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January 2020

January 2020


Original Article

The relationship between vitamin d level and disease activity in patients with rheumatoid arthritis

Gokhan Akdağ 1 , Şükran Erten 2 , Selçuk Akan 1 , Güniz Yanık Üstüner 1 , Orhan Küçükşahin 2 , Turan Hilmi Yeşil 2 , Bülent Yalçın 3 

1 Departments of Internal Medicine, 2 Rheumatology, 3 Medical Oncology, Yıldırım Beyazıt University Medical Faculty, Ankara, Turkey

DOI: 10.4328/JCAM.6081 Received: 13.11.2018 Accepted: 08.02.2019 Published Online: 11.02.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):10-14

Corresponding Author: Selçuk Akan, Instructor of Internal Medicine, 06800, Ankara, Turkey. T.: +90 3122912525 E-Mail: dr_selcukakan@hotmail.com

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Aim: In this study, we aimed to reveal the relationship between disease activity level and serum 25 (OH) vitamin D level in rheumatoid arthritis (RA), a chronic autoimmune disease. Material and Method: Ninety-one patients with RA and 90 healthy controls were included in the study. DAS28 score and 25 (OH) vitamin D levels of the patient group and control group were compared. Results: The mean serum 25 (OH) vitamin D level of patients and controls were 16,8 ± 10,1 μg / L and 28.3 ± 16 μg / L, respectively. 25 (OH) vitamin D levels were statistically significantly lower in the patients group than in the control group (p <0.001). In total, serum 25 (OH) vitamin D levels and DAS28 scores of the patients were not significantly correlated (r = -0.058, p = 0.588). Correlation analysis according to sexes showed negative correlation between serum 25 (OH) vitamin D level and DAS28 score in males (r = -0,646, p = 0,002) and no correlation was found in females (r = 0,113, p = 0,346). Discussion: Low serum 25 (OH) vitamin D may play a role in the pathogenesis of RA patients. The significant relationship between disease activity and serum 25 (OH) vitamin D level in male gender shows that this effect is more prominent in male sex.

Keywords: DAS28; Rheumatoid Arthritis; Vitamin D

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Introduction

The main source of vitamin D, which is an oil-soluble vitamin, is the cholecalciferol produced in the skin. Vitamin D, produced by sunlight (UV), is metabolized and transformed into an active form in the liver and kidneys.

Studies conducted in recent years have shown that vitamin D receptors are also involved in the immune system cells and that vitamin D may have effects on natural and acquired immunity.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune, inflammatory disease that targets synovial tissues as a primary [1,2]. Rheumatoid arthritis has the highest prevalence among the types of inflammatory arthritis seen worldwide. Although the etiology is not clearly known, it is thought that it is caused by the effects of some genetic and environmental trigger factors.

The discovery of the presence of vitamin D receptors (VDR) in various immune cells and the local vitamin D metabolism in these cells has shown that vitamin D plays an important role in the regulation of immunity [3]. 1,25-dihydroxy vitamin D acts as a kind of immunomodulator that suppresses dendritic cell maturation and functions, inhibits the proliferation of T-and B-cells, and inhibits proinflammatory excretion, thereby reducing immune system activation. For this reason, theoretically, an increase in the development of autoimmune diseases such as RA can be observed due to impaired immunological tolerance in the case of vitamin D deficiency. This has been demonstrated in animal studies [3-5].

The role of vitamin D on immunity, which is believed to be related to autoimmune diseases and that results in different outcomes in studies on this subject, is still controversial and studies are ongoing. Previously, many studies investigating the relationship between vitamin D levels and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, sjögren syndrome, ankylosing spondylitis and FMF have yielded different results [6-8]. We conducted this study to investigate the relationship between serum vitamin D levels and disease activity in patients with RA.

Material and Methods

A total of 91 patients who were referred to the Ankara Atatürk Training and Research Hospital Rheumatology polyclinic, who were diagnosed with RA according to the 2010 ACR / EULAR classification criteria and 90 healthy controls were evaluated in the study. People taking vitamin D and calcium supplements, those taking osteoporosis treatment, those with renal insufficiency, and people with inflammatory rheumatic disease other than RA were not included in the study.

Age, gender, age of onset, age at diagnosis, treatment and treatment response, smoking status, additional disease history, axial joint involvement, peripheral joint involvement, rheumatoid nodule and eye involvement were evaluated. DAS28 activity scoring was used to determine disease activity status. Deficiency of vitamin D levels was accepted as <10 μg/L, insufficiency was accepted as 10-30 μg/L and optimum level was30-80 μg/L.

RF, anti-CCP, 25 (OH) vitamin D level were evaluated in patients’ venous blood samples with the nephelometric method, electrochemiluminescence immunoassay (ECLIA) method, liquid chromatography-mass spectrometry (LC-MS) method respectively. In addition, complete blood count, biochemical parameters (liver and kidney function tests, electrolytes), thyroid stimulating hormone (TSH), CRP, ESH, parathyroid hormone (PTH) results were evaluated in the routine controls of the patients.

The present study was approved by Yıldırım Beyazıt University Ankara Atatürk Education Research Hospital Ethics Committee. During the study, the guidelines of the World Medical Association Helsinki Declaration and Good Clinical Practice Guidelines were followed.

Statistical Analysis

Statistical analysis of the data was performed with SPSS (Statistical Package for SocialSciences) for Windows 20.0 package program. Categorical measurements were shown as number and percentage, continuous measurements were shown as mean and standard deviation (continuous median and minimum-maximum where necessary). The Chi-Square test or Fisher’s test was used to compare categorical variables.

The Student’s T-test and ANOVA were used for parameters with normal distribution according to the number of variables; The Mann-Whitney U test or Kruskal-Wallis test were used for the parameters with nonnormal distribution. The Spearman and Pearson’s analyzes were used for the correlation analyzes. The statistical significance level was taken as p <0.05 in all tests.

Results

A total of 181 patients, 91 patients with RA and 90 control subjects without rheumatic and systemic disease were included in the study. The mean age of patients with RA was 53 ± 11 and the meane age of the control group was 50 ± 9. The patient group consisted of 20 (22%) male, 71 (78%) female and the control group consisted of 23 male (25.6%) and 67 (74.4%) female (Table 1). There was no significant difference between the two groups in terms of age and gender (n = 181, p = 0,050, p = 0,57, respectively).

All patients were evaluated for RF and 53 patients (58.2%) were RF positive. Anti-CCP was evaluated in 81 patients and was positive in 47 patients (58%). When seropositive patients were evaluated together, 34 (37.3%) patients were both RF and anti-CCP positive. There was no difference between the average number of painful and swollen joints in patients with positive or negative RF and anti-CCP (p> 0,05).

The RA activity status of the patients was evaluated by DAS28 scoring. According to DAS28 score, 10 (11%) patients were found to have high activity, 40 (44%) had moderate activity, 17 (18.7%) had low activity, and 24 (26.4%) patients were in remission.

Deficiency of vitamin D levels was accepted as <10 μg/L, insufficiency level was accepted as 10-30 μg/L and the optimum level was 30-80 μg/L. Thirty (33%) patients with RA had vitamin D deficiency, 56% (51) had insufficiency, and 11% (10) had optimal level.

In the control group, 3.3% (3) had vitamin D deficiency, 58.9% (53) had insufficiency, and 37.8% (34) had an optimum level. In patients with RA, 25 (OH) vitamin D and total protein levels were statistically significantly lower. There was no difference in the levels of calcium, phosphorus, albumin, and parathormone level between the RA patients and the control group (Table 2).

Serum 25 (OH) vitamin D levels and DAS28 scores were compared in patients with RA, but no significant correlation was found between them (r = -0.058, p = 0.588). Correlation analysis according to genders revealed negative correlation between serum 25 (OH) vitamin D level and DAS28 score in males (r = -0,646, p = 0,002). There was no correlation between serum 25 (OH) vitamin D levels and DAS28 in women (r = 0,113, p = 0,346). In addition, there was no significant relationship between DAS28 and 25 (OH) vitamin D groups (p = 0,322). When DAS28 and 25 (OH) vitamin D groups were compared in men with RA, there was a statistically significant relationship between low and moderate disease activity and insufficiency groups (p <0.05). There was no significant relationship between DAS28 and 25 (OH) vitamin D groups in women (p = 0.45) (Table 3).

No significant difference was found between the 25 (OH) vitamin D groups and VAS values of the patients (p = 0,65). There was no correlation between serum 25 (OH) vitamin D levels and the disease duration of RA and the time elapsed since RA diagnosis (r = -0,030, p = 0,781, r = -0,016, p = 0,879, respectively). There was negative correlation between serum albumin level and DAS28 score (r = -0,378, p = 0,000). There was no significant correlation between serum 25 (OH) vitamin D levels and number of painful and swollen joints in patients with RA (r = -0,065, p = 0,538, r = 0,098, p = 0,354, respectively).

Discussion

In our study, vitamin D deficiency was detected in 89% of patients with RA and in 62.2% of control group. The mean value of 25 (OH) vitamin D levels of the patients were significantly lower than the control group. There was no significant correlation between DAS28 activity score and serum 25 (OH) vitamin D levels in RA patients in total. In the subgroup analysis, there was a negative correlation between DAS28 score and 25 (OH) vitamin D levels in the male patient group of RA, but no correlation was found in the female patient group. In addition, insufficiency of 25 (OH) vitamin D was found to be more frequent in the male RA patients with low and moderate disease activity in the analysis made between DAS28 scores and 25 (OH) vitamin D levels. In female sex, there was no relationship between disease activity status and serum 25 (OH) vitamin D groups.

In a study of 1191 patients and 1019 healthy control groups, Rossini et al. reported that there was no difference in serum 25 (OH) vitamin D levels between the RA patients and the control group, but there was a significant negative correlation between serum 25 (OH) vitamin D levels and DAS28 score in RA patients [09]. Similarly, when Zakeri et al. conducted a study in patients with RA, a significant negative correlation was found between disease activity determined by DAS28 score and serum 25 (OH) vitamin D levels. There was also a significant correlation between elevated VAS (visual analog scale) levels and increased number of swollen joints and low serum 25 (OH) vitamin D levels [10]. Six hundred and twenty-five RA patients (529 females, 96 males) from 13 European countries were included in a multicenter study conducted in Europe. There was a negative correlation between the 25 (OH) vitamin D levels, DAS28-CRP (p <0.0001), RAID (p = 0.04) and HAQ (p = 0.02) scores in RA patients. The average serum 25 (OH) vitamin D concentration (17.62 ± 9.76 ng / ml) of the RA patients was significantly lower than the control group (18.95 ± 9.45 ng / ml) (p = 0.01) [11]. In a meta-analysis, 15 studies were analyzed. The serum 25(OH) vitamin D levels of 1143 RA patients were significantly lower than the control group (p = 0.017). The DAS28 scores and the 25 (OH) vitamin D serum levels were inversely correlated (p = 0.000) [12]. In our study, it was observed that there was a statistically significant inverse relationship between DAS28 disease activity score and serum 25 (OH) vitamin D levels in male population only, but no significant correlation was found between VAS, number of painful and swollen joints and serum 25 (OH) vitamin D levels.

In the study performed by Turhanoğlu et al., the relationship between functional health status and disease activity and vitamin D levels were evaluated in RA patients and no difference was found. When the 25 (OH) vitamin D levels were compared according to disease activity, the serum 25 (OH) vitamin D level was found to be significantly lower in the high activity group than in the medium and low activity groups. When the low activity group was compared with the medium activity group, the 25 (OH) vitamin D levels of the medium activity group were found to be significantly lower. Serum 25-OH vitamin D levels were also found to be negatively correlated with DAS28, CRP, and HAQ [13].

In a study of 176 RA patients by Higgins et al., no significant correlation was found between vitamin D levels and DAS28 scores. However, only an inverse relationship was found between VAS and vitamin D levels. In addition, there was no significant relationship between duration of illness and serum 25 (OH) vitamin D level [14]. In a study with 35 patients in the United Arab Emirates, there was no significant correlation between serum vitamin D levels and disease activity score (DAS28) or HAQ scores [15]. In another study with patients with RA, a moderately significant negative correlation was found between serum 25 (OH) vitamin D level in active disease, pain, and number of sensitive joints and DAS28, but no significant correlation was found between parameters in the remission group [16]. In our study, we did not find a significant correlation between serum 25 (OH) vitamin D levels and DAS28 scores in patients with RA. Similar to the study of Turhanoğlu et al., but only in male gender, we found that there was a significant inverse correlation between DAS28 score and serum 25 (OH) vitamin D level.

The NHANES (The National Health and Nutrition Examination Survey) and NHANES III trials have calculated the prevalence of vitamin D deficiency and insufficiency in the American public. Serum 25 (OH) vitamin D levels of 18158 participants were examined in the NHANES III study and percentage of vitamin D insufficiency (20-30 nmol / L) was found 33% and percentage of vitamin D deficiency (<20 nmol / L) was 22%. In the NHANES study, percentage of vitamin D insufficiency was found to be 41% and the percentage of vitamin D deficiency was found to be 36% by considering the serum 25 (OH) vitamin D levels of 20289 participants [17]. In our study, deficiency of vitamin D levels was accepted as <10 μg/L and insufficiency was accepted as 10-30 μg/L. In healthy control group, these rates were 3.3% and 58.9%, respectively. In the patient group, 33% and 56% respectively. The vitamin D levels of both patient and control group were found to be lower than the American population.

The relationship between serum 25 (OH) vitamin D levels and other autoimmune/autoinflammatory diseases was also investigated. 25 (OH) vitamin D levels were significantly lower in patients with FMF and Sjögren’s syndrome (SS) [6,7]. In a similar study, people with autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis (PM), dermatomyositis (DM) and multiple sclerosis (MS) were compared with healthy adults. 25 (OH) Vitamin D levels of the patient group with RA were found to be relatively low [8]. Our study was also concluded similarly and supported the hypothesis that vitamin D deficiency may play a role in the pathogenesis and disease activity of autoimmune diseases.

In the present study, we showed that vitamin D levels were lower in patients with RA than in healthy individuals and it may be related to disease activity. Therefore, it has been shown that vitamin D levels should be routinely measured in patients with RA. Especially in men, deficiencies should be eliminated. However, the different results obtained in previous studies suggests that there is a need for prospective studies on larger patient populations.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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12. Lee YH, Bae SC. Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: a meta-analysis. Clin Exp Rheumatol. 2016 ; 34(5): 827-33.

13. Turhanoğlu ADGüler HYönden ZAslan FMansuroglu AOzer C. The relationship between vitamin D and disease activity and functional heath status in rheumatoid arthritis. Rheumatol Int. 2011; 31(7):911-4.DOI: 10.1007/s00296-010-1393-6.

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Akdağ G, Erten Ş, Akan S, Üstüner GY, Küçükşahin O, Yeşil TH, Yalçın B. The relationship between vitamin d level and disease activity in patients with rheumatoid arthritis. J Clin Anal Med 2019; Ann Clin Anal Med 2020;11(1):10-14

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The essential predictors of recurrence in patients with hepatocellular carcinoma after liver transplantation

Ali Ozer

Departmen of Organ Transplantation, Acibadem Mehmet Ali Aydinlar University, Atakent Hospital, Istanbul, Turkey

DOI: 10.4328/JCAM.6128 Received: 01.08. 2019 Accepted: 18.08. 2019 Published Online: 18.08. 2019 Ann Clin Anal Med 2020;11(1):64-66

Corresponding Author: Ali Ozer, Acibadem Mehmet Ali Aydinlar University Atakent Hospital, Department of Organ Transplantation, Istanbul, Turkey. Email: e-mail:draliozerr@gmail.com GSM: +0905332122324 Corresponding Author ORCID ID: https://orcid.org/ 0000-0003-1825-6736

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Aim: Liver transplantation is the optimal treatment for a selected group of patients with hepatocellular carcinoma (HCC). Post-transplant recurrence is common and markedly reduces the long-term survival of patients with HCC. The present study focuses on determining the predictive factors affecting the recurrence of HCC. Materials and Methods: Data of 106 patients with HCC who underwent liver transplantation between May 2012 and June 2018 were collected retrospectively. Variables were as follows: age, gender, preoperative alpha-fetoprotein (AFP) levels, MELD score, number of tumors, total tumor size and histological features. Results: Recurrence-free survival and overall survival rates were 91.5% and 94.3%, respectively. Cox regression analysis demonstrated that age, gender, MELD score, and Milan criteria had no effect on recurrence. Microvascular invasion (MVI) was detected in 55 patients (52%), and 51 patients (48%) had no MVI. The presence of MVI had a negative effect on tumor recurrence, and there was a statistically significant difference (p<0.001). There was also a significant difference in tumor recurrence between patients who had AFP levels under 400 IU/mL and those who had AFP levels above 400 IU/mL (p<0.001). Discussion: AFP level and the presence of MVI are significantly useful for predicting recurrence-free survival in patients with HCC following liver transplantation.

Keywords: Liver Transplantation; Hepatocellular Carcinoma; Recurrence

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  • Introduction

    Liver transplantation (LT) is a forceful treatment and potential cure for hepatocellular carcinoma (HCC). Criteria based on the size and number of tumors are widely used for selecting HCC patients for LT. The recurrence of HCC remains the most important issue in this matter, affecting up to 20% of patients, despite the restrictive selection criteria [1].

    Tumor size, histological findings, and preoperative alpha-fetoprotein (AFP) levels are currently the most important predictors for HCC recurrence in patients after LT [2,3], to the point that some reports argue that the combination of positron emission tomography (PET) positivity and AFP levels predict the recurrence risk better than tumor and number size do. These studies utilized preoperative PET results to define the histological features of the tumors [4,5].

    In this retrospective study, we report a clinicopathological analysis of the risk factors affecting HCC recurrence after LT in a single center.

    Material and Methods

    The design of this study was retrospective in nature. The approval of the local ethics committee was obtained with the protocol number 2018-17/4. We performed 514 LTs between May 2012 and June 2018 at our institution; 106 of these LTs were conducted on patients with HCC. The patients were reviewed on a retrospective basis, and the characteristics and outcomes of the patients were recorded. The factors affecting recurrence were evaluated.

    Our selection criteria for HCC patients were mainly based on the Milan criteria, with patients selected if they demonstrated no evidence of extrahepatic metastases or macrovascular invasion. Computerized tomography angiography (CT-a) and magnetic resonance angiography (MR-a) were used to evaluate tumor size, tumor number, and any vascular invasions. PET imaging has been established as a diagnostic tool for evaluating metastatic liver tumors. Patients with AFP levels over 400 IU/mL were not accepted for LT. These patients underwent locoregional therapies (LRT), e.g. transarterial chemoembolization. If their AFP levels decreased below 400 IU/mL and did not increase above 400 IU/mL after the observation period following LRT, they were accepted for LT. Patients with a minimum one-year follow-up time and/or those who reached the end-point (recurrence and/or death) were enrolled in the study.

    Statistical Analysis

    Descriptive statistics were stated as percentages for categorical variables, and mean ± standard deviation or median and range were used for continuous variables. Comparisons were analyzed using the Chi-square test for categorical variables and the Student’s t-test for continuous variables (if normality was observed) or Cox regression analysis (in other cases). Overall survival and tumor-free survival rates were estimated using the Kaplan-Meier method. A p-value of p<0.05 was considered statistically significant in all analyses.

    Results

    The baseline clinical characteristics of the 106 patients included in the study are summarised in Table 1. HCC recurrence was detected in nine patients, and six patients were lost due to HCC recurrence or other factors, e.g. biliary complications. Hence, during the minimum one-year follow-up period, recurrence-free survival and overall survival rates were 91.5% and 94.3%, respectively.

    Age, gender, and MELD scores had no effect on recurrence. The recurrence rate was similar in patients within and beyond the Milan criteria. According to Cox regression analysis of tumor characteristics, number, size, total volume and histologic differentiation of tumors showed no significant effect on the recurrence of HCC.

    Microvascular invasion (MVI) was detected in 55 patients (52%), and 51 patients (48%) had no MVI. The presence of MVI had a negative effect on tumor recurrence, and there was a statistically significant difference (Figure 1, p<0.001). There was also a significant difference in tumor recurrence between patients who had AFP levels under 400 IU/mL and those whose AFP levels were above 400 IU/mL (Figure 2, p<0.001).

    Discussion

    In this retrospective study, univariate analysis of features of patients and tumors showed that AFP levels and the presence of MVI predicted recurrent rates of HCC in patients who underwent LT, independently of tumor size, number, grade and other clinical prognostic criteria like the Milan criteria. The recurrence rate was 8.5% in the present study, which is similar to that in the literature [6,7].

    Morphological features, such as tumor numbers, diameter, total size, and total volume are mostly used as prognostic criteria. However, there is an increasing concern that strict criteria based on morphological features may exclude a significant number of patients from LT [8]. For this reason, expanded criteria have been developed in the last several decades, and substantial outcomes have been achieved [9,10,11]. We also used the Milan criteria to select patients for LT, and analysis of outcomes for our patients demonstrated no significant difference associated with post-LT recurrence of HCC.

    AFP is commonly used as a prognostic factor and a monitoring tool for post-transplant recurrence [12]. Further, the reduction of AFP following LRTs is considered to be a positive prognostic factor. However, there is no consensus about a cut-off point in preoperative AFP [13,14]. We accepted patients with AFP levels of 400 IU/mL for LT; AFP levels over 400 IU/mL in patients were strongly associated with tumor recurrence.

    MVI has also been determined to be an important predictive factor for recurrence in some studies [1,15]. Our results, in contrast, demonstrated that MVI is a poor diagnostic factor for recurrence. However, MVI is a histopathological diagnosis, and information about MVI cannot be obtained preoperatively. Only limited studies recommended using 18F-fluorodeoxyglucose PET to predict tumor differentiation and the presence of MVI [5,16]. We routinely used PET to evaluate the metastases of HCC. However, our data did not support the role of PET in determining MVI preoperatively.

    Conclusion

    This study demonstrated that MVI and AFP levels are the most valuable prognostic factors for predicting tumor recurrence. Early identification of predictive parameters for recurrence and a careful strategy for selection should be mandatory for patients with HCC who are to undergo LT.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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    8. Piardi T, Gheza F, Ellero B, Woehl-Jaegle ML, Ntourakis D, Cantu M, et al. Number and tumor size are not sufficient criteria to select patients for liver transplantation for hepatocellular carcinoma. Ann Surg Oncol. 2012;19(6):2020-6.

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Ali Ozer. The essential predictors of recurrence in patients with hepatocellular carcinoma after liver transplantation. Ann Clin Anal Med 2020;11(1):64-66

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Analysis of 144 pediatric nosocomial candidaemia episodes over a four-year period

Emine Kocabas 1 , Ummuhan Cay 2 , Gulperi Timurtas Dayar 3 , Ceren Cetin 4 , Gulsah Seydaoglu 5 , Filiz Kibar 6

1 Department of Pediatric Infectious Diseases, Cukurova University, Adana,2 Department of Pediatric Infectious Diseases, Adana City Research and Training Hospital, Adana, 3 Department of Pediatric Infectious Diseases, Antalya Research and Training Hospital, Antalya, 4 Department of Pediatric Infectious Diseases Kocaeli Research and Training Hospital, Kocaeli, 5 Department of Biostatistics, Cukurova University, Adana,6 Department of Microbiology, Cukurova University, Adana, Turkey

DOI: 10.4328/JCAM.6090 Received: 20.11.2018 Accepted: 16.03.2019 Published Online: 27.03.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):15-19

Corresponding Author: Emine Kocabas, Department of Pediatric Infectious Diseases, Cukurova University, Adana, Turkey. E-Mail: kocabas.emine@gmail.com ORCID ID: https://orcid.org/0000-0002-1470-9740

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 Aim: The term candidemia simply indicates the presence of Candida species in the blood. Candida spp. are important pathogens in neonatal intensive care unit (NICU) patients, critically ill patients, and those with underlying immunocompromising conditions. Material and Method: In this retrospective study, 144 nosocomial candidemia episodes of 106 pediatric patients who had been admitted to pediatric units of Çukurova Univesity Hospital from 2010 January to 2013 December were evaluated. These 106 children’s demographic and clinical features, risk factors, blood and intravascular line cultures, antifungal resistance, treatment and clinical outcome were evaluated. Results: The most frequently isolated species were Candida parapsilosis (31.9%), C. albicans (29.2%). C. tropicalis (16.0%), C. kruseiandC. Famata (4.2%),C. Glabrata (3.5%). Risk factors of 106 pediatric patients with Candidemiae were investigated. The main risk factors for candidemia included the presence of intravascular (IV) lines (68.1%), multiple antibiotics therapy (79.1%), total parenteral nutrition (59.7%), nasogastric tube insertion (45.1%), mechanical ventilation (34.7%), admission to intensive care unit (32.6%), and neutropenia (22.9%). The overall mortality rate of candida species was 17.9%. Discussion: Regular surveillance of local Candida species, resistance profiles, and risk factors are important in order to identify patients at risk and to develop empirical treatment protocols to reduce the incidence and mortality of candidemia.

Keywords: Candida; Risk Factor; Mortality; Childhood

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  • Introduction

    During recent years, fungal infections are reported to constitute an increasing proportion among all nosocomial infections, only preceded by bacterial infections. Regarding invasive fungal infections, Candida species are the leading causative agents in hospitalized children. In the United States, Candidaspecies are reported as the third leading cause of healthcare-associated bloodstream infections [1,2].

    Although the most common agent in Candidemia is C. albicans, there has been an increasing incidence of non-albicans Candidaspecies in recent years [3,4]. Especially among child patients, C. parapsilosis and C. tropicalisconstitute more than half of the non-albicans Candidainfections [5,6]. According to studies, the most common risk factors for Candidemia are broad-spectrum antibiotic use, total parenteral nutrition (TPN), the presence of a central venous catheter, malignancy, chemotherapy, immunosuppressant use, neutropenia, and diabetes [7-9].

    Nosocomial fungal infections are an important cause of increased morbidity and mortality. Some causes of increased frequency of fungemia and fungemia-associated mortality are the increasing number of diagnostic and therapeutic interventions applied to patients as a result of the advances in modern medicine, widespread use of treatment regimes that suppress host defense mechanisms, and ever-growing utilization of broad-spectrum anti-bacterial drugs. Among all children with sepsis, fungal infections are the second leading cause of mortality (13%). Candidemiais often characterized by symptoms and signs of sepsis [2,3,10-12].

    In this study, we aimed to investigate the demographical and clinical features and treatment outcomes of Candidemiaepisodes that developed in patients hospitalized in pediatric wards of Çukurova University Hospital, to determine the predisposing risk factors for the purpose of taking necessary precautions, and to compare epidemiologic variations in nosocomial candidemia.

    Material and Methods

    In this study, we retrospectively examined 144 candidemiaepisodes in 106 patients who were treated as inpatients in intensive care units (pediatric, neonatal, cardiovascular surgery, pediatric surgery, neurosurgery), pediatric hematology and oncology wards, and other pediatric wards from January 2010 to December 2013. A data form was created; each patient’s demographical and clinical features, risk factors, blood and catheter culture results, antifungal resistance patterns, treatment, and clinical outcomes were obtained from patient files and were recorded on these data forms. In some patients, antifungal treatment was initiated empirically based on the patient’s age, the site of candidagrowth and underlying disease (especially febrile neutropenia); and it was adjusted according to antifungal sensitivity results. The study was approved by the institutional review board.

    Candidemiais defined as isolation of a Candidaspecies in at least one blood and/or catheter culture in the presence of systemic symptoms and signs. Catheter-associated Candidemia is regarded as >15 cfu candida growth in a catheter-tip culture. Utilization of one or more types of antibiotics for more than 14 days, neutropenia (absolute neutrophil count <1000/mm³), history of surgical operation within the last 30 days, TPN and catheter applications, chemotherapy and malignancy were accepted as risk factors. Deaths occurring within the first 30 days in the presence of clinical, microbiological and/or histological evidence were accepted as Candidemia-associated mortality.

    All the data were analyzed using SPSS version 20 (SPSS, Chicago, IL, USA) statistics package software. Student t-test and chi-square tests were used for comparison of the groups.

    p< 0.05 was accepted as the level of statistical significance.

    Results

    Table 1 shows the demographical and clinical features of 106 patients with Candidemiaincluded in this study. Mean age (± SD) was 43± 47 months (median age: 28 months). The male/female ratio was 54/52. Of these patients, 28.8% were admitted to intensive care units and 25.5% were admitted to pediatric hematology and oncology wards.

    Of the examined patients, 82 (77.3%) were younger than 60 months while 24 (22.7%) were older than 60 months. The general mortality rate was 17.9%. Of those patients who died, 68.4% (n: 13) were younger than 60 months, and 47.3% (n:9) were younger than 12 months.

    General mortality rate among cases with Candidemia was 17.9%. Mortality rate was higher among children younger than 60 months (68.4%), with C. albicansspecies (25%) and C.nonalbicansisolates (75%) (Table 7). Only one patient developed endophthalmitis (0.9%) as a complication.

    Table 2 summarizes risk factors for Candidemia. Main risk factors detected in 106 patients with Candidemiaexamined in our study were: intravascular catheter (68.1%), multiple antibiotherapy (79.1%), total parenteral nutrition (59.7%), nasogastric tube (45.1%), mechanical ventilation (34.7%), admission to intensive care unit (32.6%) and neutropenia (22.9%).

    Table 3 shows Candidaspecies isolated from blood and catheter cultures. The most frequently isolated Candidaspecies are C. parapsilosis(31.9%), C. albicans(29.2%), and C.tropicalis(16.0%).

    Table 4 shows the body fluids from which Candida species were isolated during Candidemia episodes. Candida species were isolated from blood culture in 94.4% and from catheter culture in 5.6% of Candidemia episodes.

    Table 5 shows the results of anti-fungal sensitivity test in isolated Candida species. Totally 7 of the 144 isolates (4.9%) were found to have antifungal resistance, and all of these isolates were NAC species. Amphotericin B resistance was detected in 2 (1.4%) isolates; fluconazole resistance was detected in 4 (2.8%) isolates; and voriconazole resistance was detected in 1 (0.7%) isolate. One isolated C.parapsilosisspecies had resistance against amphotericin B, while another isolated C.parapsilosisspecies had resistance against both amphotericin B and voriconazole.

    Table 6 shows sensitivity to fluconazole among Candida species, and the association between Candida species and mortality. All C. albicans isolates were sensitive to fluconazole, while 3.9% of Candida nonalbicans isolates were resistant against fluconazole. Of the 6 isolates of C. krusei, 4 (66.7%) had resistance against fluconazole.

    Treatment Outcomes of Patients

    Of all patients, 40.6% received fluconazole. According to the guideline on febrile neutropenic patients, 26.2% received amphotericin B, 15.3% received caspofungin, 9.6% received voriconazole, and 2.6% received amphotericin B + flucytosine. For those who had catheter infection, catheter was removed. When the treatment was initiated empirically in febrile neutropenic patients, the treatment was not changed if the antifungal sensitivity test results showed that the growing Candida species was sensitive to the administered drug.

