Biomedical subjects

N S Shargill

Publications and source records attributed to N S Shargill.

At least 19 recordsLinked to original sources

PubMed2001

A multicenter, prospective, randomized trial evaluating a new hemostatic agent for spinal surgery.

STUDY DESIGN: A prospective, randomized trial comparing Proceed, a gelatin-based hemostatic sealant (treatment), with Gelfoam-thrombin (control) in stopping intraoperative bleeding during spinal surgery. OBJECTIVES: To determine the effectiveness and safety of Proceed. SUMMARY OF BACKGROUND DATA: Proceed has been tested in animal models to determine its safety and effectiveness as a hemostatic agent. The current study was conducted under a Food and Drug Administration-approved Investigational Device Exemption to evaluate the effectiveness and safety of Proceed in humans. METHODS: For this study, 127 patients undergoing spinal surgery were randomized into either the treatment or control group after standard surgical means to control bleeding had failed. The bleeding site was evaluated at 1, 2, 3, 6, and 10 minutes after the hemostatic agent was applied. The application was considered successful if the bleeding stopped within 10 minutes. Follow-up evaluation was performed at 12 to 36 hours, then at 6 to 8 weeks after surgery. RESULTS: Proceed stopped bleeding in 98% of the patients (first bleeding site only) within 10 minutes, as compared with 90% of the control patients (P = 0.001). At 3 minutes, successful hemostasis had been achieved in 97% of the Proceed group, as compared with 71% of the control group (P = 0.0001). There was no difference in the adverse event profile between the two groups. CONCLUSIONS: A significantly larger number of bleeding sites had achieved hemostasis with Proceed than with Gelfoam-thrombin at 1, 2, and 3 minutes after application. Proceed was as safe as Gelfoam-thrombin when used for hemostasis during spinal surgery procedures.

Administration, Topical↗

PubMed1993

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.

Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

3T3 Cells↗

PubMed1991

Enterostatin suppresses food intake following injection into the third ventricle of rats.

The effect on food intake of an activation peptide from pancreatic pro-colipase, called enterostatin, has been studied after parenteral or third ventricular administration. The activation peptide (enterostatin = Val-Pro-Asp-Pro-Arg = VPDPR) reduced food intake when given intraperitoneally. Low doses of this peptide also reduced food intake when given into the third ventricle, but high doses were ineffective. Enterostatin did not modify the stimulatory effects on food intake of clonidine, an alpha 2-adrenergic agonist, suggesting that its anorectic effects are not mediated via the alpha 2-adrenergic system. These data suggest that enterostatin, an activation peptide from pro-colipase, may play a role in producing satiety.

Analysis of Variance↗

PubMed1991

Peripheral insulin insensitivity in the hyperglycemic athymic nude mouse: similarity to noninsulin-dependent diabetes mellitus.

Previous studies in the homozygous athymic nude mouse (USC colony) have indicated a diabetic state characterized by spontaneous hyperglycemia, abnormal glucose tolerance, and normal or relatively decreased plasma insulin levels. Pancreatic islet cell population assessed by morphometric and immunohistochemical studies demonstrated normal insulin-secreting cells in the hyperglycemic nude mouse. To further elucidate the pathogenesis of the hyperglycemic state in the athymic nude mouse, we have studied the effects of insulin on the transport of glucose in skeletal muscle by measuring basal and insulin-stimulated uptake of a nonmetabolizable glucose analogue, 2-deoxy-D-glucose by using the perfused hindquarter preparation. Although basal 2-deoxy-D-glucose uptake by peripheral skeletal muscle was similar in the hyperglycemic and control mice, the insulin-stimulated uptake of 2-deoxy-D-glucose was significantly decreased in the athymic nude mouse at both 0.1 milliunits/ml and supraphysiologic concentrations of insulin (1 milliunit/ml) when compared with control mice (P less than 0.05 and P less than 0.001, respectively). This form of peripheral insulin insensitivity with normal pancreatic beta cell reserve, in addition to the lean body mass of the diabetic animal, mimics in part the peripheral insulin insensitivity seen in non-insulin-dependent diabetes mellitus.

Animals↗

PubMed1990

Relationship between uptake of norepinephrine by hypothalamic homogenates and the activity of brown adipose tissue.

It has previously been established that norepinephrine (NE) in the central nervous system is involved in feeding and the development of obesity. The present experiments were carried out to investigate the relationship between the uptake of NE by a crude hypothalamic homogenate and NE-mediated sympathetic activity in interscapular brown adipose tissue (IBAT). Sympathetic nervous system activity was assessed by measuring the binding of the purine nucleotide guanosine-5'-diphosphate (GDP) to mitochondria isolated from IBAT. Four situations known to alter food intake and sympathetic activity, namely, corticotropin releasing factor infusion, adrenalectomy, fenfluramine treatment and obesity due to genetic transmission were studied. In each case, [3H]NE uptake by the hypothalamic preparation and GDP binding to IBAT mitochondria were measured. A highly significant negative correlation between the uptake of NE by hypothalamic homogenates and the binding of GDP to IBAT mitochondria was obtained in both lean and obese animals. These findings are discussed with regard to the regulation of food intake and sympathetic nervous system mediated thermogenesis.

