Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide.

Inflammation is a prominent feature of several disorders characterized by primary demyelination, but it is not clear whether a relationship exists between inflammation and myelin damage. We have found that substantial demyelination results from the focal inflammatory lesion caused by the injection of lipopolysaccharide (LPS; 200 ng) directly into the rat dorsal funiculus. Within 24 h, such injections caused a focal inflammatory response consisting of a substantial number of polymorphonuclear cells and ED1-positive and inducible nitric oxide synthase (iNOS)-positive macrophages/microglia.

Thiazolidinediones-benefits on microvascular complications of type 2 diabetes.

Type 2 diabetes is associated with serious microvascular complications, such as nephropathy, retinopathy, and neuropathy, which have a significant impact on patients' quality of life, morbidity, and mortality. Type 2 diabetes management strategies to reduce the risk of microvascular complications include treatment of hyperglycaemia, hypertension, and other vascular risk factors. The importance of glycaemic control in reducing the risk of microvascular complications of diabetes is well established.

An unusual case of weight loss in a patient with refractory rheumatoid arthritis.

We describe a case of metastatic malignant melanoma with no primary cutaneous lesion presenting as weight loss in a man with refractory, seropositive rheumatoid arthritis (RA). The patient had undergone multiple investigations previously and the case highlights the importance of repeat assessment in elderly patients presenting with unexplained weight loss.

Blood pressure reduction for vascular risk: is there a price to be paid?

The importance of lowering blood pressure (BP) in hypertensive subjects is well-known and recent studies suggest that lowering of BP in patients who may already be in the normotensive range further reduces the risk of vascular events, particularly stroke. Epidemiological data have also shown that lower BP and antihypertensive treatment may be associated with cognitive impairment once cerebrovascular disease is established. However, the relationship between hypertension and cerebrovascular disease is more complex than suggested by epidemiological or intervention studies.

Expression of Ras GTPase isoforms in normal and diseased pancreas.

Background: Ki-Ras is well studied in its oncogenic form in relation to pancreatic pathologies. However, the individual contribution of each of the wild-type Ras isoforms (Ha-, Ki-, and N-) in pancreatic cells in health and disease is unknown.

Methods: Archival formalin-fixed, paraffin-embedded specimens of normal (n = 6) and malignant pancreas (n = 35) were used for immuno-histochemical detection of Ras isoforms using a modified polymer system.

Single zinc-finger extension: enhancing transcriptional activity and specificity of three-zinc-finger proteins.

In order to demonstrate that an existing zinc-finger protein can be simply modified to enhance DNA binding and sequence discrimination in both episomal and chromatin contexts using existing zinc-finger DNA recognition code data, and without recourse to phage display and selection strategies, we have examined the consequences of a single zinc-finger extension to a synthetic three-zinc-finger VP16 fusion protein, on transcriptional activation from model target promoters harbouring the zinc-finger binding sequences. We report a nearly 10-fold enhanced transcriptional activation by the four-zinc-finger VP16 fusion protein relative to the progenitor three-finger VP16 protein in transient assays and a greater than five-fold enhancement in stable reporter-gene expression assays. A marked decrease in transcriptional activation was evident for the four-zinc-finger derivative from mutated regulatory regions compared to the progenitor protein, as a result of recognition site-size extension.

An evaluation of the body surface area correction for 51Cr-EDTA measurements of glomerular filtration rate.

Background: To interpret 51Cr-EDTA measurements of glomerular filtration rate (GFR) it is usual to correct results for a patient's body size by scaling values to a standard body surface area (BSA) of 1.73 m(2).

Aim: To use 51Cr-EDTA data for a large group of healthy subjects to derive the optimum mathematical function for the body size correction that minimized the variance of the corrected GFR values.

Human T-cell lymphotropic virus antibody prevalence in HIV-1-infected individuals attending a sexual health clinic in South-East London.

Human immunodeficiency virus (HIV) and human T-cell lymphotropic virus (HTLV) are both retroviruses with similar routes of transmission. A number of reports suggest variable clinical outcomes in HIV and HTLV co-infected individuals. There is no published information regarding the prevalence of HIV and HTLV co-infection in the UK.

Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis.

