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March 2020


Original Article

A novel suture technique in the percutaneous repair of Achilles tendon rupture (TANSEL TECHNIQUE)

Tansel Mutlu, Ahmet Burak Satılmış

Department of Orthopaedics And Traumatology, Karabuk University, Medical Faculty, Demircelik Campus, Karabuk, Turkey

DOI: 10.4328/ACAM.6164 Received: 13.01.2019 Accepted: 27.03.2019 Published Online: 27.03.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):110-114

Corresponding Author: Tansel Mutlu, Karabuk University, Medical Faculty, 4. Floor, Demircelik Campus, 78050, Karabuk, Turkey.GSM: +905056229175 E-Mail: tanselmutlu@yahoo.comORCID ID: https://orcid.org/ 0000-0002-8927-2664

Abstract
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Abstract

Aim: The aim of this study was to present the clinical results of patients treated with a sliding, wrapping suture technique (Tansel technique) which provides rapid recovery with fewer wound site problems compared to open surgery techniques. Material and Method: A total of 34 patients were included in the study. Following the initial diagnosis made on physical examination, routine dynamic ultrasonography (USG) was applied for the determination of the rupture gap and tendon length. All the patients were evaluated in respect of the time from trauma to surgery, etiological causes, affected side, postoperative AOFAS (The American Orthopaedic Foot & Ankle Score) and Tegner scores, cruris diameter, mean time to full weight-bearing, time of return to work, time to regain pre-trauma activity level and complications. Results: The mean follow-up period was 27.7±16.8 months. According to clinical evaluations of the patients at the final follow-up examination, postoperative dorsiflexion angle and plantar flexion angle were determined as 16.3°±4.3°, 39.7°±7.1° respectively. While postoperative Tegner score was determined as 87.6±9, AOFAS score was found as 91.3±4.7. Postoperatively at sixth months, in the measurements of the cruris area diam-eter, 1.5±0.4 cm atrophy was detected. Of the defined major complications, tendon elongation was seen on USG in 1 (2.9%) patient. No re-rupture occurred in any patient. Discussion: Treatment of acute Achilles tendon ruptures with Tansel technique provides successful results such as resolving the problems of re-rupture and tendon elongation particularly in the postoperative tendon malacia stage. So, this technique was considered as an effective technique which could be used to resolve the disadvantages of minimally invasive percutaneous repair.

Keywords: Achilles; Tendon; Rupture; Percutaneous; Repair

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Introduction

Achilles tendon rupture is one of the most frequently encountered tendon ruptures in the orthopedic emergencies and incidence is 20-fold higher among males than females [1, 2]. In the studies over the last three decades, a linear increase in the incidence of Achilles tendon rupture had been observed. This increase was particularly in the 3rd and 4th decades of the life of young adult males [1-3]. So minimally invasive techniques are needed for the treatment of Achilles tendon rupture in the young population.

Different approaches have been reported for postoperative rehabilitation in parallel with surgery and there have been recent studies showing better results in early and more aggressive rehabilitation protocols compared to traditional rehabilitation methods [4]. As a result, it has become a requirement that current treatment protocols are problem-free and provide early recovery.

The aim of this study was to present the clinical results of patients treated with a Tansel technique which provides rapid recovery with fewer wound site problems compared to open surgery techniques and it reduces complication rates, re-rupture, and inadequate clinical results compared to many percutaneous repair techniques in the treatment of acute Achilles tendon rupture.

Material and Methods

A retrospective examination was made of a total of 52 patients who were admitted to our clinic and were diagnosed with acute Achilles tendon rupture between 2010 and 2015. Criteria for inclusion in the study were acute Achilles tendon rupture with a gap of 2-4 cm. Patients were excluded from the study if there was concomitant connective tissue disease, spontaneous rupture, a history of previous surgery around the ankle and age over 60 years. A total of 34 patients were included in the study.

Following the initial diagnosis according to the physical examination, routine dynamic ultrasonography (USG) was applied for diagnosis and determination of the rupture gap and tendon length. In the first evaluation, in the gap measurements made dynamically in all the plantar and dorsal flexion ranges if any gap was determined as >4cm at any point of the range of movement, the patient was excluded from the study.

All the patients were evaluated in respect of the time from trauma to surgery, etiological causes, affected side, postoperative AOFAS (The American Orthopaedic Foot & Ankle Score) and Tegner scores, cruris diameter, mean time to full weight-bearing, time of return to work, time to regain pre-trauma activity level and complications. Data were obtained from hospital medical records and the patient’s own statements.

Ethical Approval

Approval was obtained from Karabuk University Clinical Research Ethical Committee. The principles of the Helsinki Declaration and good clinical practice guidelines were followed. All patients were provided with informed consent.

Surgical Technique

All of the patients were placed in a prone position under spinal anesthesia, intravenous 1 gr ceftriaxone prophylaxis was administered perioperatively.

Exposure

Preoperatively, the gap, the suture entry points in the proximal and distal areas of the rupture and the estimated course of the sural nerve were marked on the patient with a sterile marker pen. Then making cutaneous and subcutaneous incisions, 4mm in length, in the defined suture entry points, the Achilles tendon was reached. At the lateral of the proximal side, by extending the most proximal suture point approximately 20 mm very slightly medially (approaching the tendon) from the other incisions, the sural nerve was by defining the course towards the distal, the proximity to the distal incision sites was evaluated (Figure 1).

Double Wrapped Suture Technique

A 2/0 PDS oval needle was straightened and entered between the skin and the gap and withdrawn from the skin opening closest to the proximal tendon on the same side. It was entered again from the same opening and passing transverse within the tendon and was withdrawn from the opposite skin opening. Entering again from the exit opening passing within the tendon, it was withdrawn obliquely from the opening above on the opposite side. In the same way, the needle was again entered from the exit opening and withdrawn transversely along the tendon from the opposite opening. By entering again from the exit point, it was withdrawn from the opposite next opening obliquely along the tendon. Taking care of the sural nerve, entering again in the same opening thread was withdrawn from the opposite skin opening along the tendon on the opposite side and in the same way, entries were made from the most proximal skin opening and by withdrawing from the skin incision area opened in the opposite gap, the free end of the thread was finished (Figure 2). While passing through the skin, the sutures were tightened and thus loops were created between each skin incision.

Another free suture was taken from these created loops from one side of the last 2 skin openings closest from the gap, so as to be fully wrapped in a circular manner 3 times around the loops and by passing within the tendon at the same level, was withdrawn from the opposite skin opening and again wrapped around the loop there (Figure 3). The same procedure was applied to the next opening. Then by pulling the looseness of the loops in the skin incision furthest from the gap, from the loop in the opposite middle skin opening, the suture was tightened and the loop disappeared (Figure 4).

In the same way, by pulling the sutures from the closest skin incision to the gap, the mid-level suture loops disappeared. Finally, the suture ends in the gap were pulled. The threads were held tight and knotted by tightening the sutures which were wrapped around the loop. The same procedure was made to the part of the Achilles tendon in the distal gap. The gap sutures were sutured on both sides at the same time by bringing the tendon ends close to each other while the foot was in maximum plantar flexion. When tying the sutures, the tendon was loose and at its shortest length, bringing the ends together by elongating the muscles without creating a gap in the rupture area, and without retracting the tendon, 6 knots were applied to provide fixation.

All the patients used a circular brace for 3 weeks postoperatively. After 3 weeks, a pneumatic adjustable angle walking brace was applied, and with the aid of this brace, partial weight-bearing was permitted for approximately 4 weeks and after the 6th week, full weight-bearing was permitted. The adjustable angle ankle brace was used for up to 7-8 weeks.

Results

Demographic data of the patients were given in Table 1. Of the defined major complications, tendon elongation was determined in 1 (2.9%) patient on USG. No re-rupture occurred in the patients. Of the defined minor complications during follow-up until the final examination, transient sural nerve pathology was determined in 2 (5.9%) patients, wound site haematoma in 1 (2.9%), loss of range of motion of 8.4°±1.8° at the final follow-up in 3 (8.8%) patients and suture granuloma in 1 (2.9%) patient.

Postoperative evaluations of the patients were shown in Table 2.

Discussion

In the surgical treatment of acute Achilles tendon rupture, two principal techniques are most widely used; open surgical repair and minimally invasive percutaneous repair. Neither of these techniques has been defined as the gold standard for the treatment of these ruptures. It has also been proposed that conservative treatment is among the options. However, in respect of re-rupture rates, surgical treatment results have been reported to be superior to those of conservative treatment [5,6]. Nonetheless, conservative treatment has been said to be superior to surgical treatment in respect of surgical complications such as wound infection, fistula formation, skin necrosis, suture reactions and sural nerve damage [5-7]. Some authors have reported that the postoperative re-rupture rates of conservative treatment modalities were similar to those of percutaneous repair and there was no statistically significant difference [8,9].

In a study by Hsu et al. comparing percutaneous and open surgery techniques, complications were determined at the rate of 8.5% in all the patients who received surgery and no statistically significant difference was determined between the groups in respect of complication rates [10]. In a biomechanical evaluation of percutaneous and open surgical repair techniques, similar results were reported and it was suggested that there was a tendency for a longer postoperative rehabilitation period for clinical recovery in the percutaneous techniques compared to the open surgery techniques [11]. There are studies which have reported that there is a greater rate of sural nerve damage in the open surgical repair techniques [12].

Although there are many treatment options for the treatment of acute Achilles tendon rupture, there are new techniques continuously described by various authors and satisfactory results have been reported [13-17]. However, in the current approaches, no treatment algorithm has yet been widely shown to have any superiority over other techniques. Studies in the literature have reported conflicting results.

Several industrially-produced assistive instruments for the treatment of acute Achilles tendon rupture are available on the market. Sufficiently satisfactory clinical results have been reported with these instruments [10,11]. However, as the anatomic course of the sural nerve shows different variations, it has been suggested that the nerve protective effects of these instruments are weak [18,19]. In the routine percutaneous techniques applied, as the crossing point of the sural nerve to the Achilles tendon lateral nerve shows different variations and is affected by the extremity morphology of the individual, it can be said to be at risk [20].

In Tansel technique which was presented in this study, there were two features which are advantageous in comparison to other percutaneous applications. The first of these was that because of the mini skin incisions opened for the passing of the sutures, by extending the incision section in the area where the sural nerve crosses the Achilles tendon lateral nerve, the sural nerve can be explored, thus providing visual contact and complete protection of the nerve. In the current series, no sural nerve damage was seen to occur with this technique of percutaneous repair of acute Achilles tendon rupture. In literature, sural nerve damage has been reported at 13% with percutaneous Achilles tendon repair techniques [21]. Thus, by extending one section from the multiple skin incisions opened for passing the sutures, a strong advantage was provided in respect of nerve damage. The second feature which could be presented as an advantage of the technique originated from the suture technique.

In a biomechanical evaluation of the suture techniques used in open repair techniques and percutaneous repair techniques, it was reported that the open repair technique was approximately twice as strong [22]. This has created a disturbing problem for some authors. In addition to the single suture technique used in classic percutaneous techniques, a second suture wrapped over the main bearing suture rather than the contact surface from passing a straight suture over the same suture line provided suturation with an increased holding force. This is known to reduce both re-rupture rates and prevent loss of plantar flexion force by preventing postoperative tendon elongation.

In the surgical repair of acute Achilles tendon ruptures, in the postoperative 1st and 3rd weeks, softening associated with tendomalacia which occurs biomodally as a cause of stripping over the tendon, sometimes without breakage in the suture materials, may be a cause of the failure of the repair. Following surgical repair, the suture holding capacity of the tendon increases with intrinsic healing in the 4th week [23, 24]. Therefore, the activity and survival of the suture material in the first 3 weeks is of importance. This problem, which is encountered in early rehabilitation, originates from stripping rather than breakage of the suture from the tendon [25].

In the suture technique in this study, in two levels of the main suture fixing the tendon, a second supporting suture was used by wrapping around the suture (Figures 4 and 5). With the second suture providing support such as in the form related to the stamp effect of the screw which is placed or like the knot in the entry and exit points of the main suture to the tendon, stripping of the sutures over the tendon, particularly during the high risk time of softening and sliding and embedding within the tendon are prevented. Therefore, both clinical and cosmetic advantages can be provided by a surgical procedure with strength close to the strong stabilization obtained in open surgery, which is less invasive and has lower complication rates.

Conclusion

Treatment of acute Achilles tendon ruptures with the sural nerve protective wrapping suture technique reduced the incidence of nerve damage which was a problem in percutaneous repairs. Furthermore, this technique provided successful results in resolving the problems of re-rupture and tendon elongation by providing a, particularly in the postoperative tendonmalacia stage. This technique is considered as an effective technique which can be used to resolve the inherent disadvantages of minimally invasive percutaneous repair.

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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Mutlu T, Satılmış AB. A novel suture technique in the percutaneous repair of Achilles tendon rupture (Tansel technique). Ann Clin Anal Med 2020;11(2):110-114

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Effects of compression stockings on pain, fatigue, and quality of life among female hairdressers with varicose veins

Rashid Heidarimoghadam 1, Mohammad Babamiri 1, Shiva Rastegari Yekta 2, Ghodratollah Roshanaei 3, Fakhradin Ghasemi 4

1 Research Center for Health Sciences and Department of Ergonomics, School of Public Health, 2 Department of Ergonomics, 3 Department of Biostatistics and Modeling of Noncommunicable Diseases Research Center, School of Public Health, 4 Department of Ergonomics, Occupational Health and Safety Research Center, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran

DOI: 10.4328/ACAM.6182 Received: 22.01.2019 Accepted: 25.02.2019 Published Online: 05.03.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):133-137

Corresponding Author: Mohammad Babamiri, Department of Ergonomics, Hamadan University of Medical Science, School of Public Health, PK: 6517838736, Hamadan, Iran. T.F.: 0098-8138380398 E-Mail: Mohammad.babamiri@yahoo.comORCID ID: https://orcid.org/0000-0002-0824-8567

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Aim: Varicose veins, is one of the complications of a long standing position. Female hairdressers are among those individuals undergoing prolonged standing during the day which can have negative impacts on their quality of life. The purpose of the present study was to evaluate the effects of compression stockings on quality of life among female hairdressers suffering from varicose veins in the lower extremities (limbs). Material and Method: The statistical population included all female hairdressers in the city of Hamadan referred to Mahdieh Clinic. Using simple random sampling method, 70 individuals were selected out of the hairdressers suffered from varicose veins and then they were divided into two groups of intervention and control. The intervention implemented in this study was the use of compression stockings. The participants completed three questionnaires as follows: the Aberdeen Varicose Veins Questionnaire, the Chronic Pain Grade Scale, and the Muscle Fatigue Questionnaire in Lower Extremities. Results: The results showed that intervention could affect the scores associated with pain and swelling as well as the scores assigned to muscle fatigue in the left and right lower extremities among the intervention group and the given values also declined by 1.68, 0.57, and 0.65, respectively. Moreover, the implementation of intervention had a negative impact on the scores for varicose veins in a way that it increased by 0.9 following the intervention. Discussion: The use of compression stockings had a positive effect on reducing pain and muscle fatigue, but apparently that effectiveness could not influence the quality of life in patients suffering from varicose veins.

Keywords: Varicose Veins; Compression Stockings; Quality of Working Life

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Introduction

Varicose veins as a vascular disease are taken into account as one of the most common health problems [1] that is often neglected until its serious symptoms are revealed. Such a disease is closely associated with prolonged standing; thus, the standing position of a job is among important factors affecting its development. This fact has been mentioned in many studies. In a study in Taiwan, the relationship between prolonged standing and varicose veins was confirmed [2]. There have been also various reports associated with the prevalence of varicose veins in different populations. It is estimated that the prevalence rate of varicose veins in adults varies between 7% and 40% in men and between 14% and 51% in women [1,3]. In another study, the prevalence rate of varicose veins was reported by 18.7% in Asian nations [4].

The important risk factors associated with such a vascular disease include gender, weight, family history, and the number of births [5]. The most important symptoms of the disease are feeling of heaviness in the legs, pain and swelling, fatigue, as well as dry skin and itching [2,5]. The varicose veins disease is graded into 1) normal varicose veins, 2) varicose veins and venous edema, 3) varicose veins and skin changes, 4) varicose veins and healed wounds, and 5) varicose veins and active wounds [6]. To deal with such a disease, home treatment procedures such as changes in lifestyle are firstly recommended which includes doing regular and daily exercises as well as reaching the ideal weight. Moreover, the use of compression stockings has been suggested as a treatment in this respect. Use of compression stockings is a simple home intervention which helps patients to reduce the symptoms of varicose veins in the legs. In this way, compression stockings improve blood circulation in the legs through increasing pressure. Such stockings are available in a variety of styles on the market and their main function is to compress the legs. Thus, care professionals can prescribe a pair of appropriate stockings for individuals suffering from varicose veins. Nevertheless, the effects of compression stockings in previous studies have not been consistent. For example, in a systematic review conducted on the effects of compression stockings in 2009, the results revealed ambiguities in terms of the beneficial effects of compression stockings on varicose veins [7]. In another study conducted in 2011, researchers also found similar results [8]. Such stockings are usually sold in medical equipment stores. In more serious cases of varicose veins, other treatment procedures such as sclerotherapy, laser therapy, surgery, and most recently the use of radio frequency device by physicians have been recommended [9].

Since hairdressers are among the workforce who has to work in a standing position for long hours during the day, they are exposed to the risk of varicose veins. Over the time, physical disabilities affecting an individual can reduce the quality of life and consequently lower their efficiency. Therefore, there is a need to review this issue and take measures in order to control and prevent such a vascular disease. As it was stated, one of the simple and low-cost interventions in this respect is wearing compression stockings but due to the conflicting results of the related literature concerning the effects of compression stockings; the present study aimed to examine whether the use of compression stockings can have effects on indicators associated with pain, swelling, fatigue, as well as scores for the types of varicose veins or not.

Material and Methods

Design and participant

This controlled randomized trial study was conducted among female hairdressers in the city of Hamadan referred to Mahdieh Clinic No. 2. A total number of 70 patients whose varicose veins disease had been diagnosed by physicians were selected through simple random sampling method and then they were assigned into two groups (intervention and control) of 35 individuals.

Instruments

In this study, quality of working life associated with varicose veins was measured via three indices of varicose veins, chronic pain, and muscle fatigue. The data collection instruments also included demographic properties questionnaire as well as three other questionnaires including Aberdeen Varicose Veins Questionnaire (AVVQ), Chronic Pain Grade Scale (CPGS), and Muscle Fatigue Questionnaire (MFQ) in Lower Extremities.

Aberdeen Varicose Veins Questionnaire (AVVQ)

This questionnaire was designed to assess the quality of life in patients affected with varicose veins which consisted of 13 items [10]. In a study conducted by Clem et al. in the Netherlands in 2009, the validity and the reliability of the original form and its Dutch translation were confirmed [11,12]. The Cronbach’s alpha coefficient was also used to determine the reliability of the questionnaire which was equal to 0.81 indicating desirable reliability for the given inventory.

Chronic Pain Grade Questionnaire (CPGQ)

The questionnaire contains 25 items. After reading each item, an individual can rate their pain on a six-point scale in which the options respectively include never, very low, low, average, high, and very high. Finally, the numerical values related to the options selected are summed. The content validity and reliability of the given questionnaire have been approved.

Muscle Fatigue Questionnaire (MFQ) in Lower Extremities

This questionnaire measures the amount of muscle fatigue in the lower back, posterior legs, and anterior legs in the left and right lower extremities. The respondents complete six items with 5 options including no fatigue, limited fatigue, moderate fatigue, very fatigued, and extreme fatigue. The questionnaire was adapted from a research paper entitled “Assessment of muscle fatigue associated with prolonged standing in the workplace” which was conducted by Isa Halim et al. in Malaysia in 2012 [13]. The Cronbach’s alpha coefficient was similarly used in this study to determine the reliability of the questionnaire which was equal to 0.88.

Following the completion of the given questionnaires, the compression stockings were delivered to the intervention group and the subjects were requested to wear them at their workplace and take them off only in their leisure time.

Intervention

The participants were asked to wear the compression stockings (ADOR, Faraz Gostar Farham co., Iran) during the work and put them out at the rest time. The stockings were of AD size which covered feet and lower legs. As mentioned before, the intervention period was three months. After a 3-month period, the subjects were asked to complete the questionnaires for the second time. It should be mentioned that all participants completed the study.

Data analysis

The data analysis was performed using the SPSS18 software including descriptive indices of mean and standard deviation as well as paired-samples t-test. The research hypotheses were also tested with a confidence level of 0.05.

Results

As can be seen in Tables 1 and 2, no significant difference was found between the two study groups in terms of qualitative and quantitative demographic characteristics.

To evaluate the changes in the pain, muscle fatigue, and quality of life of patients before and after intervention in both groups, paired-samples t-test was used and results are demonstrated in Table 3.

According to the findings presented in Table 3, the scores of varicose veins increased but the rise in such values was not significant. Moreover, the mean scores for pain and fatigue on the left side and fatigue on the right side in lower extremities significantly decreased in the intervention group.

Discussion

Varicose veins in lower extremities are considered as one of the most common occupational diseases that occurdue to long-term standing and it is intensified over time. Given the working conditions of female hairdressers in which they have to experience prolonged standing during the day, the present study aimed to examine whether the use of compression stockings can help in relieving varicose veins as a vascular disease in this community or not.

The results of this study indicated that the prevalence rate of varicose veins disease among female hairdressers was 34.5%. In the same findings by Zhigler et al., the prevalence rate of chronic venous diseases in the lower extremities among hospital personnel were reported equal to 34% [14] . In another investigation in the city of Shanghai in China by Sun JM in 1990 on 30712 workers over 15 years old in various industries, a prevalence rate equal to 83% was observed in terms of varicose veins in the lower extremities [15] . In a further study conducted by Sharifnia et al. (2010), a high prevalence rate of varicose veins in the lower extremities was reported in nurses [16] . Moreover, Touchson et al. found that the prevalence of varicose veins varied from 2% to 56% in men and 1% to 73% in women [17]. In the present study, the mean difference of pain scores reduced before and after the intervention in the intervention group using compression stockings. The fatigue scores of left and right sides as well dropped compared to the pre-intervention stage. But scores assigned to varicose veins increased in individuals wearing compression stockings. Therefore, it was concluded that compression stockings had a positive effect on levels of pain and fatigue, but they had a negative impact on varicose veins and led to a rise in scores assigned to varicose veins. In a similar study, Palfreyman S et al. reached uncertainties associated with the beneficial effects of wearing compression stockings in order to reduce the rate of progression or prevent recurrence of varicose veins which could not support published evidence although compression stockings have been widely used in the prevention of symptoms associated with this vascular disease. The evidence on the usefulness and effectiveness of compression stockings in this respect have been also ambiguous and published research papers in this field have obtained conflicting results [7]. Shingler S et al. also concluded that compression stockings were not sufficient as the only treatment and they could only reduce symptoms such as pain and itching as reported by the study subjects [18].

Higher scores assigned to varicose veins in these patients following intervention through compression stockings may be also due to the increased public awareness towards the disease and also their greater sensitivity to this health problem. Since at the onset of this study it was found that a lot of subjects did not have any knowledge of varicose veins disease; they were likely to get more sensitive to the symptoms of such a disease in their limbs while completing the questionnaires over the 3 months of intervention. Undoubtedly, this community would spend much more time at workplace over the year than the normal working time and as this 3-month intervention occurred at the peak of their work, all these issues could have their own effects on higher scores for varicose veins despite the use of compression stockings.

In conclusion, the findings of this study revealed that compression stockings as an ergonomic intervention in terms of reducing pain and fatigue in the lower extremities in jobs involving prolonged standing during the day could be useful and functional. However, compression stockings are not adequate in terms of treatment or prevention of the development of varicose veins and their effects are reduced as the degree of varicose veins is increased. In other words, varicose veins progression leads to lower effects of compressionstockings. Thus, individuals working in the medical field and treatment of patients with varicose veins are recommended not to prescribe compression stockings for individuals suffering from advanced and chronic degrees of varicose veins disease. In these individuals, other interventions such as sport protocols, aerobic training can be used, which their effectiveness on cardiovascular system and body fitness in previous studies have been confirmed [19,20]. Thus, such compression stockings can be used only in the early and mild stages of the disease and in order to prevent infection among individuals with a family history of such a disease and also people with prolonged standing or pregnancy, or even those subjected to other risk factors.

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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How to cite this article:Heidarimoghadam R, Babamiri M, Yekta SR, Roshanaei G, Ghasemi F. Effects of compression stockings on pain, fatigue and quality of life among female hairdressers with varicose veins. Ann Clin Anal Med 2019; Ann Clin Anal Med 2020;11(2):133-137

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Kinematic assessment of distance and time parameters for children with cerebral palsy during the gait cycle

Mohamed N. AlKhouli 1, Anees S. Ghait 2, Amr A.Abogazya 3

1 Department of Growth&Development disorders and its Surgery in Pediatric, Faculty of Physical Therapy, Delta University for Science and Technology, 2 Department of Biomechanics, Faculty of Physical Therapy, Kafrelsheikh University, 3 Department of Basic Science, Faculty of Physical Therapy, Kafrelsheikh University, Egypt

DOI: 10.4328/ACAM.6180 Received: 22.01.2018 Accepted: 14.03.2019 Published Online: 27.03.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):129-132

Corresponding Author: Mohammed N. Alkhouli, Department of Pediatrics, Faculty of Physical Therapy, Delta University for Science and Technology, International Coastal Road, Gamsa, Mansoura, Egypt. E-Mail: dr_alkhoulim@yahoo.comORCID ID: https://orcid.org/ 0000-0002-2394-1183

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Aim: Cerebral palsy (CP) is a developmental disorder of motor, psychological and emotional functions. Its most typical symptom is a walking disorder. The aim of this study was to analyze children’s walking abilities based on basic kinematic parameters, in addition, to identify and quantify distance and time pa-rameters in hemiparesis cerebral palsy children by three-dimensional kinematic gait analysis. Material and Method: Kinematic motion analysis system during gait cycle was done in motion analysis lab in Delta University for Science & Technology which equipped with walkway and six infrared cameras operating at 60 HZ frequency. Gait analysis of (15) hemiparesis and (15) healthy children was quantified by the new anatomically based protocol of three dimensional kinematical gait analysis. Kinematic parameters in hemiparesis cerebral palsy and healthy children were identified and calculated. Results: The results of this study revealed that there was significant decrease in the speed of walking, stride length, step length and numbers of steps per unit of time (cadence) in the group of hemiparesis children during gait cycle compared to healthy children. Discussion: Current research proved that the patterns of walking of the paretic and non-paretic sides of hemiparesis CP children were different compared to healthy children.

Keywords: Cerebral Palsy; Walk, 3D Kinematics Analysis

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Introduction

Cerebral palsy (CP) describes a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, cognition, communication, perception, and/or behavior, and/or by a seizure disorder [1-10].

Cerebral palsy (CP) is a relatively prevalent neurological disorder in children, occurring in (1.5 – 2.0 per 1000) live births. Impairment of upper limb movements, characterized by increased trajectory duration, reduced speed (peak and average), increased variability and less straight hand trajectories, is present in up to 80% of children with CP [9].

The damage in (CNS) central nervous system is caused by various etiological factors. The most typical symptoms of CP are the disorders of movement activities of various degrees and different locations [4].

These are most often contractures of limbs and trunk, mostly of spastic type, balance disorders and motor hyperactivity [7].

A special disorder is the restriction of walking efficiency or a child’s inability to walk on its own. The lack of control is especially serious within the anklebone joint and foot [5].

The pathological mechanism of the foot movement is mostly visible in the stance phase of the gait cycle and it results from the foot structural deformation and/or contracture of muscles [6].

A child suffering from CP and experiencing the contractures of lower limb muscles often walks on its toes and distorts the foot in the inward direction [2,8].

In such cases, doctors can apply appropriate rehabilitation treatment or surgical operation consisting of TAL (Tendon-Achilles Lengthening). The operation does not always bring the expected results [3].

Human gait is a form of bipedal locomotion classify as continual state of imbalance caused by the integration between center of gravity (COG) and center of pressure COP. Every individual must constantly maintain postural stability while propelling himself forward to move in space [2].

From biomechanical point of view, the pattern of movement of human gait involves complex movement and requires coordination between sub phases of swing and stance phase during each gait cycle, which induce oscillations of (HAT) head, arms and trunk in both sagittal and coronal planes [1].

CP children have different levels of deficits in stability, which is a major component of the gait disorder [24].

Lack of scientific research in evaluation of the kinematic parameters of gait in children with hemiparetic cerebral palsy, so the purpose of this study is to evaluate and develop a suitable treatment plan of treatment for these cases.

Therefore, the aim of this study was to analyze children’s walking abilities based on basic kinematic parameters in addition to identify and quantify distance and time parameters in hemiparesis cerebral palsy (CP) children by three dimensional kinematical gait analysis system which may help clinicians in making treatment decisions.

Material and Methods

An Ethics Committee of Delta University for Science and Technology approved the study. Written consent and Volunteer Information Sheet had authorized to Child’s parents. All information about the aim of the study, its benefits and risks and their committee with regard to time and money have mentioned in these forms.

Subjects

The examinations of children with CP were carried out in the center for children with CP in the faculty of physical therapy at the Delta University for Science & Technology outpatient clinic and on the other hand, kinematic motion analysis during gait cycle was done in motion analysis laboratory at the Delta University for Science & Technology.

The study group consists of fifteen (15) hemiparesis CP children participated in our study with age range of (5-12) years, among them (10) were right hemiparesis and (5) left hemiparesis. The age, weight, and height of hemiparesis children were 7.6 ± 2.1 years, 26.3 ± 11.4 kg, and 124.2 ± 24.3 cm respectively.

Children with hemiparesis in the study group had no history of lower limbs surgery and absence of treatment by drugs or medication in the last year. Children with hemiparesis can walk without help or support; in addition, all patients were leg-dominant lower limb primarily involved with relative sparing of the upper limb [20].

The control group consists of fifteen (15) of healthy children; their age, weight, and height were 7.9 ± 6.1 years, 27.8 ± 16.1 kg, and 125.7 ± 11.7 respectively. The control group selection criteria included no history of cardiovascular or locomotors diseases. They had a normal degree of freedom in their joints motion, muscle power, and had no postural or balance defect.

The instrument used for gait analysis:

Gait analysis of (15) hemiparesis and (15) healthy children was quantified by the new anatomically based protocol of three-dimensional kinematical gait analysis system. Distance and time parameters in hemiparesis cerebral palsy and healthy children were identified and calculated.

Kinematic motion analysis system during gait cycle was done in motion analysis laboratory at the Delta University for Science & Technology which is equipped with a walkway and six infrared cameras operating at 60 HZ frequency. In addition, two Force plates embedded at the center of the walkway were used to determine the foot contact and foot-off events synchronized with the system made from motion analysis Company (Helen Hayes model).

