Comparative efficacy of nucleoside/nucleotide reverse transcriptase inhibitors in combination with efavirenz: results of a systematic overview.

Background: Many trials of antiretroviral therapy in treatment-naïve subjects have investigated the relative efficacy of the third drug in a treatment regimen. However, the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) components may also affect efficacy.

Method: A systematic overview of clinical trials studying initial treatment in naïve subjects receiving efavirenz-containing regimens and providing week 48 time to loss of virologic response (TLOVR) results was undertaken to compare results with different NRTI combinations.

A combined dataset of human cerebrospinal fluid proteins identified by multi-dimensional chromatography and tandem mass spectrometry.

Human cerebrospinal fluid (CSF) is an important source for studying protein biomarkers of age-related neurodegenerative diseases. Before characterizing biomarkers unique to each disease, it is necessary to categorize CSF proteins systematically and extensively. However, the enormous complexity, great dynamic range of protein concentrations, and tremendous protein heterogeneity due to post-translational modification of CSF create significant challenges to the existing proteomics technologies for an in-depth, nonbiased profiling of the human CSF proteome.

An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults.

Objective: To compare the effectiveness of three drug combination antiretroviral therapy (ART) in treatment-naive HIV-infected persons, and identify the predictors of responses.

Design And Methods: Overview of trials identified by searching public domain publications and conference presentations. The three-drug combination therapy was defined as two nucleoside reverse transcriptase inhibitors (NRTI) or nucleotide and NRTI, and either: (1) a protease inhibitor (PI); (2) a non-nucleoside RTI (NNRTI); (3) a third NRTI; or (4) a ritonavir-boosted PI (BPI).

Identification of glycoproteins in human cerebrospinal fluid with a complementary proteomic approach.

Biomarkers are pressingly needed to assist with the clinical diagnosis of neurodegenerative diseases and/or the monitoring of disease progression. Glycoproteins are enriched in bodily fluids such as human cerebrospinal fluid (CSF), an ideal source for discovering biomarkers due to its proximity to the central nervous system (CNS), and consequently can serve as diagnostic and/or therapeutic markers for CNS diseases. We report here an in-depth identification of glycoproteins in human CSF using a complementary proteomic approach which integrated hydrazide chemistry and lectin affinity column for glycoprotein enrichment, followed by multidimensional chromatography separation and tandem mass spectrometric analysis.

Retirement patterns from career employment.

Purpose: This article investigates how older Americans leave their career jobs and estimates the extent of intermediate labor force activity (bridge jobs) between full-time work on a career job and complete labor-force withdrawal.

Design And Methods: Using data from the Health and Retirement Study, we explored the work histories and retirement patterns of a cohort of retirees aged 51 to 61 in 1992 during a 10-year period in both cross-sectional and longitudinal contexts. We examined determinants of retirement patterns in a multinomial logistic regression model.

Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders.

Biomarkers are needed to assist in the diagnosis and medical management of various neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy body (DLB). We have employed a multiplex quantitative proteomics method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), in conjunction with multidimensional chromatography, followed by tandem mass spectrometry (MS/MS), to simultaneously measure relative changes in the proteome of cerebrospinal fluid (CSF) obtained from patients with AD, PD, and DLB compared to healthy controls. The diagnosis of AD and DLB was confirmed by autopsy, whereas the diagnosis of PD was based on clinical criteria.

Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition.

Background: Decreased cerebrospinal fluid (CSF) beta-amyloid 42 (A beta 42) concentration, but not A beta 40 concentration, is a biomarker for Alzheimer disease. This A beta 42 concentration decrease in CSF likely reflects precipitation of A beta 42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease.

Quantitative in vivo biomarkers of oxidative damage and their application to the diagnosis and management of Alzheimer's disease.