    Table 7 shows risk factors responsible for the development of C. albicans andC.nonalbicansinfections. In comparison to C. albicans,the major risk factors in Candida nonalbicansinfections were as follows: mechanical ventilation, presence of the urinary catheter, nasogastric tube placement and admission to intensive care units (p < 0.01, p < 0.05). Among patients with Candidemiawho did not receive gastric acid suppression treatment, C. nonalbicansinfection was more frequent (%75.2) compared to C. albicans(%24.8) (p<0.05). C. albicansinfection was significantly more frequent compared to C.nonalbicans infection among patients treated in the intensive care unit (p<0.005).

    Discussion

    Candida-associated fungemia takes the lead among all nosocomial fungal infections.

    Studies related with Candidemia report the major risk factors for the development of these infections as broad-spectrum antibiotic use, total parenteral nutrition, central venous catheter, malignancy, chemotherapy, immunosuppressant drug use, neutropenia and diabetes [7,9]. According to our results, major risk factors for the development of all Candidainfections were found as multiple antibiotic use (79.1%), the presence of central venous catheter (68.1%), total parenteral nutrition (59.7%), in decreasing order of frequency; and our results seem to be consistent with previous reports. Moreover, in comparison with patients with C.albicans infections, mechanical ventilation (34.7%), the presence of nasogastric tube (45.1%), admission to intensive care unit (32.6%) and presence of urinary catheter (29.1%) were significantly more frequent among patients with Candida nonalbicansinfections (p<0.05). Candidanonalbicans infections were significantly more frequent in comparison to C.albicansinfection among patients who receive gastric acid suppression treatment (75.2% vs. 24.8%) (p<0.05).

    Considering admission rates to intensive care and neonatal intensive care units in our study group (31.2%+20.1%=51.3%), our results are predictable and consistent with the results of previous studies.

    Recent studies related with Candidemiain child patients show that the proportion of C.albicansinfection is decreasing, being replaced by Candida non-albicans infections [9,11,13,15-17]. In our study, the most frequently isolated Candida species during Candidemia episodes within the last 3 year was (% 29,2); and the proportion Candidemiadue to non-albicans Candida was 70.8% (Figure 1). Especially between the years 2011 and 2013, we detected an increase in the proportion of Candida non-albicans (62.5%-70.8%) infections in comparison to C.albicans infections (17.6%-37.5%), which was a finding that is consistent with previous reports (Figure 2).

    Studies report the most frequently isolated non-albicans Candidaspecies as C. tropicalis, C. parapsilosis,C. glabrata and C. krusei. While C. parapsilosis takes the lead among Candidemia causes in Europe, Canada, and Latin America countries; in the US, the most frequent cause is C. glabrata [14].In their study involving 102 pediatric patients, Çelebi et al. [15] detected C. albicans in 39.2%,C.parapsilosis in21.6%, C. tropicalis in 15.7%, andC.glabrata in 6.9%of patients.In our study, we detected C. albicans in 29.2%,C. parapsilosis in 31.9%, C tropicalis in 16%, andC glabrata in 3.2% of our patients, and our rates were similar to theirs (Figure 2, Table 3).

    Studies in pediatric age group indicate that fluconazole is effective and safe in treatment of Candidemia.Accordingly, 40.6% of the patients in our study group were treated with fluconazole only as the first line of the treatment [18,19]. Additionally, 26.2% of the patients which had febrile neutropenia were treated with amphotericin B, while 15.3% received caspofungin, 9.6% received voriconazole, and 2.6% who had neonatal meningitis were treated with amphotericin B + flucytosine. When the treatment was initiated empirically in febrile neutropenic patients, the treatment was not changed if the antifungal sensitivity test results showed that the growing Candida species was sensitive to the administered drug. Four patients (2.6%) who had ongoing Candidemiarefractory to treatment were treated with a combination of amphotericin B and fluconazole.

    Fluconazole is the most commonly used antifungal for the treatment of invasive Candidainfections, and resistance against fluconazole and other azoles is an important therapeutic problem. Studies show fluconazole resistance does not exist among C.albicans isolates but is present in high rates among C.nonalbicansstrains such as C.krusei (78.5%) and C.glabrata (63.16%). In our study, all of the C.albicans isolates were sensitive to fluconazole, while 2.8% of Candida non-albicansstrains showed resistance against fluconazole, and 66.7% of these resistant strains were C.krusei. Some authors relate the increasing rate of fluconazole resistance to the fact that it is the first line of a drug in the treatment of Candida infection [20].

    One study found Candidemia associated mortality rate as 42.4%; in that study, the majority of the mortal cases were infected with Candida non-albicans isolates and under 1 year of age [21]. Among infants and children, Candidemia- associated mortality rate varies in a wide range between 11% and 54% [17,22-24] . The variation in this rate depends on the underlying disease, age and Candida species. In our study, the general mortality rate among cases with Candidemiawas 17.9%. Mortality rate was 68.4% among children younger than 60 months of age, and 47.3% below 12 months of age. Mortality was higher among patients infected with Candida nonalbicans species (75%).

    As a conclusion, in order to control nosocomial Candidainfections and to reduce mortality associated with these infections, it is of vital importance that regular surveillance studies are carried out, predisposing risk factors are taken under control, and empirical treatment schemes are established after determining resistance profiles.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Kocabas E, Cay U, Dayar GT, Cetin C, Seydaoglu G, Kibar F. Analysis of 144 pediatric nosocomial candidaemia episodes over a four-year period. Ann Clin Anal Med 2020;11(1):15-19

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Management of eosinophilic granuloma localized in the pelvis and extremities

Recep Öztürk 1 , Şefik Murat Arıkan 2 , Emin Kürşat Bulut 2 , Galip Beltir 2 , Bedii Şafak Güngör 2

1 Department Of Orthopaedics And Traumatology, Polatlı Public Hospital, 2 Department Of Orthopaedics And Traumatology, Ankara Oncology Training and Research Hospital, Ankara, Turkey

DOI: 10.4328/ACAM.6007 Received: 19.08.2018 Accepted: 27.10.2018 Published Online: 01.11.2018 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):6-9

Corresponding Author: Recep Öztürk, Polatlı Public Hospital, Ankara, Turkey. GSM: +905054634794 E-Mail: ozturk_recep@windowslive.com ORCID ID: https://orcid.org/ 0000-0002-6753-9321

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Aim: Given the benign biology, and clinical course of eosinophilic granuloma and its higher incidence in pediatric patient group, a successful treatment plan with lower risk for complications is desired. In this study, we aimed to evaluate clinical characteristics, treatment, and outcomes of patients diagnosed with eosinophilic granuloma localized in the pelvis and extremities. Material and Method: Clinical findings, treatment methods, clinical outcomes and treatment failures were evaluated in a total of 19 patients (6 males, 13 females, mean age: 16.5 years, range: 1-37 years) diagnosed with eosinophilic granuloma localized in the pelvis and extremities between 2002 and 2016. Results: The most common mass localization was acetabulum (15%, n = 3). The mean tumor size was 3,7 cm (range: 1-8 cm). All patients presented with pain and had primary tumor. All patients in the study had solitary bone lesion. The mean duration of postoperative follow-up was 46 months (range: 24-95 months). Three patients underwent biopsy alone, and followed-up with adjuvant therapies. In 14 patients, curettage of the lesion was performed at single session during biopsy, and grafting was applied in six of these patients. Two patients underwent excision of the lesion. None of the patients developed recurrence, while a new lesion was detected in the cervical vertebra in one patient after treatment of acetabulum localized lesion. Discussion: The management of eosinophilic granuloma localized in the pelvis and extremities takes place in a wide spectrum varying from observation alone, to lesion curettage, chemotherapy and radiotherapy applications, and prophylactic administration, and treatment tailored for each patient should be planned with a multidisciplinary approach.

Keywords: Eosinophilic Granuloma; Treatment; Long Bone; Pelvis

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  • Introduction

    Also known as histiocytosis X, Langerhans cell histiocytosis (LCH) contain three different conditions including eosinophilic granuloma, Hand-Schüller Christian and Letterer-Siwe diseases [1,2].

    Eosinophilic granuloma is a benign form of the disease progressing with solitary or multiple bone involvement. Although the common localizations of involvement include flat bones and especially the skull, it also may be seen in the long bones of extremities. It is known as a childhood disease, but it may be developed also in adults [2-4].

    Radiologic appearance of the eosinophilic granuloma is highly variable, and it can mimic many benign or malignant tumors, and infections with hyperbolic MRI findings [5, 6].

    The lesion can be followed-up alone because of its benign course once histopathological diagnosis is established. Further treatment is needed in the lesions with a painful course and develop the risk of fracture or deformity [4, 7, 8].

    In this study, we aimed to present the analysis of patients diagnosed with eosinophilic granuloma whom follow-up and treatment were carried out in our center for a 15-year period.

    Material and Methods

    Patients treated and followed-up in the orthopedics and traumatology clinic of our hospital with the diagnosis of eosinophilic granuloma between 2002 and 2016 were retrospectively examined. The study included only the patients who had a histopathological definitive diagnosis. The patients evaluated in the outpatient clinic, who also had Langerhans cell histiocytosis in the differential diagnosis with radiologic clinical features and followed-up without requiring tissue biopsy were excluded from the study.

    Terms “eosinophilic granuloma” and “Langerhans cell histiocytosis” were searched among the data from 2002 when pathology database of our orthopedics clinic was established in 2016. Patients’ data were obtained from the orthopedics oncology files involving clinic and radiologic evaluations at first admission and follow-up of the patients, from operation and pathology reports, and from face-to-face or phone interviews with the patients or their relatives, when deemed necessary.

    The study included a total of 19 patients with 13 being female and 6 male with a mean age of 16,5 years (range: 1 – 37 years) who had the diagnosis of eosinophilic granuloma on histopathologic examination. A written informed consent was obtained from all patients. This study followed principles of the Declaration of Helsinki.

    Patients history, physical examination, posteroanterior chest X-ray, MRI investigations of the affected extremity and routine laboratory outcomes were studied. All patients were assessed by a team consisting of an orthopedist, a radiologist, a pathologist, a medical oncologist, and radiation oncologist. Treatment and follow-up were planned and implemented with a multidisciplinary approach (Image 1).

    All patients were evaluated for the age of admission, localization of the primary tumor, symptoms, and findings, tumor size, type of the surgical procedure, and recurrence.

    Statistical analysis

    Statistical analysis was performed using SPSS 22.0 statistical software (SPSS, Chicago, IL, USA). Descriptive statistics are expressed as the mean ± standard deviation, frequency, and percentage.

    Results

    All patients presented with primary tumors at the first admission and all patients had localized disease at the time of diagnosis. The most common localization of lesions was acetabulum (n=3, 15%). Of the lesions two (10%) were localized in the diaphyseal femur, two (10%) in the proximal femur, two (10%) in the diaphyseal humerus, two (10%) in the ilium, two (10%) in the ischium, one (5%) in the diaphyseal fibula, one (5%) in the proximal humerus, one (5%) in the clavicle, one (5%) in the scapula, one (5%) diaphyseal tibia, and one (5%) in the proximal ulna.

    All patients had localized pain which was the main complaint of admission. None of the patients in this series had systemic findings that may accompany to this lesion (fever, leukocytosis, increased sedimentation rate, and liver dysfunction etc.)

    Three patients underwent diagnostic biopsy only as a surgical intervention. The first of them was an 8-year-old male patient with a lesion in the right diaphyseal fibula. He was followed-up after confirming the diagnosis and developed regression at follow-up. The second one was a 1-year-old infant with a lesion in the left proximal ulna. He was given five cures chemotherapy after confirming the diagnosis. The lesion was regressed with the administration of chemotherapeutic agents. The third patient a 10-year-old patient with a lesion in contact with the main vascular structures which showed invasion toward the acetabulum ceiling. He received a low dose radiotherapy after confirming the diagnosis.

    A total of eight patients with lesions in the scapula, iliac wings, proximal femur, and ischium underwent curettage alone. In all of these patients, the curettage operation was performed upon intraoperative frozen examination and was evaluated as benign in nature. Six patients underwent grafting along the curettage at the same time considering the localization, size, and characteristics of the lesion, one of them underwent prophylactic internal fixation. Two patients underwent en bloc resection. A 10-year-old girl patient with a lesion localized in the left diaphyseal femur, and a 17-year-old male patient with a lesion localized in the left clavicle underwent en bloc resection.

    The mean tumor size was 3,7 cm (range: 1 – 8 cm). The mean duration of follow-up was 46 months (range: 24-95 months). None of the patients developed recurrence during follow-up. In one patient, no pathology was detected on the 12th month of the follow-up after treatment applied due to the acetabular lesion, but the patient had lesion in the cervical vertebra and developed vertebra plana. The patient was referred to the neurosurgery department with the operation plan.

    Discussion

    Also known as histiocytosis X, Langerhans cell histiocytosis (LCH) is a rare disorder of the myeloid dendritic cells. However, immune system dysregulation, neoplastic processes, and viruses have been discussed for the pathogenesis of LCH [9, 10].

    According to the histiocytosis study group, Langerhans cell histiocytosis was divided into three groups in 1987. LCH consists of three separate diseases including eosinophilic granuloma (EG), Hand-Schuller Christian disease and Letterer-Siwe disease [11, 12].

    Hand-Schuller Christian disease progresses with diabetes insipidus, exophthalmos, and lytic lesions and is observed in 15 – 40% of patients. Letterer disease progresses with diffuse involvement in the bone marrow, lymph nodules, central nervous system, skin, and lungs, and is observed in less than 10% of patients. This disease is common in infants and children, and it has a rapid and poor prognosis [13-15].

    EG is the most benign localized form among LHHs with the best prognosis. It is often localized in the skull, and the other areas of common involvement include flat bones such as vertebra, mandibula, costa, and pelvis [4]. In addition, involvement of the long bones such as femur, tibia, humerus may be seen. In this study, we included cases of pelvis and extremity lesions that were treated and followed-up in the orthopedics clinic. Considering the included areas, in our study, the most common involvement was in the pelvis, consistently with the literature. Long bones of the extremity were followed by scapula and clavicle with less frequency.

    Eosinophilic granuloma has been often diagnosed in early periods of life and is rare in adulthood age groups [3]. In our study also 12 of the patients aged under 18 years, and the youngest patient was 12 months old.

    Although the bone involvement of eosinophilic granuloma is usually monostotic, polyostotic involvement has been reported in 10% of patients [16]. In our study, multiple involvements was seen in only one patient (5%).

    Radiologic findings of eosinophilic granuloma may be highly variable. It can mimic many primary bone tumors and infections. Especially, hyperbolic medullary involvement and soft tissue involvement on magnetic resonance imaging often make the differential diagnosis difficult. It can be commonly confused with Ewing’s sarcoma and osteomyelitis that are localized in the long bone diaphysis, because these three diseases can involve a wide segment, can make permeative or piecemeal form bone destruction and can produce periosteal reaction [6,17,18].

    The definitive diagnosis of histiocytosis X disease group is established with histopathological investigations as the case in many tumoral lesions. In addition, staining of histiocytoses with S-100 and CD1a antibodies with immunohistochemical technique is used in the diagnosis [13]. Definitive diagnoses of our all cases were established based on these data. Treatment of eosinophilic granulomas covers a wide spectrum depending on the degree of organ involvement and local damage. Among these, there are follow-up, surgical curettage, radiotherapy, chemotherapy, and local steroids are treatment options. These options should be tailored to each individual patient and can be used alone or in combinations. The lesions with a painful course, pathologic risk of fracture in load-bearing bones, and those producing non-acceptable dysfunction and deformity require further treatment [4, 7, 8, 18].

    Today, follow-up and treatment of benign tumoral lesions can be made in many orthopedics clinics in Turkey [19, 20]. Since our clinic is a tertiary orthopedic oncologic clinic, the majority of our patients were those referred from outer centers with the presumed diagnosis of malignant bone tumors and had aggressive MRI or painful manifestation. Therefore, although it is known from the literature searching that, most of the eosinophilic granulomas are only followed-up due to their benign progression, our study included a group of patients who required slightly more advanced treatment than the literature.

    A low dose radiotherapy is a treatment option which has been used especially in the cases where surgical treatment is not possible for a long time and it is currently used in eligible cases. Particularly side effects of radiotherapy are determinants in making decision for this option [21, 22]. In our series, radiotherapy was applied in only one patient, and regression of the lesion was noted following the treatment.

    Curettage and augmentation of the space are performed in the load bearing lesions that have fracture risk and produce dysfunction or deformity. In addition, osteosynthesis techniques can also be used for a strong reconstruction [18, 23]. In the present study, only one case required osteosynthesis.

    Another treatment method is chemotherapy which can be used alone or as a part of combined treatment. There are studies recommending chemotherapy in cases of load bearing component and especially soft tissue component [24, 25]. In our study, chemotherapy was performed in one patient.

    This study has some limitations. The study includes a retrospective evaluation and reflects data of only one clinic. Further multicenter prospective studies with a larger series of patients are warranted.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

    References

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    2. Bahadır A, Erduran E. Lymphadenopathy of A Newborn: Langerhans Cell Histiocytosis. Acta Oncol Tur. 2015: 220-3.

    3. Plasschaert F, Craig C, Bell R, Cole WG, Wunder JS, Alman BA. Eosinophilic granuloma a Different Behaviour in Children Than in adults. J Bone Joint Surg [Br]. 2002; 84-B: 870-2

    4. Erol B, States L, Pawel BR, Tamai J, Dormans JP. Musculoskeletal tumors in children. In: Dormans JP, editors. Pediatric Orthopaedics and Sports Medicine: The Requisites in Pediatrics. Philadelphia: Mosby; 2004. p. 299–336.

    5. Basmacı M, Hastürk AE. Eozinofilik Granüloma: Radyolojik ve Klinik Değerlendirme Türk Nöroşirürji Dergisi. 2011; 21(3): 262-4.

    6. Meyer JS, De Camargo B. The role of radiology in the diagnosis and follow-up of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998; 12: 307–26.

    7. Tun K, Türkoğlu ÖF, Okutan Ö, Özer O, Özlem Ö. Eosiniphilic Granuloma in the Young Adult Patient: A Case Report. Journal of Neurological Sciences 2005; 22: 421-4.

    8. Sessa S, Sommelet D, Lascombes P, Prévot J. Treatment of Langerhans-cell histiocytosis in children. Experience at the Children’s Hospital of Nancy. J Bone Joint Surg Am. 1994; 76: 1513–25.

    9. Ribeiro KB, Degar B, Gianotti Antoneli CB, Rollins B, Rodriguez-Galindo C. Ethnicity, Race, and Socioeconomic Status Influence Incidence of Langerhans Cell Histiocytosis. Pediatr Blood Cancer. 2015; 62: 982–7.

    10. Glotzbecker MP, Carpentieri DF, Dormans JP. Langerhans cell histiocytosis: a primary viral infection of bone? Human herpes virus 6 latent protein detected in lymphocytes from tissue of children. J Pediatr Orthop. 2004; 24: 123–9.

    11. Writing Group of the Histiocyte Society. Histiocytosis Syndromes in children. Lancet. 1987; 1: 208-9.

    12. DeMarino DP, Dutcher PO Jr, Parkins CW, Hengerer AS. Histiocytosis X: otologic presentations. Int J Pediatr Otorhinolaryngol. 1985; 10: 91-100.

    13. Bölükbaşı Fh, Kakşi M, Ayan E, Zemheri E, Çerçi A, Elmacı İ. Kafa Travması Öyküsü Olan Çocuk Hastada Eozinofilik Granülom. Göztepe Tıp Dergisi. 2010; 25(4): 196-200.

    14. Lipton JM. Histiocytic disorders. Hoffman R, Benz EJB, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, Mc Glave P, editors. In Hematology, Basic Principles and Practice. 3rd ed. Churchill Livingstone; 2000: 783-96.

    15. Hocazade C, Doğan M , Yorulmaz A, Güreşçi S, Cılız D, Evrim E, et al. Atypical Presentation In Langerhans Cell Hıstıocytosıs: Hearing Loss, Diabetes Insipidus, & Extensive Cutaneous Lesions with Nail Distrophy. Acta Oncol Tur. 2017; 50(1): 76-80

    16. Lieberman PH, Jones CR, Steinman RM, Erlandson RASmith JGee T, et al. Langerhans cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years. Am J Surg Pathol. 1996; 20: 519–52.

    17. Erol B, Segal L, Huff D, States L, Dormans JP. Low back pain in a 13-year-old girl. Clin Orthop Relat Res. 2003; 413: 323–31.

    18. Erol BSofulu ÖTopkar MOÇalışkan ETürköz HK. Long-term follow-up of long and flat bone eosinophilic granulomas managed only with biopsy. Acta Orthop Traumatol Turc.2015; 49(2): 144-50.

    19. Öztürk R, Aydın M, Arıkan M, Toğral G, Aydın G, Güngör BŞ. The report of tumor resection prosthesis infection due to Sphingomonas paucimobilis. Acta Oncol Tur. 2016; 49(1): 57-60.

    20. Öztürk RArıkan ŞMŞimşek MAÖzanlağan EGüngör BŞ. Management of solitary fibrous tumors localized in extremity: case series and a review of the literature. Eklem Hastalik Cerrahisi.2017; 28(2): 121-7.

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Öztürk R, Arıkan ŞM, Bulut EK, Beltir G, Güngör BŞ. Management of eosinophilic granuloma localized in the pelvis and extremities. Ann Clin Anal Med 2018; Ann Clin Anal Med 2020;11(1):6-9

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Oxidative stress and DNA damage during cardiopulmonary bypass

Reşat Dikme 1 , Mustafa Göz 2 , Mehmet Salih Aydın 2 , Hakim Çelik 3 , Mahmut Padak 1 , Ömer Göç 1 , Abdullah Taşkın 4

1 Perfusion Techniques Program, Harran University Vocational School of Health Services, 2 Cardiovascular Surgery, Harran University Faculty of Medicine, 3 Physiology, Harran University Faculty of Medicine, 4 Nursing Department, Harran University Faculty of Health Sciences, Şanlıurfa, Turkey

DOI: 10.4328/ACAM.5883 Received: 17.04.2018 Accepted: 27.03.2019 Published Online: 27.03.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):1-5

Corresponding Author: Reşat Dikme, Harran University Yenişehir Campus Vocational School of Health Services, 63300, Haliliye, Şanlıurfa, Turkey. GSM: +905354587844 F.: +90 414 3183209 E-Mail: rdikme@harran.edu.tr ORCID ID: https://orcid.org/0000-0001-9157-7830

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Abstract

Aim: The aim of this study is to measure the oxidative stress index (OSI) and DNA damage in patients undergoing cardiopulmonary bypass (CPB) surgery due to coronary artery disease. Material and Method: 25 patients operated for CPB surgery due to coronary artery disease were included in the study. By collecting heparin containing blood from the patients at 5 different times (Before CPB, during pump inlet, during placing of cross clamp, during taking out of cross clamp and after CPB) DNA damage was studied by Comet Assay method from mononuclear leucocytes and OSI in plasma was studied. Results: At 5 different times plasma OSI value was found respectively as 4.92 ± 1.73, 5.20 ± 2.69, 5.70 ± 2.06, 9.88 ± 4.88, 9.57 ± 4.54 whereas Arbitrary unit (AU), DNA damage were determined respectively as 28.48 ± 11.30, 29.04 ± 9.43, 31.44 ± 11.74, 33.92 ± 7.96, 38.56 ± 6.20 AU and p<0.001. Discussion: During CPB, OSI and DNA damage gradually increased and a positive meaningful correlation occured between these two parameters (r=0,882 p=0,048). As CPB period extended, oxidative stress and DNA damage increased as well as TOS and OSI increased, or vice versa.

Keywords:  Cardiopulmonary Bypass; CPB; Extracorporeal Circulation; Oxidative Stress; DNA damage

Full Text

  • Introduction

    During CPB, the patient’s blood is in contact with non-physiological and non-endothelial surfaces such as cannula, tubing set, reservoir, antifoaming agents, filters, pumps, heat exchangers and oxygenators. This contact activates blood proteins and immune system cells [1].As the contact surface increases, the damage in the blood contacting nonendothelial surface increases. The immune response starting during CPB may cause organ disfunction, that effects postoperative mortality and morbidity [2]. In continuity of this response, oxidative stress [3] initiated by catecholamines, complement system, oscillated cytokines from activated neutrophiles, free oxygen radicals released during ischemia-reperfusion period, endothelium damage, kallikrein cascade, endotoxine oscillation [4] and stimulated by factors such as systemic heparinization, nonpulsatile current, removal of blood stream by cross clamping, anaesthetic drugs, reperfusion, acute dilutional anaemia, perfusion pressure, stream changes and lungs being out of circulation, play an important role [5].

    Intensive reactive oxygen types (ROS) production or antioxidant defence reduction causes oxidative stress by making structural and functional modifications in biomolecules [6]. Oxidative processes start a series of events that consequently cause cell death via decrease in mitochondrial energy capacity [7]. During CPB, perfusion system, low arterial pressure, embolism and surgical manipulation also cause ischemia [8] resulting in excessive energy phosphate consumption and intracellular Ca accumulation [2]. During ischemia, fatty acid oxidation disorders and creatine phosphate anaerobic metabolism become main energy source of the cell [9]. However creatine phosphate runs short quickly, and rapidly improved acidosis limits glycolysis as well. In addition to the effect of the extracorporeal circulation, the activation of proinflammatory mediators, is also stimulated. As a result, consisted free oxygen radicals damage the cell membrane and myocardium [10]. During the restoration of the heart in CPB, the heart is stopped temporarily by putting cross clamp on aorta and the myocardium is exposed to ischemia. After taking out the cross clamp (after ischemia), reoxygenation of tissues is provided by sudden reperfusion, where the free O2 radicals cause a phenomenon named as ischemia-reperfusion damage [6, 11]. Free oxygen radicals have a property of reacting fast with proteins, phospholipids and thiols, their attacks on DNA cause mutations, even cell deaths [4, 7]. Various clinical, epidemiologic and experimental studies show that there is a relation between free radicals, lipid peroxidation and its products and DNA damage and carcinogenesis [12, 13]. CPB and the pathology of the subjects have importance at least as DNA damage.

    DNA damage can be detected in many methods. The recently developed method “Single Cell Gel Electrophoresis” (SCGE) also named as “Comet Assay” or “Microgel Electrophoretic Technique”, is sensitive, fast and cheap in obtaining the spiral fracture [14]. The easily used SCGE method, shows even low level of DNA damages, provides its analysis with only few cells, with different cell and tissue groups, does not require too many equipments and, its reliable results can be obtained economically and evaluated within just few hours [15].

    Material and Methods

    25 patients who were operated (by on pump) in the Cardiovascular Surgery Department of Harran University Hospital or The State Hospital in Sanliurfa were included in our study and 5 tubes of blood were collected from each of them consecutively before CPB, during the pump inlet, at cross clamping, at cross clamp removal and after CPB. During CPB, roller pump was used and non-pulsatile perfusion was applied. Commercial crystalloid cardioplegia (Plegisol®, 4-9 ° C) and tube sets (Bıcakcılar Extracorporeal Tubing Set-Turkey) were used during surgery. Patients were treated with 1200 ml of Ringer’s lactate or isolitol-priming solution. Routine CPB procedures were performed during surgery.

    Preperation of Samples and Studied Tests

    Collected blood samples were transferred immediately to heparin containing vacutainers. DNA oxidation levels and the damage was analyzed with Comet Assay method after separating mononuclear leucocytes from fresh blood samples. Then the rest of blood sample was centrifuged at 3000 rpm and the plasma was separated out. The samples were kept frozen and stored at -80 oC until handling. Total oxidative Status (TOS), Total Antioxidant Status (TAS) and Oxidative Stress Index (OSI) were studied as a result of lipid peroxide, lipid hydroperoxide, myeloperoxidase, ceruloplasmin, total peroxide in the separated plasma.

    DNA Damage Identification with Alkali Mono Cell Electrophoresis Method (Comet Assay)

    Comet assay method is based on agarose gel loads of DNA chain exposed to electrical field in alkali setting and their carriage according to molecular size. In this measuring method, the processes show differences according to lab conditions. Tice et. al. suggested 8 steps of SCGE method as isolation of cells, preparation of slices, lysis, disintegration of DNA spiral, electrophoresis, neutralization, coloring and evaluation [16]. In Comet assay method mono cells are placed in agar gel. After lysis, while the damaged and broken DNA pieces form tail format since they move in electrical field at different degrees due to having different loads and molecular weights, free and undamaged DNAs do not form tail because they migrate together in electical field.

    Since damaged DNA cells were evaluated by visual detection method in our study, in the examination of the undamaged cells, there were circular cells, less dense at sides, luminary outlook with brightness in the middle. This outlook of cells is evaluated as nonmigration. If DNA damage starts to occur, smooth marginated outlook becomes ragged edge outlook due to migration of DNA fractures out of the cell. Depending on the severity of the damage, there occurs a stretch from centre to the edge. This outlook is named as stretch or low migration. As the damage increases, the cells take the shape of a comet, that means high migration [17, 18]. The last stage is apoptosis in which stretching is directly proportional to the damage. Also fluorescence density at the tail is parallel to the degree of the damage. In this method, the damage was classified in 5 categories due to the degree of DNA migration. The length of migration shows difference according to quantity of fragments, DNA chain breakages and alkali-labile fields levels. The evaluation was done in five categories as undamaged DNA is evaluated as category 0, the ones having maximum damage are evaluated as category 4. (Figure 1). Totally 100 cells were evaluated from each slide. The results were calculated as arbitrary unit (AU) by considering maximum damage as 400.

    Protein oxidation (PO)

    15 µl plasma was mixed with 0,5 ml DNPH (10 milimolar 2,4-dinitrophenylhydrazine in 2 molar HCl) solution and left to incubation for 1 hour at room temperature. After incubation it was vortexed by adding 0,5 ml TCA (10% trichloroaceticacid in deionized water) solution and centrifuged for 3 minutes at 15000 rpm. After expelling supernatant, the pellet was washed 2 times with in the ratio of 1/1 ethanol/ ethyl acetate. 0,6 ml Guanidin HCl solution (6 molar guanidine HCl dissolutes in 20 milimolar pottsium phosphate (pH=2,3) was added and left to incubation for 15 minutes at 37 oC’de for dissolution. The absorbance of obtained colour was measured at 365 nm. After multiplying absorbance coefficient with (emax=22000/M/cm), the results were given as nmol (nmol/mgprot) per mg protein [17].

    Plasma Lipide Peroxidation Measurement

    25 µl plasma was mixed with 0,5 ml DETBA (10 mmol/L 1,3-diethylthiobarbituric acid, dissolved in 75 mol/L phosphate (pH=3)) and left in incubation for an hour at 96 oC. After leaving samples in ice bath for 5 minutes, 2,5 ml n-butanol was added. The mixture was vortexed and centrifuged at 1500 x g at 4 oC for 10 minutes. The supernatant was taken and analyzed in florometer (Extantion= 539 and emission= 553)(Schimatzu, Japan) [19].

