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Biomedical subjects

G Carr

Publications and source records attributed to G Carr.

At least 19 recordsLinked to original sources
PubMed2006

Disruption of clc-5 leads to a redistribution of annexin A2 and promotes calcium crystal agglomeration in collecting duct epithelial cells.

Mutations in CLCN5, which encodes the voltage-dependent Cl(-)/H(+)antiporter, CLC-5, cause Dent's disease. This disorder is characterized by low molecular-weight proteinuria, hypercalciuria, nephrocalcinosis and nephrolithiasis. Using a collecting duct cell model (mIMCD-3) in which endogenous clc-5 is disrupted by antisense clc-5 or overexpression of truncated clc-5, we demonstrate altered expression of the crystal adhesion molecule, annexin A2. Endogenously expressed annexin A2 is intracellular with limited plasma membrane localization. Following clc-5 disruption, there is both a marked increase in plasma membrane annexin A2 and an increase in cell surface crystal retention and agglomeration, which may be attenuated using pretreatment with anti-annexin A2 antibodies or wheat germ agglutinin lectin but not by concanavalin A. We hypothesize that in Dent's disease, endocytic failure leads to an accumulation at the plasma membrane of crystal-binding molecules that include annexin A2 leading to retention of calcium crystals and ultimately nephrocalcinosis and nephrolithiasis.

Animals↗
PubMed2004

Calcium phosphate and calcium oxalate crystal handling is dependent upon CLC-5 expression in mouse collecting duct cells.

Defects in an intracellular chloride channel CLC-5 cause Dent's disease, an inherited kidney stone disorder. Using a collecting duct model, mIMCD-3 cells, we show expression of dimeric mCLC-5. Transient transfection of antisense CLC-5 reduces CLC-5 protein expression. Binding of both calcium phosphate (hydroxyapatite) and calcium oxalate monohydrate (COM) crystals overlaid onto mIMCD-3 cultures was affected by altered CLC-5 expression. Calcium phosphate crystal agglomerations (>10 microm) were minimal in control (9%) and sense (13%) CLC-5-transfected cells, compared to 66% of antisense CLC-5-transfected cells (P<0.001). Small calcium phosphate crystals (<10 microm) were found associated with 45% of sense CLC-5-treated cells, of which the majority (11/14 cells) appeared to be internalised within the cell. Calcium oxalate agglomerations (>10 microm) were also largely absent for controls or sense mCLC-5 transfectants (11% and 9% of cells, respectively) with COM crystal agglomerates predominating in antisense CLC-5 transfectants (66%, P<0.0001). We conclude that collecting duct cells with reduced CLC-5 expression lead to a tendency to form calcium crystal agglomeration, which may help explain the nephrocalcinosis and nephrolithiasis seen in Dent's disease.

Animals↗
PubMed2001

Neutral inhibitors of the serine protease factor Xa.

A neutral inhibitor of the serine protease factor Xa was identified via a high-throughput screen of a commercial library. The initial lead 1 demonstrated reversible and competitive inhibition kinetics for factor Xa and possessed a high degree of selectivity versus other related serine proteases. Initial modeling efforts and the generation of a series of analogues of 1 are described.

Aniline Compounds↗
PubMed2001

Marine risk assessment: linear alkylbenzenesulponates (LAS) in the North Sea.

The fate of linear alkylbenzenesulponates (LAS) in estuaries and coastal areas of the North Sea has been characterized with simple environmental models. The predicted concentration range in the estuaries around the North Sea (0.9-9 microg LAS l(-1)) was validated by monitoring data (1-9 microg LAS l(-1)). In offshore sites of the North Sea, it is estimated--and experimentally verified for a few sites--that the LAS concentration is below analytical detection limit (i.e., 0.5 microg LAS l(-1)). The effects of LAS on marine organisms have been reviewed. For short-term acute tests, there was no significant difference (p = 0.83) between the mean LC50 values of freshwater and marine organisms (mainly pelagic species tested, 4.1 and 4.3 mg LAS l(-1), respectively). For longer-term chronic tests, it appeared that the sensitivity (mean no-observed effect concentration (NOEC) value) of marine and freshwater organisms (0.3 and 2.3 mg LAS l(-1), respectively) was significantly different pt-test = 0.007). The predicted no-effect-concentrations (PNEC) were 360 and 31 microg LAS l(-1), for freshwater and marine pelagic communities, respectively. Given that the maximum expected estuarine and marine concentrations are 3 to > 30 times lower than the PNEC, the risk of LAS to pelagic organisms in these environments is judged to be low.

Animals↗
PubMed1999

Ciprofloxacin treatment does not influence course or relapse rate of reactive arthritis and anterior uveitis.

