates in terms of normal AMH but abnormal FSH level were 4.2 %, 6.7 %, 11.0 %, and 17.9 % in the ≤ 30, 31-35, 36-39, ≥40 years age groups, respectively, whereas the discordance rates in terms of normal FSH but abnormal AMH levels were 6.2%, 8.5%, 16.7%, and 17.9% in the same age groups, respectively.

The correlation between AMH, FSH levels and age was evaluated separately (Table 2). There was a significant correlation between AMH level and age (r= -0.359, p< 0.001); AMH level decreased with aging. There was a significant correlation (r= 0.195, p<0.001) between age and FSH level; FSH level increased with aging.

Discussion

Our data showed that concordance and discordance between FSH and AMH varied between different age groups and that there was steady increase in discordance with advancing age both for concerning AMH-reassuring FSH and concerning FSH-reassuring AMH. Other studies have reported conflicting results about the consistency between AMH and FSH [6-10]. In addition, there is no adequate evidence in terms of discordance between these ovarian reserve tests and the implication of ethnicity on this discordance.

The relationship between AMH and FSH was assessed in a large study population by Leader et al. [9], where it was found that 6% of patients with reassuring AMH levels had abnormal FSH levels whereas 20% of patients with reassuring FSH levels had abnormal AMH levels. When analyzing discordance rate (FSH-reassuring but AMH concerning) according to age group, it was found to be 9.1% among patients < 35 years and 33.3% among patients aged ≥ 40 years. The discordance rates showed steady increase with aging. However, while the concerning FSH but reassuring AMH values were found to be consistent in approximately 5.6% of women, there was no statistically significant difference in rates of discordance among age groups. In conclusion, the authors stated that discordance between AMH and FSH levels was common and age dependent.

In the present study, it was found that 7.5% of patients with normal AMH levels had abnormal FSH levels while 10.1% of patients with normal FSH levels had abnormal AMH levels in whole study population. In addition, when analyzing based on age groups in our study population, discordance rates were 4.2%, 6.7%, 11.0%, and 17.9% in the ≤30, 31-35, 36-40, ≥40 years age groups, respectively, in terms of normal AMH but abnormal FSH level. In the same age groups, rates of normal FSH but abnormal AMH levels were 6.2%, 8.5%, 16.7%, and 17.9%, respectively.

The rate of discordance in patients with normal FSH but abnormal AMH levels was lower in our whole study population than in the outcomes of Leader et al. [9]. The discordance rate increased with aging in patients with reassuring AMH but concerning FSH level; this rate of increase was different than in the outcomes of Leader et al. This difference might be caused by several factors including different study populations with different genetic and environmental backgrounds, which could lead to a different ovarian biological age compared to chronological age [11,12]. That ethnicity could have a significant effect on ovarian reserve tests and ART outcomes is argued in the literature [11,13-17]. Basal FSH levels in African-American women were found to be higher than in age-matched white women [18-20]; moreover, AMH levels were found to be higher in white women compared to African-American and Hispanic women [21]. These studies support the independent effect of ethnicity on variation of basal hormone levels regarding ovarian reserve.

These differences between discordance rates and their characteristics in our study population compared to those in other studies might be associated with the characteristics of the age-specific AMH normogram of the Turkish population. Age-related distribution of basal AMH level in the Turkish population was evaluated in a study by Ozcan et al [22], and the median AMH levels were 2.16 ng/ml, 2.15 ng/ml, 1.71 ng/ml, 0.8 ng/ml, and 0.47 ng/ml in the 20-24, 25-29, 30-34, 35-39, and ≥40 years age groups, respectively. In addition, the decline in AMH concentration started at the age of 30 and became more significant by age 35. An interesting finding of that study was that approximately 40% of women with AMH ≤1 ng/ml were ≤35 years in the Turkish population. In our study the median AMH levels were 2.75 ng/ml, 1.39 ng/ml, 0.83 ng/ml, and 0.18 ng/ml for the ≤ 30, 31-35, 36-39, and ≥ 40 years age groups, respectively. The median AMH levels of our study population according to age groups were similar to the results of the study by Ozcan et al [22].

Almog B et al.[23] evaluated age-related normograms of serum anti-Müllerian hormone levels in a population of infertile women from Europe and North America and the median AMH levels according to age groups. AMH levels were 2.1 ng/ml, 1.6 ng/ml, and 1.1 ng/ml in the 24-33, 34-38, and > 39 years age groups, respectively. The median AMH levels according to age groups in European and North American populations are different from the median AMH levels of the Turkish population. Although the decrease of the AMH levels in European and North American populations seems to appear in a smoother pattern, in Turkish population this decrease occurs more rapidly with age.

One possible explanation of the frequent discordance between AMH and FSH might be related to the time difference between AMH decline and FSH increase; the AMH decline occurred at younger ages than the FSH increase [9]. In our study, we found that the AMH decline occurred earlier in a cohort of patients from the Turkish population when compared to characteristics of AMH decline in other populations. The differences in features of AMH decline among different populations may affect the discordance rates between AMH and FSH according to age groups.

Conclusion

Data from our study and the literature lead us to conclude that age-based AMH and FSH levels and also discordance between these parameters may vary among different ethnic groups. Due to these variations, in order to optimize the effectiveness of using discordance to predict ART outcome, population-specific cut-off values should be introduced and discordance should be evaluated according to the age group. A well-designed study is needed to reveal the clinical importance for ART outcomes of discordance between AMH and FSH levels.

Competing interests

The authors declare that they have no competing interests.

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Selcuk Selcuk, Mehmet Kucukbas, Belgin Devranoglu, Melda Kuyucu, Seracettin Gunaydin, Enis Ozkaya, Hüseyin Tayfun Kutlu. Discordance Rates Between AMH and FSH in Different Age Groups. J Clin Anal Med. 2016;7(5):621-624

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Thorax Computed Tomography Findings in Non-Traumatic Cases Hospitalized in the Intensive Care Unit

Mustafa Resorlu, Nilufer Aylanc, Gürhan Adam, Nebil Eker

Department of Radiology, Canakkale Onsekiz Mart University, Faculty of Medicine, Canakkale, Turkey

DOI: 10.4328/JCAM.4335 Received: 23.01.2016 Accepted: 10.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 618-20

Corresponding Author: Mustafa Resorlu, Canakkale Onsekiz Mart Universty, Terzioglu Yerleskesi, Barbaros Mh, 17100, Canakkale, Turkey. GSM: +905054548721 F.: +90 2862180393 E-Mail: mustafaresorlu77@gmail.com

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Aim: To assess thoracic CT findings in non-traumatic patients with respira-tory distress hospitalized in the intensive care unit. Material and Method: Forty-three patients treated in the intensive care unit in our hospital in 2015-2016 were included in the study. Thorax CT images obtained from the radi-ology archive were assessed by two radiology specialists. Patients’ clinical findings and laboratory results were documented from the patients’ records. Results: Nine patients (20.9%) were female and 34 (79.1%) were male. Mean age was 71.1± 15.4 (21-89) years. The most common findings in the medi-astinum were vascular atherosclerosis, lymphadenomegaly, and pericardial effusion, while the most common parenchymal findings were parenchymal fibrotic changes, pulmonary nodule, and emphysematous aeration. The prev-alence of pleural effusion was 53.5%. Discussion: The presence of underlying neurological and cardiovascular diseases in particular and general condition impairment in patients hospitalized in the intensive care unit represents a risk for the development of respiratory system pathologies.

Keywords: Intensive Care Unit; Respiratory Distress; Computed Tomography

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Introduction

Intensive care units are departments for critical patients with impaired vital functions who require continuous monitoring. It is important for personnel in these units to be specially trained, and a rapid and correct approach to changes occurring in the patients’ clinical pictures is required [1].

In addition to their primary pathologies, patients hospitalized in the intensive care unit frequently encounter respiratory tract problems including aspiration (associated with their being unconscious and receiving ventilator support), pneumonia, pulmonary edema, and atelectasis [2]. Unconsciousness and multi-organ failure in these patients mean that the data obtained from physical examination are limited, and imaging is important in diagnosis and monitoring [3].

Portable chest radiography is the main imaging technique used because it can be performed at the bedside and is simple to administer. Digital radiography has become more widely used because of the increase in image quality and lower dose adjustment, but it still has various disadvantages [4]. The main disadvantages are the limited ability to assess mediastinal structures, lack of patient cooperation, inadequacy of single-plane images, and the fact that the pleural effusion and pulmonary edema frequently seen in these patients restrict evaluation of the parenchyma [2,5]. With advantages such as high resolution, multiplanar imaging, absence of superposition, and the ability to assess mediastinal structures, computed tomography (CT) counters the defects of pulmonary radiography. The ability to differentiate consolidation, mass, and atelectasis with the administration of contrast material and to show pulmonary embolism increases the importance of tomography in thoracic evaluation in intensive care patients [6]. In this study, we assessed imaging findings of patients hospitalized in the intensive care unit for reasons other than trauma, who were undergoing CT due to respiratory difficulty.

Material and Method

Forty-three patients hospitalized in the intensive care unit for reasons other than trauma at the Canakkale Onsekiz Mart University Hospital in 2015-2016 and undergoing CT due to respiratory distress were included in the study. Age, sex, history of chronic disease, and laboratory findings were documented from patients’ records. Patients admitted to intensive care due to trauma or aged under 18 were excluded. Thorax CT imaging obtained in a routine protocol from the radiology archieve in our hospital was evaluated. (Toshiba, Asteion TSX-021B, 4 detector tomography device, 120 kV,150 mAs, 5 mm section thickness). All cases were assessed by two specialist radiologists. Statistical analysis was performed using SPSS 19.0 for Windows software. Student’s t test was used to analyze qualitative data and the chi square test was used for quantitative data.

Results

Nine (20.9%) of the 43 patients in the study were female and 34 (79.1%) were male. Mean age was 71.1± 15.4 (21-89) years. The most common primary health problems prior to hospitalization in the intensive care unit were cardiovascular diseases, stroke, and chronic obstructive pulmonary disease (COPD). Primary diseases before admission to primary care are given in Table 1.

Upon evaluation of mediastinal structures, atherosclerosis was determined in 30 (69.8%) patients, lymphadenomegaly in 9 (20.1%), pericardial effusion in 8 (18.6%), and pulmonary artery dilatation in 4 (9.3%) patients. Accompanying pleural effusion was determined in seven of the eight patients with pericardial effusion. Intense bilateral pleural calcification associated with exposure to asbestos was determined in two of the 15 cases (34.9%) with thickening in the pleura or extrapleural fat tissue and mesothelioma in one case (Figure 1). Pleural effusion was determined in 23 patients (53.5%), bilateral in form in 14.

The most common findings upon evaluation of pulmonary parenchyma were atelectasis, parenchymal fibrosis, and pulmonary nodule (46.5%, 39.5%, and 37.2%, respectively). Thickening in the interstitium was determined in 7 cases (16.3%) and bronchiectasis in 6 patients (14%). The findings most commonly accompanied by emphysematous aeration were parenchymal nodule and fibrotic parenchymal changes (68.75 % and 62.5%, respectively, Figure 2). Metastatic nodules were determined in three cases and dilation in the pulmonary arteries in four patients. Distribution of lesions in the parenchyma and mediastinum is shown in Table 2.

Discussion

Intensive care units are departments for critical patients with impaired vital functions and frequently multi-organ injury or failure. The primary pathology in these patients may be accompanied by respiratory system problems such as pulmonary edema and thromboembolic disease and particularly pneumonia [7]. Since these patients’ general condition is poor, bronchoscopy and portable radiography are used to attempt to identify respiratory system problems at the bedside. If diagnosis cannot be established, other imaging techniques, and particularly CT, are used [8].

We used CT in this study. The most common radiological finding was atherosclerotic changes in the aorta and coronary vascular structures. This was largely due to the advanced age of our study population, and the association between atherosclerosis and primary pathologies such as ischemic heart disease, COPD, and cerebrovascular disease [9]. Another common finding, observed in 53.5% of our patients, was pleural effusion. Atelectasis, paralytic drug use, fluid loading for hemodynamic support, and pneumonia developing in patients due to mechanic ventilators are predisposing factors for pleural effusion [10]. Mattison et al. reported a prevalence of pleural effusion of 62%, and determined that heart failure, atelectasis, and infections are the most common causes [11]. The prevalence of pleural effusion in our study was 53.5%, and the level of atelectasis in these patients reached 63.4%.

Atelectasis, which develops in association with obstruction caused by secretions, is common in intensive care patients, particularly in the obese, smokers, and elderly patients. It is the main cause of opacity seen at pulmonary radiography in these patients [6, 12]. It generally takes the form of subsegmental atelectasis and is localized in the lower left lobe (66%), lower right lobe (22%), and right upper lobe (11%) [13]. The incidence of atelectasis in this study was 51.2%, and of subsegmental atelectasis 34.9%. All cases of compression atelectasis developed secondary to pleural effusion.

The most common causes of hospital-acquired pneumonias are gram (-) bacilli or gram (+) cocci. Radiologically, they appear as interstitial, alveolar, or mixed pattern infiltrations. A peripheral alveolar lobar pattern frequently indicates Streptococcus pneumoniae or Klebsiella pneumoniae infections [14,15]. The pneumonic consolidation rate in this study was 34.9% (n=15). This high rate was effected by pneumonia being the primary disease in five cases, and by aspiration occurring in two cases. Other common findings included emphysematous changes, pulmonary nodule, and parenchymal fibrotic changes. All three conditions were mainly observed in patients with a history of COPD and cardiovascular disease. Acute respiratory distress syndrome is a potentially fatal condition following severe diseases such as sepsis, shock, trauma, aspiration, or intoxication. Radiological findings are nonspecific and may be confused with pulmonary edema and hemorrhage, in particular [16]. In the early period, non-dependent regions appear normal or close to normal, while ground-glass opacities and consolidation are seen in dependent regions. In the late period, subpleural bullae and cysts may develop [8,16]. In our study group, ARDS developed in two patients under monitoring due to sepsis and heart failure; CT findings in both cases were characterized by diffuse ground-glass densities.

In conclusion, respiratory system problems are commonly encountered in association with primary diseases or by an impaired general condition in patients hospitalized in intensive care units. CT is the main imaging technique in differential diagnosis and treatment planning when radiography is inadequate.

Competing interests

The authors declare that they have no competing interests.

References

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4. Krivopal M, Shlobin OA, Schwartzstein RM. Utility of daily routine portable chest radiographs in mechanically ventilated patients in the medical ICU. Chest 2003;123:1607–14.

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16. Zhao JN, Liu Y, Li HC. Aspiration-related acute respiratory distress syndrome in acute stroke patient. PloS One 2015;19:10(3):e0118682.

