Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL gene in an extended Hungarian von Hippel-Lindau family

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by development of cystic and tumorous lesions at multiple sites, including the brain, spinal cord, kidneys, adrenals, pancreas, epididymis and eyes. The clinical phenotype results from molecular abnormalities of the VHL tumor suppressor gene, mapped to human chromosome 3p25-26. The VHL gene encodes two functionally active VHL proteins due to the presence of two translational initiation sites separated by 53 codons. The majority of disease-causing mutations have been detected downstream of the second translational initiation site, but there are conflicting data as to whether few mutations located in the first 53 codons, such as the Pro25Leu could have a pathogenic role. In this paper we report a large Hungarian VHL type 2 family consisting of 32 members in whom a disease-causing AGT80AAT (Ser80Ile) c.239G>A, p.Ser80Ile mutation, but not the concurrent CCT25CTT (Pro25Leu) c.74C>T, p.Pro25Leu variant co-segregated with the disease. To our knowledge, the Ser80Ile mutation has not been previously described in VHL type 2 patients with high risk of pheochromocytoma and renal cell cancer. Therefore, this finding represents a novel genotype-phenotype association and VHL kindreds with Ser80Ile mutation will require careful surveillance for pheochromocytoma. We concluded that the Pro25Leu variant is a rare, neutral variant, but the presence such a rare gene variant may make genetic counseling difficult

Exogenous surfactant application in a rat lung ischemia reperfusion injury model: effects on edema formation and alveolar type II cells

<p>Abstract</p> <p>Background</p> <p>Prophylactic exogenous surfactant therapy is a promising way to attenuate the ischemia and reperfusion (I/R) injury associated with lung transplantation and thereby to decrease the clinical occurrence of acute lung injury and acute respiratory distress syndrome. However, there is little information on the mode by which exogenous surfactant attenuates I/R injury of the lung. We hypothesized that exogenous surfactant may act by limiting pulmonary edema formation and by enhancing alveolar type II cell and lamellar body preservation. Therefore, we investigated the effect of exogenous surfactant therapy on the formation of pulmonary edema in different lung compartments and on the ultrastructure of the surfactant producing alveolar epithelial type II cells.</p> <p>Methods</p> <p>Rats were randomly assigned to a control, Celsior (CE) or Celsior + surfactant (CE+S) group (n = 5 each). In both Celsior groups, the lungs were flush-perfused with Celsior and subsequently exposed to 4 h of extracorporeal ischemia at 4°C and 50 min of reperfusion at 37°C. The CE+S group received an intratracheal bolus of a modified natural bovine surfactant at a dosage of 50 mg/kg body weight before flush perfusion. After reperfusion (Celsior groups) or immediately after sacrifice (Control), the lungs were fixed by vascular perfusion and processed for light and electron microscopy. Stereology was used to quantify edematous changes as well as alterations of the alveolar epithelial type II cells.</p> <p>Results</p> <p>Surfactant treatment decreased the intraalveolar edema formation (mean (coefficient of variation): CE: 160 mm³(0.61) vs. CE+S: 4 mm³(0.75); p < 0.05) and the development of atelectases (CE: 342 mm³(0.90) vs. CE+S: 0 mm³; p < 0.05) but led to a higher degree of peribronchovascular edema (CE: 89 mm³(0.39) vs. CE+S: 268 mm³(0.43); p < 0.05). Alveolar type II cells were similarly swollen in CE (423 μm³(0.10)) and CE+S (481 μm³(0.10)) compared with controls (323 μm³(0.07); p < 0.05 vs. CE and CE+S). The number of lamellar bodies was increased and the mean lamellar body volume was decreased in both CE groups compared with the control group (p < 0.05).</p> <p>Conclusion</p> <p>Intratracheal surfactant application before I/R significantly reduces the intraalveolar edema formation and development of atelectases but leads to an increased development of peribronchovascular edema. Morphological changes of alveolar type II cells due to I/R are not affected by surfactant treatment. The beneficial effects of exogenous surfactant therapy are related to the intraalveolar activity of the exogenous surfactant.</p

Clostridium difficile infection among hospitalized HIV-infected individuals: epidemiology and risk factors: results from a case-control study (2002-2013).

BACKGROUND: HIV infection is a risk factor for Clostridium difficile infection (CDI) yet the immune deficiency predisposing to CDI is not well understood, despite an increasing incidence of CDI among such individuals. We aimed to estimate the incidence and to evaluate the risk factors of CDI among an HIV cohort in Italy. METHODS: We conducted a retrospective case-control (1:2) study. Clinical records of HIV inpatients admitted to the National Institute for Infectious Disease "L. Spallanzani", Rome, were reviewed (2002-2013). CASES: HIV inpatients with HO-HCFA CDI, and controls: HIV inpatients without CDI, were matched by gender and age. Logistic regression was used to identify risk factors associated with CDI. RESULTS: We found 79 CDI episodes (5.1 per 1000 HIV hospital admissions, 3.4 per 10000 HIV patient-days). The mean age of cases was 46 years. At univariate analysis factors associated with CDI included: antimycobacterial drug exposure, treatment for Pneumocystis pneumonia, acid suppressant exposure, previous hospitalization, antibiotic exposure, low CD4 cell count, high Charlson score, low creatinine, low albumin and low gammaglobulin level. Using multivariate analysis, lower gammaglobulin level and low serum albumin at admission were independently associated with CDI among HIV-infected patients. CONCLUSIONS: Low gammaglobulin and low albumin levels at admission are associated with an increased risk of developing CDI. A deficiency in humoral immunity appears to play a major role in the development of CDI. The potential protective role of albumin warrants further investigation

Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or τ lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, φ, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan β in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN

Noninvasive Markers of Hepatic Fibrosis in Chronic Hepatitis B

A serum biomarker (FibroTest; Biopredictive, Paris, France; FibroSure; LabCorp, Burlington, USA) and liver stiffness measurement (LSM) by Fibroscan (Echosens, Paris, France) have been extensively validated in chronic hepatitis C. This review updates the clinical validation of serum biomarkers and LSM in patients with chronic hepatitis B (CHB). One meta-analysis combined all published studies and another used a database combining FibroTest individual data. Sensitivity analysis assessed the impact of several factors, including authors’ independence, length of biopsy, ethnicity, hepatitis B early antigen status, viral load, and alanine aminotransferase value. Only two biomarkers had several validations: FibroTest (8 studies, 1,842 patients), and Fibroscan (5 studies, 618 patients). For the diagnosis of advanced fibrosis, the standardized area under the receiver operating curve was 0.84 (0.79–0.86) for FibroTest and 0.89 (0.83–0.96) for LSM, without significant difference. No significant factors of variability were identified for FibroTest’s performance. In conclusion, FibroTest and LSM were the most validated biomarkers of fibrosis in CHB. However, the reliability of Fibroscan must be better assessed

Early glandular neoplasia of the lung

Although bronchogenic carcinomas progress through a very well defined sequence of metaplasia, dysplasia and carcinoma in situ, very little is known about the early progression of glandular neoplasms of the lung. In particular, the early precursor lesion from which fully malignant adenocarcinomas arise has effectively eluded recognition, at least until recently. Several lines of evidence now implicate atypical adenomatous hyperplasia (AAH) as an initial morphologic stage in multistep lung tumorigenesis. Despite its small size, AAH can be appreciated at the light microscopic level and characterized at the molecular genetic level. Indeed, the genetic characterization of AAH promises to further our understanding of lung cancer development and might facilitate the design of novel strategies for early detection of lung cancer

Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer

Introduction: Endothelin (EDN) signalling plays a crucial role in cell differentiation, proliferation and migration processes. There is compelling evidence that altered EDN signalling is involved in carcinogenesis by modulating cell survival and promoting invasiveness. To date, most reports have focused on the oncogenic potential of EDN1 and EDN2, both of which are overexpressed in various tumour entities. Here, we aimed at a first comprehensive analysis on EDN3 expression and its implication in human breast cancer. Methods: EDN3 mRNA expression was assessed by Northern blotting in normal human tissues (n = 9) as well as in matched pairs of normal and tumourous tissues from breast specimens (n = 50). EDN3 mRNA expression in breast cancer was further validated by real-time polymerase chain reaction (PCR) (n = 77). A tissue microarray was used to study EDN3 protein expression in breast carcinoma (n = 150) and normal breast epithelium (n = 44). EDN3 promoter methylation was analysed by methylation-specific PCR in breast cell lines (n = 6) before and after demethylating treatment, normal breast tissues (n = 17) and primary breast carcinomas (n = 128). EDN3 expression and methylation data were statistically correlated with clinical patient characteristics and patient outcome. Results: Loss of EDN3 mRNA expression in breast cancer, as initially detected by array-based expression profiling, could be confirmed by Northern blot analysis (> 2-fold loss in 96%) and real-time PCR (> 2-fold loss in 78%). Attenuated EDN3 expression in breast carcinoma was also evident at the protein level (45%) in association with adverse patient outcome in univariate (P = 0.022) and multivariate (hazard ratio 2.0; P = 0.025) analyses. Hypermethylation of the EDN3 promoter could be identified as the predominant mechanism leading to gene silencing. Reversion of the epigenetic lock by 5-aza-2'-deoxycytidine and trichostatin A resulted in EDN3 mRNA reexpression in vitro. Furthermore, EDN3 promoter hypermethylation was detected in 70% of primary breast carcinomas with significant association to loss of EDN3 mRNA expression (P = 0.005), whilst normal matched breast tissues revealed no EDN3 promoter methylation. Conclusions EDN3 is a frequent target of epigenetic inactivation in human breast cancer, potentially contributing to imbalanced EDN signalling commonly found in this disease. The clinical implication supports the view that EDN3, in contrast to EDN1 and EDN2, may act as natural tumour suppressor in the human mammary gland