OBJECTIVE: To assess the efficacy of ciprofloxacin in the treatment of reactive arthritis (ReA) and anterior uveitis (AU) in a double-blind, randomized, placebo-controlled trial. METHODS: Seventy-two patients participated in this study, 56 with ReA and 42 with AU (26 patients had both ReA and AU). Ciprofloxacin (750 mg twice a day) was administered for 12 months with a 12-month followup. End points of the study included time to disease relapse and measures of disease severity. RESULTS: There was no difference between groups in time to disease relapse, joint inflammation, number of joints and enthesis involved in patients with ReA, or signs and symptoms of AU. CONCLUSION: Long-term treatment of ReA and AU with ciprofloxacin made no statistically significant difference to the natural history of these diseases or their severity.

Anti-Infective Agents↗
PubMed1997

Evaluation of the transgenic Lambda/LacI mouse model as a short-term predictor of heritable risk.

Transgenic male C57BL/6 lambda/lacI mice were used to assess the mutagenic response in seminiferous tubules and epididymal spermatozoa 3 days after exposure to ethylnitrosourea (ENU), iso-propyl methanesulfonate (iPMS) and methyl methanesulfonate (MMS). No significant mutagenic response was observed in epididymal spermatozoa for all three compounds, as expected 3 days after treatment. However, ENU and iPMS treated samples demonstrated significant mutagenic inductions relative to controls in seminiferous tubules while MMS treated samples did not. The failure of MMS to induce a mutagenic response in lambda/lacI transgenic mice is likely due to a combination of the low dose used, the short expression time after exposure and the reduced sensitivity to large deletion events in transgenic lambda/lacI shuttle vectors. In addition, ex vivo mutations were measured in control samples and iPMS treated samples, where 33% of mutants from control samples and 35% of mutants from iPMS treated samples were mosaic.

Animals↗
PubMed1997

Analysis of the mutagenic potential of ENU and MMS in germ cells of male C57BL/6 lacI transgenic mice.

Mutant frequencies in male germ cells were determined in mice 3 days after exposure to saline, methylmethane sulfonate (MMS), or ethylnitrosourea (ENU). DNA was isolated from seminiferous tubules by a modified version of the drop dialysis method. A 5-fold increase in mutant frequency was observed in mice treated with ENU. No statistically significant increase was observed in mice treated with MMS.

Animals↗
PubMed1997

IRAG working group 3. Cell function-based assays. Interagency Regulatory Alternatives Group.

Cell function-based tests measure responses of cells at sublytic concentrations of test agents. The fluorescein leakage assay measures effects of substances on the barrier function of epithelial monolayers or multilayers (MDCK or NHEK cells) as in vitro models of corneal epithelial function. Two IRAG data submissions suggest that the fluorescein leakage assay shows promise as a screening test for surfactants and alcohols. The test method requires further optimization, standardization and evaluation to fully determine its utility as an in vitro ocular irritancy test. The silicon microphysiometer test measures effects of test substances on the metabolic rate of cells; although a large number of cell types have been evaluated, L929 cells have been used for irritancy screening. Three IRAG data submissions on the silicon microphysiometer test showed strong in vivo/in vitro correlations for surfactants and surfactant-based personal care and household cleaning products in a range of mild to moderate ocular irritancy. This and published information support the reproducibility of the method and its use as an ocular irritancy screening test for aqueous-soluble liquid, surfactant-based formulations.

Animal Testing Alternatives↗
PubMed1997

Statistical planning and analysis considerations in the evaluation of in vitro alternatives to whole animal use for eye irritation testing.

Reports from the IRAG Working Groups assessing the current status of in vitro alternatives to whole animal eye irritation tests reflect some common approaches. Although each Working Group studied a particular class of assay, typically all Groups evaluated the in vitro alternatives on the basis of correlation with an in vivo test and the statistical significance of that correlation. However, the data furnished to them by the testing organizations had been obtained with little or no standardization of procedures for testing and evaluation of results. This paper presents issues of design and execution of such test programs that are of statistical concern, including objectives of the evaluation process; limitations of correlation; sources of variation and distinction between actual replication and repeated measurements; evaluation of the predictive ability of in vitro tests; association criteria; and other approaches to such evaluation programs. The distinction between statistical significance and toxicological significance is pointed out. Suggestions are presented for standardization of test protocols, test materials and evaluation programs for both in vitro and in vivo tests. A central repository for such standardization, under the aegis of a government agency, professional standards organization, university or research institute, would be a valuable asset. An addendum is furnished to illustrate assertions about a number of factors influencing correlations and their statistical significance.

Animal Testing Alternatives↗
PubMed1996

Themes relating to sexuality that emerged from a discourse analysis of the Nursing Times during 1980-1990.

The intention of this study was to develop insight into how the concept of human sexuality has been addressed within a popular nursing medium, namely the publication Nursing Times, during the decade 1980-1990. The study begins by clarifying discourse analysis and its role in the social construction of language. Exploration of the use of metaphors within nursing text is made to highlight the ability to convey multiple meaning and ideology within nursing practice. The 86 text papers generated during this decade were subjected to a process of qualitative data analysis entitled 'Framework'. The emerging themes from this process were used to inform a discussion of the ideological and practice relationships that exist between nursing and human sexuality.

