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.

How we developed a core curriculum in clinical skills.

This article describes the process that the authors have used in the Dundee Clinical Skills Centre to develop and maintain the core curriculum for the second-year programme in clinical skills. The programme provides medical students with basic, generic skills required in clinical medicine.

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.

The dynamic localization of the glucocorticoid receptor in rat C6 glioma cell mitochondria.

Glucocorticoids modify gene expression via the translocation of receptors from the cytosol to the nucleus following agonist-associated receptor activation. In this study, we have characterized mitochondrial glucocorticoid (GR) localization and associated translocation kinetics in the C6 mouse glioma cell line. Treatment of the cells, which were cultured in steroid-depleted culture medium, with the GR agonist dexamethasone (dex) resulted in a dramatic decrease in mitochondrial GR levels in parallel with those of the cytosolic receptor.

The role of protein phosphorylation in alpha2,6(N)-sialyltransferase activity.

Sialoglycoproteins play a key role in both brain development and neuronal plasticity with their sialylation state being controlled by the sialyltransferase (STN) family of enzymes. In this study, we have determined the role of specific kinase enzymes in the expression and catalytic activity of the alpha2,6 STN (ST6N) isozyme. The catalytic activity was moderately decreased following the inhibition of GSK3beta with LiCl.

Pattern recognition molecules and innate immunity to parasites.

Recent pioneering advances in understanding how plants, insects and worms eliminate pathogens has led to the realization that innate immunity plays a vital role in protecting humans from infection. This comprehensive review examines the molecules involved in innate immune responses, how they act to control parasites and if their engagement can explain many immune features characteristic of parasitic infections.

Limited role of charge matching in the interaction of human immunoglobulin A with the immunoglobulin A Fc receptor (Fc alpha RI) CD89.

Human immunoglobulin A (IgA) mediates protective effector mechanisms through interaction with specific cellular Fc receptors (Fc alpha RI). Two IgA Fc interdomain loops (Leu257-Leu258 in the CH2 domain and Pro440-Phe443 in the CH3 domain) have previously been identified as critical for binding to Fc alpha RI. On the receptor, the interaction site for IgA has been localized to the EC1 domain.

Neuroplasticity within the mesoaccumbens dopamine system and its role in tobacco dependence.

The development of nicotine dependence is related to stimulation of the dopamine projections to the nucleus accumbens. This review considers the evidence that the addictive potential of nicotine depends upon its ability to elicit burst firing of these neurones and, thereby, evoke a large and sustained increase in the dopamine concentration in the extracellular space between the cells. This dopamine, it is argued, stimulates extra-synaptic dopamine receptors that mediate the responses underling the development of dependence.