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Mustafa Resorlu, Nilufer Aylanc, Gurhan Adam, Nebil Eker. Thorax Computed Tomography Findings in Non-Traumatic Cases Hospitalized in the Intensive Care Unit. J Clin Anal Med. 2016;7(5):618-620

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Early Childhood Caries with the Perspective of Pediatrician

Ibrahim Hakan Bucak 1, Metin Çalışır 2, Habip Almis 3, Agah Bahadır Ozturk 4, Mehmet Turgut 5

1 Department of Pediatrics, 2 Department of Periodontology, 3 Department of Pediatrics, 4 Department of Family Medicine, 5 Department of Pediatrics, Adıyaman University School of Medicine, Adıyaman, Türkiye

DOI: 10.4328/JCAM.3810 Received: 04.08.2015 Accepted: 31.08.2015 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 614-7

Corresponding Author: İbrahim Hakan Bucak, Department of Pediatrics, Adıyaman University School of Medicine, Adıyaman, Türkiye. T.: +90 4162161015 GSM: +905072372752 F.: +90 4162250838 E-Mail: ihbucak@hotmail.com

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Aim: Early childhood caries are characterized by the presence of at least one or more decayed, missing or filled teeth surfaces in any primary tooth of a child 24-72 months of age. The prevalance of early childhood caries is variable among the world because of wide range of contributing aetiological factors. Aim of this study to determine the prevalance and aetiologic fac-tors of early childhood caries, in South East Anatolia Region of Turkey and evaluated as a pediatrician view. Material and Method: Patients admitted to pediatric polyclinics for any reason, aging between 24 to 72 months, were enrolled in this study. The children who had dental caries and who had not were examined by a dentist. Families were requested to voluntarily answer questions asked by our staff who follow a questionnaire. This questionnaire contains breastfeeding, usage of vitamin D, multivitamin formulations, iron supplements, baby bottle and pacifier, as well as consumpion of yogurt, acidic drinks, in addition to health habits of brushing teeth, check up by the dentist, cigarette usage of parents (mother, father or both). Results: 553 patients were included the study. Early childhood caries was determined to be 33,1 %. As a result of this study, we found that pacifier usage, multivi-amin supplements and acidic drinks were significantly contributing to early childhood caries. Discussion: We advise refrainment from pacifier usage and unnecesary consumption of multivitamin supplemantation, acidic drinks or at least brushing of teeth rightafter consumption of these foods in childhood.

Keywords: Early Childhood Caries; Multivitamin; Pacifier

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Introduction

Early childhood caries (ECC; formerly termed “nursing bottle caries”, “baby bottle tooth decay”); is the presence of one or more decayed (noncavitated or cavitated lesions), missing (due to caries), or filled tooth surfaces in any primary tooth in a child under the age of six [1]. ECC is a serious public health problem that affects infants and toddlers worldwide [2]. The contribution of dental caries to the burden of oral diseases is about ten times higher than that of periodontal disease, the other common oral condition [3,4]. Many conditions (otitis media, respiratory tract infections, difficulty in eating, iron deficiency, difficulty sleeping, chronic pain) have been found to be associated with ECC [5]. The prevalance of ECC is variable among many regions of the World because of the wide range of different aetiologic factors like biological (human dental flora e.g.), behavioral (brushing teeth, dietery habits e.g.) and environmental (water fluorid level e.g) causes [6,7]. In this study we aimed to determine the incidence and aetiologic factors of ECC in the city center of Adıyaman and evaluated as a pediatrician view.

Material and Method

The study was conducted in pediatri outpatient clinic of the Adıyaman University School of Medicine, dates between 01 August 2013 to 30 October 2013. Patients admitted to our outpatient clinic for any reason, aging between 24 to 72 months, were enrolled in this study. Patients who had previous chronic disease or any drug usage were excluded. We prepared a questionnaire, and asked questions face-to-face to the parents about breastfeeding, usage of vitamin D, multivitamin formulations, iron supplements, baby bottle and pacifier, as well as consumpion of yogurt, acidic drinks, in addition to health habits of brushing teeth, check up by the dentist, cigarette usage of parents (mother, father or both). Dental examination was made by a dentist. Height and weight were measured with comercial scale of model DR-MOD-85 (Baskul, Istanbul, Turkey). The patients were divided into two groups: Children with ECC is group 1(G1) and children without ECC is group 2 (G2). Findings were analyzed using the SPSS 15.0© pockets programme.

For this study ethics committee approval was taken from Adiyaman University Ethics Committee (Approval no: 2013/09-1.5). Written permission was taken before filling the questionare.

Results

Five hundred fifty three (553) patients agreed to participate in the study. Number of patients in G1 and G2 were 183 and 370, respectively (Table 1). The prevalence of dental caries in patients who participated in the study was 33.1% (183/553). In terms of gender, there was no statistically significant difference between groups (p=0.618). Considering the age distribution of cases; with increasing age, the frequency of dental caries was found to increase (Figure 1). In paralel, groups were found to differ significantly in terms of weight and height since elder the children taller and heavier than their aftercomers.

Breast milk (BM) intake and duration of breastfeeding before weaning were not different between the groups. No differences were found about vitamin D usage, iron supplement, baby bottle usage and yogurt eating habits between the groups, as well. However early childhood caries (ECC) were significantly higher in multivitamin supplement users than non-users (p<0.014). Pacifier usage was also a factor for increased ECC (p=0.022). In addition consumption of acidic drinks (p=0.002) was significantly different between the groups. Posession of any smoking parents was not a factor of difference between groups (p=0.067). All results were explained in Table 1.

 Discussion

ECC is a condition characterized by the presence of at least one or more decayed (cavitated or non-cavitated), missing filled teeth (due to caries) or filled tooth surfaces in any primary tooth in a child up to 72 months of age [1,2,4]. Epidemiological studies indicate that prevalence of ECC is quite high in pre-school (2-5 years) children and this tended to increase with age [4,8,9]. Prevalences of ECC were found to be 27-44 % in India, 32-36 % in Brazil, 40 % in Malaysia and 48-94 % in Mexico [2,10-15]. In Turkey, the prevalences were reported to be between 17.3-69.8 % [3,4,16,17]. In our study, which was carried in Adiyaman province, the prevalence was found to be 33,1 % of which was within the above range.

Despite the common sense that dental caries arise from low social status, our study found no diffecence in terms of ECC among low or higher income groups [2]. In addition, while designing the study, we expected that longer breastfeeding would protect dental caries. However there was no statistically significant difference between the groups with respect to whether breast feeding occurred or not (p=0.654) nor its duration (p=0.234).

Another point is, we believe that “baby bottle tooth decay” phrase should be re-questioned among medical communities. We found that baby bottle use did not increase ECC incidence (p=0.56). In addition to our group, Nobile et al. [18] also reported that baby bottle use did not increase ECC prevalance. American Academy of Pediatric Dentistry (AAPD) recommends that baby bottle should be used at an early age from-first twelve month’s of age and then children between 12-18 months should be made accustomed to using cup and finally children older than 18 months should only use cup [1].

We found strong relationship between pacifer usage and ECC (p=0.022). In parallel, World Health Organization (WHO) and United Nations Children Fund (UNICEF) are also recommending against the use of pacifiers since pacifier usage shortens breasfeeding duration and reported to be a factor for malocclusion of teeth [19]. In addition, many studies show strong evidence between pacifier usage and disease posession such as otitis media [20].

Dental erosion is the surface loss of tooth structure due to the action of acids without involvement of microorganisms [21]. It is a significant contributor for dental caries. In addition, acidity (pH) value and sugar percentage of a food ordrink are also important factors for the development of dental caries [22-24]. In our study, consumption of acidic beverages were shown to increase dental caries (p=0.002). AAPD uses a vague term ‘soft drink’ of which -in our point of view- should openly be described and changes as high sugar or acid containing drinks. Therefore, refrainment from acidic beverages’ should carefully be stressed or at least brushing of teeth right-after consumption of these food.

We also questioned the routine use of both vitamin D during first six months of life and prescription of multivitamin formulations after 6 months of age. Usage of vitamin D had no statistically significant effect on ECC (p=0.54). However, multivitamin usage after 6 months of age appeared to be responsible from more dental caries than non-users (p=0.014). Multivitamin usage and tooth decay relation is not a widely questioned phenomena in pediatric literature. We encountered only one study, Schroth et al. [25] stated that paediatric multivitamin usage had no effect on dental caries. It seems paradoxal at first, however, logical explanation might be the sugar content in the commonly used multivitamin formulations might be the main factor dental caries. For this reason, we advise brushing teeth of children after multivitamin usage.

Prevalance and etiology of early childhood dental caries in a city located in South East Anatolia Region of Turkey are important findings standpoints for paving the way for a healthier generation in Turkey and countries alike. We advise refrainment from pacifier usage, unnecessary multivitamin supplemantation, acidic drinks of which were found to be hazardous factors for teeth in our study.

Competing interests

The authors declare that they have no competing interests.

References

1. American Acedemy of Pediatric Dentistry. Policy on Early Childhood Caries (ECC): Classifications, Consequences, and Preventive Strategies 2011;35( 6):50-2.

2. Prakash P, Subramaniam P, Durgesh BH, Konde S. Prevalence of early childhood caries and associated risk factors in preschool children of urban Bangalore, India: A cross-sectional study. Eur J Dent 2012;6(2):141-52.

3. Topaloğlu-Ak A, Eden E, Frencken JE. Managing dental caries in children in Turkey – a discussion paper. BMC Oral Health 2009;9:32.

4. Doğan D, Dülgergil ÇT, Mutluay AT, Yıldırım I, Hamidi MM, Çolak H. Prevalence of caries among preschool-aged children in a central Anatolian population. J Nat Sci Biol Med 2013;4(2):325–9.

5. Schroth RJ, Harrison RL, Moffatt ME. Oral Health of Indigenous Children and the Influence of Early Childhood Caries on Childhood Health and Well-being. Pediatr Clin N Am 2009;56(6):1481–99.

6. Keels MA, Hale KJ, Thomas HF, Davis MJ, Czerepak CS, Weiss PA. American Academy of Pediatrics. Section on Pediatric Dentistry and Oral Health. Preventive Oral Health Intervention for Pediatricians. Pediatrics 2008;122(6):1387–94.

7. Gartner LM, Morton J, Lawrence RA, Naylor AJ, O’Hare D, Schanler RJ et al. American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2005;115(2):496–506.

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9. Warren JJ, Weber-Gasparoni K, Marshall TA, Drake DR, Dehkordi-Vakil F, Dawson DV, et al. Longitudinal study of dental caries risk among very young low SES children. Community Dent Oral Epidemiol 2009;37(2):116–22.

10. Jose B, King NM. Early childhood caries lesions in preschool children in Kerala, India. Pediatr Dent 2003;25(6):594-600.

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12. Vargas-Ferreira F, Zeng J, Thomson WM, Peres MA, Demarco FF. Association between developmental defects of enamel and dental caries in schoolchildren. J Dent 2014;42(5):540-6.

13. Masood M, Yusof N, Hassan MI, Jaafar N. Assessment of dental caries predictors in 6-year-old school children-results from 5-year retrospective cohort study. BMC Public Health 2012;12:989.

14. Zuniga-Manriquez AG, Medina-Solis CE, Lara-Carrillo E, Márquez-Corona Mde L, Robles-Bermeo NL, Scougall-Vilchis RJ, et al. Experience, prevalence and severity of dental caries and its association with nutritional status in Mexican infants 17-47 months. Rev Invest Clin 2013;65(3):228-36.

15. Dhar V, Jain A, Van Dyke TE, Kohil A. Prevalence of dental caries and treatment in children of rural areas in udairpur district. JIPD 2007;25(3):119-21.

16. Ozer S, Sen Tunc E, Bayrak S, Egilmez T. Evaluation of certain risk factors for early childhood caries in Samsun, Turkey. Eur J Paediatr Dent 2011;12(2):103-6.

17. Gökalp SG, Doğan BG, Tekçiçek MT, Berberoğlu A, Unlüer S. National survey of oral health status of children and adults in Turkey. Community Dent Health 2010;27(1):12-7.

18. Nobile CGA, Fortunato L, Bianco A, Pileggi C, Pavia M. Pattern and severity of early childhood caries in Southern Italy: a preschool-based cross-sectional study. BMC Public Health 2014;14:206.

19. Yonezu T, Arano-Kojima T, Kumazawa K, Shintani S. Association between Feeding Methods and Sucking Habits: A Cross-sectional Study of Infants in Their First 18 Months of Life. Bull Tokyo Dent Coll 2013;54(4):215-21.

20. Niemela M, Uhari M, Mottonen M. A pacifier increases the risk of recurrent acute otitis media in children in day care centers. Pediatrics 1995;96(5 Pt 1):884–8.

21. Honório HM, Rios D, Júnior ES, de Oliveira DS, Fior FA, Buzalaf MA. Effect of Acidic Challenge Preceded by Food Consumption on Enamel Erosion. Eur J Dent 2010;4(4):412–17.

22. Sardana V, Balappanavar AY, Patil GB, Kulkarni N, Sagari SG, Gupta KD. Impact of a modified carbonated beverage on human dental plaque and salivary pH: an in vivo study. J Indian Soc Pedod Prev Dent 2012;30(1):7-12.

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24. Moynihan PJ. The role of diet and nutrition in the etiology and prevention of oral diseases. Bull World Health Organ 2005;83(9):694–9.

25. Schroth RJ, Levi JA, Sellers EA, Friel J, Kliewer E, Moffatt ME. Vitamin D status of children with severe early childhood caries: a case-control study. BMC Pediatrics 2013;13:174.

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Ibrahim Hakan Bucak, Metin Calisir, Habip Almis, Agah Bahadir Ozturk, Mehmet Turgut. Early Childhood Caries with the Perspective of Pediatrician. J Clin Anal Med. 2016;7(5):614-617

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The Effects of Synthetic Cannabinoids on Alveolar-Arterial Oxygen Gradient

Egemen Küçük 1, Hikmet Çoban 2

1 Acil Tıp Kliniği, 2 Göğüs Hastalıkları Kliniği, Sakarya Üniversitesi Eğitim ve Araştırma Hastanesi, Adapazarı, Sakarya, Türkiye

DOI: 10.4328/JCAM.3153 Received: 11.12.2014 Accepted: 14.01.2015 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 610-3

Corresponding Author: Egemen Küçük, Clinic of Emergency Medicine, Sakarya University Training and Research Hospital, 54000 Sakarya, Turkey. GSM: +905077868674 F.: +90 2642552105 E-Mail: egemenkucukmd@gmail.com

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Aim: Synthetic cannabinoids are chemicals that produce several marijuana-like effects in humans. Aim of this study is to investigate the effects of syn-thetic cannabinoids on to alveolar-arterial oxygen gradient. Material and Method: A total of 112 patients, who admitted directly to emergency clinic with synthetic cannabinoid usage, were determined between February 2014 and August 2014. Blood gases of 41 patients were determined as arterial blood gases on room air, and included in to study. Patients were evaluated according to age, sex, decade, partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, pH, bicarbonate, metabolic status, age consistent expected alveolar-arterial oxygen gradient and calculated alveo-lar-arterial oxygen gradient. Results: Synthetic cannabinoid using was higher in males, mean age of patients was 23.32±6.14 years. Number of patients in the third decade were significantly higher than the other decades. The calculated alveolar-arterial oxygen gradient value of patients was signifi-cantly higher than age consistent expected alveolar-arterial oxygen gradient value. Respiratory acidosis, was significantly higher than the other types of the metabolic disorders. The best cutoff point for calculated alveolar-arterial oxygen gradient was 12.70, with sensitivity of 90% and specifity of 85%. Area under curve was 0.70 for calculated alveolar-arterial oxygen gradient. Discussion: The value of alveolar-arterial oxygen gradient has been increased due to synthetic cannabinoid usage. This can be used as a supportive param-eter in the diagnosis of synthetic cannabinoid usage.

