Molecular phenotyping of the mouse ky mutant reveals UCP1 upregulation at the neuromuscular junctions of dystrophic soleus muscle.

The ky mutant mouse displays a muscular dystrophy that affects almost exclusively slow type muscles in which persistent muscle regeneration, neuromuscular junction instability and an absence of the hypertrophic response are prominent features. In order to gain insights into the pathogenesis of this muscular dystrophy we have undertaken RNA profiling of the extensor digitorum longus, a fast unaffected muscle, and the highly pathological soleus slow muscle, followed by further expression studies to validate the results. In dystrophic soleus, there is a coordinated change in the expression level of genes encoding energy transducing mitochondrial proteins and an increase in the expression of stretch response genes.

Tumour necrosis factor alpha inhibitor treatment for sarcoidosis refractory to conventional treatments: a report of five patients.

Objective: To study the effectiveness of tumour necrosis factor alpha (TNFalpha) inhibitor treatment for sarcoidosis refractory to conventional treatments.

Methods: Five patients (two men, three women) were treated with infliximab. All patients received a loading dose of 3 mg/kg at 0, 2, and 6 weeks and then maintenance infusions every 4-8 weeks.

Expressed sequence tag profiling identifies developmental and anatomic partitioning of gene expression in the mouse prostate.

Background: The prostate gland is an organ with highly specialized functional attributes that serves to enhance the fertility of mammalian species. Much of the information pertaining to normal and pathological conditions affecting the prostate has been obtained through extensive developmental, biochemical and genetic analyses of rodent species. Although important insights can be obtained through detailed anatomical and histological assessments of mouse and rat models, further mechanistic explanations are greatly aided through studies of gene and protein expression.

Raf-1 is not required for megakaryocytopoiesis or TPO-induced ERK phosphorylation.

Thrombopoietin stimulates extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation in megakaryocytes, and the classic mitogen-activated protein (MAP) kinase (Raf/mitogen-induced extracellular kinase [MEK]/ERK) pathway has been implicated directly and indirectly to play a critical role in megakaryocytopoiesis. However, the involvement of specific Raf family members in megakaryocytopoiesis is unknown. raf-1(-/-) mice were therefore used to directly determine the role of Raf-1 in megakaryocytopoiesis.

Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer.

The murine Pten prostate cancer model described in this study recapitulates the disease progression seen in humans: initiation of prostate cancer with prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma, and subsequent metastasis with defined kinetics. Furthermore, while Pten null prostate cancers regress after androgen ablation, they are capable of proliferating in the absence of androgen. Global assessment of molecular changes caused by homozygous Pten deletion identified key genes known to be relevant to human prostate cancer, including those "signature" genes associated with human cancer metastasis.

Changing patterns of diabetic deaths in youth and young adults by gender in the major developed countries 1974-97.

Unlabelled: The objective was to examine any changes in "Diabetic Deaths" in major developed countries 1974-97 and to determine whether youth (aged 15-24 years) and young adult (aged 25-44 years) males are at greater risk of Diabetic Death (DD) than women by comparing DD with "All Cause Deaths" (ACD) by gender.

Design: Based upon WHO standardized mortality data, three year average death rates for 1974-76 were contrasted against three year average for 1995-97 for ACD and DD rate per million, by gender. Ratios of change for each country were calculated, which were then used for comparison between countries, thus ensuring comparison of like with like, resolving the inherent problem of differential recording between countries.

Raf proteins and cancer: B-Raf is identified as a mutational target.

A recent report has shown that activating mutations in the BRAF gene are present in a large percentage of human malignant melanomas and in a proportion of colon cancers. The vast majority of these mutations represent a single nucleotide change of T-A at nucleotide 1796 resulting in a valine to glutamic acid change at residue 599 within the activation segment of B-Raf. This exciting new discovery is the first time that a direct association between any RAF gene and human cancer has been reported.

Analysis of the role of the SA gene in blood pressure regulation by gene targeting.

The SA gene is expressed in the proximal tubule of the kidney and may be involved in blood pressure (BP) regulation. However, direct evidence for this is lacking. We constructed and analyzed an SA-null mouse in which exons 2 and 3 of the SA gene (including the start codon) had been deleted by homologous recombination.

Alternative splicing of Pax3 produces a transcriptionally inactive protein.

Pax3, a member of the paired-class homeodomain family of transcription factors, plays an important role in embryonic development of neurepithelium and mesenchyme-derived tissues in the mouse and is an early marker for myogenic differentiation. In the present work we identify an alternative splicing event for endogenous Pax3 in primary mouse myoblasts. The resulting splice variant arises through the utilization of a previously unreported splice donor consensus sequence present at the junction between exons 7 and 8 in the Pax3 sequence.

