1991-05-04

Abstract OBJECTIVES: To analyse the virological and clinical efficacy of cidofovir combined with highly active antiretroviral therapy (HAART) in AIDS-related progressive multifocal leukoencephalopathy (PML). DESIGN: Multicentre observational study of consecutive HIV-positive patients with histologically or virologically-proven PML. Group A, 26 patients treated with HAART; group B, 14 patients treated with HAART plus cidofovir 5 mg/kg intravenously per week for the first 2 weeks and alternate weeks thereafter. JC virus DNA was quantified in cerebrospinal fluid (CSF) by PCR. RESULTS: Baseline virological, immunological and clinical characteristics were homogeneous between the groups. In one case cidofovir was discontinued because of severe proteinuria. There was no significant difference in HIV RNA responses and changes in the number of CD4 cells between group A and B. After 2 months of therapy, five out of 12 (42%) patients from group A and seven out of eight (87%) from group B reached undetectable JC virus DNA in the CSF (Chi-square P = 0.04); moreover, 24% of group A and 57% of group B patients showed neurological improvement or stability (P = 0.038). One-year cumulative probability of survival was 0.67 with cidofovir and 0.31 without (log-rank test, P = 0.01). Variables independently associated with longer survival were the use of cidofovir, HAART prior to the onset of PML, a baseline JC virus DNA load in CSF or = 60. CONCLUSIONS: In AIDS-related PML, cidofovir added to HAART is associated with a more effective control of JCV replication, with improved neurological outcome and survival compared with HAART alone

Measurements of the Absolute Branching Ratios for the Dominant KL Decays, the KL Lifetime, and Vus with the KLOE Detector

From a sample of about 10^9 Phi mesons produced at DAFNE, we have selected KL mesons tagged by observing KS->pi+pi- decays. We present results on the major KL branching ratios, including those of the semileptonic decays needed for the determination of Vus. These branching ratio measurements are fully inclusive with respect to final-state radiation. The KL lifetime has also been measured.Comment: Submitted to Phys. Lett.

CIS-based registration of quality of life in a single source approach

Background: Documenting quality of life (QoL) in routine medical care and using it both for treatment and for clinical research is not common, although such information is absolutely valuable for physicians and patients alike. We therefore aimed at developing an efficient method to integrate quality of life information into the clinical information system (CIS) and thus make it available for clinical care and secondary use. Methods: We piloted our method in three different medical departments, using five different QoL questionnaires. In this setting we used structured interviews and onsite observations to perform workflow and form analyses. The forms and pertinent data reports were implemented using the integrated tools of the local CIS. A web-based application for mobile devices was developed based on XML schemata to facilitate data import into the CIS. Data exports of the CIS were analysed with statistical software to perform an analysis of data quality. Results: The quality of life questionnaires are now regularly documented by patients and physicians. The resulting data is available in the Electronic Health Record (EHR) and can be used for treatment purposes and communication as well as research functionalities. The completion of questionnaires by the patients themselves using a mobile device (iPad) and the import of the respective data into the CIS forms were successfully tested in a pilot installation. The quality of data is rendered high by the use of automatic score calculations as well as the automatic creation of forms for follow-up documentation. The QoL data was exported to research databases for use in scientific analysis. Conclusion: The CIS-based QoL is technically feasible, clinically accepted and provides an excellent quality of data for medical treatment and clinical research. Our approach with a commercial CIS and the web-based application is transferable to other sites

Stellar Coronal and Wind Models: Impact on Exoplanets

Surface magnetism is believed to be the main driver of coronal heating and stellar wind acceleration. Coronae are believed to be formed by plasma confined in closed magnetic coronal loops of the stars, with winds mainly originating in open magnetic field line regions. In this Chapter, we review some basic properties of stellar coronae and winds and present some existing models. In the last part of this Chapter, we discuss the effects of coronal winds on exoplanets.Comment: Chapter published in the "Handbook of Exoplanets", Editors in Chief: Juan Antonio Belmonte and Hans Deeg, Section Editor: Nuccio Lanza. Springer Reference Work

