MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family.

The melanocortin receptor (MCR) family consists of 5 G protein-coupled receptors (MC1R-MC5R) with diverse physiologic roles. MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, whereas MC3R and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the single most common cause of monogenic obesity.

Extended homozygosity is not usually due to cytogenetic abnormality.

Background: Previous studies have reported frequent stretches of homozygosity in human subjects but have failed to clarify whether these are due to cytogenetic abnormalities or to autozygosity.

Methods: Trios which had been typed for closely spaced SNPs spanning the genome were studied. Stretches of extended homozygosity were identified in the child members, as were occasions on which the child had been genotyped as not inheriting one parental allele.

Comparison of artificial neural network analysis with other multimarker methods for detecting genetic association.

Background: Debate remains as to the optimal method for utilising genotype data obtained from multiple markers in case-control association studies. I and colleagues have previously described a method of association analysis using artificial neural networks (ANNs), whose performance compared favourably to single-marker methods. Here, the performance of ANN analysis is compared with other multi-marker methods, comprising different haplotype-based analyses and locus-based analyses.

Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score.

Burning mouth syndrome (BMS) is often an idiopathic chronic and intractable pain condition, affecting 1.5-5.5% of middle-aged and elderly women.

Ultrasound findings after screening for Down syndrome using the integrated test.

Objective: To evaluate the incidence and significance of fetal anomalies and "soft markers" after screening for Down syndrome using the integrated test.

Methods: This study is a retrospective study of 2,332 women at University College London Hospitals, United Kingdom. All women were screened for Down syndrome by the integrated test.

Effects of exacerbations and seasonality on exhaled nitric oxide in COPD.

Exhaled nitric oxide (eNO) appears to be associated with airway inflammation seen in chronic obstructive pulmonary disease (COPD). The present authors studied the effects of exacerbation, season, temperature and pollution on eNO. eNO was measured seasonally and at exacerbations in 79 outpatients suffering from COPD (mean forced expiratory volume in one second=42%).

Mechanisms of high glucose-induced apoptosis and its relationship to diabetic complications.

Cellular responses to high glucose are numerous and varied but ultimately result in functional changes and, often, cell death. High glucose induces oxidative and nitrosative stress in many cell types causing the generation of species such as superoxide, nitric oxide and peroxynitrite and their derivatives. The role of these species in high glucose-mediated apoptotic cell death is relevant to the complications of diabetes such as neuropathy, nephropathy and cardiovascular disease.

Role of viruses in exacerbations of chronic obstructive pulmonary disease.

Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality and hospital admission. Respiratory viral infections, especially rhinoviruses, are a major cause of COPD exacerbations, with upper respiratory tract infections being associated with over 50% of COPD exacerbations. The presence of an upper respiratory tract infection leads to a more severe exacerbation and a longer symptom recovery time at exacerbation.

Differential pH and capsaicin responses of Griffonia simplicifolia IB4 (IB4)-positive and IB4-negative small sensory neurons.

Protons play a key role in nociception caused by inflammation and ischaemia, but little is known about the relative sensitivities of different dorsal root ganglion (DRG) neurons. We have therefore examined the responses in vitro of rat DRG cells classified according to whether or not they bind Griffonia simplicifolia IB4 (IB4), a lectin which is widely used to distinguish between two major populations of small diameter neurons. Under voltage-clamp conditions, proton-activated inward currents were found in approximately 90% of small DRG neurons and showed one of three waveforms: transient, sustained or mixed.

Genome scan of Tourette syndrome in a single large pedigree shows some support for linkage to regions of chromosomes 5, 10 and 13.

Objectives: To localize genes influencing the susceptibility to Gilles de la Tourette syndrome (GTS) and associated chronic multiple tics (CMT).

Method: A single, large, multiple affected pedigree containing 35 subjects diagnosed with GTS and a further 14 with CMT was genotyped for markers spanning the autosomes. Linkage analysis was carried out using classical lod score analysis and model-free lod score analysis.

Longitudinal changes in the nature, severity and frequency of COPD exacerbations.

Exacerbations are an important feature and outcome measure in chronic obstructive pulmonary disease (COPD), but little is known about changes in their severity, recovery, symptom composition or frequency over time. In this study 132 patients (91 male; median age 68.4 yrs and median forced expiratory volume in one second (FEV1) 38.

Plasma taurine and cysteine levels following an oral methionine load: relationship with coronary heart disease.

Objective: To test the hypothesis that endogenous synthesis of taurine from methionine is impaired in people with coronary heart disease (CHD).

Design: Nested case-control.

Subjects: Indian Asian and white European males aged 35-60 y.

The molecular and cellular basis of corticosteroid resistance.

