A rare variant of carcinoma of the cervix: neuroendocrine tumour

Neuroendocrine neoplasm that occurs in the uterine cervix is rare. It accounts for 0.5-1% of all malignant tumours of the uterine cervix. A 55 years old female patient complained of postmenopausal bleeding and history of foul smelling discharge per vagina since 1 month. On examination cervix appeared bulky, both lips indurated, bleeds on touch, both parametrium involved but not up to pelvic wall with bulky uterus. Vagina and per rectal mucosa was free. Clinical diagnosis of carcinoma cervix, stage 2B was made. Cervix biopsy with HPE revealed squamous epithelium of cervix showing neoplastic cells arranged in nests and prominent perivascular pattern, small round cells with minimal cytoplasm and hyperchromatic nucleus, abundant mitosis, cells showed rosette pattern and isolated foci of cell debris and necrosis.  Diagnosis of neuroendocrine tumour of cervix was considered. Immunohistochemistry for cytokeratin, neuron specific enolase, chromogranin and synaptophysin was positive, confirming the final diagnosis of neuroendocrine carcinoma cervix (High grade of small cell type). Recognition of Neuroendocrine carcinoma cervix is important for appropriate therapy & management since these patients have worse clinical outcomes when compared with conventional squamous /adeno carcinoma of cervix. Immunohistochemistry should be supplemented with ultrastructural studies for confirmation and correct categorisation of carcinoma cervix for appropriate management

The pH of the skin surface and its impact on the barrier function

The `acid mantle' of the stratum corneum seems to be important for both permeability barrier formation and cutaneous antimicrobial defense. However, the origin of the acidic pH, measurable on the skin surface, remains conjectural. Passive and active influencing factors have been proposed, e. g. eccrine and sebaceous secretions as well as proton pumps. In recent years, numerous investigations have been published focusing on the changes in the pH of the deeper layers of the stratum corneum, as well as on the influence of physiological and pathological factors. The pH of the skin follows a sharp gradient across the stratum corneum, which is suspected to be important in controlling enzymatic activities and skin renewal. The skin pH is affected by a great number of endogenous factors, e. g. skin moisture, sweat, sebum, anatomic site, genetic predisposition and age. In addition, exogenous factors like detergents, application of cosmetic products, occlusive dressings as well as topical antibiotics may influence the skin pH. Changes in the pH are reported to play a role in the pathogenesis of skin diseases like irritant contact dermatitis, atopic dermatitis, ichthyosis, acne vulgaris and Candida albicans infections. Therefore, the use of skin cleansing agents, especially synthetic detergents with a pH of about 5.5, may be of relevance in the prevention and treatment of those skin diseases. Copyright (c) 2006 S. Karger AG, Base

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Annual outpatient hysteroscopy and endometrial sampling (OHES) in HNPCC/Lynch syndrome (LS)

Background: LS women have a 40-60 % lifetime risk of endometrial cancer (EC). Most international guidelines recommend screening. However, data on efficacy are limited. Purpose: To assess the performance of OHES for EC screening in LS and compare it with transvaginal ultrasound (TVS) alone. Methods: A prospective observational cohort study of LS women attending a tertiary high-risk familial gynaecological cancer clinic was conducted. LS women opting for EC screening underwent annual OHES and TVS. Histopathological specimens were processed using a strict protocol. Data of women screened between October 2007 and March 2010 were analysed from a bespoke database. Histology was used as the gold standard. Diagnostic accuracy of OHES was compared with TVS using specificity, and positive (PLR) and negative (NLR) likelihood ratios. Results: Forty-one LS women underwent 69 screens (41 prevalent, 28 incident). Four (three prevalent, one incident) women were detected to have EC/atypical endometrial hyperplasia (AEH), five had endometrial polyps and two had endometrial hyperplasia (EH) on OHES. TVS detected two of four EC/AEH. OHES had similar specificity of 89.8 % (CI 79.2, 96.2 %), but higher PLR 9.8 (CI 4.6, 21) and lower NLR (zero) compared to TVS: specificity 84.75 %(CI 73, 92.8 %), PLR 3.28 (CI 1.04, 10.35) and NLR 0.59 (CI 0.22, 1.58). No interval cancers occurred over a median follow-up of 22 months. The annual incidence was 3.57 % (CI 0.09, 18.35) for EC, 10.71 % (CI 2.27, 28.23) for polyps and 21.4 % (CI 8.3, 40.1) for any endometrial pathology. Conclusions: Our findings suggest that in LS, annual OHES is acceptable and has high diagnostic accuracy for EC/AEH screening. Larger international studies are needed for confirmation, given the relatively small numbers of LS women at individual centres. It reinforces the current recommendation that endometrial sampling is crucial when screening these women. © 2012 Springer-Verlag

Magnetic Resonance Water Proton Relaxation in Protein Solutions and Tissue: T1ρ Dispersion Characterization

