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Biomedical subjects

J R White

Publications and source records attributed to J R White.

At least 19 recordsLinked to original sources
PubMed2004

Identification of potential stroke targets by lentiviral vector mediated overexpression of HIF-1 alpha and HIF-2 alpha in a primary neuronal model of hypoxia.

The identification of genes differentially regulated by ischemia will lead to an improved understanding of cell death pathways such as those involved in the neuronal loss observed following a stroke. Furthermore, the characterization of such pathways could facilitate the identification of novel targets for stroke therapy. We have used a novel approach to amplify differential gene expression patterns in a primary neuronal model of stroke by employing a lentiviral vector system to specifically bias the transcriptional activation of hypoxically regulated genes. Overexpression of the hypoxia-induced transcription factor subunits HIF-1 alpha and HIF-2 alpha elevated hypoxia-mediated transcription of many known HIF-regulated genes well above control levels. Furthermore, many potentially novel HIF-regulated genes were discovered that were not previously identified as hypoxically regulated. Most of the novel genes identified were activated by a combination of HIF-2 alpha overexpression and hypoxic insult. These included several genes with particular importance in cell survival pathways and of potential therapeutic value. Hypoxic induction of HIF-2 alpha may therefore be a critical factor in mediating protective responses against ischemic injury. Further investigation of the genes identified in this study may provide increased understanding of the neuronal response to hypoxia and may uncover novel therapeutic targets for the treatment of cerebral ischemia.

Animals↗
PubMed2003

Discontinuation of levetiracetam because of behavioral side effects: a case-control study.

BACKGROUND: Levetiracetam (LEV) is a recently approved anticonvulsant with proven efficacy and safety in the treatment of partial seizures. LEV may cause behavioral abnormalities that can be severe and require discontinuation of this drug. Risk factors for discontinuing LEV have not been established. OBJECTIVE: To determine incidence of behavioral abnormalities severe enough to require discontinuation of LEV and identify risk factors for such behavioral abnormalities. METHODS: All patients treated with LEV at MINCEP between January 2000 and February 2002 constituted the study population (n = 553). Patients who had discontinued LEV for behavioral reasons were selected as index cases. Case controls were patients starting LEV immediately after the index case. Potential risk factors for LEV discontinuation included age, gender, cognitive function, history of psychiatric diagnosis, epilepsy syndrome, number of antiepileptic drugs, titration rate, maximum dose of LEV, and LEV level at maximum dose. RESULTS: Thirty-eight patients (6.9%) discontinued LEV because of behavioral abnormalities. Variables associated with LEV discontinuation included faster titration rate to maximal dose, history of a psychiatric disorder, and diagnosis of symptomatic generalized epilepsy. Patients who discontinued LEV owing to behavioral reasons had significantly lower maximum LEV doses than controls. CONCLUSIONS: This study identified variables associated with discontinuation of LEV due to behavioral abnormalities. Slower titration of LEV should be considered in those patients at higher risk of discontinuing LEV for behavioral reasons.

Adolescent↗
PubMed2003

Ring chromosome 17: phenotype variation by deletion size.

Ring chromosome 17 is a rare cytogenetic abnormality, with 12 previous reports in the literature. Some have a relatively mild phenotype characterized by seizures, mental retardation, skin changes and short stature. Other patients have Miller-Dieker syndrome (MDS), which includes lissencephaly, multiple dysmorphic features, severe mental retardation and shortened life expectancy. We describe two new cases of ring chromosome 17 and review the literature. Our cases and the other reports of patients without a deletion encompassing the Miller-Dieker region, delineate a fairly distinctive subgroup of individuals with ring 17, whose phenotype consists of growth and mental retardation, seizures, minor dysmorphic features, café-au-lait spots and retinal flecks. This classification of ring 17 into two distinct groups based on the size of the deletion and the phenotypic manifestations should facilitate clinical suspicion of this rare chromosomal abnormality.

Abnormalities, Multiple↗
PubMed2001

Insulin glargine.