Keywords: Synthetic Cannabinoids; Blood Gases; Diagnose

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Introduction

Synthetic cannabinoids (SC) are chemicals that produce several marijuana-like effects in humans. Synthetic cannabinoids are usually known as “Spice” in Europe, “K2” in United States of America and “Bonzai or Jamaika” in Turkey. These agents are obtained by spraying several different synthetic cannabinoids onto the vegetable ingredient, and herbal cigarettes mixtures that smoking in a similar way to cannabis by users [1]. Recently, SC usage has been increased, and more common seen in young adults and males [2]. Both animal studies and anecdotal clinical evidence suggest that the SC products may lead to more severe and unusual toxic effects than natural marijuana. The euphoric and psychoactive effects of SC are similar to marijuana, but SC have additional sympathomimetic symptoms, including diaphoresis, agitation, and restlessness [3]. The chemical structures of SC are similar to marijuana but there is no correlation between SC and Δ9-tetrahydrocannabinol in terms of toxicological investigations. Recognition of the signs and symptoms of intoxication and a high index of suspicion are necessary to diagnose SC toxicity [4]. In the literature there are several reports of rhabdomyolysis, kidney failure and acute myocardial infarction after SC usage. There have been a number of reports linking cannabis to pulmonary dysfunction. However, to date there are few reports that shows a link between SC and respiratory dysfunction [5-6].

Arterial blood gas analysis is a common investigation in emergency departments for monitoring patients with acute respiratory failure and considered the gold standard to determine oxygenation, patient’s gas exchange, ventilatory control and acid-base status in the acutely injured as well as critically ill patients. The impaired pulmonary function manifests in the form of decreased partial pressure of arterial oxygen (PaO2), an increased alveolar-arterial oxygen gradient (p(A-a)O2) [7].

The depressive respiratory effect of SC inhalation has not been thoroughly investigated in the medical literature. Aim of this study is to investigate the effects of SC usage on to alveolar-arterial oxygen gradient.

Material and Method

Patients who admitted directly to our emergency clinic for SC using, were determined from forensic records of hospital between February 2014 and August 2014. Due to unknown treatment and application form, patients who referred to our emergency clinic from another hospital were excluded from the study. A total of 112 patients were determined in this time period. Synthetic cannabinoid usage was confirmed by the patient or witnesses. Laboratory and clinical data were obtained from the digital medical records database of the hospital.

In this retrospective study, the effects of SC inhalation on alveolar-arterial oxygen gradient were determined by arterial blood gases of patients that not given oxygen therapy. For this purpose, measurements of arterial blood gases were obtained from the patients that room air, and non-incubated arterial blood gas measurements were evaluated. In 18 patients, blood gas samples were not taken during emergency department evaluation, these patients were excluded from study. Blood gas measurements of remaining 94 patients, were evaluated retrospectively with a chest disease specialist to confirm arterial blood gas samples on room air.

In some studies, relationship between arterial and venous blood gases has been investigated. In these studies, mean PaO2 value has been found between 55-115 mmHg, mean partial pressure of venous oxygen (PvO2) value between 25-48 mmHg, mean partial pressure arterial of carbon dioxide (PaCO2) value between 35-42 mmHg, mean partial pressure of venous carbon dioxide (PvCO2) value between 41-42 mmHg. Partial pressure of oxygen (PO2) is significantly different between arterial and venous blood gases according to partial pressure of carbon dioxide (PCO2). The saturation of oxygen (SO2) value has been found between 87-89 mmHg, in these studies [8-9-10]. According to these results, blood gases of 40 patients that PaO2 value less than 48 mmHg accepted as venous blood gases, and these patients were excluded from study. In 13 patients, value of SO2 was higher than 89 mmHg, these samples were accepted as arterial blood gases with oxygen treatment, and excluded from study. A total of 41 patients’ blood gas samples were determined as arterial blood gases on room air, and included to study. Patients were evaluated according to age, sex, decade, PaO2, PaCO2, pH, bicarbonate (HCO3), metabolic status, calculated p(A-a)O2 and age consistent expected p(A-a)O2. The p(A-a)O2 of patients was calculated according to formula of p(A-a)O2: [150-(1.25xPaCO2)]-PaO2. Age consistent expected p(A-a)O2 of patients was calculated according to formula of p(A-a)O2: 2.5+[0.25xage(years)] [11].

Data were analyzed using the Statistical Package for Social Sciences version 16.0. (SPSS: An IBM Company, version 16.0, IBM Corporation, and Armonk, New York, USA). All data were expressed as the mean ± standard deviation. The Student’s t test was used to compare the means for the studied variables. For comparing the continued two groups, Pearson Chi-square test was used. The P value smaller than 0.05 was considered statistically significant. The cut-off values of parameters for discrimination of the groups were determined using the Receiver Operating Characteristic (ROC) curve analysis. The areas under the ROC curves were calculated and the specificity, sensitivity and accuracy, for the parameters have been determined.

Results

A total of 112 patients were analyzed, 111 patients were male and only 1 patient was female. Synthetic cannabinoid using was significantly higher in males (p < 0,001), and mean age of patients was 23.32 ± 6.14 years (ranged: 15 to 48). Sixty two percent of patients were located between age of 18–24 years. There were 35 patients in the second decade, 60 patients in the third decade,15 patients in the fourth decade and only 2 patients in the fifth decade. Number of patients in third decade were significantly higher than the other decades (p = 0,02).

The mean arterial blood gas values of 41 patients that included in the study were shown in Table 1. The value of PaO2 was reduced according to reference range, but not statistically significant (p > 0.05). The value of PaCO2 was adjacent to upper limit of the reference range, but not statistically significant (p > 0.05). The value of calculated p(A-a)O2 was significantly higher than age consistent expected p(A-a)O2 value (p = 0.02). Respiratory acidosis was significantly higher than the other metabolic disorders (p = 0.02).

Receiver operating characteristic curve for calculated p(A-a)O2 was shown at Figure 1. Best cutoff point for calculated p(A-a)O2 was 12.70, with sensitivity of 90% and specifity of 85%. Area under curve was 0.70 for calculated p(A-a)O2.

Discussion

Synthetic cannabinoids are synthesized to mimic the action of Δ9- tetrahydrocannabinol, that is an active compound in marijuana [12]. Recently, SC usage and toxicity have been increased between young adults and males all across the world. Barratt and colleagues were found, mean age was 27 for SC use in Australia and 77% of users were male [13]. Hoyte and coworkers found, mean age for SC use was 22.5 and 74.3% of users were male [2]. Consistent with the literature, we found SC using was significantly higher in males and mean age of patients was 23.32 years. Most users are young adults, with the desire to experience cannabis-like effects with a substance that cannot be detected on routine drug tests. The relatively low cost is another reason for its popularity in the younger age group [14].

Although there is an extensive literature detailing respiratory effects of conventional cannabis marijuana and non-tobacco additives in cigarettes, pulmonary toxicity in the context of SC abuse is not as well-reported as toxicity in other organs. In some studies researchers indicated that, cannabis using was associated with higher lung volumes and increased large-airways resistance, but there was a little evidence for airflow obstruction or impairment of gas transfer in these studies [15-16]. In a study on conscious monkeys, SC agonists WIN55212-2 decreased tidal and minute volume, whereas respiratory frequency was not changed [17]. Tashkin sad that, Δ9-tetrahydrocannabinol in smoked marijuana initially relaxes airway smooth muscle and causes bronchodilation in both healthy persons and stable asthmatic patients, this bronchodilator effect is relatively short-lived (lasting as long as 60 minutes and six hours) and diminishes with the repeated use of marijuana (tachyphylaxis) [18]. Taylor et al. found a declined lung function in association with the development of chronic obstructive pulmonary disease (COPD) in chronic cannabis smokers [19]. Respiratory depression in rats receiving Δ9-tetrahydrocannabinol was reported in early publications but involvement of specific cannabinoid receptors could not be demonstrated [20]. Schmid and colleagues were showed that, increasing doses of the synthetic cannabinoid agonists WIN55212-2 and CP55940 markedly and dose-dependently lowered mean arterial pressure, heart rate and the plasma noradrenaline concentration in rats. These cardiovascular effects were accompanied by a large decrease in respiratory rate. CP55940, has been caused a decrease in PO2 and pH, whereas an increase in PCO2. The natural cannabinoid agonist, Δ9-tetrahydrocannabinol also decreased mean arterial pressure, heart rate, the plasma noradrenaline concentration and respiratory rate. The first major finding of this study was, cannabinoid agonists – both synthetic and natural – also elicit respiratory depression by acting at CB1 receptors, as shown by a marked decrease in respiratory rate, hypoxia, hypercapnia and arterial blood acidosis. Researchers speculated that cannabinoids could affect the function of different peripheral receptors involved in respiratory regulation. These agents could also influence airway resistance acting directly on the bronchi [21].

Like these studies, we found a higher level of PaCO2 and lower level of PaO2 according to reference range, but not statistically significant. And also, respiratory acidosis was the most common type of metabolic disturbance in our study. These findings may be a result of increased large-airways resistance, a large decrease in respiratory rate due to SC using and respiratory supressor effects of synthetic cannabinoids.

Additionally, we found significantly higher value of calculated p(A-a)O2 according to expected p(A-a)O2. The p(A-a)O2 is a simple way to measure alterations between the alveolus and capillary, and has recently been used in the study of different critical disorders such as COPD and pulmonary thromboembolism. The normal p(A-a)O2 increases with age. An abnormally increased p(A-a)O2 suggests a defect in diffusion, ventilation/perfusion (V/Q) mismatch or right-to-left shunt [22].

The principal contributor to hypoxemia in COPD patients is V/Q mismatch resulting from progressive airflow limitation and emphysematous destruction of the pulmonary capillary bed [23]. The widening p(A-a)O2 was determined in some studies about COPD in the literature [24]. Like to COPD, cannabis usage was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance [15-16]. Additionally, Taylor and Hall were sad that, a small but significant proportion of chronic cannabis smokers will exhibit decline in lung function in association with the development of COPD [19]. Due to similar nature of COPD and cannabis using, a significant higher level of calculated p(A-a)O2 in SC using can be explained by V/Q mismatch due to higher lung volumes, suggesting hyperinflation and intrapulmonary right-to-left microshunting due to lowered mean arterial pressure and heart rate.

Limitations

Synthetic cannabinoid using was not determined by the laboratory measurements in this study. And also we couldn’t get simultaneous biochemical values. These are the most important limitations of this study. Due to retrospective nature of study, we do not know co-morbidities and how long the patients were using these agents. Additionally we do not know, if they use another agents such as cigarette.

Conclusion

Synthetic cannabinoid usage cannot be detected on routine drug tests, and has been increased between young adults and males. The calculated alveolar-arterial oxygen gradient is increased according to age consistent expected alveolar-arterial oxygen gradient in patients with synthetic cannabinoids usage. Increased alveolar-arterial oxygen gradient can be used as a supportive parameter in the diagnosis of synthetic cannabinoid usage.

Competing interests

The authors declare that they have no competing interests.

References

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Egemen Kucuk, Hikmet Coban. The Effects of Synthetic Cannabinoids on Alveolar-Arterial Oxygen Gradient. J Clin Anal Med. 2016;7(5):610-613

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The Proximal Tubal Occlusion in Women with Bilateral Hydrosalpinx Undergoing in Vitro Fertilization

Pınar Ozcan Cenksoy 1, Cem Fıcıcıoglu 1, Ozge Kızılkale 1, Mehmet Suhha Bostancı 2, Murat Bakacak 3, Cigdem Kaspar 4

1 Department of Gynecology and Obstetrics, Faculty of Medicine, Yeditepe University, Istanbul, 2 Department of Gynecology and Obstetrics, Faculty of Medicine, Sakarya University, Sakarya, 3 Department of Gynecology and Obstetrics, Kahramanmaras Sutcu Imam Universiaculty of Medicine, Kahramanmaras, 4 Department of Medical Informatics, Yeditepe University, Istanbul, Turkey

DOI: 10.4328/JCAM.3137 Received: 05.12.2014 Accepted: 05.01.2015 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 606-9

Corresponding Author: Murat Bakacak, Kahramanmaras Sutcu Imam Universitesi, Tıp Fakültesi, Avsar Kampusu, Merkez, Kahramanmaras, Turkey. T.: +90 3442803739 F.: +90 3442803738 E-Mail: muratbakacak46@gmail.com

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Aim: The hydrosalpinx impairs in vitro fertilization (IVF) outcomes by decreas-ing the implantation and pregnancy rates because of the detrimental effects on endometrium. Our retrospective study based on analysis of medical re-cords found that proximal tubal occlusion may have benefits in patients with bilateral hydrosalpinx before IVF treatment. To evaluate the impact of proxi-mal tubal occlusion in women with bilateral hydrosalpinx undergoing IVF as an effective surgical intervention for the management of these women prior to IVF and to present our outcomes. Material and Method: Sixty-one women diagnosed with bilateral hydrosalpinx during routine infertility investigations in our IVF unit between 2007 and 2013 were included in this retrospective study. All bilateral proximal tubal occlusions were performed laparoscopi-cally by bipolar diathermy on the isthmic segment at two separate sites, and drainage of the hydrosalpinx was not performed. The primary outcome was clinical pregnancy rate. Results: The clinical pregnancy rate was 59% in patients who underwent proximal tubal occlusion before IVF. Most of them eventually did conceive in the postoperative first or second cycle after proxi-mal tubal occlusion. Discussion: The laparoscopic proximal tubal occlusion might increase the probability of pregnancy, especially in younger women, and it could be viewed as a reasonable surgical approach due to the above-mentioned advantages.

Keywords: Hydrosalpinx; Proximal Tubal Occlusion; Laparoscopy; In Vitro Fertilization; Pregnancy Rates

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Introduction

The tubal factor, accounting for 25%–35% of female infertility, is one of the most frequent causes of subfertility [1]. Hence, the assessment of the cause of infertility should include hysterosalpingography to check tubal patency [1]. As well as checking tubal patency, it should be kept in mind that the presence of hydrosalpinx impairs in vitro fertilization (IVF) outcomes by decreasing the implantation and pregnancy rates because of the detrimental effect of the accumulation of hydrosalpinx fluid through the uterine cavity on the transferred embryos and endometrial receptivity, mechanical washing of the blastocyst, and deterioration of embryo development as a consequence of the hydrosalpingeal fluid’s deficiencies in nutrients and energy stores [3-7]. Reproductive surgical interventions in patients with hydrosalpinx who underwent IVF cycles, such as salpingectomy, tubal occlusion, and aspiration, have also been reported to dramatically enhance IVF outcome [8].