    Total Antioxidant Status (TAS) Level Measurement

    The measurement method, which uses Total Antioxidant Status Assay Kıt (Rel Assay, Product Code: RL0017), is based on decolorization of all antioxidant molecules in the sample in proportion to the total concentration of antioxidant molecules of colourful radicals as a result of reduced colourful ABTS* cationic radical. Trolox, a water-soluable analogue of vitamine E is used as calibrator. The results were given as mmol Trolox Equivalent/L [20].

    Total Oxidant Status (TOS) Level Measurement

    In total automatic colormetric method, Total Oxidant Status Assay Kıt (Rel Assay, Product Code: RL0024) is used. The colorimetric method is based on oxidization of ferrous ions of oxidant molecules to ferric ion cumulatively.

    The results are given as μmol H2O2 Equivalent/ L[21].

    Oksidative Stress İndex (OSI)

    OSI, as a sign of Oxidative Stress, is defined as percentage of the degree of TOS levels to TAS levels. In calculation of OSI value of samples, TAS levels are multiplied with 10 and their units are balanced with TOS levels [24].The results are defined as Arbitrary Units (AU).

    TOS, µmol H2O2 Equiv. / L.

    OSI = ————————————— X 100

    TAS, µmol trolox Equiv. / L.

    Statistical Analyses

    Stastistical analyses were done by using SPSS programme. First of all, normality evaluation was done with normality test ‘’Shapiro-Wilk’’. In normal distribution, ‘’Pearson’’analysis was used for parametric correlations, while ’Spearman’’analysis was used for nonparametric correlations in abnormal distribution. p<0.05 value was considered significant.

    Results

    Demographic and characteristic data are given in Table 1. In the table, the gender (8 Male + 17 Female), average age (45.88 years), average height (161.52 cm), average weight (68.12 kg) and average BMI (1.71 kg/m2) values were given.

    TAS, TOS, OSI and mononuclear leucyte DNA damage of patients are shown in Table 2.

    1. Blood before pump, 2. Blood taken at the pump inlet, 3. Blood taken when a cross clamp is placed, 4. Blood taken after cross-clamp removal, 5. Blood taken from the pump

    TAS level continuously reduces until the 4th blood sample (after removal cross clamp), (Table 1) and increases a little bit at the 5th blood (pump outlet) (Figure 2). TOS reduced a little as passing from the 1st blood sample (before pump) to the 2nd blood sample (at the pump inlet), then increased continuously after the 2nd blood (after pump inlet) (Figure 3). Until the 4th blood sample, OSI levels (as cross unclamping) continuously increases, at 5th blood sample there is a little reduction (Figure 4). This increase in OSI levels became maximum after unclamping. (4th blood sample). DNA damage on the other hand continuously increased from 1st blood sample (before pump) to the 5th blood sample. (pump outlet) (Figure 5). Generally TOS, OSI, DNA damage increase while TAS level decreased.

    According to the correlation analysis done at the end of study, a significant positive correlation was found (r=0,882 p=0,048) between OSI and DNA damage (Table 3). The distribution of relations between mononuclear leucyte DNA damage and oxidative stres index levels were shown in Figure 6.

    Discussion

    According to the results of our study, TAS continually decreased until unclamping the aorta, myocardium became bloodstained and TAS value increased after this period. This situation shows us that TAS value continuously decreased when there is no bloodstain, but TOS value continuously increased. This situation shows us that during CPB increases oxidative stress continuously due to either unfamiliar surface material or surgical situations. Besides, the antioxidant defence systems become insufficient due to the decrease of TAS, but the increase of TOS value. In the analysis, TAS and TOS values decreased a little during the pump inlet because of the hemodillution. OSI levels continuously increased at cross clamping and was maximum at unclamping. When the circulation of the heart stopped during the cross clamping period, oxygen derivative radicals are generated from ischemi reperfusion as a result of bloodstained heart and increase OSI levels. In other words, oxygen derivative radicals cause oxidative stress. Also due to the decrease of antioxidant level during pump period, oxidant level and oxidative stress cannot be eliminated, accordingly OSI continuously increases. Due to the increase of TOS and OSI levels and the decrease in TAS levels, DNA damage continuously increased, because of non endothelial level, non pulsatile current, insufficient perfusion, discontinuation of blood stream with cross clamping, anesthetic drugs, myocardium damage, cells in stress due to reperfusion and immune response and attacks of oxidative stress elements to DNA, during CPB. Our study shows that OSI and DNA damage continuously increased during the pump and a positive correlation between these two parameters occurred. As the length of clamping period and pump period extended, oxidative stress increased and more DNA damage occured. Many studies show that ROS levels can severely increase in stress periods and cause serious damage in many molecular molecules such as lipides, proteins and DNA.

    The results of our study are parallel to many previous studies. Starkopf et. al. stated that TAS decreases and oxidant damage occurs during ischemia and reperfusion period in CBP. Also, in coronary artery bypass facts during 72 hours after surgery, it was observed that TAS was depressed, lipid peroxidation increased and depression in TAS were in reverse relation with lipid peroxidation (23 tubing set, reservoir, antifoaming agents). According to the study of Taşkıran A. et. al. on the damage and relation of plasma TAS levels with ischemia-reperfusion damage before CBP coronary artery bypass surgery, they found out that low TAS values before surgery are in relation with ischemia-reperfusion damage and severity of myocardium damage [24, 25]. Ischemia and reperfusion damage during CPB cause proinflammatory mediators and ROS formation by causing an important myocardial stress, which harms proteins, lipides that affect postoperative cardiac function as well as DNA. The existence of positive correlation between DNA damage and oxidants and negative correlation between DNA damage and antioxidants, force to find better methods that can reduce side effects of CPB to minimum level. As a result, factors such as contact with artificial surfaces, surgical trauma, oxidative stress and ischemia reperfusion injury play an important role in the formation of DNA damage. As a result of these factors, reactions at the molecular level increase DNA damage during CPB. Among the limitations of this study is the absence of a control group from patients operated by non-pump techniques.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Dikme R, Göz M, Aydın MS, Çelik H, Padak M, Göç Ö, Taşkın A. Oxidative stress and DNA damage during cardiopulmonary bypass. Ann Clin Anal Med 2019; Ann Clin Anal Med 2020;11(1):1-5

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Urodynamic findings of multiple sclerosis patients at a single institution

Murat Akgül 1 , Cenk Yazıcı 1 , Arzu Malak 2 , Bengü Altunan 3 , Ersan Arda 4 , Nilda Turgut 3

1 Department of Urology, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, 2 School of Health, Tekirdağ Namık Kemal University, Tekirdağ, 3 Department of Neurology, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, 4 Department of Urology, Trakya University, Faculty of Medicine, Edirne, Turkey

DOI: 10.4328/ACAM.6097 Received: 01.02.2019 Accepted: 04.03.2019 Published Online: 05.03.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):20-23

Corresponding Author: Murat Akgül, Department of Urology, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, Turkey. GSM: +905053399602 E-Mail: drmuratakgul@gmail.com ORCID ID: https://orcid.org/0000-0001-6187-1940

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Aim: Multiple sclerosis (MS) is a chronic and progressive disease of the central nervous system (CNS). The destructive effect of MS on the urogenital system has been demonstrated in many studies especially in young adults. Urodynamic evaluation is recommended in the diagnosis of urogenital system pathologies for MS patients. Unfortunately, there are not enough studies evaluating the urodynamic examinations of MS patients in our country. In this study, urodynamic findings of patients with MS were evaluated. Material and Method: A total of 58 patients (39 female and 19 male) were included in the study. The urodynamic findings of the patients in the same center between January 2011 and October 2017 were evaluated retrospectively. Urodynamic evaluation was performed with 20 ml of infusion per minute according to the International Continence Society standards. Results: The mean age of the patients was 47.4 ± 8.8 years. The mean duration of multiple sclerosis was 11.8 ± 7.4 years. When the features of multiple sclerosis were evaluated, 13 (22.4%) patients had a progressive type, 20 (34.5%) had a secondary progressive type, and 25 (43.1%) had relapsing-remitting (with relapses and remissions). The urodynamic findings of the patients are shown in Table 1. Urodynamic evaluations of patients with urinary incontinence are reported as ‘Urge type urinary incontinence’ was observed in 30 (83.3%), ‘stress type urinary incontinence’ in 5 (13.9%) and ‘mixed type urinary incontinence’ in 1 (2.8%) patient. Discussion: Multiple sclerosis is a common neurological pathology which has different urinary system findings. Detrusor overactivity is the most common urinary manifestation, and patients may also have impaired contractility, detrusor sphincter dyssynergia, urodynamic stress incontinence, and bladder outlet obstruction.

Keywords: Multiple Sclerosis; Urodynamic Findings; Detrusor Overactivity

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  • Introduction

    Multiple sclerosis (MS) is a chronic and progressive immune-mediated disease of the central nervous system characterized by neural demyelination and axonal sparing [1]. It is mainly the disease of young adults with twofold female predominance, and the prevalence rates vary between 40 and 220 per 100.000 in different countries. Similar prevalence rates were reported in our country, which indicated that a significant number of the young adult population had to deal with this progressive multi-symptomatic neurological disease [2,3,4,5].

    Although MS is a local neurological disease affecting the central nervous system, it causes a broad spectrum of symptoms related to different organ systems including the lower urinary tract. Bladder dysfunction is prevalent in MS patients, affecting 50-90% of patients. Even the symptoms associated with lower urinary system dysfunction may be the first referral cause for 10% of MS patients [2,6]. Multiple sclerosis may have a deteriorative effect on storage and emptying phases of bladder function. Most common lower urinary symptoms in multiple sclerosis patients are urgency and urge incontinence, which was related to detrusor overactivity. Voiding dysfunction, incomplete emptying of the bladder and urinary retention may also be seen in patients with MS.

    According to EAU guidelines, invasive urodynamic evaluation is recommended at all neurogenic bladder patients [7]. The urodynamic assessment can document the lower urinary system dysfunction related to patients symptoms and may predict the possible risk factors for the upper urinary tract. It is also essential to define the types of the lower urinary system dysfunction at MS patients for epidemiological data. Several studies reported the urodynamic findings of MS patients in the literature [6,7,8,9]. On the other hand, this critical data is insufficient in our country. For this reason, documenting this data in our country is very important to create our epidemiologic library associated with the lower urinary system dysfunction in MS patients. In this study, we aimed to report the single institution urodynamic findings of MS patients.

    Material and Methods

    The medical records of 58 (39 female and 19 male) MS patients who applied to the urodynamic unit of our urology clinic between January 2011 and October 2017 were reviewed retrospectively. All the patients were diagnosed with MS in the neurology department of the same institution. The demographic properties of patients, including the disease pattern and the date of diagnosis, were reviewed. All patients underwent urological evaluation with a physical examination (including neurological examination), urinalysis, urine culture, plasma creatinine level, urinary system ultrasonography, urodynamic evaluation (with EMG and pressure-flow study), uroflowmetry and post voiding residual volume. In order to evaluate the neurological disability of the patients, we used the expanded disability status scale (EDSS). Urodynamic evaluation was performed according to the International Continence Society (ICS) standards (Aymed Medical Technology, Turkey) with an infusion rate of 20 ml/min [8].

    Descriptive statistical analysis with frequency and percentage data was performed by SPSS 21.0 version.

    Results

    The mean age of the patients was 47.4 ± 8.8 (24-67) years, and the mean disease duration was 11.8 ± 7.4 years (2-34 years). The type of MS was primary progressive in 13 (22.4%) patients, secondary progressive in 20 (34.5%) patients and relapsing-remitting in 25(43.1%) patients. Urinary incontinence was the most prevalent symptom in patients. A total of 30 (51.7%) patients applied to the outpatient clinic with incontinence. The type of incontinence was urge incontinence in 22 patients and mixt incontinence in 8 patients. Urgency was the second most common symptom as 14 (24.1%) patient applied to the clinic with urgency. The third most common symptom was hesitating to urinate. There were 10 (17.2%) patients with urinary hesitation, and 7 (12.1%) of them were in urinary retention. Other symptoms of the patients were bilateral flank pain in 2 (3.4%) patients and erectile dysfunction in 2(3.4%) patients. The mean serum creatinine level of patients was 0.68 mg/dl ranging bet-ween 0.40 and 0.92 mg/dl. There were only 2 (3.4%) patients with bilateral hydronephrosis, and both of them had urinary retention. Urodynamic diagnosis of patients is shown at Table 1.

    The mean maximum cystometric capacity (MCC) of patients was 414±209 ml ranging between 51ml to 980ml. There were 18 (31.0%) patients with MCC less than 350ml and 16 (27.6%) patients with MCC greater than 500ml. A total of 24 (41.4%) patients had normal bladder capacity. The compliance of the bladder was normal in 47 (81.1%) patients, whereas it was hypo-compliant at 6 (10.3%) and hyper-compliant in 5 (8.6%) patients. Incontinence was documented in 36 (62.1%) patients during urodynamic evaluation. The type of incontinence was urge-type incontinence in 30 (83.3%) patients, stress-type incontinence in 5 (13.9%) patients and mix type incontinence in 1(2.8%) patient. Most of the patients with neurogenic detrusor overactivity had also urge incontinence during the storage phase. There were only 8 (20.5%) patients without incontinence in this group.

    The mean detrusor leak point pressure of the patients with urge incontinence was 58.6±37.8 cmH2O, ranging between 13 and 183 cmH2O. The mean bladder volume at detrusor leak point pressure was 219.0 ± 161.4ml ranging between 10 and 636 ml. Valsalva leak point pressure varied from 45 cmH2O to 105 cmH2O with a mean value of 82.5 ± 24.9 cmH2O. The bladder volume at the Valsalva leak point pressure ranged from 53 ml to 442 ml with a mean volume of 204.3 ± 128.9ml. Mean post-voiding residual volume (PVR) of patients was 83.8 ± 134.6 ml (0-711ml.). There were 10 (17,2%) patients with a PVR value > 150 ml. The mean EDSS score of the patients was 3.98 ± 1.74. The mean EDSS of patients with and without detrusor overactivity was 4.26 ± 1.72 and 3.39 ± 1.67, respectively (p=0.073). The mean EDSS of patients with urge incontinence was 4,29 ± 1,79 whereas it was 3,59 ± 1,63 at patients without urge incontinence (p=0.129).

    Discussion

    Although MS is a neurological disease affecting the motor functions, urinary tract dysfunction related to this disease is also a significant problem leading to both structural and psychosocial distress. Even the symptoms of lower urinary tract dysfunction might be more challenging for patients compared to motor dysfunction. Extensive involvement of the central nervous system in MS patients leads to the high variability of voiding dysfunction [10]. Multiple sclerosis may affect both storage and emptying phase of voiding. Lower urinary tract symptoms were reported >80% of MS patients with detrusor overactivity being the leading lower urinary system pathology [9]. Detrusor underactivity and poor bladder compliance were the second and third most common findings of MS in urodynamic evaluation [10]. Although there were some studies reporting the urodynamic findings in MS patients in international literature, there islimited data in our country [6,7,8,9].

    One of the studies reporting the urodynamic results of MS patients in our country was published by Onal et al. They reported the medical records of 249 and urodynamic findings of 75 MS patients [11]. In another study, Nakipoglu et al. reported the urodynamic results of 52 MS patients [12]. According to our knowledge, these were studies with the highest number of MS patients with urodynamic results. In this study, we reported the urodynamic results of 58 patients that may intensify the related data in our country.

    Similar to the literature, there was a female predominance in our patients, and the most common MS type was relapsing remittent, which was also comparable to Onal et al.’s study [11]. Neurogenic detrusor overactivity was the most common urodynamic finding of our patients. Nearly 67% of MS patients had detrusor overactivity which was also comparable with other studies. Urodynamic evaluation of an MS patient may also be normal. The normal urodynamic evaluation rate in our study was 20%, which was reported as 15% at Onal et al.’s study [11]. On the other hand, both detrusor overactivity and normal urodynamic evaluation rates were significantly different at Nakipoglu et al.’s study. The percentage of DO was 27%, and the rate of the normal urodynamic finding was 42%. We believe that this difference was related to the study population. The patients at Onal et al.’s and our study were the patients that were referred to urology clinic for any reason. On the other hand, the patients of Nakipoglu et al.’s study were the patients at physical medicine and rehabilitation and neurology clinic [12]. The difference of patient characteristics might be responsible for this variability because the patients referred to urology clinic were supposed to have urological symptoms that directly increase the rate of abnormal urodynamic findings.

    We also observed that impaired contractility was present in 15% of MS patients in our study. The rate of impaired contractility was 1,3% at Onal et al.’s study and 6% at Nakipoglu et al.’s study, which was significantly lower than our results. As multiple sclerosis can affect different parts of the central nervous system, findings of the lower urinary tract may also differ. This may be an explanation of different rates of impaired contractility in various studies. Nearly 60% of patients with impaired contractility also had neurogenic detrusor hyperactivity that can be named as detrusor hyperactivity with impaired contractility. Urodynamic stress incontinence was also observed in 10% of the patients. All of the patients in this group were female and older than 50 years old. As the stress urinary incontinence is a prevalent disease in this group, it is impossible to make a conclusion between MS and the presence of urodynamic stress incontinence. The rate of urodynamic stress incontinence was not reported in studies by Onal et al.’s and Nakipoglu et al. [11,12].

    Detrusor-sphincter dyssynergia (DSD) is a significant risk for the upper urinary system in neurology patients. It is also prevalent in MS patients. The rate of DSD was 40% in Onal et al.’s study and %25 in Nakipoglu et al.’s study [11,12]. This rate was 24% in our study, and all patients with DSD also had neurogenic detrusor overactivity. Similar to our findings, all patients with DSD also had neurogenic detrusor overactivity in a study by Onal et al. [11]. Interestingly, although the rate of DSD with neurogenic detrusor overactivity is high in MS patients, upper urinary tract dysfunction is very rare. The rate of upper urinary tract dysfunction was 3.4% in our study, while in the study by Onal et al. it was %5.

    The degree of neurological disability is an important factor for MS. Expanded disability status scale is an objective tool to evaluate neurological disability of patients. We also used this scale to document any possible relationship between the degree of neurological disability and lower urinary tract symptoms, especially the neurogenic detrusor overactivity and urge incontinence. The patients who had neurogenic detrusor overactivity and urge incontinence had higher scores in EDSS. On the other hand, the difference was not statistically significant. This might be related to the number of patients in our study. Increasing the study population might be necessary to make a clear conclusion about the relation of neurological disability and detrusor overactivity.

    One of the main limitations of our study was related tothe study population. We were only able to evaluate the urodynamic findings of MS patients, who were referred to the urology clinic for lower urinary tract symptoms or general urological examination. For this reason, the population of the study did not cover all MS patients. As the urodynamic studies have invasive nature, it is not ethically acceptable to perform this invasive study to all MS patients. Another limitation of our study was related to the study population number. We were able to present the results of 58 patients who were evaluated in our urology clinic with urodynamic evaluation. Even the urology clinics with high patient volumes were able to publish their results with a limited number of patients. We believe that future multi-centric stu-dies documenting national data will allow enriching the national library. For this reason, we believe that the number of study population has significant value to add scientific data for national data library.

    Conclusion

    Multiple sclerosis is a prevalent neurological disease that affects the urinary system. Although several studies documented that urinary system is affected by multiple sclerosis, very limited data was reported in our country. Detrusor overactivity was the main lower urinary tract dysfunction in multiple sclerosis patients evaluated in urology clinics for lower urinary tract symptoms. Impaired contractility, detrusor-sphincter dysfunction, urodynamic stress incontinence, and bladder outlet obstruction may also be observed. Urodynamic findings of multiple sclerosis patients may also be normal and upper urinary tract dysfunction is rare.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Akgül M, Yazıcı C, Malak A, Altunan B, Arda E, Turgut N. Urodynamic findings of multiple sclerosis patients at a single institution. Ann Clin Anal Med 2019; Ann Clin Anal Med 2020;11(1):20-23

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Identifying the affecting factors in adolescents who attempt suicide

Burcu Calik 1 , Ayfer Acikgoz 2

1 Lecturer, Health Services Vocational School, Alanya Alaaddin Keykubat University, Alanya, 2 Department of Child Health and Disease Nursing, Eskisehir Osmangazi University, Faculty of Health Sciences, Eskisehir, Turkey

DOI: 10.4328/JCAM.6140 Received: 21.12.2018 Accepted: 02.03.2019 Published Online: 05.03.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):43-49

Corresponding Author:Ayfer Acikgoz, Department of Child Health and Disease Nursing, Faculty of Health Sciences, Meselik Campus, 26480, Eskisehir, Turkey. T.: +90 2222393750-1539 F.: +90 2222292695 GSM: +905352919374 E-Mail: ayferackgoz@gmail.com ORCID ID: https://orcid.org/0000-0002-3803-9678

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Aim: Suicides and suicide attempts in adolescents are important public health concerns increasing day by day. The most effective way of preventing suicides is to identify risk factors and take necessary measures before the suicidal behavior turns into action. This study is of descriptive type. It was performed in a Children’s Hospital in Ankara aiming to identify the risk factors of committing a suicide in adolescents between 13 and 18 years of age, who carried out a suicidal attempt. Material and Method: There are two groups within the study. These are the suicidal attempt group and the comparing group. The data were collected through the “Data Collecting Form”. Statistical analyses were performed using the software SPSS package program (SPSS for Windows, Version 25.0, IBM Corporation, Armonk, New York, United States). Results: The adolescents, who have a good relationship with parents, who have a good relationship with friends, whose opinion is asked for about family decisions, and whose mother and father live in the same house have less tendency and risk for committing suicide (p<0.05). Discussion: The reason of suicide attempts is mostly familial factors. Risk screening for suicide attempt in adolescents should be carried out particularly at schools, courses, adolescent clinics, and services. Those in the risk group should also be consulted for professional support in an early period.

Keywords: Adolescent; Hospital; Risk Factors; Suicide

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  • Introduction

    According to the data from the World Health Organization (2013), one million people lost their lives by committing suicide and the rate of suicide in the young population gradually increased. Although one person in every 40 seconds commits suicide in the world, suicide attempts are 20 times higher than this rate. Suicides are the second leading cause of deaths among those between 10 and 24 years of age. Deaths from suicides are estimated to reach 1.5 million in 2020. According to the data from the Turkish Statistical Institute (TUIK) (2015), the number of suicides resulting in death is 3211 in 2015, in Turkey. Among individuals who committed suicide, 34.3% are between 15 and 29 years of age that includes the adolescence period.

    The reason for this issue is that the adolescence, one of the most important periods, during which the child grows up in terms of physiological, psychological, sexual and identity development [1]. Besides, the issues and problems from childhood period are solved during this period. Finding a solution to these issues and problems is also harder than they are thought [2].

    Suicide means intentionally killing oneself, and it includes self-damaging. If the individual has not lost his/her life, then this action is named suicide attempt [3]. It is of much importance to identify the risk group and take necessary measures to prevent injuries and death before the suicide attempt turns into action [2].

    It is impossible to decrease or resolve the suicide attempts without understanding the relationship between adolescent suicides and biological, psychological, social, environmental and sociocultural factors [1, 2]. Studies in the literature mostly deal with adult age groups and usually include only individuals has attempted suicide. For this reason, only the studies covering a specified age group and comparing suicidal groups with normal ones could provide an insight into the problem. This study was carried out to identify the factors driving adolescents into suicide by comparing the traits of suicide-committing adolescents with normal ones.

    Material and Methods

    The study is of the comparative descriptive type and it was composed of two groups. These are the suicidal attempt group (n=100) and the comparing group (children applying to the clinic due to complaints other than the suicide attempt) (n=100). The study was carried out in the emergency unit of a children’s hospital in Ankara between November 2015 and March 2016.

    The population of the study is composed of two different adolescent groups admitted to the Paediatric Emergency Service between November 2015 and March 2016. One of the groups was composed of 100 children, who were taken to the emergency service due to a suicide attempt. The children in this group voluntarily took part in this study. The other group was comprised of 100 children, as well, who were taken to the emergency service due to health complaints other than a suicide attempt. These children as those in the first group voluntarily took part in this study as well.

    Power analysis was used to determine the sample size. It was detected that 32 children in suicide attempt group and 44 children in the comparing group should be reached when α accepted as = 0.05, and β as = 0.20 However, the study was planned to include 100 children for each group.

    Sample selection criteria were determined as follows: the child must be aged between 13 and 18 years, not to be mentally retarded, his/her consciousness must be open and/or verbal communication can be established with him/her, family and/or child should not become agitated, the child’s clinical situation and the interventions performed are appropriate for data collection, voluntary participation of the child and his/her family must be in the research.

    The data were collected through Data Collecting Form (39 questions in total). The data collecting form was developed by the researcher with the aim of identifying informative traits of children between 13 and 18 years of age and their families, the general state of health of children, attitudes and behaviour of parents towards adolescents, and attitudes of children towards committing suicide. In order to ensure the content validity of the survey, specialist opinions were taken from three persons, one of whom was a Child Psychiatrist (PhD), the other, a Paediatrician (PhD) and finally, a Public Health Nurse. Survey items were corrected based on the suggestions. Then, a preliminary study was conducted with a group of 10 people aged between the ages of 13 and 18 by the Child Psychiatrist, and the survey form was given its final shape in parallel with the feedbacks. The survey forms completed in the preliminary study were not included in the research.

    The aim of the study was not only to define informative traits of children between 13 and 18 years of age and their families but also revealing children’s general health state, attitudes, and behavior of families towards children, attitudes of children towards committing suicide. Emergency Department, which is the research unit, consists of triage, observation room, intervention room, a resuscitation room, Ventolin room, treatment room and polyclinics (3 units). The observation room has a capacity of 12 beds and has 1 isolated room. The first intervention of patients who come to Pediatric Emergency due to suicide attempt is performed in the Emergency Service Intervention Room. The treatment and follow-up of the patients continue in the hospital’s large children’s services where there is no need for intensive care, or in the Emergency Service Observation Room if there is no room in the services. After the clinical status of the child becomes available for data collection, the patient is sent to the psychiatry outpatient clinic and interviewed. When the patient was sent to the psychiatry polyclinic for an interview, data were collected using the face-to-face interview method with Child and Adolescent Psychiatry Specialist. In adolescents (control group) who came for various medical reasons other than a suicide attempt, the data were collected by face to face interview method in the Emergency Service Intervention Room after the medical treatment in the emergency room of the patient. During the application, adolescents participating in the research were informed about the importance of the research in order to ensure that they were honest and sincere in answering the data collection tools. It was paid attention not to be with the family and it was convinced that their information would not be shared with third parties.

    SPSS 25.0 (IBM Corporation, Armonk, New York, United States) program was used to analyze the variables. The Shapiro-Wilk test was used to determine the normal distribution of the data. The Mann-Whitney U test was used to compare the groups with respect to age quantitative variables. The Pearson Chi-Square Monte Carlo and Exact results were compared with the Fisher-Freeman-Holton test using the Monte Carlo Simulation technique and the Fisher Exact test was tested according to the Exact results. The rates of the meaningful results were compared with each other and the results of Benjamini-Hochberg corrected p-values were expressed. The quantitative variables were shown as median (1st Quartile – 3 Quartile) while categorical variables as n (%) on the tables. The variables were examined at 95% confidence level and p-value was accepted as less than 0.05.

    The Ethical Aspect of the Study

    This study started after obtaining ethical approval with 80558721/268 code number from the University of Eskisehir Osmangazi Ethics Committee. Written consent was also obtained from the hospital where the study was carried out. The opinion of the Department of Child and Adolescent Psychiatry of Gulhane Military Medical Academy was asked with the aim of evaluating the appropriateness of the research, and the scale in terms of the age and psychology of the child. Written and oral consent of the adolescent and parents voluntarily involved in the research were obtained after informing them. The study was conducted in accordance with the Second Helsinki Declaration.

    The Limitations of the Study

    Trauma cases (wrist slashing, firearm injuries, jumping off, etc.) due to a suicide attempt that were directly applied in the hospital where the study was conducted were referred to general hospitals. It might reduce the number of cases concerning suicide attempts. During the research period, the cases due to substance-use in Ankara were treated in different hospitals for 5 days in each month. The patients who were substance-users and attempted to suicide by using the substance were admitted by the hospital where the study was conducted between the first and fifth days of the month. This practice might decrease the number of suicide attempt cases related to substance use.

    Results

    Table 1 shows the descriptive characteristics of the adolescents in the study and comparing groups and intergroup comparisons. Both groups have similar characteristics in terms of average age, employment status, having a chronic disease, drug abuse, and relationship with sibling(s) (p>0.005), however, there is a difference between the groups with regard to gender, the status of going to school, school success, having a psychological disease, smoking, use of alcohol, relationship with friends, relationship with mother, and relationship with father (p<0.005). When the diagnosis of those having psychological disorders in the suicide attempt group (n=12) was examined, it was detected that eight of adolescents had the anxiety disorder, three of them had the panic attack, and one of them had attention deficit-hyperactivity disorder (ADHD). In the comparing group, the number of adolescents with psychological illness is 2. While one of them is diagnosed with depression, the other is diagnosed with attention to ADHD.

    Table 2 shows the descriptive characteristics of the parents of the adolescents in the study, comparing groups and the comparison between the groups. Both groups have similar characteristics in terms of average family type, family income status, a total number of children in families, and birth-order of the child (p>0.005), however, there is a difference between the groups with regard to parental relationship status (p<0.005). In our study, according to the information given by the adolescents (n=199) whose father is alive, there is no father who does not work and has a psychological disease diagnosis.

    Table 3 shows the attitudes of families in the study and comparing groups towards adolescents and comparison between the groups. Both groups have similar characteristics in terms of average father’s attitude towards the child (p>0.005), however; there is a difference between the groups with regard to mother’s attitude towards the child, and the decision maker of the family (p<0.005).

    When the adolescents were asked about the reasons why they attempted suicide, school failure was reported by 18% of them, having argued with father by 15% of them, parental discord by 10% of them, parental pressure by 9% of them, bad relationship with the friends by 8% of them, boredom by 8% of them, having argued and breaking up with the lover by 7% of them, having argued with the mother by 4% of them, quarrel between the siblings by 4% of them, lack of care in the family by 3% of them, divorcement by 3% of them, having a bad relationship with the others by 3% of them, economic troubles, death of father, an instant anger, and detaching from life were determined by the rest of them as the reasons for attempting suicide. When the adolescents attempting suicide (n=100) were asked for their current thought while 66% of them expressed regret for attempting suicide, 21% of them stated that they could attempt suicide again, and the rest of them declared that they were hesitant to do it.