BACKGROUND: In diabetes mellitus, the clinical goal of intensive glycemic control (lowering blood glucose concentrations to normal or near-normal levels) has been hindered by the lack of insulin regimens that duplicate the basal-bolus secretion of insulin by the healthy pancreas. In particular, intensive therapy has been associated with a risk of hypoglycemia. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, and potential drug interactions of insulin glargine, a new long-acting recombinant human insulin analogue. Results of clinical trials of its efficacy and tolerability as a basal insulin in the treatment of type 1 and type 2 diabetes are summarized. METHODS: Primary research and review articles on insulin glargine were identified through a search of MEDLINE from 1966 to July 2001. Abstracts were identified through a search of the Institute for Scientific Information Web of Science from 1995 to July 2001 and proceedings of American Diabetes Association scientific meetings. Additional information was obtained from the product information for insulin glargine. All identified articles and abstracts were evaluated for relevance, and all relevant information was included in the review. Priority was given to data from the primary medical literature. RESULTS: Insulin glargine has a slower onset of action than human neutral protamine Hagedorn (NPH) insulin, a longer duration of action (up to 24 hours), and no pronounced peak. It has similar tolerability and produces similar glycemic control to once- or twice-daily human NPH insulin, with a similar glucose-lowering effect on a molar basis. A decreased incidence of hypoglycemia, particularly at night, has been reported with insulin glargine compared with human NPH insulin. Insulin glargine appears to be comparable to human NPH insulin in terms of toxicity, adverse effects, immunogenicity, and potential for drug interactions. Results of clinical trials of insulin glargine in both type 1 and type 2 diabetes support its use in combination with a short-acting insulin, insulin lispro, or oral antidiabetic medications. Although insulin glargine cannot be mixed with other insulin preparations, it has the potential convenience of providing basal insulin with once-daily bedtime dosing. CONCLUSIONS: Based on the as yet small amount of data from full clinical study reports in peer-reviewed publications, insulin glargine appears to be a well-tolerated and effective basal insulin preparation for patients with type 1 or type 2 diabetes (including pediatric patients). Its delayed onset of action and prolonged, flat time-action profile mimic the action of endogenous basal insulin (or an insulin pump), decreasing the risk of hypoglycemic episodes. Insulin glargine may be a useful new option for meeting overnight insulin requirements, although most patients will require a rapid-acting insulin such as insulin lispro with or before meals for optimal management of blood glucose levels.

Adult↗
PubMed2001

A single chain Fv antibody displayed on phage surface recognises conformational group-specific epitope of bluetongue virus.

A single chain fragment variable (scFv) antibody gene was isolated from hybridoma cell line secreting monoclonal antibody (MAb) 20E9 that recognises bluetongue virus (BTV) VP7. DNA fragments encoding variable regions of heavy and light chains were amplified by RT-PCR and library of scFv was constructed in phage vector. Two scFv clones that were selected showed specific reactivity with conformational epitope VP7. The N-terminal 22 amino acid residues of 20E9 light chain were identical to that deduced from scFv DNA sequence. An in-frame TAG stop codon was found in the coding sequence and its potential role in regulating the expression and stability of scFv in phage is discussed.

Amino Acid Sequence↗
PubMed2001

The influence of gamma irradiation and aging on degradation mechanisms of ultra-high molecular weight polyethylene.

The aging behavior of ultra-high molecular weight polyethylene (UHMWPE) has been studied following gamma irradiation in air. Accelerated aging procedures used elevated temperature (70 degrees C), pressurized oxygen (5 bar) and applied stress. Shelf and in vivo aged components have also been investigated. The variation in polymer properties with depth into the polymer was determined using density measurements, infra-red spectroscopy and differential scanning calorimetry. Accelerated aging in pressurized oxygen resulted in peaks in polymer density and degree of oxidation up to 500 microm below the polymer surface. Shelf and in vivo aging was also found to result in increased density at or below the component surfaces. Changes in density were mainly due to changes in crystallinity within the UHMWPE and, to a smaller extent, due to oxygen incorporation within the polymer. The application of stress did not appear to influence the accelerated aging of UHMWPE. A method for estimating the residual stress distribution in the UHMWPE using the measured changes in density is proposed. This study has indicated that oxidation of UHMWPE may lead to the development of tensile residual stresses, near the component surface, in the region of 1.7 MPa. These stresses may contribute to the failure mechanism of UHMWPE acetabular cups or knee tibial trays during service.

Journal Article↗
PubMed2001

Differential response of human and bovine platelets to bovine von Willebrand factor and vascular subendothelium.

