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Biomedical subjects

R Cooney

Publications and source records attributed to R Cooney.

18 recordsLinked to original sources
PubMed2006

Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury.

Endothelial cell loss is a critical event in the pathological repair of the injured blood vessel. Impaired endothelial function results in reduced production of key vascular mediators such as nitric oxide (NO) within the vessel wall leading to enhanced smooth muscle cell proliferation and migration and ultimately intimal hyperplasia. The aim of the present study was to directly compare the effects of adenoviral-mediated gene delivery of two nitric oxide synthase (NOS) isoforms, eNOS and iNOS on endothelial regeneration and intimal hyperplasia following endothelial injury in the rabbit carotid artery. The right carotid arteries of male New Zealand white rabbits were denuded by passing a 3French Fogarty balloon catheter along the artery three times. In all, 1 x 10(9) PFU of adenoviral(Ad)eNOS, AdiNOS or Adbeta-galactosidase (Adbeta-Gal) was then delivered intraluminally and allowed to dwell for 20 min. Transgene expression was sought after 3 days by immunohistochemistry and at 7 days by quantitative reverse transcriptase PCR. The effect on intimal hyperplasia was sought using histological staining after 14 days. Evans blue staining was used to determine the effect on endothelial regeneration. eNOS and iNOS expression was detected in transduced arteries. Neointima/media ratios were significantly reduced in eNOS (0.07+/-0.044) and iNOS (0.087+/-0.086) transduced arteries compared with Adbeta-Gal (0.332+/-0.14) transduced arteries (n=7). In addition, AdeNOS treatment (4.21+/-3.12% de-endothelialized area) enhanced endothelial regeneration compared to Adbeta-Gal treatment (10.05+/-4.98), while treatment with AdiNOS (25.17+/-11.92) inhibited endothelial regeneration in the injured rabbit carotid artery (n=7-8). These results highlight the potential of NOS gene therapy, in particular, eNOS gene therapy as a potential therapeutic strategy for the prevention of restenosis after vascular injury.

Adenoviridae↗
PubMed2002

Prokinetic effect of indoramin, an alpha-adrenergic antagonist, on human gall-bladder.

BACKGROUND: The effects of alpha- and beta-adrenergic agents on gall-bladder motility remain undefined. AIM: To determine the effects of alpha- and beta-antagonists on gall-bladder motility in healthy humans. METHODS: In this single, blind, three-way crossover study, a slow-release formulation of propranolol 80 mg (beta-antagonist), indoramin 25 mg (post-synaptic alpha1-antagonist) and placebo were administered to 10 healthy volunteers on three separate days 8 h before the assessment of gall-bladder volumes by ultrasonography. Gall-bladder volumes were assessed in the fasting state and at 5-min intervals for 50 min after a standard proprietary enteral feed (Ensure 186 mL, Abbott). RESULTS: The fasting gall-bladder volumes of subjects who received placebo or indoramin were significantly different (mean +/- S.E.M.: 16.50 +/- 2.78 mL and 13.47 +/- 2.24 mL, respectively; P < 0.001, two-way analysis of variance). The fasting gall-bladder volume after the administration of propranolol was 17.49 +/- 2.37 mL and was not significantly different from placebo (16.50 +/- 2.78 mL). When the mean post-prandial gall-bladder volumes were compared, indoramin significantly enhanced post-prandial gall-bladder emptying compared to placebo (P < 0.001). There was no significant post-prandial volume difference between placebo and propranolol. CONCLUSIONS: Indoramin, an alpha-adrenergic antagonist, acts as a prokinetic agent, enhancing post-prandial gall-bladder emptying in healthy individuals.

Adrenergic alpha-Antagonists↗
PubMed2000

Inbreeding avoidance and reproductive skew in a cooperative mammal.

In animal social groups, socially subordinate individuals frequently show low reproductive success or completely fail to breed. This suppression of subordinate reproduction is currently typically attributed to control by dominant individuals. However, subordinates in cooperative groups often lack access to unrelated mates, and an alternative possibility is that their reproduction is limited by inbreeding avoidance. Using the eusocial Damaraland mole-rat Cryptomys damarensis, this paper provides the first experimental evidence, to our knowledge, for this explanation. Subordinate, non-breeding female mole-rats were given access to unrelated mates while remaining in the presence of dominant females, and many became reproductively active soon after unrelated males were introduced. Inbreeding avoidance and the availability of unrelated mates provides a plausible and untested explanation for variation in reproductive skew across animal societies.

