Whole‐exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene

As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole‐exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis‐related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well‐established cancer gene lysine (K)‐specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome‐sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D‐mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.     

Sonographic assessment of subacromial bursa distension during arm abduction: establishing a threshold value in the diagnosis of subacromial impingement syndrome

Purpose

In this study, we aimed to establish a quantitative threshold value in the diagnosis of subacromial impingement syndrome by measuring the thickness of the subacromial bursa during abduction and adduction.

Materials and methods

Forty-five patients with subacromial impingement syndrome and 54 healthy individuals underwent dynamic shoulder ultrasonography. The subacromial bursa, between the supraspinatus tendon margin and peribursal adipose tissue, was measured between the acromion and humeral head at its widest part. The subacromial impingement ratio was calculated by dividing the subacromial bursa thickness during abduction to the subacromial bursa thickness during adduction. Shapiro–Wilk test was used in the assessment of normal distribution of parameters.

Results

The mean subacromial bursa thickness in the abduction position was 1.8 ± 1.1 mm in the study group and 0.9 ± 0.3 mm in the control group. The mean subacromial bursa thickness in the adduction position was 0.9 ± 0.5 mm in the study group and 0.8 ± 0.3 mm in the control group. The subacromial impingement ratio showed a statistically significant difference between groups (p < 0.0001), and the ratio being 2.0 ± 0.5 in the study group and 1.2 ± 0.1 in the control group. For measurements performed in the abduction position, the best cut-off value was calculated as 1.3 mm, and sensitivity and specificity were 70.6 and 85.2%, respectively. The best cut-off value was 1.4 for the subacromial impingement ratio, and sensitivity and specificity were 88.2 and 96.3%, respectively.

Conclusion

Subacromial impingement ratio is a very practical and reliable method in subacromial impingement syndrome diagnosis.

     

A multicenter experience of thrombotic microangiopathies in Turkey: The Turkish Hematology Research and Education Group (ThREG)-TMA01 study

Thrombotic microangiopathies (TMAs) are rare, but life-threatening disorders characterized by microangiopathic hemolytic anemia and thrombocytopenia (MAHAT) associated with multiorgan dysfunction as a result of microvascular thrombosis and tissue ischemia. The differentiation of the etiology is of utmost importance as the pathophysiological basis will dictate the choice of appropriate treatment.We retrospectively evaluated 154 (99 females and 55 males) patients who received therapeutic plasma exchange (TPE) due to a presumptive diagnosis of TMA, who had serum ADAMTS13 activity/anti-ADAMTS13 antibody analysis at the time of hospital admission. The median age of the study cohort was 36 (14-84). 67 (43.5%), 32 (20.8%), 27 (17.5%) and 28 (18.2%) patients were diagnosed as thrombotic thrombocytopenic purpura (TTP), infection/complement-associated hemolytic uremic syndrome (IA/CA-HUS), secondary TMA and TMA-not otherwise specified (TMA-NOS), respectively. Patients received a median of 18 (1­75) plasma volume exchanges for 14 (153) days. 81 (52.6%) patients received concomitant steroid therapy with TPE. Treatment responses could be evaluated in 137 patients. 90 patients (65.7%) achieved clinical remission following TPE, while 47 (34.3%) patients had non-responsive disease. 25 (18.2%) non-responsive patients died during follow-up. Our study present real-life data on the distribution and follow-up of patients with TMAs who were referred to therapeutic apheresis centers for the application of TPE.     

The effects of connective tissue manipulation and Kinesio Taping on chronic constipation in children with cerebral palsy: a randomized controlled trial

Purpose: The aim of this study was to investigate the effects of connective tissue manipulation (CTM) and Kinesio Taping^® (KT) on constipation and quality of life in children with cerebral palsy (CP).

Method: This study was designed as a randomized controlled trial. Forty children diagnosed with chronic constipation based on Rome III criteria were randomly assigned to CTM group [6 females, 7 males; 8 y 6?mo (SD = 3y 4?mo)], KT group [7 female, 7 male; 8y 7?mo (SD =3y 5?mo)] or control group [6 female, 7 male; 8y 3?mo (SD = 3y 6?mo)]. All patients were assessed with 7-day bowel diaries, Bristol Stool Form Scale (BSFS), Visual Analog Scale (VAS), and Pediatric Quality of Life Inventory (PEDsQL). Kruskal-Wallis, Wilcoxon’s signed-rank, and Mann–Whitney U tests were used to determine intra-group and inter-group differences. The level of significance was p?Results: Among the CTM, KT, and control groups, there were statistically significant differences regarding the changes in defecation frequency (2.46, 3.00, 0.30, ES 1.16, p?p?=?0.003), BSFS (1.84, 2.14, 0.07, ES 0.91, p?p?p?Conclusions: This study revealed that CTM and KT seem equally effective physiotherapy approaches for the treatment of pediatric constipation and these approaches may be added to bowel rehabilitation program.

• Implications for rehabilitation

• CTM and KT have similar effectiveness in alleviating the constipation-related symptoms and improving quality of life in children with CP.

• CTM and KT can be integrated into bowel rehabilitation programs.

• Considering the characteristics of patients, these treatment options can be used as an alternative of each other by physiotherapists.

     

Evaluation of effects of T and N type calcium channel blockers on the electroencephalogram recordings in Wistar Albino Glaxo/Rij rats,an absence epilepsy model

Objectives:It is suggested that excessive calcium entry into neurons is the main triggering event in the initiation of epileptic discharges. We aimed to investigate the role of T and N type calcium channels in absence epilepsy experimental model.Results:Beta and delta recording ratios in 1 μM/5 μl mibefradil group was significantly different from basal and other dose-injected groups. Beta, alpha, and theta recordings in 0.2 μM/5 μl w-Conotoxin MVIIA group was significantly different from basal and other dose-injected groups. In w-Conotoxin MVIIA after mibefradil group, beta, alpha, and theta recording ratios were significantly different from basal and mibefradil group. Mibefradil and w-Conotoxin MVIIA significantly decreased the frequency and duration of SWDs. The decrease of frequency and duration of SWDs in mibefradil group was significantly different from w-Conotoxin MVIIA group. The frequency and duration of SWDs significantly decreased in w-Conotoxin MVIIA after mibefradil group compared with basal, mibefradil, and w-Conotoxin MVIIA groups.Conclusions:We concluded that both T and L type calcium channels play activator roles in SWDs and have positive effects on frequency and duration of these discharges. These results are related with their central effects more than peripheral effects.KEY WORDS: Epilepsy, mibefradil, T and N type calcium channels, Wistar Albino Glaxo/Rij rats, w-Conotoxin MVIIA     

State-of-the art review: Noncompaction cardiomyopathy in pediatric patients

Heart Failure Reviews - Noncompaction cardiomyopathy (NCCM) is a disease characterized by hypertrabeculation, commonly hypothesized due to an arrest in compaction during fetal development. In 2006,...