Corticosteroids (CS) can modulate gene expression and are often used to treat a range of immunological and inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis. However, a proportion of patients fail to show an adequate response. On this basis patients have been subdivided into CS-sensitive (SS) and -resistant (SR) subgroups.

Exacerbations of chronic obstructive pulmonary disease.

Exacerbations of chronic obstructive pulmonary disease (COPD) cause morbidity, hospital admissions, and mortality, and strongly influence health-related quality of life. Some patients are prone to frequent exacerbations, which are associated with considerable physiologic deterioration and increased airway inflammation. About half of COPD exacerbations are caused or triggered primarily by bacterial and viral infections (colds, especially from rhinovirus), but air pollution can contribute to the beginning of an exacerbation.

Targeting cytokines to inflammation sites.

To increase the half-life of a cytokine and target its activation specifically to disease sites, we have engineered a latent cytokine using the latency-associated protein (LAP) of transforming growth factor-beta 1 (TGF-beta 1) fused via a matrix metalloproteinase (MMP) cleavage site to interferon (IFN)-beta at either its N or C terminus. The configuration LAP-MMP-IFN-beta resembles native TGF-beta and lacks biological activity until cleaved by MMPs, whereas the configuration IFN-beta-MMP-LAP is active. LAP provides for a disulfide-linked shell hindering interaction of the cytokine with its cellular receptors, conferring a very long half-life of 55 h in vivo.

Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q.

Objective: To localize genes conferring susceptibility to bipolar affective disorder.

Methods: Seven families were selected on the basis of containing multiple cases of bipolar affective disorder present in three or more generations, an absence of schizophrenia and unilineal transmission. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10 cM intervals across the whole genome.

Clustering of immunoreceptor tyrosine-based activation motif-containing signalling subunits in CD4(+) T cells is an optimal signal for IFN-gamma production, but not for the production of IL-4.

CD4(+) T cells with pre-defined MHC-unrestricted specificity to type II collagen (CII) were engineered for cell-based anti-inflammatory gene therapy of autoimmune arthritis. To this end, recombinant chimeric immunoreceptors, C2gamma or C2zeta, were expressed in primary mouse keyhole limpet hemocyanin (KLH)-specific T(h)1 and T(h)2 cells using retrovirus vector-based somatic cell gene transfer. The ectodomain of these tyrosine-based activation motif (ITAM)-containing immunoreceptors is a single-chain IgG variable domain of an anti-CII mAb.

High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases.

Diabetic nephropathy is the leading cause of end-stage renal disease in the Western world. Poor glycemic control contributes to the development of diabetic nephropathy, but the mechanisms underlying high glucose-induced tissue injury are not fully understood. In the present study, the effect of high glucose on a proximal tubular epithelial cell (PTEC) line was investigated.

Longitudinal trends in exercise capacity and health status after pulmonary rehabilitation in patients with COPD.

Pulmonary rehabilitation (PR) programmes produce initial improvements in exercise tolerance and health status in patients with chronic obstructive pulmonary disease (COPD). However, there is limited data on the longer term effects of PR. This study has examined whether the initial benefits gained in exercise tolerance and health status may be maintained after a 1-year follow-up programme.

Common mental disorder and physical illness in the Renfrew and Paisley (MIDSPAN) study.

Objective And Methods: The relationship between psychological distress measured by the General Health Questionnaire 30 (GHQ-30) and risk factors for coronary heart disease, angina, electrocardiogram (ECG) abnormalities and chronic sputum was modelled using logistic regression on baseline data from a community study of 15,406 men and women.

Results: Psychological distress was associated with low forced expiratory volume (FEV(1)) and low body mass index (BMI) in men, and low systolic blood pressure only in women. There were associations between psychological distress and coronary heart disease and cardiorespiratory outcomes.

Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia.

The mitochondrial pyruvate dehydrogenase complex (PDC) catalyses the oxidative decarboxylation of pyruvate, and links glycolysis to the tricarboxylic acid cycle and ATP production. Adequate flux through PDC is important in tissues with a high ATP requirement, in lipogenic tissues (since it provides cytosolic acetyl-CoA for fatty acid (FA) synthesis), and in generating cytosolic malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase (CPT I). Conversely, suppression of PDC activity is crucial for glucose conservation when glucose is scarce.

Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.

Background: Chronic obstructive pulmonary disease (COPD) is characterised by both an accelerated decline in lung function and periods of acute deterioration in symptoms termed exacerbations. The aim of this study was to investigate whether these are related.

Methods: Over 4 years, peak expiratory flow (PEF) and symptoms were measured at home daily by 109 patients with COPD (81 men; median (IQR) age 68.