The DNA repair protein ATM as target in autism spectrum disorder

Impairment of GABAergic system has been reported in epilepsy, autism, ADHD and schizophrenia. We recently demonstrated that Ataxia Telangiectasia Mutated (ATM) shapes directly the development of GABAergic system. Here, we show for the first time how the abnormal expression of ATM impacts the pathological condition of autism. We exploit two different animal models of autism, the Mecp2y/- mouse model of Rett syndrome, and mice prenatally exposed to valproic acid, and found increased ATM levels. Accordingly, the treatment with the specific ATM kinase inhibitor KU55933 (KU) normalises molecular, functional and behavioural defects in these mouse models such as the i) delayed GABAergic development, ii) hippocampal hyper-excitability, iii) low cognitive performances, iv) social impairments. Mechanistically, we demonstrate that KU administration to wild type hippocampal neurons leads to i) higher Egr4 activity on Kcc2b promoter, ii) increased expression of Mecp2, iii) potentiated GABA-transmission. These results provide evidences and molecular substrates for the pharmacological development of ATM inhibition in autism spectrum disorders

Successful open abdomen treatment for multiple ischemic duodenal perforated ulcers in dermatomyositis

Introduction: Dermatomyositis is an autoimmune disease characterized by proximal myopathy, cutaneous Gottron papules and heliotrope rash; intestinal involvement associated to acute vasculitis is less common but could be a life-threatening condition. Methods: A 21-year-old woman, affected by dermatomyositis, presented to our attention with a three-day story of severe abdominal pain, no bowel movement and biliary vomit. She was diagnosed with acute abdomen. A CT scan with bowel contrast demonstrated the presence of a leakage from the retroperitoneal aspect of duodenum. The surgical and clinical management in the light of literature review is presented. Results: Our first approach consisted in primary repair of the duodenal perforation with omentopexy. Post-operative course was complicated by hemorrhage. A reintervention showed a new perforation associated with multiple ischemic intestinal areas. We performed a gastroenteric anastomosis with functional exclusion of the damaged duodenum and positioning of drainages to create a biliary fistula. A nutritional enteric tube and an open abdomen vacuum-assisted closure system to monitor the fistula creation and to prevent abdominal contamination and collections were positioned. To reduce the amount of biliary leakage, a percutaneous transhepatic biliary drainage was placed, with progressive fistula flow disappearance in four months. Conclusions: In patients with dermatomyositis, when clinical findings and symptoms suggest abdominal vasculitis, it is very important to be aware of the risk of bowel and particularly duodenal perforations. Open abdomen treatment favors control of contamination by gastrointestinal contents, offers temporary abdominal closure, helps ICU care and delays definitive surgery

Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data

There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

ACTION of DICLOFENAC SODIUM ON the REPARATION PROCESS of the SURGICALLY-PERFORATED MYOMETRIUM of PREGNANT ALBINO-RATS - MORPHOLOGICAL and MORPHOMETRICAL EVALUATION

1. the action of a non-hormonal anti-inflammatory agent on the reparation process of the surgically-perforated myometrium of pregnant albino rats was histologically evaluated.2 On the 14th day after perforation, the muscular layers were still interrupted.3. the morphological study was inconclusive. A morphometrical analysis, however, demonstrated that there was a meaningful diminution in the number of leucocytes and collagen fibers and an increase in the number of fibroblasts, probably with low synthetical power, in the group treated with diclofenac sodium. All these data indicate a delay in the reparation process of the uterine musculature.UNIV São Paulo, ESCOLA PAULISTA MED SCH, AV MACUCO 417, AP 214, BR-04523917 São Paulo, BRAZILUNIV São Paulo, ESCOLA PAULISTA MED SCH, AV MACUCO 417, AP 214, BR-04523917 São Paulo, BRAZILWeb of Scienc

Chronic valproate restores hyperactivity, cognitive deficits and epileptiform activity in adolescent SNAP-25 heterozygous (SNAP-25+/−) mice

