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Biomedical subjects

S E Kelly

Publications and source records attributed to S E Kelly.

At least 19 recordsLinked to original sources
PubMed2007

Synergistic effects of conjugated linoleic acid and chromium picolinate improve vascular function and renal pathophysiology in the insulin-resistant JCR:LA-cp rat.

AIMS: Conjugated linoleic acid (CLA) is a natural constituent of dairy products, specific isomers of which have recently been found to have insulin sensitizing and possible antiobesity actions. Chromium is a micronutrient which, as the picolinate (CrP), has been shown to increase insulin sensitivity in animal models, including the JCR:LA-cp rat. We tested the hypothesis that these agents may have beneficial synergistic effects on the micro- and macrovasculopathy associated with hyperinsulinaemia and early type 2 diabetes. METHODS: Insulin-resistant cp/cp rats of the JCR:LA-cp strain were treated with mixed isomers of CLA (1.5% w/w in the chow) and/or CrP at 80 microg/kg/day (expressed as Cr) from 4 weeks of age to 12 weeks of age. Plasma insulin, lipid and adiponectin levels, aortic vascular function, renal function and glomerular sclerosis were assessed. RESULTS: CLA administration reduced food intake, body weight and fasting insulin in JCR:LA-cp rats. Plasma adiponectin levels were significantly elevated in rats treated with both CLA and CrP. Aortic hypercontractility was reduced and the relaxant response to the nitric oxide-releasing agent acetylcholine (Ach) was increased in CrP-treated rats. Striking reductions were also observed in the level of urinary albumin and the severity of glomerular sclerosis in rats treated specifically with CLA. CONCLUSIONS: CLA and CrP have beneficial effects ameliorating several of the pathophysiologic features of an insulin-resistant rat model. These supplements may be useful adjuncts in the management of patients with the metabolic syndrome and warrant further study.

Adiponectin↗
PubMed2005

A novel complex of arginine-silicate improves micro- and macrovascular function and inhibits glomerular sclerosis in insulin-resistant JCR:LA-cp rats.

AIMS/HYPOTHESIS: The metabolic syndrome, with associated vasculopathy, is a major cause of cardiovascular disease and nephropathy. Impaired nitric oxide (NO) metabolism and endothelial function is an important component of the disease process. Increasing the availability of arginine, the precursor of NO, might enhance vascular function and protect against end-stage disease. MATERIALS AND METHODS: Insulin-resistant JCR:LA-cp rats were treated with arginine-silicate-inositol complex or arginine-HCl at 1.0 g kg(-1) day(-1) (expressed as arginine-HCl) from 8 to 13 weeks of age. The contractile/relaxant function of thoracic aortae and coronary arteries was assessed in vitro. Kidneys were assessed for severity of glomerular sclerosis. RESULTS: Arginine-silicate complex, but not arginine-HCl, normalised the hypercontractile response of the aorta to phenylephrine via an NO-dependent pathway. Coronary artery function, as indicated by reactive hyperaemia to warm ischaemia, was enhanced by both arginine compounds. In addition, the arginine-silicate complex increased coronary vasodilatation in response to bradykinin. Glomerular sclerosis was significantly reduced in rats treated with the arginine-silicate complex. CONCLUSIONS/INTERPRETATION: Treatment with exogenous arginine, in an efficiently absorbed form, improves vascular function and reduces nephropathy in an animal model of insulin resistance and cardiovascular disease, via mechanism(s) independent of insulin concentration. Enhancement of NO metabolism through increased availability of the precursor arginine appears to offer protection against micro- and macrovascular disease associated with the metabolic syndrome and insulin resistance.

Acetylcholine↗
PubMed2005

Insulin-sensitizing and cardiovascular effects of the sodium-hydrogen exchange inhibitor, cariporide, in the JCR: LA-cp rat and db/db mouse.

The effects of the sodium-hydrogen (Na/H) exchange inhibitor cariporide (HOE642), on insulin sensitivity and vascular function were studied in the JCR:LA-cp rat and the db/db mouse. In the insulin-resistant rat, cariporide reduced fasting insulin levels (42%, P < 0.02) and insulin response in a meal tolerance test (50%, P < 0.01), indicating increased insulin sensitivity. The ACE inhibitor, ramipril, used as a reference agent, reduced the insulin response to the meal, but not fasting levels. The EC50 for acetylcholine-mediated relaxation of phenylephrine-precontracted aortic rings was significantly lower in cariporide-treated rats (P < 0.002), but not in ramipril-treated rats. Flow response of the coronary circulation to bradykinin was significantly greater in both cariporide- and ramipril-treated rats, (3-fold decrease in the EC50, P < 0.05). Cariporide-treated hearts were smaller, slower beating, with greater developed LVP. In the obese db/db mouse, chronic treatment with cariporide obviated vascular hypercontractility and improved endothelial function. Thus, cariporide had beneficial effects on the abnormal insulin metabolism and associated vascular dysfunction in the JCR:LA-cp insulin-resistant rat, which develops advanced cardiovascular disease and ischemic myocardial lesions. It also improved vascular function in a similar mouse model of insulin resistance. These effects were markedly greater than those of ramipril.