Statistical analysis: The data, which collected from the control group and the study group, represent the statistical analysis by using the paired t test.

Sample size was almost small (N=15) because of the delimitation of study that the hemiparetic cerebral palsy children was not allowed and was not always feasible so the power analysis was low. And the confident interval was 95%.

Results

There was no significant difference between the study group (hemiparesis children) and control group (healthy children) in regards to height, weight, and age.

A p -value < 0.05, compared between paretic and non-paretic sides of hemiparesis CP children.

Our study proved that the pattern of walking of the paretic and non-paretic sides of hemiparesis CP children were different compared to healthy children.

On the paretic side of hemiparesis, CP children there was observed short duration of stance phase percent (weight bearing or supporting phase) in comparison with a non-paretic side of hemiparesis CP children and healthy children (P<0.05).

The results of this study revealed that there was a significant decrease in the speed or velocity of walking, stride length, step length and numbers of steps per unit of time (cadence) in the group of hemiparesis CP children during gait cycle compared to healthy children (P< 0.05).

The width of BOS markedly increased in hemiparesis CP children compared to healthy children. On the other hand, there was no significant difference in the double support time (DLS) in both study and control groups.

Discussion

The result of this study revealed that there were a significant decrease in walking speed, stride length and Cadence in hemiparetic cerebral palsy group compared to healthy children group.

On the paretic side of hemiparesis CP children was observed short duration of stance phase percent (weight bearing or supporting phase) in comparison with non-paretic side of hemiparesis CP children and healthy children (P < 0.05).

About 33% of CP children have hemiplegia with weakness and spasticity predominantly affecting one side of the body and the deficit concerns the motor ability of the body’s side opposite to the site of cerebral lesion [16, 17& 18].

Our study was almost agreed with the study examined the Muscles that commonly spastic in children with CP including (iliopsoases ,hamstrings ,quadriceps, gastrocnemius, soleus, and calf muscles); in addition to the ankle muscles like tibialis anterior. Spasticity of these muscles adversely affects the energy efficiency required for functional balance, and hence affects the normal gait cycle [15].

Some studies examined the distance and time parameters for children with cerebral palsy during gait cycle, one of these studies done to compare between the right and left hemiplegic pattern of walking using three-dimensional kinematical gait analysis to analyze the difference in pattern of walking. The results of this study proved that right hemiplegic gait walked with higher speed than left hemiplegic gait [21].

Another study done to assess the distance and time parameters for children with cerebral palsy during gait cycle and reported that, hemiparetic children walked more slowly with shorter step length, longer swing time than normal children and decreased cadence [23] .

Another research done to analyze the gait strategy of uninvolved limb in children with spastic hemiplegia and reported that uninvolved limbs had significant longer stance phase, knee joint more flexed, hip joint presented high flexion at the beginning of gait cycle and ankle kinematics presented values closed to normal . The results of this study support previous observations which showed that analysis of walking movement pattern of hemiparetic CP children presents unique motor strategy different from healthy subjects [22].

Current study proved that, the pattern of walking of the paretic and non-paretic sides of hemiparesis CP children were different compared to healthy children.

The results of this study revealed that, there was significantly decrease in the speed or velocity of walking, stride length, step length and numbers of steps per unit of time (cadence) in the group of hemiparesis CP children during gait cycle compared to healthy children (P< 0.05).

Width of BOS increased considerably in hemiparesis CP children compared to healthy children. On the other hand, there was no significant difference in the double support time (DLS) in both study and control groups.

Walking velocity is the product of step length and cadence, hence reduction in either one parameter may account for gait slowing and it might be considered a strategy in order to obtain a better stability and equilibrium during walking.

The shorter duration of stance phase (weight bearing or supporting phase) on the paretic side compared to non-paretic CP and healthy children is related to the deficient ability to load and transfer weight through their affected leg. It has been proposed that improving weight transfer through the affected leg during progressive training with the feet of the patients placed in a variety of diagonal position may improve gait symmetry in hemiplegic [19].

Finally from clinical point of view, the identification of the kinematic parameters either distance or time variables in hemiparetic CP children can be helpful in the diagnosis and allow physiotherapists to suggest what exercise program should be develop in order to improve the pattern of walking.

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: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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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AlKhouli MN, Ghait AS, Abogazya AA. Kinematic assessment of distance and time parameters for children with cerebral palsy during the gait cycle. Ann Clin Anal Med 2019; Ann Clin Anal Med 2020;11(2):129-132

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Prognostic significance of pretreatment lymphopenia in colorectal cancer

Dilek Erdem 1, Idris Yucel 2, Mahmut Buyuksimsek 3, Bahiddin Yilmaz 4, Guzin Demirag 4

1 Department of Medical Oncology, Bahcesehir University Medical School, Samsun Medical Park Hospital, Samsun, 2 Department of Medical Oncology, Samsun Medicana International Hospital, Samsun, 3 Department of Medical Oncology, Cukurova University Medical School, Adana, 4 Department of Medical Oncology, Ondokuz Mayıs University Medical School, Samsun, Turkey

DOI: 10.4328/ACAM.6158 Received: 09.01.2019 Accepted: 18.02.2019 Published Online: 18.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):95-98

Corresponding Author: Mahmut Buyuksimsek, Department of Medical Oncology, Cukurova University Medical School, Adana, Turkey.GSM: +905368622026 E-Mail: mahmutbuyuksimsek@gmail.com ORCID ID: https://orcid.org/ 0000-0001-6356-9059

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Aim: It is proven that pretreatment lymphopenia is a biomarker for poor prognosis at late stage solid malignancies. The purpose of the present study is to investigate the effects of pretreatment lymphopenia on prognosis and hematological toxicity in patients treated with first step systemic chemotherapy. Mate-rial and Method: Lymphocytes were counted for 386 patients with colorectal cancer before treatment. Overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) were calculated. Results: Three hundred and eighty-six patients were included in the study. The mean age was 57.4. One hundred and sixty patients were women (41%), 226 were men (59%). Mean pretreatment lymphopenia was 1964/microliter. There was no relation between lymphopenia and age, gender, performance status, the presence of metastasis at the time of diagnosis, the purpose of chemotherapy either being adjuvant or metastatic and progression into hematological toxicity (p >0.05). One-, two- and five-year overall survival was significantly lower in patients with lymphopenia when considering all patients (p:0.033). Lymphopenia was present in 27 patients (7%) who had metastasis at the time of diagnosis and 13 of them deceased in the follow-up. One-, two- and five-year overall survival was significantly lower in those patients with metastasis who have lymphopenia (p <0.043). Discus-sion: The present study supports that pretreatment lymphocyte count in colorectal cancer can be a simple yet useful prognostic and predictive marker. Overall survival found to be significantly lower in patients with low pretreatment lymphocyte counts (p <0.05). To the best of our knowledge, the present study has the largest patient population in the literature which investigates the relationship between colorectal cancer and lymphopenia.

Keywords: Colorectal Cancer; Lymphopenia; Prognosis

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Introduction

Colorectal cancer is an important health issue as being the third most common cancer diagnosed and the second leading cause of cancer-related deaths. Several prognostic factors such as local invasion, regional lymph node involvement, the presence of micrometastasis, and vascular invasion are defined. Most of these factors are used during pathological staging [1]. The relation between the immune system and cancer is known for quite a long time. Lymphocytes are the most important component of the immune system. The decrease in lymphocyte count can lead to immune system deficiency. The relation between cancer and lymphopenia has been investigated in several different studies and it is shown that patients with lymphopenia have a poor prognosis [2]. The purpose of the present study is to investigate the prognosis of patients with colorectal cancer using an easy-to-use and cheap marker, lymphocyte count, at the time of the diagnosis.

Material and Methods

Data of colorectal cancer patients who had been admitted to our center for 15 years were retrieved. Three hundred and eighty-sixpatients diagnosed with colorectal carcinoma and who did not have chemotherapy, radiotherapy or chemo-radiotherapy, granulocyte colony stimulating factor (G-CSF) for primary prophylaxis, HIV infections or bone marrow involvement, a secondary malignancy but had first chemotherapy and over 18 years of age were included in the present study. Age, gender, performance status, type of surgery, location of primary tumor, stage at diagnosis, purpose of chemotherapy, number of chemotherapy regimen, name of chemotherapy regimen, presence or absence of metastasis at diagnosis, location of metastasis at diagnosis, metastasis in the follow-up and if present, its location, relapse status are investigated retrospectively by scanning patient health records. Pretreatment leucocyte and lymphocyte counts were recorded, and it was assessed whether hematological toxicity developed or not, and if developed, the type of the toxicity, the degree of hematological toxicity and at which regimen and occurrence of additional toxicity were noted. Response type of treatment, disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) are calculated. Duration of follow-up and whether they are alive were checked. Lymphopenia was defined as lymphocyte counts lower than 1300/microliter in our laboratory. The assessment of hematological toxicity was done according to the World Health Organization (WHO) toxicity criteria. The TNM Classification system is used for staging the disease. Preferred staging system in colorectal cancers is TNM Classification which formed by the American Joint Committee on Cancer (AJCC). This system enables staging cancer according to tumor dimensions and depth of invasion, the involvement of lymph node and metastasis. The system is being maintained and updated periodically [3]. The data were statistically analyzed using SPSS 17.0. Statistical analyses were performed by the Kaplan-Meier, the Chi-Square and the Student’s t- tests and p<0.05 value was accepted as statistically significant.

Results

One hundred and sixty of 368 patients were women (41.5%), 226 were men (58.5%). The mean age was 57.4 (21-81 years). Distribution of the tumor localizations is shown in Table 1.

There was no stage I patient among our cohort. There were 93 stage II (24.1%), 158 stage III (40.9%), and 135 stage IV patients. There was no metastasis at the time of diagnosis in 251 patients (65%). One hundred and twenty-six patients (32.6%) had one or two, 10 patients (2.6%) had three or more metastases. 106 patients (27.5%) had liver metastasis among 135 patients (35%) with metastasis at the time of diagnosis. At the time of diagnosis 87 patients (22.5%) had lymphopenia. Overall survival rates for the patients with or without lymphopenia are shown in Table 2.OS rates were statistically lower for the patients with lymphopenia at diagnosis (p:0.033).

Although DFS is shorter in the group with lymphopenia when 5-year disease-free survival according to lymphocyte counts at diagnosis compared, it was not significantly different (p:0.058). There was no significant difference in progression-free survival (PFS) when both groups with or without lymphopenia are compared (p:0.55). There was no significant difference in terms of age, gender, mean age, performance status, and metastasis at diagnosis, whether chemotherapy is adjuvant or palliative, the occurrence of hematological toxicity when both groups with or without lymphopenia are compared (p>0.05) (Table 3).

While 280 patients (72.5%) had no hematological toxicity, 106 patients (27.5%) developed toxicity. Types of hematological toxicity observed in our patients are shown in Table 4.

When assessed the severity of hematological toxicity among 106 patients (27.5%) who developed hematological toxicity, 66 patients (17.1%) had grade 1-2, 34 patients had (8.8%) grade 3, and 6 patients (1.6%) had grade 4 toxicities. A comparison between patients who developed grade 3-4 toxicity and others (no toxicity and grade 1-2 toxicity) are shown in Table 5. Grade 3-4 toxicity was significantly higher in patients received palliative chemotherapy when compared with the patients who received adjuvant chemotherapy.

In the group of 135 patients with metastasis, 13 patients among 27 patients who had lymphopenia, deceased at diagnosis. One hundred and five patients who had metastasis at diagnosis did not have lymphopenia and 31 of them deceased during the follow-up. There was a significant difference among the two groups (p:0.043). OS status according to lymphopenia for the patients with metastasis at diagnosis is shown in Table 6.

Discussion

In order to estimate the prognosis, several clinical and pathological factors are defined; these can be features belonging to tumor (dimension of tumor, stage, molecular changes, local invasion, lymph node involvement, and vascular invasion), patient (age, performance status, inheritance of susceptibility, gender, ethnicity, and deficiency of vitamin D, obesity, and coronary artery disease), nature and quality of the therapy [4].

It is shown in several studies that lymphocytes play as positive regulators of immune response. In addition to ensuring host response against infection and inflammation, they are quite effective cells against cancer survival [5].

Lymphocyte count can be an indicator for host immune response. Prognosis of cancer depends on the aggressivity of tumor and immune response and the relation between lymphocyte count and cancer prognosis has been a long-standing research subject [6]. Several hypotheses has been suggested about the etiology of lymphopenia in cancer. Factors such as bone marrow involvement, cachexia, and hypoalbuminemia can contribute but the most acceptable two hypotheses suggest that lymphopenia is caused by the destruction of lymphocytes by tumor cells and/or deterioration of lymphocyte pool in cancer cells. Besides immune weakness, lymphopenia in cancer patients can also be related tochemotherapy toxicity, decreased response to chemotherapy, tumor progression, poor prognosis, and shortening of survival [7-9].

The relation between pretreatment lymphocyte counts and chemotherapy toxicity, survival and other parameters in solid and hematological malignancies (breast cancer, melanoma, cervical cancer, renal tumor, head-neck tumors, and lymphomas) are studied [10-13].

Although it changes due to the laboratory differences, the threshold value for lymphopenia is usually defined as <1000 /microliter. We accepted <1300/microliter as a threshold value. At the time of diagnosis, 22.5% of our patients had lymphopenia and this was compatible with the literature (19%,22%,28%) [14-16].

Mean age was similar in two groups (57.3 years/57.4 years) and there was no significant difference between lymphopenia and mean age. While there are similar results in the literature [17], there are studies which show that there is a significant relation between lymphopenia and age [18-20].

Development of hematological toxicity in cancer is a factor that shortens overall survival. Several different factors such as age, weight, gender, performance status, dietary status, organ functions, serum albumin and bilirubin levels, polymorphisms, drug application method have been defined in order to define hematological toxicity of chemotherapy in colorectal cancer patients [21].

In the present study, 27.5% of patients developed hematological toxicity and this rate is similar to the literature (% 10-49).

In the present study, lymphopenia did not increase hematological toxicity. However, a similar study investigating the relationship between colorectal cancer and lymphopenia showed that grade III-IV toxicity was related to lymphopenia at the time of diagnosis.

It would be significant to detect whether lymphopenia in cancer progression is a result or a cause. In some studies, correction of lymphopenia ensured full remission in solid malignancies with lymphopenia.

In the present study, the relationship between PFS and lymphopenia could not be shown. However, DFC and lymphopenia were related although it was not statistically significant; DFS was found to be better in patients without lymphopenia. In similar studies, DFS and PFS are in a significant relationship with lymphopenia. The most important result of the present study is that it proves the relationship between lymphopenia and overall survival similarly to previous studies [22,23].

Shorter one-, there-, five-year overall survival rates were detected in patients with lymphopenia likewise in other studies.

Shortening of survival in colorectal patients with lymphopenia is attributed to several different reasons. The first of these views is that host immunosuppression caused by lymphopenia decreases the response to therapy. Similarly, loss of antitumor-specific immune response due to lymphopenia can also trigger tumor progression. The other possible cause for shortening of survival is the occurrence of febrile neutropenia and related morbidity. In spite of the fact that only four among 106 patients had febrile neutropenia, it is observed that these patients could not receive their treatments on time and inadequate amounts due to dose restrictions. Prognosis of these patients was also poor as lymphopenia increased immunosuppression.

The advantage of the present study in which we obtained similar to literature lymphopenia and colorectal cancer survival rates is the excessive number of patients. The most important limitation of the present study is that the patients formed heterogeneous groups and received different regimens of chemotherapy.

In the light of the present study, it is recommended to form more homogenous groups and investigate patients who have similar chemotherapy regimens. It is going to play a critical role to show which particular lymphocyte subgroup decreased in colorectal cancer patients with lymphopenia, in order to confirm the results of the present study and bring in a correct follow-up parameter to the literature.

Conclusion

Change of overall survival because of lymphopenia is highlighting the prognostic importance of lymphopenia. Change of hematological toxicity due to lymphopenia suggests a predictive role of lymphopenia. In the light of this information, we can suggest that lymphopenia has a prognostic importance in colorectal cancer patients. Although hematological toxicity was not found in patients with lymphopenia, this needs to be investigated in aforementioned homogenous patient cohort.

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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Erdem D, Yucel I, Buyuksimsek M, Yilmaz B, Demirag G. Prognostic signifi-cance of pretreatment lymphopenia in colorectal cancer. Ann Clin Anal Med 2020;11(2):95-98

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The reliability of measurements with the spinal mouse device in frontal and sagittal planes in asymptomatic female adolescents

Erdem Demir, Nevin Atalay Guzel, Gamze Cobanoglu, Nihan Kafa

Department of Physiotherapy and Rehabilitation, Gazi University, Faculty of Health Sciences, Ankara, Turkey

DOI: 10.4328/ACAM.6201 Received: 28.02.2019 Accepted: 16.03.2019 Published Online: 27.03.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):146-149

Corresponding Author: Erdem Demir, Department of Physiotherapy and Rehabilitation, University, Faculty of Health Sciences, Ankara, Turkey.GSM: +905055615512 E-Mail: fztedemir@gmail.comORCID ID: https://orcid.org/ 0000-0002-0247-9006

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Abstract

Aim: The aim of this study is to investigate the reliability of the Spinal Mouse device in both frontal and sagittal measurements in asymptomatic female adolescents. Material and Method: A total of 28 female students aged 15-18 (16.29 ± 1.08) in high school equivalent education institutions in Antalya were in-cluded in the study. Measurements were performed with the Spinal Mouse device in both frontal and sagittal planes with a one-week interval. The reliability of the two measurements was evaluated using the intraclass correlation coefficient (ICC). Results: In this study, the test-retest results of the thoracic and lumbar region measurement in the frontal plane were found to be moderately reliable (ICC: 0.591-0.665), and the test-retest results of the thoracic and lumbar region in the sagittal plane showed good reliability (ICC: 0.867-0.876). Discussion: In this study, the test-retest results of the thoracic and lumbar region measure-ments in the frontal plane were found to be moderately reliable. The test-retest results of the thoracic and lumber curves in the sagittal plane showed good reliability. In the light of these data, we believe that, if the application principles of the device are implied carefully, the Spinal Mouse device is a practical and reliable device that can be used by physiotherapists in field screening and in clinical assessment of spine problems.

Keywords: Spinal Mouse; Scoliosis; Frontal; Sagittal; Reliability; Spine

Full Text

Introduction

The three-dimensional deviation of the vertebral column greater than 10 degrees in the frontal plane is referred to as scoliosis. Adolescent idiopathic scoliosis (AIS) is a spinal deformity seen in 2.5% of the population. In literature, it has been reported that scoliosis is seen in 2-4% of children aged between 10 and 16 years. Progressive scoliosis can lead to deformities and cosmetic problems [1,2].In adolescents, considering the effects of heavy school bags on the musculoskeletal system, it is better understood that regular screening in schools is important in the diagnosis and treatment of scoliosis [3]. Measuring the Cobb angle is the most commonly used method in the diagnosis of scoliosis [4]. Although there are methods of evaluation with low-dose radiation such as the EOS 2D / 3D vector analysis systems, the Cobb angle is still the most valid method of measurement. The progression of AIS is usually rapid, therefore, patients with AIS should be assessed routinely and often. Consequently, patients are frequently exposed to radiation in order to measure the Cobb angle [5,6,7,8,9]. This situation has led researchers to seek different assessment methods that do not emit radiation. The inclinometer, flexiruler, goniometer, kyphometer, ultrasound and other computer-assisted systems are some of the leading non-invasive and radiation-free methods [10,11,12].

The Spinal Mouse is a non-invasive device that measures the curvatures of the vertebral column in the frontal and sagittal planes [13,14]. It can give detailed information about the positions of each vertebra, as well as their position relative to each other, without generating any medical risks or emitting radiation. The data obtained is transferred instantly to the computer which connects to the device via Bluetooth connection. The obtained data can be easily interpreted using the Spinal Mouse software.

Validity and reliability studies of the spinal mouse are present in literature; however, it is noteworthy that studies on the reliability of the measurements in the sagittal plane are limited. Therefore, the aim of this study is to investigate the reliability of the Spinal Mouse device in both frontal and sagittal measurements in asymptomatic female adolescents.

Material and Methods

Twenty-eight asymptomatic female students aged 15-18 (16.29 ± 1.08) who are being studied at high school equivalent education institutions in Antalya were included in the study (Table I). Those who; had pain in the back and lumbar region in the past 3 months, those who had undergone surgery in these regions and those who had a body mass index (BMI) of 30 and above were excluded from the study.

Before the study, necessary permits were obtained from the district governorate, the national education directorate, the parents and the participating students. All of the parents and students were informed in detail about the procedures to be carried out. The necessary Ethical approval was obtained from University (document date and number: 11/10/2018-E.136654).

The measurements were performed by an experienced physiotherapist who had previously used the device. The body weights of the participants were measured using the Baurer bf-100 device (Manufacturer: Beurer GmbH Servicecenter Lessingstraße 10 b 89231 Neu-Ulm, Germany). The Spinal Mouse (Manufacturer: IdiagAG Mülistrasse 18 CH-8320 Fehraltorf, Switzerland) measurements were performed at a sampling rate of approximately 150 Hz at every 1.3 mm. Before the measurements were performed, the procedures regarding the measurements were explained and demonstrated to the participants. The measurements were taken with the Spinal Mouse in frontal and sagittal planes and were repeated by the same physiotherapist following exactly a one-week interval. In order to carry out the measurements in the frontal plane, the participants were asked to stand in a comfortable posture in standing position. The first measurement was completed by guiding the device at a constant speed over the spinous processes of the c7-s5 which were previously marked by the physiotherapist. Measurements in the sagittal plane were also measured from the marked area, as in the frontal plane. All measurements were recorded on a computer which had Spinal Mouse software. The recorded data were analyzed using the Spinal Mouse program and angular deviations between each vertebra were determined in both the sagittal and frontal plane. Additionally, segmental results were also reported by the program software (total scores of thoracal and lumbal regions). In this study, the results of the thoracic and lumbar region during upright position calculated by the Spinal Mouse’s original software (Idiag AG) were taken into consideration.

Statistical analysis

We evaluated the test re-test reliabilities with the intraclass correlation coefficient (ICC). The ICC values were graded from low reliability to high reliability between 0 and 1. Accordingly, ICC values were classified as 0.75<= good, 0.50-0.74 = moderate and 0.5>= poor [15].

Results

The demographic characteristics of the participants are shown in Table I. The test-retest results of the thoracic and lumbar region measurements were found to be moderately reliable in the frontal plane and a good reliability was found in the sagittal plane according to the ICC values (Table II).

Discussion

In this study, the reliability of the Spinal Mouse, which is a radiation-free device used frequently for clinical assesment of vertebral column in the last 10 years, was evaluated using ICC. As a result of this study, in adolescents with no defined musculoskeletal pathology who were between 15-18 ages; it was found that the Spinal Mouse device had good reliability in the measurements in the sagittal plane and moderate reliability in the measurements in the frontal plane.

It is known that the gold standard assessment method for the posture and range of motion (ROM) of the vertebral column is the X-Ray [14]. However, in situations such as AIS which require frequent radiologic assessments, clinicians are concerned on the negative effects of radiation, such as cancer [15]. This has led clinicians and researchers to seek new methods that are radiation-free, such as the Spinal Mouse. The Spinal Mouse device is a practical device that was created in the early 2000s as a result of these researches. The Spinal Mouse is guided through the spinous processes at a constant speed and transmits the data collected at every 1.3 mm to the computer at a sampling rate of approximately 150 Hz. The device provides information on the segmental and regional (thoracic and lumbar) position and mobility of the spine in the frontal and sagittal planes. Additionally, it also provides information on; the amount of inclination of the trunk to the left, right, back or front, the hip joint mobility and also about the length of the spine. The device records the movements in three planes in space by means of a gyroscope and transfers them to the computer via Bluetooth. The specific algorithm of the Spinal Mouse software makes the data obtained from the information obtained on the position of the vertebral column meaningful by interpreting this information on the computer. In the measurements performed in the frontal plane, the algorithm obtains the segmental angulation between two vertebrae accordingly; two vectors are drawn, one parallel to the top of the upper vertebra and the other parallel to the bottom of the lower vertebra. The result is obtained from the angular information obtained from the intersection of these two vectors in space. In the sagittal plane, the segmental angulation is also obtained from intersection of the two vectors of the upper and lower vertebrae. With the intersection of these two vectors, the segmental angle information in the vertical plane is obtained. Regional results are obtained from the combination of information from each segment (Thoracic and lumbar). With these regional results, comments can be made about the angular values of scoliosis, kyphosis or lordosis and progression can be followed in cases such as AIS.

In literature, there are few studies investigating the reliability of the Spinal Mouse device. In 2008, Kellis et al. performed measurements with the Spinal Mouse in the sagittal plane in 81 healthy boys aged between 8 and 12 years with three investigators who had never used the SM device before. Measurements were repeated 2 times. As a result of the measurements, parallel with our results, the Spinal Mouse device was found to be a reliable method in the assessment of the sagittal plane (Intraobserver ICC 0,61-0,96) [16]. In 2004 Mannion et al. measured segmental and total joint range of motion with a Spinal Mouse device on 20 healthy adult volunteers [13]. The measurements were performed on different days. 2 researchers performed 3 measurements in total and the ICC value was between 0.82 and 0.86. In the light of these results, Mannion et al. suggested that the device could be used for clinical data collection, and suggested further studies with larger groups in different regions and different ages. In the study performed by Ö Buyukturan et al., in 2018, the Spinal Mouse was found to be valid and reliable in the measurements of thoracic kyphosis and lumbar lordosis made in the sagittal plane in an asymptomatic geriatric group (68,12 ± 2,67 y) of 46 individuals (29 females and 17 males). However, they did not assess the reliability of frontal plane measurements on geriatrics [17]. Together with chronological aging, changes in; collagen structure and glycosaminoglycan (GAG) / proteoglycan ratios are observed [18]. A decrease in elastin fibrils occurs with age [13,18]. The fact that the tension of the skin structure is less in geriatric patients suggests that the reliability of Spinal Mouse measurements in the frontal plane may be found to be lower in the elderly who had low BMI, parallel to the findings of our study. In a study conducted by Ripani et al. on 26 volunteers, measurements of 2 repetitions were performed with the Spinal Mouse and with X-Rays. The measurements were performed by two researchers on the same day and also on different days. However, there was no information regarding the number of days between the two measurements and which planes the measurements were performed in. The researchers conducted the statistical analysis according to the results obtained from each vertebral segment. As mentioned previously, the Spinal Mouse device provides regional results as well as the position of the vertebrae in each segment. This situation increased the number of data in their study. Considering that the total test measurement variance has the greatest impact on the alpha coefficient, the increase in the total test measure variance in the studies of Ripani et al., may have led to a different result than the other two reliability studies. Additionally, Ripani and his colleagues formed a sample group of both students and of workers in different sectors. As it is known, heterogeneous samples often lead to more variable measurements and therefore to higher reliability [19]. Ripani et al., have reported in their article that the correlation between the measurements performed by the same researcher was higher. At the end of the study, they found a high correlation between the repeated measures of the researchers. (ICC = 0.879-0.995) [20]. Similarly, in a study conducted by Guermazi et al. in 2006, intraclass ICC was found to be higher than interclass ICC [21]. In their validity and reliability study of the Spinal Mouse in 2014, Ayşe Livanelioğlu et al., found that the measurements of the Spinal Mouse device in the frontal plane were valid and reliable (ICC = 0.879 Sp0.995). Livanelioğlu et al., conducted their study, unlike ours, on AIS patients (42 females, 9 males: 14.37 ± 2.89 years). When the results of these two studies are compared, the difference in the results of the lumbar region can be attributed to the fact that the population is different. Mikko Poussa and Guy Melli investigated the spinal mobility of subjects with AIS in 1992 and found that the mobility decreased in parallel with the severity of scoliosis [22]. In the study by Livanelioğu et al., the decrease in spinal mobility of individuals with AIS may have decreased the deviations in upright posture during measurement and may have led to a decrease in the ICC values. Livanelioğlu et al., found a high standard deviation between the measurements made by the researchers and attributed this to the attention of the researchers who performed the measurement. The ICC value that we found in our measurements supports this determination. High standard deviation between interobserver measurements and low standard deviation in intraobserver measurements emphasizes the importance of measurement standards. The experience of the investigator performing the measurements and the careful application of the measurement standards are the most important factors in order to obtain the correct results in measurements made with the Spinal Mouse device. Besides, it should be kept in mind that the error rate of the measurements made with the Spinal Mouse device is similar to the human-based error rate in x-ray devices which are accepted as the gold standard in scoliosis measurements [17,24]. Livanelioğlu et al. did not perform any measurements for the reliability of the measurements in the sagittal plane [23]. In this study, we performed the measurements in both sagittal and frontal plane. We found that the measurements in the sagittal plane showed good reliability, unlike the frontal plane. When the devices’ principles of measurement are considered, it was seen that during the measurements in the frontal plane, the device could slide laterally due to the elastic properties of the skin in subjects who were very thin and had very prominent spinal processes. However, in the sagittal plane, sliding of the device anteriorly or posteriorly was not possible. This may be the reason why measurements in the frontal plane were found to be lower than the sagittal plane measurements.

Limitation

The limitation of the study is that our sample group consisted only of female subjects.

Conclusion

In this study, the test-retest results of the thoracic and lumbar region measurements in the frontal plane were found to be moderately reliable. The test-retest results of the thoracic and lumber curves in the sagittal plane showed good reliability. In the light of these data, we believe that, if the application principles of the device are implied carefully, the Spinal Mouse device is a practical and reliable device that can be used by physiotherapists in field screening and in clinical assessment of spine problems. We suggest further studies with larger sample size.

