Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: role of glycogen synthase kinase-3beta inhibition.

Objective: Insulin reduces morbidity and mortality among critically ill patients, but the molecular mechanisms of its effect remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3, which may play an important role in systemic inflammation and shock. Here we investigate the role of blood glucose and glycogen synthase kinase-3beta inhibition in the protective effect of insulin on the organ injury/dysfunction associated with excessive systemic inflammation.

Importin beta: a novel autoantigen in human autoimmunity identified by screening random peptide libraries on phage.

By screening random peptide libraries (RPLs) with sera of Type 1 diabetes (T1D) patients, we previously identified 5 disease-specific 'mimotopes' displayed on phages (phagotopes). We already characterised 1 phagotope (CH1p), as an epitope of human osteopontin, an autoantigen expressed within the somatostatin cells of human islets. In this paper, we report the characterization of the second phagotope, 195Dyn, by immunohistochemistry, Western Blotting and screening of a human islet cDNA library using rabbit anti-195Dyn antibodies.

Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain.

Ageing is associated with a decrease in the brain content of omega-3 polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and with decreased neuroplasticity. The glutamate receptor subunits GluR2 and NR2B play a significant role in forebrain synaptic plasticity. We investigated GluR2 and NR2B in the aged prefrontal cortex, hippocampus and striatum, and tested if treatment with a preparation containing EPA and DHA can reverse age-related changes.

Peroxisome proliferator-activated receptor-gamma antagonists GW9662 and T0070907 reduce the protective effects of lipopolysaccharide preconditioning against organ failure caused by endotoxemia.

Objective: There is evidence that a) ligands of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma and b) lipopolysaccharide preconditioning protect the organs against the multiple organ injury and dysfunction caused by endotoxemia. Here we investigate the hypothesis that the protective effects of lipopolysaccharide preconditioning are due to an enhanced formation of endogenous ligands of PPAR-gamma.

Design: Prospective, randomized study.

The role of adenosine in chondrocyte death in murine osteoarthritis and in a murine chondrocyte cell line.

Objective: To investigate the role of adenosine in chondrocyte death in murine osteoarthritis (OA).

Methods: 5'-Nucleotidase (5'NT) generates adenosine. Enzyme activity was measured histochemically in normal murine and osteoarthritic STR/ort strain tibial cartilage.

Exogenous expression of glucagon-like peptide 1 receptor and human insulin in AtT-20 corticotrophs confers cAMP-mediated gene transcription and insulin secretion.

The insulinotrophic effects of glucagon-like peptide 1 (GLP-1) are mediated by its seven-transmembrane receptor (GLP-1R) in pancreatic beta-cells. We have transiently transfected the GLP-1R and a proopiomelanocortin (POMC) promoter-driven human preproinsulin gene vector (pIRES) into the AtT-20 pituitary corticotrophic cell line, to investigate the possibility of creating a regulated, insulin-expressing cell line. Receptor expression was confirmed by RT-PCR and functionality was demonstrated by measuring changes in cAMP levels in response to GLP-1.

The effect of a mandibular advancement splint in subjects with sleep-related breathing disorders.

Objective: This study assessed the effectiveness of a mandibular advancement splint (MAS) in subjects with sleep-related breathing disorders using both objective and subjective outcome measures.

Design: The study was carried out as a retrospective analysis.

Setting: The study was conducted within the Sleep Studies Unit at the Queen Victoria Hospital, East Grinstead, between May 1997 and March 2000.

Heat-shock proteins and their role in chondrocyte protection, an application for autologous transplantation.

Articular cartilage injury presents a unique therapeutic challenge. As cartilage possesses no blood or nerve supply of its own it has a particular susceptibility to early injury and a poor capacity for self-repair. Treatment options are limited and injury can eventually lead to osteoarthritis.

The peroxisome proliferator-activated receptor alpha activator, Wy14,643, is anti-inflammatory in vivo.

The peroxisome proliferator-activated receptor system is exciting much interest as a novel point of therapeutic intervention in inflammation. Here, the effect of a peroxisome proliferator-activated receptor alpha agonist, [4-chloro-6-(2,3-xylidine)-pyrimidinylthio]acetic acid (Wy14,643), was examined in arachidonic acid-induced murine ear inflammation. 3-[1-(4-Chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK886, a 5-lipoxygenase inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) were used as reference compounds.

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat.

Aims/hypothesis: Hyperthyroidism modifies lipid dynamics (increased oxidation), impairs insulin action and can suppress insulin secretion. We therefore examined the impact of hyperthyroidism on the relationship between glucose-stimulated insulin secretion (GSIS) and insulin action, using late pregnancy as a model of physiological insulin resistance that is associated with compensatory insulin hypersecretion to maintain glucose tolerance. Our aim was to examine whether hyperthyroidism compromises the regulation of insulin secretion and the ability of insulin to modulate circulating lipid concentrations in late pregnancy.

Prenatal screening for Down syndrome and neural tube defects in twin pregnancies.

Prenatal screening and diagnosis in a twin pregnancy is not straightforward. Once a twin pregnancy has been identified, women and their partners need time to consider the implications and decide whether they wish the pregnancy to be screened for Down syndrome or neural tube defects. We discuss here how multiple marker screening for Down syndrome and alpha-fetoprotein screening for neural tube defects can be carried out, given that this is the parents' chosen option and that the health professionals involved are capable of performing a diagnosis and selective feticide, should this arise.