Reproductive surgery’s role in treating infertile patients with tubal diseases, periadnexal adhesions, or endometriosis has recently been of great importance through dramatic improvements in pregnancy rates of IVF treatment. Reproductive surgery could be classified as a primary treatment for infertility, in-vitro fertilization outcome-enhancing surgery, and surgery for fertility preservation. With the improvement in assisted reproductive technologies (ARTs), the value of reproductive surgery by minimally invasive techniques and the shift from primary treatment for infertility to in-vitro fertilization outcome-enhancing surgery have been questioned. Suggested surgical interventions for hydrosalpinx before IVF treatment include salpingectomy, salpingostomy, aspiration of hydrosalpinx fluid, and proximal tubal occlusion [9].

Reproductive surgery plays an important role in the management of infertility in the era of ART. The responsibility of the reproductive specialist is to understand the role of reproductive surgery and utilize in-vitro fertilization outcome-enhancing surgery appropriately and effectively in properly selected reproductive cases in women with defined hydrosalpinx who plan to undergo IVF treatment. For a considered decision, it is important to have the best available evidence provided by trials that evaluate the beneficial effects of these interventions. The aim of the present study was to evaluate the impact of proximal tubal occlusion in women with bilateral hydrosalpinx undergoing IVF as an effective surgical intervention for the management of these women prior to IVF and to present our outcomes.

Material and Method

Participants:

This retrospective study was based on analysis of the medical records of all patients who underwent laparoscopy to confirm hydrosalpinx and all hydrosalpinges were managed by the same operator (C.F.) due to the presence of bilateral hydrosalpinx defined by hysterosalpingography during routine infertility investigations in our IVF unit between 2007 and 2013. It was conducted at the Department of Obstetrics and Gynecology, Yeditepe University Hospital, Istanbul, Turkey. The study protocol was approved by the Ethical Committee of the Medical Faculty of Yeditepe University. Sixty-one women were included in the study. The subjects included were primary infertile patients programmed for IVF, with absence of any other obvious uterine disorder, with BMI≤25 kg/m2, between 18 and 41 years old, with FSH levels on cycle day 3 of ≤12 mIU/mL, and with no contraindications for laparoscopic surgery. None of the patients had a history of previous ectopic pregnancy, of previous use of an intrauterine contraceptive device, of previous abdominal surgery including appendectomy, of smoking, of medical illness, and of medication use or of additional male-factor infertility.

In our IVF unit, evaluation of the patients, laparoscopic procedures, and embryo transfer are performed by one operator (C.F.), and we routinely recommend a laparoscopic examination to confirm and manage hydrosalpinx in patients with defined hydrosalpinx by hysterosalpingography prior to IVF treatment. Appropriate counseling was given to these patients regarding the risks and benefits of surgery.

Laparoscopic procedure:

All bilateral proximal tubal occlusions were performed laparoscopically by bipolar diathermy on the isthmic segment at two separate sites, and drainage of the hydrosalpinx was not performed. Patients were discharged the day after surgery.

Assisted reproduction procedures:

IVF was undertaken within 2 months of surgery. Controlled ovarian stimulation protocols were used: luteal leuprolide acetate downregulation (long) or antagonist protocol and stimulation with recombinant follicle stimulating hormone (recFSH). Initial doses ranging from 150 to 450 IU daily were based upon age, early-follicular phase serum FSH and E2 levels, and resting antral follicle count, detected by follicular phase ultrasonography. Doses were adjusted on the basis of serial sonographic measurements of follicular development and serum E2. HCG was administered when at least two follicles reached a mean diameter of >17 mm. Transvaginal ultrasound-guided oocyte retrieval was performed 36 hours after hCG administration. Fertilization of the oocytes was performed using the standard ICSI techniques. Embryo transfers were performed on day 3 or 5. Transfers were performed with the Wallace catheter (Smiths Medical International Ltd., Hythe, Kent, UK) using after load transfer under abdominal ultrasonographic guidance. Luteal phase support was provided using Crinone vaginal gel (Crinone 8%, 90 mg; Merck Serono, Central Pharma Ltd, Bedfordshire, UK) daily. Serum quantitative b-hCG levels were obtained 12 days after embryo transfer. A clinical pregnancy was defined as the presence of a fetal sac visualized by transvaginal ultrasound examination. Patients who did not conceive had undergone four consecutive cycles. The patients who did not conceive were defined as Group I and patients who conceived were defined as Group II.

Statistical Analysis:

Analyses were done using the Statistical Package for the Social Sciences, version 20 (SPSS, Chicago, IL, USA). Data were reported as mean±SD or number and percentage. The two-independent samples t-test was used to compare the group means of the continuous variables; P≤.05 was considered significant.

Results

There were no postoperative complications in the 61 patients. Patient characteristics including age, attempt number, duration of infertility, total dosage of gonadotropins, maximum estradiol levels, and total number of oocytes retrieved are summarized in Table 1. The clinical pregnancy rate was 59%. Most of them eventually did conceive in the postoperative first or second cycle after proximal tubal occlusion. The cumulative conception curve is shown in Figure 1. In women who did not conceive (Group I), age, attempt number, duration of infertility, and total dosage of gonadotropins were significantly higher, while maximum estradiol levels and total number of oocytes retrieved were significantly lower compared to women who conceived (Group II)(Table 2). The mean age of patients at surgery was 34.12±4.065 vs. 31.44±3.79 years and the average duration of infertility before surgery was 6.08±4.25 vs. 5.11±2.82 years in groups I and II, respectively. There was no difference in the duration of infertility and stimulation among those patients who conceived and those who did not.

Discussion

Many reports have confirmed that the presence of bilateral hydrosalpinx is associated with pregnancy rates decreased by half and with significantly increased miscarriage rates; and the management of hydrosalpinx by laparoscopic salpingectomy or proximal tubal occlusion prior to IVF improves subsequent pregnancy and live birth rates [10]. Therefore, nowadays, reproductive surgery plays a crucial part in enhancing IVF outcome; and the management of women with defined hydrosalpinx who plan to undergo IVF treatment is of great importance because of the detrimental effect of hydrosalpinx on the outcome of ARTs.

In the Cochrane Database Systematic Review, 2010, a meta-analysis including five randomized controlled trials with 646 women concluded that surgical treatment should be recommended to all women with hydrosalpinx before an IVF attempt; and laparoscopic tubal occlusion is an alternative to laparoscopic salpingectomy in improving IVF pregnancy rates in women with hydrosalpinx [9]. The favorable effect of laparoscopic salpingectomy on pregnancy and implantation rates in patients with hydrosalpinx before IVF cycle was already demonstrated by previous studies [11, 12]. A prospective randomized trial by Kontoravdis et al. also supported the beneficial effect of prophylactic salpingectomy before IVF treatment [13]. Although the benefits of salpingectomy include the removal of chronically infected tissue that tends to lead to abscess formation or torsion and increasing the accessibility of the ovary during oocyte retrieval in IVF and reducing the risk of infection, the procedure has some disadvantages, such as being more invasive, more difficult or risky in patients with extensive pelvic adhesions or previous abdominal surgery, and associated with an increased risk of interstitial pregnancy. Of greater importance is that salpingectomy may cause a theoretical decrease in ovarian blood perfusion, as demonstrated in a rat model [14]. Moreover, a previous study demonstrated that the procedure has significant adverse effects on ovarian hyperstimulation parameters [15].

In view of the above-mentioned reasons, in-vitro fertilization outcome-enhancing surgery should be seriously considered before applying IVF treatment involving significant cost and/or potential risks. In addition, to minimize injury to the ovary, especially in infertile patients, surgery should be performed carefully and newer laparoscopic approaches that might be less invasive, easier, and as effective and safe as salpingectomy adopted. The favorable features of laparoscopic proximal tubal occlusion, such as its being easier to perform, its low morbidity rate, its speed, its minimal invasiveness, and its short hospitalization period, may make it an eligible option with a good probability of achieving an intrauterine pregnancy.

Which surgical interventions to perform depends on the advantages or disadvantages of the techniques: salpingectomy versus proximal tubal occlusion. Many studies have confirmed the beneficial effects of salpingectomy and recommended salpingectomy for all women with hydrosalpinx undergoing IVF, and the majority of clinicians have frequently carried out laparoscopic salpingectomy in clinical practice prior to IVF [16, 17]. Salpingectomy commonly remains the most frequently undertaken procedure. Despite this fact, when compared with salpingectomy, proximal tubal occlusion could be considered an effective alternative in-vitro fertilization outcome-enhancing surgery for women with hydrosalpinx prior to IVF because of some advantages, including being less invasive, safer, with a shorter learning curve and easier to perform in selected patients, and shorter hospitalization [8, 18-20].

In the present study, the clinical pregnancy rate in women who underwent laparoscopic proximal tubal occlusion because of bilateral hydrosalpinx was 59%. Most of them eventually did conceive in the postoperative first or second cycle after the procedure. The results of the present study revealed that proximal tubal occlusion in patients with bilateral hydrosalpinx before IVF treatment may have benefits. However, some limitations of the present study need to be pointed out: (1) the relatively small sample size, (2) being a retrospective study, not being a randomized controlled trial. On the other hand, we selected cases carefully and only included patients with primary infertility and bilateral hydrosalpinx. The main purpose of the current study is to present our outcomes because we think that the results might contribute to the literature. Furthermore, all laparoscopic proximal tubal occlusions were performed by the use of a single surgical technique and by one surgeon. In addition, there are several factors that are known to independently influence pregnancy rates during IVF treatment. Prognostic variables affecting pregnancy outcome such as age and the duration of infertility were also examined in the present study. We noted that women who conceived were younger, they had shorter infertility duration, they had less need for the total dosage of gonadotropins, they had higher maximum estradiol levels, and greater total oocyte numbers were retrieved from them. In the light of our results, the current study has shown that proximal tubal occlusion substantially improved pregnancy rates when we controlled for other patient characteristics noted to affect pregnancy rates.

In coclusion, the management of hydrosalpinx prior to IVF treatment is one of the most frequent in-vitro fertilization outcome-enhancing treatment modalities. There is a wide variation in practice for hydrosalpinx management options. We think that there is need for standardized guidelines for hydrosalpinx management to improve IVF outcomes and we suggest that the importance of diagnosis of hydrosalpinx and the treatment options according to the available evidence and the patient’s suitability should be defined. In line with the results of this study, laparoscopic proximal tubal occlusion might increase the probability of pregnancy, especially in younger women, and it could be viewed as a reasonable surgical approach due to the above-mentioned advantages. We think that the present study will contribute to the drawing up of guidelines for assessment of the value of proximal tubal occlusion as a reasonable surgical intervention to improve IVF outcomes in the management of patients with hydrosalpinx. Further well-designed randomized controlled trials are required to assess the value of proximal tubal occlusion prior to IVF procedures as an alternative.

Acknowledgment

We thank Caroline Walker for English editing

Competing interests

The authors declare that they have no competing interests.

Financial Disclosure

The authors declared that this study has received no financial support.

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Pinar Ozcan Cenksoy, Cem Ficicioglu, Ozge Kizilkale, Mehmet Suhha Bostanci, Murat Bakacak, Cigdem Kaspar. The Proximal Tubal Occlusion in Women with Bilateral Hydrosalpinx Undergoing in Vitro Fertilization. J Clin Anal Med. 2016;7(5):606-609

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Conservative Treatment of Distal Radius Fractures, Importance of Radial Height

Gökhan Keleş 1, Engin Eren Desteli 2, Murat Erdoğan 3, Bülent Köksal 4, Ebru Kelsaka 5, Sabit Numan Kuyubaşı 6

1 Department of Orthopaedics, Bafra State Hospital, Bafra, 2 Department of Orthopaedics, Uskudar State Hospital, Istanbul, 3 Orthopaedics, Ondokuz Mayıs University, Samsun, 4 Department of Orthopaedics, Yuksek Ihtisas Hospital, Kırıkkale, 5 Anaesthesiology, Ondokuz Mayıs University, Samsun, 6 Department of Orthopaedics, Ondokuz Mayıs University, Samsun, Türkiye

DOI: 10.4328/JCAM.2820 Received: 15.09.2014 Accepted: 30.12.2014 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 601-5

Corresponding Author: Engin Eren Desteli, Uskudar Devlet Hastanesi, Ortopedi Bölümü, İstanbul, Türkiye. E-Mail: erendesteli@yahoo.co.uk

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Abstract

Decision of conservative treatment or surgery still remains a debate for some particular types of radius distal fractures. We aimed to evaluate the clinical and radiological results of a patient group treated in our clinic with closed reduction and plaster cast fixation and tried to evaluate the prime fac-tors affecting stability and prognosis of conservative treatment. The study comprised 51 patients (34 males, 17 females; mean age 39.8 ± 11.3 years) treated with closed reduction and plaster cast fixation for radius distal end fracture at our clinic during the period January 2007 to September 2010. Ob-tained clinical results were scored according to the Gartland and Werley clini-cal evaluation system12 and the Disability Arm, Shoulder and Hand Surgery Questionnaire (DASH), for radiological examination; arthritic changes were evaluated according to the Knirk and Jupiter arthritis scoring system and an-gulation evaluation was made according to the Stewart’s radiological evalu-ation criteria. Mean follow-up period time was 17.1 months (range, 6-48 months). According to the Gartland and Werley clinical evaluation system 23 patients had (45.1%) 0-2 points (excellent), 19 (37.3%) had 3-8 points (good) and 9 (17.6%) had 9-20 points (moderate). No poor results were determined. Loss of radial height had a negative effect on functional outcome, radial height is one of the prime factors affecting the prognosis of the treatment. Impairment of the radial inclination, radial shortening or loss of palmar incli-nation were not observed to negatively affect the prognosis.

Keywords: Radius Distal Fractures; Closed Reduction; Radial Height

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Introduction

Radius distal end fractures are the most frequently seen of all bone fractures and comprise 8-15% of all fractures [1]. 75-80% of radius distal end fractures are extra-articular stable fractures and can be treated conservatively in the Emergency Department2 [2]. However, approximately 20% of these fractures are unstable and surgical treatment is required and decision on conservative treatment or surgery still remains a debate for some particular types of fractures [1,2]. In the choice of treatment methods, factors such as the type of fracture, the patient’s age, lifestyle, accompanying health problems, compliancy to treatment, physical and mental capacity must be considered [3,4]. Depending on the physician’s experience and the facilities available, several methods including simple plaster cast or percutaneous nailing, various external and internal fixation and grafting techniques can be used. The basic principles of treatment are to obtain the most appropriate reduction and the fixation of this reduction [5].

