The bone transcription factor Osterix controls extracellular matrix- and node of Ranvier-related gene expression in oligodendrocytes.

Oligodendrocytes are the primary producers of many extracellular matrix (ECM)-related proteins found in the CNS. Therefore, oligodendrocytes play a critical role in the determination of brain stiffness, node of Ranvier formation, perinodal ECM deposition, and perineuronal net formation, all of which depend on the ECM. Nevertheless, the transcription factors that control ECM-related gene expression in oligodendrocytes remain unknown. Here, we found that the transcription factor Osterix (also known as Sp7) binds in proximity to genes important for CNS ECM and node of Ranvier formation and mediates their expression. Oligodendrocyte-specific ablation of Sp7 changes ECM composition and brain stiffness and results in aberrant node of Ranvier formation. Sp7 is known to control osteoblast maturation and bone formation. Our comparative analyses suggest that Sp7 plays a conserved biological role in oligodendrocytes and in bone-forming cells, where it mediates brain and bone tissue stiffness by controlling expression of ECM components.

Identification of gene mutations associated with type 1 diabetes by next-generation sequencing in affected Palestinian families.

Introduction: Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycemia secondary to insulin resistance or deficiency. It is considered a major health problem worldwide. T1DM is a result of a combination of genetics, epigenetics, and environmental factors. Several genes have been associated with T1DM, including HLA, INS, CTLA4, and PTPN22. However, none of these findings have been based on linkage analysis because it is rare to find families with several diabetic individuals. Two Palestinian families with several afflicted members with variations in the mode of inheritance were identified and selected for this study. This study aimed to identify the putative causative gene(s) responsible for T1DM development in these families to improve our understanding of the molecular genetics of the disease. Methods: One afflicted member from each family was selected for Whole-Exome Sequencing. Data were mapped to the reference of the human genome, and the resulting VCF file data were filtered. The variants with the highest phenotype correlation score were checked by Sanger sequencing for all family members. The confirmed variants were analyzed in silico by bioinformatics tools. Results: In one family, the IGF1R p.V579F variant, which follows autosomal dominant inheritance, was confirmed and segregated in the family. In another family, the NEUROD1 p.P197H variant, which follows autosomal recessive inheritance, was positively confirmed and segregated. Conclusion: IGF1R p.V579F and NEUROD1 p.P197H variants were associated with T1DM development in the two inflicted families. Further analysis and functional assays will be performed, including the generation of mutant model cell systems, to unravel their specific molecular mechanism in the disease development.

Effects of extended abstinence on cognitive functions in tramadol-dependent patients: A cohort study.

BACKGROUND: Some pieces of the literature report impaired cognitive functioning in tramadol dependence. Whether extended abstinence improves cognitive functioning or not is not well studied. AIM: We aimed to measure the change in cognitive functioning following complete abstinence among individuals with tramadol dependence. METHODS: Eighty-three male tramadol-dependent (TD) and 57 matched healthy controls participated in this study. Cognitive functions were assessed using: The Trail making test (TMT), Wechsler Memory Scale-Revised (WMS-R), and Wechsler Adult Intelligence Scale (WAIS). Patients were assessed in the first week immediately after the end of the in-patient treatment program (T1), and after six months of sustained abstinence (T2). RESULTS: At T1, the TD group showed deficits on all tested cognitive parameters (visual attention, task switching, working memory, visual memory, verbal memory, verbal knowledge, Verbal IQ, Performance IQ, and Full-Scale IQ) in comparison to the control group. At T2, significant improvements had occurred in all the tested parameters except performance IQ. The cognitive performance of the abstinent individuals at T2 was comparable to the control group for the verbal subsets of WMS-R, Verbal IQ, Performance IQ, and Full-Scale IQ. Nevertheless, it was still worse than the control group in TMT, and all other WMS subsets. CONCLUSION: tramadol dependence has negative effects on cognitive performance, which improves with extended abstinence.

Evaluation of psychiatric comorbidity in attention-deficit hyperactivity disorder with epilepsy: A case-control study.

OBJECTIVE: Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder caused by structural and functional brain abnormalities as well as genetic and environmental factors. ADHD symptoms are commonly observed in individuals with epilepsy. A few studies have reported a pattern of behavioral problems in children with combined epilepsy and ADHD. We aimed to evaluate comorbid behavioral problems and mental health concerns among children with epilepsy with ADHD and without ADHD including autism spectrum disorder, anxiety, depression, somatic problems, oppositional defiant disorder, and conduct disorder. METHODS: A total of 100 children aged between 6 and 11 years were recruited and categorized into 1 of 5 groups (20 child/group): (1) epilepsy, (2) epilepsy with ADHD, (3) ADHD with electroencephalogram (EEG) changes, (4) ADHD without EEG changes, and (5) healthy control. The scales used in our study included the Childhood Autism Spectrum Test (CAST) to screen autism spectrum conditions and related social and communication conditions, Conners' Parent Rating Scale (CPRS) to assess ADHD and other comorbid behavioral and social-emotional difficulties, and Children Behavior Checklist (CBCL) to evaluate behavior problems. RESULTS: The CAST scale score showed no significant difference among the studied groups. Regarding the Conners-3 scale, the combined type of ADHD was predominant in the ADHD with EEG changes group and the ADHD with epilepsy group, while hyperactive ADHD was predominant in the ADHD without EEG changes group. The ADHD with EEG changes group and the ADHD with epilepsy group had equally high clinical rating scores for CBCL in internalizing and externalizing problems. There was a significant difference in the profile of all Diagnostic and Statistical Manual of Mental Disorders (DSM-5) scales of CBCL among the studied groups. CONCLUSION: This is the first study to use EEG in patients with ADHD in comparison with epilepsy. ADHD with epilepsy is closely related to ADHD with EEG changes regarding psychiatric comorbidity in terms of anxiety, depression, somatic problems, oppositional defiance problems, and conduct problems.

Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility.

The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.

Pure dysgerminoma of the ovary: a single institutional experience of 65 patients.

Ovarian dysgerminomas are rare entity and account for only about 2% of all malignant ovarian neoplasm. The aim of this study was to evaluate the clinicopathologic characteristics, treatment, long-term survival, and fertility outcome of women diagnosed with ovarian dysgerminoma at our institution. Sixty-five women with histologically proven pure ovarian dysgerminoma were identified in this retrospective study. They were treated at King Faisal Specialist Hospital, Riyadh; Saudi Arabia between 1976 and 2010. The median age was 20 years. The most frequent symptoms at presentation were abdominal pain and abdominal/pelvic mass. Thirty-three patients (50.7%) presented with stage I, 2 (3.1%) had stage II, 22 (33.8%) had stage III, and 4 (6.2%) had stage IV (4 unknown stage). Unilateral oophorectomy was performed in 50 patients (76.9%) while bilateral oophorectomy±hysterectomy was done in 12 patients (18.4%). Three patients had biopsy only. Forty patients (61.5%) received only chemotherapy, and 4 patients (6.2%) received radiotherapy alone. Recurrence was observed in 6 patients (9.2%). With median follow-up of 54 months, the 5-year disease-free survival (DFS) and overall survival (OS) were 88 and 95%, respectively. On univariate analysis, adjuvant chemotherapy was independent better prognostic factor for DFS (HR, 0.09; 95% CI, 0.01-0.84; P=0.034). Of the 50 patients treated with fertility-sparing surgery, 16 patients (32%) achieved pregnancy with 14 live births. Patients with pure ovarian dysgerminoma have excellent long-term outcome. There is no difference at outcome between fertility-sparing and nonconservative surgeries. Adjuvant chemotherapy was associated with significant improvement in DFS. It is possible to maintain good reproductive function after conservative surgery followed by chemotherapy in our series.

Evaluation of adjuvant therapy in women with uterine papillary serous cancer.

BACKGROUND AND OBJECTIVE: Uterine papillary serous cancer (UPSC) represents only 10% of all uterine cancers and is associated with a significantly worse prognosis compared with other histological types of endometrial cancers. It closely resembles the behavior of ovarian carcinoma. DESIGN AND SETTING: Retrospective study in a referral center covering period from February 1989 to January 2009. PATIENTS AND METHODS: Eighteen patients who underwent definitive surgery followed by adjuvant therapy-platinum-based chemotherapy, radiotherapy, or both-were reviewed. Median age was 62 years (range, 52-76 years). All patients underwent total abdominal hysterectomy and salpingo-oophorectomy. Positive lymph nodes were found in 4 of 7 patients who underwent lymph node sampling/dissection. Seven patients had stage I/II disease, whereas 11 patients had stage III disease. Six patients received chemotherapy, 5 patients received radiation therapy, while 7 patients received both chemotherapy and radiation therapy. RESULT: Median follow-up was 27 months. The median survival and relapse-free survival were 33 and 23 months, respectively. Eight patients were alive and free of disease, of whom 5 patients were stage I/II and 4 patients were stage III. Distant metastasis was the most common site of relapse. Early stage (I/II) was associated with significant improvement in relapse-free survival (RFS) and overall survival (OS) (P=.004 and P=.05, respectively). The combined-modality treatment including chemotherapy-radiotherapy showed statistically significant improvement in RFS (P=.012), while the improvement in OS did not reach statistical significance (P=.12). CONCLUSION: This study indicates that postoperative combined treatment with chemotherapy and radiation therapy plays a role in the management of UPSC by improving RFS. Distant metastasis remains the major site of relapse. Future studies using combined-modality therapy are needed to improve the outcome in patients with UPSC.

Whole body 18F-FDG PET predicts progression free and overall survival in squamous cell carcinoma of the esophagus: results of a prospective trial.

BACKGROUND AND OBJECTIVES: 18F-FDG PET yields physiologic information that allows for identifying cancer based on altered tissue metabolism. The aim of this study was to prospectively validate the predictive value of positron emission tomography (PET) in squamous cell carcinoma (SCC) of the esophagus treated by pre-operative chemotherapy followed by esophagectomy. DESIGN AND SETTING: Prospective efficacy and toxicity study of patients enrolled between January 1999 and September 2003. PATIENTS AND METHODS: Twenty-one patients with SCC of the esophagus who were potentially resectable underwent 18F-FDG PET imaging before the first cycle of neoadjuvant chemotherapy and at least 14 days after the third cycle. A patient was classified as a metabolic responder when the metabolic activity of the primary tumor as measured by the maximum standardized uptake values had decreased by 50% or more at the time of the second 18F-FDG PET. RESULTS: The median age of the study cohort was 60 years with a range of 39-70 years; 12 patients were males and 9 were females. 18F-FDG PET had increased activity in the primary tumor in all patients. Metabolic response occurred in 14/21 patients (66%), while 7/21 (33%) patients did not show a metabolic response. Metabolic responders had a high clinical response rate (92%), a median progression free survival (PFS) of 16.4 months and a median overall survival (OS) of 35.3 months. In contrast, prognosis was poor for metabolic non-responders with a clinical response rate of 42% (P=.025), a median PFS of 7.13 months (P=.032) and median OS of 12 months (P=.038). CONCLUSION: Our results demonstrate that changes in tumor metabolic activity after neoadjuvant chemotherapy predicts PFS and OS in esophageal SCC patients.