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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Demir E, Guzel NA, Cobanoglu G, Kafa N. The reliability of measurements with the spinal mouse device in frontal and sagittal planes in asymptomatic female adolescents. Ann Clin Anal Med 2020;11(2):146-149

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A novel missense mutation that may be associated with the polydactyly in the HOXD13 gene: Q241H

Hasibe Vural 1, Ebru Avcı 1, Canan Eroğlu 1, İlknur Çınar 1, Serhat Yarar 2, Özlem Gündeşlioğlu 3

1 Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, 2 Department of Plastic Reconstructive and Aesthetic Surgery, Konya Numune Hospital, Konya, 3 Department of Plastic Reconstructive and Aesthetic Surgery, Health Practice and Research Hospital, Balıkesir University, Balıkesir, Turkey

DOI: 10.4328/ACAM.6205 Received: 08.02.2019 Accepted: 06.03.2019 Published Online: 27.03.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2): 155-158

Corresponding Author: Ebru Avcı, Dept of Medical Biology, Necmettin Erbakan University, Meram Faculty of Medicine, Meram, Konya, Turkey.E-Mail: ebruavc.87@gmail.comORCID ID: https://orcid.org/ 0000-0001-5330-6159

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Aim: HOX gene cluster which is termed as architectural genes and affects the expression of certain genes on DNA are effective in the development of limb. Therefore, mutations are observed in HOX genes, particularly HOXD13, lead to various congenital limb malformations. In this context, it was aimed to deter-mine the expression level of HOXD13 gene and screening of HOXD13 mutations in patients with congenital lower/upper limb malformations who applied to Clinic of Plastic Reconstructive and Aesthetic Surgery of Meram Faculty of Medicine Hospital in this study. Material and Method: The case group of the study was composed of 20 unrelated patients with congenital lower/upper limb malformations and the control group was composed of 20 healthy individuals. Mu-tation analysis was performed using NGS and Sanger sequencing methods. The expression level of the HOXD13 gene was determined by the qPCR. Results: According to the qPCR results, in the case group, a 3.43 fold decrease was observed in the expression of HOXD13 gene when compared with the control group. However, this result was not statistically significant. According to NGS and Sanger sequencing results, a 723G> T variation that could lead to amino acid changes (Q241H) and could be defined as a missense mutation was detected in a patient. Discussion: 723G> T variation observed in a patient with a polydac-tyly anomaly was found in the patient’s mother. However, more detailed studies are needed to assess this variation, which are not found in the literature, as a missense mutation in HOXD13 associated with polydactyly.

Keywords: HOXD13; Missense Mutation; Next-Generation Sequencing; Polydactyly

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Introduction

Limb malformations are one of the most frequent congenital malformations in infants with an occurrence of 1 in about 500 live births [1]. These malformations may be caused by environmental factors such as teratogens or may be caused by mutations that occur in the genes involved in embryonic development and differentiation of the limb [2,3].

Limb formation is initiated in the very early stages of pregnancy. The limb buds are observed on day 26 in the upper limb and day 28 in the lower limb [4,5]. The limb derives from the mesenchymal cells of the lateral mesodermal plate and develops along three major axes depending on the efficiency of the various signal centers [6]. Apical ectodermal ridge (AER), one of these centers, controls the limb growth along the proximal-distal axis via fibroblast growth factors (Fgfs). The development of limb along the anterior-posterior axis is provided by the zone of polarizing activity (ZPA) signaling center where the Sonic hedgehog (Shh) is effective. Finally, the third signal center, non-AER limb ectoderm, regulates the limb growth along the dorsal-ventral axis. At this stage, Wnt7A, which is expressed by the dorsal limb ectoderm and is a member of the Wnt family, plays an important role [6-9].

As well as the signaling centers, various transcription factors are also involved in the formation of the limb. The most known of these are the transcription factors encoded by the HOXgene clusters [3]. HOXgenes, a subgroup of homeobox genes, encode highly conserved transcription factors contain a homeodomain which is a 60 amino acid helix-turn-helix DNA-binding motif [10]. The homeodomain binds to specific DNA sequences and it is known that such a binding regulates the expressions of the target genes [11]. In vertebrates, there are 39 HOXgenes, key regulatory factors of morphogenesis and cell differentiation in embryonic development, organized into 4 clusters as follows: HOXA, HOXB, HOXCand HOXD[12]. HOXgene clusters are particularly important regulators in development along the anterior-posterior axis. Specifically, the 3’ genes of a cluster are expressed in the anterior part of the developing embryo and in early stages of the development, while the 5’ genes are more effective in the posterior part and in the later stages [13]. Expression errors in these genes are associated with limb malformations in connection with the efficiency of HOXgenes in the developmental process. HOXD13is the first HOXgene known to be associated with developmental disorders in human [14].

The HOXD13gene (OMIM:142989), located at the 5’ end of the HOXDgene cluster localized on chromosome 2q31, is 1365 bp and its coding region is 1008 bp. The first exon located at the 5’ end of the gene, comprising of two exons, contains the triple repeat sequences forming the chain of polyalanine, while the second exon located at the 3’ end encodes a highly conserved homologous box domain [15]. HOXD13gene mutations are known to cause variable expression in a wide spectrum of clinical manifestations of limb malformations [16].

Based on the activity of HOXD13 in the developmental process, in this study, it was aimed to screen the possible mutations of the HOXD13 gene in unrelated 20 patients with congenital lower/upper limb malformations using next-generation sequencing (NGS) technology and to reveal the HOXD13gene expression level in the anomalies.

Material and Methods

Sample Collection

The case group of the study was composed of 20 unrelated patients with various congenital lower/upper limb malformations who applied to the Clinic of Plastic Reconstructive and Aesthetic Surgery of Meram Faculty of Medicine Hospital. For using qPCR analysis, the control group was composed of 20 healthy individuals without limb malformations who applied to the same department. The study was approved by the Ethics Committee of Necmettin Erbakan University, Meram Faculty of Medicine (2016/414) and was carried out in accordance with the principles of the declaration of Helsinki. Written informed consents were obtained from each individual or legal guardians. Peripheral blood was collected from the individuals in EDTA tubes for DNA and RNA isolation.

NGS analysis and Sanger validation for determination mutation in cases

Genomic DNA was isolated from peripheral blood lymphocytes using standard Phenol/Chloroform method. For each sample, a PCR mix containing primer mix, DNA (50ng), master mix, Enhancer master mix, and dH2O was prepared as two reactions and PCR protocol was performed. After the reaction, non-specific PCR products were cleaned by magnetic beads. Resuspension buffer was added to the bead to obtain a purified PCR product.

Adapters were attached to the ends of the DNA sequences for binding of barcodes used to identify samples. In this stage, the PCR products which were prepared in two tubes were combined into a single tube, and purification was repeated using beads. A reaction was prepared by combining the adapter-coupled purified DNA with the master mix and the barcode primer mix. Thus, a library was created and each sample was barcoded. The purification process was applied again to the samples and measurement was performed with a spectrophotometer. Finally, PCR products were assembled and an amplicon library was constructed. The library was prepared to be 4 nM. The gene sequencing was done on the Illumina MiSeq platform. Coverage of HOXD13was screened in Integrative Genomics Viewer software (IGV-2.3.91). For validation of results with Sanger sequencing, all samples were sequenced using ABI 3500 Genetic Analyser with both forward and reverse primers. The sequence data were analyzed with the BioEdit Sequence Alignment Editor.

RNA isolation, cDNA synthesis and qPCR analysis

For RNA isolation, 1X Red Blood Cell Lysis Buffer (RBCL; 1.68M NH4Cl, 0.1M KHCO3, 0.5 M EDTA) was added to 2 ml of the blood sample, and the supernatant was removed after centrifugation. After the same procedure was repeated several times, RNA isolation was performed by adding TRIzol Reagent on the pellet. cDNA synthesis was performed using the iScript™ cDNA Synthesis Kit (Bio-Rad) according to the manufacturer’s instructions. The expression level of HOXD13was analyzed by qPCR using cDNAs from each of the control and case groups. The qPCR reaction was performed using EvaGreen Mastermix.Briefly, the qPCR mix was conducted in 10 μl volume containing 5 μl 2x EvaGreen Mastermix, 5 pMol forward primer, 5 pMol reverse primer, and 2 μl cDNA. The qPCR protocol was applied as denaturation at 95°C for 10 min, followed by 35 cycles consisting of denaturation at 95°C for 30 s, annealing at 60°C for 30 s, and extension at 72°C for 30 s. The primers for HOXD13 (Forward primer: 5’-GGAAGAAGAGAGTGCCTTACAC-3’; Reverse primer: 5’-GTCCTTCACTCTTCGGTTCTG-3’) and ACTB(Forward primer: 5’-TGAACGGGAAGCTCACTG-3’; Reverse primer: 5’-TCCACCACCCTGTTGCTGTA-3’) genes were designed using IDT PrimerQuest (https:// eu.idtdna.com/site) and ACTBwas used in the normalization of the results as housekeeping genes.

Statistical analysis

The gene expression analysis was performed by using the 2–ΔΔCTmethod with RT2Profiles™ PCR Array Data Analysis. A p-value <0.05 was considered to be statistically significant.

Results

According to NGS analysis results, a variation that can be defined as a novel missense mutation (723G> T) was found in a patient. This variation in the 1st exon of the HOXD13gene was confirmed by the Sanger sequencing method. It was observed that the patient who possesses an extra finger in his right hand has the heterozygous genotype for this variation. The Sanger sequencing analysis with the mother and the father of the patient revealed that the patient’s mother had the same mutation and also had the heterozygous genotype for this mutation (Figure 1). Normally, glutamine is encoded in the region where the variation is located, but G-T transversion causes histidine to be involved in the protein structure. Accordingly, this variation observed in the HOXD13gene is thought to be regarded as a missense mutation.

The expression level of the HOXD13gene was evaluated with the qPCR analysis in control and case groups. According to the qPCR results, a decrease was observed in the expression of HOXD13 gene in case of group as 3.43 fold when compared with the control group. However, this decrease was not statistically significant (p>0.05) (Figure 2).

Discussion

In epidemiological studies, it has been shown that HOX gene groups play a role in a wide variety of extremity anomalies. Mutations in HOXD13gene, a member of HOX gene groups, are also associated with congenital limb malformations. Mutations observed in the HOXD13gene are classified into three groups as loss of function mutations, increase in the N-terminal polyalanine tract and missense mutations [17]. It is thought that nonsense and frameshift mutations lead to haploinsufficiency in the HOXD13protein, but this has not yet been proven experimentally [18].

The expansion in trinucleotide repeat, which locates on the 1st exon of HOXD13 gene and encodes a 15-residue polyalanine tract, is associated with synpolydactyly [15]. Although the addition of six or fewer alanine does not lead to pathological results, the increase as 7-14 alanine may result in limb malformations that are reflections of different phenotypes [19]. It is known that such mutations disrupt protein stabilization. It has also been shown that the expansion of polyalanine has caused settlement of the protein which is normally located in the nucleus as a transcription factor, into the cytoplasm [20].

Up to now, five missense mutations (R298W, R298Q, S308C, I314L, and Q317R) which are associated with limb malformations in different phenotypes have been identified in the homeodomain region of HOXD13 gene [21]. One of these, R298W, is associated with synpolydactyly and there is a C-T transition in position 892 of HOXD13gene in affected individuals. This transition causes the change of arginine, in position 31 of the homeodomain, to tryptophan, thus it has been suggested that the stability of homeodomain-DNA complex is impaired [22]. R298Q, another missense mutation associated with the syndactyly, also affects amino acid residue at position 31 like R298W mutation and causes arginine to glutamine substitution in homeodomain. It is thought that this alteration disrupts the role of HOXD13in the regulation of transcription and affects the formation of the limbs by acting as a partial loss of function mutation [23].

S308C and I314L missense mutations are associated with the brachydactyly phenotype. In the S308C mutation, there is C-G transversion at position 923 in the second exon of HOXD13. This transversion causes cysteine replacing with serine which is the 41st amino acid of the homeodomain. In the I314L mutation, the 47th amino acid found in the homeodomain structure is leucine instead of isoleucine. The binding activities of two proteins resulting from these mutations have been examined and it has been determined that the S308C mutation has not led to a change in binding of the protein to DNA. However, in the I314L mutation, it has been shown that the mutant protein has higher affinity to the target sequence containing the 5’-TTAC-3 recognition region and lower affinity to the target sequence containing the 5’-TTAT-3 ‘recognition region compared with the wild protein [24]. The Q317R mutation causes arginine replacing with glutamine which is highly conserved amino acid at the 50th position of the homeodomain. It is known that this region is important for DNA binding and specificity. This mutation, which has been found to disrupt transcription from the EPHA7 promoter that has a binding region for HOXD13, is associated with syndactyly [25].

In this study, it was aimed to identify possible mutations in HOXD13gene which plays a role in congenital lower/upper limb malformations and to investigate the efficiency of HOXD13 gene expression. For this purpose, the HOXD13gene was screened in 20 unrelated patients with syndactyly or polydactyly in the upper or lower limbs; and the expression level of HOXD13gene in the anomalies was determined by comparing with 20 control individuals.

According to the qPCR results, when compared with the control group, a 3.43 fold decrease was detected in HOXD13gene expression in the case group, but this decrease was not statistically significant. On the other hand, NGS and Sanger sequencing results revealed the presence of a novel missense mutation in a 3-year-old patient with polydactyly anomaly with an extra finger in his right hand. The mutation is a G-T transversion and is located at position 723 (723G>T) in the 1st exon of HOXD13 gene. This region encodes glutamine which is the amino acid 241 of the protein. 723G>T will lead to the presence of histidine instead of glutamine in the region involved in the construction of the protein (Q241H). This may also result in loss of protein function. The patient was heterozygous for the Q241H mutation and in terms of this mutation, the mother and the father of the patient have also been investigated and it has been shown that the mother has the same mutation for HOXD13with heterozygous genotype and polydactyly phenotype. However, there is no information about Q241H mutation which is considered to be a missense mutation in the HOXD13gene in the literature. When considered in terms of genes, polydactyly is a disease in genetically and clinically complex. Identifying the underlying causes of congenital diseases requires accurate interpretation of genetic variants. Therefore, this finding should be supported by more comprehensive studies in order to evaluate the Q241H mutation as a novel missense mutation that may be associated with congenital lower/upper limb malformations in the HOXD13gene. Furthermore, this finding is thought to be effective in evaluating the wide range of limb malformations when considering the developmental activity of HOXD13.

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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Vural H, Avcı E, Eroğlu C, Çınar İ, Yarar S, Gündeşlioğlu Ö. A novel missense muta-tion that may be associated with the polydactyly in the HOXD13 gene: Q241H. Ann Clin Anal Med 2020;11(2): 155-158

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Reconstruction of nasal defects using subcutaneous axial pedicled forehead flaps

Asım Uslu

Department of Plastic and Reconstructive Surgery, University of Health Sciences, Antalya Education and Research Hospital, Antalya, Turkey

DOI: 10.4328/ACAM.6186 Received: 25.01.2019 Accepted: 25.02.2019 Published Online: 01.03.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):138-141

Corresponding Author: Asım Uslu, Department of Plastic and Reconstructive Surgery, University of Health Sciences, Antalya Education and Research Hospital, Antalya, Turkey. T.: +90 2422494400 F.: +90 2422494487 E-Mail: asimuslu78@hotmail.comORCID ID: https://orcid.org/ 0000-0002-2592-1805

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Aim: The forehead region is the ideal site for nasal reconstruction, and the biggest disadvantage of the forehead flap used for this purpose is that it requires two or three sessions of surgery. Subcutaneous pedicled forehead flap was described previously. However, venous congestion was observed because the vein was ignored while the flap was planned. For this reason, we made nasal reconstruction with forehead flap in one stage and planned the flap pedicle to include the vein and artery together. Material and Method: The data of 8 patients who underwent axial subcutaneous pedicled forehead flap due to a defect in the proximal 2/3 of nose between January 2016 and January 2018 were analyzed retrospectively. The mean age of the patients was 62.88 and the mean follow-up period was 14.13 months. Results: The operations lasted 85 minutes on average and nasal defects were reconstructed with a single stage forehead flap. Clini-cally, we observed less venous congestion and less bleeding. No partial or total loss was observed in any flap. All patients were discharged on postoperative day 1. Discussion: The subcutaneous axial pedicled forehead flap can be safely used for defects in the superior 2/3 of the nose. However, larger superficial vein should be determined first and then the flap pedicle should be planned by marking the artery while planning this flap. In this way, nasal reconstruction is made in one session with a subcutaneous pedicled axial forehead flap that includes both artery and vein.

Keywords: Forehead Flap; Subcutaneous Pedicled Flap; Nasal Reconstruction; Axial Flap

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Introduction

The use of the forehead in nasal reconstruction dates back to 1000 BC and is known as the India method [1]. At the time of the introduction of this flap, the flap was planned to have a wide pedicle and to be in the midline. The pedicle contained supratrochlear artery of both sides, and sometimes both the supratrochlear and supraorbital arteries of both sides, and the rotation arc of the flap was quite limited [1]. Later on, anatomical studies have shown that the paramedian forehead flap can be lifted through the narrow pedicle, including one side of the supratrochlear artery and the angular artery [2-5]. However, the pedicle of these flaps was made to include the supratrochlear artery and the skin island on it. Therefore, the second operation was required to cut the pedicle in the paramedian forehead flap [6,7].

Later, the forehead flap was started to be made in one stage. For this purpose, in the first defined forehead flap, wide subcutaneous pedicle in the middle part of the forehead was turned under the skin of the glabellar region. This planning resulted in significant venous congestion in the flap and glabellar fullness [8]. This limited the use of the single-stage forehead flap. Recently, mostly small nasal defects were reconstructed with a single-stage forehead flap [9,10]. The most important problem was venous congestion and to reduce this congestion the resection of the procerus muscle and extensive undermine the skin in the glabellar region was performed [9].

We used the subcutaneous axial pedicled forehead flap for defects in proximal 2/3 of the nose. This flap has been previously described [8-11]. However, in these patients, we planned the pedicle of the flap to include both the artery and the vein in order to be a complete axial flap.

Material and Methods

This study included 8 patients who underwent subcutaneous axial pedicled forehead flap due to a defect in proximal 2/3 of the nose between January 2016 and January 2018. Data of these patients were analyzed retrospectively. The mean age of the patients was 62.88 and the mean follow-up period was 14.13 months (Table). Ethics committee approval was obtained from the Antalya Education and Research Hospital Ethics Committee.

Surgical Procedure

First, the excision of the nasal lesion was planned and the size of the defect was measured. While the patients were at the supine position the supratrochlear vein was marked on the forehead where the vein was larger. The vein was easily seen by the Valsalva maneuver when the vein could not be seen directly. On the prominent vein side, 16-20 mm lateral to the midline, the possible localization of the supratrochlear artery was marked. The subcutaneous pedicle was designed to include both the superficial supratrochlear vein and the deeper supratrochlear artery and 2-3 mm intact tissue on the edge thereof. The length of the pedicle was planned as the pivot point of the flap would be superior orbital rim so that the flap could reach the defect without tension. The size of the flap was planned according to the size of the defect (Figure 1).

The lesion in the nose was excised with proper intact margin. Then the forehead flap was lifted from the distal to proximal part from the vicinity and at the base from between the frontal muscle and the periosteum except for the pedicle portion. An incision extending from the flap to the defect was performed on the pedicle and the skin on the pedicle was lifted with the thin subcutaneous fat tissue on both sides of the incision, up to the edge of the pedicle. At the base, up to two cm superior to the orbital rim, pedicle was lifted over periosteum, below this level under periosteum. Then the flap was rotated 180 degrees and sutured in the defect. The flap donor area was repaired primarily in five patients and full-thickness skin graft from the supraclavicular region was performed to the remaining three patients (Figure 2,3). In a patient with a skin graft, the donor area was expanded with tissue expander and then was repaired primarily. In one patient, tumor excision resulted in a full thickness defect in the nose. Nasal mucosa was repaired with full thickness skin graft for this patient.

Results

All operations were performed under sedoanalgesia and the operations lasted 85 minutes on average. The nasal defect in all patients was reconstructed with a single stage forehead flap. Clinically, patients had less venous congestion and hemorrhage than the two-stage forehead flaps that we did. No partial or total loss was observed in any flap. All patients were discharged on the first postoperative day. The glabellar fullness observed at the pivot point of the pedicle was spontaneously resolved within a few months as a result of atrophy of the frontal muscle. The symmetry of the eyebrows was not impaired in any patient. The results were more satisfactory for both the surgeon and the patients than the previous two-stage forehead flaps (Figure 4).

Discussion

The forehead area is the ideal area for nasal reconstruction. Advantages of using forehead flap versatile for nasal reconstruction are good color and texture match. The forehead flap is usually performed in two or three sessions [6,12]. The disadvantages are multiple-session surgery, cost more, long stay away from work, long-term wound care, being unable to wear glasses, being isolated from the community due to elephant’s trunk deformity [6,7,13].

The paramedian forehead flap is defined as an axial flap because it is fed from the supratrochlear artery. While an axial flap should contain a vein, in the traditional forehead flap the pedicle is harvested with a skin strip to provide venous drainage. The supratrochlear artery is the terminal branch of the ophthalmic artery and approximately 2 cm from the midline enters the forehead from the supratrochlear notch. It pierces the procerus and corrugator supercilii muscles and feeds the paramedian forehead by running a course in the frontal muscle [14,15].

The supratrochlear artery has no accompanying vein but has only the surrounding adventitial vasa vasorums [16]. The venous drainage of the forehead, eyebrow, and upper eyelids is provided by the frontal branch of the supraorbital, supratrochlear and superficial temporal veins. The supratrochlear vein emerges from the venous plexus in the forehead. Then the supratrochlear veins take the course down in the midline and they are connected to each other by the transverse nasal arch at the dorsum of the nose [17].

The supratrochlear vein does not coexist with the supratrochlear artery. The average distance of the supratrochlear vein from the midline is 9.7 mm and the supratrochlear artery is 16.2 mm at the level of the superior orbital rim. The distance from vein to the midline varies from right to the left [18]. The localization of the supratrochlear artery in the forehead is fixed. However, the vein draining the forehead skin is thicker on one side [16].

Venous congestion due to extensive planning of subcutaneous pedicle was a significant problem in patients undergoing single-stage forehead reconstruction [8]. To reduce this, some methods were performed such as procerus muscle resection and dissection under the skin of the glabellar region. Later a one-stage subcutaneous island-shaped forehead flap was used in the reconstruction of the nose, medial canthus and lower eyelid [8,9]. Venous congestion and partial flap loss were reported in 50% of the forehead flap planned in this way [11]. In addition, this technique has been proposed only in patients with nasal upper region defects, who have no history of peripheral vascular disease, hypertension, diabetes, and radiotherapy [9].

Venous congestion is the major problem in the subcutaneous forehead flap [8,11]. The reason for this is that the pedicle is planned by considering only the localization of the artery. Whereas, the supratrochlear vein is more superficial than the artery, takes course apart from the artery, it is thicker on one side [16,18]. Therefore, the subcutaneous pedicle was planned on the side where the supratrochlear vein was prominent and we selected the supratrochlear artery according to the vein placement side. In this way, a real axial flap was made. No venous congestion and related flap loss were observed in any of the patients.

While flap pedicle was prepared, an incision was performed between the flap and defect along the pedicle. The vein under the skin in the pedicle was protected and the skin flaps were lifted from both sides. The pedicle width was planned to include an additional 2-3 mm intact tissue from the vein and artery edge. Inserting the pedicle to the defect through the incised skin rather than the subcutaneous tunnel had two benefits. First, the superficial vein was fully preserved and the pedicle was opened wide enough. The second is that this incision was sutured intermittently, which prevented possible hematoma and its pressure on the pedicle.

Conclusion

The subcutaneous axial pedicled forehead flap can be safely used for defects located in the superior 2/3 of the nose. However, when planning this flap, the first thicker superficial vein should be determined, and then the flap and the pedicle should be planned by marking the artery of the same side. In this way, nose reconstruction was performed in one stage with axial forehead flap including both artery and vein.

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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5. Millard DR. Reconstructive rhinoplasty for the lower two-thirds of the nose. Plast Reconstr Surg. 1978;57:722-8.

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7. Menick FJ. Nasal reconstruction. Plast Reconstr Surg. 2010;125:138–50.

8. Converse JM, Wood-Smith D. Experiences with the forehead island flap with a subcutaneous pedicle. Clin Plast Surg. 1963;31:521-37.

9. Park SS. The single-stage forehead flap in nasal reconstruction: an alternative with advantages. Arch Facial Plast Surg. 2002;4:32-6.

10. Har-El G. Single-stage paramedian forehead flap for nasal reconstruction. Operat Tech Otolaryngol Head Neck Surg. 1999;10:127-30.

11. Cordova A, D’Arpa S, Massimiliano T, Toia F, Moschella F. A propeller flap for single-stage none reconstruction in selected patients: supratrochlear artery axial propeller flap. Facial Plast Surg. 2014;30:332-41.

12. Menick FJ. Aesthetic refinements in use of the forehead for nasal reconstruction: The paramedian forehead flap. Clin. Plast. Surg. 1990;17:607-22.

13. Fudem GMMontilla RDVaughn CJ. Single-stage forehead flap in nasal reconstruction. Ann Plast Surg. 2010;64:645-8.

14. Yang D, Tang M, Geddes CR, Morris SF. Vascular anatomy of the integument of the head and Neck. In: Blondeel PN, Morris SF, Hallock GG, Neligan PC, editors. Perforator Flaps Anatomy, Tecknique and Clinical Applications. St. Louis, MO: QMP; 2006.p.134-60.

15. Skaria AM. The median forehead flap reviewed: a histologic study on vascular anatomy. Eur Arch Otorhinolaryngol. 2015;272:1231-7.

16. Shimizu Y, Imanishi N, Nakajima T, Nakajima H, Aiso S, Kishi K. Venous architecture of the glabellar to the forehead region. Clin Anat. 2013;26:183-95.

17. Standring S. Gray’s Anatomy: The Anatomical Basis of Clinical Practice. In: Gleeson M, editor. Head and neck. 41st ed. London: Elsevier; 2015. p.416-29.

18. Cai X, Li Z. Applied anatomy study of the supratrochlear vein in reconstruction of nasal defect. Article in Chines. 2009;23:219-21.

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Uslu A. Reconstruction of nasal defects using subcutaneous axial pedicled fore-head flaps. Ann Clin Anal Med 2019; Ann Clin Anal Med 2020;11(2):138-141

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Anesthesiology experience with patients underwent renal transplantation at a university hospital: first-year results

Sinan Yılmaz, Kamil Varlık Erel

Department of Anaesthesiology and Reanimation, Aydın Adnan Menderes University School of Medicine, Aydin, Turkey

DOI: 10.4328/ACAM.6204 Received: 07.02.2019 Accepted: 25.02.2019 Published Online: 01.03.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2): 150-154

Corresponding Author: Sinan Yılmaz, Department of Anaesthesiology and Reanimation, Adnan Menderes University, School of Medicine, 09100, Aytepe, Aydin, Turkey. T.: +90 2564441256-2109 F.: +90 2562136064 E-Mail: dr_snnylmz@hotmail.comORCID ID: https://orcid.org/ 0000-0002-5281-137X

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Aim: Renal transplantation (RT) is the most effective treatment modality for end-stage renal disease (ESRD). Transplantation process requires a multidisci-plinary (nephrologist, surgeon, anesthetist, pathologist, immunologist, and experienced nurse) approach. This study presents the first-year experience of the anesthesiology department of a university hospital where renal transplantation program just started. Material and Method: The digital medical files of 14 patients who underwent renal transplantation due to ESRD between 2017 and 2018 were evaluated retrospectively. The hemodynamic and demographic parameters of all the patients were examined and analyzed. Results: Eleven (78.6%) of the donors were provided from deceased and 3 (21.4%) from living individuals. The mean age of all transplantation patients were 39.9±13.3 years (range 21-61). Concerning cause, “unknown etiology” was detected in 8 (57.1%) of the patients. None of the patients experienced difficult intubation. The mean duration of anesthesia was 242.8 ± 85.2 min. Intraoperative hypotension was detected in 6 (42.8%) patients. During the intraoperative period, 1535 ± 771 ml of 0.9% NaCl was administered as the fluid maintenance. Only 2 patients had intraoperative complications. No mortality was observed during the perioperative period. Two of the 14 patients experienced loss of the transplanted kidney. The survival rate of the grafts was 85.8%. Discussion: Management of renal transplantation is a serious task which requires teamwork and coopera-tion as it can favorably change the patient’s life quality when implemented successfully. In renal transplantation, achieving the post-transplantation survival rate (90-96%) reported in the literature requires detailed preoperative evaluation of patient along with appropriate intraoperative fluid administration and hemodynamic control.

Keywords: Renal Transplantation; Anesthesia; End-Stage Renal Disease; Survival

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Introduction

Renal transplantation (RT) is the most effective treatment modality for end-stage renal disease (ESRD) [1]. The incidence (for 2017, 146 cases per one million population [pmp]) and the prevalence (for 2017, 957 cases pmp) of ESRD requiring renal replacement treatment (RRT) have increased as the average life expectancy has increased in Turkey. The number of patients waiting for organ transplantation is growing day by day [1]. Although the number of renal transplantation has increased in recent years, the number of renal transplantation procedures performed in 2017 (n = 3330) still lags behind the demand in our country. The most important reason for this situation is the lack of the expected increase in cadaver donors [1].

The organ transplantation procedure, which allows the transplantation of the organs taken from the cadaver or live donor to the recipient, requires a multidisciplinary (nephrologist, surgeon, anesthetist, pathologist, immunologist, and experienced nurse) approach [2].

The renovation of renal transplantation, which is the most cost-effective treatment option for patients, is essential for the patients’ health and the health expenditures of the country. To increase the number of cadaveric organ donations, the awareness of the whole community on organ donation -particularly the health and educational institutions- should be increased [3].

In this study, we presented the first year experience of the anesthesiology department of a university hospital in which renal transplantation has just started.

Material and Methods

Renal transplantation was first performed on 16 December 2017 at Aydın Adnan Menderes University, Training and Research Hospital. The study was approved by the Local Ethics Committee of the university (Ethics committee decision no: 2018/1508). The digital medical files of 14 patients who underwent renal transplantation due to ESRD between 2017 and 2018 were evaluated retrospectively. The patients’ demographic data, concomitant diseases and the source of the transplanted kidney, whether from live donor or cadaver, were noted.

All patients included in the study had been subjected to a comprehensive multidisciplinary evaluation by an anesthesiologist, nephrologist, surgeon and experienced transplantation nurse before the enrollment into the transplantation waiting list.

Informed consent was obtained from all patients prior to the surgery. Electrocardiography (ECG), oxygen saturation (SpO2) and non-invasive blood pressure and body temperature monitoring were performed after the receiver patients were transferred into the operation room. Hypotension was defined as the systolic arterial blood pressure dropping below 90 mmHg or as a decrease by 20-30% from the baseline [4].

Two (20G) peripheral vascular accesses were opened to the arm without arteriovenous fistula. During the induction of anesthesia, fentanyl 1 mg/kg, propofol 2-2.5 mg/kg, rocuronium bromide 0.6 mg/kg were administered intravenously. For infusion, 10 mg/ml of rocuronium bromide and 0.04 µg/ml of remifentanil were prepared.

Neuromuscular monitoring was initiated immediately after anesthesia induction before the administration of muscular relaxant. Endotracheal intubation was performed 60-90 seconds after the administration of rocuronium bromide at the intubation dose. During the surgery, rocuronium bromide was administered at a dose of 0.2 mg/kg/h with continuous infusion. From the ventilation parameters, FiO2 was controlled to maintain 50% and EtCO2 between 35-40 mmHg. End-tidal desflurane concentration was maintained at 5-6%, and fresh gas flow was applied at a rate of 1.2 lt / min.