    Discussion

    The study was carried out on adolescents between 13 and 18 years of age. The average age of both the suicide attempt group and the comparing group was 15 years (Table 1). There is a difference between both groups in terms of gender factor and the suicide attempt of adolescents. It was detected that the rate of suicide attempt in females was higher than that of males (p=0.017) (Table 1). Studies [3-12] indicate that the suicide attempts are more frequently seen in females than males in the most countries and this fact may be associated with the place and roles of women in society [11]. Experiencing an oppressive attitude in society and having a more emotional nature may be another reason for the higher rate of suicide attempts in women.

    There is a difference between the groups in terms of attending rates to school and suicide attempts of adolescents. All the dropouts are in the suicide attempt group (p<0.001) (Table 1). It was found that the suicide attempt was higher in adolescents who did not attend school than adolescents attending school. The research results are similar to other studies [7, 8]. Higher rates of suicide attempts in adolescents who do not attend school may be linked to negative feelings such as separation from friends, the thought that he/she can not have the profession he wants to do in the future, and the loneliness.

    It was detected in the study, that there was a significant relationship between the school success and suicide attempt of adolescents (p<0.001) (Table 1). The rate of the suicide attempt is higher in the group with low school success. This result is similar to that of other studies [5, 8, 13]. This fact reveals that school failure is a risk factor for suicide attempt.

    There is no difference between the groups in terms of the presence of chronic disease and suicide attempt (p=0.051) (Table 1). In a study carried out on a similar problem by Hawton et al. [14], it was detected that physical disorders or injuries increase the risk of suicidal behavior in adolescents. The difference of our study result from those in the literature may be linked to the small number of adolescents with chronic disease in our sample group.

    Psychiatric disease is present in 14 of the adolescents (n = 200). While the rate of suicide attempt of adolescents with the psychiatric disease is 85.7% (n=12), it decreases to 47.3% (n=88) in those without a psychiatric disease. This result is statistically significant (p=0.010) (Table 1). In adolescents with psychiatric disorders, suicide attempts were found to be higher than in adolescents without psychiatric disorders. Other studies [4, 15] also support this result. Apart from psychological balance, psychiatric disease which deteriorates physical and social balance can cause to an increase in the rate of suicide attempts by negatively affecting adolescents’ ability to cope with problems and their ability to understand, comprehend and think. This result is important because it shows that adolescents with psychiatric disorders are in a risk group for suicide attempts.

    There is a significant difference between both groups in terms of smoking and suicide attempt of adolescents (p<0.001) (Table 1). The results are similar to those of other studies [4, 16]. This result reveals that adolescents who are the smokers and sometimes smokers have a higher risk of suicide than those who are not. It was detected that there was a significant difference between both groups regarding alcohol use and suicide attempts of adolescents (p<0.001) (Table 1). The rate of the suicide attempt is higher in the alcohol-using and sometimes alcohol-using group than that of the teetotal group. Other studies [16, 17] also support this relationship. For this reason, adolescents who are the smokers and/or using alcohol should be detected and be assessed for the risk of depression, hopelessness, and a suicide attempt by the nurses and the other health workers. Early diagnosis of the risky group is important to provide treatment before the situation turns into behavior.
 It was not detected that there was a significant difference between the groups in terms of drug abuse and suicide attempt of adolescents (p=0.097) (Table 1). However, studies in the literature [5, 6, 10, 15, 18] reveal that substance-use takes place at the top of the factors driving adolescents into suicide. The patients who have substance-users’ story were admitted by the hospital where the study was conducted only between the first and fifth days of the month during the research period. This procedure might decrease the number of suicide attempt cases related to substance use. The difference in this study from the other studies concerning the results may be linked to this practice.

    It was detected that having a good relationship with friends (p=0.001), mother (p=0.005), and father (p<0.001) decreased the risk of the suicide attempt while there was no difference between the groups regarding the relationship with siblings and suicide attempt (p=0.060) (Table 1). In adolescents with a moderate and bad relationship with friend(s) and father, suicide attempt was found to be higher than adolescents with a good relationship with friend(s) and father. In adolescents with a moderate relationship with their mothers, suicide attempts were found to be higher than adolescents with a good relationship with their mothers.

    Other studies in the literature reveal that having a good relationship with friends [9, 12, 19], mother, father [19] and sibling(s) [20] decreases the risk of suicide attempts in adolescents. The results of our study are similar to other studies in the literature with the exception of those related to sibling relationships.

    There is a significant difference between the groups in terms of parental relationship status and suicide attempts of adolescents. Those having divorced parents have a higher risk of suicide attempt (p<0.001) (Table 2). The results of other studies [7, 20] are similar to those in our study, as well. It is stated in a study of Gould and Kramer [15] that separation, divorcement and the parental loss increase the risk of suicide attempt in adolescents. Loneliness in this situation, longing for the parents caused by parental separation, financial difficulties, the lack of support and care in parents may increase the risk of suicide attempt by creating the traumatic effect in adolescents.

    Another important finding of our study is that adolescents having a working mother has higher risk of suicide attempt (p<0.001). This finding is similar to that of Duman and Inci [7]. In our literature review, we could not reach another study on this subject. It also reveals that adolescents who want to be independent need a continuous mother’s care and supervision.

    There is a significant difference between the two groups regarding the mother’s attitude and suicide attempt of adolescents (p=0.023) (Table 3). Suicide attempt rate was found to be high in adolescents whose mothers exhibited repudiative attitude. On the other hand, there is no difference between the groups regarding the father’s attitude and suicide attempt (p=0.148) (Table 3). According to the study by Zaborskis et al. [21], a non-intact family structure and weak family functioning are significant predictors of suicidal ideation and attempts among adolescents. It is essential to consider family life practices in planning intervention programs for the prevention of suicides among adolescents. Adolescents facing the lack of care and love in the family and having a continuous conflict with the parents feel unloved, weak, insecure, and have difficulty in fitting into society.

    There is a difference between the two groups regarding those who get decisions in the family and suicide attempt of the adolescents. Suicide attempt rate is lower in the families where the shared decision-making is employed by the whole family including children (p=0.004) (Table 3). It was determined that the rate of attempted suicide was higher in the families decided by the father and/or the parents (grandparents) than in the families decided by the parents and/or parents and children.

    There is no research result concerning this study in the literature. This difference may be explained that adolescents who participate in the decisions making by the families feel valuable.

    There is a significant difference between the groups regarding whether the child’s opinion is asked for the family decisions and its relationship with the suicide attempt. The group whose opinion is not asked for has higher rates of suicide attempt (p<0.001) (Table 3). There is no research result in the literature concerning this. This result may be linked to a feeling of being ignored and feeling worthless of an adolescent when the child’s opinion is not asked for, especially during a period in which personality development, as well as physical development, occurs. That’s why the risk of suicide attempt may increase in adolescents.

    When asked for the reasons of attempting to commit suicide, school failure was remarked as the main reason by 18%, quarreling with the father by 15%, interparental conflict by 10%, and the family pressure by 9%. The most common reason for the adolescent suicides in the study is familial factors. The results of other studies [4, 5, 7, 9, 12] which are similar to those of our research detect the familial problems as the main reason for adolescent suicide. It also reveals that the adolescence period may affect the individual’s whole life. An adolescent determines his/her place in the society with the help of his/her gender and personality development, and relationship with the opposite sex. Therefore, the potential problems with the opposite sex, family, and friends may drive adolescents into suicide, and suicide attempt may seem as a solution to solve their problems.

    When asked for current thoughts, 66% of the adolescents in the suicidal attempt group (n=100) showed their regrets for attempting suicide while 21% indicated that they could attempt to do it once again and 13% stated that they are neutral. In other words, more than half of the adolescents in the study regret what they did. It was stated in the study conducted by Gulec and Aksaray that half of the cases were in the search for help after attempting suicide [8]. According to the results of this study, it appeared that the suicide attempt was not carried out to end their lives. It was also detected in this research that the adolescent who attempted suicide regret for their action. However, it is very important to prevent repetition that may result in death by applying appropriate treatment and approach to the group which states that they may attempt suicide again and group that is hesitant.

    Conclusion

    As a result of the study, it has been identified that females, dropouts, the ones failing at school, bad school success, having psychological disorders, who are smokers, the ones having alcohol use, having bad relationship with his/her friends, having bad relationship with his/her mother, and having bad relationship with his/her father have more tendency towards suicide attempt.

    Although suicide attempts are mainly carried out for the purpose of intentionally killing oneself, they may also be carried out to attract attention, to express desperation and hopelessness. Whatever the reason might be, every attempt should be taken seriously into consideration. Nurses, an important member of the health team, should play an active role not only for the patients in the hospital but also in the early diagnosis and treatment of suicidal behavior by evaluating risky groups in society.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Calik B, Acikgoz A. Identifying the affecting factors in adolescents who attempt suicide. Ann Clin Anal Med 2020;11(1):43-49

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The process of how mothers with down’s syndrome children learn about the diagnosis: A qualitative research

Şaziye Senem Başgül 1 , Duygu Mutlu 2 , Yasemin Alanay 3 , Merih Toker 4

1 Child and Adolescent Psychiatrist, Hasan Kalyoncu University, Gaziantep, 2 Clinical Psycholog, Hasan Kalyoncu University, Gaziantep, 3 Child Genetics, Acibadem University, İstanbul, 4 Clinical Psycholog, Hasan Kalyoncu University, Gaziantep, Turkey

DOI: 10.4328/JCAM.6146 Received: 02.01.2019 Accepted: 17.02.2019 Published Online: 19.02.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):54-58

Corresponding Author: Şaziye Senem Başgül, Chil and Adolescent Psychiatrist, Hasan Kalyoncu University, Gaziantep, Turkey. GSM: +905324746004 E-Mail: ssenembasgul@gmail.com ORCID ID: https://orcid.org/ 0000-0002-5205-0275 

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Abstract

Aim: Healthcare providers have an important role in notifying mothers about their children’s handicap, in other words, the bad news. The mothers’ acceptance of the newborns, adapting to the process and the family dynamics are thought to be affected by this first notification period, so it is assumed to be a very important period. There have been important speculations about notifications regarding the child’s physical and psychological well-being and about the parent’s unhappiness. It was found that there is insufficient literature about how and when the parents should be notified about their child’s handicap; in fact, it was noticed that this topic was not covered in our country at all. In this light, the aim of this study is to determine how mothers who have children with Down’s syndrome are notified, and how they prefer to be notified. Material and Method: In order to determine the mothers’ preferences for the notification, a comprehensive literature survey, and interviews that are a qualitative method have been used. The participants consisted of 21 mothers whose children attended two different private rehabilitation centers in Istanbul and Karabük. In analyzing the data, the “Interview Form” and the transcripts of the interview recordings were used. Consecutive coding from A1 to A21 was done to describe the participants. Results: The findings show that the mothers were not pleased with the first notifications and that they are critical of the current notification system. According to our results, various suggestions to doctors were done. Discussion: Informing mothers that they have a different child is an important task for doctors that will affect the relationship between thischild and the mother throughout their lives. For this reason, it is very important that doctors are knowledgeable and sensitive about the reporting process.

Keywords: Down Syndrome; Parents; Diagnose; Acceptance

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  • Introduction

    Down’s syndrome was the first chromosomal disease defined in the literature. It was defined by J. Langdon Down in 1866. In 1959, Lejeune, Gautier, and Turpin proved that the reason of the disease is the extra numbers of chromosomes. Resulting from the trisomy of the 21st chromosome, Down’s syndrome can occur in 1 out of 700 births and can be diagnosed during pregnancy [6]. These children may have phenotypic conditions as well as a deficiency in growth and cognition and also many health problems in different body systems [2]. From their birth onwards, they need to receive care and support to cope with these difficult conditions.

    All parents would like to have a completely healthy child. “To have a special child” is experienced differently in all families and for some, it can be more painful and hard. They want to employ positive methods to handle or their coping skills may fade. As a result, they can experience physical and emotional burnout syndrome, psychosomatic illnesses, social isolation, drug addiction, inappropriate anger problems, ignorance for the child’s illness and they might keep away from the child, wearing themselves and the children out [9]. For this reason, the first approach while giving information to the parents about the medical condition of the child and the statements used are very important for the process which follows.

    Informing mothers of disabled children can be seen as delivering bad news and the role of healthcare professionals is very important. After the diagnosis, healthcare professionals will be faced with various questions such as: “How to explain the diagnosis? What are some appropriate responses? How to deliver the news in a birth environment? How should the situation be discussed with the other parents informed about the birth?” It is very important that mothers are provided with the correct approach in the first process of learning about the syndrome that is thought to affect many areas such as acceptance of the newborn, adapting to the process and family dynamics. The timing of giving the news to the mother, choosing “the correct words” and up-to-date information are very crucial. According to researches, the positive approaches of healthcare professionals adopted towards the mother might determine the reaction of the mother to this unexpected situation. However, when there is a doubt about the disability of the baby or it needs confirmation, healthcare professionals feel disturbed about giving information or are unprepared. Doctors might refrain from giving information to the parents about the ultimate diagnosis. In the literature, it is reported that birth centers have made protocols on this subject, it is standing out that there is not enough study on how and when to give information to the parents about the physical or mental disabilities of the child and in our country, there is not any research on this topic [10].

    This study aims toexplain how the mothers learn about the Down’s Syndrome diagnosis, what they learn about the diagnosis and their choice of being informed; giving a draft to healthcare professionals on how to communicate and inform the parents about such a delicate subject and give information to parents both before and after birth.

    Accompanying a sensitive and appropriate treatment, the sincere and affectionate approach of healthcare professionals will help the family accept the fact and assist the parents of the disabled child in this lifelong journey.

    Material and Methods

    This research is structured by using qualitative research methods and techniques. Qualitative research is a process of making meaning by questioning social life and human problems with their own methods [3]. In the qualitative research process, the researcher presents the integrated research table, uses word analysis, detailed participant interview reports, and organizes the research in a natural setting. The qualitative research process is generally followed from part to entire /whole (inductive).

    In general terms, the qualitative researcher maintains the process by explaining concepts, meanings, and relationships, starting from observations, interviews and documents [5]. In this study, the semi-structured interview model was used as a qualitative research model.

    Population and Sampling:

    The population of the research was formed of 21 mothers having child with Down syndrome in two separate Special Education and Rehabilitation Centers training from different states which are Karabük and İstanbul. The average age of the mothers is 42.3 and their ages range from 28 to 63 years. The average age of children is 8.3, the oldest being 25 and the youngest being 1 year. There are six mothers who graduated from high schools, and six mothers from primary schools, five mothers from high schools, and three mothers from junior high schools. Lastly, one mother was not literate.

    Collection of Data:

    The data of the study were collected using the semi-structure. The semi-structured interview form was developed by researchers, taking into account similar studies in the literature. The form contains demographic information and 9 open-ended questions (Table 1.). The boundary of interview topics and questionnaires were defined and the interviews were recorded in this framework by recording with a voice recorder. Each interview lasted approximately 20 minutes, at least six minutes and maximum 73 minutes in accordance with the intended purpose and in the interactive environment. Mothers who agreed to participate in the interviews organized at the Special Education and Rehabilitation Centers were interviewed at the time of their child’s education at the institution. Interviews were organized in an empty room provided by the institution. Mothers who participated in the research were given a “consent form” to explain the purpose of study and to approve their participation.

    Analysis of Data

    In the analysis of the data, “Interview Form” and written records of the data were used. These were obtained by recording with a voice recorder. Sequential coding was performed from A1 to A21 for identifying the participants. The analysis process was modeled by Marshall and Rossman (1999) in five models: a) Organizing the data; b) Definition of themes and categories; c) Testing the emerging hypothesis with data; d) the search for alternative explanations of the data and e) writing the report. In this context, when creating themes, titles can be gathered under the same heading, and titles are arranged by making quotations from appropriate speeches.

    Results

    The Time of Learning the Down’s syndrome Diagnosis of the Children:

    When the answers of the mothers to the question about when they had learnt about the Down’s syndrome diagnosis of their children are investigated, it can be seen that they learnt it in time ranging from 3 days to 6 months after the birth (Table 2).

    Mothers expressed that they were relieved upon receiving the news. Two participants told that waiting for the final diagnosis was much more stressful.

    A3: “For three months, I had such a doubt which made me even worse. Isn’t it so? Uncertainty is really bad. I would constantly search for children with Down’s syndrome online. When my husband told me that our child has the syndrome, a huge burden was lifted off my shoulders. I calmed down, I settled down.”

    A5: “I lived with that suspicion for 6 months. Then, it took one more month before it became certain. For 6 months, I prayed for it not to happen. Waiting for 7 months was worse than learning about it.”

    A18 stated that learning about the syndrome before the birth was very important in order to be prepared for it: “It is an advantage to learn about the syndrome before birth. At least, one gets used to the idea and prepares herself for the possibility. I no longer pray for the syndrome not to occur, sure. If I had learnt about it after giving the birth, the shocking effect could have lasted longer. It could have been much more difficult to accept. Facing the fact all of a sudden while expecting a normal child would be harder.”

    A14 who said that she could have had an abortion: “To tell the truth, I would have had abortion thinking about the difficulties and distress that my child endured from his family life to school performance. I would not do it for myself, thinking about my ego or for feeling comfortable, but for my child so as not to make him endure such a difficulty”.

    Our participant A21 argues that not knowing about the syndrome increases anxiety and sadness. Learning about the disease makes the hard period of pregnancy more difficult: “I think that learning about the syndrome after giving birth contributed to my beautiful period of pregnancy. Luckily, I learnt it after the birth because I do not know what I would do if I learnt it before. I would not know how to cope with it, my pregnancy would be painful. Fortunately, I learnt it after the birth.”

    Nine mothers who learnt about the first suspicion of the child after the birth got the information from the pediatrician, two of got them from the gynecologist, two of them got the information from the explanation of both the pediatrician and the gynecologist; two mothers had a suspicion from their prior knowledge about the symptoms (Table 2).

    The evaluation of how and from whom the mothers learnt that their children had Down’s syndrome:

    Participant mothers explained their negative experiences with regard to the question: “Who gave you the informationthat your child has Down’s syndrome and how?”

    A16: “The Pediatrician told me: “Your child is retarded. He will not ask for any bread, water or do anything. He will eat only what you feed him or ask nothing.” This is how I learnt my child was disabled.”

    A11: “Our obstetrician told me the news right before he cut the umbilical cord. It was a vaginal delivery, he told me during delivery. It was awful. He told me that my child was a healthy Mongolian baby. I was devastated. I did not know what a Mongolian baby was. He told me that he would not be able to talk, walk or go to school like normal children. He told all this at the delivery room”.

    A19: “I no longer go to the genetics department. There was a woman whose name started with Z and she directly told me: “Why did you give birth?” When I left her room

    I was like “I gave birth to a monster, why did they give it to me, what am I supposed to do with it ’? When I went there for the second time, there was another professor. “You gave birth to this baby because of motherly instincts but he will suffer a lot. You did a wrong thing, why did you bring this child to this world” he said.

    A21: “The information given was very insufficient. It was this ambiguity that made me uncomfortable. It was the missing information. It was a wrong information. Maybe I was not given any information because I was a doctor. However, it is very incorrect. The person who is explaining should explain the facts with great care and detail as if the person who he/she is talking to is not a professional and knows about nothing”.

    The evaluation of opinions about how to deliver the news to the families

    When the answers provided by the mothers to the question “How would you prefer that this news is told to the families and when’’ were examined, it is seen that they provided a range of suggestions in parallel with their own experiences of distress (Table 4).

    Nine participants suggested that the initial information on Down syndrome should also include the positive aspects of the disease. One of these propositions was included in the participant’s statements as follows:

    A5: “They say it will be good, not bad. No need to talk about bad probability. He will be fine when I deal with him. Then I would be happier and I would not get exhausted. There is a choice of telling good news before telling bad. When doctors say bad things, you think your kid will not have a reason.”

    According to the distribution of the data, the second most frequent respondent is “the husband should be next to his wife (mother)” and as the reason for this:

    A14: “A person should not be alone when learning this news. I would very much like to share this burden with my husband. What mother and father need to do, two people who bring the child to the world, also father should do the truth consciously. The couples must be together when this news is given so that they can learn what to do.”

    Six participants expressed similarity with A7 that it is important to be informed about the development of their children and possible health problems:

    “What the Down syndrome is, what features does it have, deficiencies, improvements, developments should be explained, and it should be said that there may be some discomforts after giving birth. It should be said that they can come up to a certain degree with education. Physical therapy should be recommended. I mean they need to focus on education. If they have discomfort, they should be directed to the treatment.”

    The evaluation in terms of how mothers felt when they learnt about the syndrome

    Mothers were asked the following questions: “What was your first reaction after learning about the syndrome? What did you think? How did you feel?” and their answers are collected under five categories namely future anxiety, sorrow, acceptance, denial and despair. Table 5 consists of the distribution of the mothers’ first feelings.

    Mentioning problems about future anxiety, A8 has important expressions: “How can I look after my baby? Will I be powerful enough? Will I have any patience? What can I offer him? People are not informed about these issues. This child is special and first we thought about what we can offer him. I was sorry. It was my first child. I got married late. I was pregnant without any treatment. We were really happy because we didn’t think of another child because of my age. We hoped for the best.”

    Participant A21 says the first feelings changed during this process: “I wanted to get an eraser and erase it or change the time. I cursed my faith. When my baby came out of the incubator, all these feelings changed. I took my baby in my arms and we made a good connection from that moment onwards.”

    The evaluation in terms of factors, which have effect on the acceptance process of mothers

    Elevenparticipants gave answers to the question abouthow they got over the process of accepting the fact that their children have Down’s syndrome as they believed in faith. Other participants gave information about how they coped with and accepted the situation with a range of answers. The distribution of answers is given in Table 6.

    Because of their religious beliefs, they saw this as a “trial” or “grace” during the acceptance of the child.

    A11: “We thought that this is a grace from God. We always think about good things. We accepted and I recovered. I hugged her differently. I have two more children, but I can say that I have learned and experienced the feeling of motherhood with my daughter.

    A19: “I said one night: “My God, this human being is yours, and you gave the feeling of motherhood, and you gave me this child. You gave the health. If it is a punishment it’s my punishment if it is a reward, it’s my reward. If I deserved it, this came from you. But this person is very incapable. You lead me to an exit” I prayed.”

    A4: “It lasted no more than a week. What are you going to do? God has appreciated and gave. You can not put your child outside the door, or you cannot give your child to someone else, you have to look after your child.”

    Stating that she has received too much support to get through the acceptance process, A21 said she feels better when she sees that her child can do something. Unlike all participants, she asserted that the acceptance process precedes life long: ‘’The admission process is something that you have to face again when that child encounters everything that needs to be done. I accept it is not a completed process. You are constantly facing. When someone comes and asks you what problem does the child have, then you remember once again even if you forgot it.”

    The evaluation in terms of being informed about special education

    Mothers who learned about the importance of physical therapy and special education started physical education and the training process a couple of months after giving a birth with the guidance of a genetic doctor. Being different from the other candidates, A1 who learnt about special education via a radio channel expressed what she experienced 13 years ago: “When the baby was 3-4 years old, we used to hear every announcement made listening to the radios and leant about special education back then. The doctors did not mention any education when we visited the hospital for the vaccines. We never thought that education needed to start early. We thought it needed to start at the schooling age.”

    Discussion

    After the doubt disappears and diagnosis is accurate, families are informed by an expert. An Expert should consult the family in a suitable time and context. Both of parents should take part in this interview and one of the relatives can come next to them. This information should be given with pediatrist who follow up the child should be together with them. Parents should be welcomed with a positive and sincerely facial expression. Parents should be met with a positive and intimate facial expression. Parents should not be approached with pity as if doctors were giving bad news, or on the contrary, they should not have a paternalistic sense of air. It should be kept in mind that this interview is an informative meeting. Firstly, an expert should start with brief information about what is the Down syndrome and he should talk about the positive characteristics of these children. Afterwards, should be explained in a very brief way the medical and social difficulties life related to DS that will affect the child’s. It should be guided about the importance of the early start of special education, physical therapy and the process where to be applied. In this first meeting, the questions of the family must be answered clearly and briefly and then the family should be referred to a Medical Genetics or Child Genetics Specialist for further genetic counseling. Resource books list and the names of the institutions and associations to which they can apply should be given to family. Legal and social rights should be briefed. If the child is diagnosed during pregnancy, under no circumstances should not be given to directive about he termination or continuation of pregnancy to the family.

    “The doctor has a heavy rock in his hand, how can he deliver it so that the mother is not crushed under this rock. It is also possible to stay under this rock or holding this rock properly and also sculpting it.”

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

    References

    1. Abdelmoktader AM, Abd Elhamed KA. Egyptian mothers’ preferences regarding how physicians break bad news about their child’s disability. A structured verbal questionnaire. BMC Med Ethics.2012;13-14. DOI: 10.1186/1472-6939-13-14.

    2. Beckman PJ. Influence of selected child characreristics on stress in families of handicapped infants, Am J Intellect Dev Disabil.1983; 88 (2):150-6.

    3. Creswell JW. Qualitative inquiry and research design: Choosing among five traditions. Thousand Oaks, CA: Sage Publications.1988.

    4. Marshall C, Rossman GB. Designing qualitative research.3rd ed. London: Sage Publications.1999.

    5. Merriam S. Qualitative research and case study applications in education. San Francisco: Jossey-Bass.1998.

    6. Lejeune J, Gautier, M, Turpin R. Study of somatic chromosomes from 9 mongoloid children. CR Hebd Seances Acad Sci. 1959;248:1721-22.

    7. Shepard MP, Mahon MM. Chronic conditions and the family. In P. L. Jackson & J. A. Vessey (Eds.), Primary care of the child with a chronic condition . 3rd ed. New York: Mosby; 2000.p.50-65.

    8. Skotko BG, Kishnani PS, Capone GT. Prenatal diagnosis of Down syndrome:

    How best to deliver the news. Am J Med Genet A. 2009; 149A: 2361-67. DOI: 10.1002/ajmg.a.33082.

    9. Whaley LF, Wong DL. Nursing Care of Infants and Children, 5th ed. Mosby Company, Missouri.1995; 1017-22.

    10. Wright DB, Gronroos N, Burkhartsmeyer J., Johnson D. Delivering the Hard News Well: Your Child Has Mental Retardation. Southern California: Diagnostic Center. 2008.

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Başgül ŞS, Mutlu D, Alanay Y, Toker M. The process of how mothers with down’s syndrome children learn about the diagnosis: A qualitative research. Ann Clin Anal Med 2020;11(1):54-58

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Prognostic factors in mechanically ventilated patients

Saniye Goknil Calık 1 , Mustafa Calik 2 , Basar Cander 3

1 Department of Emergency and First Aid, KTO Karatay University Vocational School of Health, 2 Department of Thoracic Surgery, Health Sciences University, Konya Training and Research Hospital, 3 Department of Emergency Medicine, Necmettin Erbakan University Meram Faculty of Medicine, Konya, Turkey

DOI: 10.4328/JCAM.6131 Received: 17.12.2018 Accepted: 08.02.2019 Published Online: 19.02.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):33-37

Corresponding Author: Mustafa Calik, Department of Thoracic Surgery, Health Sciences University, Konya Training and Research Hospital, 42090, Meram, Konya, Turkey. GSM: +905058584898 T.: +90 3323236709 F.: +90 3323236723 E-Mail: drmcalik@hotmail.com ORCID ID: https://orcid.org/0000-0001-9963-5724

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Aim: In this study, we aimed to investigate the prognostic values of respiratory parameters recorded within the first 48 hours in patients connected to mechanical ventilation in the intensive care unit (ICU), in terms of 30-day mortality. Material and Method: This prospective study included patients who received mechanical ventilation due to acute respiratory failure between 2011 and 2013. The demographic characteristics of the patients, Glasgow Coma Score (GCS) scores, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) values, vital signs, the results of complete blood count, biochemistry parameters and blood gas analyses were recorded. Patients were divided into two groups as survivors and non-survivors, and the differences in the parameters between the groups were analysed. Results: The study included 99 mechanically ventilated patients with the mean age 71.73 (18-105) years. Of the patients, 56 (56.6%) were male and 43 (43.4%) were female. Comparison of the survivors (n=37) with the non-survivors (n=62) indicated that the non-survivors had no statistical differences in terms of age, gender, or concomitant diseases. The values of GCS, APACHE II, and SOFA were significantly different between survivors and non-survivors (for all, p<0.001). Significant differences were also noted in FiO2 (p<0.001), pH (p=0.001), PO2 (p=0.044), PCO2 (p=0.046), A-a Gradient (p<0.001) and the expected increase of O2 gradient (p=0.026) between two groups. Discussion: Our findings indicate that, during the follow-up of the mechanically ventilated patients, respiratory parameters measured within the first 48 hours are cheap and easy-to-use parameters to predict the prognosis.

Keywords: Intensive Care; Mechanical Ventilation; Prognosis; Blood Gases; Scoring

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  • Introduction

    Contrary to the common belief, intubation and mechanical ventilation are not recent discoveries. Their roots are as old as modern science. However, mechanical ventilation became available at the beginning of the 20th century [1]. Its widespread applications started during the North European polio outbreak in the 1950s.

    Drinker suggested that these patients could be saved by providing respiratory support in the paralytic period. He developed the “Iron Lung”, which worked with negative pressure similar to the normal respiratory physiology. The little girl, who was the first polio patient to receive mechanical ventilation via the “Iron Lung”, even wanted an ice-cream after mechanical ventilation was withdrawn after four hours, but she eventually died due to pneumonia. Despite its short-term success, patients died in the long term due to “Tank Shock” which caused abdominal vascular ponding and low cardiac output. Consequently, this technique was replaced by ventilation that works with positive pressure. Dr. Bjorn Ibsen, who observed this situation attentively and systematically, noticed that many patients died due to inadequate ventilation during the polio epidemics. He reduced the mortality rate from 85% to 15% by providing only close and intense follow-up, sedation, monitoring, proper airway ventilation with positive pressure at intervals and aspiration of secretions. Following such a sharp drop in the mortality rate, ideas to form units that are reserved for the care of patients who are connected to mechanical ventilation, which are now known as “Intensive Care” units, emerged. For this reason, mechanical ventilation is the core of intensive care units and their reason for being [1,2].

    Material and Methods

    The present study was carried out in the emergency unit of the emergency medicine department of a tertiary university hospital between November 2011 and October 2013. All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethics committee approval was received for this study from the ethics committee of local University. All the participants who are legally responsible or first-degree relatives of the patient in the study gave their informed consent prior to the commencement of the research. Written informed consent was obtained from the patient’s legal custodian or first-degree relatives of the patient for publishing the individual medical records.

    Study population

    A total number of 99 consecutive patients, 27 of which constituted the control group and 72 of which were connected to MV in the emergency critical intensive care unit of a tertiary university hospital due to acute respiratory failure between November 2011 and October 2013, were included to this prospective study. Patients with congestive heart failure, cardiomyopathy, patients who recently had a myocardial infarction, patients under the age of 18 years, patients with a neuromuscular disease and pregnant patients were excluded from the study.