This retrospective study aimed to evaluate the functional and radiological results of a patient group treated in our clinic with closed reduction and plaster cast fixation for distal radius fracture and to evaluate the prime factors affecting stability and prognosis of conservative treatment.

Material and Method

Local ethics committee approval from Ondokuz Mayıs University and written informed consent was obtained for the study. This retrospective study comprised 51 patients (34 males, 17 females; mean age 39.8 ± 11.3 years) treated with closed reduction and plaster cast fixation for radius distal end fracture at our clinic during the period January 2007 to September 2010. Patient selection criteria were, i) to have been treated and followed up at our clinic, ii) aged over 18 years, iii) pre and post-treatment radiographs available, iv) to have had a final clinical evaluation after at least 6 months polyclinic follow-up, v) to have been diagnosed with distal radius fracture which was treated with closed reduction and plaster casting. During the reduction maneuvre made to patients presenting with a radius distal end fracture, analgesia was administered to patients who could not tolerate the pain (those with cardiovascular diseases, hypertension or those who stated that they would not be able to tolerate pain). A singular dose of intramuscular Diclofenac Na or Metamizol Na was administered as analgesia and intramuscular Diazepam (10mg) as sedative. With the patient in a supine position and the affected arm in abduction with the elbow at 90° flexion, one assistant applied traction above the elbow (opposite traction) and another person applied traction holding the thumb in one hand and the 4 fingers in the other. After 2-3 minutes of continuous traction, the reduction manoeuvre was made according to the fracture type and estimated mechanism of the fracture.

An above-the-elbow brace which allowed movement of the metacarpophalangeal joint was applied to all patients. At this stage, the standard position for the wrist was not used but care was taken to apply the brace in the position in which reduction was made.

That the reduction was within acceptable measurements was checked by post-reduction radiographs. The patients were called to follow-up one day later to inform them about brace complications and compartment syndrome. For patients where the oedema had reduced, radiographs were repeated within the brace and if the reduction was protected, an above-the-elbow plaster cast was applied and radiographs were repeated after the plaster casting. For patients with continuing oedema, elevation was explained again and they were called for frequent follow-ups until the oedema had recovered and the above-mentioned procedure for a circular plaster cast was applied. After the application of a circular plaster cast, circulation follow-up and elevation were explained and they were called for follow-up 2 days later for circulation monitoring. Patients with good circulation had follow-up radiographs taken after 4 weeks and the plaster cast was removed to below the elbow. They were followed up in this way for 2 weeks. At this stage, elbow exercises were recommended to the patients. At the end of 6 weeks, the plaster cast was removed and radiological and clinical examinations were made. For rehabilitation, isotonic and isometric wrist, finger and elbow exercises were taught to the patients.

At the final follow-up, the patients were questioned about any complaints. The wrist shape, forearm rotation and wrist movements were examined in the clinical examination. Grip strength was measured comparatively with a dynamometer (Jamar, Baseline hydraulic hand dynomometer, Irvington, NY, USA) with the elbow at 90° and the forearm and wrist in a neutral position. In this measurement, the gripping arm is held tight and gripping force is applied at a single time by the patient using maximum strength. The test was applied by making two measurements for each hand alternately. Each force was recorded. There may be 5-10% difference between the dominant and non-dominant hand. The obtained clinical results were scored according to the Gartland and Werley clinical evaluation system12. For the final evaluation the patients were questioned using the Disability Arm, Shoulder and Hand Surgery Questionnaire (DASH), which consists of 30 questions. Of these 30 questions, 21 evaluate daily activities of the patients, 5 are related to symptoms and 1 to sleep. In this system, no complaint or performing the specified activity without any difficulty is scored as 1 and excessive complaints or inability to perform the activity as 5 [6].

At the same time, anterior-posterior and lateral radiographs of the wrist were taken. In the radiological examination, arthritic changes were evaluated according to the Knirk and Jupiter arthritis scoring system [4]. and angulation evaluation was made according to the Stewart et al radiological evaluation criteria [7]. In addition, the patients were evaluated by direct radiographs taken after plaster casting using the above-mentioned scoring systems.

Results

The mean follow-up period of the 51 patients in the study was 17.1 months (range, 6-48 months). Distribution of the patients according to the Frykman and AO Classifications is shown in Table 1.

According to the Gartland and Werley clinical evaluation system the patients were evaluated as 23 (45.1%) at 0-2 points (excellent), 19 (37.3%) at 3-8 points (good) and 9 (17.6%) at 9-20 points (moderate). No poor results were determined.

The mean DASH score was 35.9 ± 4.2. When muscle strength was compared with the healthy side, the healthy side was found to be mean 34.1 ± 10.0 kg, and the fractured side, 27.9 ± 9.6 kg. Preoperative mean radial height was 12 mm. Postoperative mean radial length was measured to be 11.8 mm. Total of 6 patients had decreased radial heights and mean muscle strengths of these 6 patients was found to be 22.5 this value was found to be statistically significantly lower than patients who had post-treatment normal radıal heights. (p<0.05).

When the patients were examined according to the Stewart et al radiological criteria, results were obtained of 18 (35.3%) excellent, 28 (54.9%) good and 9 (17.6%) moderate. No poor results were obtained.

Osteoarthritis was determined radiologically in 14 (27.4%) patients according to the Knirk and Jupiter arthritis scoring system. Of 11 patients determined with Grade 1 arthritis, 4 (36.3%) fractures were Frykman Type 7, 5 (45.4%) Frykman Type 8, 1 (9%) Frykman Type 3 and 1 (9%) Frykman Type 4. Of the 3 patients determined with Grade 2 arthritis, 1 fracture was Frykman Type 7 and 2 fractures were Frykman Type 6. In addition, it was determined that as the Frykman degree increased so there was an increase in clinical score, DASH and the radiological anatomic score.

32-year old male with left side radius distal end complex fracture, Frykman Type 6, AO A3, AP and Lateral Roentgenogrambefore closed reduction (Figure 1), after closed reduction (Figure 2) and after follow-up period of 10 months (Figure 3).

Discussion

Radius distal end fractures are fractures which are anatomically in the distal of the distal radius metaphysis. Although these are the most frequently encountered fractures during an orthopaedic career, there is still no consensus on classification, treatment and the evaluation of treatment results.

To obtain good functional results in radius distal end fractures it is necessary to correct radial shortness, radial inclination, dorsal curve and distal radioulnar joint incongruity.

In a study by Karalezli et al, anatomic results of 40.7% excellent, 44.4% good, 9.9% fair and 5% poor were obtained according to the Stewart score system, clinical results of 30.8% excellent, 47% good, 17.2% fair and 5.0% poor and it was advocated that to achieve a good functional result, it is necessary to obtain a good anatomic result [8]. In the current study, when the results obtained were evaluated, it was determined that as the anatomic result worsened so the clinical result also worsened. In addition, patients who did not have good functional and anatomic results had a high DASH score.

In the treatment of radius distal fractures, it is still a matter of debate as to which is the most important criteria defining prognosis of the result of reduction. According to Palmer, it is the restoration of radial length, while Gartland and Werley reported it to be the presence of residual dorsal tilt [9,10]. Fernandez et al stated that dorsal angulation >25° will negatively affect the prognosis and Pogue et al claimed that more than 20° will lead to poor results [11,12]. Frykman and de Palma reported that it is necessary to provide radial length to be able to obtain good functional results [10,13]. In the current study, that loss of radial height had a negative effect on both grip strength and clinical results, supports the view that radial height is the most important criteria defining the prognosis of the treatment. Impairment of the radial inclination, radial shortening or loss of palmar inclination were not observed to negatively affect the prognosis.

In a study by Vural et al where a comparison was made of the Kapandji technique with plaster casting, there was no difference between the groups in respect of radial length and radial inclination but palmar inclination was determined to have been better restored in the Kapandji technique [14]. In the current study, when evaluation was made of the final follow-up measurements of all the patients, the mean radial curve angle was found to be 19.4 ± 4.4°, the mean palmar curve angle 0.3 ± 8.5° and radial height 8.5 ± 2.6 mm. According to these results from the current study, it was concluded that the palmar inclination angle was more difficult to correct than the other angles, although as the most obvious limitation of this study is that there was no control group, we are in support of further studies to be made on the subject of by which method the palmar inclination can be corrected.

It is known that when the treatment of radius distal fractures results in insufficient anatomic restoration, this creates a loss of grip strength. McQueen found more than 2mm shortening in the radius to be an indicator of grip strength loss [15]. In a study by Özdemir et al, while it was observed that as angulation increased dorsally, grip strength decreased, no relationship was found between the radial angle and grip strength [16]. In the current study, in the correlation between grip strength and radius distal end anatomy, the conclusion was reached that as radial length decreased, so grip strength also decreased. No significance was found between grip strength and radial and palmar inclination.

One of the most frequently encountered problems in conservative follow-up of radius distal end fractures is that the reduction is not protected inside the plaster cast. This problem is more evident particularly in unstable fractures [17]. It has become known that even if there is successful reduction initially in radius distal end fractures with metaphyseal fragmentation, loss of reduction develops inside the plaster cast in approximately 60% of these cases [18]. In this respect, these fractures require careful monitoring in conservative follow-up with plaster cast. Jenkins et al reported that reduction loss of 5% was observed as a result of conservative treatment in unstable intra-articular fractures and this required correction with a new reduction [19]. In a study by Warwick with a 10-year follow-up period, it was reported that plaster casting treatment could not provide sufficient radial length and thus external fixators should be preferred [20].

In the current study, anatomic angles were measured following plaster casting and at the final follow-up. In the light of these values, the radial inclination angle and radial height within the plaster cast were found to be statistically significantly higher than the values measured at the final follow-up. However, no significant difference was found between the value of the palmar tilt angle in the plaster cast and that at the follow-up following bone union. In addition, while the radial height and radial inclination values in the plaster cast of elderly patients and those with metaphyseal fragmentation were found to be significantly higher than the follow-up values, no statistically significant difference was determined in the palmar tilt. That no difference was determined between the palmar tilt angles in the plaster cast and at follow-up is thought to be associated with the provision of sufficient support from the dorsal of the plaster cast which was applied after oedema had recovered. However, osteopenic fractures in elderly patients have a tendency to displacement particularly in the late period and this can be considered to conform with the view of Warwick that plaster casting treatment cannot provide sufficient radial length [20,21].

Another subject for debate in radius distal fractures is the effect on prognosis of an ulnar styloid fracture together with a radius fracture. According to Knirk et al, non-union of the styloid affects the prognosis negatively [4]. Smaill et al reported that an ulnar styloid fracture may cause restricted wrist movement [22]. However, in a study by Bradway et al, it was stated that non-union of an ulnar styloid fracture did not affect functional results. [23]. In the current study, 21 (41.1%) patients had an ulnar styloid fracture as well as the radius distal fracture. At the final follow-up, union of the ulnar styloid was determined in 6 (28.5%) patients and non-union in 15 (71.5%) patients. Although the number of patients was low in the current study, as there was no statistically significant difference in the follow-up mean clinical evaluation score and DASH score between the patients with union of the ulnar styloid and those with non-union, the presence of a styloid fracture was not thought to affect the functional results.

Conclusion

The currently accepted view of radius distal end fractures is that they are complex fractures and prognosis varies depending on the type of fracture and the treatment applied. Treatment with closed reduction and plaster cast fixation is extremely cheap and is an easy method to apply in a short time. In the current study, that loss of radial height had a negative effect on both grip strength and clinical results, supports the view that radial height is the most important criteria defining the prognosis of the treatment. Impairment of the radial inclination, radial shortening or loss of palmar inclination were not observed to negatively affect the prognosis.

Competing interests

The authors declare that they have no competing interests.

References

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Gokhan Keles, Engin Eren Desteli, Murat Erdogan, Bulent Koksal, Ebru Kelsaka, Sabit Numan Kuyubasi. Conservative Treatment of Distal Radius Fractures, Importance of Radial Height. J Clin Anal Med. 2016;7(5):601-605

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Developing a Scale for Both Students and Facilitators to Evaluate Problem Based Learning Efficiency

Erol Gurpinar 1, M. Kemal Alimoglu 1, Cem Guzelle 2

1 Department of Medical Education, Akdeniz University Faculty of Medicine, 2 Ölçme ve Değerlendirme Bölümü, Akdeniz University Faculty of Education, Antalya, Turkey

DOI: 10.4328/JCAM.3141 Received: 07.12.2014 Accepted: 27.12.2014 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 595-600

Corresponding Author: Erol Gurpinar, Department of Medical Education, Akdeniz University Faculty of Medicine, 07070 Antalya, Turkey. T.: +90 2422496189 F.: +90 2422274482 E-Mail: eg@akdeniz.edu.tr

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Abstract

Aim: The purpose of this study was to make validity and reliability analyses of a scale developed for both students and facilitators to evaluate PBL efficien-cy in medical education. Material and Method: A measuring tool was devel-oped for the students and PBL facilitators by compiling evidence based facts in literature showing benefits of PBL against classical education. Scale for students (SS) composed of 19 items classified in 3 dimensions (knowledge (5), skill (7) and attitude (7)) while the scale for the facilitators (SF) had 14 items in one dimension. As an answer to the main question the participants were asked to give a score for each subject statement on a five item Likert-type scale between 1 and 5. First year medical students in Akdeniz University Faculty of Medicine (n=1265) and their facilitators in PBL sessions (n=392) composed of the study group. Results: Validity analysis results of the SS are as follows: Confirmatory Fit Index (CFI) >0.9, Standardized Root Mean Square Residual (SRMR)=0.05 and Root Mean Square Error of Approximation (RM-SEA) = 0.07. Cronbach Alpha values for knowledge, skill and attitude dimen-sions were found 0.72, 0.81 and 0.73 respectively. Total reliability score of the SS was calculated 0.86. Validity analysis results of the SF are as follows: Confirmatory Fit Index (CFI) >0.9, Standardized Root Mean Square Residual (SRMR)=0.04 and Root Mean Square Error of Approximation (RMSEA) = 0.09. Cronbach Alpha value was found 0.96. Discussion: Consequently, the SS was determined to be valid and reliable for 16 items and the SF for 14 items.

Keywords: Medical Education; Problem Based Learning; Medical Students; Facilitator

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Introduction

Problem-Based Learning (PBL) is an education method being more widespread since 1969.One of the most important reasons for that is their benefit [1]. This education method gives the student skills of reasoning while solving problems, analyzing, and synthetizing, reaching information and commenting. Thus providing student with ability of developing knowledge and skill in the meantime, synthetizing and analyzing knowledge, and constant self-learning [2-5]. PBL, teaches the student to learn efficiently by being active, questioning, investigating, wondering, discussing with a little group instead of being a passive receiver. PBL teaches the student how and where to use the learned knowledge [6-10]. It helps student improve problem solving, make counter hypothesis, learning new knowledge to support this hypothesis skills. While doing this, it adds useful values for medical purposes to students such as scanning resources, using and evaluating them, group study and communication skills [11-14]. With the effect of these benefits, PBL is being used more in faculties of medicine each day.