Mannitol (30 mg), 81.4±42.5 mg furosemide, and 500 mg methylprednisolone were administered intravenously just after clamp placement. The oblique incision in the lower quadrant revealed the iliac fossa. For postoperative analgesia, morphine was administered intravenously at 0.04 mg/kg dose. Sugammadex 4-8 mg/kg was applied intravenously to the patients just after the end of the surgical operation. The patients were extubated in the operation room.

Statistical Analysis

The appropriateness of the data to the normal distribution was examined with the Kolmogorov- Smirnov test. The correlations between the numerical variables were analyzed using the Pearson or Spearman correlation analysis. Descriptive statistics were given as mean ± standard deviation, median (25th-75th percentiles), and frequency (percentage) according to the data structure. Results were considered statistically significant when p-value was <0.05.

Results

A total of 14 kidney transplantations (male/female= 7/7) were performed within one year at our department. Table 1 shows the demographic and intraoperative data of transplanted cases. The mean age of the patients was 39.9 ± 13.3 years (min-max: 21-61 years), and the mean body weight was 62 ± 15.4 kg. Eleven of the donors (78.6%) were provided from the deceased. Among the etiologic causes of 14 ESRD patients who underwent renal transplantation, no primary etiology was detected in 8 (57.1%) of the patients (Figure 1). There were comorbid conditions present in only 5 patients (Table 1). Dialysis was performed in all cases before transplantation. Of the 14 cases, 11 had undergone hemodialysis (HD) and 3 had periton dialysis (PD). None of our patients received preemptive transplantation.

Eleven patients were considered as ASA-II and 3 patients as ASA-III. None of the patients experienced difficult intubation. All patients were given desflurane in the maintenance of anesthesia. The mean duration of anesthesia was 242.8 ± 85.2 min. Two arterial catheters, four central venous catheters (CVC) and one hemodialysis catheter were inserted during the operation (Table 1). Intraoperative hypotension was detected in 6 (42.8%) patients. The warm ischemia duration of the organs was 143 ± 20 sec and the total ischemia duration was 720 ± 216 min (min-max= 530-1200 min). In the intraoperative period, 1535 ± 771 ml of 0.9% NaCl was administered as the fluid maintenance. The limit values for blood and blood products transfusion were below 7 g/dl for hemoglobin and below 50,000/mm3 for platelet count [5]. However, none of the patients required transfusion. Only 2 patients (14.2%) had intraoperative complications. Only one patient underwent re-intubation due to respiratory depression in a post-anesthesia care unit (PACU) and required mechanical ventilation. A thoracic tube was placed in the second patient due to pneumothorax.

No mortality was observed during the perioperative period. Two of the 14 patients (14.2%) experienced the loss of the transplanted kidney. In the first case, renal vein thrombosis developed due to vascular injury during surgery and the kidney was lost at the postoperative 48thhour. In the other patient, the transplanted kidney was lost due to hyperacute rejection. Currently, 12 patients are being followed up with a functional graft. The mean survival duration of the transplanted organs was 5.5 ± 3.3 months (min-max = 3-11 months).

There was a strong negative correlation between recipient age and organ survival (r = -0.729, p = 0.001). The survival rate of our patients was 100% while the survival rate of the grafts was 85.8% for the same period.

Discussion

Renal transplantation led to a decrease in mortality and increased the quality of life in ESRD patients. Although the number of patients in the organ waiting list increases every year in our country, the number of patients undergoing RT is still far behind this demand. Turkey’s population was 80,810,525 people in 2017 while the number of ESRD patients required RRT was 77,311 people in the same year [1]. A total of 72 centers were capable of RT in Turkey in the year 2017. These centers were university hospitals (n = 35 – 48.6%), hospitals of Health Ministry (n = 19 – 26.4%) and private centers (n = 18 – 25.0%) in decreasing order respectively [1]. In 2017, 2646 (79.3%) of the 3330 RTs were performed from living donors and 684 (20.7%) were from deceased donors [1]. In developed countries, 70-80% of kidney transplantations are reported from a deceased and 20-30% from living donor [6]. In our study, we found that the cadaveric transplantation rate (78.6%) was similar to that in developed countries. We believe that this is a successful outcome for such an inexperienced center with one-year experience on renal transplantation. This result might be due to the relatively higher awareness of the population living in the Aegean region and the high motivation of the renal transplantation team with cadaveric donors.

With the help of the National Transplant and Dialysis Monitoring System in Turkey (TDIs), each transplantation center can load their data to the system. In this way, a scoring system is used in the distribution of cadaver kidneys throughout the country. In this scoring system, tissue type adherence, the age of the patient and the duration of dialysis are taken into consideration. In particular, if the length of the patient’s dialysis period increases, the total score increases. In parallel with the prolongation of life expectancy and the increasing prevalence of chronic diseases (such as diabetes mellitus (DM), hypertension (HT)) in our country, the incidence of ESRD and the number of patients in organ waiting lists will increase. So, the number of cadaveric kidney donations should be increased by informing the public, especially health institutions, and raising their awareness about organ donation in various ways.

It is known that preemptive transplantation improves graft function and decreases mortality compared to transplantation in patients undergoing dialysis. However, it has also been reported that if the patient requires dialysis, initiation of dialysis together with scheduled transplantation within six months does not affect organ survival [6-7]. For this reason, the current guidelines recommend that patients should be enrolled in the transplantation list within six months from the estimated date of dialysis initiation [6, 8]. On the other hand, it is observed that the number of transplantation in our country has increased in recent years and this increase is mainly due to the increase in preemptive transplantations (38.4%) [1]. However, it is thought that some cases undergo transplantation prematurely and preemptive transplantation cases are abused [1]. Necessary arrangements should be made to prevent premature preemptive transplantations. None of the patients in our study was a preemptive transplantation case.

While 5-year survival rate is as high as 96% in renal transplantation patients, this rate is quite low in patients undergoing hemodialysis (46%) or peritoneal dialysis (66%) [8]. In our study, the 1-year survival rate of renal transplantation (85.8%) was slightly lower than that reported in the literature. This result might be due to the fact that the center has just started transplantation operations, so has not yet had sufficient experience and most donors had been cadavers. The first of the failed transplantations was risky transplantation from a man to his wife with a total of 6 mismatches. This transplantation, which was risky immunologically, failed after the development of a surgical vascular complication. The other failed transplantation was from a cadaver with three mismatches and resulted from hyperacute rejection. In order to increase the organ survival in the transplantation, we think that a successful surgical procedure is also critical together with the detailed immunological evaluation during the preparation phase. In the forthcoming years, we aim to increase our organ survival rate by increasing our experience.

According to the records of the Turkish Nephrology Association by the end of 2017, ESRD causes of the patients who underwent renal transplantation were ‘unknown etiology’ in the first rank (28.5%) [1]. In our study, among the ESRD patients who underwent transplantation, ‘unknown etiology’ (57.1%) was in the first rank in accordance with our country, but at a higher rate.

Comorbid diseases in patients undergoing renal transplantation may affect postoperative organ survival [9]. Cardiovascular diseases are the main causes that determine the postoperative mortality of ESRD patients [10-11]. In our study, since most of our patients were young, the rate of patients with severe comorbidity was not so high. However, there was no mortality developed in our patients. In the pre-transplantation evaluation, we think that the comorbid conditions that would affect survival should be evaluated in detail.

The functions of the graft depend on the condition of the kidney prior to transplantation, cold/warm ischemia durations, and post-transplant graft perfusion [5]. The shorter the cold ischemia time, the better the long-term survival of the graft is [12]. In our study, the duration of cold ischemia was shorter than 24 hours in all cadaveric donors.

In the preoperative evaluation, dialysis modality, the last dialysis time, dry weight and preoperative fluid status (ranging from severe hypovolemia to hypervolemia) should be evaluated in detail. Especially in ESRD patients, the measurement of dry weight and serum potassium levels after dialysis is important in the management of fluid-electrolyte balance during operation [5]. Previous publications have reported that performing dialysis 24 hours prior to transplantation cause delay in graft functions. However, in recent years it has been emphasized that treatment should be managed on a case basis manner [6, 13]. All of our patients underwent dialysis in the pre-transplantation period. We have not experienced such a problem in our diabetic patient.

In the evaluation of intravascular volume during transplantation, central venous pressure (CVP) was recommended to be maintained between 10-15 mmHg [5-6, 14]. In recent years, it has been reported that this is not completely valid and hypovolemia can also be determined by intra-arterial dynamic measurements (pulse pressure, stroke volume variability, etc.). However, many centers still advocate CVC placement necessity. In particular, CVC is widely used for induction therapy [6,15]. In our study, CVC was placed in only 4 cases. In addition, arterial catheterization was performed in two of our patients who had been undergoing hemodialysis and had had cardiac problems. Arterial catheterization is not recommended in patients who may need fistula during the post-transplantation period. Therefore, we believe that invasive catheterization procedures should be decided for each patient individually as stated in the literature.

Appropriate intraoperative fluid management is independently associated with renal functions after transplantation. For this reason, kidney transplantation should be performed with adequate-moderately perfused kidney under an ideal mean arterial blood pressure (10-20% above or below the basal value). In this way, hypotension during organ reperfusion can be avoided [5]. On the other hand, excessive fluid administration may lead to fluid overload, particularly in patients with cardiac problems. Classically, after exclusion of cardiac problems, giving a total of 30-40 ml/kg of 0.9% sodium chloride fluid intraoperatively during transplantation is recommended. Balanced salt solutions are reported to be safely used in ESRD patients with a mild increase in lactate levels without changing serum potassium levels [5,16-17]. In our study, the recommended volume of 0.9% NaCl treatment was administered to the patients except for those with cardiac problems.

In most of our patients, antihypertensive treatments were discontinued before the operation. However, we had taken precautions for refractory hypotension after anesthesia induction in very few patients who had taken their medication. Despite these measures, intraoperative hypotension developed in 6 patients. In patients with suspected hypovolemia, fluid boluses were rapidly administered and their fluid status was monitored closely during the perioperative period.

Limitations

The most important limitation of the study was the small number of sample size. However, we hope to reach an increased number of cases in the following years by increasing the experience of our center and the number of live donors. Besides, the retrospective design of the study was another limitation.

Conclusion

Management of renal transplantation is a serious job which requires team cooperation, and it can favorably change the patient’s life quality when it results successfully. In renal transplantation, achieving the post-transplantation survival rate (90-96%) reported in the literature requires a detailed preoperative evaluation of patient along with appropriate intraoperative fluid administration and hemodynamic control.

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. Wray CL. Advances in the Anesthetic Management of Solid Organ Transplantation. Adv Anesth. 2017;35:95-117. DOI: 10.1016/j.aan.2017.07.005.

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4. Mark JB, Steele SM. Cardiovascular effects of spinal anesthesia. Int Anesthesiol Clin 1989; 27:31-9.

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6. Mittel AM, Wagener G. Anesthesia for Kidney and Pancreas Transplantation. Anesthesiol Clin. 2017;35:439-52. DOI: 10.1016/j.anclin.2017.04.005.

7. Goldfarb-Rumyantzev A, Hurdle JF, Scandling J, Scandling J, Wang Z, Baird B, et al. Duration of end-stage renal disease and kidney transplant outcome. Nephrol Dial Transplant 2005; 20:167–75.

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Yılmaz S, Erel KV. Anesthesiology experience with patients underwent renal transplantation at a university hospital: first-year results. Ann Clin Anal Med 2020;11(2): 150-154

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Evaluation of Turkish pediatric voice handicap index in children with asthma

Serkan Filiz 1, Ömer Tarık Selçuk 2, Rıza Taner Baran 3

1 Department of Pediatric Allergy and Immunology, 2 Department of Otorhinolaryngology, 3 Department of Pediatric Endocrinology, Antalya Training and Research Hospital, Antalya, Turkey

DOI: 10.4328/JCAM.6195 Received: 31.01.2019 Accepted: 22.02.2019 Published Online: 28.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):142-145

Corresponding Author: Serkan Filiz, Antalya Training and Research Hospital, Varlık Mahallesi, Kazım Karabekir Cad. Soğuksu, 07100, Antalya, Turkey. T.: +90 2422494400/5715 GSM: +905056715830 E-Mail: serkanfiliz75@gmail.com, ORCID ID: https://orcid.org/ 0000-0002-7733-9067

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Aim: The purpose of the study was to evaluate the voice quality in children with asthma by subjective methods. Material and Method: Children with mild-to-severe asthma (n=91) and age-sex matched healthy controls (n=79) without present or past history of voice disorders were included in the study. The Turkish version of the Pediatric Voice Handicap Index (pVHI) was used to access the impact on functional, physical, and emotional aspects of voice and oral communication. Results: A significant difference was noted between patients with asthma and controls with regard to pVHI scores. Indicating a greater chance of voice disorders was observed in patients with asthma (P<0.005). The scores of three domains and the total score of pVHI were prevalent in children with asthma. In addition, as the severity of asthma increased, high scores of pVHI were observed (p:0.01). Discussion: Our study showed that children with asthma had higher scores on pVHI compared to healthy children, indicating a greater likelihood of the development of voice complaints. A positive correlation was found between the severity of asthma and pVHI scores

Keywords: Pediatric; Voice Handicap Index; Asthma

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Introduction

Asthma is a common childhood illness and generally associated with numerous multi-morbid disorders [1]. Pediatric dysphonia is common in children and have a negative effect on family and social life. A majority of research suggests that patients with asthma display more voice abnormalities than their healthy peers [2-6]. Many studies have focused on the association between inhaled corticosteroids (ICSs) and voice changes. ICSs can cause local adverse effects in the oral cavity, oropharynx, and larynx such as hoarseness, and pharyngitis [7-9]. In patients with asthma, allergen exposure of the larynx may lead to viscous secretions in the larynx and may cause vocal fold edema and erythema [10]. Gastroesophageal reflux (GER) and nasal polyposis, which are frequently observed in patients with asthma, are other factors that may cause voice disorders [11, 12].

On the other hand, there are also studies which found no relationship between asthma and voice disorders. A past study showed no evidence to suggest that children with asthma suffer more voice disorders than non-asthmatics [13]. A recent study also demonstrated that there was no significant connection between having an asthma diagnosis and having frequently occurring vocal symptoms [6].

There is limited valid and reliable information in objective and subjective studies on voice disorders in asthma and these are based upon studies of the adult population [5]. In addition to objective tests such as acoustic and aerodynamic testing, subjective tests such as voice handicap index can be performed in evaluation voice disorders. The Pediatric Voice Handicap Index (pVHI) is a self-assessment tool for pediatric voice disorders which assigns a numerical value to quantify the parent’s perception of the child’s functional, physical and emotional disability related to voice use. It has become the most accepted subjective tool in the evaluation of subjective pediatric voice disorders [14].

We hypothesized that asthmatic children might have more subjective voice complaints than non-asthmatic children. It is important to Pediatricians and Otorhinolaryngology (ENT) specialists to identify asthma-related voice disorders in children. Recently, the original Voice Handicap Index has been translated into Turkish and validated the Turkish version for use with the pediatric population [15]. To the best of our knowledge, the Turkish version of the pVHI has not been used in Turkish children with asthma. So the aim of the study was to use the Turkish version of the pVHI in school-age children with asthma and to compare the results with healthy children.

Material and Methods

Participants

A total of 91 children aged 6-17 years with mild-to-severe asthma were enrolled from the Pediatric Allergy Department and invited to attend for a formal voice assessment to Otorhinolaryngology Department between January and September 2017. The diagnosis and severity of asthma were defined according to the Global Initiative for Asthma guidelines [16].

Children were defined as asthmatic according to the following criteria:

a) Recurrent episodes of one symptom of asthma, including cough, wheezing, breathlessness, and chest tightness;

An improvement of at least 12% in base forced expiratory volume in 1 s(FEV1) after bronchodilator use.

Patients receiving concomitant systemic steroids, with active upper respiratory tract infection, gastroesophageal reflux disease, aged < 6 years, or with a history of endotracheal intubation and with cord vocal nodules and polyps that were seen in video laryngoscopy examination were excluded from the study. The demographic data included age, gender, allergen sensitization, asthma severity, asthma medication. The control group consisted of 79 age-and gender-matched children selected from the Pediatric Department without any present or past history of voice disorder, hearing loss or related disability that might affect the child’s speech and voice and no signs of atopic disease. The Ethics Committee of our hospital approved the study and written informed consent was given by the parents or legal guardians of the patients (2017-035). All patients underwent video laryngoscopy examination using a flexible Mooncare fiberscope 3.4 mm (8300019728, Germany).

The Pediatric Voice Handicap Index (pVHI)

The pVHI is a self-assessment tool for pediatric voice disorders, which is filled by children’s parents and consists of 23 questions divided into functional (7 questions), emotional (7 questions) and physical domains (9 questions). The scores range from 0 to 4 according to the frequentcy of the problem from 0=never to 4=always. Patients with a total score below 20 were considered normal. The parents of each participant in both the study and control groups independently completed the Turkish-pVHI [15].

Statistical analysis

Data were analyzed using Statistical Package for the Social Sciences (SPSS) ver. 20.0, (SPSS Inc, Chicago, Illinois, USA). Numerical variables were defined as mean ± standard deviation and/or median (min-max), and categorical variables as number and percentage. The normality hypothesis was tested using the Kolmogorov-Smirnov test. For continuous numerical variables, a t-test or Mann-Whitney U test was used to determine whether there was any difference between the experimental and control groups, and for categorical variables, the Chi-Square test. When the experimental group stratified according to the severity of asthma, the intergroup analysis was performed by using the Kruskal-Wallis test. The level of statistical significance was accepted at p<0.05.

Results

A total of 91 children with asthma and 79 children in the control group with a mean age of 11.6±3.27 years were recruited into the study. The demographic, clinical and medical characteristics of the patients were seen in Table 1. According to the severity of asthma (GINA 2016), 38 patients (41.8%) were classified as mild asthma, 35 (38.5.%) as moderate asthma and 18 (19.8%) as severe asthma. The mean total Turkish- pVHI score was 13.12±11.81 in the asthma group and 6.43±8.49 in the control group. According to the Mann-Whitney U test, the difference between the mean scores of the three domains and the total score of the Turkish version- pVHI was significant between the two groups (p<0.005)(Table2).

The overall mean values for p-VHI total and each domain are shown in Table 2. In the asthmatic group, 6 (6.7%) patients were receiving only montelukast, 49 (54.4%) only ICSc (Flixotide), 19 (21.1%) patients inhale corticosteroids plus montelukast, 4 (4.4%) ICSc+ long-acting ß2 agonist (Fluticasone-Salmeterol).

Twelve (%13.3) of them used salbutamol as required (Table1). There was a significant relationship between asthma severity and the pVHI total score (p:0.01). There was also observed to be a relationship between physical and emotional domains and asthma severity, but no significant relationship was seen between the functional domain and asthma severity ( p=0.006, p=0.001, p= 0.08 respectively) (Table3).

Discussion

There is only very limited information on the subjective evaluation of voice disorders in children with asthma [6]. We hypothesized that children with asthma might have more subjective voice complaints than non-asthma participants. Our study showed that children with asthma had higher scores on pVHI compared to healthy children, indicating a greater likelihood of the development of voice complaints. These results are similar to the findings of two studies with adult studies where the participants with asthma scored significantly higher on voice quality parameters than the control group [16,17]. In addition, patients with allergy have also been reported to have a higher degree of vocal dysfunction measured with VHI than patients without allergy [18]. Our recent study showed that children with allergic rhinitis had more frequent subjective voice disorders measured with pVHI than patients without allergy [19].

In contrast to our study findings, in a cross-sectional, large cohort study to evaluate dysphonia in children, Carding et al. [13] found that although the parental report suggested significant risk factors for dysphonia in asthma, children with asthma were no more likely to be dysphonic than non-asthmatic children. Kallvik et al. [6] demonstrated that although 18.2% of the children with asthma had frequently occurring vocal symptoms, such as throat clearing and coughing, there was no significant connection between asthma diagnosis and frequently occurring vocal symptoms. In these two studies, voice complaints were evaluated subjectively with questionnaires on vocal symptoms not with p-VHI. There are differences in clinician and parental results regarding the symptoms of voice disorders.
In our recent study, we have demonstrated that children with allergic rhinitis show higher scores on pVHI compared to healthy children, indicating a greater chance of voice disorders observed in them. In addition, we showed that pVHI scores were correlated positively with AR severity [19].

Previous studies with adult participants have shown that dysphonia was significantly more prevalent in patients with asthma compared to healthy participitans [5,16,17]. Restricted expiration, decreased lung volume, diaphragm, together with fluctuations in intra-thoracic and intra-abdominal pressures might hypothetically explain the significantly higher prevalence of voice disorders in patients with asthma. Additionally, mucosal changes due to obstructive respiratory disease, accompanying rhinosinusitis, the influence of laryngopharyngeal reflux and side effects of the inhaled corticosteroids may be responsible for the voice disorders [5,6,16].

To the best of our knowledge, this is the first study to examine the subjective evaluation of children with asthma using p-VHI and to compare the results with healthy controls. In the current study, it was also shown that as the severity of asthma increased, so did the pVHI scores. Laryngitis, prolonged cough, high doses of inhaled corticosteroids use and accompanying asthma comorbidities such as chronic rhinosinusitis may explain these symptoms [20-22]. The medications especially inhaled corticosteroids used by the participants in this study did have a significant connection to frequently occurring voice complaints. Fifty- four percent of our asthmatic children were using ICS in our study. The severity of voice disturbances may be increased due to increased inhaler corticosteroid dose. There are numerous reports in the literature on dysphonia in patients using ICS [7-9]. The use of inhaled steroids affects the phonation even in healthy individuals, not only in asthmatics. Sahrawad et al. [23] reported that inhaled corticosteroids (ICS) has a short-term detrimental effect on various acoustic properties of voice on healthy persons. These effects were more evident in connected speech compared to isolated vowel productions.

This study had some limitations. First is that our results are from a relatively small group (n=91). Second is that no further objective tests could be performed due to technical conditions. Subjective voice disorders were analyzed using only the Turkish- pVHI.

Conclusion

Based on the results of our study, the Turkish-pVHI seems to be a useful subjective tool for clinicians to assess voice disorders in children with asthma. Higher pVHI scores were observed in our asthmatic children. As the severity of asthma increased, pVHI scores were increased. Our findings suggest that children with asthma would have more subjective voice disorders than healthy children. We recommend future studies with larger populations to further explore this. Therefore, clinicians should be more aware of voice disorders developing in children with asthma.

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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Filiz S, Selçuk ÖT, Baran RT. Evaluation of Turkish pediatric voice handicap index in children with asthma. Ann Clin Anal Med 2019; Ann Clin Anal Med 2020;11(2):142-145

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The effectiveness of reflexology in children with cerebral palsy with constipation

Tomris Duymaz

Physiotherapy and Rehabilitation, Istanbul Bilgi University, Faculty of Health Sciences, Istanbul, Turkey

DOI: 10.4328/ACAM.6173 Received: 19.01.2019 Accepted: 05.02.2019 Published Online: 11.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):120-124

Corresponding Author: Tomris Duymaz, Physiotherapy and Rehabilitation, Istanbul Bilgi University, Faculty of Health Sciences, 34440, Beyoğlu, Istanbul, Turkey.GSM: +905446302676 E-Mail: tomrisduymaz@gmail.comORCID ID: https://orcid.org/ 0000-0003-0917-2098

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Abstract

Aim: The aim of this study was to investigate the effects of reflexology on constipation severity, defecation frequency, pain and quality of life in the treatment of children with cerebral palsy (CP) with constipation. Material and Method: This study was conducted with a total of 50 SP children aged 4-12 years. The patients were randomized into two groups (n = 25), neurodevelopmental treatment with reflexology, and the other group (n = 25) only neurodevelopmental treatment. Reflexology and neurodevelopmental therapy were applied to all patients in each of the 2 groups, 2 sessions per week for 12 weeks. The functional levels of the patients were evaluated by the gross motor functional classification system. Bristol Stool Scale was used to assess the severity of constipation, Visual analog scale was used to assess pain during the defecation, WeeFIM was used to assess functional independence levels. P-value £ 0.05 was accepted as meaningful for all statistical levels. Results: The mean age of the patients was 7.75 ± 2.70. In the pre- and post-treatment evaluations, a statistically significant improvement was observed in the patients who underwent reflexology in all of the measurements of defecation frequency, stool score, pain and functional in-dependence (p=0.023, 0.026, 0.025, 0.027). However, only a significant improvement in pain assessment was found in the control group (p=0.046). Discussion: As a result of the study, it was found that reflexology treatment applied to children with CP with constipation decreased the severity of pain during defecation with the severity of constipation and increased defecation frequency and functional independence level.

Keywords: Reflexology; Cerebral Palsy; Constipation

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Introduction

Cerebral palsy (CP) is a chronic disease characterized by non-progressive voluntary motor mobility with various medical problems. Constipation is one of the common gastrointestinal problems in children with cerebral palsy [1]. Constipation is seen in 74% of children with CP. The source of constipation is organic and secondary to extra-intestinal abnormalities. Dysphagia is seen as dry, insufficient water and food intake, as well as dysphagia, occurs due to inactivity and slow peristaltic movements of intestinal muscles. The probability of occurrence in quadriplegic type CPs is higher due to increased activity limitation and spasticity [2,3]. Constipation can be a chronic condition that causes social isolation by reducing the quality of life of both the family and the child. It causes complications such as megarectum, variation in bowel movement, soiling, and anal fissures with a lower quality of life if not treated in the early period [4]. Healthy children with regular intestinal movements often have defecation 3-4 times a week [5]. As seen in Park et al.’s study, children with SP have defecation frequency less than once a week or 10 days with longer colonic transit passage [6].

Brain damage in different studies has also been shown to cause gastrointestinal problems. Although dysphagia, vomiting, and constipation are common in children with neurological problems, constipation is the most common among them. Lifestyle and neurological factors such as malnutrition, increased extensor muscle tone or generalized hypotonus, musculoskeletal anomalies, decreased defecation and immobilization together with neurological factors constitute important risk factors for the occurrence of constipation in children with CP [7]. Among the children with CP, especially in patients with a quadriplegic and severe diplegic type involvement, gastrointestinal problems such as reduced quality of life and constipation are more common [8].

Effective bowel management program requires the recognition of predisposing factors and defecation problems in children with disabilities. Conservative methods of treatment of children with CP include pharmacological and non-pharmacological approaches. Stimulant medication and stool softeners help children by reducing symptoms but may cause some side effects. Side effects include colicky abdominal pain, bloating, flatulence, diarrhea, discomfort and nausea drug adverse effects (40.3%). Although physiotherapy methods such as reflexology, abdominal massage, electrical stimulation, biofeedback, exercise, connective tissue manipulation, banding can be used safely in the treatment, the number of studies related to these methods in literature is quite low [9]. Other conservative methods used in the treatment of constipation include intestinal massage, abdominal press, increasing water intake, increasing the use of vegetable oil in main meals, increasing fruit consumption, consuming fiber-rich foods and reducing the food that causes constipation [3].

Reflexology is one of the complementary treatment methods used in the treatment of children with CP. It is a massage technique applied to reference points in hands and feet that affect various parts of the body and visceral parts [10,11]. Reflexology is a technique applied by giving warnings to the trigger points on the feet, hands, and ears without any slider intermediate with hands within certain rules [12]. Reflexology has no known side effects. There are various studies on the historical development of reflexology. It was observed that the pressure applied to certain parts of the body caused anesthesia in certain parts of the hands and feet. These results are divided into 10 meridians with 5 regions on each side of the body. These regions are associated with organs and have ended in the feet with the fingertips. Reflexology and meridian regions are incompatible according to modern reflexology, but the same energy blocks in both of them cause disease. As a result of this information, the external stimulus affects the central nervous system, improves homeostasis, regulates blood flow, provides relaxation and provides general well-being. For these reasons, the importance of reflexology has also increased in recent years and has created hope for families [13].

Few studies have investigated the efficacy of conservative treatment methods on constipation. Therefore, the aim of this study was to investigate the effects of reflexology on constipation severity, defecation frequency, pain, and quality of life in the treatment of children with CP with constipation.

Material and Methods

Participants:

This is a prospective randomized controlled trial conducted in Istanbul Mavi Pusula Special Education Center with 50 children over 4 years old with cerebral palsy diagnosed with chronic constipation according to Rome III criteria. The Rome III diagnostic criteria require 2 or more of the following complaints within the last 2 months: 2 or less defecation per week, having at least 1 fecal incontinence per week, history of excessive volitional stool retention or retentive posturing, history of painful or hard bowel movements, large fecal mass in the rectum, large diameter stools to prevent defecation [14]. Before initiating the study, the signed informed free consent forms were obtained from the enrolled subjects and families of the children. The approval of the Istanbul Bilgi University Clinical Investigations Ethics Committee was obtained with a decree number of 2018-40016-62 dated 2/5/2018.

Inclusion criteria included no surgical intervention in the last 6 months between 4-12 years of age, who had been diagnosed with chronic constipation according to the spastic type CP and Rome III criteria, with GMFCS levels 4 and 5 who had not used laxative medications and enemas for at least 4 weeks prior to the start of the treatment, patients who have not undergone complementary treatment methods such as botulinum toxin injection and reflexology. Exclusion criteria were congenital malformations, inflammatory and metabolic diseases in the gastrointestinal tract, active epileptic attack, dyskinetic, ataxic, and mixed type CP patients with impaired joint deformation to prevent reflexology.

Intervention:

Patients were randomly divided into 2 groups of 25 people.A randomized list is prepared in a computer environment by a statistician for randomization. In this list, the odd numbers for the control group and the reflexology group were given double numbers. The group identification is printed on sequentially numbered cards placed in sealed envelopes. After enrollment, the numbered envelope was opened by the patient and the blind investigator. Neurodevelopmental therapy was applied to all patients in each of the 2 groups, 2 sessions per week for 12 weeks. In the neurodevelopmental therapy sessions, exercises were performed to provide normal motor development according to the current motor development levels of the patients. Duration of the session is 45 minutes.