    Study protocol

    The demographic characteristics, Glasgow Coma Score (GCS) scores, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) values, vital signs, CBC, biochemical parameters and blood gas levels of the patients were analysed. Glasgow coma scale score was recorded. For APACHE II and SOFA, the scores were calculated by taking the worst parameters recorded within the first 48 hours into account. Although the criteria defined by Christie HA et al. were used in order to start MV, these criteria alone were not considered as the definite indication [3]. The decision to start MV was given by taking not only the respiratory factors but also the specific clinical factors relevant to other body systems into consideration, especially circulatory, central nervous and hemopoietic systems. Synchronized Intermittent-Mandatory Ventilation (SIMV) mode was used as the start mode in patients connected to mechanical ventilation. Other parameters were adjusted by treating physicians individually for each patient. When deemed necessary, patients were sedated at the onset of mechanical ventilation.

    Statistical analysis

    All data were transferred into Statistical Package for Social Sciences version 18 (SPSS v18) (IBM Corp., Chicago, IL, USA). The package software was used for data analysis. For the assessment of mortality, statistical analysis of normally distributed numeric data was performed by the Student’s T-test; data that did not fit the normal distribution were analysed by the Mann-Whitney U Test. Patients were divided into two groups as the survivors and the deceased, and the differences between two groups were analysed for all parameters. The confidence interval was considered as 95% in all statistical analyses and p-values < 0.05 (two-way) were accepted statistically significant.

    Results

    A total number of 99 patients with a mean age of 71.73 years (range: 18-105 years) were included in the study. Fifty-six of them (56.6%) were male and 43 (43.4%) were female. The patients were assessed based on the data collected within the first 48 hours and on the 30th day (Table 1). When the patients who survived (n=37) and who died (n=62) were compared, no significant difference was detected in 30-days mortality based on age (p=0.092), gender (p=0.697), or concomitant diseases (p=0.283) (Figure 1). Differences between GCS (p<0.001), APACHE II (p<0.001) and SOFA (p<0.001) scores were significant (Figure 2). In terms of respiratory parameters, FiO2 (p<0.001), pH (p=0,001), PO2 (p= 0,044), PCO2 (p=0,046) (Figure 3), A-a Gradient (p<0.001) and the expected O2 gradient differences (Figure 4) were statistically significant between two groups.

    Discussion

    Patients who cannot be treated by conventional methods, patients who lost organ functions due to severe disease progression or patients with a disease associated with a high mortality rate are monitored and treated in the ICUs. MV is commonly used in the ICUs [4]. With the increasing life expectancy worldwide, it causes a high rate of chronic diseases. Up to 20 million people worldwide are admitted to ICUs and require MV [5]. Only 30.000 patients undergo mechanical ventilation in the United Kingdom and 500.000 in the United States annually. [6,7]. In the United States, ICU care is approximately four times more expensive compared to the regular care provided in the hospital wards [4]. The incidence may even differ between countries and even between regions in the same country. The extent of the incidence rate is bound to local risk factors such as etiology prevalence, equipment and the number of intensive care units. High incidence can be seen in countries with high ICU bed capacity and populations at risk. [6,7].

    MV is “a necessary evil”, a lifesaving treatment but with important potential complications, it can cause or deteriorate lung damage through mechanisms such as barotrauma, volutrauma or atelectrauma, which is also called ventilator-associated lung injury and represents the human counterpart of the ventilator-induced lung injury observed in lab animals [8,9]. In addition to giving direct structural damage, these mechanical forces can trigger a local and systemic inflammatory response (biotrauma) and a series of complex inflammatory mediators, which result in multiple organ system dysfunctions and eventually cause death [10]. The lung is the first organ to show signs of failure and this failure is a reason to start or continue MV [11]. Mortality among these patients depends on many factors. It is difficult to estimate the prognosis in a patient only based on certain parameters, if the patient has concomitant cardiovascular, renal, haematological, neurological or infectious complications, all of which strongly affect the prognosis [12].

    Intensive care scoring systems are used to estimate the recovery and severity of the disease and the level of organ dysfunction, to evaluate treatment outcomes, to standardize the patient care and to compare the performances between intensive care units [13]. For this purpose, patient data obtained from daily specific measurements are used. Scoring systems are divided into two groups: prognostic (estimates mortality) and organ failure scoring systems (measures morbidity). However, the level of organ failure is not only related to morbidity, but it also has a considerable correlation with mortality [14]. Scoring systems that assess both mortality and morbidity were used in our study. The factors that determine the mortality in intensive care patients include the patients’ physiological reserve, type, and severity of their disease, and their response to the treatment. Moreover, chronological age and chronic disorders can affect patients’ physiological reserve by impairing functions of organ systems. The severity of the disease can be evaluated according to the anatomical trauma or through functions [14].

    According to the current epidemiologic studies, the median age of patients who receive mechanical ventilator support, 40% of which are women, is 63 years (48-73 years) [15]. In our study, the median age was 74 years (18-105 years), higher than the literature. Similarly, the percentage of male patients was slightly higher than the literature with 56.6% and the percentage of female patients was slightly lower with 43.4%. This trend appears to continue in the future. The reason for the use of MV was a postoperative respiratory failure in most of the patients (65%), followed by traffic accidents in the literature [15]. Traffic accidents, the most frequent cause of hospitalization and MV are anticipated to increase by 65% until 2033 in developing countries. For this reason, it seems certain that we will encounter more MV in the coming years [6,7]. In our study, only an 18-year-old patient received mechanical ventilation following a motorcycle accident. The remaining 71 patients received respiratory support due to secondary respiratory failure. The lack of postoperative respiratory failure can be attributed to the monitoring of these patients by the intensive care units of surgical clinics and by reanimation clinics.

    The rate of mortality on MV as reported by previous studies varied between 34 and 81%. The rate of 30-day mortality was not significantly different between the survivors and non-survivors based on age, gender or concomitant diseases. Consistent with the literature, age was shown to be an important factor determining in-hospital mortality among older intensive care patients, but it was not sufficient alone. The mean age of survivors was 5 years lower than that of non-survivors. Also, it was demonstrated in the literature that concomitant diseases also affect the rate of mortality, but we could not detect a significant difference in 30-day mortality rate based on concomitant diseases. In terms of respiratory parameters, FiO2 (in survivors 42.6 ± 22.5; in non-survivors 70.6± 26.6 p<0.001), pH (in survivors 7.35; in non-survivors 7.27 p=0.001), PO2 (in survivors 92.2±36.3; in non-survivors 82.3±42 p= 0.044) , PCO2 (in survivors 34.6±14.9; in non-survivors 41.2±19 p= 0.046), A-a Gradient (in survivors 344.8±108.9; in non-survivors 387.8±121 p<0.001) and the expected O2 gradient (in survivors 19.4 ± 4.1; in non-survivors 21.8 ± 2.7 p= 0.026) differences were statistically significant (Table 1). In other words, within the first 48 hours of ventilation, the mortality rate was high among the patients receiving high concentrations of O2, patients with a high O2 gradient and difference. We could not determine a similar relation in the literature. In addition, our study planned between November 2011 and November 2019 has been going on.

    Like any study, our study has some limitations. The first point is that it is a single-center study and a tertiary step, relatively limited and low number of patients, non-gender equality, a short period of time, and the common point in almost all studies conducted in our country is lack of knowledge about the long term results of the patients due to lack of follow-up and medical records. In particular, the prospective nature of the study and potential for era bias can be considered limitations.

    We have learned a lot about intensive care since Dr. Bjorn Ibsen’s time. Scoring systems and parameters are surplus, complex, and usually difficult to learn and practice. This mandates us to search for parameters that are easy to learn and practice. There’s so much we have to learn. There is a large, multicentre, multinational wide scientific research lack of MV. These researches should be promoted and supported. We believe that new parameters will contribute to the evaluation, monitoring, and treatment of MV patients. In conclusion, in the follow-up of patients receiving MV, A-a Gradient and expected O2 gradient difference values are inexpensive and easy-to-use parameters to predict the prognosis based on data recorded within the first 48 hours.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

    References

    1. Karcz M, Vitkus A, Papadakos PJ, Schwaiberger D, Lachmann B. State-of-the-art mechanical ventilation. J Cardiothorac Vasc Anesth. 2012; 26(3): 486-506. DOI: 10.1053/j.jvca.2011.03.010.

    2. Chen K, Sternbach GL, Fromm RE Jr, Varon J. Mechanical ventilation: past and presentJ Emerg Med. 1998; 16(3): 453-60.

    3. Christie HA, Goldstein LS. Respiratory failure and the need for ventiletory support. In: Egan’s Fundamentals of Respiratory Care, Wilkins RL, Stoller JK, Scanlan CL, editors. Mosby; 2003.p.913.

    4. Knaus WA, Wagner DP, Zimmerman JE, Draper EA. Variations in mortality and length of stay in intensive care units. Ann Intern Med. 1993; 118:753-61.

    5. Ambrosino N, Vitacca M. The Patient Needing Prolonged Mechanical Ventilation: A Narrative Review. Multidiscip Respir Med. 2018; (26) 13: 6. DOI: 10.1186/s40248-018-0118-7.

    6. Nouraei S R, Battson R M, Koury E F, Sandhu G S, Patel A. Adult post-intubation laryngotracheal stenosis: an underestimated complication of intensive care. Journal of the Intensive Care Society. 2009; 10(3): 229

    7. Farzanegan R, Feizabadi M, Ghorbani F, Movassaghi M, Vaziri E, Zangi M, et al.An overview of tracheal stenosis research trends and hot topics. Arch Iran Med. 2017; 9: 598 – 607.

    8. Pham T, Brochard LJ, Slutsky AS. Mechanical Ventilation: State of the Art 2017; 92(9): 1382-1400. DOI: 10.1016/j.mayocp.2017.05.004

    9. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med. 2006; 32:24–33. DOI: 10.1007/s00134-005-2817-8

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    14. Ball JAS, Redman JW, Grounds RM. Severity of illness scoring systems. In: Vincent JL, editors. 2002 Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer; 2002.p.911-33.

    15. Kramer AA. Taking a closer look at mechanical ventilation in the United States. Crit Care Med. 2010; 38(10):2067. DOI: 10.1097/CCM.0b013e3181f179d2

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Calık SG, Calik M, Cander B. Prognostic factors in mechanically ventilated patients. Ann Clin Anal Med 2020;11(1):33-37

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Evaluation of acute stroke patients applying to a university emergency service in terms of risk factors

Suheyp Tuncay 1 , Ahmet Yilmaz 2 , Ömer Göcen 3 , Hamza Aslanhan 2 , Emre Dirican 4

1 Department of Family Medicine, Mardin Public Health Directorate, Mardin, 2 Department of Family Medicine, Dicle University Medical Faculty, Diyarbakir, 3 Çınar Family Health Center, Diyarbakir, 4 Department of Biostatistics, Mustafa Kemal University, Hatay, Turkey

DOI: 10.4328/ACAM.6149 Received: 31.12.2018 Accepted: 29.01.2019 Published Online: 08.02.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):59-63

Corresponding Author: Ahmet Yilmaz, Department of Family Physicians, Dicle University Medical Faculty, Diyarbakir, Turkey. T.: +90 41224888001 (4276) F.: +90 4122488004 E-Mail: dearahmetyilmaz@hotmail.com ORCID ID: https://orcid.org/ 0000-0002-2648-2824

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Aim: Stroke is a group of diseases that causes morbidity and loss of function at the highest rate worldwide that mostly affects the quality of life and is the second leading cause of death after heart diseases. In the present study, we aimed to determine the risk factors of the patients who applied to the emergency service and their distributions. Material and Method: Our study was formed retrospectively by evaluating the follow-up files of 194 patients who applied to Dicle University Medical Faculty Emergency and Traumatology Polyclinic and were diagnosed with stroke and were followed between June1, 2014 and June 1, 2016. Results: Of the 194 patients included in the study, 98 (51%) were female and 96 (49%) were male, the mean age was 69.6±13.4. One hundred and seventeen of patients (60%) were diagnosed with ischemic stroke, 77 of them (40%) were diagnosed with a hemorrhagic stroke. The mean age of men and women were 69.9±10 and 69.3±15.7 years respectively. According to the types of stroke, the mean age for those with ischemic stroke was 69.9±12.6, for those with hemorrhagic stroke was 69.3± 14.8. In both types of stroke, the values of systolic and diastolic blood pressure were higher than normal. When the age of the patients was compared in terms of both sex and type of stroke, no significant difference was determined in terms of age in the groups. The incidence of stroke was greater between the ages of 45 and 84 in 164 patients (84.5%). Discussion: The average age of the patients was in the advanced group and their average tension values were higher than normal. For this reason, advanced age and high blood pressure were considered as risk factors contributing to stroke development in our study group. It is significant to evaluate the risk factors of the patients during the continuous health services given to the patients and to provide appropriate treatment and regular follow-ups for those with risk factors.

Keywords:  Ischemic Stroke; Hemorrhagic Stroke; Chronic Diseases; Risk Factors

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  • Introduction

    Stroke is a group of diseases that causes morbidity and loss of function at the highest rate worldwide that mostly affects the quality of life and is the second leading cause of death after heart diseases. It is the most common cause of epilepsy, the second most common cause of dementia and also one of the most common causes of depression [1,2,3]. In the world, 17 million people suffer from stroke, 6 million people die of stroke, in every 40 seconds a stroke occurs and in every 4 minutes, a death occurs [4].

    The mortality rate for patients with stroke is 10-20 % in the first following month. On the other hand, 30 % of all patients die in one year. Of the patients who suffer from stroke and survive, only 10 % do not develop any sequel, 30 % show low disability, 50 % show severe disability and 10 % need continuous institutional care. The survival rate of the patients after stroke in ten years is 35 %. Due to the high mortality and morbidity rate, stroke is not only a significant health problem but also a big social and economic problem. In the UK, almost half of the health expenses are used for stroke treatment and following social care [5].

    While productivity loss created by patient care, labor loss, disability, and death cases is 2 billion dollars, daily treatment in the unit of stroke costs 900 dollars, thrombolytic treatment for once costs 750 dollars and patient care at home for a week costs 8000 dollars. The average cost is approximately 36.000 dollars. After a stroke, only 7 % of the patients live more than 10 years and it is thought that real cost is much higher off the books [6,7].

    In the USA, 795.000 stroke cases occur in a year and of those cases, 610.000 are the first stroke experiences whereas 185.000 are the recurrent ones. The total cost for the treatment and rehabilitation of those patients is approximately 73,7 billion dollars. Only 10 % of the patients can go on their lives without any disabilities [8,9].

    Similar to the other diseases, we confront the fact that knowing especially the preventable risk factors for stroke and developing solutions are strategies which are both problem-effective and cost-effective.

    Within this study, it was aimed to determine the distributions of the stroke types considering the patients with stroke who applied to the emergency service according to their sociodemographic features, clinical, and laboratory parameters.

    Material and Methods

    Within the study, the follow-up files of patients who applied to Dicle University Medical Faculty Emergency Service between June 1, 2014 and June 1, 2016 and were diagnosed with stroke were evaluated retrospectively. Within this evaluation, the stroke types, sociodemographic features, laboratory parameters, and anamnesis data of the patients were reached and they were registered into the data gathering forms. Having applied to the emergency service with the diagnose of acute stroke, the patients whose ages were above 18 were involved in the study. The ethics committee approval for the study was taken from Dicle University Non-invasive Investigation Ethics Committee with the date of 02.06.2016 and the number of 218.

    Statistical Analysis

    The evaluation of the data was made with IBM SPSS Statistics for Windows, version 18 (IBM Corp., Armonk, N.Y., USA) programme. Basic statistical evaluations were made as descriptive statistics, average, standard deviation, and frequency tables. Continuous variables were expressed as average ± standard deviation while categorical data were expressed frequency and percentage. The conformity of the data to the normal distribution was evaluated with the Kolmogorov-Smirnov test. The evaluation for the qualitative variables was made with the Chi-square (χ2). The Student-t and Mann-Whitney U tests were used in order to evaluate continuous variables and the value of p<0,05 was found significant.

    Results

    Among the files of evaluated 194 patients, 98 (51%) were female and 96 (49%) were male. The mean age of the whole patients was 69.6±13.4. The mean age for male patients was 69,9±10,7 while it was 69,3±15,7 for female patients. A significant difference could not be found between the stroke types and age average for both women and men (Table 1).

    According to the types of stroke, the mean age for those with ischemic stroke was 69.9±12.6 and for those with hemorrhagic stroke was 69.3± 14.8. No significant difference was found between age groups after categorizing the patients according to their ages (Table 2). The most common complaints among the patients were impairment of consciousness and speech disorder. The complaints of the patients were summed up (Table 3).

    For the patients with hemorrhagic stroke, 72 patients had intraparenchymal bleeding and 5 patients had subarachnoidal bleeding. Of the applying patients, 117 (60,3 %) patients were discharged from the hospital whereas 77 (39,7 %) patients ended up with exitus. Of the patients who lost their lives, 52 % had an ischemic stroke and 48 % had a hemorrhagic stroke.

    Comparing the patients with ischemic and hemorrhagic strokes in terms of mortality, the mortality rates were found similar in both stroke types (Table 4).

    When vital findings and laboratory values of the patients with ischemic and hemorrhagic were compared at the time of applying, there could not be found a significant difference between groups (Table 5).

    Discussion

    Stroke is one of the most important causes of mortality and morbidity resulting from some risk factors such as hypertension (HT) and hyperlipidemia which get more common with aging [10]. Stroke is a disease which gets more and more common each passing day in our country and in the world. Since it can end up with high morbidity and mortality, it is getting more and more important. Treatable risk factors such as hypertension and hyperlipidemia should be determined in order to minimize mortality and morbidity based on stroke and prevent the reccurrence.

    The risk of stroke increases comparatively with age and this risk gets double in each decade after the age of 55 [10,11]. Strokes that occur below the age of 45 are in the rate of 4-10 % [12]. Of the studies made with different age groups which suffer from stroke, the rate was found higher between the ages of 60-70 [13,14]. In the study by Kıyan et al. [15], the incidence of stroke below the age of 45 was found 5 % and it was found 6,1 % in the study by Şahin et al. [16]. In our study, compatible with the literature, the rate of stroke increases with age.

    In the literature researches, it has been revealed that gender is one of the important factors in the etiology of stroke and the rate of male patients is more than the rate of female patients [17,18]. In many studies made in our country, for all of the age groups, it has been found that acute stroke is seen more common inmen [14,15,19-22]. Accompanying and cardiovascular diseases in men might cause early deaths. In the researches related to stroke etiopathogenesis, most commonly known risk factors are considered hypertension, diabetics and high cholestrol [21,23,24]. There are reliable proofs that HT and DM are serious risk factors especially for the patients who cannot be controlled with medical treatment [23,25]. High blood pressure and increased risk in stroke are directly proportional. It is stated in the studies that HT is available at the rate of 75 % with ischemic strokes where it is available in the rate of 72-81 % with hemorrhagic strokes [26,27]. In many studies made in our country, those risk factors have also been determined as the most common ones [15,21,23]. Similar results were found in the studies made in the Middle East and Asian countries [28-30]. There are also studies showing that the patients already have hypertensive findings at the time of applying to the emergency service among the researches related to tension values of the patients with stroke [14,15,23]. In the study by Efstathiou et al. [25], it was found that the mean of systolic blood pressure (SBP) in the patients with ischemic stroke was 161,7±21,5 mmHg and 165,4±15,3 mmHg for the patients with hemorrhagic stroke. Whereas the mean of diastolic blood pressure (DBP) was 96,5±11,5 mmHg in the patients with ischemic stroke, it was found as 100,5±8,6 mmHg in the patients with hemorrhagic stroke. In our study, incompatible with the literature, while the mean of SBP in the group with ischemic stroke was found 165,8±38,1 and 159,2±36,3 in the group with hemorrhagic stroke, the mean of DBP was detected 92,3±18,9 in the group with ischemic stroke and 91,2±23,5 in the group with hemorrhagic stroke. High blood pressure confronts us as a physical examination finding and a valid risk factor for all types of strokes in the physical examination. In our study, the most explicit risk factor was that the patients were hypertensive. The fact that our patients receiving treatment for hypertension disrupted their medications and could not fully implement their lifestyle recommendations could have been effective in these results. Regular follow-up in terms of hypertension and end organ damage cannot be done regularly in terms of the presence of hypertension infrastructures in stroke patients, may be an etiological factor.

    It was found in the study by Soyama et al. [31], development of stroke based on aging got four times more in the ones with HDL<30 mg/dL than in the ones with HDL≥60 mg/dL. In the study by Ralph et al. [32], of 539 patients with ischemic stroke, the mean of total cholesterol was 193 mg/dL, LDL median was 121 mg/dL, HDL mean was 40 mg/dL and the median of triglyceride was 136 mg/dL. It was found that the increase in the level of HDL decreased the risk of ischemic stroke in a study with different ethnic groups and old patients. In the study by Şahin et al. [16], HDL median of the patients with ischemic stroke was found lower than the one in the patients with hemorrhagic stroke. In 86,8 % of the patients whose HDL level was below 45 mg/dl and in 68,2 % of the patients whose HDL level was 65 and above had an ischemic stroke and the inverse relation between HDL level and ischemic stroke was found statistically significant. In our study, the mean HDL value of all patients was 39,9±13,9 and comparing the stroke types it was found 39,8±11,9 in the ones with ischemic stroke and 39,9±16,6 in those with hemorrhagic stroke. Unlike the study conducted by Şahin et al. in our study, there was no significant difference in terms of HDL levels between the hemorrhagic and ischemic stroke groups.

    In the literature, although hemorrhagic stroke is seen less than ischemic stroke, the death rate is higher in hemorrhagic strokes than the ischemic ones and death occurs in the early period in the hemorrhagic strokes [33]. Mortality rate based on stroke was found 17 % in the study by Yılmaz et al. [34]. In 40 % of the hemorrhagic strokes and in 13 % of the ischemic strokes there was a fatal course. Statistically, significant difference was found between stroke type and matter of death-life in the study by Şahin et al. Whereas mortality was 34,1 % in hemorrhagic stroke, it was 13,3 % in ischemic stroke [16]. It was stated that the death rate was higher in the case of hemorrhagic strokes in the study by Alp et al. [35]. It was observed that 24 % of the patients died at the time of their hospitalization and 26 % of the patients died in the first three months after the stroke in the study by Nakayama et al. [36]. In our study, incompatible with the literature, death rate in hemorrhagic strokes (48 %) was detected higher than the rate in ischemic strokes (34 %).

    The death rate in the patients with stroke ranges from 12,7 % to 33 % [17,37,38]. In our study, the death rate was found higher (39,7%). The reasons of this result may be that the rate of the patients with hemorrhagic stroke was higher, the patients were in advanced age, the hospitalization duration was long, the addition of hospital infections to the table and the effect of previous diseases.

    In the study by Şahin et al. [16], the hospitalization duration of the patients with hemorrhagic stroke was 11,0 ±10,0 days and 8,0 ±9,0 days for the patients with ischemic stroke. On the other hand, in the study by Yılmaz et al. [34], the hospitalization duration was found 7,6±6,5 days on average. In the study by Nakayama et al. [36], it was found that as the ages of the patients increased the hospitalization duration got longer. In our study, the hospitalization duration of the patients applying with stroke was 38,8±67 days and this value was 36,3±49,7 days in the patients with ischemic stroke whereas it was 42,8±87,7 days in the patients with hemorrhagic stroke. Incompatible with the literature, in our study, the hospitalization duration of the patients with hemorrhagic strokes was found longer. However, the comparison of the days was apparently higher. The obstacles that the patients involved in our study came across while trying to reach the health center, the development of some additional complications, the fact that supplying medical support to the patients under custody could be much easier are regarded as effective factors on the duration of hospitalization.

    Conclusion

    In our study, in terms of stroke development, hypertension was considered as a changeable risk factor; age and gender were considered as unchangeable risk factors and it was seen that they were all effective. Although much progress have been made in the treatment of stroke, we anticipate that the primary prevention is an effective approach and determining changeable risk factors in the stroke etiology through primary prevention and preventing them with follow-ups and treatment can minimize mortality and morbidity.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Tuncay S, Yilmaz A, Göcen Ö, Aslanhan H, Dirican E. Evaluation of acute stroke patients applying to a university emergency service in terms of risk factors. Ann Clin Anal Med 2020;11(1):59-63

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Serum vitamin d levels in children with vitiligo

Vildan Manav 1 , Soysal Baş 2 , Gökhan Çakırca 3

1 Department of Dermatology, 2 Department of Plastic Aesthetic Reconstructive Surgery, 3 Department of Biochemistry, University of Health Sciences Mehmet Akif İnan Research and Training Hospital, Şanlıurfa, Turkey

DOI: 10.4328/ACAM.6141 Received: 25.12.2018 Accepted: 27.01.2019 Published Online: 29.01.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):50-53

Corresponding Author: Vildan Manav, Department of Dermatology, University of Health Sciences Mehmet Akif İnan Research and Training Hospital, Şanlıurfa, Turkey. GSM: +905334323524 E-Mail: drvildanmanav@gmail.com ORCID ID: https://orcid.org/ 0000-0002-0044-7414

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Abstract

Aim: In this study, we aimed to investigate the clinical profile of pediatric vitiligo in Turkey by analyzing differences in gender, clinical features, triggering factors, age of onset, duration of disease, atopy, familial history, and sun exposure in order to report the serum vitamin D levels of children with vitiligo. Material and Method: During a six-month period, 39 children with vitiligo and 39 healthy controls were studied. Demographic details were noted, and dermatological examination was performed to note the areas involved, leukotrichia, and halo nevus. 25-OH vitamin D was carried out by chemiluminescent enzyme immunoassay. Results: The group of girls with vitiligo was compared for serum 25-OH vitamin D levels. Significant differences were found between the girls in the control group, even if there were no significant differences between the group of boys with vitiligo and the control group. There were statistically significant differences in 25-OH vitamin D levels between the groups of girls and boys with vitiligo. Only 12 children had a history of more than 15 minutes of sunshine exposure per day, and a significant difference was noted among the boys. Vitamin D deficiency and insufficiency was found in 20 (5%) and 46 (1%) of children, respectively. Discussion: The antioxidant properties of vitamin D show protection from vitiligo. The low levels of vitamin D in girls with vitiligo are caused by concealing clothing, no daily supplementation of vitamin D, exposure to sunlight, more indoor work, and dark skin. These factors may contribute to the pathogenesis of vitiligo.

Keywords: Children; Vitamin D; Vitiligo

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Introduction

Vitiligo is a pigmentary disorder caused by autoimmune destruction of melanocytes [1]. Vitiligo affects about 0.5-2% of people worldwide, with half of the cases of vitiligo beginning under the age of 18, mostly in females [2]. The pathogenesis of vitiligo includes the unification of genetic propensity paired with environmental triggers such as stress, sun exposure, koebnerization and oxidative stress [3].

Vitamin D is a fat-soluble prohormone steroid that ensures the integrity of epidermal melanin units by controlling the activation, proliferation, and migration of melanocytes and pigmentation pathways as a result of modulating T-cell activation, which is apparently correlated with melanocyte disappearance in vitiligo [4]. Although it is known that the protective mechanism of vitiliginous skin is caused by an antioxidant activity of vitamin D and regulatory function against the reactive oxygen species, the full relationship between vitamin D and vitiligo is not yet fully understood.

In the literature, there are a few studies that analyze the clinico-epidemiologic profile of pediatric vitiligo through the clinical features of different ages of onset and the relationship of pediatric vitiligo to other autoimmune diseases.

This study aims to establish the profile of pediatric vitiligo in the southeastern region of Turkey by analyzing differences in gender, clinical features, triggering factors, age of onset, duration of disease, atopy, family history, and sun exposure in order to report the serum vitamin D levels of children with vitiligo.

Material and Methods

In this prospective study, the data of 78 children up to 17 years old were collected from July 2016 to December in 2016 in Mehmet Akif Inan Research and Training Hospital in Sanliurfa, Turkey. Demographic details such as age, gender, family history, age of onset, duration of disease, atopy, autoimmune diseases, triggering factors, sun exposure, distribution of lesions, and medical history were noted for all 39 children with vitiligo. A complete dermatological examination was performed, and the areas involved, leukotrichia, and halo nevus were noted. 25-OH vitamin D was carried out by chemiluminescent enzyme immunoassay from blood samples that were collected in the morning.

In the study, vitamin D deficiency, insufficiency, and sufficiency were defined as serum 25-OH vitamin D levels of <15ng/ml, 15-30ng/ml, and >30ng/ml, respectively.

In this study, patients were divided into six groups according to the standard study classification of vitiligo as follows: focal, segmental, vulgaris (generalized), acrofacial, mucosal, and universal. The participants were excluded if they had any other autoimmune or chronic diseases (e.g. thyroid disease, Addison’s disease, diabetes mellitus, pernicious anemia, alopecia areata) or had been using vitamin D supplements, NSAIDs, systemic steroids in the previous three months. The controls were 39 healthy gender- and age-matched children with no family history of vitiligo or systemic autoimmune diseases. They were enlisted on the same day as the patients to avoid seasonal effects.

This study was approved by the University of Harran ethical committee (Report number: 161215). All of the parents were informed about the study and written approvals were received from them.

Statistical Analysis

The Kolmogorov-Smirnov test was used to determine the distribution normality of each variable. The Students’ T-test was used for the comparison of means between the two groups. The Chi-Square test was applied for the analysis of categorical variables. SPSS 22.00 for Windows was used for all the analyses. The results with p-values of < 0.05 were defined as significant.

Results

Of the 39 children with vitiligo who visited the dermatology outpatient department over a period of six months, their ages, genders, and Fitzpatrick skin types were similar to those of children with vitiligo and the controls. In the present study, 22 (56.4%) were boys and 17 (43.6%) were girls. The mean age of onset was 9.1 years old, ranging from 1-16. The mean age of children at the visit was 10.7, ranging from 1-17. The duration of the disease varied from less than one month to 96 months with a mean duration of 19 months. Three patients (7.6%) had an onset between the ages of 0-4, seven (17.9%) between 5-8 years, 12 (30.7%) between 9-12 years, and 17 (43.8%) after 12 years. There was no statistical difference between genders with respect to the mean age of onset (p=0.216) or duration of disease (p=0.435). The most common type of vitiligo in the present study was acrofacial (41.0%), followed by vitiligo vulgaris (30.8%), focal vitiligo (25.6%), and segmental vitiligo (2.6%). Mucosal and universal vitiligo were not seen in either gender. The difference was not significant when the frequencies of the different types of vitiligo were compared with gender (p=0.260).

The clinical characteristics, treatment history, and serum 25-OH levels of girls and boys are shown in Table 1. Eleven boys and one girl with vitiligo experienced exposure to natural sunlight for more than 15 minutes per day, and there was a statistical difference between genders (p=0.002). Emotional stress was a triggering factor of vitiligo in 12 girls and four boys. There was a statistical difference between genders (p=0.001).

When 25-OH vitamin D levels were evaluated, vitamin D deficiency and insufficiency was found in 20.5% and 46.1% of children, respectively.