Mutations of PIK3CA in gastric adenocarcinoma

BACKGROUND: Activation of the phosphatidylinositol 3-kinase (PI3K) through mutational inactivation of PTEN tumour suppressor gene is common in diverse cancer types, but rarely reported in gastric cancer. Recently, mutations in PIK3CA, which encodes the p110α catalytic subunit of PI3K, have been identified in various human cancers, including 3 of 12 gastric cancers. Eighty percent of these reported mutations clustered within 2 regions involving the helical and kinase domains. In vitro study on one of the "hot-spot" mutants has demonstrated it as an activating mutation. METHODS: Based on these data, we initiated PIK3CA mutation screening in 94 human gastric cancers by direct sequencing of the gene regions in which 80% of all the known PIK3CA mutations were found. We also examined PIK3CA expression level by extracting data from the previous large-scale gene expression profiling study. Using Significance Analysis of Microarrays (SAM), we further searched for genes that show correlating expression with PIK3CA. RESULTS: We have identified PIK3CA mutations in 4 cases (4.3%), all involving the previously reported hotspots. Among these 4 cases, 3 tumours demonstrated microsatellite instability and 2 tumours harboured concurrent KRAS mutation. Data extracted from microarray studies showed an increased expression of PIK3CA in gastric cancers when compared with the non-neoplastic gastric mucosae (p < 0.001). SAM further identified 2910 genes whose expression levels were positively associated with that of PIK3CA. CONCLUSION: Our data suggested that activation of the PI3K signalling pathway in gastric cancer may be achieved through up-regulation or mutation of PIK3CA, in which the latter may be a consequence of mismatch repair deficiency

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

Tetraspanin CD151 is a novel prognostic marker in poor outcome endometrial cancer

BACKGROUND: Type II cancers account for 10% of endometrial cancers but 50% of recurrence. Response rates to chemotherapy at recurrence are poor and better prognostic markers are needed to guide therapy. CD151 is a small transmembrane protein that regulates cell migration and facilitates cancer metastasis. High CD151 expression confers poor prognosis in breast, pancreatic and colorectal cancer. The prognostic significance of tetraspanin CD151 expression in poor outcome endometrial cancers was evaluated, along with oestrogen receptor (ER), progesterone receptor (PR), p53, human epidermal growth factor receptor -2 (HER-2), and CD 151 staining compared with α6β1, α3β1 integrins, and E-cadherin. METHODS: Tissue microarray constructed from 156 poor outcome endometrial cancers, tested with immunohistochemistry and staining correlated with clinicopathological data were used. A total of 131 data sets were complete for analysis. RESULTS: Expression of CD151 was significantly higher in uterine papillary serous and clear cell carcinoma than in grade 3 endometrioid carcinoma, sarcoma or carcinosarcoma (P<0.001). In univariate analysis, age, stage, histology type and CD151 were significant for both recurrence free (RFS) and disease specific survival (DSS). In multivariate analyses, CD151 was significant for RFS and DSS (P=0.036 and 0.033, respectively) in triple negative (ER, PR and HER-2 negative) tumours (88/131). The HER-2, p53, ER and PR were not prognostic for survival. There was strong concordance of CD151 with E-cadherin (98%), but not with α6β1 (35%), α3β1 staining (60%). CONCLUSION: The CD151 is a novel marker in type 2 cancers that can guide therapeutic decisions. CD151 may have an important role in tumourigenesis in some histology types

The location of the axon initial segment affects the bandwidth of spike initiation dynamics

The dynamics and the sharp onset of action potential (AP) generation have recently been the subject of intense experimental and theoretical investigations. According to the resistive coupling theory, an electrotonic interplay between the site of AP initiation in the axon and the somato-dendritic load determines the AP waveform. This phenomenon not only alters the shape of AP recorded at the soma, but also determines the dynamics of excitability across a variety of time scales. Supporting this statement, here we generalize a previous numerical study and extend it to the quantification of the input-output gain of the neuronal dynamical response. We consider three classes of multicompartmental mathematical models, ranging from ball-and-stick simplified descriptions of neuronal excitability to 3D-reconstructed biophysical models of excitatory neurons of rodent and human cortical tissue. For each model, we demonstrate that increasing the distance between the axonal site of AP initiation and the soma markedly increases the bandwidth of neuronal response properties. We finally consider the Liquid State Machine paradigm, exploring the impact of altering the site of AP initiation at the level of a neuronal population, and demonstrate that an optimal distance exists to boost the computational performance of the network in a simple classification task. Copyright