Patients in the treatment group received reflexology in addition to neurodevelopmental treatment. Reflexology sessions were also given as 24 sessions for 12 weeks in 2 sessions a week. Reflexology session time is 20 minutes. Reflexology application was cleaned every 2 feet. The therapist applied pressure to the reflex points at each of the 2 soles at the base of the right foot without using any intermediate. There are 6 different techniques applied in reflexology as follows: caterpillar, birds’ beak, tornado, butterfly, hooking, and tearing. These techniques differ according to the finger movements of the therapist. In the caterpillar technique, the therapist’s thumb moves by applying pressure up and down on the plantar side of the foot. In the beak technique, the therapist’s thumb and forefinger make a pinch movement. In the tornado technique, the therapist’s hand acts as a circular movement. In the butterfly technique, the therapist places his thumb on the flexed index finger and acts as a butterfly. In the hooking technique, the therapist applies pressure with the thumb and index finger. In the technique of tearing, the therapist applies a four-way pressure to the wider and deeper areas. The technique is selected according to the application area. Low pressure is applied to sensitive areas. In reflexology, the rule is to apply pressure with the thumb and index finger to increase the activation of weak areas. In this way, the stimulation of the surrounding tissues is achieved with more light and rapid movements [12]. In this study, rapid, light worm-like movements were applied to stimulate the gastrointestinal system instead of constant pressure. Slow and strong pressures are considered painkillers, while softer and faster movements are considered stimulants. The gastrointestinal and nervous system at the bottom of the foot is more stimulated for constipation therapy. Patients were given a cup of water to increase blood circulation and accelerate the removal of toxins after the session.

Assessment:

Age, gender, height, weight, body mass index and clinical involvement were recorded in all patients. The functional levels of the patients were evaluated by the gross motor functional classification system. Bristol Stool Scale was used to assess the severity of constipation, Visual analog scale was used to assess pain during the defecation, WeeFIM was used to assess functional independence levels.

Gross Motor Function Classification System (GMFCS) is a standard classification system for classifying the gross motor functions of children with CP. Palisano et al. (1997) developed a 5-level classification system. Level 1: Independent walk. There is a limitation in advanced gross motor skills. Level 2: Walk without aids. There is a limitation when walking in the community. Level 3: Walk with aids. There is a limitation when walking in the community. Level 4: Limitation. Self-mobilization. Moves in public or uses wheelchairs. Level 5: Mobilization is severely limited, although assistive technologies are used [15].

The Bristol Stool Scale (BSS) was developed by Lewis and Heaton at the University of Bristol in 1997 and categorizes the human feces in 7 groups. Fecal form varies according to the time in the column. Therefore, BSS is a fast and reliable indicator of transit time. Although not entirely scientific, this table helps health professionals to better understand the stool patterns when diagnosing. According to the BSS, Type 1: harder stools like nuts; Type 2: sausage-like, lumpy, hard; Type 3: sausage-like surface-slit, Type 4: like sausage or snake, but flat and smooth; Type 5: Soft drops with sharp edges; Type 6: embossed parts with rough edges; Type 7: aqueous, no solids, completely liquid. According to the BSS 1-2 points are shown as “hard stool”, 3-4-5 points “normal stool” and 6-7 points “soft-watery stool (diarrhea)” [16].

Visual Analogue Scale (VAS) was asked to mark a suitable point on a horizontal line with an actual length of 10 cm in order to determine the degree of impact of constipation severity and current conditions on individuals. “0” in terms of the influence of the current situation on the life: no effect on my life, “10” means living unbearable [17].

Functional Independence Measure for Children (WeeFIM) was developed to assess the functional independence of children aged from 6 months to 12 and Turkish validity and reliability made by Tur et al. [18]. WeeFIM includes a total of 18 items in 6 areas, including self-care, sphincter control, transfers, locomotion, communication, social and cognitive. When performing the function of each item in these areas, the score is scored from 1 to 7 depending on whether he/she has received help, on time, or if an auxiliary device is needed. When given task was completed with help, it is evaluated as 1, completely independent, 7 at the appropriate time and safely. Depending on the amount of help, points from 1 to 7 are given. According to this, at least 18 (full dependent), maximum 126 are fully independent points [19].

Statistical analysis

SPSS 22.0 program was used to analyze statistical data. Continuous and categorical data are reported as mean ± standard deviation and number (percentages), respectively. Kolmogorov- Smirnov test was performed to determine the suitability of the data for normal distribution. Wilcoxon and Friedman K, Mann-Whitney U tests were used to compare the variables between the intra and inter groups. P-value £ 0.05 was accepted as meaningful for all statistical levels.

Results

The sociodemographic data of the patients (60% girl, 40% boy) were shown in Table 1. Although the distribution of inter-group patients was homogeneous, 9 of the patients with CP were severe diplegic and 16 were quadriplegic in the reflexology group; 10 patients had severe diplegic and 15 had quadriplegic in the control group involvement.

In the pre- and post-treatment evaluations, a statistically significant improvement was observed in the patients who underwent reflexology in all of the measurements of defecation frequency, stool score, pain and functional independence (p=0.023, 0.026, 0.025, 0.027). However, only a significant improvement in pain assessment was found in the control group (p=0.046). There was a statistically significant improvement in favor of reflexology group in all evaluations after intergroup treatment (p=0.003, 0.003, 0.004, 0.010) (Table 2).

The correlation analysis of the post-treatment evaluations revealed no significant difference between the groups (p>0.05) (Table 3).

Discussion

Many studies have included several methods for the treatment of children with constipation, but the number of studies investigating the efficacy of reflexology is quite low [20]. Therefore, the efficacy of reflexology on constipation, pain, and quality of life was investigated in this study. As a result of the study, it was found that reflexology treatment applied to children with CP with constipation decreased the severity of pain during defecation with the severity of constipation and increased defecation frequency and functional independence level.

Constipation is more common in children with spastic type CP because it is frequently exposed in the presence of spasticity and adversely affects the quality of life [21]. Low ambulation ability in children with CP negatively affects digestive system and is one of the major causes of chronic constipation [20]. Parallel to the literature, the children who participated in this study were observed to have high disability levels as they were at GMFCS IV and V levels.

According to most studies, reflexology has been reported to stimulate the autonomic nervous system. It is thought to affect the body systems by increasing the activity of the parasympathetic system during the application. It has been shown to have an effect on the autonomic nervous system by means of baroreceptor reflex by affecting the heart rate and blood pressure values in healthy individuals when applied reflexology. The effect of reflexology on the autonomic nervous system supports nerve theory. The sensory nervous system is in the organization with the upper enters in brain such as hypothalamus, cortex, and amygdala. These centers include nuclei that affect the central nervous system, such as blood pressure, heart rate, and baroreceptor reflex [22]. In another study, the status of the heart was monitored by connecting the electrocardiogram to the patients during reflexology practice. The results of the study showed that reflexology affects the autonomic nervous system and changes the heart rate. Studies of different populations have been reported to have a sedative effect on stress and anxiety. In patients with cerebral palsy with constipation, reflexology facilitates parasympathetic activity and increases motility and provides defecation facilitation. In addition, it provides general relaxation in the body, lowers abdominal pressure, facilitates parasympathetic activity in the body, stimulates intestinal reflex points and increases intestinal function [23].

The mechanism of action of reflexology enables the patients to relax. Endorphins, known as endogenous opioids, are released when reflexology is applied. In addition, the endorphins are released with the chemical process in the plasma membrane due to the stimulation applied. Electrochemical nerve stimulation is activated when pressure is applied to reference points. In this way, reflexology improves healing and homeostatic balance. This improvement and pain relief is caused by increased blood flow and encephalin release through pituitary gland stimulation [11]. Bishop et al. found that 50 children underwent 30 minutes of reflexology during 6 sessions and increased intestinal function [24]. Woodward et al. applied reflexology to 19 women for 6 weeks and reported that the defecation frequency increased and constipation decreased after the treatment [25]. As a result of this study, it was found 34% improvement in constipation severity of the patients receiving reflexology according to the Bristol Stool scale.

Health-related quality of life is a multidimensional concept and is an important outcome measure involving combined evaluation of main areas and indicators in clinical trials. Children with CP with constipation are more adversely affected by the quality of life than healthy people [26]. Constipation significantly reduces the quality of life of both children and families when seen in addition to other problems [20]. Faleiros et al. reported that in non-pharmacological conservative treatment of quadriplegic children with constipation, 90% or about 70% of patients recovered completely and improved quality of life [3]. Ozkan et al. applied reflexology for 20 minutes in 45 children with spastic type CP and improved their quality of life when compared to the placebo group compared to the WeeFIM questionnaire [27]. In another study by Ozkan et al., they reported a decrease in constipation and an increase in quality of life when they applied reflexology to 12 children with spastic type CP who were aged between 2 and 18 years [26]. In this study, when the quality of life and pain of the children were evaluated, it was determined that reflexology had a curative effect up to 20% in pain intensity and % 29 in life quality by decreasing constipation severity and symptoms.

One of the limitations of this study is that no comparison was made with sham reflexology. The second limitation is the low number of cases, the same therapist doing the treatment and evaluation. The third limitation is that the recovery is not physiologically evaluated. The fourth limitation is the lack of long-term follow-up with short-term effects. The fifth limitation is that there is no comparison with children living in different regions.

Conclusion

Reflexology is a safe method in constipation treatment. As a result of the study, it was found that reflexology treatment applied to children with CP with constipation decreased the severity of pain during defecation with the severity of constipation and increased defecation frequency and functional independence level. According to the results of this study, it has been shown that reflexology can be a part of the methods that can be included in the bowel rehabilitation program in the treatment of children with CP with constipation. It is recommended to use reflexology as a complementary treatment and to apply reflexology application absolutely in constipation treatment.

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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The effects of music therapy on gross motor functions, pain and level of functional independence in children with cerebral palsy

Tomris Duymaz

Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul Bilgi University, Istanbul, Turkey

DOI: 10.4328/ACAM.6171 Received: 19.01.2019 Accepted: 06.02.2019 Published Online: 11.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):115-119

Corresponding Author: Tomris Duymaz, Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul Bilgi University, 34440 Istanbul, Turkey. GSM: +905446302676 E-Mail: fzt_tomrisduymaz@yahoo.comORCID ID: https://orcid.org/ 0000-0003-0917-2098

Abstract
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Abstract

Aim: In this study, we aimed to observe the effects of music therapy on gross motor functions, pain, and functional independence measurement in children with cerebral palsy(CP). Material and Method: One hundred and twenty children with CP between 5-11years of age,were randomly divided into a music therapy(MT)+Neurodevelopmental techniques(NDT) group and only NDT group. The children listened to Classical music disc for 45 minutes. Children were treated by NDT while listening to this music. Children were evaluated with Gross Motor Function Measurement (GMFM-88), WeeFIM for functional indepen-dence measurement,Wong-Baker faces pain rating scale (FACES) for pain intensity before, at the end of treatment and after 3 months of treatment. The treat-ments were given 3 times every week, and totally 15 treatments were applied for 5 weeks. Results: GMFM, functional independence and pain were also im-proved in Group MT+NDT. The differences in improvement of creeping and kneeling, standing, and walking were significant between the two groups (p<0.001), showing the effect in Group MT+NDT was better than that in Group NDT. Discussion: MT, which is applied additionally in the treatment of children with spastic CP, reduces the pain of children more and increases the gross motor functions and functional capacities according to the rehabilitation program applied alone.

Keywords: Music Therapy; Cerebral Palsy; Gross Motor Functions

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Introduction

Cerebral palsy (CP) is a disorder characterized by cerebral functional impairment, often occurring in children in congenital or perinatal, postnatal periods. According to epidemiological studies, the incidence of SP has been reported to be 2-3 in 1000 liveborns in most communities, although the incidence varies between countries and regions [1].The studies show that the prevalence is 4.4 per 1,000 live births in Turkey have been made CP [2]. In children with CP, motor disorders, cognitive deficits, visual and speech disorders are also seen [3]. Functional deficits due to these disorders in children with CP make it difficult for children to fulfill their roles in society and thus affect their quality of life [4,5]. Besides the physical limitations of the child, a life-long treatment process can affect psychosocial development and daily life activities by isolating the child from family and society [6]. The functional level of the child with CP and the level of skill in daily living activities are important parameters in determining and monitoring rehabilitation goals or in shaping the rehabilitation program [7]. Quality of life assessment studies, which determine the level of wellness of the individual from physical, psychological, and social aspects and address the awareness of the effects of the disease on daily life in the event of disease, are increasingly important.

Clinically integrated and multidisciplinary treatment approaches are being implemented to improve disease defects, treat children’s functions, and make them as independent as possible in the social setting [8]. Physical therapy is needed to improve the physical functioning of children with CP. Rhythmic auditory stimulation has been found to be an effective method of additional conventional physical therapy in the rehabilitation of child or adult patients and the ability to perform rough motor activities. It is suggested that rhythmic auditory stimulation and rehabilitation program will be more beneficial in coordination and muscle control losses especially in children with CP. Rhythmic auditory stimulation is defined as a neurological technique with auditory rhythm and physiological effects in motion control and motor system improvement in the rehabilitation program. Rhythmic auditory stimulation in CP type regulates motor control by stimulating functions in the basal ganglion, cerebellum, and spinal cord levels with difficulty in performing rhythmic movements such as walking patterns [9]. Compared to other methods, music therapy (MT) is a cost-effective, noninvasive method that can easily be applied in any environment.

Music is a good tool that attracts children’s attention, motivates and strengthens social communication [10]. Rhythm is the basic element of music [9]. Rhythmic musical stimulation is successful in the treatment of diseases such as CP, traumatic brain injuries, Parkinson’s, stroke in the rehabilitation of motor diseases. Multiple treatment techniques in neurological MT have beneficial effects on sensorimotor, cognitive, and language speech training. In recent years, music has begun to be widely used for surgical and medical treatments, emotional state in chronic situations, anxiety and pain relief. Listening to music can reduce the severity and frequency of pain by affecting the release of opioid substances [11].

MT is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program. MT interventions can be designed to promote wellness, manage stress, alleviate pain, express feelings, enhance memory, improve communication, promote physical rehabilitation [12]. MT has been one of the methods used to heal patients since ancient times [13]. Yu et al. observed that blood pressure and heart rate decreased significantly in children who were treated with MT [3]. Heart rate is also the simplest and the most effective way to evaluate the autonomic nervous system. Sympathetic nervous system depression has also shown a reduction in anxiety and depression levels [14]. MT is characterized by rhythmic melodies and functional movements by increasing attention and memory. Music-based therapeutic exercises will functionally reduce dysfunction by acting on the nervous system [15]. MT can be used to ensure the smoothness of movements that need to be done rhythmically and constantly, such as walking. The music during the exercises was observed to increase strength, endurance, and motivation in the extremity muscles in healthy subjects. It has been reported that the exercises made with commands given in the context of simple rhythmic music are more effective. In a study with spastic diplegic children, it was determined that the performance of children was improved in this way [16].

The aim of this study was to investigate the effect of cerebral palsied children who were rehabilitated with MT on the development of gross motor function, pain, and functional independence only in children who were rehabilitated.

 

Material and Method

Participants

One hundred and twenty children with spastic CP between ages 5 and 11 years were enrolled in this study. The children were classified according to the Gross Motor Function Classification System. The patients were randomized and divided into 2 groups of 60 people. A randomized list was prepared in a computer environment by a statistician for randomization. In this list, the odd numbers for the control group and the MT group were given double numbers. The group identification is printed on sequentially numbered cards placed in sealed envelopes. After enrollment, the numbered envelope was opened by the patient and the blind investigator. The researcher started the session by placing the proper disc CD player before the beginning of the work. Children from 5 to 11 years of age, who had a spastic type CP diagnosis and were able to understand the commands as co-operative, with no hearing problems between GMFCS levels I and III were included in the study. Acute and chronic infectious diseases, coagulation diseases, progressive cerebral diseases such as neoplasms, inherited diseases such as trisomy 21 syndrome, hearing loss, surgery from the upper and lower extremity in the last 1 year, psychiatric problems, weak cooperatives were excluded from the study.

Study design

Neurodevelopmental therapy was applied in the first group music accompaniment and only the neurodevelopmental therapy was applied in the second group without music. A total of 15 treatments were administered for 5 weeks, 3 sessions per week for all patients. The sessions lasted45 minutes. Classical music is preferred as a musical style. The exercises performed in the musical accompaniment are made according to the rhythms in the music. The treatment schedule was planned so that the commands given to the illness and the movements required to be removed are made in the presence of rhythms. The age and body mass index (BMI) of all patients were recorded. The children were evaluated with Gross Motor Function Measurement (GMFM-88), WeeFIM for functional independence measurement, Wong-Baker faces pain rating scale (FACES) for pain intensity before, at the end of treatment and after 3 months of treatment. Outcome measures are described in more detail below. According to the power analysis results, when sufficient the number of participants was reached, the study was stopped. Ethics committee approval for the study was obtained from the Istanbul Science University Ethics Committee for Clinical Researches. The written informed consent was obtained from families of all children.

Outcome measurements

Gross Motor Function Classification System

The gross motor function classification system is a classification system (1997) that was developed in 2007 by Palisano et al. to classify gross motor functions of children with CP. Gross motor function in children with CP, is a standardized method that classifies differences in motor function between sitting and walking in 5 levels. Level 1: Walk independently. There is a limit to advanced gross motor skills. Level 2: Walk without assistive device. There are limitations when walking in society. Level 3: Walk with assistive device. There are limitations when walking in society. Level 4: There is a limit. It’s self-contained. It is carried within the community or uses a wheelchair. Level 5: Even if assistive technology is used, mobility is severely limited [17].

Gross Motor Function Measurement

The gross motor functions of children with CP have been evaluated with the Gross Motor Function Measurement (GMFM-88), which has been widely used in recent years. There are 5 main divisions. It consists of a total of 88 items consisting of 17 in the supine, prone position and turning section, 20 in the sitting section, 14 in the crawling-laptops section, 13 in the standing section and 24 in the walking-running-stair climbing section. Score 0- The movement cannot start. 1- Actively initiates a certain amount of movement (<10%) 2- Completely completes the movement but cannot finish (10% – 90%). 3- Completes the movement independently. Each section score is calculated within itself as a percentage, then the five percent score is summed, divided by 5, and the total percentile score is found [18].

Functional independence measurement (WeeFIM)

It is a useful, short, comprehensive method of measuring functional, educational, and socially functional limitations of the children with CP and other developmental disabilities. The WeeFIM includes 6 items in total, 18 items including selfcare, sphincter control, transfers, locomotion, communication, social and cognitive. In performing the functions of each item in these areas, the score is scored from 1 to 7, depending on whether they get help, whether they do it on time, or whether an auxiliary device is needed. When the task is done with help completely 1; 7 is considered to be totally independent, at the appropriate time and in a safe manner. From 1 to 7 points are awarded depending on the amount of the help. Accordingly, scores of at least 18 (fully dependent) and 126 (fully independent) can be taken [19].

Pain

FACES is a pain severity scale that scales from 0 to 10, which can be determined by the child’s face expressions without the need for communication that will force them to express the pain they feel when they are 3 years old and older. Zero point means no pain at all, 10 points means severe pain at irresistible levels [20].

Statistical analysis: All statistical analyses were performed using SPSS 22.0 (SPSS Inc. Chicago, IL, USA). Continuous and categorical data are reported as mean ± standard deviation and number (percentages), respectively. Kolmogorov-Smirnov test was performed to determine the suitability of the data for normal distribution. Wilcoxon and Friedman K tests were used to compare the variables between the intra and inter groups. P value £ 0.05 was accepted as meaningful for all statistical levels.

Results

Patients participating in the study had the mean age of 7.47±2.38 and a BMI of 14.08±3.15, indicating that the distributions among the groups were homogeneous (p>0.05) (Table 1).

When the pain evaluations were compared, it was determined that there was a significant difference between the groups at the end of the treatment and 3 months after the end of the treatment, but this difference was statistically significant at the advanced level in the MT group (p=0.016, 0.021, <0.001) (Table 2).

In the functional independence measures, there was no significant difference between pre- and post-treatment groups, but there was no significant improvement only in the rehabilitation group in the intra-group evaluations, but there was a statistically significant improvement in the MT rehabilitation group (p<0.001) (Table 3).

Compared within the groups, the mean motor function measurements showed significant improvement in favor of the MT group only at the end of treatment and 3 months after the end of therapy (p=0.014), but there was no significant change in any parameters of the control group in the MT group, while sitting, crawling, standing, walking and total score were statistically improved after the treatment compared to before treatment (p=0.004, <0.001, <0.001, <0.001, <0.001) (Table 4).

Discussion

CP is a disease caused by brain damage that occurs in the process of fetal development and localized in a certain part of the brain. Another method of treatment that has become popular in recent years, while proving the efficacy of neurodevelopmental therapies in CP treatment is music therapy [3,10,11]. In this study, we also investigated the effect of MT on the development of gross motor function, pain and functional independence of the children with CP, and found that the rehabilitation program combined with MT improved gross motor development, functional independence and decreased pain in the children with CP.

There are few studies in the literature about music therapy applications with neurodevelopmental therapy. MT has been known since ancient times, but it is one of the new methods of treatment for CP. People in ancient times have established a connection between music melody and vital rhythm. Researchers have shown that neural functions and music are closely related to each other and that various musical elements can affect different brain regions. Musical rhythms resonate because of the endogenous rhythms in the human body. Musical activities are not related to right or wrong movement, thus children with CP are willing to act in the presence of musical sounds. Various musical activities that can be adapted to all different movements of the children with CP can be applied. For example, percussive musical instruments are useful for improving rough and fine motor skills, improving voice and singing respiratory ability, improving string skill for fine motor skills and hand-eye coordination skills. At the same time, the coordination between musical activities, hands, eyes and the brain is beneficial to the faculty. By means of musical instruments, sounds, auditory perception can make a conscious speech and movement skills become appropriate expressive. During MT activities, many activities such as mental level, coordination, communication skills, social skills, emotional status can be improved [8].

It is known that the rhythms in music are effective on the motor system and that they have developed functional movements, motor planning, and motor neuron activation. In the training of the hemiparetic patients, it was found that the rhythmic music had beneficial effects on the parameters such as walking speed, step length, step symmetry, and it could be used during walking training. At the same time, musical rhythms have been shown to have beneficial effects on cerebellar dysfunction, balance, and coordination by acting on the cerebellum, basal ganglion, cortical lobes, corticocerebellar tract, prefrontal and primary hearing cortex [21]. According to the study by Yu et al., it has been reported that children with 30 CP who are treated with acupuncture have more improvement in their cognitive function, speaking skills, motor skills, self-care skills and social participation than only acupuncture children. In the GMFM, score improvement images in both groups indicated that in the creeping, kneeling, standing and walking parameters more improvement was observed in children treated with MT [8]. Kwak et al. reported that ambulations of 25 children with spastic type CP between 6 and 20 years of age who underwent MT during walking training were better [9]. In this study, it was observed that children who were rehabilitated with MT had a 5.6% improvement in sitting, 12.75% in crawling, 37.5% in standing, 26.31% in walking and 8.82% in total compared to rehabilitated children without music in GMFM scores.

In the literature, MT has been reported to have depressive effects on anxiety and pain in children with SP [3,22]. Klassen et al. found that children with CP who underwent medical treatment in their systematic compulsory examination of randomized controlled trial decreased music pain and anxiety in music [23]. Other studies have reported that MT administered in children with CP is good for the emotional state and reduces the level of anxiety [14]. In this study, it was seen that 16.58% of pain complaints were found in children who were exercised with MT, using the sedative effect of the music mentioned in the literature.

Peng et al. emphasized that MT is a useful treatment modality for MT in total and knee extensor muscle strength, mobility and performance improvement in the rehabilitation of children with CP, as compared to the study of 23 children aged 5-12 years with spastic diplegia [24]. Nasuruddin found that a child with 30 SP between 7 and 12 years old had a group MT of 2 groups separated by 2 groups and found that there was more improvement in motor functionalities, cognitive levels, concentration and quality of life in postures of MT children compared to GMFM-66 score [25]. In this study, the level of functional independence was found to increase by 11.26% in the level of independence of children working with MT.

Conclusion

In conclusion, MT, which is applied additionally in the treatment of children with spastic CP, reduces the pain of children more and increases the gross motor functions and functional capacities according to the rehabilitation program applied alone.

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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Duymaz T. The effects of music therapy on gross motor functions, pain and level of functional independence in children with cerebral palsy. Ann Clin Anal Med 2020;11(2):115-119

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Effect of dehydroepiandrosterone on ovarian morphology and follicular apoptosis following 4-vinylcyclohexene diepoxide induced premature follicle loss in rats

Mehmet Caner Özer 1, Mehmet Kaya 2, Ahmet Berkız Turp 3, Cengiz Bal 4, Nilüfer Erkasap 5, Didem Turgut Coşan 6, Hikmet Hassa 7

1 Department of İnfertility Center, Denizli State Hospital, Denizli, 2 Department of Obstetrics and Gynecology, Mersin State Hospital, Mersin, 3 Department of Obstetrics and Gynecology, Harran University Medical Faculty, Şanlıurfa, 4 Department of Bioistatistics, Eskisehir Osmangazi University Medical Faculty, Eskisehir, 5 Department of Physiology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, 6 Department of Medical Biology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, 7 Department of Obstetrics and Gynecology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey

DOI: 10.4328/ACAM.6163 Received: 13.01.2019 Accepted: 13.02.2019 Published Online: 19.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):104-110

Corresponding Author: Mehmet Caner Özer, Department of İnfertility Center, Denizli State Hospital, Denizli, Turkey.GSM: +905052990855 E-Mail: mc.ozer77@gmail.com.ORCID ID: https://orcid.org/ 0000-0002-4398-9598

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Aim: Chemical-induced depletion of ovarian follicle pool can lead to premature ovarian failure in rats. In the rat model of 4-vinylcyclohexene diepoxide (VCD)-induced ovarian follicular loss, we tested the hypothesis that Dehydroepiandrosterone (DHEA) could be reversed by short and long-term treatment of follicular loss. Material and Method: All rats were divided into groups for study and treated with dimethylsulfoxide (DMSO) (control group), VCD alone, DHEA and VCD + DHEA for only 15 days. At the end of 15 days, some of the rats were killed as a group of 15 days. Others continued their treatment with DHEA to form groups of 35 and 55 days, respectively. For each animal, follicle numbers were counted and photographed. Results: VCD treatment produced a sustainable state of ovotoxicity throughout the experiment, diminishing the numbers of both primordial and primary follicles (p<0.05). Only VCD-treated rats showed apoptotic cells at very high rates with TUNEL and caspase-3 immunohistochemical staining (p <0.05). On 15th day, concurrent use of DHEA increases the percentages of both normal primordial and primary follicles. More cystic follicles were observed in both VCD- and DHEA-treated rats, compared to controls (p<0.05). Discus-sion: In this ovotoxicity model with VCD in rats, administration of DHEA provides protection in the number of primordial follicles in the short and long term.

Keywords: Premature Ovarian Failure; 4-Vinylcyclohexene Diepoxide; Dehydroepiandrosterone; Apoptosis; Rats

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Introduction

Dehydroepiandrosterone sulphate (DHEA) is an endogenous steroid originating from zona reticularis of the adrenal cortex and human ovarian theca cells [1]. It is an essential hormone for ovarian folliculogenesis [1,2 ]. Several studies in the literature have addressed the potential ameliorating role of DHEA supplementation on ovulation, pregnancy and even the miscarriage rates among women with premature ovarian failure or diminished ovarian reserve in IVF cycles [2-6 ].

DHEA supplementation has been found to increase ovarian response, reduce cancellation cycles and increase the embryo quality in poor responder IVF cases [7,8]. Proposed mechanisms for DHEA action have been documented as either acting as a promoting factor for gonadotropin effect by increasing insulin-like growth factors (IGF-1) or by decreasing the atretic follicles, as well as the formation of the polycystic environment in the ovaries [9,10 ]. In addition, it has been reported that there is a synergistic effect between DHEA and gonadotropins or positive effects on follicle recruitment [3,11].

On the other hand, chemical-induced depletion of ovarian follicle pool can also lead to premature ovarian failure in rats and has been proved by several studies using 4-vinylcyclohexene diepoxide (VCD), an occupational chemical used as an industrial diluent for epoxides [12-15]. Collectively, morphological and biochemical findings suggest that VCD results in a follicle loss by accelerating the normal process of atresia in small preantral follicles via apoptosis [13-15].

DHEA induced apoptosis in hippocampal neurons after increased caspase 3 activity and poly (ADP (adenosine diphosphate) ribose) polymerase activity in the absence of trophic factors, and decreased apoptosis induced by DHEA after IGF-1 administration [16]. It has been shown that DHEA (S) protects rat hippocampal neurons against NMDA-induced excitotoxicity and Allopregneline reduces NMDA-induced excitotoxicity in human neurons, DHEA(S) protects allogpregnolon’s chromophore cells and sympathoadrenal PC12 cells against apoptosis in a dose- and time-proportional manner [17].VCD may be thought to be beneficial against apoptosis in response to increased apoptosis in the overlying micro-environment.

The aim of this experimental study is to investigate the effect of DHEA 15, 35, and 55 days of treatment on ovarian follicles following the 15 days of VCD administration and to determine whether VCD-induced ovotoxicity in rat model can be reversed by prolonging DHEA treatment.

Material and Methods

Animals

Immature female Sprague-Dawley rats (28 days old), weighing 40 to 60 gr, were obtained and housed in plastic cages (4 to 6 animals per cage). They were maintained on 12-h light/dark cycles in a well-ventilated room at a controlled temperature of 22±20C. The animals were allowed to acclimate to animal facilities for one week before the initiation of experiments. Rats were provided with food (Purina rat chow, St Louis, MO) and water ad libitum. All the experiments were approved by the Eskisehir Osmangazi University Institutional Animal Care Ethical Committee (TICAM; 02.01.2008/29) and conformed to the Guide for the Care and Use of Experimental Animals.

Treatment

A total number of 120 rats were allocated to this study. Rats were initially treated daily for 15 days with dimethyl sulfoxide (n:10, DMSO, ip; Sigma Chemical CO. St Louis MO, USA,48H0074,11) as vehicle control group; VCD alone (n:10, 160mg/kg/d, ip; Fluka, 1302946, 250 ml, dissolved in 1.1 mixture of DMSO, VCD group) alone and concurrently with DHEA (n:10; Sigma, D4000, 25 g; ip, 6mg/100g body weight/ 0.2 ml DMSO, VCD+DHEA group) and DHEA alone (n:10; Sigma, D4000, 25 g; ip, 6mg/100g body weight/ 0.2 ml DMSO, DHEA group), respectively. After 15 days of dosing, rats were either sacrificed or treatment with DHEA was prolonged to complete total treatment days of 35 (n:40) and 55 days (n:40), respectively.

Estrous cycles of each animal were monitored daily at 08.00 by vagina cytology from the date of vaginal opening to in all rat groups. Rats were sacrificed under the combination of 90 mg/kg ketamine (Ketalar flacon®, 50mg/ml, Pfizer Turkey) and 10mg/kg Xylazine ( Rompun DS® 2% injectable solution, Bayer, Turkey) anesthesia. Sacrification of animals was performed on the evening of days 15, 35, and 55, based on the treatment arms.