Aggression↗
PubMed2000

Oxalate toxicity in renal epithelial cells: characteristics of apoptosis and necrosis.

Studies in various tissues, including the kidney, have demonstrated that toxins elicit apoptosis under certain conditions and necrosis under others. The nature of the response has important consequences for the injured tissue in that necrotic cells elicit inflammatory responses, whereas apoptotic cells do not. Thus, there has been considerable interest in defining the mode of cell death elicited by known cytotoxins. The present studies examined the response of renal epithelial cells to oxalate, a metabolite excreted by the kidney that produces oxidant stress and death of renal cells at pathophysiological concentrations. These studies employed LLC-PK1 cells, a renal epithelial cell line from pig kidney and NRK-52E (NRK) cells, a line from normal rat kidney, and compared the effects of oxalate with those of known apoptotic agents. Changes in cellular and nuclear morphology, in nuclear size, in ceramide production, and in DNA integrity were assessed. The ability of bcl-2, an anti-apoptotic gene product, to attenuate oxalate toxicity was also assessed. These studies indicated that oxalate-induced death of renal epithelial cells exhibits several features characteristic of apoptotic cell death, including increased production of ceramide, increased abundance of apoptotic bodies, and marked sensitivity to the level of expression of the anti-apoptotic gene bcl-2. Oxalate-induced cell death also exhibits several characteristics of necrotic cell death in that the majority of the cells exhibited cellular and nuclear swelling after oxalate treatment and showed little evidence of DNA cleavage by TUNEL assay. These results suggest that toxic concentrations of oxalate trigger both forms of cell death in renal epithelial cells.

Animals↗
PubMed2000

Tat mediates apoptosis in vivo in the rat central nervous system.

The HIV-1 transactivator of transcription, Tat, mediates apoptosis in neurons and may cause AIDS-associated neurologic disorders, which include dementia and loss of motor control. Here we investigate the ability of Tat to stimulate apoptosis in the rat central nervous system in vivo. Using the TUNEL assay, treatment of rat pheochromocytoma (PC12) cells with 1.0 microgram/ml of Tat for 24 h was found to stimulate apoptosis. Further, electrophoresis of DNA from Tat-treated PC12 cells demonstrated fragmentation. To investigate Tat mediated apoptosis in vivo, 20 microgram of Tat was infused into the striatum of Sprague-Dawley rats. Histochemical analysis (TUNEL) of the Tat-infused area demonstrated apoptosis. Further, these rats demonstrated postural deviation ipsilateral to the infusion. These data demonstrate that Tat stimulates apoptosis in vivo and causes neurologic dysfunction in the intact animal.

Animals↗
PubMed1999

TNF-binding protein ameliorates inhibition of skeletal muscle protein synthesis during sepsis.

We examined the effects of TNF-binding protein (TNFBP) on regulatory mechanisms of muscle protein synthesis during sepsis in four groups of rats: Control; Control+TNFBP; Septic; and Septic+TNFBP. Saline (1. 0 ml) or TNFBP (1 mg/kg, 1.0 ml) was injected daily starting 4 h before the induction of sepsis. The effect of TNFBP on gastrocnemius weight, protein content, and the rate of protein synthesis was examined 5 days later. Sepsis reduced the rate of protein synthesis by 35% relative to controls by depressing translational efficiency. Decreases in protein synthesis were accompanied by similar reductions in protein content and muscle weight. Treatment of septic animals with TNFBP for 5 days prevented the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. TNFBP treatment of Control rats for 5 days was without effect on muscle protein content or protein synthesis. We also assessed potential mechanisms regulating translational efficiency. The phosphorylation state of p70(S6) kinase was not altered by sepsis. Sepsis reduced the gastrocnemius content of eukaryotic initiation factor 2Bepsilon (eIF2Bepsilon), but not eIF2alpha. The decrease in eIF2Bepsilon content was prevented by treatment of septic rats with TNFBP. TNFBP ameliorates the sepsis-induced changes in protein metabolism in gastrocnemius, indicating a role for TNF in the septic process. The data suggest that TNF may impair muscle protein synthesis by reducing expression of specific initiation factors during sepsis.

Animals↗
PubMed1999

Oxalate-induced changes in the viability and growth of human renal epithelial cells.