Single primer amplification (SPA) of cDNA for microarray expression analysis.

The potential of expression analysis using cDNA microarrays to address complex problems in a wide variety of biological contexts is now being realised. A limiting factor in such analyses is often the amount of RNA required, usually tens of micrograms. To address this problem researchers have turned to methods of improving detection sensitivity, either through increasing fluorescent signal output per mRNA molecule or increasing the amount of target available for labelling by use of an amplification procedure.

Non-sentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance.

Aims: It has been suggested that patients with T1-2 breast tumours and sentinel node (SLN) micrometastases, defined as foci of tumour cells smaller than 2 mm, may be spared completion axillary lymph node dissection because of the low incidence of further metastatic disease. To gain insight into the extent of non-sentinel lymph node (n-SLN) involvement, SLNs and complementary axillary clearance specimens in patients with SLN micrometastases were examined.

Methods: A set of 32 patients with SLN micrometastases was selected on the basis of pathology reports and review of SLNs.

National Institute for Clinical Excellence (NICE): Is economic appraisal working?

This paper analyses the 32 technology appraisals completed by the National Institute for Clinical Excellence (NICE) in the UK from its establishment to the end of January 2002. It looks at why technologies have been rejected, what has happened to products reviewed at launch, evidence of rationing on cost-effectiveness grounds, and the issues raised for manufacturers and for NICE in the collection and analysis of economic data. It finds that around two-thirds of NICE appraisals have been of pharmaceuticals.

cAMP-dependent protein kinase and Ca2+ influx through L-type voltage-gated calcium channels mediate Raf-independent activation of extracellular regulated kinase in response to glucagon-like peptide-1 in pancreatic beta-cells.

Glucagon like peptide-1 (GLP1) is a G(s)-coupled receptor agonist that exerts multiple effects on pancreatic beta-cells, including the stimulation of insulin gene expression and secretion. In this report, we show that treatment of the mouse pancreatic beta-cell line MIN6 with GLP1 leads to the glucose-dependent activation of Erk. These effects are mimicked by forskolin, a direct activator of adenylate cyclase, and blocked by H89, an inhibitor of cAMP-dependent protein kinase.

The use of ACE inhibitors in the treatment of heart failure in Kentucky Medicare beneficiaries: a quality improvement project.

Heart failure (HF) is a highly prevalent and frequently fatal condition. During 1998, 10,815 Medicare beneficiaries in Kentucky were diagnosed as having HF; 14,777 beneficiaries were hospitalized for the condition, and 696 Medicare beneficiaries died with HF as the primary diagnosis. Proper diagnosis and subsequent treatment with angiotensin converting enzyme (ACE) inhibitors improve functional status, quality of life, and survival among HF patients.

Isolation and characterization of the murine prostate short-chain dehydrogenase/reductase 1 (Psdr1) gene, a new member of the short-chain steroid dehydrogenase/reductase family.

We report the isolation and characterization of a complementary DNA (cDNA) encoding a novel member of the short-chain dehydrogenase/reductase (SDR) gene family that we have designated murine prostate short-chain dehydrogenase/reductase 1 (Psdr1). Psdr1 was cloned as a 3.2 kbp transcript from mouse testis cDNA based on the sequence of the recently described androgen-regulated human PSDR1 gene (Cancer Res.

Expression of kinase suppressor of Ras in the normal adult and embryonic mouse.

Recent studies indicate that kinase suppressor of Ras (KSR)is a scaffold protein for the Ras/Raf/MEK/ERK signaling cascade in mammals. To help determine the in vivo function of KSR, we have examined the tissue-specific distribution of this protein in the embryonic and adult mouse using a rat monoclonal antibody raised against the mouse protein. Western blot analysis indicates that the protein is expressed at highest levels in the adult brain.

Prehension and perception of size in left visual neglect.

Right hemisphere damaged patients with and without left visual neglect, and age-matched controls had objects of various sizes presented within left or right body hemispace. Subjects were asked to estimate the objects' sizes or to reach out and grasp them, in order to assess visual size processing in perceptual-experiential and action-based contexts respectively. No impairments of size processing were detected in the prehension performance of the neglect patients but a generalised slowing of movement was observed, associated with an extended deceleration phase.

Promoting health in the construction industry?

The construction industry has long been regarded as a high-risk industry in relation to health and safety issues. The purpose of this research was to investigate the extent of occupational health and safety provision within the residential development sector of the construction industry in Britain. An additional aim was to gauge the sectors' attitudes toward health promotion.