Histologic evaluation of follicle numbers

Ovaries were trimmed free of fat and placed in Bouin fixative (2h), dehydrated with serials of ethanol, cleared in xylene, and embedded in paraffin paraffin-embedded and serially sectioned (4-5μm) mounted and stained with hematoxylin and eosin.

Follicles were counted in every 40th section (10-13 sections per ovary) to avoid double counting of small preantral follicles (25-100μm in diameter). Unhealthy follicles were distinguished from healthy follicles by their granulosa cell content pyknotic bodies and intense eosinophilic staining of oocytes, as shown in Figure 1 and 2. Based on the procedure of Flaws et al. [19 ] and briefly summarized as follows: follicles were classified as primordial (oocyte surrounded by a single layer of flattened cuboidal cells), primary (enlarged oocyte surrounded by a single layer of <20 cuboidal cells with no oocyte growth), secondary (oocyte surrounded by multiple layers of granulosa cells), antral (follicles containing a fluid-filled antrum) and atretic follicles (presence of pyknosis and chromatin dispersion and eosinophilic stained oocytes). Sections obtained through the center of the follicles (largest cross-section) were chosen for the immunohistochemistry. Histologic images were captured with an Olympus DP 70 inverted microscope (Olympus Corp, Tokyo, Japan). The final magnification was 40X.

Immunohistochemical evaluation

For all immunostaining procedures, tissues embedded in paraffin were cut in 5μm-thick sections, then deparaffinized in xylene and rehydrated through a graded ethanol series in distilled water. Endogenous peroxidase activity was blocked by immersing the sections in 3% hydrogen peroxide in methanol for 30 min at room temperature.

DNA fragmentation characteristic of apoptosis was detected with TUNEL (TdT-mediated biotin nick end-labeling) test, and by using and Apoptag Plus Peroxidase In Situ Apoptosis Detection Kit (S7101, Chemicon International, USA). After intense washing with distilled water, the sections were then soaked in TdT buffer for 15 min and then incubated with TdT buffer containing biotin for 60 min at room temperature. The biotinylated dUTP molecules incorporated into the nuclear DNA were reacted with HRP-conjugated streptavidin (1:100 dilution) for 30 min at room temperature, after which the peroxidase coloring reaction was performed by immersing section into Tris-HCL buffer (pH 7.6) containing 0.3mg/ml DAB, 10nmol/l imidazole and 0.003%H202. The sections were counterstained with hematoxylin and eosin. Negative controls were reacted in parallel with the omission of the terminal transferase. The evaluation was carried out by counting dark brown cells stained at ×40 magnification in randomly selected sections of each over-tissue with light microscopy (Figure 3).

Caspase-3 immunostaining was performed on tissue sections by using Rabbit Anti-Active Caspase-3 Polyclonal Antibody (AB3623 Chemicon International, USA) as a primary antibody and HRP/AEC (Thermo Fisher Scientific Anatomical Pathology, USA) as a secondary antibody. The intensity of caspase-3 immunostaining was scored by two experienced investigators semiquantitatively on a scale of 0 to 3 as follows: 0- no staining (in follicle developmental stages, in certain oocytes, granulosa, or somatic cells); 1- mild staining; 2- intense staining (Figures 4, 5 and 6). The investigators were blind to the samples of the study groups.

Statistical analysis

Statistical analyses were performed using SPSS for Windows version 15.0 (SPSS, Chicago, IL, USA). Data are presented as mean ± SE or median ± (min, max values) depending on the distribution of variables. The effect of treatments on follicle number (percent normal) and follicle damage (percent atretic) was determined by one-way analysis of variance (ANOVA) with posthoc Tukey test and by the Mann-Whitney U test when necessary. Analyses of TUNEL and caspase-3 immunohistochemical stainings on follicles or ovarian stroma were performed by using the Kruskal–Wallis analysis and the Pearson’s Chi-Square tests, respectively. Significance was assigned at p<0.05.

Results

Menstrual cyclicity, based on vaginal cytology was not abolished in all rat groups during 55 days of the experiment. After 15 days of daily dosing with VCD alone, DHEA, VCD+DHEA, and finally DMSO as a vehicle substance, percentages of follicles in the ovarian tissue sections were shown in Table 1. Based on follicle counting, in the present study, 15 days of VCD treatment alone resulted in a significant loss of normal primordial and primary follicles together with increased atretic follicles, compared to other groups (p<0.001). Additionally, DHEA group has less atretic primordial and primary follicles, compared to DHEA +VCD group, as shown in Table 1. Using DHEA concurrently with VCD increased the percentages of both primordial and primary follicles (p<0.05).

The same scenario was also evident on the 35th day of the experiment. More primordial and primary follicles became atretic in VCD-treated group, compared to other groups, as shown in Table 2. Interestingly, DHEA following VCD use appeared to increase the percentage of normal primordial follicles (p<0.001 compared to VCD group). While, DHEA treatament alone (DHEA group) resulted in a reduced percentage of primary follicles, compared to controls (p<0.05). The same observation is also evident for the findings on 55th day is shown in Table 3, with no effect on primordial follicles.

On the 55th day of the experiment, VCD arms showed similar patterns of results with much higher percentages of atretic follicles and less normal primordial and primary follicles compared to other groups, as shown in Table 3. In addition, VCD+DHEA group had a decrease in the percentage of atretic primordial follicles and a remarkable increases in primordial follicle percentage (p<0.001 compared to VCD group). However, it did not restore the primordial follicle numbers to control levels. On 35th and 55th days of the experiment, prolonging the use of DHEA following the first 15 days of VCD use did not result in an increase in the percentages of primary follicles.

Table 4 shows the distributions of TUNEL positivity among all types of follicles on 15th day of the experiment. As clearly shown in Table 4, both VCD and VCD+DHEA group had a significant TUNEL positive follicles, compared to controls (p<0.01). On 35th day of the experiment, a higher number of TUNEL positive cells were observed, compared to controls, as shown in Table 5. TUNEL positive cells were also evident in secondary follicles of VCD group. On 55th day of the experiment, apoptotic process is only observed in primary follicles of VCD group, compared to controls (p=0.009) and VCD+DHEA group (p=0.01), respectively, as shown in Table 6.

As determined by caspase-3 immunohistochemical staining, there were no apparent differences in the degree of caspase-3 immunostaining of primordial and primary follicles among four groups (p>0.05 in all comparisons, Pearson’s χ2 test). Conversely, on all three planned days of the experiments, VCD group had the highest degree of staining compared to other groups, as shown in Figure 7, 8, and 9, respectively (p<0.05 in all comparisons, Pearson’s χ2 test).

Discussion

The present study has definitely established a rat ovotoxic effect of VCD following 15 days of the treatment. This finding is in agreement with previous studies that have shown that repeated treatment of rats with VCD selectively destroys small preantral (primordial and primary) follicles by accelerating apoptotic events associated with the normal process of atresia [13-15, 18-20]. Following the cessation of VCD dosing, relative to controls, lower percentages of normal primordial, primary follicles were observed in long term, as shown in Tables 1, 2, and 3 respectively. During this period, all treated rats did not exhibit any persistent diestrus state. Mayer et al. [18 ] have shown that 15 days of VCD treatment on rats resulted in a follicular loss by 30th day and an evident disruption in the cyclicity by day 360 following the onset of VCD dosing. Hence, VCD-induced follicular disruption follows a sequence of events with the loss of follicles firstly, followed by loss of cyclicity.

The primordial follicle is the most immature stage of development, largely after birth [21]. As the pool of primordial follicles is depleted, there is a subsequent reduction in the numbers of developing follicles to the point where they can’t be regenerated. Hence, the stage of follicular development disrupted by exposure to environmental and occupational chemicals like VCD determines the detrimental effect on the future reproduction function. DHEA treatment following a concurrent use with VCD for 15 days, resulted in remarkably high percentages of both primordial and primary follicles, is shown in Table 1. As has been explained, following 15 days of VCD dosing DHEA, DHEA treatment was continued. On 35th and 55th days of the experiment, animals were again sacrificed and ovarian morphology was assessed. Interestingly, only the percentage of normal primordial follicles was increased, compared to VCD-treated group. Hence, these findings provide support that concurrent use of DHEA has a long-term protective effect against VCD-induced ovotoxicity on primordial follicles. Which mechanisms are involved in this increment of primordial follicles remains to be elucidated. This observation led us to think of two possible explanations: either the primordial follicles escaped from the VCD-induced ovotoxicity via apoptotic signal reduction or some new follicles were formed to overcome VCD-induced follicle depletion. Bukovsky et al. [22 ] addressed the follicular renewal in adult human and rat ovaries, emphasizing the ovarian surface epithelium (OSE)- derived stem cells. Most probably, diminished apoptotic signaling together with OSE-derived stem cell activation may play a role in mediating the effect of DHEA on primordial follicle pool. However, this possible association requires further evaluation. Elbetagy et al. [23] treatment of granulosa cells with low dose DHEAS increased the expression of androgen receptor, aromatase, 3-beta-hydroxysteroid dehydrogenase, and cyclooxygenase-2, reduced the expression of estrogen receptor beta, and increased estrone and estradiol levels. To sum up, DHEA not only has a beneficial effect on the percentages of primordial follicles but also affects the steroidogenesis. Another important remark is the fact that the percentage of normal primary follicles was decreased and atretic primary follicles were decreased in DHEA arms, as shown in Table 2, 3. Hence, a long-term supplement of DHEA alone has a negative impact on folliculogenesis.

Hassa et al. [11] performed an increase in primordial, primer and growing follicles when DHEA was administered to rats subjected to VCD. In this study, DHEA decreased in the rate of atresia in the given group. It is thought that it may be connected to the change in the microenvironment rubbing together with unexplained reason.

Furthermore, DHEA effect on primordial follicles was observed to be mediated via reduction of apoptosis. On the 35th day of the experiment, apoptotic cell count assessed via TUNEL was decreased in both primordial and primary follicles as shown in Table 5; whereas on the 55th day of the study, TUNEL positivity of primary follicles was low among DHEA+VCD group, compared to VCD-treated group. Meanwhile, at the time points of day 35th and 55th days, the follicles began to exhibit various stages of cystogenesis up to the complete transformation into a follicular cyst together with follicular atresia, often referred as a state of DHEA-polycystic ovary rat model [24,25]. Therefore, dosage and duration of use should be taken into account in implementing DHEA treatment in rat models. Thompson et al. [26] studied repeated dose of VCD on female F344 rats for 15 days with a coinjection of E2 (0.1mg/kg) and concluded that this co-injection protocol selectively protected primary follicles from VCD-induced follicular loss. Same authors also used an estrogen receptor agonist (genistein) in the same setting and found that its concurrent treatment with genistein and VCD restored caspase-3 activity to control levels. Current study together with those of Thompson et al. [26] and Elbetagy et al. [23] emphasizes that hormonal modification of ovarian milieu may be protective against apoptosis.

In summary, our work has clearly shown that over a short and long term, DHEA affords protection against VCD-induced ovotoxicity by increasing the numbers of small preantral follicles and decreasing apoptotic cells in a rat model of ovotoxisity. Extrapolating these results to human tissues needs to be well elucidated. However, long-term administration of DHEA alone may increase atresia. When used with VCD, an increase in normal primordial follicles was thought to be due to a condition affecting the mechanism of apoptosis in the ovarian microenvironment. Further work is needed to explain its mechanism.

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: This project was supported by Eskişehir Osmangazi University scientific committee with the number of 200811013.

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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Özer MC, Kaya M, Turp AB, Bal C, Erkasap N, Coşan DT, Hassa H. Effect of de-hydroepiandrosterone on ovarian morphology and follicular apoptosis following 4-vinylcyclohexene diepoxide induced premature follicle loss in rats. Ann Clin Anal Med 2020;11(2):104-109

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The relationship between serum vitamin D levels and dry eye syndrome in postmenopausal women

Ayşegül Arman 1, İkbal Seza Petriçli 1, Caner Kara 1, Zuhal Köksal 2, Funda Güçel 3

1 Ophthalmology Clinic, 2 Internal Medicine Clinic, 3 Biochemisry Clinic, Etlik Zübeyde Hanım Women Health Education and Research Hospital, Ankara, Turkey

DOI: 10.4328/ACAM.6157 Received: 10.01.2019 Accepted: 12.02.2019 Published Online: 19.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):91-94

Corresponding Author: Ayşegül Arman, Department of Ophthalmology, Etlik Zübeyde Hanim Women Health Education and Research Hospital, 06010, Etlik, Ankara, TurkeyORCID ID: https://orcid.org/ 0000-0003-4223-8570

Abstract
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Abstract

Aim: In this study, we aimed to investigate the association between serum vitamin D levels and dry eye signs and symptoms in postmenopausal women. Mate-rial and Method: Postmenopausal women with severe vitamin D deficiency (Group 1, n=30), moderate deficiency (Group 2, n=27) and those with optimal serum vitamin D levels (Group 3, n=30) were recruited for this cross-sectional study. Dry eye complaints were evaluated by the Ocular Surface Disease Index (OSDI) questionnaire and dry eye signs were evaluated by the Schirmer’s test I, the Tear break up time (TBUT) test, and ocular surface fluorescein staining. Results: The mean vitamin D level of the Group 1 was 7.82± 1.80 ng/ml, that of the Group 2 was 15.88±1.70 ng/ml and Group 3 was 33.47±7.00 ng/ml The percent-ages of patients diagnosed as dry eye were 53.33% for Group 1, 44.44% for Group 2, and 33.33% for Group 3 (p₌0.29). There was no statistically significant difference between Group 1 (37.55 ± 19.20Group 2 (43.58 ±16.79), and Group 3 (40.87 ± 21.32) in respect to the mean OSDI scoresIn addition, there was no any statistically significant difference between the three groups in terms of the mean TBUT (Group 1: 7.73±3.25 secs, Group 2: 6.78±2.99 secs and Group 3: 6.70 ± 3.37 secs) and Schirmer’s test I scores in (Group 1: 9.30 ± 4.86 mm, Group 2: 8.07 ± 4.09mm and Group 3: 9.40 ± 5.49mm) (p₌0.33 vs p₌0.72). Eight patients (26.7%) in Group 1, 5 patients (18.5%) in 19.20 Group 2, and 3 patients (10%) in Group 3 have positive corneal fluorescein staining (p₌0.25). Discus-sion: Serum vitamin D levels have no association with dry eye complaints evaluated by OSDI questionnaire and tear film deficiency and functional integrity detected by the tests in postmenopausal women.

Keywords: Dry Eye Syndrome; Vitamin D; 25-hydroxyvitamin D; Menopause

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Introduction

Vitamin D is a prohormone in steroid structure and has two major forms D2 (ergocalciferol) and D3 (cholecalciferol). D3 is synthesized in human skin by ultraviolet-B radiation (UVB 290-315nm) and consumed in animal-based food, whereas D2 is derived from plant sources and not human-made. Both forms are biologically inactive and activated by enzymatic hydroxylation in liver 25(OH) D and kidney 1, 25(OH)2 D. The synthesis of vitamin D is regulated by the parathyroid hormone in response to fluctuations in serum calcium levels. As a fat-soluble vitamin, it breaks down quickly leading to the stores to deplete and hence deficiency. Worldwide an estimated one billion people have inadequate levels of serum vitamin D in all ethnicities and age groups [1].

The action of vitamin D is mediated by the vitamin D receptor (VDR), a subfamily of nuclear receptors which is found virtually in all cell types [2]. This explains the multiple actions of vitamin D in different tissues. Vitamin D has a substantial role in the regulation of calcium and phosphate metabolism and maintenance of healthy bones. Vitamin D has been reported to relieve inflammatory reactions and regulate cell cycles, increase defence capacity of macrophages, inhibit proinflammatory responses of antigen presenting cells and reduce cell cytokines mainly IL-1, IL-6, IL-12, and TNFα and hence has a key role in immune responses of both adaptive and innate immunity [2,3].

Dry eye syndrome (DES) is a multifactorial disorder of the tear film and ocular surface which causes ocular discomfort, pain, redness, irritation, eye fatigue, itching and vision-related complaints [4]. Studies have shown that inflammation is the core mechanism in the pathogenesis of DES and characterized by increased osmolarity of the tear film and inflammation of the ocular surface [5,6]. Activation of inflammatory pathways by proinflammatory cytokines of IL-1 and TNFα in conjunctival, limbal, and corneal epithelial cells plays a critical role in ocular surface inflammation in DES [7]. Supporting this, increased levels of inflammatory cytokines in the tear film, corneal and conjunctival epithelial cells and infiltration of inflammatory CD4+ T cells into the conjunctival epithelia have been demonstrated [8]. The generally recognized risk factors for DES include elder age, reproductive factors, contact lens use, refractive surgeries, systemic autoimmune diseases, environmental and occupational factors, drugs (antihistaminics, β-blockers, and estrogens) and recently nutritional factors especially essential fatty acid and vitamin D deficiency [9,10].

We hypothesized that vitamin D with its anti-inflammatory and immunomodulatory actions may have releiving effects on ocular discomfort and vision- related complaints related with dry eye. To test this hypothesis we statistically examined the correlation of OSDI, TBUT, the Schirmer’s test I scores and ocular surface fluorescein staining results of postmenopausal women with severe, moderate vitamin D deficiency and optimal vitamin D levels.

Material and Methods

This prospective cross-sectional study was approved by the ethics board of the University of Health Sciences, Etlik Zübeyde Hanım Women’s Health Education and Research Hospital and the guidelines followed were in accordance with the tenets of the Declaration of Helsinki. Written informed consents were obtained from all patients according to the ethics board guidelines. The subjects consisted of postmenopausal women referred from Internal Medicine and Gynecology outpatient clinics to the Ophthalmology outpatient clinic because of complaints of ocular discomfort between March 2018 and July 2018. Patients with Sjögren’s Syndrome, chronic inflammatory and autoimmune diseases; ocular infectious, allergic and cicatricial diseases; eyelid abnormalities; contact lens users, systemic β blocker, antihistaminic estrogen, and any ophthalmic eye drop users and patients underwent any ocular surgeries within last 6 months were excluded from the study. A total of 87 postmenopausal women participated and all patients had serum vitamin D level measurements before referral to the ophthalmology outpatient clinic. After thorough clinical history was taken, comprehensive ophthalmologic examination including dry eye investigations, TBUT, Schirmer’s test I and ocular surface fluorescein staining were performed. OSDI questionnaire was applied to detect patient discomfort and vision-related complaints. Patients were divided into three groups: the first group included patients with severe vitamin D deficiency (n₌ 30), second group included patients with moderate deficiency (n₌27) and the third group included patients with optimal vitamin D levels (n₌30).

Vitamin D measurement

Because of the longer plasma half-life (2 weeks) and higher circulating concentrations, 25(OH)D is the most stable form of vitamin D and serum 25(OH)D measurement is indicative of the body vitamin D storage and status. Peripheral blood samples were collected from each patient after 8 hours of fasting and transported to a certified laboratory. Serum 25(OH)D levels were measured by liquid chromatography/mass spectrometry technique (ThermoFisher Scientific). Optimal level of serum 25(OH)D is >26,8 ng/ml; moderate deficiency is defined as serum vitamin D levels 10,24-26,8 ng/ml and severe deficiency is defined as serum 25(OH)D <10,24ng/ml.

DES evaluation

Dry eye evaluation was made by OSDI questionnaire, TBUT, the Schirmer test, ocular surface fluorescein staining. TBUT is a measure of tear film stability and quality. For TBUT evaluation fluorescein strips (ERC Fluorescein Sodium Strip, Turkey) were placed in the lower conjunctival fornices and patient was asked to blink for a few seconds. After the strips were removed, the patient was asked to blink and then open eyes steady. The time in seconds until the first defect in tear film developed was recorded and the mean of three consequtive measurements was accepted as TBUT. The Schirmer’s test I evaluates tear volume and the integrity of the lacrimal secretion system. Patients were instructed to look up and test strips (ERC Schirmer Tear Test Strip, Turkey) were hooked over the lateral two-thirds of the lower lid and kept there for 5 minutes. The amount of wetting is measured in millimeters. Ocular surface fluorescein staining was evaluated after fluorescein sodium was applied on the ocular surface and after a few blinks were recorded as present or absent in respect to corneal and conjunctival staining. DES was diagnosed according to the expert’s consensus on the clinical diagnosis and treatment of dry eye (2013). The diagnostic criteria: (1) subjective symptoms of dryness and TBUT test ≤ 5 seconds or the Schirmer’s test without surface anesthesia ≤ 5 mm/5 minutes; (2) subjective symptoms of dryness and TBUT test 5-10 seconds or the Schirmer’s test without anesthesia 5-10 mm/ 5 seconds combined with positive corneal fluorescein staining.

OSDI Questionnaire

OSDI (Allergan, Irvine CA) is a DES specific questionnaire developed by the Outcomes Research Group at Allergan. It consists of 4 questions on vision-related functions, 5 questions regarding eye symptoms and 3 questions about environmental triggers on DES. Each question is scored from 0 to 4 and the total OSDI score is calculated according to a standard formula. OSDI score < 13 is defined as normal; scores 13 and above are defined as DES. The validity of OSDI on DES symptoms and vision-related quality of life is confirmed by studies.

Statistics

All statistical analyses were performed with IBM SPSS Statistics version 24. One-Sample Kolmogorov-Smirnov test was used to check the normality of data distribution in each group. Patient characteristics were described using means and standard deviations for continuous variables and percentages and standard errors for categorical variables. The Kruskal-Wallis test was used to analyze the association between groups for continoous variables. The Chi-Square test was used to analyze the association between groups for categorical variables p-value < 0.05 indicted statistical significance.

Results

The clinical characteristics of the study groups are given in Table 1. The mean age of Group 1 was 56±10 (range 38-78), Group 2 was 54±6 (range 44-70), and Group 3 was 56±8 (range 72-74) years (p =0.60).

Although the numbers and percentages of dry eye patients, diagnosed according to the experts’ consensus on dry eye criteria (2013) decreased as serum vitamin D levels increased, the correlation was not statistically significant (p=0.29).

The mean OSDI scores, the Schirmer’s test I levels, and TBUT levels of the groups are given in Table 2. There was no statistically significant difference between groups with respect to mean OSDI scores (p=0.80), the Schirmer’s test I values (p=0.72), and TBUT values (p 0.33). Additionally, there was no any statistically significant difference between groups in terms of corneal fluorescein staining results. (p=0.25)

Discussion

Vitamin D, both a prohormone and vitamin, has receptors in virtually all cell types and has actions in cell proliferation and differentiation, regulation of innate and adaptive immunity [2]. In the eye, vitamin D receptors (VDR) are present on the corneal, lens, and ciliary body epithelial cells, retinal pigment epithelium, corneal endothelial cells, ganglion cells, and photoreceptors. The two potential pathways of vitamin D to enter the eye are either via the circulation or through UV-B induced synthesis. Lin et al. [11] have detected measurable concentrations of vitamin D in tear fluid and in aqueous and vitreous humor; they have shown that tear and aqueous humor 25(OH) D and 24,25 (OH)D2 levels have increased after dietary vitamin D supplementation. In addition, the corneal limbal epithelial cells are able to produce vitamin D, de novo, in culture when exposed to UVB radiation, similar to the cells of the skin [12].

In vivo study by Dang et al. [13], they have shown that vitamin D inhibits proinflammatory cytokines IL-1α and TNFα on corneal grafts and it has significantly suppressed graft rejection and inhibited corneal neovascularization in rat keratoplasty models. In addition, studies have shown that decreased ionized calcium levels in VDR deficient animals, caused the rate of corneal epithelial wound healing to decrease and mucin packaging in conjunctival goblet cells to be altered [14,15]. Vitamin D may play a role in Sjögren Syndrome (SS) pathogenesis and low levels of vitamin D have been found in SS patients [16]. These studies suggest that vitamin D with anti-inflammatory actions and positive effects on corneal epithelial cells and goblet cells may have relieving effects on dry eye symptoms and signs. Massingale et al. [17] have found a correlation between tear IL-6 levels and dry eye complaints of burning, discomfort, and pain. Shetty et al. [18] have found that decreased vitamin D levels were associated with exaggerated symptoms. In our study, we did not find any difference between mean OSDI scores of the groups. The mean OSDI scores and percentages of dry eye patients were high and these results may be explained by the elder age group and postmenopausal hormonal status of the patients. Supporting this, studies have shown that dry eye prevalence increases with advancing age and female gender [19,20].

In our study, although the percentages of dry eye patients increased as the serum vitamin D levels decreased, this was not statistically significant. There are conflicting results about the relationship between dry eye disease and serum vitamin D levels in literature. Jee et al. [21] had not found an association between serum vitamin D levels and dry eye syndrome in a study conducted on 16 396 participants over 19 years of age. Jeon et al. [22] in a study conducted on 740 participants in the Study Group for Environmental Eye Disease, had found no association between serum vitamin D levels and dry eye disease. Additionally, Kim et al. [23] had found no association between severe vitamin D deficiency and dry eye syndrome in the adjusted model. On the other hand, Meng et al. [24] have found a significant association between serum 25(OH)D levels and DES incidence in a study conducted on 70 DES patients and 70 controls.

We did not find any statistically significant difference between the mean Schirmer’s test I and TBUT scores of the three groups respectively. Kurtul et al. [25] demonstrated that vitamin D deficiency decreased TBUT and Schirmer’s test values in non-Sjögren Syndrome dry eye patients. Similar to our study, Shetty et al. [18] have not found any significant correlation between vitamin D levels and DES parameters. Meng et al. [24] have found a positive correlation between serum 25(OH)D levels and Schirmer’s test I scores and conflicting to this, they have found a negative correlation between serum 25(OH)D levels and TBUT scores.

A major strength of our study isthat this is the first study to assess and compare dry eye parameters in three groups with moderate and severe vitamin D deficiency and optimal vitamin D levels in postmenopausal women. Our study has several limitations to interpret the results. First, we measured tear parameters at a single time point but DES is a disease with temporal variations. Secondly, the sample size was relatively small because of being a hospital-based study and larger sample sizes and population-based studies are required to confirm results. Thirdly, our study group consisted of postmenopausal women and we expect a high incidence of dry eye because of the elder age and hormonal status.

In conclusion, the present study revealed no significant association between serum vitamin D levels and dry eye parameters in postmenopausal women. Further studies are required to confirm the results.

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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5. Wei Y, Asbell PA. The core mechanism of dry eye disease is inflammation. Eye & contact lens. 2014;40(4):248-56.

6. [Anonymous]. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92.

7. Pflugfelder SC, de Paiva CS, Li DQ, Stern ME. Epithelial-immune cell interaction in dry eye. Cornea. 2008;27 (Suppl. 1):S9-11.

8. Zheng X, de Paiva CS, Li DQ, Farley WJ, Pflugfelder SC. Desiccating stress promotion of Th17 differentiation by ocular surface tissues through a dendritic cell-mediated pathway. Investigative ophthalmology & visual science. 2010;51(6):3083-91.

9. Lee JH, Lee W, Yoon JH, Seok H, Roh J, Won JU. Relationship between symptoms of dry eye syndrome and occupational characteristics: the Korean National Health and Nutrition Examination Survey 2010-2012. BMC Ophthalmol. 2015;15(1):147.

10. Galor A, Gardener H, Pouyeh B, Feuer W, Florez H. Effect of a Mediterranean dietary pattern and vitamin D levels on Dry Eye syndrome. Cornea. 2014;33(5):437-41.

11. Lin Y, Ubels JL, Schotanus MP, Yin Z, Pintea V, Hammock BD, et al. Enhancement of vitamin D metabolites in the eye following vitamin D3 supplementation and UV-B irradiation. Curr Eye Res. 2012;37(10):871-8.

12. Yin Z, Pintea V, Lin Y, Hammock BD, Watsky MA. Vitamin D enhances corneal epithelial barrier function. Investigative ophthalmology & visual science. 2011;52(10):7359-64.

13. Dang ST, Lu XH, Zhou J, Bai L. Effects of 1alpha, 25-dihydroxyvitamin D3 on the acute immune rejection and corneal neovascularization in high-risk penetrating keratoplasty in rats. Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA. 2004;24(8):892-6, 903.

14. Elizondo RA, Yin Z, Lu X, Watsky MA. Effect of vitamin D receptor knockout on cornea epithelium wound healing and tight junctions. Investigative ophthalmology & visual science. 2014;55(8):5245-51.

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17. Massingale ML, Li X, Vallabhajosyula M, Chen D, Wei Y, Asbell PA. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea. 2009;28(9):1023-7.

18. Shetty R, Sethu S, Chevour P, Deshpande K, Pahuja N, Nagaraja H, et al. Lower Vitamin D Level and Distinct Tear Cytokine Profile Were Observed in Patients with Mild Dry Eye Signs but Exaggerated Symptoms. Transl Vis Sci Technol. 2016;5(6):16.

19. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol. 2009;127(6): 763-8.

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Arman A, Petriçli İS, Kara C, Köksal Z, Güçel F. The relationship between serum vitamin d levels and dry eye syndrome in postmenopausal women. Ann Clin Anal Med 2020;11(2):91-94

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Effects of menstrual cycle phases on preoperative anxiety: A randomized prospective observational trial

Nureddin Yuzkat 1, Celaleddin Soyalp 1, Canser Yılmaz Demır 2, Mehmet Kılıç 1, Nurcin Gulhas 1

1 Department of Anesthesiology and Reanimation, 2 Department of Plastic, Reconstructive and Aesthetic Surgery, Van Yuzuncu Yıl University, Van, Turkey

DOI: 10.4328/ACAM.6159 Received: 11.01.2019 Accepted: 12.02.2019 Published Online: 19.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):99-103

Corresponding Author: Nureddin Yuzkat, Department of Anesthesiology and Reanimation, Van Yuzuncu Yıl University, Dursun Odabaş Medical Center, Zeve Kampus, 65080, Tuşba, Van, Turkey. GSM: +905052294728 F.: +904322168352 E-Mail: nyuzkat@gmail.comORCID ID: https://orcid.org/ 0000-0002-8218-1217

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Abstract

 Aim: Women experience physical and psychological changes as a result of their menstrual cycle. This study aimed to investigate whether the menstrual cycle had any effect on the preoperative anxiety experienced by women who were scheduled to have an operation. Material and Method: One hundred female patients who were scheduled to undergo a septorhinoplasty, and who met the inclusion criteria, were enrolled in the present study. The patients were divided into two groups according to the phase of their menstrual cycle: Group F (follicular phase) and Group L (luteal phase). The patients’ anxiety level was measured preoperatively using the State-Trait Anxiety Inventory Scale. The patients’ heart rate and blood pressure measurements were performed preoperatively as well as at 1 min, 5 min, and 10 min after intubation. Results: The preoperative anxiety scores of the patients in the luteal phase (41.14) were statistically signifi-cantly higher than those of the patients in the follicular phase (36.04). The blood pressure, heart rate, and peripheral oxygen saturation values were found to be similar between the two groups. Discussion: We believe that preoperative anxiety is higher during the luteal phase of the menstrual cycle than during the follicular phase, but the hemodynamic data were similar in both phases.