Previous studies on the porcine renal epithelial LLC-PK1 cell line demonstrated that oxalate exposure produces concentration-dependent effects on renal cell growth and viability via process(es) involving free radicals. The present studies were conducted to determine whether these findings could be extended to a renal proximal tubular epithelial cell line derived from the human kidney. These studies examined oxalate-induced changes in membrane integrity after short-term exposure (4 h) and changes in cell survival after longer-term exposure (24 to 72 h). Oxalate-induced changes were also assessed in the expression of two genes: egr-1, a zinc-finger transcription factor, and osteopontin, a protein associated with tissue remodeling. The present studies also determined whether oxalate-induced changes in either cell viability or gene expression depended on free radicals. Oxalate at a concentration > or = 175 microM (free) produced membrane damage within 4 h. This effect was inhibited by Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP), a superoxide dismutase mimetic, but not by N-acetyl cysteine, a glutathione precursor, or by deferoxamine, an iron chelator. Acute oxalate-induced injury was followed by cell loss within 24 h, an effect maintained at 48 and 72 h at high concentrations of oxalate. Oxalate also promoted DNA synthesis. This mitogenic effect offset cell loss at lower oxalate concentrations (88 microM) leading to a small but significant increase in cell number at 72 h. Treatment with oxalate also increased expression of egr-1 mRNA within 1 h, a response that was attenuated by MnTMPyP; oxalate treatment for 8 h also increased abundance of osteopontin mRNA. These studies suggest that oxalate exposure produces changes in human renal cell growth and viability via a process(es) dependent on reactive oxygen intermediates. Such changes may play a role in the development and/or progression of renal disease via generation of reactive oxygen intermediates.

Cell Division↗
PubMed1998

Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group.

BACKGROUND: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock. METHODS: In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. FINDINGS: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, p=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, p<0.001; day 28, p=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group. INTERPRETATION: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

Adult↗
PubMed1998

Role of central IL-1 in regulating peripheral IGF-I during endotoxemia and sepsis.

Inflammatory cytokines may mediate the host response to infection via central nervous system, endocrine, and/or paracrine/autocrine signaling mechanisms. Previous studies have shown that intravenous administration of interleukin (IL)-1 beta alters the concentration of the anabolic hormone insulin-like growth factor (IGF)-I in plasma and various tissues. The purpose of the present study was to determine 1) whether the intracerebroventricular injection of IL-1 beta can influence peripheral IGF-I levels in control animals and 2) whether the central administration of a IL-1 receptor antagonist (IL-1ra) can prevent the changes in peripheral IGF-I induced by endotoxin [lipopolysaccharide (LPS)] or sepsis produced by cecal ligation and puncture. In the first experiment, injection of IL-1 beta (100 ng/rat) decreased IGF-I levels in plasma, liver, and gastrocnemius muscle 28-36% by 1.5 h in conscious fasted rats. IGF-I levels remained reduced at 3 h, but returned to baseline by 6 h. IGF-I content was not altered in soleus, kidney, spleen, intestine, or whole brain after IL-1 beta. In the second series of experiments, LPS injected intravenously decreased IGF-I levels in plasma, liver, and gastrocnemius at 1.5 h, and levels were even further reduced at 3 and 6 h in these tissues (59, 57, and 48%, respectively). Moreover, the IGF-I content was also decreased in soleus (30-35%) and increased in kidney (2- to 3-fold) after LPS. In the third experiment, changes in IGF-I levels in plasma and tissues, similar to those seen in LPS-treated rats, were detected 24 h after induction of peritonitis. Intracerebroventricular infusion of IL-1ra did not alter any of the changes in IGF-I produced by either LPS or sepsis, although it did attenuate the concomitant changes in growth hormone levels. These data suggest that, although central IL-1 beta is capable of modulating peripheral IGF-I levels, central administration of IL-1ra was unable to modulate the changes in peripheral IGF-I in blood and tissues produced by either endotoxemia or peritonitis.

Animals↗
PubMed1997

AIDS-associated Kaposi's sarcoma cells secrete a neurotrophic growth factor(s).

Here we treat neuronal cells with AIDS-Kaposi's sarcoma cell conditioned medium (A-KSCM) in order to determine if AIDS-Kaposi's sarcoma (A-KS) cells secrete neurotrophic factors. PC12 and NG108-15 cells were differentiated and allowed to form neuronal processes. Under these conditions and in the presence of A-KSCM, PC12 cells exhibited more than a twofold increase in the number of branches per process and a 40% increase in the number of processes per cell. For NG108-15 cells, A-KSCM treatment resulted in a three-fold increase in the number of branches per process and nearly a twofold increase in the number of processes per cell. A-KS cells secrete at least seven known growth factors; however, when tested, none of these growth factors mimicked the effect of A-KSCM on neuronal cell processes. Therefore A-KS cells secrete a neurotrophic factor(s) which remains to be identified and may play a critical role in the progression of A-KS.