Acetylcholine↗
PubMed2001

A newly discovered bacterium associated with parthenogenesis and a change in host selection behavior in parasitoid wasps.

The symbiotic bacterium Wolbachia pipientis has been considered unique in its ability to cause multiple reproductive anomalies in its arthropod hosts. Here we report that an undescribed bacterium is vertically transmitted and associated with thelytokous parthenogenetic reproduction in Encarsia, a genus of parasitoid wasps. Although Wolbachia was found in only one of seven parthenogenetic Encarsia populations examined, the "Encarsia bacterium" (EB) was found in the other six. Among seven sexually reproducing populations screened, EB was present in one, and none harbored Wolbachia. Antibiotic treatment did not induce male production in Encarsia pergandiella but changed the oviposition behavior of females. Cured females accepted one host type at the same rate as control females but parasitized significantly fewer of the other host type. Phylogenetic analysis based on the 16S rDNA gene sequence places the EB in a unique clade within the Cytophaga-Flexibacter-Bacteroid group and shows EB is unrelated to the Proteobacteria, where Wolbachia and most other insect symbionts are found. These results imply evolution of the induction of parthenogenesis in a lineage other than Wolbachia. Importantly, these results also suggest that EB may modify the behavior of its wasp carrier in a way that enhances its transmission.

Animals↗
PubMed2000

Chelation therapy in the JCR:LA-cp rat: experimental assessment of a putative antiatherosclerotic treatment.

OBJECTIVE: To test the efficacy of chelation therapy, an alternative medical treatment, as an antiatherosclerotic procedure, using an animal model of insulin resistance and vascular disease. DESIGN: A prospective animal experiment with procedures modelled on human chelation treatments. SUBJECTS: The JCR:LA-cp rat, a strain that, if homozygous for the autosomal recessive cp gene, becomes obese and insulin resistant, with marked hyperinsulinemia and hypertriglyceridemia, and is unique in the spontaneous development of atherosclerosis and ischemic myocardial lesions. EXPERIMENTAL PROTOCOL: Eight-month-old, obese, male JCR:LA-cp rats were fitted with indwelling venous cannulae and infused over 4 weeks with ethylenediaminetetraacetic acid (EDTA) 5 days a week at a daily dose of 40 mg/kg body weight. At the end of the treatment period, samples were taken for assay of blood parameters and for mineral content of bone. The rats were sacrificed and perfusion-fixed for scanning electron microscopy of the aortic arch. RESULTS: Plasma cholesterol concentrations were not changed by the EDTA treatment. In contrast, plasma triglyceride concentrations were raised significantly (74%, p < 0.05). Lean control rats showed minimal abnormality of the aortic arch, whereas the obese control rats had raised intimal lesions, frequent adherent macrophages and endothelial damage. The frequency of these vascular abnormalities in the EDTA-treated rats was not different from that seen in the obese controls. The bone contents of calcium and magnesium were not significantly reduced. CONCLUSIONS: Chelation therapy using intravenous EDTA has no beneficial effects on the arterial lesions in the atherosclerotic JCR:LA-cp rat. The increase in plasma triglyceride concentrations would be grounds for concern in human patients.

Animals↗
PubMed2000

Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat.

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.

Animals↗
PubMed1999

Defining dementia: social and historical background of Alzheimer disease.

Though Alzheimer disease (AD) has been recognized as a distinct entity since 1907, scientific understanding of, and public interest in, the disease remained very limited until the 1970s. The perception of AD as a significant problem has been substantially affected by cultural and demographic changes and by interest group and federal government initiatives. The recognition of AD has transformed senility from an expected stage of life into a "disease." It has also increased fear both of the individual effects of having AD and of the social consequences of AD in the population. Both the biotechnology industry and AD activist organizations will play a role in the social implications of genetic testing for AD.

