Quantitative Circulatory Physiology: an integrative mathematical model of human physiology for medical education.

We have developed Quantitative Circulatory Physiology (QCP), a mathematical model of integrative human physiology containing over 4,000 variables of biological interactions. This model provides a teaching environment that mimics clinical problems encountered in the practice of medicine. The model structure is based on documented physiological responses within peer-reviewed literature and serves as a dynamic compendium of physiological knowledge.

Prevalence of maternal smoking and environmental tobacco smoke exposure during pregnancy and impact on birth weight: retrospective study using Millennium Cohort.

Background: Meta-analyses of studies investigating the impact of maternal environmental tobacco smoke (ETS) on birth weight have not produced robust findings. Although, ante natal ETS exposure probably reduces infant's birth weights, the scale of this exposure remains unknown. We conducted a large, cohort study to assess the impact of ETS exposure on birth weight whilst adjusting for the many factors known to influence this.

Impact of contractual financial incentives on the ascertainment and management of smoking in primary care.

Background: The April 2004 contract for UK general practitioners (GPs) is an ambitious attempt to produce substantial changes in clinical practice. We investigated the impact of this on delivery of primary care smoking cessation interventions.

Methods: We analysed data from patients' medical records that were held within a large database called The Health Improvement Network (THIN).

An assessment of radionuclidic impurities of (210)Po produced via neutron irradiation of (209)Bi for use in targeted alpha-particle radiotherapy.

Radionuclidic impurities of (210)Po prepared by neutron irradiation of (209)Bi via the (209)Bi(n,gamma)(210)Bi reaction were investigated. Following irradiation and ingrowth, a pure (210)Po solution was obtained by sublimation and dissolution. Results were obtained by liquid scintillation (LS) counting, isotope dilution alpha (alpha)-spectrometry, and high-purity germanium gamma-ray spectrometry.

Epstein-Barr virus inhibits Kaposi's sarcoma-associated herpesvirus lytic replication in primary effusion lymphomas.

The majority of AIDS-associated primary effusion lymphomas (PEL) are latently infected with both Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). PELs harboring two viruses have higher oncogenic potential, suggesting functional interactions between EBV and KSHV. The KSHV replication and transcription activator (K-RTA) is necessary and sufficient for induction of KSHV lytic replication.

Grb2 is required for atherosclerotic lesion formation.

Objective: Grb2 is a ubiquitously expressed linker protein that couples growth factor receptor activation to downstream mitogen-activated protein kinase (MAPK) cascades. Macrophage proliferation and uptake of modified lipoproteins are critical components of atherogenesis which require MAPK activation. However, the precise role of upstream signaling factors and the interrelationship of various MAPK cascades in the pathogenesis of atherosclerosis remains uncertain.

An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension.

Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARalpha (Ppara) is required for glucocorticoid-induced insulin resistance. Here we demonstrate that afferent fibers of the vagus nerve interface with hepatic Ppara expression to disrupt blood pressure and glucose homeostasis in response to glucocorticoids.

Protocol for the smoking, nicotine and pregnancy (SNAP) trial: double-blind, placebo-randomised, controlled trial of nicotine replacement therapy in pregnancy.

Background: Smoking in pregnancy remains a public health challenge. Nicotine replacement therapy (NRT) is effective for smoking cessation in non-pregnant people, but because women metabolise nicotine and cotinine much faster in pregnancy, it is unclear whether this will be effective for smoking cessation in pregnancy. The NHS Health Technology Assessment Programme (HTA)-funded smoking, nicotine and pregnancy (SNAP) trial will investigate whether or not nicotine replacement therapy (NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women.

1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives.

Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.

Communication between South Asian patients and GPs: comparative study using the Roter Interactional Analysis System.

Background: The UK South Asian population has poorer health outcomes. Little is known about their process of care in general practice, or in particular the process of communication with GPs.

Aim: To compare the ways in which white and South Asian patients communicate with white GPs.

Optimal random libraries for the isolation of catalytic RNA.

The relationship between ribozyme size and catalytic activity is of fundamental importance for RNA catalysis and molecular evolution in the RNA world. We have performed a series of competitive in vitro selection experiments to probe the relationship using RNA libraries containing size-heterogeneous random regions. Our experiments have established an inverse correlation between RNA replication efficiency (the combined efficiency of PCR amplification, transcription, and reverse transcription) and RNA size.

1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists: Structure-activity relationships of 4- and 5-substituted benzoic acid derivatives.

This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure.

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia.

Ischemia and chronic hypoxia (CH) trigger a variety of adverse effects arising from metabolic stress that injures cells. In response to reduced O2, hypoxia-inducible factor 1alpha (HIF-1alpha) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O2 deficiency. Epo produced by the kidney stimulates erythrocyte production, leading to decreased HIF-1alpha production by improved tissue O2 delivery.

