Sequential genome-wide association studies for monitoring adverse events in the clinical evaluation of new drugs

Pharmacovigilance, the monitoring of adverse events (AEs), is an integral part in the clinical evaluation of a new drug. Until recently, attempts to relate the incidence of AEs to putative causes have been restricted to the evaluation of simple demographic and environmental factors. The advent of large-scale genotyping, however, provides an opportunity to look for associations between AEs and genetic markers, such as single nucleotides polymorphisms (SNPs). It is envisaged that a very large number of SNPs, possibly over 500 000, will be used in pharmacovigilance in an attempt to identify any genetic difference between patients who have experienced an AE and those who have not. We propose a sequential genome-wide association test for analysing AEs as they arise, allowing evidence-based decision-making at the earliest opportunity. This gives us the capability of quickly establishing whether there is a group of patients at high-risk of an AE based upon their DNA. Our method provides a valid test which takes account of linkage disequilibrium and allows for the sequential nature of the procedure. The method is more powerful than using a correction, such as idák, that assumes that the tests are independent. Copyright © 2006 John Wiley & Sons, Ltd.

Over the counter medicines and the need for immediate action: a further evaluation of European Commission recommended wordings for communicating risk

A study examined people's interpretation of European Commission (EC) recommended verbal descriptors for risk of medicine side effects, and actions to take if they do occur. Members of the general public were presented with a fictitious (but realistic) scenario about suffering from a stiff neck, visiting the local pharmacy and purchasing an over the counter (OTC) medicine (Ibruprofen). The medicine came with an information leaflet which included information about the medicine's side effects, their risk of occurrence, and recommended actions to take if adverse effects are experienced. Probability of occurrence was presented numerically (6%) or verbally, using the recommended EC descriptor (common). Results showed that, in line with findings of our earlier work with prescribed medicines, participants significantly overestimated side effect risk. Furthermore, the differences in interpretation were reflected in their judgements of satisfaction, side effect severity, risk to health, and intention to take the medicine. Finally, we observed no significant difference between people's interpretation of the recommended action descriptors ('immediately' and 'as soon as possible'). (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

A critical evaluation of the ability of the Spinning Enhanced Visible and Infrared Imager (SEVIRI) thermal infrared red-green-blue rendering to identify dust events: theoretical analysis

Using a combination of idealized radiative transfer simulations and a case study from the first field campaign of the Saharan Mineral Dust Experiment (SAMUM) in southern Morocco, this paper provides a systematic assessment of the limitations of the widely used Spinning Enhanced Visible and Infrared Imager (SEVIRI) red-green-blue (RGB) thermal infrared dust product. Both analyses indicate that the ability of the product to identify dust, via its characteristic pink coloring, is strongly dependent on the column water vapor, the lower tropospheric lapse rate, and dust altitude. In particular, when column water vapor exceeds ∼20–25 mm, dust presence, even for visible optical depths of the order 0.8, is effectively masked. Variability in dust optical properties also has a marked impact on the imagery, primarily as a result of variability in dust composition. There is a moderate sensitivity to the satellite viewing geometry, particularly in moist conditions. The underlying surface can act to confound the signal seen through variations in spectral emissivity, which are predominantly manifested in the 8.7μm SEVIRI channel. In addition, if a temperature inversion is present, typical of early morning conditions over the Sahara and Sahel, an increased dust loading can actually reduce the pink coloring of the RGB image compared to pristine conditions. Attempts to match specific SEVIRI observations to simulations using SAMUM measurements are challenging because of high uncertainties in surface skin temperature and emissivity. Recommendations concerning the use and interpretation of the SEVIRI RGB imagery are provided on the basis of these findings.

Comparative study of disk diffusion and microdilution methods for evaluation of antifungal activity of natural compounds against medical yeasts Candida spp and Cryptococcus sp

Antifungal activity of natural products has been tested by adapting methods designed for synthetic drugs. In this study, two methods for the determination of antifungal activity of natural products, agar diffusion and broth microdilution, the CLSI reference methods for synthetic drugs, are compared and discussed. The microdilution method was more sensitive. The minimal inhibitory concentrations (MIC) of crude extracts, fractions and pure substances from different species of the plant families Piperaceae, Rubiaceae, Clusiaceae, Fabaceae and Lauraceae, from the Biota project, were determined. Antifungal activities against Candida albicans, C.krusei, C.parapsilosis and Cryptococcus neoformans were produced by several samples.