Keywords: Anesthesia; General Anesthesia; Follicular Phase; Luteal Phase; Menstrual Cycle; Preoperative Anxiety

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Introduction

Preoperative anxiety is a condition that can negatively affect anesthesia, surgery, and postoperative recovery [1]. In fact, it has been shown that preoperative anxiety affects patients in both cognitive and physiological ways. If such anxiety is not correctly managed, it may lead to surgical procedures being postponed or canceled, or it may result in delayed postoperative wound healing. Anxiety can arise for a number of reasons, including a patient’s concern about his/her health and surgery, uncertainty regarding possible outcomes, fear of not waking up after surgery, and fear/experience of pain. It has been suggested that preoperative anxiety might be experienced by as many as 80% of patients [2,3]. It has also been reported that anxiety directly increases a patient’s blood pressure and changes his/her pulse rate, which might lead to hemodynamic instability during anesthesia [4,5].

The menstrual cycle is a physiological event accompanied by fluctuations in certain hormones, including estrogen and progesterone [6]. The menstrual cycle involves two basic phases, namely the follicular phase and the luteal phase [7]. Hormonal, physical, and psychological changes occur in women as a result of the menstrual cycle. Hence, it has been suggested that there is a strong relation between the menstrual cycle and an individual’s emotional state [8]. It has previously been established that women feel well during the first phase of the menstrual cycle, while they face emotional, physical, and behavioral difficulties toward the end of the cycle [9]. Indeed, studies have shown that women experience anxiety, dysphoric discomfort, irritability, mood changes, depression, anger, and sleep disorders prior to menstruation [10,11]. In addition, the hemodynamic response might increase, depending on the physiological and psychological stress condition, during the luteal phase [12].

Various studies have been conducted with regard to the physiological and hemodynamic effects of the menstrual cycle. However, the effects of the different phases of the menstrual cycle on preoperative anxiety have not yet been investigated to an adequate extent. The present study hypothesizes that preoperative anxiety will vary according to the phases of the menstrual cycle.

The aim of this study was hence to investigate the effects of the different phases of the menstrual cycle on preoperative anxiety in patients scheduled to have surgery.

Material and Methods

The present study was conducted among patients who were scheduled to undergo a septorhinoplasty. All prospective septorhinoplasty patients who attended the hospital for a routine preoperative examination were informed about the study. After ethical approval had been received (Ethics Committee IRB Approval Date: 17 Jan 2018, Decision number: 02) and written informed consent had been obtained from the patients, the study was initiated. After the clinical trial had been recorded, the cases were started (NCT03708679).

Inclusion criteria for the study

Patients who did not smoke, did not drink alcohol, and did not use oral contraceptives; who did not report any irregular menstrual cycles (28±2-day menstruation cycle); who were between 18 and 45 years of age; and who were considered to be in the American Society of Anesthetics (ASA) I-II Group were included in the study.

Exclusion criteria for the study

Patients who were determined to exhibit difficulties in communication; who reported experiencing amenorrhea, pregnancy, delirium, psychological diseases, and major depressive disorders; who had malignancy and acute kidney failure; and who were older than 45 years of age were excluded from the study.

Groups

Information regarding their menstrual cycles was obtained from all the patients. The length (days) of the menstrual cycle was counted from the first day of the last cycle. Those patients who were found to be between the 8th and 12th days of the menstrual cycle were enrolled in Group F (follicular phase), while those who were found to be between the 20th and 24th days of the menstrual cycle were enrolled in Group L (luteal phase) [13]. The follow-up of the cases and the recording of the measurements were carried out by an anesthesiologist who was unaware of the patient groups.

Study procedure

The ages, heights, weights, and ASA scores of the patients were recorded while they were in the preoperative unit. The patients were divided into groups based on the dates of their last menstrual cycles. Standard monitoring procedures were used with all the patients, including electrocardiogram (ECG), heart rate (HR), non-invasive blood pressure (NIBP), and peripheral oxygen saturation (SpO2). After 10 minutes of resting, the patients’ hemodynamic measurements were recorded at both the 5th and 10th minutes post-resting. Instant anxiety measurements were also performed. For this, the State-Trait Anxiety Inventory for AdultsTM (STAI-AD) [14] scale was used. When using this scale, scores of between one and four are awarded for each of the 20 included statements. The sum of the points awarded with regard to positive feelings (statements 1, 2, 5, 8, 10, 11, 15, 16, 19, and 20) was subtracted from the sum of the points awarded with regard to negative feelings (statements 3, 4, 6, 7, 9, 12, 13, 14, 17, and 18), with the resultant figure then being multiplied by a constant of 50. The scores for all the patients were added together to obtain the overall STAI-AD scores for the groups (Figure 1).

The standard monitoring process continued after the patients were transferred to the operating room. The patients’ values were recorded before and after the induction of anesthesia, and again at the 1st, 5th, and 10th minutes after intubation. The venous vein was opened using a 20 G i.v. cannula. Then, 1 mg/kg of lidocaine, 2 μg/kg of fentanyl, 2 mg/kg of propofol, and 0.6 mg/kg of rocuronium were administered to induce anesthesia. If a maintenance dose was required, 0.5 mcg/kg of fentanyl, 0.2 mg/kg of rocuronium, and 1% of sevoflurane were used. Throughout the operation, 40% oxygen and 60% of medical air were used. The maintenance fluid required for the patients was provided with 0.9% NaCl. Once the procedure had been completed, the durations of both the surgery and the anesthesia were recorded.

Statistical analyses

The descriptive statistics concerning the investigated characteristics were expressed as the mean, standard deviation, minimum, and maximum values for the continuous variables, while they were expressed as the number and percentage for the categorical variables. The independent t-test was employed to compare the group means for the continuous variables. The Chi-Square test was employed to determine the relation between the groups and the categorical variables.

Based on the recommendations of previous studies [15-17], the standard deviation (σ) was considered to be 2.5 due to the number of anxiety scores (STAI-AD). The effect size (d) was assumed to be 0.9, while a Z value of 1.96 was used for the 0.05 type I error rate. The sample size was determined to be 45 by using the equation for sample size calculation (n = Z2.σ2/d2), and 50 patients were included in each group. A p-value of <0.05 was considered to be statistically significant. Statistical Package for the Social Sciences (SPSS) v. 20.0 software (IBM SPSS for Windows, SPSS Inc., Chicago, IL, USA) was used to analyze the data.

Results

A total of 100 female patients were included in the present study. The patients’ demographical data were found to be similar (p>0.05) (Table 1).

The mean anxiety score for Group L was determined to be statistically significantly higher than that for Group F (p<0.05) (Figure 2). The highest anxiety scores were found to be 71 in Group L and 50 in Group F, respectively.

No statistically significant differences were detected between the groups with regard to the systolic, diastolic, and mean blood pressures, heart rates or the peripheral oxygen saturation values (p>0.05). The average blood pressure values of the groups are shown in Table 2.

Discussion

This study showed that the level of preoperative anxiety was higher in the septorhinoplasty patients who were in the luteal phase of their menstrual cycle. However, it was also determined that the blood pressure, heart rate, and peripheral oxygen saturation values were similar between the two groups. Our findings are consistent with those of previous studies, which reported higher levels of anxiety during the luteal phase of the menstrual cycle [6,7,18].

Premenstrual stress, which is observed during the luteal phase of the menstrual cycle, is characterized by physical, psychological, and behavioral changes, which are believed to affect 75% of women of reproductive age [19]. Previous studies have suggested that the functioning of the autonomic nervous system during the luteal phase might be related to various psychosomatic and behavioral symptoms that occur during the premenstrual period [20].

Kanojia et al. [7] conducted a study among healthy young women, and they reported that the average anxiety score during the luteal phase (46.96) was higher than that during the follicular phase (40.64). In the present study, it was likewise determined that the level of preoperative anxiety was higher during the luteal phase than during the follicular phase. The results of our study are hence in line with those reported in the literature. These results are consistent with the notion of psychological changes being induced by stress and with the stress-related psychological changes reported to occur during the luteal phase of the menstrual cycle. Similar to the present study, Gonda et al. [18] investigated the fluctuations in psychological symptoms that occur during the menstrual cycle. They determined that the anxiety level during the luteal period was higher than that during the follicular period. According to the utilized measurement scales, they detected psychological fluctuations, at least to some degree, in all participants. The fact that all our patients were scheduled to undergo aesthetic surgeries might have influenced both the anxiety measurements and hemodynamic reflections. The hemodynamic effects might differ in relation to different surgeries.

The luteal stage, during which the estrogen and progesterone hormone levels decrease, is associated with high irritability and negative mood. Thus, ovarian steroids are considered to be important predictors of fluctuations in women’s moods during the menstrual cycle [21]. However, several prior studies have reported there to be no change in women’s moods during the luteal phase [22,23]. Natale et al. [24] considered that this difference might be due to the scales employed in such studies. For instance, Redei et al. [25] directly compared the daily hormone measurements and the reported moods of women, and they concluded that there was no relation between the estradiol and progesterone levels and women’s moods. Schwartz et al. [26] measured the daily ovarian hormone levels in women and reported that women’s moods were not related to their hormone levels. They also reported that individuals’ stress level and physical health status exerted a major impact on their mood, although fluctuations in ovarian hormones had little effect. In our study, while there were differences in the anxiety scores between the groups, the blood pressure, heart rates, and peripheral oxygen saturation values were not found to differ. This caused us to consider that the increased anxiety scores did not reach a level that might affect the hemodynamics during the luteal phase. In addition, the fact that the participants in our study were young and healthy individuals might also have influenced their hemodynamic stability. It is likely that different results would be found in older individuals and those with comorbidities.

Hemodynamic changes might also be observed during different phases of the menstrual cycle due to the effect of the hormones secreted during those phases [6,13]. In previous studies, it has been reported that the plasma norepinephrine levels and sympathetic activity in healthy women were found to be higher during the luteal phase than during the follicular phase [13,27]. It has also been reported that there were higher systolic blood pressure levels, as well as lower diastolic blood pressure levels, during the luteal phase due to the physiological and psychological stress that occurs during that phase impacting the hemodynamic response [12]. In our study, however, we did not find any differences between the patients’ systolic, diastolic, and mean blood pressures. This difference might be due to the fact that our patients were all healthy and young individuals. Further, our patients were all ASA I-II patients, and they did not have any comorbidities. Similar to our study, Kanojia et al. [7] reported that the menstrual cycle only affected participants’ hemodynamics to a minimal extent, while Gonda et al. [18] did not report any hemodynamic changes related to the different phases of the menstrual cycle.

Various studies have investigated the effects of the menstrual cycle on anesthesia, traumatic intubation, and the hemodynamic response to laryngoscopy. Hanci et al. [13] reported that the heart rates and blood pressures that were measured one minute after intubation were significantly higher in those patients who were in the luteal phase than in patients who were in the follicular phase. They reported that the altered hemodynamic responses observed in the face of intubation during the different menstrual cycle phases (rate pressure product [RPP]) might be associated with the increased response to plasma norepinephrine levels and sympathetic activity seen during the luteal phase. Khan et al. [28], however, reported that they detected more stable hemodynamic responses during the luteal phase. They also detected higher blood pressures and lower heart rates during the follicular phase. Hence, they recommended that any required surgeries should be scheduled during the luteal phase [28]. Yet, in a meta-analysis, it was reported that the current evidence is inadequate to determine the most appropriate phase of the menstrual cycle (luteal or follicular) during which to schedule anesthesia and surgery. The authors, therefore, stated that further randomized clinical trials were needed [29].

Limitations of the study

It must be acknowledged that the present study did have a number of limitations. The fact that the majority of patients were in the third decade of life might have had an impact on the finding of similar hemodynamic results. Further, we were unable to measure the patients’ estrogen and progesterone levels in the present study. The inability to evidence the accuracy of the patients’ menstruation phases using hormonal parameters hence represents another limitation of the study.

As a result, based on the results of the present study, we believe that the level of preoperative anxiety is higher during the luteal phase of the menstrual cycle than during the follicular phase, but the hemodynamic data were similar in both phases. However, more randomized studies are required to confirm our results.

Acknowledgments

We would like to thank Prof. Sıddık Keskin M.D. for performing the statistical analysis of the data in this study.

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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10. Erden V, Yangn Z, Erkalp K, Delatioglu H, Bahçeci F, Seyhan A. Increased progesterone production during the luteal phase of menstruation may decrease anesthetic requirement. Anesthesia Analg. 2005;101(4):1007-11.

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Yuzkat N, Soyalp C, Demır CY, Kılıç M, Gulhas N. Effects of menstrual cycle phases on preoperative anxiety: A randomized prospective observational trial. Ann Clin Anal Med 2020;11(2):99-103

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Rib fractures: Could we accelerate the healing?

Mustafa Calik 1, Saniye Goknil Calik 2, Mustafa Dagli 3, Mustafa Cihat Avunduk 4

1 Department of Thoracic Surgery, Health Sciences University, Konya Training and Research Hospital, 2 Department of Emergency and First Aid Program, Vocational School of Health Services KTO Karatay University, 3 Department of Cardiovascular Surgery, Health Sciences University, Konya Training and Research Hospital, 4 Department of Pathology, Necmettin Erbakan University Meram Faculty of Medicine, Konya Turkey

DOI: 10.4328/ACAM.6156 Received: 07.01.2019 Accepted: 18.02.2019 Published Online: 19.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):86-90

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

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Aim: We thought about “How fractures are improving more rapidly.” For this purpose, we made an experimental model to investigate the effect of zinc supple-mentation on the development of new bone in young rabbits. Material and Method: Six weeks of age, male New Zealand white rabbits were evaluated in four groups, each including five subjects. To simulate the RFs, subperichondrial costal cartilage resections beginning from the third costal cartilage were carried out in the right hemithorax according to groups. Rabbits in Group 1 and 2 underwent partial resection of the two ribs; rabbits in Group 3 and 4 underwent total resection of those. Zinc was administered by intraperitoneal injection of 6 mg/kg/ day for four weeks after the surgery for group 2 and 4. The animals were followed-up at the twenty-fourth week of their life. Results: We analyzed histologic changes in the bone. There were statistically significant differences for osteoblasts and osteoclasts among all subgroups. Histologic consolidation was significantly increased by zinc supplementation. According to the literature, in our study, while zinc stimulates osteoblastic bone formation, suppresses osteoclastic bone resorption. Discussion: Although the proper treatment of rib fracture (RF), long-term disability and persistent chest wall pain frequently develop and may take several months to recover, leads to the high hospital, medicine, labor, and social burden. Our findings indicate that zinc supplementation accelerates the consolidation of ribs. Zinc can be used to increase the bone maturation such as the site of new bone formation in RF.

Keywords: Zinc; Supplementation; Rib Fracture; Rabbits

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Introduction

Mortality due to trauma ranks third after cardiovascular diseases and cancers among the causes of adult death worldwide [1]. Rib fractures (RFs) are a common injury affecting greater than 145,000 people each year in the United States, with at least one-third of patients requiring hospital admission [2]. It is clear that this number is higher, considering that 77% of patients with rib fractures are not applying to emergency departments.

Historically RF’s treatment is symptomatic, based on pain control with analgesics including narcotics and non-steroidal anti-inflammatory drugs (NSAIDs), respiratory physiotherapy, and specific treatment of associated complications [3]. Approximately 31% of them will encounter complications including nosocomial pneumonia, prolonged respiratory failure, prolonged hospitalization, or death, due to coexisting injuries, age, and comorbidities [2-4].

Hydroxyapatite crystals, which are the mineral structure of bone, contain many trace elements such as zinc (Zn), first described in 1941. Although these trace elements are a very small part of the bone mass, they are very important and vital for bone metabolism. [5,6]. Zinc promotes bone formation in both people and animals by stimulating osteoblast proliferation and differentiation, increases stimulating osteoblastic bone mineralization by way of alkaline phosphatase activity and collagen synthesis. Also, while inhibiting bone resorption suppresses differentiation of osteoclasts [6-8]. Despite up-to-date treatment, long-term disability and persistent chest wall pain frequently develop and may take several months to recover, leads to the high hospital, medicine, labor and social burden [2-4]. We thought about “How fractures are improving more rapidly.” For this purpose, we made an experimental model to investigate the effect of zinc supplementation on the development of new bone in young rabbits.

Material and Methods

This experimental study was carried out at the Experimental Medicine and Research Centre of local University. A total of the same generation six weeks of age, male New Zealand white rabbits ( 740-980 gr ) were randomly evaluated in four groups, each including five subjects. All animals received humane care and were used in compliance with standards established by the European Convention for Animal Care and Use of Laboratory Animals. The rabbits were fed a standard pelleted diet and were allowed to access tap water ad libitum. The animals were housed in standard individual cages on a 12-h light/dark cycle at room temperature in a humidity-controlled environment. The local Animal Ethical Committee approved all study-related procedures (2006/03). This study was approved and funded by the School of Medicine Animal Care and Investigational Committee in our institution. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

Study Design

Groups

The subjects were divided into four equal groups, each containing five rabbits. Before the operation, the rabbits were numbered and weights were noted in grams. The entire process was performed under general anesthesia under sterile conditions. Subperichondrial costal cartilage resections beginning from the third costal cartilage were carried out in the right hemithorax. Rabbits in Group 1 and 2 underwent partial resection of the two ribs; rabbits in Group 3 and 4 underwent total resection of those. Costochondral joints were saved in partial resections and removed in total resections. Three-quarters of the costal cartilages were removed in partial resections.

Anesthesia

Ketamine HCl induced general anesthesia (Ketanest, Pfizer Pharma GmbH, Karlsruhe, Germany) 15-20 mg/kg i.v. or 20-25 mg/kg i.m. moreover, maintained by Xylazine (Alfazyne 2%; Alfasan International. BV, Woerden, Netherlands) 0.5-1 mg/kg i.v. or 1-2 mg/kg i.m. If needed, same dosages of Ketamine HCl and Xylazine were repeated with reflex responses (pedal reflex, palpebral, and corneal reflexes) to keep the anesthesia depth constant. Body temperature was monitored by inserting a heat probe into the ECG and rectum with the aid of needle electrodes. Heating lamps were used to keep the animals at 37±5°C body temperature during the surgical preparation and working period. The mean anesthesia time was 12-15 min for each rabbit. No animals were treated with any local and systemic antibiotics.

Operation technique

Subjects were placed in the right lateral decubitus position on the operating table with spontaneously breathing.Then, chests were shaved and cleaned with a povidone-iodine solution (10% povidone-iodine, Betadine, Kansuk, Istanbul, Turkey); lateral thoracotomy incision was carried out after infiltrating with 1% lidocaine and with 1:100000 epinephrine (Jetokain Simplex ampule; Adeka Pharmaceutical Company, Istanbul, Turkey). The pectoral muscles were divided along the laterally to allow exposure of the costal cartilages and thoracic wall. A horizontal incision was made over the third and fourth costal cartilage level. Subperichondrial costal cartilage resections were carried out in the right hemithorax according to groups. In each subject, bleeding and pneumothorax control was performed with sterile serum saline. After all controls, the chest wall was closed with continuous sutures by anatomical layers without any grafting.

Postoperative Care and Follow-Up

Pain control in animals was provided by Tradomol HCl (Contramal, 100 mg 2 ml, Abdi Ibrahim Ltd., Istanbul, Turkey) 1-2 mg/kg/day i.m. for five days during the postoperative period. The animals were followed-up untill the rabbits were accepted to go into adulthood at the twenty-fourth week of their life. All animals were euthanized with a lethal IV dose of Non-barbiturate anesthetic (Ketamine/Xylazine) painlessly according to the existing instructions established by the latest report of the AVMA Panel on Euthanasia. Three times the anesthetic dose was used for euthanasia [9].

Zinc protocol

Zinc sulfate (ZnSO4) (Merck, CAS number 7446-20-0 Darmstadt, Germany) was in crystalline form. The solution was prepared by dissolving 1 mg/ml in distilled water to make the stock solution. It was stored at 4°C at which it could remain stable for at least a month. The solutions to be injected were prepared by diluting stock solutions using 0.9% NaCl (0.1 mg/1 ml) on a daily basis. Working solutions were used within 1 hour following the preparation. Zinc was administered with 0.5 ml of saline by intraperitoneal injection of 6 mg/kg/ day at 10-12 every day for four weeks after the surgery for Groups 2 and 4 [10].

Pathological Evaluation

All materials were decalcified in 10% buffered formaldehyde for 48 hours after the fixation period until they were tempered enough to be cut with a microtome. Tissue specimens from appropriate sites were then taken for the autotechnical follow-up, embedded in paraffin and stained with Hematoxylin & Eosin (H&E) and sectioned with a microtome to calculate the osteoclast, osteoblast, lymphocyte count and the area of new bone formation (Figure 1). All stained preparations were examined with Nikon Eclipse E400 light microscope (Nikon Corporation. Minato-ku, Tokyo Japan). Care was taken to select as possible as the same areas for each case in evaluating. The selected areas were scanned with a Nikon Coolpix 5000 digital camera (Nikon Corporation. Minato-ku, Tokyo Japan) with a microscope mounted at the same microscope magnification. At the same time, Nikon Stage Micrometer (MBM11100, Nikon Corporation. Minato-ku, Tokyo Japan) images were also taken for calibration with the same microscope magnification. All images were transferred to a PC environment for analysis with Clemex Vision Lite 3.5 (Clemex Technologies inc. Longueuil, Quebec Canada) (Figure 2). First, the length was calibrated with Nikon Stage Micrometer (MBM11100, Nikon Corporation. Minato-ku, Tokyo Japan). After the calibration, the area to be examined was determined as 38732.7μm2. The osteoblasts, osteoclasts, and lymphocytes on the 38732.7 μm2 areas selected on the digital images of H&E stained preparations were marked and automatically counted by the mentioned image analysis program. The damaged cells were excluded from the evaluation during the examination.

Statistical analysis

All data were assessed using the Statistical Package for Social Sciences (SPSS) 18.0 portable for Windows (SPSS Inc, Chicago, Illinois, USA). In every subgroup, we analyzed histologic changes in the bone. The effect of zinc treatment between groups was evaluated by using the Kruskal-Wallis test and the Mann-Whitney U test. There were statistically significant differences for osteoblasts and osteoclasts between all subgroups (Table 1). A p-value (<0.05) was used to indicate a significant difference.

Results

Regardless of the cause of deaths animals were replaced with new ones. All rabbits have been included in our experiment lived up to the end of the study. There were no local complications such as skin reaction, wound infections, or bleeding around the operating. There were statistically significant differences for osteoblasts and osteoclasts among all subgroups (Table 1). Table 1 shows no statistically significant difference between groups in Groups 1 and 2 except fibroblasts, Lymphocytes, and VEGF when compared to in Zn (Groups 2 and 4) and non-Zn groups (Groups 1 and 3). The difference was in osteoblasts, osteoclasts, and fibroblasts between only Groups 1 and 2. Table 2 shows the mean and standard deviation values of all groups. While there was no difference in VEGF between the groups, the numerical difference was higher in Zn than in non-Zn groups. They were affected by the shape of the surgical dissection.

There was no difference in lymphocytes. However, there were more lymphocytes in the Zn group than in the non-Zn groups. Zinc application increased the number of lymphocytes. Besides, the number of lymphocytes was affected by the shape of the resected ribs.

There was no significant difference between the groups except for the Groups 1 and 2. There is only a significant difference between these groups. We believe that growth center conservation and limited resection are the causes of this difference. Although the same numbers of ribs were removed, there was no statistically significant difference between the Groups 3 and 4 in which the growth center was not preserved, and the mean and standard deviation values were higher. Fibroblasts increased in groups where the growth center was not preserved. There were more fibroblasts in the Zn group than non-Zn.

Osteoblasts were significantly higher in each group of zinc than in each group without zinc. However, the groups in which the growth center was resected (Groups 3 and 4) were lower than the non-resected groups (1 and 2). Even the positive effect of zinc did not prevent this decline. However, the partial resection in Group 1 was similar to the total resection in Group 4 with Zn. Zinc has the same effect on the conservation of the growth center.

Osteoclasts were statistically significant and low in Zn groups compared to those without zinc. However, in the groups in which the growth center was resected (Groups 3 and 4), it was more than the groups that were not resected (Groups 1 and 2). Zinc groups are less in zinc-free groups. Zinc decreases osteoclasts and increases bone mass. Osteoclasts are less in Zn groups than in non-Zn groups. It decreases osteoclasts, thus increasing bone mass and consolidation. Histologic consolidation was significantly increased by zinc supplementation. By the literature, in our study, while zinc stimulates osteoblastic bone formation, suppresses osteoclastic bone resorption.

Discussion

Traffic accidents are the most frequent cause of hospitalization and RF, and anticipated to increase by 65% until 2033 in developing countries. For this reason, it seems certain that we will encounter more RF in the coming years. Chest pain depending on RFs is caused by broken bones and injured muscles. It is generally exacerbated by any movement of the chest wall including deep breathing and coughing in even normal breathing movements. The current standard treatments especially inpatients (patients be in the hospital) are based on powerful pain control intervention such as epidural analgesia, intrapleural local anesthetics instillation, rib blocks, and intravenous narcotics/NSAIDs. Outpatients with RFs are most commonly treated only with relatively powerless oral analgesics such as narcotics and NSAIDs (NSAIDs). After being discharged from the hospital these powerful treatments are terminated. Patients are to be left alone with severe pain that takes several weeks to heal [4]. Despite all treatment options, 31% of the cases get into complications such as nosocomial pneumonia, prolonged respiratory failure, long-term hospitalization, or death due to age, accompanying the comorbid disease, and traumas [2-4]. Although the number of RFs and the age of the patient are designated as the factors that increase mortality and morbidity in the literature, this situation is controversial [11]. While high morbidity is defined in patients older than 65 years, a similar high mortality and morbidity tendency has been described in younger patients [12]. The number of RF is similar. Whitson and colleagues showed that high mortality and morbidity were not associated with the number of RF in 35.467 disease series. However, they did not assess whether rib fractures worsened or exacerbated existing comorbidities or had any effect on the severity of the accompanying injuries [13]. On the other hand, Jones et al. identified five and more RFs as an independent cause of mortality in 98.836 series of disease. This needs to be explained [14]. Mortality that ranges from 2 to 20% and morbidity mostly due to the accompanying injuries are reduced with the control of pain in chest traumas and especially in RFs. They are reduced by the provision of pain and bone stability [15].

In the literature, there are a lot of experimental studies relating to Zn and bone healing. To our knowledge, this is the first study about the zinc and RF. It is the only trace element affecting the basic structure or functions of osteogenic enzymes involved in bone development and healing. [6]. In many parts of medicine including cardiothoracic surgery, oral surgery and orthopedics, controlled and guided bone growth is based as well on bone metabolism consisting of osteogenesis, bone modeling and bone remodeling [16]. According to the significant effect on the bone formation by zinc, we hypothesized that the in the treatment of rib fractures after median sternotomy the oral surgery can be used to accelerate healing. Our experimental model was similar to a rib fracture model, in addition, the growth center of the ribs was resected. [11]. In the literature, minimal cartilage resection and saving the growth center of the ribs at costochondral junctions has been suggested in order to produce faster healing [17]. Nevertheless, histologic consolidation was significantly increased by zinc supplementation even in the group where growth centers were resected (Table 2). In accordance with the literature, in our study, while zinc stimulates osteoblastic bone formation, it suppresses osteoclastic bone resorption.

Like in every study, there are some limitations in our study. Firstly, as an experimental animal study cannot entirely be applicable to humans, therefore, additional prospective human studies are needed. Secondly, the method of administration, dose, and additional cost of Zinc should be investigated in humans.

Conclusion

Although human beings have been trying to overcome chest trauma, especially rib fractures from the first people, even today, it is still painful and can be potentially disabling. The actual figures and costs are much higher than expected. Because of the inadequacy of existing or traditional treatment, 30% of patients do not return to entirely their work or normal activities. This results in social and economic costs both to the national healthcare system and to individuals in the form of lost productivity and decreased the quality of life. Any improvements to its treatment would have evenly had agreat benefit not only on the individual but also on society [4, 18]. Our findings indicate that zinc supplementation accelerates the consolidation of ribs. Zinc can be used to increase the bone maturation such as the site of new bone formation in rib fracture. Healing modulation or acceleration may alleviate pain, enhancing recovery and reduce disability on the treatment of RFs. Zinc supplementation could be a next step that we are looking for a long time.

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: This study was approved and funded by the School of

Medicine Animal Care and Investi-gational Committee in our

institution.

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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Evaluation of right ventricular function in patients with copd and its correlation with respiratory functions

Şule Taş Gülen 1, Ufuk Eryılmaz 2

1 Department of Chest Diseases, 2 Department of Cardiology Disease, Adnan Menderes University, Aydın, Turkey

DOI: 10.4328/ACAM.6174 Received: 22.01.2019 Accepted: 13.02.2019 Published Online: 19.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2):125-128

Corresponding Author: Şule Taş Gülen, Department of Chest Disease, Adnan Menderes University Faculty of Medicine, 9100 Aydın, Turkey.GSM: +905056919099 E-Mail: dr_suletas@yahoo.com.trORCID ID: https://orcid.org/ 0000-0002-0517-2376

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Aim: In this study, we aimed to evaluate the right ventricle functions in COPD and to investigate its relationship with the stage of the disease and respiratory functions. Matrial and Method: This retrospective study was conducted in our Pulmonology and Cardiology clinics between December 2015 and 2016. Thirty-four patients with COPD (who did not show any evidence of cardiac failure), 21 healthy subjects were included in the study. The patients with GOLD stages 1 and 2 COPD were included in Group 1, while Group 2 included the cases of GOLD stages 3 and 4. For each participant, the medical files were reviewed and the following data were recorded: the BODE index and PFT parameters, left ventricle ejection fraction, systolic pulmonary arterial pressure (SPAP), systolic and diastolic dimensions of the right ventricle, tricuspid annular plane systolic excursion (TAPSE) and right ventricle myocardial perfusion index (Tei index). Results: The mean ages in the COPD and the control groups were 66.0 ± 9.0 and 51.7 ± 6.8 (p=0.001). Group 1 and Group 2 and analyzed, the advanced disease group showed significantly lower six-minute walk test results and significantly higher Tei index values (p=0.001 and p=0.040). TAPSE was found to be negatively correlated with CAT score and SPAP. Also, the Tei index was negatively correlated with the six-minute walk test and positively correlated with the BODE index. Discussion: COPD patients may show symptoms of right ventricle dysfunction depending on the stage of the disease. TAPSE and the Tei index, seem to be closely related to the functional status and prognosis in this patient population.