CXCL13 and CCL21 have been functionally implicated in lymphoid tissue organization both in the upstream phases of lymphoid tissue embryogenesis and in ectopic lymphoid neogenesis in transgenic mice. Here, we analyzed the relationship between CXCL13 and CCL21 production and lymphoid tissue organization in rheumatoid synovitis as a model of a naturally occurring ectopic lymphoneogenesis. Through systematic analysis of mRNA and protein expression, we defined the microanatomical relationship between CXCL13 and CCL21 in progressive aggregational and structural phases of synovial inflammatory infiltrate.

DNA topoisomerase II in therapy-related acute promyelocytic leukemia.

Background: Chromosomal translocations leading to chimeric oncoproteins are important in leukemogenesis, but how they form is unclear. We studied acute promyelocytic leukemia (APL) with the t(15;17) translocation that developed after treatment of breast or laryngeal cancer with chemotherapeutic agents that poison topoisomerase II.

Methods: We used long-range polymerase chain reaction and sequence analysis to characterize t(15;17) genomic breakpoints in therapy-related APL.

Novel approaches to the measurement of arterial blood flow from dynamic digital X-ray images.

We have developed two new algorithms for the measurement of blood flow from dynamic X-ray angiographic images. Both algorithms aim to improve on existing techniques. First, a model-based (MB) algorithm is used to constrain the concentration-distance curve matching approach.

An in vitro assessment of gas trapping during high frequency oscillation.

Our aim was to assess the influence of oscillatory frequency, inspiratory-to-expiratory (I:E) ratio and airway pressure on gas trapping during high frequency oscillatory ventilation (HFOV). A lung model was used, which had a high compliance (4.0 ml (cmH(2)O)(-1)) and resistance (160 cmH(2)O l(-1) s(-1)) resulting in a long time constant (0.

Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates from England and Wales reveals the phylogenetic significance of the ahpC -46A polymorphism.

The present study investigated the prevalence and diagnostic potential of the most commonly reported mutations associated with isoniazid resistance, katG 315Thr, katG 315Asn, inhA -15T, inhA -8A, and the oxyR-ahpC intergenic region, in a population sample of 202 isoniazid-resistant Mycobacterium tuberculosis isolates and 176 randomly selected fully sensitive isolates from England and Wales identified by using a directed oligonucleotide array and limited DNA sequencing. The strains were recovered from patients originating from 29 countries; 41 isolates were multidrug resistant. Mutations affecting katG 315, the inhA promoter, and the oxyR-ahpC intergenic region were found in 62.

The low oxygen-carrying capacity of Krebs buffer causes a doubling in ventricular wall thickness in the isolated heart.

The buffer-perfused Langendorff heart is significantly vasodilated compared with the in vivo heart. In this study, we employed ultrasound to determine if this vasodilation translated into changes in left ventricular wall thickness (LVWT), and if this effect persisted when these hearts were switched to the "working" mode. To investigate the effects of perfusion pressure, vascular tone, and oxygen availability on cardiac dimensions, we perfused hearts (from male Wistar rats) in the Langendorff mode at 80, 60, and 40 cm H2O pressure, and infused further groups of hearts with either the vasoconstrictor endothelin-1 (ET-1) or the blood substitute FC-43.

Waiting times for radiotherapy: variation over time and between cancer networks in southeast England.

The aim of this study was to investigate variations in the length of time that patients with cancer wait from diagnosis to treatment with radiotherapy. A total of 57,426 men and 71,018 women diagnosed with cancer between 1992 and 2001 and receiving radiotherapy within 6 months of diagnosis were identified from the Thames Cancer Registry database. In total, 12 sites were identified for which a substantial number or proportion of patients received radiotherapy: head and neck, oesophagus, colon, rectum, lung, nonmelanoma skin cancer, breast, uterus, prostate, bladder, brain and non-Hodgkin's lymphoma.

Electromagnetic hypersensitivity: a systematic review of provocation studies.

Objectives: The objectives of this study were to assess whether people who report hypersensitivity to weak electromagnetic fields (EMFs) are better at detecting EMF under blind or double-blind conditions than nonhypersensitive individuals, and to test whether they respond to the presence of EMF with increased symptom reporting.

