Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin.

Aims/hypothesis: The aim of this study was to evaluate the risk of adverse cardiovascular outcomes in patients with type 2 diabetes newly treated with sulfonylureas and metformin.

Subjects And Methods: The Diabetes Audit and Research in Tayside Scotland (DARTS) diabetes information system and the Medicines Monitoring Unit (MEMO) dispensed prescribing database for the population of Tayside, Scotland (400,000 people) were employed. Patients newly prescribed with oral hypoglycaemic agents between 1994 and 2001 were classified into five study cohorts according to the treatment received: metformin only, sulfonylureas only, sulfonylureas added to metformin, metformin added to sulfonylureas, and both drugs simultaneously.

Systematic review of antimicrobial drug prescribing in hospitals.

Prudent prescribing of antimicrobial drugs to hospital inpatients may reduce incidences of antimicrobial drug resistance and healthcare-associated infection. We reviewed the literature from January 1980 to November 2003 to identify rigorous evaluations of interventions to improve hospital prescribing of antimicrobial drugs. We identified 66 studies with interpretable data, of which 16 reported 20 microbiologic outcomes: gram-negative resistant bacteria, 10 studies; Clostridium difficile-associated diarrhea, 5 studies; vancomycin-resistant enterococci, 3 studies; and methicillin-resistant Staphylococcus aureus, 2 studies.

The function of immunoglobulin A in immunity.

The vast surfaces of the gastrointestinal, respiratory, and genitourinary tracts represent major sites of potential attack by invading micro-organisms. Immunoglobulin A (IgA), as the principal antibody class in the secretions that bathe these mucosal surfaces, acts as an important first line of defence. IgA, also an important serum immunoglobulin, mediates a variety of protective functions through interaction with specific receptors and immune mediators.

Comparison of opinions and profiles of late or non-responding medical students with initial responders to a course evaluation questionnaire.

This study examined whether students requiring prompting to evaluate an educational module differed from initial responders in their rating of the experience and their profile (academic ability, age and gender). At the end of a 4th year induction Module, medical students completed an evaluation questionnaire. Those who did not respond were followed-up.

Structural requirements for the interaction of human IgA with the human polymeric Ig receptor.

Transport of polymeric IgA onto mucosal surfaces to become secretory IgA is mediated by the polymeric Ig receptor (pIgR). To study the interaction of human dimeric IgA (dIgA) (the predominant form of IgA polymer) with the human pIgR (hpIgR), we generated recombinant wild-type dIgA1 and dIgA2m(1) and various mutant dIgA1 and analyzed their interaction with a recombinant human secretory component and membrane-expressed hpIgR. We found that wild-type dIgA1 and dIgA2m(1) bound to recombinant human secretory component with similar affinity and were transcytosed by the hpIgR to the same extent.

Colonization of mucin by human intestinal bacteria and establishment of biofilm communities in a two-stage continuous culture system.

The human large intestine is covered with a protective mucus coating, which is heavily colonized by complex bacterial populations that are distinct from those in the gut lumen. Little is known of the composition and metabolic activities of these biofilms, although they are likely to play an important role in mucus breakdown. The aims of this study were to determine how intestinal bacteria colonize mucus and to study physiologic and enzymatic factors involved in the destruction of this glycoprotein.

Annual increase in body mass index in children with asthma on higher doses of inhaled steroids.

There is a greater annual increase in body mass index in children with asthma receiving inhaled steroids at a dose > or =400 microg/day (0.5 kg/m2/year; n=100) compared with those receiving < or =200 microg/day (0.1 kg/m2/year; n=98) (P=.

Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform.

Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials.

Mucosal immunoglobulins.

Due to their vast surface area, the mucosal surfaces of the body represent a major site of potential attack by invading pathogens. The secretions that bathe mucosal surfaces contain significant levels of immunoglobulins (Igs), which play key roles in immune defense of these surfaces. IgA is the predominant antibody class in many external secretions and has many functional attributes, both direct and indirect, that serve to prevent infective agents such as bacteria and viruses from breaching the mucosal barrier.