Aging↗
PubMed1999

The Genetic Knowledge Index: developing a standard measure of genetic knowledge.

This paper reports on the development of a unidimensional genetic knowledge index that has been tested and validated in a general population sample. The Index is intended to provide the basis for a standard measure of basic genetic knowledge that can be applied across diverse populations and research settings. The study group was composed of 330 European Americans selected randomly in the Louisville, KY, metropolitan area. The final version of the Genetic Knowledge Index (GKI) consisted of five items identified by principle components analysis, correlation coefficients, and the alpha measure of internal consistency. Construct validity of the GKI was determined by appropriate statistical correlations with educational attainment and attitudes toward genetic discrimination. The Index provides a numerical ranking of subjects' knowledge of practical genetics. Implications for research are discussed.

Data Interpretation, Statistical↗
PubMed1997

Nuclear factor I family members regulate the transcription of surfactant protein-C.

Transcription of the surfactant protein-C (SP-C) gene is restricted to Type II epithelial cells in the adult lung. We have shown previously that the 0.32-kilobase pair (kb) mouse SP-C promoter is functional in transient transfection assays of the lung epithelial cell-derived cell line, MLE-15, and that thyroid transcription factor 1 (TTF-1) transactivates promoter activity. The 0.32-kb SP-C promoter can be separated into a proximal promoter region (-230 to +18) and an enhancer region (-318 to -230). Three DNase I footprints were mapped in the promoter region (C1 through C3) and two in the enhancer region (C4 and C5). We now show that nuclear factor I (NFI) family members bind to both individual NFI half-sites in footprints C1, C3, and C5, and to a composite site in footprint C4 by competition gel retardation and antibody supershift analyses. Mutational analysis of the 0.32-kb mouse SP-C promoter and transient transfection of MLE-15 cells demonstrated that the NFI binding sites are required for promoter activity in this cell type. Site-specific mutation of the proximal or distal NFI sites drastically reduced transactivation by a co-transfected NFI-A expression vector in HeLa cells. These data indicate that NFI family member(s), binding to sites in both the promoter and enhancer regions, regulate SP-C gene expression in a process independent of TTF-1.

Animals↗
PubMed1996

Transcription of the lung-specific surfactant protein C gene is mediated by thyroid transcription factor 1.

Surfactant protein C (SP-C) is expressed in alveolar Type II epithelial cells of the lung. In order to determine the mechanism(s) that regulate gene transcription, we have analyzed the activation of the murine SP-C promoter in mouse lung epithelial cells (MLE cells) and in HeLa cells after co-transfection with a vector expressing rat thyroid transcription factor-1 (TTF-1). TTF-1 transactivated SP-C-chloramphenicol acetyltransferase constructs containing -13 kilobase pairs to -320 base pairs (bp) of the 5 flanking region of the SP-C gene. Essential cis-acting elements were functionally localized to between -320 and -180 bp from the start of transcription by transfection analysis. Five DNase-protected regions, indicating multiple protein-DNA interactions within the -320 bp TTF-1-responsive region of the SP-C gene, were identified by DNase footprint analysis. A 40-bp segment of SP-C DNA from -197 to -158 linked to a heterologous promoter-chloramphenicol acetyltransferase construct activated expression after co-transfection with CMV-TTF-1 in HeLa and MLE cells. The -197 to -158 segment contained two consensus TTF-1 sites, which were specifically identified as TTF-1 binding sites by gel retardation and antibody supershift with MLE cell nuclear extracts and purified TTF-1 homeodomain protein. Site-specific mutagenesis of either of the TTF-1 binding sites completely blocked activation by TTF-1, indicating both sites are required for TTF stimulation of SP-C transcription.

Animals↗
PubMed1996

Reproducibility of videokeratographic digital subtraction maps after excimer laser photorefractive keratectomy.

BACKGROUND: Digital subtraction photokeratography can best identify topographic changes after excimer laser photorefractive keratectomy (PRK). To evaluate the reproducibility of these topographic maps, the authors used a topographic modeling system to generate multiple subtraction maps from different combinations of technically acceptable preoperative and postoperative maps for eyes that underwent PRK. The assigned patterns for each patient then were evaluated for consistency. METHODS: Seven hundred twenty-two individual subtraction maps were generated for 64 eyes that underwent PRK. A mean of 11.3 maps were generated for each eye. The topography of each map was individually classified as normal, central island, peninsula, or asymmetric. All maps within a set (consisting of examinations for 1 patient at a single postoperative interval) then were examined as a unit to determine the overall topographic classification for that set of maps. Each set in which each constituent map had the same topographic assignment as the set was considered "nonvariant," whereas those sets in which one or more individual subtraction maps had different topographic assignments were considered "variant." RESULTS: Of the 64 sets, 33 (52%) were variant and 31 (48%) were nonvariant. CONCLUSIONS: Any one subtraction map produced by the topographic modeling system may not be a reliable indicator of the excimer effect.