GSK-3beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat.

Objective: Serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in regulation of many cell functions, but its role in regulation of inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat.

Design: Prospective, randomized study.

Characterization of non-neuronal elements within fibronectin mats implanted into the damaged adult rat spinal cord.

Previous studies have shown that mats made from fibronectin (FN) integrate well into spinal cord lesion sites and support extensive axonal growth. Using immunohistochemistry, we have investigated the non-neuronal factors that contribute to these properties. Extensive vascularization was observed in FN mats by 1 week along with heavy macrophage infiltration by 3 days post-implantation.

Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia.

Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the organ injury caused by severe endotoxemia in the rat. Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg(-1) intravenously (i.

Cushing's disease in children and adolescents: 20 years of experience in a single neurosurgical center.

Objective: This is a retrospective analysis of 25 consecutive pediatric patients with Cushing's disease who underwent transsphenoidal surgery performed by a single neurosurgeon in a specialist center during a 20-year period. This article discusses the presentation of Cushing's disease, the endocrinological investigation with particular reference to bilateral inferior petrosal sinus sampling (BIPSS), the operative management with reference to specific pediatric difficulties of the transsphenoidal approach and the use of intraoperative image guidance, and the analysis of these cases as regards postoperative complications and outcomes of this rare condition in young patients.

Methods: All patients underwent detailed endocrine investigation and imaging in the form of computed tomography and/or magnetic resonance imaging.

Sleep nasendoscopy: a diagnostic tool for predicting treatment success with mandibular advancement splints in obstructive sleep apnoea.

This prospective, cohort study evaluated the role of sleep nasendoscopy (SNE) with simultaneous mandibular protrusion in predicting successful mandibular advancement splint (MAS) therapy in subjects with obstructive sleep apnoea (OSA). Nineteen OSA subjects diagnosed by overnight polysomnography were referred for MAS therapy, following SNE investigation. A Herbst MAS was fabricated for each subject.

The selective PPARgamma antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion.

Background: We have recently reported that pretreatment of rats with endotoxin (lipopolysaccharide, LPS) and selective agonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) protect the kidney against ischemia/reperfusion (I/R) injury. Here we investigate the hypothesis that the renoprotective effects of LPS may be due to an enhanced formation of endogenous ligands of PPARgamma, rather than an up-regulation of PPARgamma expression.

Methods: Rats were pretreated with LPS (1 mg/kg, IP, 24 hours prior to ischemia) in the absence (control) or presence of the selective PPARgamma antagonist GW9662 (1 mg/kg, IP, 24 and 12 hours prior to ischemia).

Differential gene expression in pituitary adenomas by oligonucleotide array analysis.

Objectives: Microarray technology allows for the expression profile of many thousands of genes to be quantified at the same time, and has resulted in novel discoveries about the tumour biology of a number of cancers. We sought to do this in pituitary adenomas, the most common intracranial neoplasm.

Methods: Affymetrix GeneChip HG-U133A oligonucleotide arrays covering 14 500 well-characterised genes from the human genome were used to study pooled RNA for each of the four major pituitary adenoma subtypes.

Uterus-conserving surgery for invasive cervical cancer.

Standard treatment for cervical cancer is either radical hysterectomy or radiotherapy to the pelvis. Either will inevitably compromise fertility, rendering future childbearing impossible. Precise staging and magnetic resonance imaging can indicate the site and location of the tumour.

A review of tositumomab and I(131) tositumomab radioimmunotherapy for the treatment of follicular lymphoma.

The CD20 antigen has become a major therapeutic target in the management of follicular and other B cell non-Hodgkin's lymphomas. The murine monoclonal antibody, tositumomab, on binding CD20, is able to induce antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis. In addition, when radioiodinated, the antibody exploits the tumour's sensitivity to ionising radiation by direct targeting of the malignant cell.

A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma.

The role of TP53 mutation in transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (t-FL) was examined in a panel of 91 lymph node biopsies derived from 29 patients pre- and post-transformation. The entire TP53 coding sequence was screened and immunocytochemistry performed to determine expression of p53 and its key regulator MDM2. A total of 10 mutations were detected in eight patients (28%), although none were present at FL diagnosis.

Clinical service organisation for heart failure.

Background: Chronic heart failure (CHF) is a serious, common condition associated with frequent hospitalisation. Several different disease management interventions (clinical service organisation interventions) for patients with CHF have been proposed.

Objectives: To assess the effectiveness of disease management interventions for patients with CHF.

Dental side-effects of mandibular advancement splint wear in patients who snore.

Objectives: (a) To evaluate the longer term orthodontic side-effects of a Herbst mandibular advancement splint (MAS) in subjects with sleep disordered breathing. (b) To determine whether these are related to dental occlusion, degree of mandibular advancement or duration of appliance wear.

Design: Retrospective, cohort study.

Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-year retrospective study.

Objective: To evaluate the long-term efficacy of systemic retinoids in reducing the incidence of cutaneous squamous cell carcinomas (SCCs) in organ transplant recipients (OTRs), who are at greatly increased risk of SCCs.

Design: A retrospective before-after study of OTRs who had received low-dose systemic retinoids during 1 to 16 years for prevention of SCCs.

Setting: A specialist dermatology clinic for organ transplant recipients at St Bartholomew's and the Royal London Hospital, University of London, London, England.