Lipopolysaccharide stimulates the secretion of the amyloid precursor protein via a protein kinase C-mediated pathway.

The processing of the amyloid precursor protein (APP) by the secretase family of protease enzymes can be influenced by a variety of diverse factors, including elements of the immune response. In this study, we have investigated the effect of the pro-inflammatory lipopolysaccharide (LPS) on APP processing in rat glial cell cultures derived from both cortex and cerebellum. LPS activation of the cells, as monitored by the induction of the pro-inflammatory nitric oxide synthase (iNOS) enzyme, elicited no change in the overall cellular expression levels of APP, although there was a marked concentration-related increase in the secretion of the soluble APPs following both short- (4 h) and long-term (18 h) drug treatment times.

The influences of hinge length and composition on the susceptibility of human IgA to cleavage by diverse bacterial IgA1 proteases.

The influences of IgA hinge length and composition on its susceptibility to cleavage by bacterial IgA1 proteases were examined using a panel of IgA hinge mutants. The IgA1 proteases of Streptococcus pneumoniae, Streptococcus sanguis strains SK4 and SK49, Neisseria meningitidis, Neisseria gonorrhoeae, and Haemophilus influenzae cleaved IgA2-IgA1 half hinge, an Ab featuring half of the IgA1 hinge incorporated into the equivalent site in IgA1 protease-resistant IgA2, whereas those of Streptococcus mitis, Streptococcus oralis, and S. sanguis strain SK1 did not.

Genotype-dependent induction of transmissible chromosomal instability by gamma-radiation and the benzene metabolite hydroquinone.

Although it is well established that ionizing radiation and benzene are epidemiologically linked to acute myeloid leukemia (AML), the underlying mechanisms are not understood. We have shown that gamma-radiation can induce a persisting genomic instability in the clonal descendants of hemopoietic stem cells manifested as a high frequency of nonclonal chromosome and chromatid aberrations. A strikingly similar instability is shown after exposure to the benzene metabolite hydroquinone.

Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress.

It has been suggested that physiological resistance to repeated stress is associated with increased 5-hydroxytryptamine (5-HT) release in the dorsal hippocampus and that dysregulation of this neuroadaptation may be implicated in the psychopathology of depression. This study used 5,7-dihydroxytryptamine lesions to investigate the role of 5-HT projections to the hippocampus in physiological responses to repeated stress and putative changes in corticosteroid receptor immunoreactivity in the brain. Repeated exposure to elevated open platform stress (1 h/day) caused regionally selective changes in glucocorticoid and mineralocorticoid receptor immunoreactivity in the dorsal hippocampus that were not observed in ventral hippocampus, frontal cortex, hypothalamus or parietal cortex.

The neurobiology of tobacco dependence: a preclinical perspective on the role of the dopamine projections to the nucleus accumbens [corrected].

It is now widely accepted that nicotine is the primary addictive component of tobacco smoke and that a majority of habitual smokers find it difficult to quit smoking because of their dependence upon this component of the smoke. However, although nicotine replacement therapy elicits a clinically valuable and significant improvement in the number of quit attempts that are ultimately successful, its efficacy remains disappointingly low. This review considers some of the reasons for this problem.

Effect of mutations in the human immunoglobulin A1 (IgA1) hinge on its susceptibility to cleavage by diverse bacterial IgA1 proteases.

Components of the human immunoglobulin A1 (IgA1) hinge governing sensitivity to cleavage by bacterial IgA1 proteases were investigated. Recombinant antibodies with distinct hinge mutations were constructed from a hybrid comprised of human IgA2 bearing half of the human IgA1 hinge region. This hybrid antibody and all the mutant antibodies derived from it were resistant to cleavage by the IgA1 proteases from Streptococcus oralis and Streptococcus mitis biovar 1 strains but were cleaved to various degrees by those of Streptococcus pneumoniae, some Streptococcus sanguis strains, and the type 1 and 2 IgA1 proteases of Haemophilus influenzae, Neisseria meningitidis, and Neisseria gonorrhoeae.