One of the important components of education program is the evaluation. The reaction of the student for the applied methods, whether if it made a difference in student’s knowledge, skill or attitude, whether if it reached the goals are main questions to be answered in evaluation [15]. It is also important to take note of comments of students, facilitators and executives which are part of the education programme. It is seen that PBL evaluation studies in litterateur mostly consists of questions about whether PBL is making a difference in contentment, knowledge and skill. Also the studies are either on students or on facilitators. In most of these researches, it is seen that researchers come to these conclusions from surveys or exam results. To our knowledge, there is no such a tool considering views of medical students and PBL facilitators together.

The purpose of this study was to make validity and reliability analyses of a measuring tool which has been used for program evaluation purposes since 2003 to determine opinions of students and facilitators on PBL.

 Material and Method

Data Acquiring Tools

Scale to Evaluate Efficiency of PBL: When literature was examined it is noticed that different suggestions were made for evaluation. In this study, the stages suggested by, DeVellis (2003), Tavşancıl (2006), Tezbaşaran (1997) were followed [16-18]. In 2003, in direction of theoretical definition, present measuring tools in litterateur were examined and no record of a tool used to evaluate efficiency of PBL was found. In this case, acknowledged subjects in which PBL has more benefits than classic learning are taken into consideration and a measuring tool for students consisting of 19 items with 3 sub dimensions (Knowledge (5), skill (8), and attitude(6)) and for facilitators 14 items with one sub dimension was developed.

These written 3 items were prepared by taking opinions and suggestions of experts in field of medicine. Prepared items were then examined and edited by measuring and evaluating expert for comprehensibility and finally scale was prepared.

For each item in scale, 5 Likert type options were given between 1 (I totally do not agree) and 5 (I totally agree) and the person answering the survey was asked to pick the most suitable answer for him/herself.

Study Group

For scale development operations, data was collected from 2 different study groups. First group was Akdeniz University Faculty of Medicine 1st semester students and second group was PBL directing facilitators in the same faculty. Data from 1161 people in first group and from 375 people in second group was acquired. First study group was used to determine psychometric features of the scale for students while second group was used to determine psychometric features of the scale for facilitators.

Acquiring Data

Taking legal consent, prepared scale was applied to 1st semester students at the end of the semester (May-June) since 2003. Also same scale was applied to facilitators working with PBL at the end of each semester since 2005 once in two years.

İtems in each surveys, were asked as follows; “How did PBL help students in the following subjects?” for facilitators, and “How did PBL help you in the following subjects?” for students.

Analyzing Data

The statistical package for the Social Science (SPSS) was used. Group differences were analyzed using univariate analysis of variance (ANOVA). A principal component analysis was performed using Kaiser’s criterion (Eigenvalue > 1), followed by an oblimin rotation. The internal consistency of the overall scale and subscales was measured by Cronbach’s alpha coefficient. Confirmatory Factor Analysis (CFA) using LISREL [19].

The data showed anunivariant normal distribution, because the skewness and kurtosis values placed themselves within the range -1.0 and +1.0. The skewness values ranged from -.90 to +.11 while the kurtosis values ranged from .-97 to +.19. Also, correlation values were examined in order to state whether if there is a multiple connection problem or not. It is observed that values changed between.134 and .734. Since correlation value is below .90 there is no multiple connection problem [20].

As results of 3 items in survey for students are very low, they are subtracted from analysis and the statistical evaluation is made using 16 items.

Results

As a result, as validity and reliability analyze results of scale which is developed to evaluate PBL events came out high, both student and facilitator scales are considered to be useful in faculties which are using PBL for evaluation in acknowledged subjects in which PBL is more effective than classic learning.

Exploratory Factor Analysis (Scale for students)

First of all, measures of sampling adequacy were conducted on the 17-item Scale for students (SS) to see whether it was suitable for factor analysis. Barttett’s test of sphericity indicated a chi square value of 4252,24, p < 0.000, while Kaiser-Meyer-Olkin measure of sampling adequacy indicates a value of 0.918. When a basic scree-test and eigenvalue at > 1.0 criteria were used, four factors were generated from the SS. The scree plot suggested that three factors should be extracted (Kline, 1994). These three factors, which were rotated through the varimax procedure, explained 55.04 percent of the variance (Table 2). Factor 1 (four items) accounted for 38.2 percent of the variance and measured interference with knowledge. Factor 2 (seven items) accounted for 13.0 percent of the variance and measured salience and skills. Factor 3 (five items) accounted for 5.9 percent of the variance and measured overindulgence in attitude.

The reliabilities of the MSLSS dimensions were assessed by Cronbach’s a coefficient and each dimension’s item-total correlations. Here acceptable criteria were ≥.70 for Cronbach’s a coefficients [21]. (Table 1).

Confirmatory factor analysis of Scale for students

The evaluation of model fit was done by using confirmatory factor analysis (CFA). In order to perform the CFA, LISREL 8.7 was used and the model parameters were estimated by using maximum likelihood [20]. LISREL 8.5 provides a full range of goodness-of-fit measures. The three types of overall model fit measures useful in CFA can be represented by absolute, incremental and parsimonious fit.

In this study, in order to evaluate the absolute fit, X2 (X2: minimum fit function test), Root Mean Square Error of Approximation (RMSEA), goodness of fit index (GFI), and standardized root mean square residual (SRMR) were used. Adjusted goodness of fit index (AGFI), Normed fit index (NFI), Tucker–Lewis index (TLI), comparative fit index (CFI), were used as incremental fit measures. The results related to models were summarized in Table 2.

When table-2 was examined, the probability levels of all X2 statistics were less than 0.01, indicating a rather poor absolute fit [22]. X2 value usually gives significant value with large samples. For this reason, instead of using X2 value by itself, it is suggested to use calculated value to degree of freedom ratio. This ratio (X2/df) is wanted to be below 5. When Table 2 was examined, it is seen that X2 value (X2=189.14, sd=71, X2/df=2.66, p=.000) is significant. In fit indexes GFI, AGFI, NFI, TLI and CFI values above .90 means fine fit [23]. RMSEA and SRMR are wanted to be below<0.08. When calculated values are examined, it shows that there is an acceptable fit. The item-factor loading estimates, estimated error variances and t values in Table 3.

Convergent Validity Scale for students

Item reliability indicates the amount of variance in an item due to the underlying construct rather than to error. Either an item reliability of at least 0.50, or a significant t value, or both, observed for each item, is considered to be evidence of convergent validity [24]. As seen from Table. 3, all t-values of the items were significant and all item reliabilities were greater than 0.50, except one items.

The composite reliability of each construct is one of the principal measures used in assessing the measurement model and commonly used higher value for acceptable composite reliability is 0.70. [25] (Table 3).

Exploratory Factor Analysis (scale for the facilitators)

First of all, measures of sampling adequacy were conducted on the 14-item SF to see whether it was suitable for factor analysis. Barttett’s test of sphericity indicated a chi square value of 3806,54; p < 0.000, while Kaiser-Meyer-Olkin measure of sampling adequacy indicates a value of 0.937. When a basic scree-test and eigenvalue at > 1.0 criteria were used, four factors were generated from the SF. The scree plot suggested that three factors should be extracted. (Kline, 1994) These three factors, which were rotated through the varimax procedure, explained 58.22 percent of the variance (Table 4). Factor 1 (eight items) accounted for 58.22 percent of the variance and measured interference with. The reliabilities of the MSLSS dimensions were assessed by Cronbach’s a coefficient and each dimension’s item-total correlations. Here acceptable criteria were ≥.70 for Cronbach’s a coefficients [21].

Confirmatory factor analysis of scale for the facilitators

The evaluation of model fit was done by using confirmatory factor analysis (CFA). In order to perform the CFA, LISREL 8.7 was used and the model parameters were estimated by using maximum likelihood [20]. LISREL 8.5 provides a full range of goodness-of-fit measures. The three types of overall model fit measures useful in CFA can be represented by absolute, incremental and parsimonious fit.

In this study, in order to evaluate the absolute fit, X2 (X2: minimum fit function test), Root Mean Square Error of Approximation (RMSEA), goodness of fit index (GFI), and standardized root mean square residual (SRMR) were used. Adjusted goodness of fit index (AGFI), Normed fit index (NFI), Tucker–Lewis index (TLI), comparative fit index (CFI), were used as incremental fit measures. The results related to models were summarized in Table 5.

When Table 5 was examined, the probability levels of all X2 statistics were less than 0.01, indicating a rather poor absolute fit [22]. X2 value usually gives significant value with large samples. For this reason, instead of using X2 value by itself, it is suggested to use calculated value to degree of freedom ratio. This ratio (X2/df) is wanted to be below 5. When Table 2 was examined, it is seen that X2 value (X2=299.65, sd=70, X2/df=4.28, p=.000) is significant. In fit indexes GFI, AGFI, NFI, TLI and CFI values above .90 means fine fit [23]. RMSEA and SRMR are wanted to be below<0.08. When calculated values are examined, it shows that there is an acceptable fit. The item-factor loading estimates, estimated error variances and t values in Table 6.

Convergent Validity for scale for the facilitators

Item reliability indicates the amount of variance in an item due to the underlying construct rather than to error. Either an item reliability of at least 0.50, or a significant t value, or both, observed for each item, is considered to be evidence of convergent validity [24]. As seen from Table. 3, all t-values of the items were significant and all item reliabilities were greater than 0.50, except one items.

The composite reliability of each construct is one of the principal measures used in assessing the measurement model and commonly used higher value for acceptable composite reliability is 0.70 [25] (Table 6).

Discussion

As validity and reliability analyze results of scale which is developed to evaluate PBL events came out high, both scales are considered to useful for evaluation. In student format of the scale, 3 items received low values in validity analyses and thus these items were subtracted for analyses. 3 subtracted items are; “I believe I will be more successful with my Professional life in subjects I learned with PBL”, “PBL helps relations between people and group study”, and “PBL helped me use internet to reach information”.

Evaluation of Data Acquired from Scale:

Suggested method to evaluate the scale results; when comparing arithmetic averages In Likert-type survey items, interval coefficient of classification scale should be calculated using “row width/group number” formula. Classification scale was found 0.80 (5–1=4 and 4/5=0.80). Arithmetic average intervals which are taken primarily in evaluating findings are interpreted as follows; 1.00-1.80; “I totally do not agree”, 1.81-2.60; “I do not agree”, 2.61-3.40; “I partially agree”, 3.41-4.20; “I agree”, 4.21-5.00; “I totally agree”.

Situations Where PBL Could be used

All the items in the scale are items in which PBL is specified to be more effective than classic learning. For this reason, it is thought to be helpful to evaluate the results of the scale whether if the results were the same with previous studies. The reasons for trying to Show what is already shown before are the fact that different infrastructure for each school, different student, facilitator profiles, and different applications could give different results. Using the scale, there is a possibility to compare different faculties which are using PBL. It is known that PBL is becoming widespread in faculties of medicine. While some faculties have been using this method for a long time, some faculties are new to this subject. Also some faculties structured their education programme on PBL; some faculties are using hybrid programmes. Each faculty using PBL are expecting to benefit advantages and superiorities of this programme. So naturally, there is a question about the sufficiency of PBL. It is thought that the scale of which validity and reliability analysis were completed could be a solution to these questions.

In both scales, apart from the items which are analyzed, there are also suggestions like, “Are you content with PBL?” and “PBL is a helpful application for students in general” for facilitators. The answers for these suggestions should are expected to be “yes”, “no”, or “hesitant”. These suggestions are not included in validity and reliability analysis. But as it is thought that these suggestions could help evaluate the results, they are added to the scale. Also some independent variables are added to facilitator scale such as, department of the facilitator (internal medicine, surgical etc.), title (prof. Associate prof. Expert etc.) how long and how many times the facilitator has been working with PBL. The results for these questions are added to instruction in order to be help for evaluation. Apart from this, other independent variables asked in a different survey could help evaluate the result. For example, for students sex, whether if they entered faculty of medicine voluntarily, success, and for facilitator, sex, age, working period in the faculty questions could be helpful for evaluation.

For a learning method being used more lately in faculties, being able to evaluate on a comparable scale in all faculties using the method, having both student and facilitator level is a strong side of this scale. Also in a large group, having high results in validation and reliability analysis is a positive side of this scale. Having both student and facilitator level is also a strong side of this scale.

Acknowledgments

The authors thank to Akdeniz University Research Fund for financial support.

Competing interests

The authors declare that they have no competing interests.

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Erol Gurpinar, Mustafa Kemal Alimoglu, Cem Guzeller. Developing a Scale for Both Students and Facilitators to Evaluate Problem Based Learning Efficiency. J Clin Anal Med. 2016;7(5):595-600

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Drainage Systems’ Effect on Surgical Site Infection in Children with Perforated Appendicitis

Şeref Selçuk Kılıç 1, Saniye Ekinci 2, İbrahim Karnak 2, Arbay Özden Çiftçi 2, Feridun Cahit Tanyel 2, Mehmet Emin Şenocak 2

1 Department of Pediatric Surgery, T. R. M. H. Ahi Evran University Education and Research Hospital, Kırşehir, 2 Department of Pediatric Surgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey

DOI: 10.4328/JCAM.2865 Received: 30.09.2014 Accepted: 16.12.2014 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 591-4

Corresponding Author: Şeref Selçuk Kılıç, Ahi Evran Üniversitesi Eğitim ve Araştırma Hastanesi Çocuk Cerrahisi Kliniği, Kırşehir, 40100, Türkiye. T.: +90 3862134515 E-Mail: serefselcukkilic@gmail.com

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Aim: Effect of replacing open drainage system to closed drainage system on surgical site infection (SSI) in children operated for perforated appendicitis was evaluated. Material and Method: Hospital files and computer records of perforated appendicitis cases operated in 2004-2010 were evaluated retro-spectively. Open drainage systems were used for 70 in cases (group I) and closed systems were used in the others (group II). Results: Eleven of SSI cases had superficial infection and 3 had the organ/space infection. SSI rate was 15.7% for group I and 7.5% for the group II. The antibiotic treatment length was 7.5 ± 3.4 days for group I and 6.4 ± 2.2 days for group II and the differ-ence between groups was not statistically significant. Hospitalization length for group I was 8.2 ± 3.1 days and 6.8 ± 1.9 days for group II and the differ-ence was statistically significant. Discussion: SSI is an important problem increasing morbidity and treatment costs through increasing hospitalization and antibiotic treatment length. Open drainage system used in operation in patients with perforated appendicitis leads an increased frequency of SSI when compared to the closed drainage system. Thus, closed drainage sys-tems should be preferred in when drainage is necessary in operations for perforated appendicitis in children.