Keywords: Chronic Obstructive Pulmonary Disease; Echocardiography; Right Ventricle Dysfunction; Tei Index

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Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease characterized by progressive respiratory symptoms and airflow limitation [1]. Numerous comorbid conditions bearing similar risk factors and systemic inflammation accompany COPD. These comorbidities may occur at any time during the disease and may significantly alter its severity and prognosis. The most commonly encountered and the most important one among these comorbidities are cardiovascular disorders [1-3]. They worsen the overall quality of life and survival rates of patients with COPD, being responsible for 20-25% of all COPD-related deaths. COPD leads to pulmonary hypertension and cor pulmonale via its effects on the pulmonary vessels and the right ventricle [4]. Therefore, cardiovascular parameters should also be evaluated in this patient population. Echocardiography is a fast and non-invasive method that can accurately evaluate the frequently affected functions of the right and the left ventricle in COPD [4,5].

There are many numbers of studies on the cardiovascular comorbidities that accompany COPD that investigates the relationship between these comorbidities and respiratory functions but the disease verity and COPD flare-up frequency are not clear. The aim of our study is to evaluate the right ventricle functions in COPD and to investigate its relationship with respiratory functions, the severity of COPD and incidence of attacks.

Material and Methods

Following approval ofthe local ethics board, the study was conducted asretrospective in our Pulmonology and Cardiology clinics between December 2015 and December 2016. A total of 34 male patients who were diagnosed with COPD according to clinical history, physical findings, imaging studies and pulmonary function tests (PFT), who did not show any evidence of cardiac failure and in whom echocardiography was performed were included in the study. The patients who were not able to cooperate with the PFT procedures or who were in an unstable COPD phase were excluded. A total of 21 healthy male subjects without any chronic conditions (i.e. COPD, cardiovascular problems, neurovascular problems and metabolic problems) who were admitted to the echocardiography laboratory were included in the control group.

Study Protocol

Medical files of all participants were evaluated in details, and the demographical data regarding age, occupation, smoking history, body mass index (BMI) and medical history were noted. Also, for each participant in the COPD group, PFT parameters, COPD assessment test (CAT) results and the BODE index result consisting of BMI value(B), the severity of airway obstruction (O), the severity of dyspnea (D) and exercise capacity (E) was recorded. Additionally, the Modified Medical Research Council (MMRC) dyspnea scale resultused for assessment of dyspnea severity and the number of attacks and hospitalizations over the past year were also recorded.

Pulmonary Function Tests (PFT)

All PFT evaluations were performed using a Jaeger Master Scope spirometer. Measurements were standardized as recommended by the American Thoracic Society [6]. COPD diagnoses were made according to the GOLD criteria (Global Initiative for Chronic Obstructive Lung Disease). A post-bronchodilator FEV1/FEVC ratio of <70% was considered as COPD. Post-bronchodilator FEV1 values of ≥80%, 50%≤FEV1<80%, 30%≤FEV1<50% and <30% were classified as mild (GOLD stage 1), moderate (GOLD stage 2), severe (GOLD stage 3) and very severe (GOLD stage 4) COPD, respectively [1]. The patients with GOLD stages 1 and 2 COPD were included in Group 1, while Group 2 included the cases of GOLD stages 3 and 4.

Echocardiography

All echocardiographic assessments were run by a single experienced cardiologist using a General Electric VIVID S5 system and a 3 MHz probe. For each participant, the medical files were reviewed and the following data were recorded: left ventricle ejection fraction, systolic pulmonary arterial pressure(SPAP), systolic and diastolic dimensions of the right and left ventricles, tricuspid annular plane systolic excursion (TAPSE) and right ventricle myocardial perfusion index (RV-MPI = Tei index).

Statistical Analysis

Similar literature results and a prior power analyzes performed with the Chi-Square test showed that at least 44 individuals in total were required, with a total sample size of at least 22 individuals in each group. In this case, the power of the test > %80 was obtained. Statistical analysis of the data was performed using SPSS 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0, Armonk, NY: IBM Corp.) statistical software package. The variables were represented as means ± standard deviation, percentages or frequency values, where appropriate. The prerequisite of variance homogeneity for the parametric variables was assessed with Levene’s test. Shapiro-Wilk test was used to evaluate the assumptions of normality. Intergroup comparisons were made using the Student’s t-test or the Mann-Whitney-U test, for the variables which met or did not meet the parametricity criteria, respectively. Categorical data were analyzed with the Fisher’s Exact and the Chi-Square tests. When the expected outcomes were lower than 20%, the Monte Carlo Simulation method was used to estimate values for those outcomes to be included in the analysis. The relationship between the two variables was assessed by the Kendall Rank Correlation Test when the parametric test prerequisites were not met. P-values of <0.05 and<0.01 were accepted as statistically significant.

Results

A total of 55 participants, including 34 COPD patients and 21 healthy control subjects were evaluated in this study. All cases were male. The mean ages in the COPD and the control groups were 66.0 ± 9.0 and 51.7 ± 6.8, respectively (p = 0.001). In the COPD group (when it is aged as covariance), the BMI was 25.13 ± 3.89, and in the control group, it was 25.52 ± 1.83 (p = 0.675). Table 1 shows the demographical data, pulmonary function results, and the echocardiography findings. In the COPD group, 4 patients were in stage 1 (11.7%), 17 in stage 2 (50%), 9 in stage 3 (26.4%) and 4 in stage 4 (11.7%) according to the GOLD classification. All patients in the COPD group and five subjects in the control group (23.8%) had a smoking history (p=0.001). Eight COPD patients (23.5%) also had arterial hypertension, whereas none of the subjects in the control group had.

Abbreviations: BMI: Body mass index. FEV1. forced expiratory volume in 1 second; FVC. forced vital capacity. SPAP: Systolic pulmonary artery pressure.

When the COPD patients were divided into Group 1 (GOLD stages 1 and 2) and Group 2 (GOLD stages 3 and 4) and analyzed, the advanced disease group showed significantly lower six-minute walk test results and significantly higher Tei index values (p=0.001 and p=0.040, respectively).

As for the incidence of COPD exacerbations over the past year, in Group 1, five patients (23.8%) had one and 1 patient (4.76%) had three attacks whereas, in Group 2, two patients (15.3%) had one, 6 patients (46.1%) had two and 1 patient (15.3%) had three attacks. The results regarding the hospitalization frequency over the past year were as follows: 1 patient in Group 1(4.8%) had one course of hospitalization whereas in Group 2, four patients (30.8%) were hospitalized for once and two patients (15.4%) were hospitalized twice. Attack and hospitalization frequencies were found to increase as COPD stage advanced (p=0.004 and p=0.01, respectively).

No correlation was detected between the pulmonary function test parameters and echocardiographic measurements. TAPSE was found to be negatively correlated with CAT score and SPAP (r=-0.341, p=0.049 and r=-0.412, p=0.016, respectively). Also,the Tei index was negatively correlated with six-minute walk test results and positively correlated with the BODE index (r=-0.377, p=0.028 and r=-0.378, p=0.027, respectively) (Table 2).

Attack frequency over the past year had a negative correlation with six-minute walk test, whereas it was positively correlated with MMRC dyspnea score, CAT score, the BODE index and the Tei index (r= -0.794, p=0.000; r= 0.855, p= 0.000; r= 0.657, p= 0.000; r= 0.841, p= 0.000; r= 0.358, p= 0.038, respectively).

Hospitalization frequency, on the other hand, was found to be negatively correlated with six-minute walk test, whereas it was positively correlated with MMRC dyspnea score, CAT score and the BODE index (r= -0.666, p=0.000; r=0.741, p=0.000; r=0.442, p=0.009; r=0.762, p=0.000, respectively) (Table 3).

Discussion

Cardiovascular changes are the most commonly encountered extra-pulmonary complications of COPD due to systemic inflammation. Right ventricular dysfunction and pulmonary vascular changes are the most common two of such changes, and these are associated with survival in COPD [3,7]. Alpsoy and colleagues found in a previous study that while SPAP, diameter and free-wall thickness of the right ventricle were higher in COPD patients than the healthy subjects, the Tei index, on the other hand, was similar between the two groups [8]. Geyik et al. reported that COPD patients showed significantly lower TAPSE values, higher SPAPs and higher right ventricle systolic and diastolic diameter measurements [9]. Our results were in accordance with the previous reportsthat TAPSE values as an indicator of right ventricle dysfunction were detected to be lower and SPAP, Tei indices, and right ventricle systolic and diastolic diameters were higher in the COPD patients.

The main functional assessment and mortality prediction parameters in COPD are six-minute walk test, MMRC dyspnea score, CAT score and the BODE index [1]. When intergroup comparisons were made between the patient subgroups (i.e. Group 1 which includes GOLD stages 1 and 2, and Group 2 which includes GOLD stages 3 and 4), it was found that the parameters mentioned above were significantly lower in the cases with advanced stage. In echocardiography, we identified that, among the markers of right ventricular function only the Tei index was significantly higher in the advanced cases. The Tei index is easily measured by echocardiography, is well correlated with tricuspid failureand indicates right ventricular damage [5,10].

TAPSE and the Tei index, the two markers of right ventricular dysfunction, are accepted to be closely associated with disease progression and overall quality of life. Caminiti and colleagues in their study evaluating the relationship between exercise intolerance and right ventricle functions in COPD, demonstrated that TAPSE was positively correlated with six-minute walk test and was an independent indicator of pulmonary functions [11]. In a similar study, Tannus-Silva et al. underscored that the Tei index was not only positively correlated with the BODE index but also was closely associated with deterioration in the quality of life [10]. Burgess and colleagues concluded that the Tei index is an important prognostic marker [12]. Our results revealed that TAPSE is negatively correlated with CAT score and SPAP and that the Tei index is negatively correlated with six-minute walk test results and positively correlated with the BODE index. These findings altogether suggest that both parameters are closely associated with disease progression.

Our results demonstrated no correlation between PFT parameters and echocardiographic measurements. In a study by Das et al., which evaluated right ventricular dysfunction in COPD, SPAP, and the Tei index were found to be negatively correlated with FEV1, FEV1/FVC, PEF and FEF25-75 [5]. The BODE index, which is constituted by BMI (B), the severity of airway obstruction (O), the severity of dyspnea (D) and exercise capacity (E) is a better predictor of prognosis than when its components are evaluated separately. We found a negative correlation between the BODE and Tei indices, which is suggestive that the BODE index not only is a predictor of prognosis but also may be negatively correlated with pulmonary functions.

The number of exacerbations and hospitalizations over the past year are other parameters associated with the progression of the disease in COPD, and both affect the overall quality of life, functional status, and survival of the patients. In their study, Tanaka and colleagues underlined that right ventricular dysfunction affects daily activities in COPD and is related to the prognosis of the disease; they suggested the Tei index as an indicator of right ventricular function. In the same study, the Tei index was found to be positively correlated with the MMRC dyspnea scores, overall survival rates and hospitalization frequency [13]. Similarly, our study also revealed a positive correlation between exacerbation rates and the Tei index.

The first limitation of our study is the limited number of patients. Another limitation is that the average age of the study and control group is not similar. However, the age factor was eliminated by covariance analysis. Echocardiographic parameters to assess pulmonary pressures and right ventricular functions are load-dependent. The lack of load-independent parameters is another limitation of the study. The strength of the present study is that a single expert investigator recruited and appraised patients and performed all PFT and echocardiographies, thus reducing analytical variability.

Conclusion

COPD patients may show symptoms of right ventricle dysfunction depending on the stage of the disease. The parameters of right ventricle function, particularly TAPSE and the Tei index, seem to be closely related to the functional status and prognosis in this patient population.

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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4. Gupta NK, Agarwal RK, Srivastav AB, Ved ML. Echocardiographic evaluation of heart in chronic obstructive pulmonary disease patient and its co-relation with the severity of disease. Lung India. 2011; 28(2): 105-9.

5. Das M, Tapadar SR, Mahapatra ABS, Chowdhury SP, Basu S. Assessment of RV Function in Patients of (COPD). Journal of Clinical and Diagnostic Research. 2014; 8(3): 11-13.

6. Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. General considerations for lung function Testing. Series ATS/ERS Task Force: Standardisation of Lung Function Testing. Eur Respir J. 2005; 26: 153-61.

7. Epping-Jordan JE, Galea G, Tukuitonga C, Beaglehole R. Preventing chronic diseases: taking stepwise action. Lancet. 2005; 366: 1667-71.

8. Alpsoy S, Akyuz A, Akkoyun DC, Oran M, Mutlu LC, Topcu B, et al. The effect of respiratory functions and pulmonary artery pressure on right and left ventricular diastolic function. Kosuyolu Heart J. 2013; 1683: 205-13.

9. Geyik B, Tarakci N, Ozeke O, Ertan C, Gul M, Topaloglu S, et al. Right ventricular outflow tract function in chronic obstructive pulmonary disease. Herz. 2015; 40: 624-8.

10. Tannus-Silva DG, Masson-Silva JB, Riberio LS, Conde MB, Rabahi MF. Myocardial performance index correlates with the BODE index and affects quality of life in COPD patients. International Journal of COPD. 2016; 11: 2261-8.

11. Caminiti G, Cardaci V, Conti V, D’Antoni V, Murugesan J, Battaglia D, et al. Right Ventricular Systolic Dysfunction Is Related to Exercise Intolerance in Patients With Chronic Obstructive Pulmonary Disease. Journal of Cardiopulmonary Rehabilitation and Prevention. 2015; 35(1): 70–74.

12. Burgess MI, Mogulkoc N, Bright-Thomas RJ, Bishop P, Egan JJ, Ray SG. Comparison of echocardiographic markers of right ventricular function in determining prognosis in chronic pulmonary disease. Journal of the American Society of Echocardiography. 2002; 15(6): 633-9.

13. Tanaka Y, Hino M, Mizuno K, Gemma A. Evaluation of right ventricular function in patients with COPD. Respir Care. 2013; 58(5): 816-23.

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Şule TG, Ufuk E. Evaluation of right ventricular function in patients with copd and its correlation with respiratory functions. Ann Clin Anal Med 2020;11(2):125-128

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Case Report

Reversible oral EBV related-lymphoma in a patient with myasthenia graves disease: a case report and review of the literature

Hikmet Saçmacı 1, Emel Köseoğlu 2, Bilge Karaatlı 3, Özlem Canöz 4

1 Department of Neurology, Faculty of Medicine, Bozok University, Yozgat, 2 Department of Neurology, Faculty of Medicine, Erciyes University, Kayseri, 3 Nevşehir State Hospital, Nevşehir, 4 Department of Pathology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

DOI: 10.4328/ACAM.6166 Received:16.01.2019 Accepted: 20.02.2019 Publihed Online: 28.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2): 162-165

Corresponding Author: Hikmet Saçmacı, Department of Neurology, Faculty of Medicine, Bozok University, Yozgat, Turkey.GSM: +905052621012 E-Mail: hsacmaci@hotmail.comORCID ID: https://orcid.org/0000-0003-1480-0562

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Abstract

Thiopurines are widely used for remission maintenance and recurrence prevention in Myasthenia Graves disease (MG). We report a case of a 78-year-old man with MG treated with azathioprine (AZA) for 3 years earlier and who developed an intraoral ulcerated lesion. The biopsy specimen revealed a lymphoma and after discontinuation of AZA therapy the ulcerated lesion showed complete regression at 8 weeks, and no subsequent treatment was required.

Keywords: Myasthenia Graves; Azathioprine; Oral Lesion

Full Text

Introduction

MG is an autoimmune neuromuscular junction disease that causes muscle weakness [1]. If immunosuppression is required for MG treatment, it is recommended that the use of AZA therapy is recommended as a priority [1]. AZA is converted to 6-thioguanine after absorption and then incorporated into the DNA of the regenerating cells including mucosal cells [2]. AZA has been classified as ‘carcinogenic to humans’ by the International Agency for Research on Cancer (IARC) [3]. Likewise, a prospective, open, observational study was done to evaluate the long-term adverse effects profile of AZA in 163 MG patients in a larger patient cohort that they did not detect any lymphoma during the follow-up period [4].

We report a case of oral EBV-positive Hodgkin Lymphoma with an MG patient treated with AZA for 3 years and the lesion regressed spontaneously after AZA therapy was stopped.

Case Report

A 78- year- old man with a 5-year history of MG, complained ofa painful ulcer in his mouth for the last two months. He wastreated with 4×1 pyridostigmine for 5 years and 2mg/kg/day AZA for 3 years. A 1×1 cm whitish ulcerated lesion was identified at the left inferior retromolar trigone (Figure 1). The extraoral examination found no enlargements of the regional lymph node. The lesion biopsy revealed a leukemia or lymphoma infiltration.

His personal and family history were unremarkable, except a history of osteoporosis, treated with cholecalciferol. He was regularly seen by dentists and was using his prosthesis carefully for many years. He has never smoked and drunk alcohol.

Routine laboratory works up including erythrocyte sedimentation rate, levels of lactate dehydrogenase and C-reactive protein, and renal, liver function tests showed bisitopenia (WBC: 4.74 10^3/μL, Hb: 12 g/dL). Computed tomography scan of the chest, abdomen, and pelvis didn’t reveal any pathologic findings. A peripheral blood smear showed marked leukocytosis consisting of medium to large atypical lymphoid cells (Figure 2). A biopsy material (0,4X0,3X0,3cm) appearing as an inflammated white soft tissue was examined via light microscope evaluation, revealed distinctive necrotic tissue with diffuse infiltration by a polymorphous cellular infiltrate consisting of small lymphoid cells, histiocytes, some eosinophils, a single layer of scattered large blastic cells with prominent eosinophilic nucleoli, as well as Reed Stenberg cells which were typical for Hodgkin Lymphoma (Figure 3 and Figure 4).

At immunohistochemistry, the large cells showed strong positivity for CD30 and CD20 “Cluster of Differentiation, CD”. The morphology, architectural features, and immunohistochemical findings were consistent with the diagnosis of classic Hodgkin’s Lymphoma (cHL). In blood tests, the number of EBV DNA copies < 150 copy/ml indicating a low positivity. In the context of this, the disease was diagnosed as cHL associated with iatrogenic immunosuppression because of the long-term use of the drug (Figure 5).

During the follow- up of the patient, after the discontinuation of AZA, the oral lesions disappeared in two months period. Afterward, the patient who had ulcerated lesion for 3 years has remained stable. Repeated EBV testing was negative. The patient was treated with pyridostigmine and intravenous immunoglobulin. This treatment was successful in controlling the symptoms without ulcer and myasthenic crisis.

Discussion

We describe a case of EBV-positive cHL in patients receiving therapy for MG with spontaneous regression after stopping of AZA. The patient presented with a well-circumscribed mucocutaneous ulcer in the mouth.

The complete involution of the lesion in a short time after discontinuation of AZA therapy indicates a pathogenetic role for AZA. Although the exact mechanism of action of 6-MP/AZA remains unknown, they do suppress the immune system, increasing the risks of infections and malignancies, precise pathogenesis may be related to the immunodulating effects of AZA. EBV-related lymphoproliferative disease (LPD) occurs most often in immunodeficient people [2].Also, there have been reported similar cases associated with using immunosupressive therapy in the literature. There have been reported in cases that apparent spontaneous regression can be following the withdrawal of immunosuppressive therapy 1-3 months after the diagnosis. We want to attract attention to some points with this case. For example, this case has been seen in a short time with AZA therapy as three years. Another careful point is that spontaneous regression occured in a short time as 8 weeks after stopping AZA therapy.

The data on risk of cancer using AZA therapy for myasthenia are investigated in several studies. The further insight of this reseach has come from a large nationwide study in Denmark. According to this study, Pedersen et al. found that a high cumulative dose and long-term treatment with azathioprine was associated with a slightly increased risk of non-tobacco-related cancers, but not of tobacco-related cancers. However, the statistical precision was limited in the subcategory analyses. The results were similar in men and women for both time and dose of azathioprine MG [5].

Two other studies reported no increase in the risk of overall cancer with the use of azathioprine in patients by means of meaningful analyses of azathioprine use. All of the aforementioned studies included patients with MG with thymoma that were excluded in their study. They found that a high cumulative dose and long-term treatment (>10 years) with azathioprine may be associated with a small increase in the risk of overall cancer in patients with non-thymoma MG [6].

Evoli et al. have collected nationwide data since 1998. Their study has provided risk estimates of the effect of duration of immunosuppressive treatment on the risk of cancer in patients with MG. In that study, long duration (> 10 years) of AZA therapy increased the risk of cancer (OR: 2.2; 95% CI: 0.91– 5.72) [16]. Small numbers (n =18), however, prevented meaningful analyses of azathioprine use.

In addition, in the literature, there have been reported cases of spontaneous regression of malignancy following AZA therapy withdrawal in patients receiving therapy for autoimmune disease like MG.

The EBV-positive mucocutaneous ulcer was recently described as a clinicopathologic entity secondary to AZA therapy. According to some studies and cases which have been taken into consideration, age is an important factor. Usually, advanced age has facilitated to developing cancer in the immunocomproise patients and receiving immunosuppressive medication has accelerated to malign transformation. Age may be a confounding feature in the patients in whom EBV-lymphoma was linked to iatrogenic immunodeficiency. Notably, in a study by Docinov et al., they provided an analysis of 26 cases with a view to highlighting their clinicopathologic category, they provided discussion on the possible common pathogenetic mechanisms of EBV-induced ulcer in a different immunosuppressive setting including old age. Three patients had multiple episodes of oral mucosal ulceration with spontaneous resolution, others received chemotherapy, radiotherapy or combination therapy [7].

Conclusion

The case we described is unusual and to the best of our knowledge, an oral malignancy in an MG patient taking thiopurines is reported in the literature. In summary, the case highlights a patient with chronic immunosuppression secondary to azathioprine who developed EBV-positive mucocutaneous ulcer. The lesion involuted completely after discontinuation of azathioprine. The advanced age of the patient and the intake of immunosuppressive medications and EBV-positivity have contributed to improved lymphoma in our case. Further descriptions are required which prognosis of lymphoma in MG following treatment with thiopurines. Neurologist and other practitioners need to be aware of this complication of long-term medication-induced immunosuppression. The close follow-up of the patient beyond more frequent adverse effects should be paramount. In our opinion, any suspicious oral lesions should be referred for biopsy. As we have shown, oral malignancy, even in the absence of the classical risk factors, is possible.

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.Pedersen EG, Hallas J, Pottegård A, Hald SM, Jensen PEH, Gaist D. Oral Immunosuppressive Treatment of Myasthenia Gravis in Denmark: A Nationwide Drug Utilization Study, 1996-2013. Basic Clin Pharmacol Toxicol. 2018; 123(4): 486-493. DOI: 10.1111/bcpt.13034. Epub 2018 Jun 13.

2. O’Donovan P, Perrett CM, Zhang X,  Montaner BXu YZHarwood CA, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 2005;309:1871–74.

3. IARC. A Review of Human Carcinogens. Part A: Pharmaceuticals, Vol. 100A. Lyon: International Agency for Research on Cancer; 2008.p.319–31.

4. Rozsaa C, Lovasa G, Fornadia L, Szabo G, Komoly S.Safety of long-term combined immunosuppressive treatment in myasthenia gravis – analysis of adverse effects of 163 patients. European Journal of Neurology. 2006; 13: 947–52.

5. Pedersen EG, Pottegardb A, Halas J, Friis S, Hansen K, Jensen P E H, et al. Use of azathioprine for non-thymoma myasthenia and risk of cancer: a nationwide case–control study in Denmark. European Journal of Neurology. 2013; 20: 942–8.

6. Evoli A, Batocchi AP, Tonali P, Marciano M. Risk of cancer in patients with myasthenia gravis. Ann N Y Acad Sci. 1998;841:742–5.

7. Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES. EBV positive mucocutaneous ulcer-a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010; 34: 405–17.

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Saçmacı H, Köseoğlu E, Karaatlı B, Canöz Ö. Reversible oral EBV related-lympho-ma in a patient with myasthenia graves disease: a case report and review of the literature. Ann Clin Anal Med 2020;11(2): 162-165

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Late onset hirayama disease: Characteristic magnetic resonance imaging features hirayana disease

Kemal Murat Haberal 1, Aynur Yılmaz Avcı 2, Mert Bayramoğlu 1, Ahmet Muhteşem Ağıldere 1

1 Department of Radiology, 2 Department of Neurology, Baskent University, Alanya, Turkey

DOI: 10.4328/ACAM.6154 Received: 09.01.2019 Accepted: 25.01.2019 Publihed Online: 05.02.2019 Printed: 01.03.2020 Ann Clin Anal Med 2020;11(2): 159-161

Corresponding Author: Kemal Murat Haberal, Yukarı Bahçelievler Mah. Mareşal Fevzi Çakmak Cad. No:45, 06490, Çankaya, Ankara, Türkiye.E-Mail: kmhbjk@hotmail.comORCID ID: https://orcid.org/0000-0002-8211-4065

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Hirayama Disease is a rare benign lower motor neuron disorder which is primarily affecting young males. It is characterized by the progressive weakness of the distal upper extremities followed by spontaneous stabilization of the symptoms. In this paper, we describe a 58 year- old female patient with a complaint of weakness in the right hand and forearm. Magnetic resonance imaging of the cervical spine established the final diagnosis of Hirayama disease. Hirayama disease when detected and intervened at an early stage of the disease process, can have a good prognosis. Clinicians and radiologists should be aware of the clinical features, as well as suspicious findings on neutral-position MR imaging and an additional neck-flexion MR imaging study should be arranged to confirm the diagnosis.

Keywords: Hirayama Disease; Motor Neuron Disorder; Myelopathy; Magnetic Resonance Imaging

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Introduction

Hirayama disease(HD) is a lower motor neuron disease characterized by unilateral weakness and atrophy of the distal muscles of the upper extremity in the distribution of C7-T1 myotomes. Bilateral involvement is rare. It is a rare non-progressive spinal muscular atrophy seen predominantly in young men in late adolescents and third decadence. The onset is insidious, the symptoms progress from three to five years, then the disease progresses spontaneously [1,2].

In this case report, a 58-year-old woman with gradually increasing weakness in the forearm was presented with MRI findings.

Case Report

A 58-year-old female patient; was admitted to the neurology clinic for 25 days with complaints of the increased weakness and occasional numbness in the right forearm. Physical examination of the patient was normal. Neurological examination revealed numbness in the distal right arm and muscle strength was 2/5. No pathology was found in the other neurological examination. Blood investigations including complete blood count, sedimentation rate, renal, liver, and thyroid function tests, creatine kinase, and vitamin B12 and vitamin D3 level were within normal range.

Electromyography (EMG) examination showed that the right radial and ulnar nerve combined muscle action potential (CMAP) amplitude was lower than the left. Other messages were in the normal range. In the right radial and ulnar nerve innervated muscles, there was a slight increase in polyphyletic, motor unit potential (MUP) times. No denervation potential was observed. The other muscles examined were normal.

In the cervical magnetic resonance radiography (MRI), sagittal plane T1 and T2 weighted sequences, axial gradient echo sequence for the discs and axial and sagittal postcontrast T1 weighted sequences were applied at a neutral position. MRI revealed flattening in cervical lordosis, spinal cord atrophy under C5-C6 intervertebral disc in T2-weighted sagittal sections, and increased signal in the posterior spinal cord at C2-C5 levels (Figure 1). In the differential diagnosis of the patient, the cervical MRI examination was refreshed with flexion in view of the Hirayama disease. Flexion MRI, in addition to neutral MRI findings, showed posterior dural displacement between C5-T1 levels, forward displacement in the spinal cord, enlargement in the posterior epidural space, and homogeneous contrast enhancement in the epidural distance in the postcontrast series (Figure 2). The patient was diagnosed with HD by MRI findings and was offered cervical neck and physical therapy exercises.

Discussion

Hirayama disease was first described by Hirayama et al. in 1959 [1]. The exact pathogenesis of the disease is still unclear. The generally accepted hypothesis is cervical myelopathy induced by flexion. The underlying mechanism is the disproportion with the duramater and the growth of the vertebral column. While the length of the spinal canal increases with flexion, the duramater is stretched and separated from the vertebral canal wall.

Anterior spinal artery irrigations may occur in the lower cervical spinal cord with anterior spinal cord compression and anterior displacement. Recurrent flexion may lead to chronic circulatory disorder, gliosis, and localized cord atrophy [3].

HD is more common in young males, especially among 15-25 years. Our patient is one of the few cases sampled in the literature in term of age and sex. For HD, self-limiting weakness and insidious onset in the hand and forearm, which are mostly unilateral, are typical. In our case, there were atrophy and numbness symptoms in unilateral forearm and hand muscles and there was no sensory or pyramidal path involvement, typical for HD.

In HD, cervical radiographs revealed no specific finding except for flattening in lordosis or scoliosis. Specific features in neutral and flexion MRI have been defined in the diagnosis of HD in the literature. These are mainly spinal cord atrophy, asymmetric cord flattening, intramedullary signal changes in the cervical cord, abnormal cervical axis in neutral position, and the loss of the connection between the posterior dural sac and the lamina, forward displacement of posterior dura, the expansion in the posterior epidural space and contrast enhancement in this region with/without signal void areas suggesting dilated epidural venous plexus in flexion [4].
In our case, findings consistent with the literature were defined in the cervical MRIs in neutral-flexion positions and a diagnosis of Hirayama disease was made.

The differential diagnosis of HD includes spinal muscular atrophy, amyotrophic lateral sclerosis, post-polio syndrome, multifocal motor neuropathy, toxic neuropathy, and structural lesions of the cervical cord such as syringomyelia. These clinical entities are characterized by their characteristic clinical, radiological, and electrophysiological characteristics [1]. In degenerative diseases, disc-osteophyte complex, which may lead to secondary cord compression, can be seen in T1A sequences. In demyelinating diseases, T1A hypointense, T2A hyperintense, focal or diffuse cord lesion with variable diffusion characteristics can be seen in the spinal cord. In spinal cord infarction, T1A hypointense, T2A hyperintense, diffusion-restricting spinal cord lesion is seen in arterial irrigation area [5].

Dynamic cervical MRI, which has an important role in diagnosis in HD, is used in increasing frequency in patients who are investigated in terms of positional spinal cord compression, cervical degenerative disease, cervical myelopathy, rheumatoid arthritis, cervical trauma [6,7].

Conclusion

Limitation of neck flexion can be extremely beneficial if the myelopathy symptoms and signs of Hirayama occur early, even if they are nonprogressive. Clinicians and radiologists should be familiar with imaging findings of the disease, and the key role of flexion cervical MRI should be kept in mind when considering the differential diagnosis.

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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How to Cite

Haberal KM, Avcı AY, Bayramoğlu M, Ağıldere AM. Late onset hirayama disease: Characteristic magnetic resonance imaging features hirayana disease. Ann Clin Anal Med 2020;11(2): 159-161

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