Identification of internal sequences in the 3' leader region of human respiratory syncytial virus that enhance transcription and confer replication processivity.

Previous studies of respiratory syncytial virus have shown that the 44-nucleotide (nt) leader (Le) region is sufficient to initiate RNA replication, producing antigenome RNA, and that the Le and adjoining gene start (GS) signal of the first gene are sufficient to initiate transcription, producing mRNA. A cis-acting element necessary for both transcription and replication was mapped within the first 11 nt at the 3' end of Le. In the present study the remainder of the Le region was mapped to identify sequences important for transcription and replication.

The potential role of tau protein O-glycosylation in Alzheimer's disease.

Single O-linked N-acetylglucosamine (O-GlcNAc) sugar residues can compete with phosphate groups to occupy specific sites on certain nuclear and cytosolic proteins. Here we show that inhibiting cellular kinase activities resulted in changes in protein O-glycosylation levels in heat-stable cytoskeletal protein fractions derived from primary neuronal cells. As increased phosphorylation of the microtubule-associated protein tau is one of the pathological hallmarks of Alzheimer's disease and glycosylation may play an influential role in this process.

Inducible form of nitric oxide synthase expression in rat cortical neuronal cells in vitro.

The inducible form of nitric oxide synthase (iNOS) is an essential element of the immune response, which is expressed primarily in microglial cells within the CNS. Exposure of rat cortical neuronal cells to the pro-inflammatory bacterial endotoxin lipopolysaccharide (LPS) resulted in a significant increase in the expression of the cellular iNOS protein expression and NO generation (which serves as an indirect measure of NOS catalytic activity). These effects were potentiated by costimulation with interferon-gamma (IFNgamma) and the increase in NO generation was abolished by the iNOS selective inhibitor 1400W, although this did not attenuate the toxin-induced increase in the enzyme expression.

Docking-dependent regulation of the Rb tumor suppressor protein by Cdk4.

Phosphorylation of target proteins by cyclin D1-Cdk4 requires both substrate docking and kinase activity. In addition to the ability of cyclin D1-Cdk4 to catalyze the phosphorylation of consensus sites within the primary amino acid sequence of a substrate, maximum catalytic activity requires the enzyme complex to anchor at a site remote from the phospho-acceptor site. A novel Cdk4 docking motif has been defined within a stretch of 19 amino acids from the C-terminal domain of the Rb protein that are essential for Cdk4 binding.

Human antibody-Fc receptor interactions illuminated by crystal structures.

Immunoglobulins couple the recognition of invading pathogens with the triggering of potent effector mechanisms for pathogen elimination. Different immunoglobulin classes trigger different effector mechanisms through interaction of immunoglobulin Fc regions with specific Fc receptors (FcRs) on immune cells. Here, we review the structural information that is emerging on three human immunoglobulin classes and their FcRs.

Association of a salivary acetylcholinesterase with Alzheimer's disease and response to cholinesterase inhibitors.

Objectives: A decrease in cholinergic activity is a key event in the biochemistry of Alzheimer's disease (AD). The aim of the study was to investigate the expression levels of markers of cholinergic function in saliva, which is a readily accessible body fluid that can be obtained from subjects with minimal distress.

Design And Methods: Salivary samples were obtained from people with NINCDS-ARDRA "probable" Alzheimer's disease and age- and sex-matched controls.

Concomitant occasional use of salbutamol influences bronchoprotective responsiveness afforded by formoterol in patients with the glycine-16 genotype.

Background: Predisposition to subsensitivity with long-acting beta(2)-agonists (LABA) or regular short-acting beta(2)-agonists (SABA) is related to polymorphisms at codon 16 of the beta(2)-adrenoceptor.

Objective: To determine whether the use of occasional SABA induces further baseline downregulation of the beta(2)-adrenoceptor to that of endogenous catecholamines alone, in Gly-16 patients.

Methods: A post-hoc analysis of two studies was performed.