Keywords: Perforated Appendicitis; Children; Drainage System; Surgical Site Infection

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Seref Selcuk Kilic, Saniye Ekinci, Ibrahim Karnak, Arbay Ozden Ciftci, Feridun Cahit Tanyel, Mehmet Emin Senocak. Drainage Systems Effect on Surgical Site Infection in Children with Perforated Appendicitis. J Clin Anal Med. 2016;7(5):591-594

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A Simple Method for Thoracotomy Closure Avoiding Intercostal Nerve Damage

Ufuk Çağırıcı 1, İlker Akçam 2

1 Ege Üniversitesi Tıp Fakültesi, Göğüs Cerrahisi Anabilim Dalı, Bornova, 2 Dr. Suat Seren Göğüs Hastalıkları ve Cerrahisi Eğitim ve Araştırma Hastanesi, 2.Göğüs Cerrahisi Kliniği, Yenişehir, İzmir, Türkiye

DOI: 10.4328/JCAM.3110 Received: 26.11.2014 Accepted: 09.12.2014 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 589-90

Corresponding Author: Ufuk Çağırıcı, Ege Üniversitesi Tıp Fakültesi, Göğüs Cerrahisi Anabilim Dalı, 35100, Bornova, İzmir, Türkiye. T.: +90 2323904919 F.: +90 2323904681 E-Mail: ufuk.cagirici@ege.edu.tr

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It is well known that intercostal nerve damage during thoracotomy closure causes severe postoperative pain. A simple closure technique is proposed for intercostal nerve-sparing during thoracotomy opening and closure. We think that this maneuver may avoid intercostal nerve compression.

Keywords: Thoracotomy; Intercostal Nerves; Postoperative Pain

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Ufuk Cagirici, Ilker Akcam. A Simple Method for Thoracotomy Closure Avoiding Intercostal Nerve Damage. J Clin Anal Med. 2016;7(5):589-590

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Demographic Characteristics of 796 Patients Operated for Lumbar Disc Herniation in Thrace Region, Turkey

Emre Delen 1, Ahmet Tolgay Akıncı 2, Banu Tütüncüler 2, Muzaffer Memiş 1, Nebile Müge Kunduracılar 1, Soner Şahin 3

1 Edirne State Hospital Dept. of Neurosurgery, Edirne, 2 Trakya University Dept. of Neurosurgery, Edirne, 3 Kocaeli Derince Training and Research Hospital, Kocaeli, Türkiye

DOI: 10.4328/JCAM.3068 Received: 10.11.2014 Accepted: 05.12.2014 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 585-8

Corresponding Author: Emre Delen, Edirne Devlet Hastanesi Beyin Cerrahisi Kliniği. Edirne, Türkiye. GSM: +905306144646 F.: +90 2845138305 E-Mail: emredelen1979@yahoo.com

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Aim: This study was designed was to determine the demographic character-istics of patients operated for lumbar disc herniation in Thrace Region, Tur-key. Material and Method: We retrospectively searched our data to find out patients who had one sided, one level and only one spinal surgical interven-tion for herniated lumbar disc. Results: Among 796 cases, 336 (42%) were men and 460 (58%) were women. The level of the pathology is determined as L1 – 2 for 4 cases (0.5%), L2 – 3 for 15 cases (1.9%), L3 – 4 for 51 cases (6.4%), L4 – 5 for 412 cases (51.8%) and as L5 – S1 on 314 cases (39.4%). While a total of 70 cases (8.9%) were identified on upper-levels ( L1 – 2, L2 – 3, L3 – 4); 726 cases (91.1%) were found to be on lower-levels ( L4 – 5, L5 – S1). A mild positive correlation between the pathology level and physical activity intensity (P < 0.05, P = 0.103) has been demonstrated; as well as a strong negative correlation between pathology level and mean age (P < 0.05, P = -0.404). Discussion: The demographic characteristics are consistent with the literature. Physical activity intensity influence on lower-level herniations might have significance due to the large sample size. The strong negative correlation between pathology level and mean age suggests that the degen-eration raises the frequency of upper-level herniations.

Keywords: Intervertebral Disc Disease; Discectomy; Demographic Analysis

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Emre Delen, Ahmet Tolgay Akinci, Banu Tutunculer, Muzaffer Memis, Nebile Muge Kunduracilar, Soner Sahin. Demographic Characteristics of 796 Patients Operated for Lumbar Disc Herniation in Thrace Region, Turkey. J Clin Anal Med. 2016;7(5):585-588

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Case Report

Gangrene of Meckel’s Diverticulum Secondary to Axial Torsion in a Child: An Unusual Complication

Alev Suzen 1, Nazile Erturk 2, Yasar Topal 3

1 Department of Pediatric Surgery, Mugla Sıtkı Kocman Univercity Research and Training Hospital, 2 Department of Pediatric Surgery, Mugla Sıtkı Kocman Univercity, Medical Faculty Hospital, 3 Department of Pediatrics, Mugla Sıtkı Kocman Univercity, Medical Faculty Hospital, Mugla, Turkey

DOI: 10.4328/JCAM.4590 Received: 27.04.2016 Accepted: 16.05.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 717-9

Corresponding Author: Alev Suzen, Department of Pediatric Surgery, Mugla Sıtkı Kocman Univercity Research and Training Hospital, Muğla, Turkey. GSM: +905052103440 E-Mail: alevsuzen@hotmail.com

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 Axial torsion and gangrene of Meckel’s diverticulum (MD) causing small bowel obstruction is the rarest complication of the congenital anomaly. Only 8 cases in children and approximately 20 cases in adults were found in the literature. Our case is a 2-year-old Caucasian male who presented to our pediatric department with gastroenteritis. The following day bilious vomiting and colicky episodic ab-dominal pain started. Clinical and laboratory findings were suggestive of acute intestinal obstruction or appendicitis. Exploratory laparotomy suggested that 2 peritoneal bands of diverticulum to the mesentery of non-adjacent small bowel were the cause of axial torsion of MD; herniation of small bowels under the bands were observed. Wedge resection of the MD was performed. Complicated MD has no specific value. The preoperative diagnosis is difficult. Early surgery is important for correct diagnosis and for preventing strangulation and gangrene of the bowel.

Keywords: Meckel’s Diverticulum; Axial Torsion; Children; Gastroenteritis

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Alev Suzen, Nazile Erturk, Yasar Topal. Gangrene of Meckels Diverticulum Secondary to Axial Torsion in a Child: An Unusual Complication. J Clin Anal Med. 2016;7(5):717-719

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Cardiac Arrest in a Pregnant Patient Diagnosed with Bochdalek Hernia

Pınar Karabacak, Hacı Ömer Osmanlıoğlu, Berit Gökçe Ceylan, Mehmet Ali Yağlı, Mustafa Kemal Yıldırım

Department of Anesthesiology and Reanimation, Suleyman Demirel University Faculty of Medicine, Isparta, Turkey

DOI: 10.4328/JCAM.4675 Received: 31.05.2016 Accepted: 19.07.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 746-8

Corresponding Author: Pinar Karabacak, Department of Anesthesiology and Reanimation, Suleyman Demirel University Faculty of Medicine, Isparta, Turkey. GSM: +905056846286 F.: +90 2462237831 E-Mail: drpinara@gmail.com

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Bochdalek hernia is thought to be the result of a defect of the pleuroperitoneal fold and the septum transversum fusion in the 8th week of gestation. The majori-ty of these patients present with respiratory distress after delivery; asymptomatic progress until adulthood is an extremely rare clinical occurrence. The adult form of a Bochdalek hernia accompanying pregnancy is a rare entity. A 39-year-old, 24-week pregnant patient applied to Emergency service with epigastric pain and vomiting. Abdominal ultrasonography was planned due to the abdominal pain; sudden cardiopulmonary arrest occurred during the procedure. In this case report, congenital diaphragmatic hernia in a young pregnant woman who underwent car-diac arrest is presented.

Keywords: Bochdalek Hernia; Cardiac Arrest; Pregnancy

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Pinar Karabacak, Haci Omer Osmanlioglu, Berit Gokce Ceylan, Mehmet Ali Yagli, Mustafa Kemal Yildirim. Cardiac Arrest in a Pregnant Patient Diagnosed with Bochdalek Hernia. J Clin Anal Med. 2016;7(5):746-748

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Cardiac Arrest due to Pneumoperitoneum After PEG Insertion in ALSPatient

Berit Gokce Ceylan, Pinar Karabacak, Hasan Saygin, Hüzeyfe Feyyaz Demirel, Fusun Eroglu

Department of Anesthesiology and Reanimation, Suleyman Demirel University Faculty of Medicine, Isparta, Turkey

DOI: 10.4328/JCAM.4692 Received: 07.06.2016 Accepted: 12.07.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 743-5

Corresponding Author: Pinar Karabacak, Department of Anesthesiology and Reanimation, Suleyman Demirel University Faculty of Medicine, Isparta, Turkey. GSM: +905056846286 F.: +90 2462237831 E-Mail: drpinara@gmail.com

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Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is characterized by motor neuron degeneration in the primary cortex, brainstem, and spinal cord. Percutaneous endoscopic gastrostomy (PEG) is a preferable method of nutritional support in patients with normal gastrointestinal function who can- not be fed orally for various reasons. PEG tube placement is recommended in amyotrophic lateral sclerosis (ALS) patients with dysphagia to provide reliable access for medications and nutrition. We report a case of a 63-year-old man with amyotrophic lateral sclerosis presenting with dysphagia and pneumoperitoneum following percutaneous endoscopic gastrostomy (PEG) placement. We also report on the intensive care period of this patient. PEG is a widely used nutrition therapy in these cases but complications such as pneumoperitoneum result in long term ICU stays and higher mortality rates.

Keywords: Amyotrophic Lateral Sclerosis; Percutaneous Endoscopic Gastrostomy; Pneumoperitoneum; Cardiac Arrest

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Ceylan BG, Karabacak P, Saygın H, Demirel HF, Eroğlu F. Cardiac Arrest due to Pneumoperitoneum After PEG Insertion in ALSPatient. J Clin Anal Med 2016;7(5): 743-5.

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Review Article

Ipsilateral Rotational Autokeratoplasty

Yeşim Altay

Department of Ophthalmology, Ufuk University Faculty of Medicine, Ankara, Turkey

DOI: 10.4328/JCAM.4599 Received: 01.05.2016 Accepted: 23.06.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 753-6

Corresponding Author: Yeşim Altay, 48. Cadde No: 33/31 Cukurambar, 06520, Ankara, Turkey. GSM: +905324902298 E-Mail: altayye@yahoo.com

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Corneal opacity is a leading cause of monocular blindness, and corneal trans-plantation is the most commonly performed solid organ transplantation in the world. Keratoplasty techniques for corneal opacities include lamellar al-lokeratoplasty and penetrating allokeratoplasty. Ipsilateral rotational auto-keratoplasty can be an effective alternative to penetrating allokeratoplasty for some patients with corneal scars. This procedure involves a rotation of the patient’s own cornea to move opacity out of the visual axis. An important consideration when selecting cases for rotational autokeratoplasty is the di-mensions of the corneal scar. Although ipsilateral autokeratoplasty may not provide as good a quality of vision as penetrating allokeratoplasty because of higher astigmatism and reduced corneal pupillary clear zone, these disad-vantages are often outweighed when the risk of allograft rejection is high, as in pediatric patients and those with vascularised corneas. This technique would at least partially resolve the issue of scarcity of donor corneal tissue in developing countries.

Keywords: Cornea; Corneal Transplantation; Corneal Opacity

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Introduction

Corneal opacity is a leading cause of monocular blindness worldwide. The definitive treatment of visually-impairing corneal opacity is penetrating allogenic keratoplasty using donor corneal tissue. Although corneal scar and keratitis are the most frequent indications for keratoplasty in developing countries, corneal edema and keratoconus constitute the majority of patients undergoing penetrating keratoplasty in developed countries. The reported success rate for penetrating corneal grafts is 73% at 5 years, and 62% at 10 years [1]. However, endothelial rejection rates are 15-20% in adults and 10-50% in pediatric grafts [2,3]. Rejection rates are higher in pediatric corneal transplantation because of the more active immune systems of younger patients [4]. In addition to rejection, late corneal failure is anticipated due to the continuing loss of donor corneal endothelial cells with time [5]. More importantly, the accessibility to corneal tissue for corneal grafting is a major limiting factor. Because of the increasing gap between demand and supply of donor corneal tissue, alternative techniques have been devised.

One of them is rotational autokeratoplasty, which is indicated for patients with a limited corneal opacity involving the visual axis. This procedure involves a rotation of the patient’s own cornea to move opacity out of the visual axis and to replace it with clear cornea [4,6-9].

Several authors have suggested the use of different graft shapes for ipsilateral autokeratoplasty, such as a triangle or a figure eight [9,10]. However, none has replaced the standard circular graft with an eccentric center [11-15].

Like any other surgical technique, appropriate patient selection is required for successful rotational autokeratoplasty. Usually rotational autokeratoplasty is chosen for nonprogressive corneal scars following blunt and penetrating corneal trauma, postinfectious keratitis scar, chemical injuries, and idiopathic or postherpetic lipid keratopathy [6,8,9,16,17]. These patients are at high risk of allograft corneal rejection if subjected to a conventional keratoplasty. Other than the usual indications, Cunha et al. described ipsilateral penetrating autokeratoplasty associated with a crescent-shape resection of 0.5 mm of the inferior cornea as an alternative method to corneal transplantation for keratoconus. They reported reduction of visual acuity with increased astigmatism during the follow-up period [18].

An important consideration during selection of cases for rotational autokeratoplasty is the dimensions of the corneal scar. A four to five mm of clear peripheral cornea is required to obtain at least 3 mm of central clear cornea, free of suture track scars.

Surgical Technique

The surgical technique performed is identical to that of conventional penetrating keratoplasty, with the exception that the host cornea is eccentrically cut and then rotated before suturing. Because of the more rapid loosening of sutures that occurs when they are placed into the anterior sclera, interrupted sutures are recommended for rotational autokeratoplasty.

Several authors have described methods for determining the size and location of the trephination. McDonnell et al. [9] recommended the following guidelines:

“1. Use the maximum area of available clear cornea (this usually meant making the peripheral edge of the graft very near the limbus).

2. Try to ensure that the opacity to be rotated is as near the edge of the graft as possible; this allows maximum movement of the opacity by the rotation and its replacement with the maximum area of the clear cornea.

3. Make the central edge of the graft at least 3 mm away from the visual axis. This ensures clear cornea at the visual axis and minimizes the affect [sic] of the suture.

4. If possible, rotate the opacity under the upper lid.”

In guidelines formalised by Roa and Lam [14], the center of the cornea is marked and a point 2.5 mm away from the center is marked in the opacity. A third mark is made 2.0 mm away from the central mark in line with the second mark, and a fourth mark is made 3.5 mm away from the third. The distance between marks 2 and 4 is taken as the trephine size to be used [14] (Figure 1).

