Indices of obesity and cardiovascular risk factors in British women.

Background: Obesity increases cardiovascular risk through effects on blood pressure, lipoproteins, coagulation factors and inflammatory cytokines, but in women variation in fat distribution complicates these relationships. Central (male-type or visceral) obesity confers greater risk than the more generalised (female) type. This is recognised by the metabolic syndrome which employs waist circumference rather than body mass index (BMI).

A new subtype-specific monoclonal antibody for IAP-survivin identifies high-risk patients with diffuse large B-cell lymphoma and improves the prognostic value of bcl-2.

Anti-apoptotic factors including IAP-survivin and bcl-2 are involved in carcinogenesis and predict for disease outcome for patients with cancer. We used RT-PCR and specific primers to generate two recombinant IAP-survivin proteins; one encoding for the full-length protein and the second comprising the survivin sequence incorporating amino acids 98 to 142. Both proteins were used to immunize mice and as capture antigens to screen NS1/immune splenocyte hybridoma supernatants for anti-survivin antibody in ELISA assays.

The construction and in vitro testing of photo-activatable cancer targeting folated anti-CD3 conjugates.

The construction and in vitro testing of a photo-activatable anti-tumour immuno-regulatory antibody is described. In this 'cloaked' folated anti-CD3 antibody conjugate, the folate portion of the conjugate is free to bind to folate receptor expressing cancer cells, whilst the anti-CD3 activity is effectively rendered inert by a coating of photo-labile 2-nitrobenzyl groups. On irradiation with UV-A light the activity of the anti-CD3 antibody is restored, not only when it is required, but more importantly, only where it is required.

Haematopoietic stem cell transplantation: can our genes predict clinical outcome?

Haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for many patients with malignant and non-malignant haematological diseases. The success of HSCT is greatly reduced by the development of complications, which include graft-versus-host disease (GVHD), relapse and infection. Human leukocyte antigen (HLA) matching of patients and donors is essential, but does not completely prevent these complications; non-HLA genes may also have an impact upon transplant outcome.

Hydrolysis of a series of parabens by skin microsomes and cytosol from human and minipigs and in whole skin in short-term culture.

Parabens are esters of 4-hydroxybenzoic acid and used as anti-microbial agents in a wide variety of toiletries, cosmetics and pharmaceuticals. It is of interest to understand the dermal absorption and hydrolysis of parabens, and to evaluate their disposition after dermal exposure and their potential to illicit localised toxicity. The use of minipig as a surrogate model for human dermal metabolism and toxicity studies, justifies the comparison of paraben metabolism in human and minipig skin.

An overview of Notch3 function in vascular smooth muscle cells.

Proteins of the Notch family are cell surface receptors that transduce signals between neighbouring cells. The Notch signalling pathway is highly evolutionarily conserved and critical for cell fate determination during embryonic development, including many aspects of vascular development. The interaction of Notch receptors with ligands leads to cleavage of the Notch intracellular domain (NICD) which then translocates to the nucleus and activates the transcription factor CBF1/JBP-Jkappa, regulating downstream gene expression.

Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study.

Data implicate IL-1 in the altered matrix biology that characterizes human intervertebral disc (IVD) degeneration. In the current study we investigated the enzymic mechanism by which IL-1 induces matrix degradation in degeneration of the human IVD, and whether the IL-1 inhibitor IL-1 receptor antagonist (IL-1Ra) will inhibit degradation. A combination of in situ zymography (ISZ) and immunohistochemistry was used to examine the effects of IL-1 and IL-1Ra on matrix degradation and metal-dependent protease (MDP) expression in explants of non-degenerate and degenerate human IVDs.

The distribution of esterases in the skin of the minipig.

Skin esterases serve an important pharmacological function as they can be utilised for activation of topically applied ester prodrugs. Understanding the nature of these enzymes, with respect to their role and local activity, is essential to defining the efficacy of ester prodrugs. Minipigs are used as models to study the kinetics of absorption of topically applied drugs.

Non-HLA gene polymorphisms in stem cell transplantation.

An increasing number of gene polymorphisms of immune regulatory molecules are being associated with clinical performance following stem cell transplantation (SCT). These polymorphisms affect structural or regulatory changes on immune regulatory molecules including cytokines . In contrast to polymorphisms of the major histocompatibility complex, the genome variations found in these non-human leukocyte antigen genes are simple to detect, allowing studies to be done in many laboratories and transplant centres.

Specificity of procaine and ester hydrolysis by human, minipig, and rat skin and liver.

The capacity of human, minipig, and rat skin and liver subcellular fractions to hydrolyze the anesthetic ester procaine was compared with carboxylesterase substrates 4-methylumbelliferyl-acetate, phenylvalerate, and para-nitrophenylacetate and the arylesterase substrate phenylacetate. Rates of procaine hydrolysis by minipig and human skin microsomal and cytosolic fractions were similar, with rat displaying higher activity. Loperamide inhibited procaine hydrolysis by human skin, suggesting involvement of human carboxylesterase hCE2.