Human platelets undergo agglutination when stirred with bovine plasma (BP), but bovine platelets do not. The present study has shown that exposure of washed bovine platelets to subthreshold concentrations of adenosine diphosphate or thrombin before stirring restores their sensitivity to BP, and the cells undergo rapid agglutination. This agglutination was prevented by a monoclonal antibody, to glycoprotein GPIb. Flow cytometry studies revealed that exposure of bovine platelets to thrombin caused an increase in their ability to bind antibodies known to react with human GPIb or GPIIb-IIIa receptors. Interaction of bovine and human platelets with vascular subendothelium revealed additional differences in reactivity. Bovine platelets in citrate anticoagulant reacted poorly with subendothelium under flow conditions compared with human platelets. In contrast, bovine platelets in blood with low molecular weight heparin as anticoagulant adhered more readily than human cells. These findings suggest that different mechanisms are involved in hemostasis in human and bovine species.

Adenosine Diphosphate↗
PubMed2001

Predictors of outcome in severely head-injured children.

OBJECTIVE: Determine variables in the acute care period associated with survival and pediatric intensive care unit (PICU) length of stay (LOS) for children with severe traumatic brain injury. DESIGN: Retrospective cohort. SETTING: Level 1 pediatric trauma center. PATIENTS: Children (0-17 yrs) admitted 1991 to 1995 with nonpenetrating traumatic brain injury and admission Glasgow Coma Scale score of or=14. Predictors of outcome were abstracted, including Pediatric Trauma Score, Glasgow Coma Scale score, Pediatric Risk of Mortality, physiologic variables, computed tomography evidence of brain injury, and neuroresuscitative medications. The fatality rate was 24%. Age and gender were similar between groups (p >or= .1). Survival was independently predicted by 6-hr Glasgow Coma Scale score (odds ratio [OR] 4.6; 95% confidence interval [CI] 2.06-11.9; p < .001) and maximum systolic blood pressure (OR 1.05; 95% CI 1.01-1.09; p < .02). Odds of survival increased 19-fold when maximum systolic blood pressure was >or=135 mm Hg (OR 18.8; 95% CI 2.0-178.0; p < .01). By discharge, 67% of patients had an age-appropriate Glasgow Coma Scale score. Median hospital costs were 8,798 dollars for survivors: only mannitol use independently predicted high cost (odds ratio 4.9; 95% CI 1.2-19.1; p < .01). For survivors, median PICU LOS was 2 days, although 25% had LOS >6 days. Six-hour Glasgow Coma Scale score (OR 0.62; 95% CI 0.48-0.80; p < .001) and mannitol (OR 7.9; 95% CI 2.3-27.3; p < .001) were each independently associated with a prolonged LOS among survivors. CONCLUSIONS: Patients with higher 6-hr Glasgow Coma Scale scores were more likely to survive. Adjusting for severity of injury, survival was associated with maximum systolic blood pressure >or=135 mm Hg, suggesting that supranormal blood pressures are associated with improved outcome. Mannitol administration was associated with prolonged LOS, yet conferred no survival advantage. We suggest reevaluation of blood pressure targets and mannitol use in children with severe traumatic brain injury.

Adolescent↗
PubMed2001

Nateglinide therapy for type 2 diabetes mellitus.

OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of nateglinide. DATA SOURCES: Primary and review articles regarding nateglinide were identified by MEDLINE search (from 1966 to January 2001); abstracts were identified through the Institute for Scientific Information Web of Science (from 1995 to January 2001) and the American Diabetes Association; additional information was obtained from the nateglinide product information. STUDY SELECTION/DATA EXTRACTION: All articles and meeting abstracts identified from the data sources were evaluated and all information deemed relevant was included in this review. Much of the information was from abstracts or the product labeling, since few clinical studies have been published in the medical literature. DATA SYNTHESIS: Nateglinide is a novel nonsulfonylurea oral antidiabetic agent that stimulates insulin secretion from the pancreas. It has a rapid onset and short duration of action, allowing administration before a meal to reduce postprandial hyperglycemia. Improvement in glycemic control with nateglinide monotherapy has been demonstrated in patients not previously treated with antidiabetic medications. Greater improvement in glycemic control was observed when nateglinide was administered in combination with metformin. CONCLUSIONS: Nateglinide is similar to repaglinide, but has a quicker onset of action, quicker reversal, and does not usually require dosage titration. Based on the pharmacodynamics of nateglinide and repaglinide, nateglinide produces a more rapid postprandial increase in insulin secretion, and its duration of response is shorter than that of repaglinide. The risk of postabsorptive hypoglycemia should be lower than with either sulfonylureas or repaglinide.

Animals↗
PubMed2001

Nonpeptide CXCR2 antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats.