Dementia from Alzheimer's disease (AD) represents a significant and growing public health burden and presents a clear therapeutic imperative. Key to success in this undertaking will be biomarkers for the objective assessment of disease progression and response to therapeutics. Oxidative damage is one facet of AD pathogenesis for which there are experimentally validated quantitative in vivo biomarkers, the F2-isoprostanes (IsoPs).

Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression.

Alzheimer's disease (AD) is a complex, neurodegenerative disease characterized by the impairment of cognitive function in elderly individuals. In a recent global gene expression study of APP transgenic mice, we found elevated expression of mitochondrial genes, which we hypothesize represents a compensatory response because of mitochondrial oxidative damage caused by the over-expression of mutant APP and/or amyloid beta (Abeta). We investigated this hypothesis in a series of experiments examining what forms of APP and Abeta localize to the mitochondria, and whether the presence of these species is associated with mitochondrial dysfunction and oxidative damage.

Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice.

Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Here, the effects of the antioxidant, alpha-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.

Safety and acceptability of the research lumbar puncture.

Three hundred forty-two subjects underwent 428 research lumbar punctures for studies of cerebrospinal fluid (CSF) biomarkers. Subjects were 67 Alzheimer disease or mild cognitive impairment (AD/MCI) patients and 275 cognitively normal adults aged 21 to 88. Lumbar puncture was performed in the lateral decubitus or sitting position using the Sprotte 24 g atraumatic spinal needle.

Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease.

Biochemical characterization of the major detergent-insoluble proteins that comprise hallmark histopathologic lesions initiated the molecular era of Alzheimer's disease (AD) research. Here, we reinvestigated detergent-insoluble proteins in AD using modern proteomic techniques. Using liquid chromatography (LC)-mass spectrometry (MS)-MS-based proteomics, we robustly identified 125 proteins in the detergent-insoluble fraction of late-onset AD (LOAD) temporal cortex that included several proteins critical to Abeta production, components of synaptic scaffolding, and products of genes linked to an increased risk of LOAD; we verified 15 of 15 of these proteins by Western blot.

Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease.

Biomarkers to assist in the diagnosis and medical management of Alzheimer disease (AD) are a pressing need. We have employed a proteomic approach, microcapillary liquid chromatography mass spectrometry of proteins labeled with isotope-coded affinity tags (ICAT), to quantify relative changes in the proteome of human cerebrospinal fluid (CSF) obtained from the lumbar cistern. Using CSF from well-characterized AD patients and age-matched controls at 2 different institutions, we quantified protein concentration ratios of 42% of the 390 CSF proteins that we have identified and found differences > or = 20% in over half of them.

Reduced CSF PLTP activity in Alzheimer's disease and other neurologic diseases; PLTP induces ApoE secretion in primary human astrocytes in vitro.

Phospholipid transfer protein (PLTP) plays a pivotal role in cellular lipid efflux and modulation of lipoprotein metabolism. PLTP is distributed widely in the central nervous system (CNS), is synthesized by glia and neurons, and is active in cerebrospinal fluid (CSF). The aims of this study were to test the hypothesis that patients with Alzheimer's disease (AD) have altered PLTP-mediated phospholipid transfer activity in CSF, and to examine the potential relationship between PLTP activity and apolipoprotein E (apoE) levels in CSF.

Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials.

Melatonin has been proposed as a treatment for Alzheimer's disease based on the demonstration of antioxidant and "anti-amyloid" effects in vitro and in vivo. Chronic melatonin therapy in old, amyloid plaque-bearing transgenic mice was studied. Tg2576 mice started melatonin treatment at 14 months of age.

Consumption guideline for cadmium in moose meat in northern British Columbia, Canada.

Introduction: Disturbed by reports of high concentrations of cadmium in large land mammals in Arctic Canada, community members wondered if they should eat less moose (Alces alces).

Study Design: Risk assessment modelling.

Methods: We measured cadmium concentrations in moose tissues donated by food hunters.

Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects.

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms.

apoE isoforms and measures of anxiety in probable AD patients and Apoe-/- mice.