Inter-individual variability in esterases in human liver.

Human liver has numerous hydrolytic enzymes involved in metabolism of endogenous and exogenous esters. Of these enzymes, carboxylesterases (EC 3.1.

Ultraviolet radiation exposure accelerates the accumulation of the aging-dependent T414G mitochondrial DNA mutation in human skin.

The accumulation of mitochondrial DNA (mtDNA) mutations has been proposed as an underlying cause of the aging process. Such mutations are thought to be generated principally through mechanisms involving oxidative stress. Skin is frequently exposed to a potent mutagen in the form of ultraviolet (UV) radiation and mtDNA deletion mutations have previously been shown to accumulate with photoaging.

Factors affecting drug concentrations and QT interval during thioridazine therapy.

The objective of this study was to investigate factors affecting steady-state plasma concentrations of thioridazine. A cross-sectional study of patients receiving chronic thioridazine was employed. Common allelic variants of CYP2D6 and CYP2C19, as well as thioridazine and metabolite concentrations and QTc intervals, were determined.

Risk assessment in haematopoietic stem cell transplantation: pre-transplant patient and donor factors: non-HLA genetics.

Non-HLA genetics involving the study of single-nucleotide polymorphisms (SNPs) and microsatellites of cytokine and cytokine receptor genes, and as well as genes associated with response to infection and therapeutic drugs, are currently being studied for associations with diseases, including autoimmune disease, cancer and solid-organ transplant rejection. This chapter will summarize the potential role of non-HLA genetics in predicting outcome of haematopoietic stem-cell transplantation (HSCT) and how genotyping for non-HLA genes may give insight into the immunobiology of HSCT complications, including GvHD and infectious episodes. Future directions - including the role of pharmacogenomics, use of the research results for individualized medicine, and interpretation of data - will also be discussed.

Comparison of the effects of thioridazine and mesoridazine on the QT interval in healthy adults after single oral doses.

We compared the effects of single doses of thioridazine and mesoridazine on the heart rate-corrected QT (QTc) interval in healthy adult volunteers. QTc intervals and plasma concentrations of thioridazine, mesoridazine, and metabolites were measured after single oral doses of thioridazine hydrochloride 50 mg, mesoridazine besylate 50 mg, or placebo in a double-blind, crossover study. Mean maximum increases in the QTc interval following thioridazine (37.

The diffuse stellate cell system.

Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. Morphologically similar cells have been found at extrahepatic sites such as pancreas, kidney and colon. The true phenotypic relationship between these cells has not been fully established.

Embryonic-like stem cells from umbilical cord blood and potential for neural modeling.

Stem cells offer the distinct prospect of changing the face of human medicine. However, although they have potential to form different tissues, are still in the early stages of development as therapeutic interventions. The three most used stem cell sources are umbilical cord blood, bone marrow and human embryos.

Individualized drug therapy.

The pharmacogenetics of either individual patients or tumors has been used to aid the progress of personalized medicine to generate antitumor drugs (eg, trastuzamab and erlotinib) that are active against tumors expressing particular growth factor receptors. Outside the field of cancer therapeutics, pharmacogenetic tests have been introduced to detect patient genotypes with the aim of individualizing existing treatments. For example, the analysis of thiopurine S-methyltransferase genotypes enables the prediction of toxicity in patients to be treated with either 6-mercaptopurine or azathioprine, while the uridine 5'-diphosphoglucuronosyl-transferase 1A1 genotype may predict irinotecan toxicity.

Chemical introduction of disulfide groups on glycoproteins: a direct protein anchoring scenario.

The present work reports a direct glycoprotein immobilization protocol where the protein is chemically modified with disulfide groups which act as anchor molecules able to chemisorb spontaneously onto clean gold surfaces. The specificity of the chemical reaction, for disulfide introduction, toward carbohydrate moieties prevents any cross-reaction with other functional groups present in the protein structure. Horseradish peroxidase (HRP) was chosen as a model glycoprotein, and a biologically active densely packed SAM was obtained on gold, as demonstrated by spectrophotometry and surface plasmon resonance (SPR) spectroscopy.

Flow measurements: can several "wrongs" make a "right"?

Aims: Although measurement of maximum flow rate (Qmax) is a standard and straightforward test, it is often difficult to obtain reliable readings. We obtained multiple measurements using a simple home uroflow device which categorizes Qmax into ranges. We hypothesize that the average of a series of relatively coarse measurements of Qmax would be more repeatable and therefore more representative of an individual's voiding function than a single, albeit more precise measurement.

Liver unit admission following paracetamol overdose with concentrations below current UK treatment thresholds.

Background: It has been suggested that current UK thresholds for treating paracetamol overdose should be reduced, following case reports of patients developing fatal liver failure after presenting with paracetamol concentrations below these thresholds.

Aim: To determine the frequency of severe liver dysfunction following paracetamol overdose when paracetamol concentrations are below current UK antidote thresholds.

Design: Retrospective case note review.