Neutrophil influx in lung injury is controlled in part by chemokines acting through the receptor, CXCR2. To avoid adverse effects of steroids typically used to modify inflammation, we evaluated the effects of competitive blockade of CXCR2 in rats on neutrophil function in vitro and on neutrophil influx in vivo in hyperoxia-induced newborn lung injury, a model of bronchopulmonary dysplasia. In vitro, SB-265610 antagonizes rat cytokine-induced neutrophil chemoattractant-1 (CINC-1)-induced calcium mobilization, IC50 = 3.7 nM, and rat neutrophil chemotaxis in a concentration-dependent manner, IC50 = 70 nM. In vivo, newborn rats exposed to 95% O2 for 8 days had increased lung neutrophil content. Injection with 1 to 3 mg/kg SB-265610 on days 3 to 5 reduced hyperoxia-induced neutrophil accumulation in bronchoalveolar lavage and whole lung myeloperoxidase accumulation at the highest doses. To determine whether these effects might be due in part to increased neutrophil apoptosis, peripheral neutrophils were cultured with and without SB-265610. Apoptosis was assessed by morphology, viability, and terminal transferase deoxyuridine triphosphatidyl nucleotide nick-end labeling. Treatment of neutrophils with CINC-1 reduced apoptosis compared with untreated neutrophils. SB-265610 reduced the antiapoptotic effect of CINC-1 to the levels of those untreated with CINC-1. A selective CXCR2 antagonist may be useful in diseases where neutrophil-mediated exacerbation is present.

Animals↗
PubMed2000

Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration.

Eosinophils have been implicated in the pathogenesis of asthma and other allergic diseases. Several CC chemokines including eotaxin (CCL-11), eotaxin-2 (CCL-24), RANTES (CCL-5), and monocyte chemotactic protein-3 (MCP-3, CCL-7) and 4 (MCP-4, CCL-13) are potent eosinophil chemotactic and activating peptides acting through CC chemokine receptor-3 (CCR3). Thus, antagonism of CCR3 could have a therapeutic role in asthma and other eosinophil-mediated diseases. A high throughput, cellular functional screen was configured using RBL-2H3 cells stably expressing CCR3 (RBL-2H3-CCR3) to identify non-peptide receptor antagonists. A small molecule CCR3 antagonist was identified, SK&F 45523, and chemical optimization led to the generation of a number of highly potent, selective CCR3 antagonists including SB-297006 and SB-328437. These compounds were further characterized in vitro and demonstrated high affinity, competitive inhibition of (125)I-eotaxin and (125)I-MCP-4 binding to human eosinophils. The compounds were potent inhibitors of eotaxin- and MCP-4-induced Ca(2+) mobilization in RBL-2H3-CCR3 cells and eosinophils. Additionally, SB-328437 inhibited eosinophil chemotaxis induced by three ligands that activate CCR3 with similar potencies. Selectivity was affirmed using a panel of 10 seven-transmembrane receptors. This is the first description of a non-peptide CCR3 antagonist, which should be useful in further elucidating the pathophysiological role of CCR3 in allergic inflammatory diseases.

Asthma↗
PubMed2000

Identification of unique truncated KC/GRO beta chemokines with potent hematopoietic and anti-infective activities.

SK&F 107647, a previously described synthetic immunomodulatory peptide, indirectly stimulates bone marrow progenitor cells and phagocytic cells, and enhances host defense effector mechanisms in bacterial and fungal infection models in vivo. In vitro, SK&F 107647 induces the production of a soluble mediator that augments colony forming cell (CFU-GM) formation in the presence of CSFs. In this paper we purified and sequenced the stromal cell-derived hematopoietic synergistic factors (HSF) secreted from both murine and human cell lines stimulated with SK&F 107647. Murine HSF is an N-terminal 4-aa truncated form of the CXC chemokine, KC, while human HSF was identified as an N-terminal 4-aa truncated form of the CXC chemokine, GRO beta. In comparison to their full-length forms, truncated KC and truncated GRO beta were 10 million times more potent as synergistic growth stimulants for CFU-GM. Enhanced potency of these novel truncated chemokines relative to their full-length forms was also demonstrated in respiratory burst assays, CD11b Ag expression, and intracellular killing of the opportunistic pathogen, Candida albicans. Administration of truncated KC significantly enhanced survival of mice lethally infected with C. albicans. The results reported herein delineate the biological mechanism of action of SK&F 107647, which functions via the induction of unique specific truncated forms of the chemokines KC and GRO beta. To our knowledge, this represents the first example where any form of KC or GRO beta were purified from marrow stromal cells. Additionally, this is the first demonstration of in vivo efficacy of a CXC chemokine in an animal infectious fungal disease model.