AIDS-Related Opportunistic Infections↗
PubMed1997

Tumor necrosis factor mediates impaired wound healing in chronic abdominal sepsis.

BACKGROUND: The role of systemic tumor necrosis factor (TNF) as a mediator of impaired wound healing in sepsis is unclear. The purpose of this study was to examine the effects of a specific TNF antagonist (TNFbp) on wound healing during chronic abdominal sepsis. METHODS: Male Sprague-Dawley rats were divided into four groups: control, control + TNFbp, sepsis, and sepsis + TNFbp. Saline (1.0 mL) or TNFbp (1 mg/kg, 1.0 mL) was injected subcutaneously daily, polyvinylalcohol (PVA) sponge implants were placed in subcutaneous pockets, and sepsis was induced by creation of a chronic, intra-abdominal abscess. Sponge implants were removed on day 5 and examined histologically. Granulation tissue infiltration and quality (connective tissue, cellularity, vascularity) were scored on a scale from 1 to 4 in a blinded fashion. RESULTS: Septic mortality (19 vs. 25%) was not influenced by TNFbp. Granulation tissue penetration and quality were decreased in septic animals. The administration of TNFbp significantly attenuated the effects of sepsis on granulation tissue histology, but not to control levels. CONCLUSIONS: These studies provide evidence that TNF contributes to the impaired wound healing observed in this model of chronic abdominal sepsis.

Abdomen↗
PubMed1996

IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF system and protein synthesis.

The purpose of the present investigation was to determine whether endogenously produced interleukin (IL)-1 mediates the changes in insulin-like growth factor (IGF) I and IGF binding proteins (IGFBP) induced by chronic abdominal sepsis in rats and to correlate the changes in the IGF system with the alternations in protein synthesis. A constant infusion of IL-1 receptor antagonist (IL-1ra) was begun after the induction of sepsis and was continued for 5 days. Sepsis decreased IGF-I levels in the blood, liver, and gastrocnemius muscle, increased the content in the kidney, and did not alter IGF-I levels in heart, jejunum, and spleen. IL-1ra attenuated the sepsis-induced decrease in plasma IGF-I and completely prevented the changes in IGF-I observed in liver, kidney, and the gastrocnemius. IGFBP-1 was increased in the blood, liver, and muscle of septic rats. IL-1ra prevented this increase in IGFBP-1 in blood and liver but not in muscle. The rate of in vivo protein synthesis was decreased in the gastrocnemius and kidney and unaltered in the heart, liver, jejunum, and spleen. A strong linear correlation existed between levels of IGF-I and the rate of protein synthesis determined simultaneously in the gastrocnemius. These results provide evidence for the role of IL-1 as an endogenous mediator of the sepsis-induced changes in IGF-I and IGFBP-1 and suggest that the accompanying changes in muscle protein synthesis are partially mediated via changes in IGF-I.

Animals↗
PubMed1996

Central interleukin-1 partially mediates endotoxin-induced changes in glucose metabolism.

The purpose of the present study was to determine whether intracerebral interleukin (IL)-1 mediates the endotoxin [lipopolysaccharide (LPS)]-induced increase in glucose flux. To accomplish this goal, a specific receptor antagonist for IL-1 (IL-1ra) or artificial cerebrospinal fluid was infused into the lateral ventricle via an intracerebroventricular cannula before, and for 4 h after, the intravenous injection of LPS. Whole body glucose flux was measured in conscious unrestrained rats using [3-3H]glucose. LPS increased both the plasma glucose concentration and the rate of glucose production (95 and 80%, respectively). In contrast, intracerebroventricular infusion of IL-1ra (2 mg/kg + 2 mg-kg-1.h-1) attenuated by approximately 50% the LPS-induced changes in glucose metabolism. IL-1ra also blunted the increase in plasma catecholamines, but not the elevation in glucagon and corticosterone concentrations, observed after LPS. Intracerebroventricular infusion of IL-1ra greatly reduced the LPS-induced hyperlactacidemia but did not alter the increase in muscle pyruvate dehydrogenase activity. An intravenous infusion of a 10-fold greater dose of IL-1ra, however, did not antagonize the LPS-induced increase in glucose flux. These data indicate that a major portion of the stimulation of glucose flux, as well as the increase in plasma catecholamines in response to LPS, is mediated by IL-1 within the central nervous system.

Animals↗
PubMed1994

Memory for spatial layouts in relation to age and schema typicality.