SNAP-25 is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the SNARE complex and modulates voltage gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, ADHD and bipolar disorders and low levels of SNAP-25 have been described in the brain of schizophrenic patients. Recently, we have behaviorally characterized adult SNAP-25+/ 12mice and found the occurrence of frequent spikes during 24-hour electroencephalographic (EEG) recordings, associative memory deficits and impaired social behavior, compared to the littermates (Corradini et al., 2012). Notably, acute treatment (250 mg/kg) with valproate sodium salt (VLP) rescued these impairments. A motor hyperactivity and a lack of response to amphetamine, specifically occurring in adolescent SNAP-25+/- mice (6-7 weeks), was also shown. On this basis, our aim was :1) to better investigate adolescent SNAP-25+/- mice (6-7 weeks old ) for memory and EEG profile ; 2) to evaluate the effect of VLP given chronically on behavioral and EEG defects. We found that adolescent SNAP-25+/ 12mice show reduced social interaction in the sociability test, cognitive deficits evaluated through object recognition test and lack of conditioned taste aversion. Furthermore, adolescent mice showed increased EEG spike occurrence and altered relative spectral power, in terms of reduced alpha (8-13 Hz) and beta (13-25Hz) and increased delta (0.1-4 Hz) activity during 2-hours recordings. Chronic VLP (0.1% dissolved in plain water for 3 weeks) reduced all the behavioral deficits. EEG spectral power alteration and enhanced spike activity were absent until two weeks from drug cessation. Experiments are in progress to investigate the possible effect of VLP on the expression of SNAP-25 by means of Western Blotting analysis of wild-type and heterozygous mice cortices. Behavioural SNAP-25+/- mice profile appears to recapitulate some of the core symptoms of ADHD. Repeated treatment with VLP ameliorated all the behavioral and EEG impairments suggesting the beneficial effect of this antiepileptic drug for some of ADHD-like behavioral feature

Hpv genotyping and p16 expression in xingu indigenous park, brazil

The association between high-risk human papillomavirus (HPV) genotypes and p16 expression in indigenous women from the Xingu Indigenous Park, Brazil, was unknown. This study evaluated p16 expression in women with a histological diagnosis of cervical intraepithelial neoplasia (CIN) 3 or higher and correlated this expression with HPV genotypes to determine possible discrepancies in the expression of this marker. We evaluated 37 previously collected samples with different HPV genotypes and high-grade lesions diagnosed based on cytology, histology, and colposcopy. Immunohistochemical analysis was performed using paraffin-embedded tissue sections and the CINtec (R) Histology Kit. p16 protein expression was investigated by immunostaining with an anti-p16 antibody. HPV genotyping was performed by reverse hybridization. The age of the study population ranged from 22-75 years (43.81 +/- 15.89 years) and parity ranged from 1-11 (5.92 +/- 2.58). Thirteen different HPV genotypes were found using the INNO-LiPA kit. Single and multiple infections by HPV were found with prevalence of single infections (P = 0.029). Comparison between HPV genotype and simple or multiple infections was highly significantit was observed more HPV 52 followed by HPV 16 in single infections (P < 0.001). p16 expression was predominantly diffuse, which was observed in 91.7% of lesions, whereas 8.3% were focal (P < 0.001). HPV 52, HPV 16 and 31 were the most prevalent HPV types in high-grade CIN in these indigenous women. Diffuse p16 expression in high-grade CIN was not influenced by the viral genotypehowever, more studies are necessary to further our understanding of this restricted group.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) grantNúcleo de Prevenção de Doenças Ginecológicas, Departamento de Ginecologia, Universidade Federal de São Paulo, São Paulo, SP, BrasilDepartamento de Patologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, BrasilDepartamento de Medicina Preventiva, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, BrasilInstituto de Medicina Tropical da Universidade de São Paulo, São Paulo, SP, BrasilNúcleo de Prevenção de Doenças Ginecológicas, Departamento de Ginecologia, Universidade Federal de São Paulo, São Paulo, SP, BrasilDepartamento de Patologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, BrasilDepartamento de Medicina Preventiva, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, BrasilWeb of Scienc

Comparative study of MMP-2 (matrix metalloproteinase 2) immune expression in normal uterine cervix, intraepithelial neoplasias, and squamous cells cervical carcinoma

Objective: This study was undertaken to evaluate the levels of matrix metalloproteinase 2 (MMP2) in the precursors lesions and in the invasive cervical carcinoma and to quantify the immune reactive expression of MMP-2, using MMP-2 immunohistochemistry, in intraepithelial cervical neoplasias and in the invading cervical carcinoma. Study design: We evaluated 60 samples of cervical tissues using immunohistochemistry for MMP2 in 5 distinct groups. the groups were divided in control, cervical intraepithelial neoplasia I (CIN I), CIN II, CIN III, and cervical invading carcinoma. Results: MMP-2 expression was found gradually increased according to the degree of cervical intraepithelial neoplasia and cervical carcinoma. (Control < CIN I < CIN II < CIN III < Carcinoma) Conclusion: Our results suggest that the expression of MMP-2 can distinguish CIN I, II, and III grades and the invading carcinoma. (C) 2004 Elsevier Inc. All rights reserved.Universidade Federal de São Paulo, Dept Gynecol, Mol Gynecol Lab, Escola Paulista Med, BR-04039001 São Paulo, SP, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Pathol, São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Gynecol, Mol Gynecol Lab, Escola Paulista Med, BR-04039001 São Paulo, SP, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Pathol, São Paulo, SP, BrazilWeb of Scienc