Cornea↗
PubMed1996

Ocular deviation following excimer laser photorefractive keratectomy.

We present a case of ocular deviation and diplopia that developed 9 months after monocular excimer laser photorefractive keratectomy. In this case, decompensation occurred because of a breakdown of fusion at distance. We suggest a cover test to assess the presence of significant phorias in all candidates for refractive surgery procedures.

Cornea↗
PubMed1995

Tumor necrosis factor-alpha inhibits surfactant protein C gene transcription.

Pulmonary surfactant protein C (SP-C) is a 3.7-kDa, hydrophobic peptide secreted by alveolar type II epithelial cells. SP-C enhances surface tension lowering activity of surfactant phospholipids that is critical to the maintenance of alveolar volume at end expiration. The proinflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), decreased SP-C mRNA within 24 h of intratracheal administration to mice. In vitro, TNF-alpha decreased SP-C mRNA in a time-and dose-dependent manner, reducing the steady state levels of SP-C mRNA by 3-5 fold. In contrast, TNF-alpha induced intercellular adhesion molecule-1 expression in both mouse lung and murine lung epithelial cell lines. Nuclear run-on analysis demonstrated that transcription of both the endogenous SP-C gene and a human SP-C promoter-driven transgene was inhibited by TNF-alpha. TNF-alpha decreased mouse SP-C chloramphenicol acetyltransferase mRNA in stably transfected murine epithelial cells. Deletion analysis of the SP-C promoter region demonstrated that TNF-alpha inhibited gene expression in constructs containing 320 base pairs 5' from the start of transcription of the mouse SP-C gene. Inhibition of surfactant protein C gene transcription by TNF-alpha may contribute to the abnormalities of surfactant homeostasis associated with pulmonary injury and infection.

Animals↗
PubMed1995

Class II MHC typing in pemphigoid gestationis.

Pemphigoid gestationis (PG) is a rare, autoimmune skin disease associated with pregnancy or the immediate post-partum period, previously shown to be associated with the HLA class II antigens DR3 and DR4. Advances in molecular analytical techniques now allow the identification of HLA alleles previously difficult to define by serological assays. Unsuspected polymorphism within the HLA-DR3 and DR4 classes can, therefore, be identified. The aim of our study was to apply these newer techniques to the question of genetic predisposition in PG by re-evaluating the association with DR3 and by studying a possible link with DQ. We have investigated by restriction fragment length polymorphism, the DQA, and by sequence specified oligonucleotide probing the DQB and DRB1 (HLA DR) specificities of 41 women with immunofluorescence-confirmed PG. The principal finding of this study is that there is an association between PG and DRB1*0301 (DR3) and DRB1*0401/040X (DR4). Although there is also an increase (P = 0.06) in the concurrent presence of both antigens, this appears to be due to the association with either antigen alone. We also found an increase in the frequency of DQA1*2 (P = 0.016 vs. control) and a decrease in frequency of DQB1*0201 (P = 0.022 vs. controls) and DQB1*0602 (P = 0.026 vs. controls).

Case-Control Studies↗
PubMed1995

Surgical repair of fracture of the os penis in a dog.

An eight-year-old male Australian cattle dog cross was presented with complete urethral obstruction secondary to fracture of the os penis which had occurred two years earlier. Obstruction was associated with callus and fibrous tissue proliferation compressing the urethra at the fracture site. The problem was satisfactorily resolved by removing excess bone and fibrous tissue and stabilising the fracture with a stainless steel finger plate.

Animals↗
PubMed1995

Long-term survival of four dogs with disseminated Aspergillus terreus infection treated with itraconazole.

Four dogs with disseminated aspergillosis caused by Aspergillus terreus were treated with oral itraconazole for 190 to 1095 days. Infection was eliminated in 1 dog. Two dogs were treated for 1000 and 1095 days but were eventually euthanased 572 and 485 days after treatment was stopped. At necropsy both dogs had widespread aspergillosis. The fourth dog was euthanased for other reasons after 190 days of treatment when it was showing a good clinical response although there was radiographic evidence that the disease was progressing.

Animals↗