Recurrent urinary tract infections: Evaluation of the prophylactic efficacy of urinary antiseptics methenamine and methylthioninium chloride

Introduction: Urinary tract infection (UTI) is a very common condition in clinical practice, affecting an estimated 50% of all adult women during a lifetime. The most common causative agent is E. coli; UTI may also be caused by S. saprophyticus, Enterobacteria (Klebsiella sp and Serratia sp.), Enterococcus sp., and P aeruginosa. Recurrent UTIs occur at least twice per semester or three times a year. Prophylactic measures to prevent recurrent UTIs include changes in contraception methods, cranberry products, increased fluid intake, urination after intercourse, vaginal estrogen therapy for post-menopausal women, antibiotics, and urinary tract antiseptic agents. Objectives: To evaluate the use of a combination of methenamine and methyl-thioninium chloride in the prophylaxis of recurrent uncomplicated lower UTIs, with respect to: • Signs and symptoms of UTI • Etiologic agent(s) • Recurrence rates • Need for antibiotic therapy in case of recurrence • Incidence of adverse events associated with the treatment, including any reported alterations of laboratory tests Materials & methods: A descriptive, analytic, restrospective study was performed at Hospital Universitário Constantino Otaviano - UNIFESO. Medical charts from patients presenting recurrent uncomplicated lower UTI attended from 2001-present were analyzed, including the following information: Demographic data (age, gender, weight, ethnicity, living conditions): medical history/signs and symptoms of UTI; identification of treatment and dosing regimens; treatment duration; recurrence rates and need for antibiotic therapy in case of recurrence; other medications prescribed; and records of adverse events. Results: E. coli was identified as etiologic agent in 80% of the patients. Following antibiotic therapy, all patients received prophylactic treatment with the combination of methenamine and methylthioninium chloride. Treatment duration ranged from three to six months. Adverse events were observed in 13/60 patients (21.7%). At the end of the respective treatment periods, a statistically significant (p<0.0001) number of patients showed no UTI recurrence. Conclusion: Based on the results from the collected data, we conclude that an orally administered combination of methenamine and methylthioninium chloride is safe and effective in the prophylactic treatment of recurrent uncomplicated lower urinary tract infection. © Copyright Morelra Jr. Editora.

Cytogenetic characterization and evaluation of c-MYC gene amplification in PG100, a new Brazilian gastric cancer cell line

Gastric cancer is the fourth most frequent type of cancer and the second cause of cancer mortality worldwide. The genetic alterations described so far for gastric carcinomas include amplifications and mutations of the c-ERBB2, KRAS, MET, TP53, and c-MYC genes. Chromosomal instability described for gastric cancer includes gains and losses of whole chromosomes or parts of them and these events might lead to oncogene overexpression, showing the need for a better understanding of the cytogenetic aspects of this neoplasia. Very few gastric carcinoma cell lines have been isolated. The establishment and characterization of the biological properties of gastric cancer cell lines is a powerful tool to gather information about the evolution of this malignancy, and also to test new therapeutic approaches. The present study characterized cytogenetically PG100, the first commercially available gastric cancer cell line derived from a Brazilian patient who had a gastric adenocarcinoma, using GTG banding and fluorescent in situ hybridization to determine MYC amplification. Twenty metaphases were karyotyped; 19 (95%) of them presented chromosome 8 trisomy, where the MYC gene is located, and 17 (85%) presented a deletion in the 17p region, where the TP53 is located. These are common findings for gastric carcinomas, validating PG100 as an experimental model for this neoplasia. Eighty-six percent of 200 cells analyzed by fluorescent in situ hybridization presented MYC overexpression. Less frequent findings, such as 5p deletions and trisomy 16, open new perspectives for the study of this tumor.

Synthesis and preliminary evaluation of N-oxide derivatives for the prevention of atherothrombotic events

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Evaluation of Viral Load Thresholds for Predicting New World Health Organization Stage 3 and 4 Events in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy

Background: This study evaluated a wide range of viral load (VL) thresholds to identify a cut-point that best predicts new clinical events in children on stable highly active antiretroviral therapy (HAART). Methods: Cox proportional hazards modeling was used to assess the adjusted risk for World Health Organization stage 3 or 4 clinical events (WHO events) as a function of time-varying CD4, VL, and hemoglobin values in a cohort study of Latin American children on HAART >= 6 months. Models were fit using different VL cut-points between 400 and 50,000 copies per milliliter, with model fit evaluated on the basis of the minimum Akaike information criterion value, a standard model fit statistic. Results: Models were based on 67 subjects with WHO events out of 550 subjects on study. The VL cut-points of >2600 and >32,000 copies per milliliter corresponded to the lowest Akaike information criterion values and were associated with the highest hazard ratios (2.0, P = 0.015; and 2.1, P = 0.0058, respectively) for WHO events. Conclusions: In HIV-infected Latin American children on stable HAART, 2 distinct VL thresholds (>2600 and >32,000 copies/mL) were identified for predicting children at significantly increased risk for HIV-related clinical illness, after accounting for CD4 level, hemoglobin level, and other significant factors.

Evaluation of a multi variated analysis for the selection of t-tbar multijet events in the current CMS implemented environment at LHC

In the present study we are using multi variate analysis techniques to discriminate signal from background in the fully hadronic decay channel of ttbar events. We give a brief introduction to the role of the Top quark in the standard model and a general description of the CMS Experiment at LHC. We have used the CMS experiment computing and software infrastructure to generate and prepare the data samples used in this analysis. We tested the performance of three different classifiers applied to our data samples and used the selection obtained with the Multi Layer Perceptron classifier to give an estimation of the statistical and systematical uncertainty on the cross section measurement.