The hypothesis that prior experience, specifically a knowledge-based schema for typical house layouts, can compensate for age declines in spatial memory was evaluated in 4 experiments. Old and young adults explored and subsequently recalled house layouts presented 1 room at a time on a computer screen. The findings failed to support the compensation hypothesis in that schema-relevant layouts facilitated recall equivalently for the 2 age groups. Violation of a typical house schema had a more negative effect on recall of the older group. Individual differences in spatial visualization ability explained much of the age difference in performance but not the effects of schema manipulations. It was concluded that there is age invariance in the facilitatory effects of relevant prior knowledge on spatial memory but an age-related decrease in the ability to inhibit irrelevant prior knowledge.

Adult↗
PubMed1994

Interleukin-1 receptor antagonist prevents sepsis-induced inhibition of protein synthesis.

To understand the role of interleukin-1 (IL-1) as a mediator of the sepsis-induced skeletal muscle catabolism, we investigated the effects of a specific IL-1 receptor antagonist (IL-1ra) on skeletal muscle protein metabolism in a rodent model of chronic abdominal sepsis. A constant infusion of IL-1ra (2 mg.kg-1.h-1) or saline was begun immediately after the induction of sepsis and continued for 5 days. The effect of IL-1ra on protein metabolism was examined in individual muscles (gastrocnemius, soleus, heart) containing different fiber types. Infusion of IL-1ra in control animals did not alter protein metabolism in any of the muscles examined. Muscle weight, protein content, and the rate of protein synthesis in gastrocnemius were reduced by sepsis, whereas none of these parameters were affected in soleus or heart. Infusion of IL-1ra prevented the sepsis-induced loss of muscle protein and inhibition of protein synthesis in gastrocnemius but was without effect in soleus or heart. IL-1ra infusion restored translational efficiency in the gastrocnemius of septic rats and was without effect on the RNA content. These results provide evidence for a role of IL-1 as a mediator of the sepsis-induced abnormalities in skeletal muscle protein metabolism.

Abdomen↗
PubMed1993

Mycobacterium hiberniae sp. nov.

Strains of a new type of slowly growing scotochromogenic, rose-pink-pigmented mycobacterium were isolated repeatedly from sphagnum vegetation, true moss, and soil in Ireland. These strains grew at 22, 31, and 37 degrees C but not at 45 degrees C and possessed acid phosphatase and arylsulfatase activities. They reduced nitrate, tolerated 0.1% NaNO2, did not split amides, and were resistant to most of the antituberculous drugs tested, except ethambutol. They did not form acid from glucose and mannose. Their internal phenetic similarity was 97.08% +/- 2.07%. The whole mycolate pattern confirmed the homogeneity of the taxa sharing similar mycolate types with several other mycobacterial species. However, on the basis of the nature of the major pyrolysis esters, the taxon appeared unique. The phylogenetic analysis based on evolutionary distance values revealed that the strains belong to a new species of slowly growing mycobacteria. The DNA-DNA hybridization values confirmed that these strains differ significantly from Mycobacterium nonchromogenicum, M. terrae, M. triviale, and M. thermoresistibile. The strains produced a unique rose-pink pigment and were nonpathogenic for mice, guinea pigs, and rabbits, but they provoked a nonspecific hypersensitivity reaction to bovine tuberculin in guinea pigs and cattle. Hence, they are considered a member of a new species of nonpathogenic slowly growing mycobacteria, for which the name Mycobacterium hiberniae is proposed. Strain Hi 11 is the type strain, a culture of which has been deposited in the American Type Culture Collection as strain ATCC 49874.

Bacterial Typing Techniques↗
PubMed1983

Cloning of the pif region of the F sex factor and identification of a pif protein product.

This paper reports a detailed investigation of the pif region of the F factor responsible for inhibition of development of T7 and related "female-specific" phages. We have mapped a series of pif::Tn5 insertions to a region between 39.6 and 42.8 kilobases on the physical map of F. All pif::Tn5 insertions plated T7 at full efficiency; most were clustered in a 1.8-kilobase interval on both sides of the EcoRI site located at F coordinate 40.3 kilobases. A 5.2-kilobase Pst-I fragment with F coordinates 38.9 to 44.1 has been cloned into a pSC101 vector to create the Pif+ plasmid pGS103. A series of Pif- deletion mutants and nonsense mutants were isolated from pGS103. Using minicells carrying pGS103 or its derivatives, we have identified a 70,000-dalton pif protein.

Bacterial Proteins↗