Adjuvants, Immunologic↗
PubMed2000

Selective binding of the truncated form of the chemokine CKbeta8 (25-99) to CC chemokine receptor 1(CCR1).

Human CC chemokine receptor 1 (CCR1) has been proposed as a receptor for CKbeta8. To obtain conclusive evidence, binding-displacement studies of 125I-CKbeta8 (25-99) were performed on membranes of Chinese hamster ovary cells expressing human CCR1. The Ic50 for displacement of 125I-CKbeta8 (25-99) with CKbeta8 (25-99) was 0.22 nM. The longer forms of CKbeta8 (24-99 and 1-99) also displaced 125I-CKbeta8, with Ic50 values of 6.5 and 16 nM, respectively. Displacement profiles of 125I-CKbeta8 (25-99) on freshly prepared human monocytes indicated that CCR1 was the major receptor for CKbeta8. We conclude that CCR1 is a receptor for different-length CKbeta8 and that CKbeta8 (25-99) has a similar affinity for CCR1 as macrophage inflammatory protein-1alpha (MIP-1alpha). The longer variants of CKbeta8 are significantly less potent than CKbeta8 (25-99) and MIP-1a on CCR1 and monocytes (P < 0.05).

Animals↗
PubMed2000

Myb is required for self-renewal in a model system of early hematopoiesis.

In hematopoiesis, self-renewal, proliferation, differentiation and apoptosis represent opposing decisions made by stem cells and progenitor cells, which when dysregulated can result in leukaemia. Here, we have investigated the function of Myb proteins in regulating these key cellular decisions, using the cell line FDCP-mix A4 as a model of early hematopoiesis. High concentrations of IL-3 in these cells favour self-renewal over differentiation and apoptosis. However when endogenous Myb activity was inhibited with an inducible dominant interfering protein, self-renewal was replaced by apoptosis and differentiation. Differentiation was to granulocytes and monocyte/macrophages and was closely associated with a G1-S phase block in the cell cycle. As for normal hematopoiesis, cytokine-induced terminal differentiation of FDCP-mix cells is associated with concomitant proliferation prior to its completion. However, when Myb activity was inhibited during this process, proliferation and survival were both reduced, resulting in a much lower yield of mature cells. These results indicate multiple cellular roles of Myb proteins during normal hematopoiesis.

Animals↗
PubMed2000

CKbeta-8 [CCL23], a novel CC chemokine, is chemotactic for human osteoclast precursors and is expressed in bone tissues.

We have previously demonstrated that a tartrate-resistant acid phosphatase (TRAP)-positive subpopulation of mononuclear cells isolated from collagenase digests of human osteoclastoma tissue exhibits an osteoclast phenotype and can be induced to resorb bone. Using these osteoclast precursors as a model system, we have assessed the chemotactic potential of 16 chemokines. Three CC chemokines, the recently described CKbeta-8, RANTES, and MIP-1alpha elicited significant chemotactic responses. In contrast, 10 other CC chemokines (MIP-1beta, MCP-1, MCP-2, MCP-3, MCP-4, HCC-1, eotaxin-2, PARC, SLC, ELC) and 3 CXC chemokines (IL-8, GROalpha, SDF-1) were inactive. None of these chemokines showed any chemotactic activity for either primary osteoblasts derived from human bone explants or the osteoblastic MG-63 cell line. The identity of the osteoclast receptor that mediates the chemotactic response remains to be established. However, all three active chemokines have been reported to bind to CCR1 and cross-desensitization studies demonstrate that RANTES and MIP-1alpha can partially inhibit the chemotactic response elicited by CKbeta-8. CKbeta-8, the most potent of the active CC chemokines (EC(max) 0.1-0.3 nM), was further characterized with regard to expression in human bone and cartilage. Although expression is not restricted to these tissues, CKbeta-8 mRNA was shown to be highly expressed in osteoblasts and chondrocytes in human fetal bone by in situ hybridization. In addition, CKbeta-8 protein was shown to be present in human osteophytic tissue by immunolocalization. These observations suggest that CKbeta-8, and perhaps other chemokines, may play a role in the recruitment of osteoclast precursors to sites of bone resorption.

Bone Neoplasms↗