The mean levels of 25-OH vitamin D in children with vitiligo were 26.8 ± 9.6 ng/ml, ranging from 8.14 ng/ml to 58.07 ng/ml. The control group’s mean level was 28.5 ± 9.4 ng/ml. The serum 25-OH vitamin D levels were not significantly different between children with vitiligo and the controls, but there were statistically significant differences in 25-OH vitamin D levels between the group of girls and boys with vitiligo (p< 0.001) (Table 1). When the group of girls with vitiligo was compared for serum 25-OH vitamin D levels, significant differences were found between the control group of girls, even if there were no significant differences between the group of boys with vitiligo and the controls (Table 2).

Discussion

The pathogenesis of vitiligo is not clear, but a high frequency of cytotoxic T lymphocytes specific to melanocytic antigens in reactive oxygen species are produced in vitiligo lesions. Vitamin D plays a role in the protection of vitiliginous skin from reactive oxygen species. In addition, vitamin D reduces the apoptotic activity induced by UVB and provides protection for the melanin unit [4,5].

Although there have been several studies about pediatric vitiligo in Korea, China, India, the United States, and Kuwait, only one study was done in Turkey in 2016 [1,4,6-13]. To our knowledge, this was the first study that separately compared serum vitamin D levels in girls and boys with vitiligo.

The prevalence of pediatric vitiligo in girls was reported in previous studies; in Korea and China, however, a practically equal incidence in girls and boys was noticed [10,14,15]. In Turkey, Topal et al. and Gonul et al. reported almost similar results in adults with vitiligo [6]. In contrast, we observed gender equality in children [10,14].

The mean age of onset was between the ages of 4-8 in the United States, Korea, and China [9, 10, 14, 15] except two studies in India which were between the ages 8 and 12 [12,13]. In our study, the mean age of onset was 9.1, and 43% of children with vitiligo had an onset between the ages of 8-12. In Korea, the reason was a lack of clear pathogenesis of vitiligo, but in Kuwait, it was a lack of awareness and illiteracy. This was also true in Turkey.

In previous studies in Turkey, India, and China, the average duration of the disease ranged from 13-27 months, but our result, 19 months, was consistent with the result of Hu et al. [7,12,14].

In pediatric vitiligo, a family history of vitiligo from 3.3% to 46% has been reported [6-13]. However, Topal et al. noted a family history in 27% of patients, which was similar to our findings [6]. Depending on the frequency of consanguineous marriages in Turkey and surrounding countries high rates could be observed.

Acrofacial vitiligo was the most common clinical type of pediatric vitiligo which is in contrast to previous studies in which vitiligo vulgaris was the most commonly reported type in adults. Agarwal et al. found that acrofacial was the most common due to ethnic and genetic diversity, as in Turkey [12].

As a triggering factor of vitiligo, koebnerization was noted in 15% of the subjects in our study. The prevalence of koebnerization in pediatric vitiligo is not clear. However, other triggering factors such as emotional stress and sunburn were observed in 41% and 30.8% of subjects, respectively. The level of emotional stress was significantly higher in girls with vitiligo. This may be caused by proximity to the civil war in Syria and exposure to the psychological trauma of social pressure to get married at an early age.

Halder et al. reported only two cases of alopecia areata in 82 children, which was similar to our study [8]. As already known in previous studies, the frequency of autoimmune diseases in children with vitiligo is very low [11].

In the present study, serum vitamin D deficiency and insufficiency were noted in 20.5% and 46.1% of patients, respectively. Similar observations were reported in a study by Hatun et al., in Turkey [18]. When the group of girls with vitiligo was compared for serum 25-OH vitamin D levels, significant differences were found between them and the control group of girls. Therefore, vitamin D deficiency in vitiligo may be among the factors that cause it, as mentioned in previous studies. In addition, there were statistically significant differences in 25-OH vitamin D levels between the group of girls and the group of boys with vitiligo. This is thought to be related to the exposure of boys to more than 15 minutes of sunlight per day. In Turkey and the Middle-East, a few studies showed that important factors in vitamin D deficiency were concealing clothing, no supplementation of vitamin D in daily use, less exposure to sunlight, more indoor work, and dark skin [16-20].

In conclusion, pediatric vitiligo may differ between genders in children as well as in adults. This may be a result of many factors, though vitamin D has attracted attention recently. We suggest that antioxidant activity of vitamin D may be a protective mechanism of vitiligo in patients who have a higher risk for deficiency and insufficiency of vitamin D, have a history of less than 15 minutes of sunlight exposure per day, spend most of the daytime at home, or wear concealing clothing. This study showed that girls are at greater risk for these reasons. The clinician should keep in mind that serum vitamin D levels may be lower in girls with vitiligo, but studies of larger groups of various racial identities are needed to verify or confirm our findings.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Manav V, Baş S, Çakırca G. Serum vitamin d levels in children with vitiligo. Ann Clin Anal Med 2020;11(1):50-53

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Anxiety and cortisol levels during circumcision

Duygu Kara 1 , Erkan Cem Celik 1 , Yener Yesiltepe 2 , Fatih Ozdemir 3

1 Anesthesiology and Reanimation Unit, 2 Biochemistry Unit, 3 Urology Unit, Palandoken Government Hospital, Erzurum, Turkey

DOI: 10.4328/ACAM.6106 Received: 08.12.2018 Accepted: 25.01.2019 Published Online: 29.01.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):24-27

Corresponding Author: Duygu Kara, Anesthesiology and Reanimation Unit, Palandoken Government Hospital, Postal Zip Code: 06230, Erzurum, Turkey. GSM: +905069288141 T.: +90 4422325000 F.: +90 4422325000 E-Mail: drduygukara@yahoo.com ORCID ID: https://orcid.org/0000-0003-3325-2565

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Aim: In this study, we aimed to investigate whether circumcision is a stressor ambulatory surgical intervention for children and demonstrate the relationship between pre- and post-operative anxiety levels, blood cortisol levels (BCL), and salivary cortisol levels (SCL) in these children. Material and Method: Boys aged between 5 and 17 years, with a plan of circumcision, were prospectively included. Their preoperative anxiety levels, salivary cortisol levels (SCL), and blood total cortisol levels (BCL) were measured. After the operation, the same parameters were measured and preoperative values were compared with postoperative values. Also, the correlation between anxiety scores, SCL, and BCL was assessed. The Yale Preoperative Anxiety Scale was used to calculate the anxiety scores. Results: The mean age of 81 patients was 6.62 ± 1.40 years. The preoperative anxiety scores, SCL, and BCL were significantly lower than post-operative values (p<0.001 for each). The preoperative SCL were positively correlated with BCL and anxiety scores. Postoperative SCL were positively correlated with BCL and anxiety scores. Discussion: Circumcision is a cause of increment in anxiety, serum, and salivary cortisol levels in children. Salivary cortisol levels were correlated with simultaneously drawn serum cortisol levels. The preoperative and postoperative anxiety scores were correlated with BCL and SCL in children with circumcision operation.

Keywords: Anxiety Score; Circumcision; Salivary Cortisol; Serum Cortisol

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  • Introduction

    Circumcision is the surgical removal of the foreskin of the penis. Motivation arising from either some personal or religious reasons makes the procedure prevalent in especially Muslim and Jewish populations. It is also one of the oldest surgical procedures, performed for medical indications, such as phimosis, balanitis xerotica obliterans, recurrent balanoposthitis, paraphimosis, and urine outlet obstruction, as well [1]. Recommendations of American Academy of Pediatrics, American College of Obstetricians and Gynecologists, Centers for Disease Control and Prevention, and World Health Organization are present, based on its long-term benefits which outweigh any risks [2].

    Circumcision is performed as an ambulatory surgery, which can provide more improved patient satisfaction, reduced complications, and more efficient care. Anyway, as well as many other surgical procedures, circumcision is a source of anxiety, fear, and pain for children [3]. Increased preoperative anxiety levels result in negative consequences, such as challenges in the induction of anesthesia, increase in the need of anesthetic drugs during the operation and analgesic drugs after the operation, and increased risk of infections [4]. Following any surgical interventions and trauma, the stress response is triggered by impulses sent from the injured site to the hypothalamus. As well as activation of hypothalamic-pituitary-adrenal (HPA) axis, the serum levels of glucagon, catecholamines, and host of inflammatory cytokines are increased [5].

    Total serum cortisol is the main parameter that is routinely measured in the assessment of HPA axis. Due to the changes in levels of the affinity of corticosteroid-binding globulin and misinterpreting in some patient groups, underestimation of the cortisol response in stress may happen [6]. Measuring salivary cortisol level (SCL) is a promising alternative, because of its strong correlation with serum-free cortisol, hence safe, easy, and non-invasive, and rapid method that is especially appropriate for pediatric patients [7]. Previously, SCL has been shown to reflect the stress in obstructive sleep apnea syndrome, dental caries, and burn wounds in children [8-10].

    In this study, we aimed to investigate and confirm whether circumcision is a stressor ambulatory surgical intervention for children, and also we aimed to demonstrate the relationship between pre- and post-operative anxiety levels and blood and salivary cortisol levels in these children.

    Material and Methods

    A prospective, observational study was planned to conduct in Erzurum Palandoken Government Hospital, between January 1, 2017 and December 31, 2017. Boys aged between 5 and 17 years, with a plan of circumcision, were included. Children with a known chronic disease (cardiac, respiratory, endocrinologic, and neurologic, etc.) and history of receiving any kind of corticosteroid therapy during the last month, were excluded. Local ethical committee approved the study protocol (Date:06/21/2016, Number: 2016/12-79) and the patients were included in the study after written informed consent was obtained from the parents of each child.

    Preoperative anxiety levels of all children were calculated by means of the Yale Preoperative Anxiety Scale Modified – Short form (M-YPAS-SF), just 30 minutes before the surgery [11]. Additionally, salivary cortisol levels (SCL) and blood total cortisol levels (BCL) of all children were measured three times; between 08.00-13.00, on the day before the surgery (basal level); 30 minutes before the surgery (preoperative level); 2 hours after the surgery (postoperative level)

    For sedation of the children, the protocol for anesthetic drugs was as follows: midazolam (after an initial intravenous dose (0.05 mg/kg), careful titration up to 0.4 mg/kg total dose was used (not exceeding 10 mg) until appropriate sedation and anxiolysis were achieved before the procedure); propofol (repeated bolus method; after an initial intravenous induction dose (2 mg/kg, 0.5 mg/kg) was given, additional bolus doses in every 3-5 minutes were applied until moderate sedation could be achieved).

    No additional sedatives were used. During the monitorization, the duration of procedure, sedation, and recovery, and the doses of propofol and midazolam were recorded. And after the surgery, the Aldrete (recovery) scores were calculated [12]. Deep sedation/general anesthesia was defined as the state of blunted consciousness produced by anesthetic medications, resulting in partial loss of protective reflexes and purposeful responses to various stimuli [13]. During and after the surgery, complications such as apnea, O2 desaturation, bradycardia, hypotension, cough, nausea, and vomiting were recorded and managed accordingly. 

    All SCL samples were drawn from the patients after at least 6 hours of fasting. For basal SCL samples, patients rinsed their mouth or drank water 10 minutes before sampling, between 08.00-13.00 am. Examination of cortisol levels (ng/ml) in saliva were performed in clarified saliva supernatants, which centrifuged (at 3500xg for 20 minutes) after sampling and stored at -80°C until analysis. ELISA kit (DRG Salivary Cortisol ELISA; DRG International, Inc., USA) was used following the manufacturer’s instructions. BCL’s were measured by Cobas e 601 (Roche Diagnostics GmbH; Manheim, Germany). Blood samples were centrifuged (at 3500 rpm for 10 minutes) and serum samples were stored at -80°C until analysis.

    The statistical analyses of the data of the present study were performed by means of IBM SPSS 20.0 software. The Kolmogorov–Smirnov test was used to evaluate the data distribution. To evaluate the changes in anxiety and cortisol levels, paired samples T-test was used to check differences before and after the surgery, at a significance level of 5% for normally distributed continuous variables. The correlation between anxiety, blood, and salivary cortisol levels was evaluated with the Pearson correlation test. Differences were considered significant if the p-value was < 0.05.  Descriptive statistics were expressed as a mean ± SD. 

    Results

    Eighty-one patients were included in the study. Mean age of the patients was 6.62 ± 1.40 years. The data regarding the intra- and post-operative properties of the children were shown in Table 1. The preoperative anxiety scores, SCL, and BCL were significantly lower than post-operative values (p<0.001 for each) (Table-2). The pre-operative SCL were positively correlated with BCL and anxiety scores (Table 3). Similarly, post-operative SCL were positively correlated with BCL and anxiety scores.

    During and after the surgery, no serious complications, such as hypotension, arrhythmia, and cardiopulmonary arrest were experienced. Fifteen (18.5%) patients had a cough and 12 (14.8%) patients had nausea and vomiting in the post-operative period.

    Discussion

    In this study, postoperative anxiety, blood, and salivary cortisol levels were higher than preoperative levels. It is expected that a surgical procedure can induce a physiological stress response. Nevertheless, an increased level of anxiety may reflect the surgical and anesthetic experience. Increased postoperative cortisol levels are assumed as instant values without long-term effects. A healthy and functional HPA axis has been proven in adulthood after circumcision [14]. Similar to this study, Hsu et al. [15] reported that sedation and anesthesia induced a significant rise in SCL in children, independent from the level of sedation or the type of procedure performed. Additionally, it was reported that preoperative anxiety of parent and child, the child’s temperament, birth order, previous experience of hospitalization for surgery, preoperative premedication and preparation, the presence of parents at the induction of anesthesia and in the post-anesthetic care unit, or the different use of anesthetic drugs provided at induction in anesthesia may help to predict the postoperative anxiety of the children [3]. Anyway, general anesthesia without surgical intervention may not induce a stress response in children [16].

    The measurement of hormones in saliva has been in development since the last decades. SCL is correlated with serum cortisol levels and displays a circadian rhythm similar to that of BCL, with a nadir at night and a peak level just after awakening [7]. Similarly, in this study, it was shown that preoperative SCL was correlated with preoperative BCL, while postoperative SCL was correlated with postoperative BCL. In a recent review, SCL has been proposed to asses cortisol excess, deficiency and hydrocortisone replacement in clinical settings, having the advantage of detection when serum cortisol levels are low [17]. SCL has been shown to correlate with BCL in response to stress, similar to this study [18-20].

    The anxiety of the children in this study was evaluated by modified YPAS, which included the assessments including the child’s interaction with the environment, vocalization, expression of emotions, and interaction with family members [4]. The preoperative and postoperative anxiety scores were positively correlated with BCL and SCL in this study. It was noted that children who experience perioperative anxiety become prone to altered immunity, hence increased sensitivity to infections and subsequent consumption of analgesics postoperatively [21, 22]. These parameters were not studied because they were beyond the scope of this study. The use of SCL as a stress marker has been supported by previous studies [15, 23].

    Although Jewish communities perform circumcision on the 8th day of life in accordance with the rules of Judaism given in Torah, many Muslims are circumcised in different ages [2]. The mean age of the study population was seen to correspond to the school ages. Younger ages could increase the risks of mental disorders, developmental delay, and attention deficit hyperactivity disorders, related to general anesthesia [24]. Additionally, greater behavioral distress and more pain, hence higher BCL and SCL would be experienced [25]. Nevertheless, this evaluation is beyond the scope of this study.

    This study should be evaluated with accompanying limitations. Although the associations between the anxiety levels and cortisol levels were assessed, their association with anesthetic drug doses and durations of anesthesia and operation could not be evaluated. Anyway, this is a well-designed study to show an increased stress burden of circumcision, although it is a simple, ambulatory surgery.

    As a conclusion, the results of this study have shown that circumcision induced an increment in anxiety, serum, and salivary cortisol levels in children. Salivary cortisol levels were in correlation with simultaneously drawn serum cortisol levels. Also, the preoperative and postoperative anxiety scores were correlated with BCL and SCL in children with circumcision operation.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Kara D, Celik EC, Yesiltepe Y, Ozdemir F. Anxiety and cortisol levels during circumcision. J Clin Anal Med 2019; Ann Clin Anal Med 2020;11(1):24-27

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The factors affecting the distant recurrence in patients with non-small cell lung cancer (NSCLC) and our results

Ferdane Melike Duran, Süleyman Emre Akın, Mustafa Calik, Hidir Esme

Department of Thoracic Surgery, Health Sciences University, Konya Training and Research Hospital, Konya, Turkey

DOI: 10.4328/JCAM.6108 Received: 09.12.2018 Accepted: 24.01.2019 Published Online: 29.01.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):28-32

Corresponding Author: Mustafa Calik, Department of Thoracic Surgery, Health Sciences University, Konya Training and Research Hospital, PK: 42090 Meram, Konya, Turkey. T.: +90 3323236709 F.: +90 3323236723 E-Mail: drmcalik@hotmail.com ORCID ID: https://orcid.org/0000-0001-9963-5724

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Aim: The long-term survival in Non-Small Cell Lung Cancer (NSCLC) following tumor-free resection is less than fifty percent. The most important cause affecting the mortality following the resection is the development of recurrence. This study aims to determine the factors affecting the recurrence, to increase the awareness concerning this topic and to enlighten this challenge by virtue of new studies. Material and Method: In this study, the data were obtained by studying retrospectively the database of the patients who underwent complete resection due to the NSCLC between January 2008 and December 2012 in our Thoracic Surgery Clinic. The effects of the clinicopathologic variables on the distant recurrence were assessed. Results: Fifty male patients (87.7%) and seven female patients (12.3%) with NSCLC were included in the study. Distant recurrence was developed in seven of the patients. During the three-year follow-up, we obtained statistically significant values in comparing the parameters affecting the survival such as differentiation (p=0.012), pathological stage (p=0.02), development of distant recurrence (p=0.014), the location of the distant recurrence (p=0.011), the duration spent in the intensive care unit (p=0.018), the length of stay (p=0.018) and the time for the postoperative distant recurrence (0.048). A statistical significance was detected between the distant recurrence and the hilar lymphadenopathies larger than one centimeter in computerized tomography (p=0.049). Discussion: We found that the presence of the hilar lymphatic node larger than one centimeter in computerized tomography is the most important parameter in the development of distant recurrence.

Keywords: Non-Small Cell Lung Cancer; Distant; Recurrence

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  • Introduction

    While pulmonary carcinoma is the most common in males in terms of incidence and mortality worldwide, it ranks in females in number three in terms of incidence and in number two in terms of mortality following the breast carcinoma. In 2012, it was the cause of 19.4% of the deaths due to cancer with 1.56 million deaths and with 1.82 million new cases. In Non-Small Cell Lung Cancer (NSCLC), the survival following the resection is less than fifty percent (50%) despite the chemotherapy and developed molecular target treatments. Most of the mortality after the resection depends on the development of the recurrence [1]. The aim of this study is to investigate the relationship between the clinicopathological factors and the recurrence in the patients who underwent complete resection.

    Material and Methods

    Data were created from 50 (fifty) male patients and 7 (seven) female patients who underwent complete resection between January 01, 2008 and December 31, 2012 in our Thoracic Surgery Clinic. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was not obtained from patients due to the retrospective nature of this study. Ethics committee approval was received for this study from the ethics committee of local University (2016/477). All patients were staged with seventh TNM classification which was published in 2009. Follow-up data were completed in January 2016.

    The parametric data such as the gender of the patients, their ages, their accompanying diseases, their findings in thoracic computerized tomography (CT) (the presence of the hilar and mediastinal lymphatic nodes larger than one centimeter), mediastinal-hilar lymphadenopathy (LAP) maximum Standard Uptake Value (SUV-max) in the positron emission tomography-computerized tomography (PET-CT), histological type, clinical stage, neoadjuvant chemotherapy (Table 1), pathological findings after the surgery (tumor diameter, differentiation, the presence of N1, the presence of N2, pericapsular invasion in the lymphatic node), pathological stage, the length of stay in the intensive care unit, total length of stay, the development of the distant recurrence, the location of the distant recurrence, the treatment applied after the recurrence, the complications causing mortality, the three-year survival data were studied (Table 2).

    In the beginning, the patients were called every two to three weeks and then they were called every three to six months to the control examinations. Three-year follow-up was completed in all patients. There were ten exitus cases (17.5%) at the end of the follow-up. The causes of death included two respiratory failure cases (3.5%), one myocardial infarction case (3.5%), four organ failure cases (7%) and three pneumonia and sepsis (5.3%). Local recurrence was developed in nine patients and distant recurrence was developed in seven of them (12.3%). At the end of this time interval, forty-seven patients (82.5%) were alive.

    Descriptive statistics for quantitative data such as mean, maximum, and minimum values were computed. The relationship between the distant metastasis after the surgery and clinicopathologic data were studied through the statistical methods. Statistical analysis was applied by using SPSS for Windows version 15.0 (SPSS Inc. Chicago, Illinois, USA). The Kaplan-Meier survival analysis was used for survival and the Cox Regression was used to determine the prognostic factors for the variables with significant differences between the groups. The level of statistical significance was considered as p<0.05.

    Results

    In the comparison of the distant recurrence with other parameters, the differences between hilar lymphadenopathies larger than one centimeter in computerized tomography were detected as significant (p=0.049). In the comparison between the three-year mortality and other parameters, the differences between the tumor diameter in computerized tomography (p=0.02), the pathological tumor diameter (p=0.003), SUV-max of the tumor in the PET-CT (p=0.004) were found as statistically significant (Table 3). In the comparison between the distant recurrence and other parameters, the differences between the hilar lymphadenopathies larger than one centimeter in computerized tomography were as statistically significant (=0.049). The lonely accompanying disease seen in the patients in whom distant recurrence was developed was Chronic Obstructive Pulmonary Disease (COPD). The most common localization of carcinoma in the patient who developed distant recurrence was the left upper lobe. No primary tumor localization was detected in the left lower lobe and in the right middle lobe. The most commonly seen stage in the patients who developed the distant recurrence was Stage 3. While the most common histological type was adenocarcinoma, no carcinoid tumor was seen. In the patient in which distant recurrence was either developed or not developed, invasion to surrounding tissue, N1, and N2 involvements were seen in a lower ratio.

    While the most commonly seen complication was arrhythmia in patients with distant recurrence, no pneumonia, no prolonged air leakage, and no wound site infection were seen. In patients who developed distant recurrence, the organ in which metastasis was most commonly detected was brain. The second most common organs in which metastases were seen were adrenal glands and bone. In the patient who developed distant recurrence, three-year mortality was more observed. When the relationship between the survival and the clinical stage was investigated, the lower survival was in Stage 3, Stage 2, and Stage 1 respectively. Thus, as the stage increases, the risk of an earlier death inpatients increases (Table 4).

    In the comparison between the parameters affecting three-year survival such as differentiation (p = 0.012), postoperative stage (p = 0.027), the development of distant recurrence (p = 0.014), the localization of the distant recurrence (p = 0.011), the length of stay in the intensive care unit (p=0.018), hospitalization time (p = 0.018) and postoperative duration of distant recurrence (0.048), we found statistically significant values. Table 5 shows the results of the Kaplan-Meier survival analysis by determining the main factor of differentiation groups. Survival graphs related to differentiation, postoperative stage, and localization of the distant recurrent are shown in Figure 1, 2, and 3, respectively. Values closer to the statistically significant value were found between the pathological tumor diameter and tumor SUV-max in PET-CT.

    Discussion

    Following the surgery of pulmonary cancer, recurrence is the most important cause of the failure in treatment. The recurrence percentage of patients with cancer is between 30% and 70% [2]. The recurrence ratio within two years following the surgery is more than 80% (early recurrence) and the ratio of repeating five years later (late recurrence) was 9% [3,4].

    In NSCLC cases, various prognostic factors have been defined. Age, gender, pulmonary functions, accompanying diseases, the performance status of the patient, tumor stage, tumor type, molecular biological factors are primary factors affecting the prognosis [5]. Tumor stage is the most important among these factors. In a study conducted by Stanley et al. [6], seventy-seven factors having the potential to affect the pulmonary cancer were investigated and it was seen that fifty of them affect the prognosis. The three most important among these fifty prognostic factors were identified as the physical performance status of the patient, the extensity of the patient and the loss of weight for the last six months. We obtained statistically significant values consistent with the literature in comparison between the parameters affecting three-year survival such as differentiation, postoperative stage, development of the distant recurrence, the localization of the distant recurrence, the length of stay in the intensive care unit, the total length of stay in the intensive care unit and the duration of the distant recurrence.

    It is obvious that surgical resection is a treatment method being more effective compared to other treatment forms. The patients of Stage III constitute the most critical patient group for the resection decision. The treatment should be planned by assessing the situation of the primary lymphatic nodes and it should be selective in the decision of resection in this patient group. There are many surgical series reporting results being much different from each other in the treatment of the N2 stage IIIa patients [7]. For fifty-seven patients with NSCLC diagnosis that we have studied, the mean survival duration was found as 29.6 months and the three-year survival ratio was found as 82.5%. When we compared our mean survival values, we revealed that these values were higher. We suggest that this is due to the inclusion of the patients who underwent complete resection.

    Pulmonary carcinoma is seen particularly in the fifth and sixth decades of the life and the number of cases seen under thirty-five years old is quite small [8]. In our study, the mean age of fifty-seven patients was 59.7 years. No statistically significant difference was found between age and recurrence.

    The male/female ratio of our patients was 7.1/1. In other studies, performed in our country, this ratio was found as 3.5 to 9.5/1 [9]. The reason why the number of our female patients is lower can be explained by the fact that smoking is not common in our country.

    In the literature, there are many studies showing that the prognosis is better in males compared to females. In a meta-analysis of 2531 patients performed by Albain et al. [10], they have reported that the survival in males was shorter. In our study also, three-year mortality was found as negative in all of the female patients that is consistent with the literature and no recurrence was seen in six of the seven female patients (85.7%). In our results, there was no statistically significant difference between recurrence and gender.

    In many studies, it is reported that there is no significant difference between the histologic type and the survival [11]. Tanaka et al. [12] report that cell type is not influential on survival in T1-2N1M0 cases with NSCLC in which resection was performed. Fang et al. [13] have reported in their study, that neither resection type nor histologic type has any significant effect on survival. While the most common histologic type was adenocarcinoma in patients who developed distant recurrence, no carcinoid tumor was seen. In our study, when all stages were studied, the effect of the cell type on survival could not be shown.

    The presence of tumors with a diameter larger than three centimeters is interpreted as the poor prognosis. In the literature, in a study conducted by Vansteenkisre JF et al. [14], with one hundred twenty-five cases it was shown that the survival is longer in a patient with NSCLC in which tumor diameter was less than three centimeters. In our study, tumor diameter was studied in both computerized tomography and pathologically and no statistically significant difference was detected between both parameters and the recurrence. Despite this, the differences between both parameters and gender, clinical stage and mortality (for three years) were statistically significant.

    There is a relationship between the distant recurrence and advanced T and N stage. The incidence of distant metastasis increases in those with N2 disease [15]. N1 positiveness was detected in eight of our thirty-seven cases and N2 positiveness was detected in three of them. Both N1 and N2 involvements were lower in our patients in which distant recurrence was detected. However, the difference between N1 and N2 involvement and the recurrence was not significant.

    In our study, in patients who did not developed local recurrence and in those who developed distant recurrence, while the least commonly seen stage was Stage III, the most commonly seen stage was Stage I. In the patients who developed distant recurrence, while the least commonly seen stage was Stage II, the most commonly seen stage was found as Stage III, but no statistically significant difference was detected. When we investigated the relationship between the mortality time (postoperative months) and the clinical stage, it was seen that the risk of losing a patient in an earlier period increases as the stage rises. This demonstrates us that the tumor stage is an important factor in terms of mortality time. Again in our study, the differences between the tumor diameter in CT, pathological tumor diameter, mediastinal LAP SUV-max in PET-CT, hilar LAP SUV-max in PET-CT, the presence of hilar LAP larger than one centimeter in computerized tomography were detected as statistically significant in the comparison of the clinical stage with other parameters. In the comparison of other parameters, no statistically significant difference was detected.

    When the diagnosis is established for the patients with NSCLC, distant organ metastasis is detected in forty percent (40%) of them. The most common extra-thoracal metastatic regions were found as follows: brain (43%), adrenal glands (40%), liver (40%), bone (33%), kidneys (23%) and abdominal lymphatic nodes (30%) [16]. In our study also, the organ in which metastasis was detected most commonly was brain that is consistent with the literature. However, we could not detect a statistically significant difference between the distant recurrence and the organ where the metastases took place.

    Complications concerning the cardiovascular system are the main complications that can be encountered after the surgery of pulmonary carcinoma. Arrhythmia, myocardial infarction (MI) and cardiac failure are the most commonly observed complications. Arrhythmia is developed depending on the width of the resection, on the patient age, and particularly on the intrapericardial pneumonectomy procedures [17]. While the most commonly seen complication was arrhythmia in patients who developed distant recurrence, neither prolonged air leakage nor wound site infection was seen. In our study, we could not detect any relationship between the recurrence and the complications.

    Like in any work, there are some limitations in our study such as a small number of patients, gender inequality, because of the retrospective nature of the research. This might have led to selection bias.

    Conclusion

    In our study, we detected that the most important prognostic factors affecting the three-year survival were differentiation, post-operative pathological stage, the development of distant recurrence, the localization of distant recurrence, time of postoperative distant recurrence, the length of stay in the intensive care unit, the total length of stay. These prognostic factors that we have detected should be evaluated in all patients after the surgery.

    We found that the presence of the hilar lymphatic node larger than one centimeter in CT is the most important parameter in the development of distant recurrence. As a result, our study in which many parameters were assessed reveals the importance of the detection of the parameters leading to distant recurrence and their prevention besides the treatment regimens of pulmonary carcinoma. The assessment of mediastinal and hilar lymphatic nodes in detail by means of radiological examinations before the surgery and absolutely histopathologically in case of suspicion plays a vital role. Furthermore, we suggest that the additional systemic dissection of the mediastinal lymphatic node is obligatory in the prevention of the distant recurrence.

    Scientific Responsibility Statement

    The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

    Animal and human rights statement

    All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

    Funding: None

    Conflict of interest

    None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

    References

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    2. Maeda R, Yoshida J, Ishii G, Hishida T, Nishimura M, Nagai K. Risk factors for tumor recurrence in patients with early-stage (stage I and II) non-small cell lung cancer. Patient selection criteria for adjuvant chemotherapy according to the seventh edition TNM classification. Chest. 2011; 140(6): 1494-1502. DOI: 10.1378/chest.10-3279

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    4. Choi JP, Jeong SS, Yoon SS. Prognosis of recurrence after complete resection in early-stage non-small cell lung cancer. Korean J Thorac Cardiovasc Surg. 2013; 46: 449-56. DOI: 10.5090/kjtcs.2013.46.6.449.

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    11. Tanoue LT, LoCicero J III, Shields TW LJ, Ponn RB, Rusch VW, editors. General thoracic surgery 6th, ed. Philadelphia B, New York, London: Lippincott Williams & Wilkins; 2000. 2: 1426-42.