The mathematical formulas for determining the size of the donor and host trephination have been described by several authors. The two most useful are described by Bourne and Brubaker [19] and Jonas et al. [7]. In Bourne and Brubaker’s method [19], two measurements were taken. First, the diameter of the largest circle of the clear cornea was measured. Second, the shortest distance from the edge of this circle to the geometric center of the cornea was assessed (this was considered positive if the opacity involved the center of the cornea and negative if the opacity was within the largest area of the clear cornea). The required trephine size was obtained with the following equation: 1.5 multiplied by the diameter of the largest clear circle added to the shortest distance from the circle to the corneal center [19]. The other formula, by Jonas et al. [7], utilises a trephine size of 0.75 of the overall corneal diameter, when the scar lies at the geometric center of the cornea, and adjusts this according to extent of the scar. Both the Jonas et al. [7] and Bourne and Brubaker formulas [19] give similar results, with the Jonas et al. [7] formula resulting in a slightly larger trephine size.

Another approach to postoperative simulation of rotational autokeratoplasty uses digital imaging. Agarwal et al. [15] have described the use of digital image manipulation software (Adobe Photoshop, version 5.0) to plan the size, location, and rotation of the graft. Using the drawing tool, a circle approximating the pupil was drawn on a new transparent layer created on the original image of the eye. Subsequently, a circle was drawn on the original photograph of the cornea to simulate corneal trephination. The corneal area within this circle was rotated on the image to simulate rotational autokeratoplasty. This step was repeated using varying sizes and positions of the larger circle, which simulated the corneal trephine, to include the maximum area of the clear cornea within the pupillary axis [15].

Outcomes

Several case series have been reported, as presented in Table 1.

In previously published studies of autokeratoplasty, graft survival was noted to be ≥ 90%. In a study by Murty et al. [6], only 3 of 22 grafts failed, two because of prolonged operative time and one because of uncontrolled glaucoma. Ramappa et al. [4] reported that the success rate was 81.25% over a mean follow-up of 29.43 months in pediatric patients. Bertelmann et al. [18] reported only one failure out of seven cases, which they attributed to a triple procedure and preoperative poor endothelial cell count (1200 cells/mm2). Continued endothelial loss is the major cause of graft failure following allograft corneal transplantation. Although long-term results are unknown, Bertelmann et al. [20] showed that mean endothelial cell loss at 1 year was 15% in rotational autografts compared with 40% in homografts.

The published case series in the literature have reported significant number of patients achieving good visual outcomes. In a report by McDonnell and Falcon [9], 2 patients did not have any astigmatic correction and four other patients had correction ranging from 1.25 to 4 D cyl. Murty et al. [6] reported 1 to 2.5 D cyl in 58.8% of patients, 3 to 5.5 D cyl in 23.5%, and 6 to 9 D cyl in 29.4%. Only Jonas et al. [7] compared visual outcomes after rotational autokeratoplasty with those of a nonrandomized control group of penetrating allografts, and found significantly lower postoperative visual acuity and higher corneal astigmatism in patients having rotational autokeratoplasty. The eccentric trephination, disparity of corneal thickness between the peripheral clear cornea and the central scarred cornea into which it is sutured, and the proximity of one edge of the trephination to the center of the cornea are potential reasons for increased astigmatism after rotational autokeratoplasty [7].

The most common postoperative complication reported after rotational autokeratoplasty was wound leak [6]. This was probably because of the difficulties in tissue apposition while suturing due to differences in the thickness of the central and peripheral cornea as well as scarred versus normal tissue. Also, the cosmetic outcome of autokeratoplasty is inferior to that of conventional penetrating keratoplasty. The corneal opacity is visible postoperatively, although it seems smaller because it is bisected during trephination.

Although rotational autokeratoplasty does not provide as high a level of best-corrected visual acuity as penetrating keratoplasty due to higher astigmatism, there are several advantages that outweigh these disadvantages in many patients whose risk of allograft rejection is higher than normal, such as pediatric patients and those with vascularised cornea:

1. This technique does not require a donor cornea and there is no risk of transmission of infection such as human immunodeficiency virus or hepatitis.

2. Most importantly, this technique obviates the lifelong risk of allograft rejection. This can be a very important factor in some patients, such as those with traumatised eyes with extensive corneal vascularisation, in children or young adults, and in those where follow-up is difficult.

3. Another advantage is reduced healing time, which allows early suture removal and reduction in the dose and duration of corticosteroid use postoperatively, thus avoiding steroid-induced complications such as cataract and glaucoma.

Conclusions

Ipsilateral rotational autokeratoplasty can be a viable alternative to conventional penetrating keratoplasty in some patients whose risk of allograft rejection is higher than normal. It avoids the risk of allograft rejection or long-term use of corticosteroids and obviates the waiting period for high-quality donor cornea tissues. Careful selection of patients can yield encouraging results with the use of this alternative technique.

Competing interests

The authors declare that they have no competing interests.

 References

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Glutathione S-Transferase Enzyme Gene Polymorphisms and Cardiovascular Diseases

Ayşe Yiğit , Hasan Basri Savaş 2

1 Tıbbi Genetik ABD, 2 Tıbbi Biyokimya ABD, Süleyman Demirel Üniversitesi Tıp Fakültesi, Isparta, Türkiye

DOI: 10.4328/JCAM.4323 Received: 19.01.2016 Accepted: 09.02.2016 Printed: 01.09.2016 J Clin Anal Med 2016;7(5): 749-52

Corresponding Author: Hasan Basri Savaş, Tıbbi Biyokimya ABD, SDÜ Tıp Fakültesi, Isparta, Türkiye. GSM: +905075240737 E-Mail: drhbs63@gmail.com

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Abstract

Cardiovascular diseases still ranks in first place among causes of death around the world. Environmental and genetic factors both play roles in the pathogenesis of cardiovascular diseases. One of the genetic changes that are claimed to contribute to the occurrence of cardiovascular diseases is the Glutathione S-Transferase (GST) family that has been intensely exam-ined recently. GST gene polymorphisms, which are among antioxidant system enzymes, have a relationship with each of the factors that are considered among the risk factors for cardiovascular diseases. Consequently, it can be said that the polymorphisms of GST genes are effective both in the risk fac-tors of cardiovascular diseases and directly in cardiovascular diseases.

Keywords: Cardiovascular Diseases; Glutathione S-Transferase; Gene Polymorphisms

Full Text

Introduction

Cardiovascular diseases still rank in first place among the causes of death around the world [1]. Environmental and genetic factors play roles in the pathogenesis of cardiovascular diseases [2]. One of the genetic changes that is claimed to contribute to the occurrence of cardiovascular diseases is the Glutathione S-Transferase (GST) family which has been intensely examined recently. The GST family consists of many genes, and 5 of them have been defined in humans. The polymorphisms in m, t, and p classes of GSTs were assessed in many diseases, and their relations were explained. GST was frequently examined in diseases in which environmental xenobiotics are thought to have an impact, especially cancer, cardiologic diseases, and dermatologic diseases. [3-5].

Many risk factors that play a role in the pathogenesis of cardiovascular diseases were defined, but the failure to carefully take these known risk factors under control to improve the outcome of the disease or to prevent its advancement shows that these risk factors are not the only ones responsible for the high incidence of cardiovascular diseases. Among the risk factors for cardiovascular diseases are genetics, age, family history, hypertension, hypercholesterolemia, low HDL-cholesterol, diabetes, obesity, stress, low physical activity, menopause, consumption of cigarettes and alcohol, and xenobiotic exposure [2, 6-9]. It is indicated that GST genes are the genes that are responsible for the formation of hypercholesterolemia, hypertension, cigarette, alcohol, xenobiotics, and cardiovascular diseases. It is known that many different pathways are effective in the pathomechanism of hypertension. Firstly, the defects in the genes that are responsible for ensuring electrolyte balance [10-14], the defects that play a role in vascular structure and function [15], and the defects in the genes that are related to oxidative stress may affect hypertension. As it is known, GSTs detoxify certain compounds that are of endogenous and exogenous origin. Especially the GSTM class among GST enzymes is responsible for the detoxification of free radicals. M-class genes are protective against oxidative stress, and it was indicated that decreasing GSTM1 expression is related to hypertension [16-18]. GST enzymes protect cell types of different origins, such as smooth muscle cells and endothelial cells, against oxidative damage [19-21]. Different studies have examined the different existence of GST M1 and T1 genes with hypertension. In the study carried out by Marinho et al., it has been indicated that GSTT1 deletion may be a protective factor for hypertension. No significant difference has been found between GSTM1 genotype frequency and hypertension. However, the frequency of GST M1/T1 null genotype is significantly low in the group with hypertension when compared to the control group (78% against 19%). In the study, it has been also observed that individuals with GST M1/T1 non-null genotype are the candidates for hypertension disease, and it is a protective mutation for the development of cardiovascular disease [22].

In the study carried out by Saadat et al., the effect of GST T1 and M1 gene polymorphisms has been examined in the regulation of blood pressure of the individuals who are exposed to natural source gases containing sulfur compounds. In the study where it is observed that blood pressures vary in different genotypic combinations, systolic blood pressure decreased significantly in GSTM1 null and GSTT1 positive individuals, and diastolic blood pressure increased significantly in GSTM1 positive and GSTT1 null individuals. The results have made us think that the polymorphism changes of GSTs play a physiological role in the regulation of blood pressure in individuals who are exposed to natural gases that contain sulfur [23].

Another study showing the relationship between hypertension and GST has been carried out by Capoluongo et al. This study shows that individuals with GSTM1-null genotype are in the significantly high-risk group in terms of hypertension. Because there was no difference in the study between the individuals in the case group and the control group in terms of smoking (no difference of detoxification of polycyclic aromatic hydrocarbons) or in the state of consuming alcohol and kidney functions (similar urea, creatine values), this excludes those factors from being the reasons for hypertension. In the study, it is indicated that the main cause of the effect on blood pressure is the antioxidant effect of GSTs [24].

The levels of cholesterol and triglyceride, being another important factor in the occurrence of cardiovascular diseases, and the connection between GST enzyme gene polymorphisms and enzyme levels have been indicated in the literature [25-26]. In a study carried out by Gannage-Yared et al., glutathione and Glutathione S-Transferase were measured spectrophotometrically, and it was observed that the blood cholesterol levels of the amount of leukocyte and Glutathione S-Transferase enzyme increase significantly by gender and body mass index [25].

In the study carried out by Maciel et al., it has been expressed that there is a difference between GST polymorphism and triglyceride and HDL-cholesterol [26]. 1577 individuals from the general population and 871 individuals to whom coronary angiography was applied were taken as two different study groups. In the study, it was found that the ratio of triglyceride (TG), HDL-cholesterol, and triglyceride/HDL is significantly related to GSTM1,T1 null genotype (double deleted genotype) in the general population. These results were confirmed with a second population to which coronary angiography was applied, independently from the first study group. Furthermore, it was also shown that types of coronary artery disease are also associated with GST genotype. The relevant study shows that the existence of GSTM1, T1 genes null deletion is associated with hypertriglyceridemia and low HDL-cholesterol level. In the light of these findings, it was thought that there may be a connection between lipid metabolism and GSY balance, and it was explained as follows: that GSTs have Peroxisome Proliferator-Activated Receptor (PPAR) preventing effect may be associated with reverse cholesterol transport system. PPARs are defined as a group of nuclear proteins in the field of Molecular Biology. It has been found that PPARs act as transcription factors regulating gene expression. Their main roles have been determined in the regulation of cell differentiation and development, carbohydrate, protein and lipid metabolism, and also tumour formation. Retinoid X Receptor (RXR) becomes dimerized with PPAR and starts the transcription by connecting to a suitable part of the target gene on DNA. 15-Deoxy-Δ [12,14] is among the final products of prostaglandin J2 (15-d-PGJ2), prostaglandin D2 metabolism, and its biological effect is to mediate PPAR γ.

In the studies, it has been observed that the cytotoxicity of 15-d-PGJ2 and the activation of PPAR γ-dependent transcription decrease. This decrease happens with the Glutathione conjugates of 15-d-PGJ2 and 15-d-PGJ2-SG (oxidized form) and the expressions of MRP ensuring its transportation outside the cell.

GSTs that catalyze glutathione conjugates have no effect on 15-d-PGJ2 cytotoxicity alone or in combination with MRP1. Nevertheless, PPARγ that is 15-d-PGJ2-dependent activator inhibits PPARγ-responsible target gene. The level of this inhibition is in direct proportion to the level of GST expression.

The prevention of PPAR activation leads to the increase in TG level, and it is expected that HDL-cholesterol level decreases with reverse cholesterol transport system [27].

As also indicated in the study in question, the fact that GSTs do not have both alleles (null deletion) is associated with hypertriglyceridemia and low level of HDL-cholesterol. It is possible that this connection affects the risk of coronary artery disease.

Diabetes, which is regarded as another risk factor in the occurrence of cardiovascular diseases, has been associated with GST. In a study carried out in the Chinese population by Wang et al., whether there is a connection between GSTM1, T1 and quinone oxidoreductase 1 (NQO1) gene polymorphisms and type 2 diabetes has been assessed, and it has been found that T2 diabetes risk has statistically significantly decreased 0,49 times when compared to GSTT1 positive individuals. Starting from here, it has been put forward that the GSTT1 gene may be a candidate gene in the development of T2 in the Chinese population [28]. Also, in a study carried out in India, it is indicated that different combinations of GST gene polymorphisms affect T2 diabetes risk [29].

Connections between GSTM1 and T1 gene polymorphisms and the possibility of coronary artery disease have been defined in previous studies [9, 30-32].

Conclusion

There is a constant free radical formation in the organism as a result of the effect of oxygen in metabolic pathways, and the exposure to radiation, drugs, and harmful chemical substances. These free radicals create oxidative stress. Antioxidant system enzymes ensure the protection of the balance in the organism and the maintenance of life by deactivating these free radicals. Oxidative damage, which is formed as a result of the increase in oxidative stress and the insufficiency of the antioxidant system against this situation, exists in the formation of more than 100 diseases, including cardiovascular diseases. Free radicals deteriorate cell structure by damaging lipids, proteins, and nucleic acids because of their reactive structure. The organism has many proteins that bind enzymes such as Superoxide dismutase (SOD), Glutathione Peroxidase (GSH-Px), Glutathione S-Transferase (GST), Catalase (CAT), Glutathione Reductase, vitamins, and metal ions that act as an antioxidant system component in the organism and deactivate free radicals [33]. GST gene polymorphisms, which are among antioxidant system enzymes, have a relationship with each of the factors that are considered among the risk factors for cardiovascular diseases. Consequently, it can be said that the polymorphisms of GST genes are effective both in the risk factors of cardiovascular diseases and directly in cardiovascular diseases.

Competing interests

The authors declare that they have no competing interests.

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Ayse Yigit, Hasan Basri Savas. Glutathione S-Transferase Enzyme Gene Polymorphisms and Cardiovascular Diseases. J Clin Anal Med. 2016;7(5):749-752

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