Increased anxiety may occur in up to 70% of AD patients during the course of their illness. Here we show that human apoE isoforms, which differ in AD risk, have differential effects on measures of anxiety in adult Apoe-/- male mice expressing human apoE3 or apoE4 in their brains and male probable AD (PRAD) patients. Compared with wild-type mice, Apoe-/- mice without human apoE or with apoE4, but not apoE3, showed increased measures of anxiety.

Characterization of a 2.6 kbp variable region within a class 1 integron found in an Acinetobacter baumannii strain isolated from a horse.

Objectives: A complete gene cassette contained in a class 1 integron from a multidrug-resistant (MDR) isolate of Acinetobacter baumannii cultured from a horse was characterized by molecular methods.

Methods: Template genomic DNA purified from the A. baumannii isolate was investigated by PCR.

F2-isoprostanes in Alzheimer and other neurodegenerative diseases.

Increased free radical-mediated injury to brain is proposed to be an integral component of several neurodegenerative diseases, including Alzheimer's disease (AD). Lipid peroxidation is a major outcome of free radical- mediated injury to brain, where it directly damages membranes and generates a number of oxidized products. F2-Isoprostanes (F2-IsoPs), one group of lipid peroxidation products derived from arachidonic acid, are especially useful as in vivo biomarkers of lipid peroxidation.

Quantitative proteomic analysis of age-related changes in human cerebrospinal fluid.

Identification of cerebrospinal fluid (CSF) biomarkers of the common age-related neurodegenerative diseases would be of great value to clinicians because of the difficulties in differential diagnoses of these diseases in clinical practice. Proteins are one class of potential biomarkers currently under investigation in the hope that different ensembles of proteins will aid in the diagnosis of these diseases, as well as in the assessment of progression and response to therapy. However, before undertaking a rational approach to CSF protein biomarkers of age-related neurodegeneration, we must first systematically identify CSF proteins and determine whether their levels change with normal aging.

A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV.

Background: Once daily (QD) dosing facilitates regimen simplification and adherence to antiretroviral therapy. Emtricitabine (FTC) QD is a newly approved nucleoside reverse transcriptase inhibitor compared in this study to twice daily lamivudine (3TC BID).

Methods: Controlled, open label equivalence trial of 440 HIV-1-infected patients with plasma HIV-1 RNA stably suppressed on a regimen of 3TC 150 mg BID, stavudine or zidovudine, and a protease inhibitor or non-nucleoside reverse transcriptase inhibitor.

A bi-directional mu-opioid-opioid connection between the nucleus of the accumbens shell and the central nucleus of the amygdala in the rat.

The central nucleus of the amygdala (CeA) and the nucleus of the accumbens shell (NAc) have been shown to be involved in opioid-mediated feeding behavior. The present study examined whether mu-opioid signalling between the CeA and NAc affected feeding. Male Sprague-Dawley rats were fitted with one cannula placed in the CeA and two cannulae placed in the NAc, which allowed for coadministration of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) in one site and the opioid antagonist naltrexone (NTX) in the other site.

Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial.

Context: Emtricitabine is a new, once-daily nucleoside reverse transcriptase inhibitor (NRTI) with potent activity against human immunodeficiency virus (HIV).

Objective: To assess the efficacy and safety of emtricitabine as compared with stavudine when used with a background regimen of didanosine and efavirenz.

Design, Setting, And Patients: Randomized, double-blind, double-dummy study conducted at 101 research clinics in North America, Latin America, and Europe.

Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the impairment of cognitive functions and by beta amyloid (Abeta) plaques in the cerebral cortex and the hippocampus. Our objective was to determine genes that are critical for cellular changes in AD progression, with particular emphasis on changes early in disease progression. We investigated an established amyloid precursor protein (APP) transgenic mouse model (the Tg2576 mouse model) for gene expression profiles at three stages of disease progression: long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of Abeta plaques.