    12. Tanaka F, Yanagihara K, Otake Y, Yamada T, Shoji T, Miyahara R, et al. Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg. 2001; 19(5): 555-61.

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Duran FM, Akın SE, Calik M, Esme H. The factors affecting the distant recurrence in patients with non-small cell lung cancer (NSCLC) and our results.. Ann Clin Anal Med 2020;11(1):28-32

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Quantitative GC-FID analysis of heroin for seized drugs

Bayram Yüksel 1,2

1 Department of Forensic and Investigative Science, West Virginia University, Morgantown, WV, USA 2 Giresun University, Espiye Vocational School, Giresun, Turkey

DOI: 10.4328/JCAM.6139 Received: 28.12.2018 Accepted: 26.01.2019 Published Online: 29.01.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):38-42

Corresponding Author: Bayram Yüksel, Department of Forensic and Investigative Science, West Virginia University, Morgantown, WV, USA. Giresun University, Espiye Vocational School, Giresun, Turkey. T.: +1-304-276-6820, +90-454-310-1430 E-Mail: bayramyuksel83@gmail.com, bayram.yuksel@mail.wvu.edu ORCID ID: https://orcid.org/0000-0001-7686-8648

Abstract
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Abstract

Aim: Heroin is a semi-synthetic opioid, which is widely abused due to its euphoric effects. It is responsible for numerous deaths or diseases each year throughout the world. The goal of this work was to validate and establish a simple and reliable GC-FID method for quantitative analysis of heroin in seized drug samples in accordance with the predicted sample matrix. Material and Method: Detection parameters and chromatographic conditions were optimized in order to achieve an advanced method. Separation was accomplished on a HP-5 column (30 m-0.32 nm ID-0.25 μm) utilizing n-tetracosane as an internal standard at the concentration of 0.25 mg/mL in chloroform/methanol (1:1) mixture. Method validation was processed by means of specificity, linearity, accuracy, precision, range, quantitation limit and detection limit. Results: Method provided a great linearity with correlation coefficients (r2 =0.9994) for heroin. The limit of detection and limit of quantification values of GC-FID method for heroin analysis were 2.20 µg/mL and 7.33 µg/mL, respectively while the limit of linearity was 1000 µg/mL. Mean recovery value obtained from spike study was 99.89%, and relative error calculated after CRM analysis was equal to 1.80%, indicating that the method was accurate. Discussion: Inter-day stability of the instrument was demonstrated by use of the control chart. The method represented is comparatively simple, fast, precise, and pertinent for clandestine drug analysis in toxicological, pharmaceutical, and forensic laboratories.

Keywords: Drug Abuse; Clandestine Drug; Heroin; Toxicology; Forensic Chemistry; Validation; GC-FID

Full Text

Introduction

Heroin is a semi-synthetic drug formulated by acetylation of morphine presenting as the main opiate in opium poppy tears. As an intravenous illicit drug, heroin addiction is a phenomenon involving all age groups in Europe, and it is responsible for many deaths or diseases each year throughout the world [1,2]. Although some individuals may use heroin in a controlled manner [3], most of those who try to use heroin become addictive to this substance [4]. Chemical structure of heroin, 6-monoacetylmorphine (6-MAM) and morphine, are shown in Figure 1.

Following oral administration, heroin is subjected to comprehensive pre-systemic biotransformation by deacetylation, resulting in a pharmacologically active drug for the systemic delivery of morphine [5]. Although injection of heroin bypasses of pre-systemic metabolism effect, it can pass the blood-brain barrier quickly by reason of the acetyl groups causing it further lipophilic than morphine [6,7]. Nevertheless, heroin is rapidly metabolized first to 6-MAM following systemic administration, and the half-life of heroin in humans is nearly 1.8 to 7.8 minutes [8]. Like other opioids, morphine also causes euphoric, analgesic, and anxiolytic effects that is liable for its addictive function. The µ-opioid receptor in the brain intermediates to these effects of heroin [9]. However, heroin itself shows a comparatively small affinity for the μ receptor [10].

Heroin is converted to morphine through the 6-MAM in the body within minutes. In cases, morphine is usually a dominant active metabolite and is excreted from the body by transformation 3- and 6-glucuronides through the urine and bile. The existence of 6-MAM in urine differentiates the use of heroin from morphine. Low amount of codeine can also be involved in the urine of abusers by reason of acetyl codeine in heroin [11].

Heroin arrives Europe through four major transportation ways. The two essential directions are the Balkan and southern routes. The Balkan route passes Turkey through Bulgaria, Greece or Romania as well as the central, southern and Western Europe. Furthermore, Syria and Iraq have also appeared as an outgrowth of the Balkan route. The southern route which involves transition directions from Pakistan and Iran through African countries or directly into Europe by air or sea has recently been used. Northern route and the southern Caucasus crossing the Black Sea are the remaining minor routes [12]. Based on the Turkey Drug Report (2018): toxicological examination was accessible for the entire approved drug-related deaths. More than half of expirations was associated with multi-substances involving opioids, particularly heroin, engaged in approximately one-third of the deaths. The statistic of opioid-linked deaths recorded in Tukey has been approximately steady from 2014 up to now. Moreover, 8179 heroin cases were reported in 2016, and 5585.1 kg of heroin were seized in Turkey.

In the last decades, many chromatographic assays were advanced to determine heroin concentration in seized drugs as well as biological samples for toxicological, clinical, pharmaceutical, and forensic purposes [13-17]. As an alternative to immunoassays, thin-layer chromatography (TLC) appears as a beneficial method by reason of it is one of the practical and the cheapest techniques. Yet, such screening methods can fail to detect low concentration of drugs. For this reason, mass spectroscopy (MS) connected to liquid chromatography (LC) and gas chromatography (GC) are good instrumental examples for quantification and confirmation [18,19].

The aim of this research essentially focuses on validation and development of a GC-FID system for quantitative determination of heroin in clandestine drug specimens in order to improve the criminal justice system by providing enhanced objective conclusions. There are numerous works on this topic. However, major significance and novelty of this paper fundamentally depends on the advanced chromatographic resolution and detection sensitivity throughout validation and optimization of the technique designed in accordance with the predicted sample matrix. Ultimately, the study showed a satisfactory separation of all analyte peaks within 13 minutes.

Material and Methods

Instrumentation

The analysis was performed using Agilent GC 6890N (Santa Clara, California, USA) equipped with a flame ionization detector (FID) and an automated liquid sampler. An Agilent 7683 Series Auto-Injector was utilized for the injection of samples. This instrumentation was utilized for validation and optimization of an analytical method based on the determination of heroin in illicit samples.

Standard Solutions and Reagents

Stock solutions of methanol, chloroform, and n-tetracosane powder were obtained from Merck (Darmstadt, Germany). Certified reference material (CRM) of heroin, and caffeine, codeine, morphine, and 6-MAM solutions were obtained from Lipomed Services to Health®, Switzerland. All the other solvents and chemicals used during laboratory work were of analytical reagent grade. Ultrapure water (Merck Millipore Direct-Q8, Germany) with a resistivity of 18MΩ.cm, was used to prepare the solutions during the experimental process.

Sample Preparation and Procedure

An Agilent Model 6890N gas chromatograph was utilized during analyses. One mL of the prepared solutions was placed into an autosampler vial for analysis, and separation was achieved on an HP-5 column (30 m, 0.32 mm ID, 0.25 μm) using an IS (tetracosan at the concentration of 0.25 mg/mL) in chloroform/methanol (1:1, v/v) mixture. Ultrahigh purity (99.999 percent) hydrogen was chosen as the carrier gas with a flow rate of 1.5 mL/minute. The flame ionization detector and the injection port were sustained at 280 °C. An Agilent 7683 Series Auto-Injector was used during injection of samples. In the splitless mode (20:1), 2 mL amounts of samples were injected. Then, isothermally programmed oven temperature was adjusted to 180 °C for 10.00 minutes, and nitrogen was utilized as the auxiliary make-up gas for the detector. Operating parameters of the GC-FID system for heroin analysis was given in Table 1.

All samples and calibration standard solutions were prepared by use of an appropriate amount of our working solution: chloroform/methanol (1:1, v/v) mixture containing the IS (tetracosane at the concentration of 250 μg/mL). In order to prepare the calibration standards at the concentrations of 0, 50, 100, 250, 500 and 1000 μg/mL, heroin powder standards were diluted in our working solution described above. The solution was kept at 4±1°C when not in use and warmed to room temperature before use.

Method Validation

As outlined in International Conference on Harmonization (ICH) guidelines, this GC-FID method for analysis of heroin content in illicit specimens was validated based on specificity, accuracy, precision, range, linearity, quantitation limit and detection limit.

Results

Calibration

All calibration standards were analyzed 5 times, and a calibration curve of area heroin/area tetracosane versus concentration of heroin standards was drawn (Figure 2). The correlation coefficient (r2) and equation of the calibration curve for heroin were respectively found to be r2=0.9994 and y=2.1106x-0.0003 where y stands for area heroin/area tetracosane, and x is the heroin concentration in μg/mL. The chromatogram of heroin standard at 600 μg/mL, obtained after analysis according to proposed GC-FID method, was illustrated in Figure 3.

Limit of Detection, Quantification, and Linearity

The limit of detection (LOD) and lowest limit of quantification (LOQ) were determined by means of the standard deviation of the response and the slope of the calibration curve, according to International Conference on Harmonization (ICH) guidelines, LOD=3.3σ/S, LOQ=10σ/S, where σ is the standard deviation of the response and S is the slope of the calibration curve. The LOD and LOQ values of GC-FID method for heroin analysis were 2.20 µg /mL and 7.33 µg /mL, respectively. Limit of linearity (LOL) is the concentration at which the calibration curve departs from the linearity. Dynamic range refers to concentration intervals from LOQ to LOL, which was found between 7.73 µg/mL and 1000 µg/mL, in this study.

Precision

The precision of the method was assessed by means of repeatability, intermediate precision, and reproducibility parameters. The reproducibility of the recommended method was characterized by analysis of six different samples at the same concentration of 700 μg/mL from the same certified reference solution of heroin. Caffeine concentration of these samples was adjusted as 300 µg/mL to make sure the matrix effect. The mean of measured heroin concentrations was found as 699.17±9.64 μg/mL with 1.38% relative standard deviation (RSD). The result of the reproducibility study was shown in Table 2. Repeatability was controlled by injecting six individual samples of heroin at 200 μg/mL concentration while the intermediate precision was assessed by two analysts. Mean heroin concentrations from Analyst-A and Analyst-B were calculated as 202.17±2.56 μg/mL and 201.33±2.50 μg/mL, respectively. Repeatability study was summarized in Table 3.

Control Chart

The control chart study provides observation of inter-day and intra-day differences in peak intensity. From this point of view, a convenient procedure for monitoring the inter-day stability of the instrument was verified by use of the control chart. A mixture solution containing heroin at 500 µg/mL and caffeine at 500 µg/mL concentration was analyzed by GC-FID method once a month during a year, and the mean concentration of heroin was found as 499.330±10.30 µg/mL. After that, warning limits were calculated from the following formula: Warning Limits = xmean±2σ. Lowest warning limit (LWL) and upper warning limit (UWL) were equal to 478.73 µg/mL and 519.93 µg/mL, respectively. Similarly, control limits were calculated from the formula: Control Limits = xmean± 3 σ. Lowest control limit (LCL) and upper control limit (UCL) were equal to 468.43 µg/mL and 530.23 µg/mL, respectively. The control chart study was demonstrated in Figure 4.

Discussion

Optimization

Several essential parameters were improved in order to accomplish the most excellent performance from this chromatographic study. The main principle was based on a choice of the convenient column, deciding the best oven temperature program, selection of a suitable internal standard (IS), the election of concentration range due to heroin concentration in illicit drug specimens, and building the linearity. From this perspective, preliminary investigations were performed for arrangement and decision of the chromatographic conditions for the GC-FID determination of heroin.

As the column shows a critical role in an improved chromatographic separation [20], the selection of the favorable capillary column was decided on the basis of four necessary items: column length, stationary phase, film thickness, and column I.D. [19]. According to Tony Taylor’s 2015 paper, temperature has an effect on retention and relative retention in GC. Once the temperature is varied, the selectivity of the separation is also changed [21]. In order to obtain the excellent chromatographic resolution and detection sensitivity, an outcome of the oven temperature rate was analyzed by examining not only various oven temperature programs but also ramp rates up to highest oven temperature of 300 oC. Hence, 280 oC was decided as the final temperature. Then, the gradient temperature program in the injection and the GC oven were examined. Subsequently, the improved program provided an adequate separation of entire analyte peaks within 13 minutes. Since utilizing of IS is suggested to avoid potential miscalculations following injection of different sample volumes in the chromatographic equipment [18], n-tetracosane was therefore chosen as IS. Selection of a favorable solvent is important to provide that both the IS and the target analyte are completely dissolved. Therefore, chloroform/methanol mixture (1:1, v/v) was chosen as a solvent.

Selectivity/ Specificity

Selectivity/Specificity of an analytical assay can be characterized as the detection ability of the desired component in the existence of alternative analytes which can be supposed to be present in a complex matrix such as impurities, degradation products, and diluents [19,21]. The components in the seized illicit drug are generally country dependent. For this reason, a method must either be validated or revised according to the predicted sample matrix [14]. To appraise the specificity of this chromatographic method, our working solution: chloroform/methanol (1:1, v/v) mixture and placebo solution containing the IS (n-tetracosane at the concentration of 0.25 mg/mL) without the heroin were injected into the GC-FID system. The specificity of the method was carried out in existence of our working solution and placebo, which has heroin free solution. A characteristic chromatogram of heroin standard solution is presented in Figure 3(A). As can be observed in Figure 3(B), there is no peak correlated to placebo or dilution solution was identified at the retention time of heroin. Figure 3(C) demonstrates the sample chromatogram in which heroin was mixed with compounds (caffeine, codeine, morphine, and 6-MAM) usually encountered in real cases. Satisfactory selectivity was verified for heroin and IS by investigating whether all these analytes were separated adequately from one another on a chromatogram.

Accuracy

Accuracy can be described as the proximity of a quantified magnitude to an approved certified value or known value [19]. The accuracy of the assay was evaluated by means of the percentage of recovery data from spike analysis. According to our experience, heroin samples seized in Turkey generally contain caffeine. Reference caffeine and heroin solution were therefore spiked in three different amounts. The mean of recovery was found as 99.89% for heroin (see Table 4). In addition, relative error (RE) and coefficient of variation (CV) were also used to assess the accuracy of the method (see Table 5).

Conclusion

Heroin addiction is still a global public health problem through new psychoactive substances such as synthetic cannabinoids have been widely used by abusers. Turkey is exposed to international illegal heroin trafficking as transit and/or destination country. Hence, a significant amount of heroin has been seized by law enforcement agencies, indicating the importance of forensic drug analysis. In this study, GC-FID method for heroin analysis in illicit drug samples was developed and validated for accuracy, precision, and linearity. The mean recoveries obtained from CRMs analysis were found as 99.89% with relative error equal to 1.8%, indicating the method was accurate. The method provided LOD and LOQ equal to 2.20 μg/mL and 7.73 μg/mL, respectively. The GC-FID method is relatively fast, simple, precise, and applicable for routine forensic and pharmaceutical analysis. This work will improve the criminal justice system by providing quantitative and objective conclusions while examiners are presenting forensic evidence in the court.

Acknowledgment

Dr. Bayram Yuksel would like to express his gratitude to TUBITAK-BIDEB-2219 Program for the financial support

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Yüksel B. Quantitative GC-FID analysis of heroin for seized drugs. Ann Clin Anal Med 2020;11(1):38-42

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Case Report

Tuberculous meningitis: starting with unilateral ptosis: a case report

Ertan Karaçay 1 , Mustafa Öğüt 2 , Serhan Yıldırım 3 , Nihat Şengeze 4

1 Health Sciences University Antalya Training and Research Hospital, Antalya, 2 Gaziantep University Faculty of Medicine, Gaziantep, 3 Kocaeli University of Health Sciences Derince Education and Research Hospital, Kocaeli, 4 Süleyman Demirel University Faculty of Medicine, Isparta, Turkey

DOI: 10.4328/ACAM.5985 Received: 06.08.2018 Accepted: 08.02.2019 Publihed Online: 18.02.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):70-72

Corresponding Author: Ertan Karaçay, Sağlık Bilimleri Üniversitesi Antalya Eğitim ve Araştırma Hastanesi, Antalya, Türkiye. GSM: +905335671596 E-Mail: Ertan.karacay1@hotmail.com

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Tuberculosis is one of the human beings’ oldest and most common infectious diseases. Tuberculosis has resurfaced in endemic societies in recent years, and there is a reported increase in global prevalence. The central nervous system (CNS) is affected in approximately 1% of tuberculosis cases. Adult tuberculosis has high morbidity and mortality due to meningitis, rapid progression, and neurological sequelae. It is an important health problem, because of the difficulties in diagnosis and treatment, and also because of its serious complications. Delay in diagnosis increases the risk of mortality and further complications. This article draws attention to the differential diagnosis of tuberculous meningitis in patients who suffer from ptosis complaints in daily neurology practice by presenting notable clinical features and the presence of tuberculous meningitis.

Keywords: Tuberculosis Meningitis; Ptosis

Full Text
Introduction

Tuberculosis is one of the human beings’ oldest and most common infectious diseases. Tuberculosis has resurfaced in endemic societies in recent years, and there is a reported increase in global prevalence. Increased migration, the HIV epidemic, organ transplants, and weakened immune system due to nutrition disorders are thought to be the most significant causes of this problem. Tuberculosis of the central nervous system (CNS) is seen in approximately 1% of tuberculosis cases. Tuberculous meningitis is the most serious clinical form of extrapulmonary tuberculosis. Adult tuberculosis has high morbidity and mortality, due to meningitis, rapid progression, and neurological sequelae. It is an important health problem, both because of the difficulties in diagnosis and treatment, and also because of its serious complications. Delay in diagnosis increases the risk of mortality and further complications [1,2,3]. This article draws attention to the differential diagnosis of tuberculous meningitis in patients who suffer from ptosis complaints in daily neurology practice, by presenting notable clinical features and the presence of tuberculous meningitis.

Case Report

The subject is a 47-year-old male patient. One week ago, he developed ptosis of the left eyelid. He subsequently developed double and blurred vision in the left eye, contraction of the left side of his body and a loss of consciousness. His relatives brought him to the emergency department. A written informed consent was obtained from the patient in this case presentation.

According to his medical history, the patient had undergone surgery for aneurysm of the left arteria cerebri media approximately 15 years previously. There was nothing relevant in family history. The results of his physical examination were normal, except for a high fever (37.4°C). During his neurological examination, the patient was conscious and cooperative. His left eye was mydriatic and showed no reflex reaction to direct and indirect light, and it was concluded that his left eye had ptosis with limited up and down and inward vision. The results of his motor examination were normal, there was no pathological reflex and he had moderate neck stiffness. He was hospitalized in our clinic for cranial nerve involvement and seizure etiology. The examination was initiated for various etiologies, notably infectious (HIV, Syphilis), metabolic, paraneoplastic and vascular reasons. There was no pathology in routine blood and urine tests, except for the occurrence of 10 leukocytes in the urine examination. Blood and urine cultures were negative. Chest radiography was evaluated as being normal. During cranial magnetic resonance imaging (MRI), increased intensity on the pial surface of the brain stem of the FLAIR sequence, and leptomeningeal contrast involvement of the T1 sequence were observed (Figure 1). In electroencephalography, a paroxysmal irregularity characterized by slow ground activity and sharp-slow and sharp waves was detected. Levetiracetam 1000 mg/day was started. Cerebrospinal fluid (CSF) in the lumbar puncture had a blurry appearance. Opening pressure was measured as being 650 mmH2O. A count of 220 leukocyte/mm3 (>50% lymphocyte) was detected. CSF protein, CSF glucose, and concomitant serum glucose were measured as being 310 mg/dL, 11 mg/dL, and 130 mg/dL, respectively. The results of CSF culture, HSV PCR, adenovirus PCR, and enterovirus PCR were negative. The patient was started on quad anti-tuberculosis treatment, with tuberculous meningitis diagnosis upon infectious diseases consultation, but there was no significant improvement in the overall clinical condition. After the other eye also developed ptosis, an appearance concordant with hydrocephalus was observed in control brain MRI (Figure 2). External ventricular drainage was performed by the neurosurgery clinic. In his latest neurological examination, the patient was conscious, cooperative, oriented, had bilateral ptosis, his left eye was mydriatic, he showed no reflex to direct and indirect light, his motor examination result was normal and he had no pathological reflex. Since shunt treatment was done, we did not give steroid treatment to the patient. Nine months of tuberculosis therapy was planned. His clinical follow-up and treatment are ongoing.

Discussion

Tuberculosis is a significant global health problem. According to data provided by the World Health Organization, 10.4 million new cases of tuberculosis occurred worldwide in 2015. Tuberculous meningitis is the most common form of CNS tuberculosis. Although it generally develops with a hematogenous spread, it can also develop as a secondary effect to the rupture of subependymal or subpial focuses, or by direct extension of CSF infection. Adult tuberculosis has high morbidity and mortality due to meningitis, rapid progression, and neurological sequelae. Characteristics of mortality are more distinctive in patients with advanced disease. Therefore, early diagnosis and treatment are vital [4]. Our patient did not have any systemic signs suggesting the early onset of tuberculosis. He was at “stage 2”, in terms of clinical neurology at the time of admission, and cranial complications developed at the time of diagnosis. The most significant clue in the diagnosis of tuberculous meningitis is a history of contact with a known case of tuberculosis. There was no evidence of tuberculosis in our patient’s family history. Differential diagnosis of patients should be conducted properly. Temporal arthritis, HIV, Legionella infections and slow virus infections may be mistaken for viral encephalitis, particularly in cases involving stroke and optic nerves [5,6,7].

At first, aneurysm operation, ptosis, and seizure in the medical history of our patient suggested a new cerebrovascular attack. As can be understood upon a meticulous examination of the defined characteristics of our patient, accompanying results and signs such as fever and meningeal irritation suggested meningitis.

In diagnosis, the gold standard is manifestation or production of the factor in CSF. However, this is not always possible. In 45-90% of the patients, M. tuberculosis is isolated in the culture. The factor was not seen or produced in CSF with our patient. Tuberculosis PCR was negative in CSF sample. However, the examination findings of CSF supported typical tuberculous meningitis. A typical radiological finding in tuberculous meningitis is an increase in abnormal meningeal enhancement. Furthermore, the increase in basal cisterns is generally distinctive. Also, in the Sylvian fissures of many cases, an increased enhancement in sulcal meninges on cerebral convexities can be observed. The MRI findings of our case were also typical. The radiological examination findings were evaluated with CSF examination findings and clinical data in forming a diagnosis.

Tuberculous meningitis is characterized by the slow progressive granulomatous inflammation of basal meninges. Inflammation of basal meninges causes the occurrence of various manifestations of tuberculous meningitis, such as hydrocephalus and cranial nerve paralysis. Tuberculous meningitis tends to particularly affect basal regions of the brain. Basal exudate that accumulates around the Sylvian fissure, basal cisterns, the brain stem, and the cerebellum causes hydrocephalus by blocking CSF flow. In our patient, the third ventricle and both lateral ventricles were dilated as secondary to distinctive involvement in basal cisterns. He also had communicating hydrocephalus. Moreover, resorption of CSF was observed around both lateral ventricles, depending on the increase in intraventricular pressure. For that reason, the patient was referred for immediate surgical treatment.

Twenty-five percent of the cases have cranial nerve palsies. The most frequently seen form is the sixth cranial nerve palsy. Less frequent are the third and fourth cranial nerves. Cranial nerve palsy is caused by the compression of the nerve trunk through thick basal exudate. Increased intracranial pressure is another cause [8]. Our patient was characterized by unilateral ptosis during the early period. However, bilateral ptosis, total third cranial nerve, and optic nerve involvement were observed during the follow-up.

Diagnosis and treatment of tuberculous meningitis is difficult, even though it is a rare disease. Despite treatment, half of all patients die or only survive with severe neurological sequelae. A significant cause of this pessimistic picture is delayed diagnosis and therefore treatment [9].

Consequently, tuberculous meningitis is a form of extrapulmonary tuberculosis which is still significant in our country. Early diagnosis is of importance in cases with atypical onset. The clinical stage of the patient at the time of presentation, the time taken to start treatment and neurological complications are the most significant factors that affect the prognosis.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

References

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3. Marais S, Pepper DJ, Schutz C, Wilkinson RJ, Meintjes G. Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting. PLoS One. 2011; 6(5). DOI: 10.1371/journal.pone.0020077.

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9. Davis A, Meintjes G, Wilkinson RJ. Treatment of Tuberculous Meningitis and Its Complications in Adults. Current treatment options in neurology 2018; 20(3):5. DOI:10.1007/s11940-018-0490-9

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Karaçay E, Öğüt M, Yıldırım S, Şengeze N. Tuberculous meningitis: starting with unilateral ptosis: a case report. Ann Clin Anal Med 2020;11(1):64-66

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Bilateral abducens nerve palsy during treatment of a pediatric brucellosis

Ummuhan Cay 1 , Emine Kocabas 2 , Ceren Cetin 3 , Gulperi Timurtas Dayar 4 , Gulen Gul Mert 5 , Filiz Kibar 6

1 Department of Pediatric Infectious Diseases, Adana City Research and Training Hospital, Adana, 2 Department of Pediatric Infectious Diseases, Cukurova University, Adana, 3 Department of Pediatric Infectious Diseases, Kocaeli Research and Training Hospital, Kocaeli, 4 Department of Pediatric Infectious Diseases, Antalya Research and Training Hospital, Antalya, 5 Department of Pediatric Neurology, Cukurova University, Adana, 6 Department of Microbiology, Cukurova University, Adana, Turkey

DOI: 10.4328/JCAM.6091 Received: 20.11.2018 Accepted: 21.03.2019 Publihed Online: 22.03.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):67-69

Corresponding Author: Ummuhan Cay, Department of Pediatric Infectious Diseases, Cukurova University, Adana, Turkey. GSM: +905054940831 E-Mail: ucay-1205@hotmail.com

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Brucellosis is a multisystemic zoonosis caused by the bacteria of the genus Brucella particles or direct contact with infected animal parts. Due to the involvement of various organ systems, its clinical spectrum is wide. Neurobrucellosis occurs in 3-13% of all brucellosis cases and rarer in children. Involvement of various cranial nerves may be seen very rarely as a component of neurobrucellosis. We present here a case of a 3-year-old girl with sixth cranial nerve palsy that occurred during treatment for brucellosis. Our patient is the first pediatric neurobrucellosis case with isolated 6th nerve palsy in English-language literature. Neurobrucellosis should be considered in the differential diagnosis of patients of any age with unexplained neurological symptoms living in endemic regions

Keywords: Pediatric; Neurobrucellosis; Abducens Nerve Palsy

Full Text

Introduction

Brucellosis is a multisystemic zoonosis caused by the bacteria of the genus Brucella. It is a worldwide health concern but endemic in certain geographic parts of the world such as the Mediterranean countries, Central Asia, Middle East and certain regions of South America. Brucellae are facultative intracellular, non-motile, Gram-negative coccobacilli. Transmission is through consumption of unpasteurised milk and milk products, inhalation of infected aerosolised particles or direct contact with infected animal parts [1] . Due to the involvement of various organ systems, neurobrucellosis occurs in 3-13% of all brucellosis cases. Neurobrucellosis can have a variety of clinical and radiological manifestations such as acute, subacute or chronic meningitis, meningoencephalitis, meningovascular complications, multifocal white matter disease, intradural or epidural abscesses, arachnoiditis, ruptured mycotic aneurysm, hydrocephalus, presudotumor cerebrii, parkinsonism, polyradiculopathy (especially lumbosacral), mononeuropathy, compressive myelopathy due to spondylitis, cerebellar syndrome, calcification in basal ganglia, 2nd, 6th, 7th and 8th cranial nevre palsies [2-4] .

Involvement of various cranial nerves may be seen very rarely as a component of neurobrucellosis.We present here a 3-year-old girl with sixth cranial nerve palsy that occurred during treatment for brucellosis.

Case Report

She was initially admitted to another hospital 10 days before admission to our clinic with fever, vomiting, fatigue . On the fifth day of treatment, patient was referred to our clinic because of developing bilateral strabismus. Her personal history revealed that they as a family consumed cheese prepared from unpasteurized milk and that her grandmother had received treatment for brucellosis too. Her physical examination was normal except findings of bilateral abducens nerve palsy. she developed strabismus, she was unable to fixate her eyes on anything and she had difficulty reaching objects and grasping them. Her blood leukocyte count was 15.200/mm3 ( the differential 44% neutrophiles, 52% lymphocytes, 4% monocytes ), hemoglobin 11.2 gr/L, thrombocyte count 369.000/mm3, erythrocyte sedimentation rate 23 mm/hour and C-reactive protein level was 4.8 mg/dl (0-5 mg/dl). Her blood chemistry was normal. Serum agglutination test was positive for Brucella at 1/320. Her blood culture was negative. Her personal history revealed that they as a family consumed cheese prepared from unpasteurized milk and that her grandmother had received treatment for brucellosis too. The patient was diagnosed with neurobrucellosis due to evident brucella infection and concurrent 6th nerve palsy. She was started on trimethoprim-sulphametoxazole, rifampicin, cephtriaxone and gentamicin. She was consulted with ophthalmology department. She had no papillary stasis on fundus examination. Her examination was normal except findings of bilateral abducens nerve palsy. Cranial Magnetic Resonance Image (MRI) was normal. Lumbar puncture was performed. The cerebral spinal fluid (CSF) was colorless. Microscopic examination of CSF showed 10 cells per mm3. CSF glucose and protein levels were normal. CSF culture abd brucella agglutination tests yielded negative results. After three days of treatment, her eye movements were completely normal. Her family was screened for brucellosis too. Her mother and 13-month-old brother had brucellosis too and were given treatment. She was hospitalized for two weeks and sent home with oral rifampicin and Trimethoprim Sulfamethoxazole (TMP-SMX) treatment due for 3 months. She was complaint-free and her physical examination was normal at one-month follow-up visit.

Our patient is the first pediatric neurobrucellosis case with isolated 6th nerve palsy in English-language literature. Neurobrucellosis should be considered in the differential diagnosis of patients of any age with unexplained neurological sypmtoms living in endemic regions.