BACKGROUND: Image contrast in clinical MRI is often determined by differences in tissue water proton relaxation behavior. However, many aspects of water proton relaxation in complex biological media, such as protein solutions and tissue are not well understood, perhaps due to the limited empirical data. PRINCIPAL FINDINGS: Water proton T(1), T(2), and T(1rho) of protein solutions and tissue were measured systematically under multiple conditions. Crosslinking or aggregation of protein decreased T(2) and T(1rho), but did not change high-field T(1). T(1rho) dispersion profiles were similar for crosslinked protein solutions, myocardial tissue, and cartilage, and exhibited power law behavior with T(1rho)(0) values that closely approximated T(2). The T(1rho) dispersion of mobile protein solutions was flat above 5 kHz, but showed a steep curve below 5 kHz that was sensitive to changes in pH. The T(1rho) dispersion of crosslinked BSA and cartilage in DMSO solvent closely resembled that of water solvent above 5 kHz but showed decreased dispersion below 5 kHz. CONCLUSIONS: Proton exchange is a minor pathway for tissue T(1) and T(1rho) relaxation above 5 kHz. Potential models for relaxation are discussed, however the same molecular mechanism appears to be responsible across 5 decades of frequencies from T(1rho) to T(1)

Attitude towards pre-implantation genetic diagnosis for hereditary cancer

The use of pre-implantation genetic diagnosis (PGD) for hereditary cancer is subject to on-going debate, particularly among professionals. This study evaluates the attitude towards PGD and attitude-associated characteristics of those concerned: family members with a hereditary cancer predisposition. Forty-eight Von Hippel-Lindau and 18 Li–Fraumeni Syndrome families were identified via the 9 family cancer clinics in the Netherlands. In total, 216 high risk family members and partners were approached, of whom 179 (83%) completed a self-report questionnaire. Of the high risk family members, 35% expressed a positive attitude towards PGD. Those with a current desire to have children were significantly more likely to have a positive attitude: 48% would consider the use of PGD. No other sociodemographic, medical or psychosocial variables were associated significantly with a positive attitude. The most frequently reported advantage of PGD is the avoidance of a possible pregnancy termination. Uncertainty about late effects was the most frequently reported disadvantage. These results indicate that approximately half of those contemplating a future pregnancy would consider the use of PGD. The actual uptake, however, is expected to be lower. There is no indication that psychosocial factors affect interest in PGD

The Depletion of Nuclear Glutathione Impairs Cell Proliferation in 3t3 Fibroblasts

BACKGROUND:Glutathione is considered essential for survival in mammalian cells and yeast but not in prokaryotic cells. The presence of a nuclear pool of glutathione has been demonstrated but its role in cellular proliferation and differentiation is still a matter of debate. PRINCIPAL FINDINGS:We have studied proliferation of 3T3 fibroblasts for a period of 5 days. Cells were treated with two well known depleting agents, diethyl maleate (DEM) and buthionine sulfoximine (BSO), and the cellular and nuclear glutathione levels were assessed by analytical and confocal microscopic techniques, respectively. Both agents decreased total cellular glutathione although depletion by BSO was more sustained. However, the nuclear glutathione pool resisted depletion by BSO but not with DEM. Interestingly, cell proliferation was impaired by DEM, but not by BSO. Treating the cells simultaneously with DEM and with glutathione ethyl ester to restore intracellular GSH levels completely prevented the effects of DEM on cell proliferation. CONCLUSIONS:Our results demonstrate the importance of nuclear glutathione in the control of cell proliferation in 3T3 fibroblasts and suggest that a reduced nuclear environment is necessary for cells to progress in the cell cycle

Nocturnal Hypoxia and Loss of Kidney Function

Background: Although obstructive sleep apnea (OSA) is more common in patients with kidney disease, whether nocturnal hypoxia affects kidney function is unknown. Methods: We studied all adult subjects referred for diagnostic testing of sleep apnea between July 2005 and December 31 2007 who had serial measurement of their kidney function. Nocturnal hypoxia was defined as oxygen saturation (SaO2) below 90 % for $12$4 ml/min/1.73 m2 per year. Results: 858 participants were included and followed for a mean study period of 2.1 years. Overall 374 (44%) had nocturnal hypoxia, and 49 (5.7%) had accelerated loss of kidney function. Compared to controls without hypoxia, patients with nocturnal hypoxia had a significant increase in the adjusted risk of accelerated kidney function loss (odds ratio (OR) 2.89, 95 % confidence interval [CI] 1.25, 6.67). Conclusion: Nocturnal hypoxia was independently associated with an increased risk of accelerated kidney function loss. Further studies are required to determine whether treatment and correction of nocturnal hypoxia reduces loss of kidney function

Development of the social brain from age three to twelve years

Human adults recruit distinct networks of brain regions to think about the bodies and minds of others. This study characterizes the development of these networks, and tests for relationships between neural development and behavioral changes in reasoning about others' minds ('theory of mind', ToM). A large sample of children (n = 122, 3-12 years), and adults (n = 33), watched a short movie while undergoing fMRI. The movie highlights the characters' bodily sensations (often pain) and mental states (beliefs, desires, emotions), and is a feasible experiment for young children. Here we report three main findings: (1) ToM and pain networks are functionally distinct by age 3 years, (2) functional specialization increases throughout childhood, and (3) functional maturity of each network is related to increasingly anti-correlated responses between the networks. Furthermore, the most studied milestone in ToM development, passing explicit false-belief tasks, does not correspond to discontinuities in the development of the social brain.National Science Foundation (U.S.) (Award 1122374)National Science Foundation (U.S.) (Award 095518)National Institutes of Health (U.S.) (Award R01-MH096914-05