Methods: An extensive systematic search was used to identify relevant blind or double-blind provocation studies. This involved searching numerous literature databases and conference proceedings, and examining the citations of reviews and included studies.

Cytidine deamination and resistance to retroviral infection: towards a structural understanding of the APOBEC proteins.

The human apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, or hA3G) protein, provides cells with an intracellular antiretroviral activity that is associated with the hypermutation of viral DNA through cytidine deamination. Indeed, hA3G belongs to a family of vertebrate proteins that contain one or two copies of a signature sequence motif unique to cytidine deaminases (CTDAs). We have constructed secondary structure models of the APOBEC proteins through a combination of structure prediction and subsequent alignment with nucleotide CTDAs whose structures have been solved to high resolution.

RNA interference mediated in human primary cells via recombinant baculoviral vectors.

The success of RNA interference (RNAi) in mammalian cells, mediated by siRNAs or shRNA-generating plasmids, is dependent, to an extent, upon transfection efficiency. This is a particular problem with primary cells, which are often difficult to transfect using cationic lipid vehicles. Effective RNAi in primary cells is thus best achieved with viral vectors, and retro-, adeno-, and lentivirus RNAi systems have been described.

What happens to British veterans when they leave the armed forces?

Background: Little is known about the factors associated with leaving the armed forces, or what predicts subsequent employment success for veterans. It is likely that there is a complex interaction of adverse social outcomes and mental health status in this group.

Method: Analysis of existing data from the King's Military Cohort, a large, randomly selected, longitudinal cohort of service personnel, many of whom have now left the armed forces.

Lessons from the English smoking treatment services.

This paper summarizes and discusses the key findings of the evaluation of the English smoking treatment services, which were established in 1999 as part of the English National Health Service. Within 4 years these services existed throughout the country and were working at full capacity, a total of pound 76 million having been spent on them over this period, excluding medication costs. In the fourth year almost 235,000 people attended treatment and set a quit date, and the total budget, including medications, was approximately pound 50 million.

Melanogenesis: a photoprotective response to DNA damage?

Exposure to ultra violet radiation (UVR) is associated with significant long-term deleterious effects such as skin cancer. A well-recognised short-term consequence of UVR is increased skin pigmentation. Pigmentation, whether constitutive or facultative, has widely been viewed as photoprotective, largely because darkly pigmented skin is at a lower risk of photocarcinogenesis than fair skin.

Acute tumor necrosis factor alpha signaling via NADPH oxidase in microvascular endothelial cells: role of p47phox phosphorylation and binding to TRAF4.

Tumor necrosis factor alpha (TNF-alpha) receptor-associated factors (TRAFs) play important roles in TNF-alpha signaling by interacting with downstream signaling molecules, e.g., mitogen-activated protein kinases (MAPKs).

Perceptions of dissection by students in one medical school: beyond learning about anatomy. A qualitative study.

Introduction: The practice of dissection, as part of undergraduate medical education, has recently resurfaced in the public eye. This paper focuses on a number of important learning outcomes that were reported by Year 1-5 medical students in a British medical school, during the dissection sessions in the first 2 years of their training, as part of a wider qualitative research project into undergraduate medical education.

Methods: A group of 29 students was selected by quota sampling, using the whole student population of the medical school as the sampling frame.

Fetal fibronectin test predicts delivery before 30 weeks of gestation in high risk women, but increases anxiety.

Objective: To assess efficacy of cervico-vaginal fetal fibronectin as a predictor of spontaneous preterm birth in a high risk antenatal population, and to evaluate the psychological impact of fetal fibronectin testing.

Design: An observational study.

Setting: The antenatal clinic at a tertiary referral hospital.

Multiple beta 1 integrins mediate enhancement of human airway smooth muscle cytokine secretion by fibronectin and type I collagen.

Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with interstitial collagen and fibronectin are major pathological features of airway remodeling in asthma. We have previously shown that these ECM components confer enhanced ASM proliferation in vitro, but their action on its newly characterized secretory function is unknown. Here, we examined the effects of fibronectin and collagen types I, III, and V on IL-1beta-dependent secretory responses of human ASM cells, and characterized the involvement of specific integrins.