Cultural Characteristics↗
PubMed1996

Altered urinary interleukin-8/creatinine ratio in peptic ulcer disease: pathological and diagnostic implications.

OBJECTIVES AND METHODS: To assess its clinicopathological and diagnostic significance, interleukin-8 (IL-8) was measured by radioimmunoassay in fasting urine specimens and in gastric mucosal incubates taken from 54 patients with dyspepsia. The presence of Helicobacter pylori, the activity of gastritis, and urine creatinine levels were also assessed. RESULTS: The median urinary IL-8/creatinine ratio was 0.1 x 10(-6) in patients with current peptic ulcers (n = 13) and 0.2 x 10(-6) in patients with a history of ulcers (n = 8), compared with 0.4 x 10(-6) (p < 0.0001) in patients without ulcers who were infected with H. pylori (n = 20) or not infected (n = 13). The activity of gastritis had a positive correlation with gastric IL-8 (r = 0.5870, p < 0.01) and a negative correlation with urinary IL-8/creatinine ratio (r = -0.6447, p < 0.005). The improvement in the activity of gastritis in 20 patients given anti-H. pylori triple therapy was associated with a significant fall in gastric mucosal IL-8 and a rise in urinary IL-8/creatinine ratio. CONCLUSIONS: An inverse relationship seems to exist between urinary IL-8 and the activity of gastritis and gastric IL-8. This may represent another concept in the pathogenesis of peptic ulcers and can assist in the noninvasive diagnosis of peptic ulcer disease.

Adult↗
PubMed1993

Thymidine phosphorylase activity of platelet-derived endothelial cell growth factor is responsible for endothelial cell mitogenicity.

Recombinant human platelet-derived endothelial cell growth factor, expressed in the yeast Saccharomyces cerevisiae was purified to greater than 98% purity by anion-exchange and hydroxyapatite chromatography. It was shown to possess thymidine phosphorolytic activity in vitro (pH optimum, pH 5.3; Km, 0.11 mM; Vmax, 12.5 mmol min-1 mg-1; turnover number, 9.4 s-1). Covalent modification simultaneously inhibited the enzymatic and mitogenic properties of the protein, while interaction with a cell-surface receptor was not required to stimulate mitogenesis. Purified Escherichia coli thymidine phosphorylase was also mitogenic toward endothelial cells. It is proposed that platelet-derived endothelial cell growth factor is human thymidine phosphorylase which promotes endothelial cell proliferation by reducing thymidine levels that would otherwise be inhibitory to endothelial cell growth.

Cells, Cultured↗
PubMed1992

Opportunistic infections and pharmacology.

The most common acute complication in HIV infection is likely to be one of the many possible opportunistic infections caused by immunodeficiency. These infections may be the index diagnosis of AIDS or occur in previously diagnosed patients as additional problems. Monitoring for the symptoms of disease and monitoring patients while undergoing treatment are frequently included in nursing care. This article discussed the diagnosis and treatment of some of the more common of the major opportunistic infections seen in AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1990

Positron emission tomographic scanning demonstrates a presynaptic dopaminergic lesion in Lytico-Bodig. The amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam.

We performed positron emission tomography using 18F-6-fluorodopa on four Guamanians with an amyotrophic lateral sclerosis syndrome, eight Guamanians with parkinsonism, and seven clinically normal Guamanians; the results were compared with those of nine Vancouver control subjects. The Guamanian subjects had all been exposed to similar Chamorro lifestyles. The scans were analyzed using a graphic method that calculates a constant for whole striatal 18F-6-fluorodopa uptake. The parkinsonian subjects all had significantly reduced striatal 18F-6-fluorodopa uptake. The group with amyotrophic lateral sclerosis had significantly reduced uptake that was intermediate between that of the control group and the parkinsonian group. Two Guamanian normal subjects had reduced striatal 18F-6-fluorodopa uptake. The nigrostriatal dopaminergic lesion in Guamanian parkinsonism is similar to that found in idiopathic parkinsonism. The nigrostriatal lesions in the subjects with amyotrophic lateral sclerosis and the Guamanian normal subjects are examples of subclinical neuronal damage demonstrable in living subjects with positron emission tomography.

Adult↗
PubMed1990

Red cells suspended in a phosphate-fortified additive: biochemical enhancement and longer storage.

When compared to our current storage regime, an additive solution, with 75 mM inorganic phosphate, improved certain biochemical and morphological parameters measured in suspensions of packed red cells throughout 49 days of liquid storage. In particular, the mean ATP level of 20 donations stored with the high phosphate additive was consistently and significantly higher than in standard (n = 6) suspensions. The increased amount of inorganic phosphate and the higher pH of the new additive stimulated ATP production and provided better pH buffering than the standard solution currently in use. Although survival study results indicated adequate 24h survivals for erythrocytes stored for 42 days with the new solution, after 49 days storage, the mean 24h survival of autologous erythrocytes was only 58 +/- 7% (n = 6).

Adenosine Triphosphate↗