Discussion

Brucellosis is an infectious disease with a wide clinical spectrum that can involve any organ system in human body. Neurobrucellosis is the involvement of central nervous system in brucellosis. It is either due to direct invasion by bacteria or autoimmune reactions to bacterial toxins [5,6]. Neurobrucellosis can present itself in various clinical manifestations as acute, subacute or chronic meningitis, meningoencephalitis, meningovascular complications, multifocal white matter disease, intradural or epidural abscess, arachnoditis, ruptured mycotic aneurysms, hydrocephalus, parkinsonism, polyradiculopathy (especially lumobosacral), mononeuropathy, compressive myelopathy due to spondylitis, myelitis, cerebellar syndrome, calcification of basal ganglia, 2nd, 6th, 7th, 8th cranial nerve palsies [1,7,8]. Isolated cranial nerve involvement is especially rare, with 7th cranial nerve being the most common [9,10]. 6th cranial nerve is the most frequently involved cranial nerve in case reports from Turkey, followed by 7th and 8th [11,12]. There are a few case reports of isolated cranial nerve involvement due to brucellosis in adults in the literature [13-16].

Neurological complications of brucellosis in adults have been classified in two groups. The first is an acute toxic-febrile state, usually non-specific (e.g. headache and neuropsychiatric manifestatios) that occur in systemic (bacteraemic or Brucella serological tests are positive) forms of the disease, and the second is that of actual invasion and localization of the pathogen in the CNS [9] . Our case seemed to be in the first group because she had high grade fever, vomiting and fatigue when 6th cranial nerve palsy developed, although the pathogen could not be shown in cerebrospinal fluid. In a case published by Yılmaz et al, the patient developed 6th nerve palsy on the eleventh day of treatment and no pathogen could be shown in CSF [13]. The inability to show any pathogen in CSF may be due to patients having received treatment in advance.

Brucellosis is diagnosed by either serological tests and/or culture positivity. Neurobrucellosis is diagnosed by showing the pathogen in CSF culture, the presence of antibodies in CSF and presence of meningeal involvement [17]. But it is not always possible to show the pathogen in CSF. Ceran et al. have taken four criteria into consideration for diagnosis of neurobrucellosis in a study of 18 patients. These criteria were presence of neurological symptoms in the absence of another disease, isolation of bacteria from blood and other body, positivity of standard tube agglutination (STA) titers in serum and/or cerebrospinal fluid (CSF) and presence of CSF findings revealing chronic meningitis (lymphocytic pleocytosis, increased protein level, decreased glucose level). Presence of any of these four criteria was sufficient for the diagnosis [18]. In our case clinical history, symptoms and laboratory findings with the presence of 6th cranial nerve palsy supported the diagnosis of neurobrucellosis. However, CSF agglutination test and culture were both negative.

There is no consensus on optimal treatment regimen of neurobrucellosis. Different antibiotic combinations and durations of treatment were reported in different studies. Treatment with combinations of two or three antibiotics for at least three months is advised. Rifampicin, TMP-SMX, ceftriaxone and aminoglycosides are the preferred antibiotics as combinations [17,18] .

Our patient was diagnosed with brucellosis under the light of clinical history, physical examination findings and laboratory results. Accompanying 6th nerve paly led to the diagnosis of neurobrucellosis. The patient was given ceftriaxone, rifampicin and TMP-SMX. Ceftriaxone treatment was continued for fourteen days. Rifampicin and TMP-SMX combination treatment was planned to be continued for a total of three months. On first month follow-up, the patient was free of any complaints.

Neurobrucellosis is rare in adults, but even rarer in children. And there are a few adult cases with abducens nerve palsy due to neurobrucellosis, but no pediatric cases. Our patient is the first pediatric neurobrucellosis case with isolated 6th nerve palsy.

Finally, neurobrucellosis should be considered in the differential diagnosis of patients of any age with unexplained neurological sypmtoms living in endemic regions.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

References

1.Young EJ. BrucelIa species. Ln Mandell GL, Bennet JE, Dalin R(eds). Principles and practice of infections disease (5th ed). Vol. 2, Philadelphia: Churchill Livingstone, 2000:2386-93.

2. Al Deeb S, Yacub B, Sharif HS, Phadke JG. Neurobrucellosis: Clinical characteristics, diagnosis and outcome. Neurology. 1989; 39: 498-501.

3. Young EJ. Brucella species. Mandell GL, Bennett JF, Dolin R(eds). In: Principles and Practice of Infectious Diseases (6th ed). Philadelphia:Churchill Livingstone, 2005; 2669-74.

4. Lubani MM, Dudin KI, Araj GF, Manandhar DS. Neurobrucellosis in children. Pediatr Infect Dis J. 1989; 8:79-82.

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15. Esra Özkavukcu, Zeynep Tuncay, Ferda Selçuk, İlhan Erden An unusual case of neurobrucellosis presenting with unilateral abducens nerve palsy: clinical and MRI findings Diagn Interv Radiol 2009; 15:236–8.

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18. Ceran N,Turkoglu R, Erdem I, Inan A, Engin D, Tireli H et al. Neurobrucellosis: clinical, diagnostic, therapeutic features and outcome. Unusual clinical presentations in an endemic region. Braz J Infect Dis 2011;15:52-9

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Cay U, Kocabas E, Cetin C, Dayar GT, Mert GG, Kibar F. Bilateral abducens nerve palsy during treatment of a pediatric brucellosis. Ann Clin Anal Med 2020;11(1):67- 69

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Acute occlusion of the right superficial femoral artery following endovascular stent grafting of the right common iliac artery

Görkem Yiğit, Hamdi Mehmet Özbek, Anıl Özen, Hakkı Zafer İşcan

Department of Cardiovascular Surgery, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey

DOI: 10.4328/ACAM.6145 Received: 28.12.2018 Accepted: 24.01.2019 Publihed Online: 05.02.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):73-76

Corresponding Author: Görkem Yiğit, Altınkuleler Sitesi, Altındağ Sakarya Mahallesi, Yönü Sokak, 06080 Ankara, Turkey. GSM: +905066777577 E-Mail: drgorkemyigit@gmail.com ORCID ID: https://orcid.org/ 0000-0002-9500-720X

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Percutaneous transluminal angioplasty (PTA) is a safe and effective procedure for the treatment of aortoocclusive disease. However, procedural complications and stent restenosis may occur. Distal embolization is one of the complications that require urgent intervention. Here, we present a 70-year-old male patient presenting with severe pain and loss of motor function of the right leg, following right common iliac artery balloon expandable stent implantation. Embolization of the right superficial femoral artery occurred as an acute complication of the surgery. The patient’s past medical history included lung cancer and an operative procedure on bowels. Emergency embolectomy of the right superficial femoral artery resulted in the reversal of the symptoms. Randomized studies have shown that thrombolysis is as effective as surgery. Nevertheless, embolectomy or thrombectomy is accepted as the gold standard treatment with low morbidity and mortality rates. In this case, we chose to perform an embolectomy instead of treating the patient with local thrombolytic agents; following the procedure, there was complete resolution of ischemia and motor function loss.

Keywords: Endovascular Stenting; Acute Oclusion; Embolectomy

Full Text

Introduction

Endovascular balloon expandable stent implantation in the treatment of atherosclerotic iliac artery stenoses is becoming widely used. Numerous studies estimate the complication rate to be 8-12%[1]. Distal embolisation is one of the complications that require urgent intervention. Randomized studies have shown that thrombolysis is as effective as surgery. Thrombolytics have been used in the treatment of native artery and graft thromboses complicated by acute leg ischemia as an alternative to surgery and safer option [2,3]. Alongside this, embolectomy or thrombectomy is accepted as the gold standard treatment option with low morbidity and mortality rates [4,5].

Here, we represent a 70-year-old male patient presenting with severe pain and loss of motor function of the right leg due to embolization of the right superficial femoral artery, following right common iliac artery balloon expandable stent implantation. Balloon expandable stent implantation was the choice of treatment despite total occlusion of the right common iliac artery which was a TASC D (TransAtlantic Inter-Society Consensus stratification) lesion. This was the preferred treatment option as the patient had a history of lung cancer and an operative procedure of the bowels, making the patient a high-risk candidate for surgery. Emergency embolectomy of the right superficial femoral artery enabled removal of the embolus material andresulted in the reversal of the symptoms.

Case Report

A 70-year-old male patient who was being followed up in the outpatient clinic was admitted to the vascular surgery ward having presented with claudication at fifty meters. A physical examination revealed absent pulses on the right lower extremity. However, there was no sign of an ischemic change in the extremity. He has been smoking two packs per day for twenty years. He also had a history of chronic obstructive pulmonary disease, treatment for lung cancer as well as an operative procedure on the bowels. Blood tests and echocardiogram values were all within the normal range. DSA (Digital Subtraction Angiography) revealed total occlusion of the right common iliac artery (CIA). Right common femoral artery (CFA) was filled by the collateral vessels proximally. Right superficial femoral artery (SFA), popliteal artery and distal vessels were patent (Figures 1, 2, 3).

Open surgery was deemed high risk due to the patient’s comorbidities, and so balloon expandable stent implantation of the right common iliac artery was performed (Figure 4). Ten minutes postoperatively, the patients complained of severe pain distal to the right knee with pallor and motor function loss distal to the ankle. DSA showed an absence of blood flow distal to the right knee, findings compatible with an embolus (Figure 5). Emergency embolectomy was planned. Following the right femoral incision, CFA (Common femoral artery), SFA (Superficial femoral artery) and DFA (Profunda femoris artery) were encircled with tapes. One milliliter of heparin was administered and vascular clamps were placed onto the arteries. Arteriotomy was performed. The antegrade flow was good after removal of the clamp. However, there was no backflow when the distal clamp was removed. 3 F (Fogarty) embolectomy catheter was advanced up to 45 cm twice which enabled the removal of the embolus debris that was 2×0.5 cm in size (Figure 6). The backflow was good. The arteriotomy was repaired using a 5/0 prolene suture. Control DSA revealed normal blood flow into the distal vessels (Figure 7).

The patient was heparinized; the activated clotting time (ACT)level was maintained at 200-250 seconds in the intensive care unit. Dual antiplatelet treatment was started (clopidogrel and acetylsalicylic acid). All distal pulses were palpable and the patient was discharged onthe third day postoperatively. The patient was free of claudication on the sixth postoperative month.

Discussion

Percutaneous transluminal angioplasty is a safe and effective procedure for the treatment of aortoocclusive disease and is becoming more widely used. On the other hand, procedural complications, stent restenosis, and distal embolization may occur. Distal embolization requires urgent intervention. The incidence of distal embolization following iliac and femoropopliteal angioplasty or stenting is 2.3-4.5% [6,7].

Primary endovascular revascularization is recommended for TASC A and B lesions. However, surgical revascularization is the choice of treatment for TASC C and D lesions in patients with suitable preoperative risk and appropriate conduit arteries [8]. The effect of such factors as patient comorbidity, patient choice, and the experience of the patient on decision making is emphasized. We chose to perform endovascular revascularization in our patients due to high surgical risk.

A study of 75 patients undergoing PTA due to iliac occlusion reported distal embolization in 18 (24%) of the patients [9]. To date, embolectomy, bypass, and amputation have so far been used in patients with iliac artery occlusion. Randomized studies have revealed that thrombolysis is generally as effective as surgery [2,3,10,11]. Local thrombolysis may be a good option especially in appropriately selected patients [10,11]. Nevertheless, embolectomy or thrombectomy is accepted as the gold standard treatmentand has low morbidity and mortality rates.

In this case, embolectomy was the chosen treatment option, rather than a local thrombolytic agent, due to the possibility of a debris embolus occurring in a patient who was evaluated as high risk for surgery and had undergone angioplasty and stenting. Embolectomy resulted in total improvement of the patient’s symptoms including motor function loss.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

References

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2. Dotter CT, Rösch J, Seaman AJ. Selective clot lysis with low-dose streptokinase. Radiology.1974;111: 31-7.

3. Ouriel K, Shortell CK, DeWeese JA, Green RM, Francis CW, Azodo MV, et al.A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia. J Vasc Surg. 1994;19: 1021-30.

4. Norgren L, Hiatt WR, Dormandy JA, TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASCII). J Vasc Surg. 2007;45 Suppl. S:S5-67.

5. Karnabatidis D, Spiliopoulos S, Tsetis D, Siablis D. Quality improvement guidelinesfor percutaneous catheter-directed intra-arterial thrombolysis and mechanical thrombectomy for acute lower-limb ischemia. Cardiovasc Intervent Radiol. 2011; 34(6):1123-36.

6. Papavassiliou VG, Walker SR, Bolia A, Fishwick G, London N. Techniques for the endovascular management of complications following lower limb percutaneous transluminal angioplasty. Eur J Vasc Endovasc Surg. 2003; 25: 125–30.

7. Pentecost MJ, Criqui MH, Dorros G, Goldstone JJohnston KWMartin EC, et al.Guidelines forperipheral percutaneous transluminal angioplasty of theabdominal aorta and lower extremity vessels. A statementfor health professionals from a Special Writing Group ofthe Councils on Cardiovascular Radiology, Arteriosclerosis,Cardio-Thoracic and Vascular Surgery, Clinical Cardiology,and Epidemiology and Prevention, the American HeartAssociation. J Vasc Interv Radiol.2003; 14(9 Pt. 2): S495-515.

8. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR, et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007; 45 Suppl S: S5-67.

9. Leu AJ, Schneider E, Canova CR, Hoffmann U. Long-term results after recanalisation of chronic iliac artery occlusions by combined catheter therapy without stent placement. Eur J Vasc Endovasc Surg.1999; 18: 499-505.

10. The STILE Investigators. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. Ann Surg. 1994; 220(3): 251-66.

11. Ouriel K, Veith FJ, Sasahara AA. Thrombolysis or peripheral arterial surgery: phase I results. J Vasc Surg. 1996; 23: 64-73.

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13. Giaquinta A, Ardita V, Ferrer C. Iliac Branch Stent-Graft Italian Trial Collaborators. Isolated Common Iliac Artery Aneurysms Treated Solely With Iliac Branch Stent-Grafts: Midterm Results of a Multicenter Registry. J Endovasc Ther. 2018; 25(2): 169-77.

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Yiğit G, Özbek HM, Özen A, İşcan HZ. Acute occlusion of the right superficial femoral artery following Endovascular stent grafting of the right common iliac artery. Ann Clin Anal Med 2020;11(1):73-76.

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Review Article

Telocytes: history, character and importance in medicine

Etedal Abbas Huwait

Biology Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

DOI: 10.4328/ACAM.6144 Received: 27.12.2018 Accepted: 30.01.2019 Published Online: 08.01.2019 Printed: 01.01.2020 Ann Clin Anal Med 2020;11(1):81-85

Corresponding Author: Etedal Abbas Huwait, Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. E-Mail: Dretedalahuwait@gmail.com, ehuwit@kau.edu.sa ORCID ID: https://orcid.org/ 0000-0002-8946-6071

Abstract
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Abstract

Telocytes (TCs), recently identified interstitial cells, have been frequently investigated in many researches. This review summarized, in brief, the morphological features, distribution, immunohistochemical, and genomic characteristics of TCs. This review identified in brief the difference between Telocytes and stem cells. The functions of TCs and their potential application in regenerative medicine have been reviewed. The genetic analysis of TCs and the functional relationship with other neighboring cells including stem cells were also briefly described. Many future researches are still needed to discover more about the telocytes and its utilization in improving the fate of regenerative medicine.

Keywords: Telocytes; History; Structure; Electron; Microscope; Function; Stem Cells; Fibroblasts

Full Text

Introduction

Telocytes (TCs) are considered recently discovered interstitial cells characterized by having very elongated, thin cellular prolongations called telopodes have alternating thin segments (podomers) with dilatations (podoms) [1]. When the TCs were initially recognized by Popescu et al. they were named “cells with telopodes” [2].

When the electron microscope (EM) was utilized, the special interstitial cell type was found to coincide with cells that were described by Cajal in the early 1970s. These cells were present in the gut muscle coat, later on, it was clear that they were not neurons, and were noted ‘interstitial cells of Cajal’ (ICC) [3].

Since their discovery in 2010, TCs were frequently studied. About 132 records have been found to describe “telocyte” from 2010 to 2015 and they have been cited in the Web of Science more than two thousand time [4]. On routine histological examination using light microscopy, TCs could not be discriminated from the surrounding fibroblast-like cells due to the similarity in appearance and proximity to these cells [5].

Telocytes are distinguished from the other interstitial cell types “e.g. fibroblasts, fibrocytes, fibroblast-like cells, mesenchymal cells”, because of their prolongations, based on the morphological characters through electron microscope [6].

Sites of TCs:

Telocytes were initially described in mouse trachea and were successfully isolated and cultured from mouse lung tissues [7]. Telocytes have been identified in the interstitial space of many organs e.g. skin [8], exocrine pancreas [9], pericardium [10], pleura [11] uterus and fallopian tube [12], prostate [13], heart [14], kidney [15], intestine [16] stomach [17], liver [18], lung and trachea [19] and many other organs [4] (Figure 1).

Electron microscopic character of Telocytes:

Transmission electron microscopy (TEM), scanning electron microscopy (SEM), electron tomography, focused ion beam-scanning electron microscopy (FIB-SEM) are currently used techniques to localize in different organs and tissues (Figure 2). TEM still represents the “golden standard” in the identification of TCs (Figure 3) [6, 20]. Telocytes might be spindle, pyriform or triangular in shape and they possess many elongated long and thin processes that range from1 to 5 per cell. The cell body shape of TCs is depending on the number of telopodes emerging from it as follows: the pyriform cell body has only one telopode, the spindle cell body possesses two telopodes, the triangular cell body has three telopodes, while the stellate cells have over three telopodes. The nucleus of TCs occupies about 25% of the cell body. It is oval in shape with no apparent nucleolus, while the heterochromatin masses are seen on the inner nuclear envelope. The nucleus is enclosed by a small amount of cytoplasm with Golgi complex, mitochondria, rough and smooth endoplasmic reticulum and cytoskeletal elements [6].

Cretoiu et al. observed that TCs present in the jejunum of rat in 2 sites; the sub-epithelial lamina propria and in-between the smooth muscle fibers in the muscularis mucosae. Telopodes of the telocytes display podomeres and podoms (dilations containing mitochondria and endoplasmic reticulum). Telopodes have dichotomous branching and make a three-dimensional network close to immune cells, smooth muscle cells or nerve bundles [21].

Telocytes also have numerous cytoskeleton components like the intermediate filaments and caveolae on the cell membrane, while a basal lamina is lacking. The caveolae make up 2–3 % of the cell body and present ~0.5 caveolae/μm of cell membrane length [6].

The presence of telopode is a distinguishable character of TCs to differentiate it from all interstitial cells like ICCs, fibroblasts, neuronal dendrites, and mesenchymal stem cells. Telopode is considered the longest process found in the tissue in comparison to some axons of certain neurons. Telocytes, via intercellular junctions “as a gap or adherens junctions”, may communicate with the surrounding TCs or other cell types to form “a 3D network, budding shed vesicles, and exosomes” [14].

Sequenced series of EM images are much better to visualize the ultrastructure of TCs because of their cellular prolongations (Figure 4) [22]. Intercellular signaling through secreting small molecules in the surrounding areas was observed to occur between TCs and the adjacent cells either in normal or pathological conditions [23]. Extracellular vesicles including essential macromolecules like RNAs or proteins were continuously shedded from the telocytes. Using TEM, three types of extracellular vesicles were recognized near the cardiac TCs based on their size. These vesicles are known as multivesicular cargos, exosomes, and ectosomes [23].

Immunohistochemical Identification of Telocytes:

Although there is no single specific immunostaining for identification of TCs available till now, double immunolabeling represents a current beneficial technique for TCs identification and assessment [24, 25]. Hematopoietic stem cell marker CD34/c-kit and CD34/vimentin, mesenchymal cell marker, are relevant immunomarkers for TCs [24].

Unfortunately, CD34 immunostaining does not provide clear identification of TCs as it does not stain all telocytes. However, it is the superior method, till now, to identify TCs when combined with vimentin or c-kit [26]. Tissue- and organ-specific immunomarker are now available for TCs [24]. Cardiac TCs were described to express “CD34, vimentin, myocardial stem cell markers sca-1 and c-kit, and embryonic stem cell-associated gene of Nanog” [30].

Telocytes could be immunohistochemically differentiated from many other interstitial cells as they are negative for fibroblasts-specific markers (CD90/Thy-1) and endothelial cells-specific markers (procollagen 1, CD31/PECAM-1). In addition, TCs are negative to α-SMA which is essentially expressed by vascular smooth muscle cells, myofibroblasts, pericytes and are negative to CD68, CD1a and CD62-P which are essentially expressed by macrophage [24, 26].

It was reported that TCs observed in skeletal muscle expressed platelet-derived growth factor receptor- β (PDGFR-β). These TCs control microvessel cell recruitment during angiogenesis [7, 27]. Thus, “double positive immunostaining with CD34/PDGFR-β is considered a suitable marker for the detection of TCs in the esophagus, corpus and antrum, gastric fundus, liver, and intestine” [26, 28, 29].

Splenic TCs were reported to have vimentin, CD34, Nanog, and sca-1 antigens but they do not have c-kit [30]. Podoplanin (D2-40) was considered as a marker of telocytes in the bladder” although it could not be a single reliable marker for these cells and should be combined with other markers as it is normally expressed by other cells like chondrocytes and osteocytes [31].

Genomics of TCs:

TCs are regarded as a special type of interstitial cells with developmental and functional characteristics that differ from both the mesenchymal stem cells and the fibroblasts as they express different genes from these cells.

Several up-regulated genes were recognized in telocytes like “transgelin (Tagln), matrix metallopeptidase 10 (Mmp10), retinol-binding protein 1 (RBP1), nidogen 1, connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 3 (TIMP3), collagen type IV, alpha and matrix metallopeptidase 3 (Mmp3)”. All these genes recorded to have an essential role in tissue remodeling and repair [32].

The microRNA signatures have been studied in cardiac cells by Cismasiu et al. and they observed “the alteration in microRNA expression between telocytes and cardiomyocytes [33]. Telocytes keep the mesenchymal origin by considerably up-regulating miR-21, miR-22, miR-29, and miR-199a-5p and down-expressing miR-1, miR-133a, and miR-208a”. Proteomic analysis of human lung TCs was conducted by Zheng et al. in comparison with fibroblasts and they found that myosin-4, periplakin, and oxidoreductase activity linked proteins are up-regulated in TCs [34].

What are the differences between Telocytes and fibroblasts?

Based on the structure elicited using the EM as well as gene expression profile, TCs are clearly distinguished from the fibroblasts. More than 2000 genes were found to be up-regulated and > 4000 genes were down-regulated in telocytes in comparison to mesenchymal stem cells and fibroblasts”. When it comes to the function, TCs are concerned with the intercellular signaling, through connection with the nearby components or through the release of extracellular vesicles. On the other hand, fibroblasts function is mostly concerned with the formation of collagen and other matrix components [23].

Regarding the differences in shape between TCs and fibroblasts, in contrast to the shape of the TCs described above, the fibroblasts are spindle-shaped, possess a large amount of cytoplasm, a single oval nucleus with typically euchromatic chromatin and one or two nucleoli (Figure 5). The fibroblasts have prominent Golgi apparatus, the smooth endoplasmic reticulum (ER) nearly lacking, but rough ER is noticeable, present mostly in cell body but also in processes. Caveolae are hardly seen in the fibroblast and no junctions could be detected with other cells. The fibroblast usually shows 2 tapered -ends prolongations with several micrometers with neither podomers nor podoms [18].

The relationship between telocytes and stem cells:

TCs were described, based on many studies, to be involved in tissue development, homeostasis, and occurrence of diseases [35]. Based on their situation, near stem cells or progenitor cells in many tissues like skeletal muscle, heart, choroid plexus, lung, skin, meninges, liver eye, TCs were proposed to be responsible for tissue renewal [29, 36].

The concept of the possible role of telocytes in tissue renewal after the damage was reported in many previous studies [37]. TCs also were described to show stem cell markers like c-kit, Sca-1, and Oct 4. Although expression of these stem cell markers was different in tissues, this proposes a crucial role of TCs in regeneration [24].

Establishment of a good microenvironment that helps survival, dissemination, and renewing potential of the injected stem cells is crucial for the success of both stem cells and the progenitor cells applications in regenerative medicine [38].

There is still a controversy between researchers regarding the mechanism of interaction between stem cells and telocytes. Among the hypotheses suggested to explain this relation was that of Zheng et al., who proposed direct cell to cell signaling and close cross talk as telocytes may afford antioxidant protective effect to stem cells [34]. In addition, TCs also expressed both in situ and in vitro vascular endothelial growth factor and PDGFR-b, explaining their potential effect in angiogenesis during tissue repair [7].

Ceafalan et al. proposed that TCs have a role in the differentiation of mesenchymal SC [5]. On the other hand, Zhao et al. claimed that telocytes might be a subpopulation of mesenchymal stem cells because they have some markers of stromal niche cells” [39]. Not only that, but telocytes were suggested to play a vital role in cell signaling, therefore adjusting the microenvironment in intact as well as diseased tissues [40].

Li et al. claimed that adding TCs to stem cell niches, in certain tissues, will help to create “a compound interstitial network with resident stem cells, nerve endings, blood vessels as well as other interstitial components which can participate in tissue renewal [37].

Importance of TCs:

Among the postulated roles of TCs, was “in juxta signaling” – or “paracrine signaling” [9]. It was evidenced that telocytes are able to create both homocellular and heterocellular junctions and can release extracellular vesicles [18, 21]. TCs could mechanically support the surrounding structures as they possess a three-dimensional structure. They can regulate the blood vessel closing in rat mesentery. Another proposed function of TCs in the neuromuscular spindles was the regulation of muscular tone [42]. TCs might control and adjust the tissue remodeling activity performed by mesenchymal cells, neural stem cells and myocardial precursors [43].

Being closely related to the cardiomyocyte progenitors, cardiac stem cells, TCs were thought to be important for the proliferation and differentiation of myocardial precursors into new cardiac muscle fibers in both intact and injured heart as well as for new blood vessels formation (Figure 6) [44, 45]. TCs in the lung possess the latent participation in tissue homeostasis, stem cell niche modulation, reserving oxidative stress, and delaying cellular aging [34].

It was reported that smooth muscle fibers are electrically joined to ICC, thus TCs were proposed to be involved in neurotransmission as well as “spreading the slow waves generated by the ICC” [17]. TCs also were reported to be involved in supplying data required for the immune response [32]. In the reproductive system, telocytes are described to have estrogen and progesterone receptors and hence were involved in coordinating the contractility and proliferation of smooth muscle cells [41].

Decreased number of telocytes was evident in the fibrotic areas in experimental myocardial infarction [39]. Zhao et al. have reported that “intramyocardial transplantation of telocytes from the heart can reduce myocardial infarction and recover post-infarcted cardiac function through enhancing cardiac angiogenesis and reconstruction of the telocytes networking and reducing cardiac fibrosis” [46].

Tissue engineering and regenerative medicine community possess great expectations for TCs in the regenerative medicine. The TCs are possibly innovative target for therapeutic strategies as advanced molecular and cellular researches on TCs roles might give new tools for regenerative potential of damaged organ [40, 47].

Summary: Although telocytes were recently discovered, they have been investigated frequently to identify their morphological features, distribution, immunohistochemical and genomic characteristics, the difference in their structure compared to other cells like fibroblasts and stem cells. TCs perform many important functions like supporting the surrounding structures, controlling, and adjusting the tissue remodeling activity besides other tissue-specific functions. Their functions and potential application in regenerative medicine have been also studied. The genetic study of teleocytes on many organs and the functional connection with other adjacent cells as the stem cells were also described. Many future researches are still needed to discover more about the telocytes and its utilization in improving the fate of regenerative medicine.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Huwait EA. Telocytes: history, character and importance in medicine. Ann Clin Anal Med 2020;11(1):81-85

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A rare presentation of vena cava superior syndrome: ascending aorta dilatation

Yasemin Kaya 1 , Ali Aygün 2 , Sevda Önder 3 , Hilal Altaş 4 , İsmail Yıldız 5

1 Department of Internal Medicine, Ordu University Medical School, 2 Department of Emergency Medicine, Ordu University Medical School, 3 Department of Dermatology, Ordu University Medical School, 4 Department of Radiology, Ordu University Medical School, 5 Department of Intensive Care Unit, Ministry of Health and Ordu University Research Hospital, Ordu, Turkey

DOI: 10.4328/JCAM.5928 Received: 09.06.2018 Accepted: 26.06.2018 Publihed Online: 03.07.2018 Printed: 01.01.2020 Ann Clin Anal Med 2020; DOI: 10.4328/JCAM.5928

Corresponding Author: Yasemin Kaya, Department of Internal Medicine, Ordu University Medical School, 52000, Ordu, Turkey. T.: +90 4522252342 F.: +90 4522250190 E-Mail: ysmnkcmz@gmail.com ORCID ID: https://orcid.org 0000-0001-7360-8090

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A 72-year-old male patient with past medical history of hypertension and coronary artery disease was admitted to the emergency clinic after two hours of acute-onset- edema of the lower part of the head and neck. The patient was using acetylsalicylic acid, angiotensin converting inhibitor and beta blocker agents. On his physical examination, blood pressure and heart rates were 125/70 mmHg and 95 bpm, respectively. Heart and respiratory auscultation findings were normal. Electrocardiogram showed sinus rhythm. The initial evaluation of the emergency physician was angioedema and patient was consulted to the dermatology. However, there was an increase in clinical progression, head, and neck swelling in the patient. The patient was quickly drawn to computer tomography. Computed tomography showed that the ascending aorta was highly dilated (Figure-1). The dilated ascending aorta was obstructed by the vena cava superior (Figure-2 and Figure-3). It was also showed that the right atrium was pressed by the dilated ascending aorta (Figure-4). Left ventricular systolic functions were normal in the echocardiography of the patient, and ascending aortic diameter of 9.8 cm was measured in parasternal long axis images. The patient was immediately transferred to cardiovascular surgery for surgical treatment purposes.

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A 72-year-old male patient with past medical history of hypertension and coronary artery disease was admitted to the emergency clinic after two hours of acute-onset- edema of the lower part of the head and neck. The patient was using acetylsalicylic acid, angiotensin converting inhibitor and beta blocker agents. On his physical examination, blood pressure and heart rates were 125/70 mmHg and 95 bpm, respectively. Heart and respiratory auscultation findings were normal. Electrocardiogram showed sinus rhythm. The initial evaluation of the emergency physician was angioedema and patient was consulted to the dermatology. However, there was an increase in clinical progression, head, and neck swelling in the patient. The patient was quickly drawn to computer tomography. Computed tomography showed that the ascending aorta was highly dilated (Figure-1). The dilated ascending aorta was obstructed by the vena cava superior (Figure-2 and Figure-3). It was also showed that the right atrium was pressed by the dilated ascending aorta (Figure-4). Left ventricular systolic functions were normal in the echocardiography of the patient, and ascending aortic diameter of 9.8 cm was measured in parasternal long axis images. The patient was immediately transferred to cardiovascular surgery for surgical treatment purposes.

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Yasemin Kaya, Ali Aygün, Sevda Önder, Hilal Altaş, İsmail Yıldız. A rare presentation of vena cava superior syndrome: ascending aorta dilatation. Ann Clin Anal Med 2019; DOI: 10.4328/ACAM.6088.

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