The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain.

The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes.

Identification of a novel targeting sequence for regulated secretion in the serine protease inhibitor neuroserpin.

Ns (neuroserpin) is a member of the serpin (serine protease inhibitor) gene family that is primarily expressed within the central nervous system. Its principal target protease is tPA (tissue plasminogen activator), which is thought to contribute to synaptic plasticity and to be secreted in a stimulus-dependent manner. In the present study, we demonstrate in primary neuronal cultures that Ns co-localizes in LDCVs (large dense core vesicles) with the regulated secretory protein chromogranin B.

Carbamylated erythropoietin reduces radiosurgically-induced brain injury.

Gamma knife radiosurgery is an attractive noninvasive treatment of brain tumors and vascular malformations that minimizes collateral tissue damage. However, exposure of normal tissue to even low-dose radiation triggers a cascade of acute and chronic injury and potentially significant morbidity and mortality. Because many irradiated patients now survive for years, identifying methods to prevent radiotherapy-induced collateral tissue damage is a major focus of current research.

Blockade of postsynaptic activity in sleep inhibits developmental plasticity in visual cortex.

Ocular dominance plasticity is enhanced by sleep and reduced by sleep deprivation or when all neural activity in the sleeping visual cortex is reversibly inhibited. These latter findings demonstrate that the mechanisms responsible for the effects of sleep on cortical plasticity are activity dependent. To better isolate this activity dependent mechanism, we investigated the role of postsynaptic activity by inactivating the sleeping visual cortex after a period of monocular deprivation with the gamma-amino-n-butyric acid agonist muscimol.

Designing smoking cessation services for school-age smokers: A survey and qualitative study.

To identify the preferred design characteristics of smoking cessation services for school-age smokers, we conducted focus groups with teenage smokers motivated to stop smoking. We surveyed all pupils in years 9-11 (aged 13-16) in a random sample of 10 schools in Nottinghamshire, United Kingdom, to elicit details of smoking behavior, and conducted 25 focus groups in 6 schools with current smokers who wanted to stop smoking. Of 4,065 pupils surveyed, 888 (22%) were current smokers, and 438 (50% of smokers) wanted to quit smoking.

Polymeric conjugates of mono- and bi-cyclic alphaVbeta3 binding peptides for tumor targeting.

The alphaVbeta3 integrin plays important roles in tumor-induced angiogenesis and tumor metastasis and hence, many small molecule alphaVbeta3 ligands have been developed for cancer diagnosis and therapy. Although these show good alphaVbeta3 targeting, most have suboptimal pharmacokinetics and show rapid tumor washout. We studied the biodistribution and tumor targeting properties of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer based conjugates of mono-(RGDfK) and doubly cyclized (RGD4C) alphaVbeta3 binding peptides.

Drugs to support smoking cessation in UK general practice: are evidence based guidelines being followed?

Background: Prescribing drugs to support smoking cessation is one of the most cost effective interventions in primary care, but there is evidence they are underused. Little is known about how far guidelines have been adopted.

Aims: To examine the context in which nicotine replacement therapy (NRT) and bupropion are prescribed in UK general practice and whether guidelines are being followed.

Identification of novel pyrazole acid antagonists for the EP1 receptor.

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.

Reliability of clinician-based (GRBAS and CAPE-V) and patient-based (V-RQOL and IPVI) documentation of voice disorders.

This study examined the reliability of two methods for documenting voice quality by clinicians and compared the methods for documenting patients' perceptions of voice quality. It involved a prospective reliability study and a retrospective chart review. Reliability of two clinician-based voice assessment protocols-Grade, Roughness, Breathiness, Asthenia, Strain (GRBAS) and Consensus Auditory Perceptual Evaluation-Voice (CAPE-V)-was evaluated.

Computer systems analysis of spaceflight induced changes in left ventricular mass.

Circulatory adaptations resulting in postflight orthostasis have frequently been observed in response to space travel. It has been postulated that a decrement in left ventricular mass (LVM) found after microgravity exposure may be the central component in this cardiovascular deconditioning. However, a physiologic mechanism responsible for these changes in the myocardium has not been determined.

Sleep and sleep regulation in the ferret (Mustela putorius furo).

We investigated sleep-wake (S-W) architecture and sleep regulation in the ferret: a phylogenetically primitive mammal increasingly used in neurobiological studies. Twenty-four hour S-W baseline data were collected in eight adult ferrets. Seven ferrets were then sleep deprived for 6h at the beginning of the light period.

Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists.

The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group.