Adipose Tissue, Brown↗

PubMed1989

Effects of MSH on food intake, body weight and coat color of the yellow obese mouse.

Viable yellow obese mice (Avy/a) were treated for 10 days with 5, 15, 50 or 150 micrograms/d of either alpha-MSH or desacetyl-MSH. The half-maximal effect on weight gain occurred with a dose of 5 micrograms/d for desacetyl-MSH and at a 30 fold higher level of 150 micrograms/d for alpha-MSH. In contrast, the half-maximal stimulation of eumelanin production by alpha-MSH occurred at 15 micrograms/d and with desacetyl-MSH at 150 micrograms/d, a 10-fold increase. Desacetyl-MSH produced a dose-related increase in the weight of muscle, as well as white and brown adipose tissue. Desacetyl-MSH and alpha-MSH both increased plasma corticosterone concentrations, but desacetyl-MSH was more potent. In a 2 x 2 factorial designed study, body weight was significantly increased in viable yellow mice only by treatment with desacetyl-MSH but in the lean animals, both alpha-MSH and desacetyl-MSH increased body weight. Food intake was significantly different between genotypes, and was stimulated by desacetyl-MSH. These studies demonstrate potent differences in biological actions on food intake, body weight, and a variety of organ weights between acetylated and desacetylated forms of MSH.

Animals↗

PubMed1989

Interaction of adrenalectomy and fenfluramine treatment on body weight, food intake and brown adipose tissue.

Three experiments have examined the interaction of adrenalectomy and fenfluramine on food intake, body weight and the binding of guanosine-5'-diphosphate (GDP) to interscapular brown adipose tissue (IBAT). In the first experiment, GDP-binding by IBAT mitochondria from adrenalectomized or sham-operated animals was measured for 3 hr after one of 3 doses of fenfluramine. Fenfluramine stimulated GDP-binding at lower doses in the adrenalectomized animals than in the controls. In the first chronic experiment, adrenalectomy prevented the restoration of normal food intake observed 8-10 days after the beginning of fenfluramine treatment. Adrenalectomy also increased weight loss and enhanced GDP binding to mitochondria from IBAT in rats treated with fenfluramine. In the second chronic experiment, the combination of fenfluramine and adrenalectomy led to a progressive weight loss, continuing hypophagia and stimulation of GDP-binding by IBAT, whereas rats treated with fenfluramine alone showed a recovery of food intake at a stabilized but lower body weight. These data are consistent with the hypothesis that adrenalectomy and fenfluramine disable two separate components of the food intake system and that when combined, produce a profound and persisting disturbance in energy or nutrient balance.

Adipose Tissue, Brown↗

PubMed1989

Effects of corticotropin releasing factor on genetically obese (fatty) rats.

Corticotropin releasing factor (CRF) has been administered into the third ventricle of lean and genetically obese Zucker fatty rats in both acute and chronic experiments. Following a single injection of CRF (5 micrograms or approximately 1 nmole) there was an acute reduction of food intake in both the lean and obese animals, but the effect was greater in the obese. This effect persisted for the first three hours but was no longer detectable in either lean or genetically obese animals at 6 hours. Binding of GDP to mitochondria from interscapular brown adipose tissue in 21-hour deprived animals was lower in the fatty rats than in the lean controls. The injection of CRF significantly increased GDP binding in both the lean and fatty rats. During chronic infusion of CRF into the third ventricle of fatty rats, there was a significant decrease in food intake in the obese rats and fall of body weight in both groups. The basal levels of GDP binding were significantly lower in the saline-infused fatty rats than in the saline-infused lean controls. The chronic infusion of CRF increased GDP binding in the fatty rats but not in the lean animals. The CRF-treated values for GDP binding in fatty rats however, remained significantly below the baseline values in the control animals. Chronic CRF infusion also significantly lowered glucose levels in the fatty rat. These studies are consistent with the hypothesis that CRF may be involved in the decreased food intake and increased sympathetic activity observed in genetically obese fatty rats following adrenalectomy.

Adipose Tissue, Brown↗

PubMed1989

Adrenalectomy in genetically obese ob/ob and db/db mice increases the proton conductance pathway.

Adrenalectomy (ADX) prevents the excessive weight gain in the genetically obese ob/ob and db/db mice. To test the possibility that this results from increased energy expenditure due to increased thermogenesis in brown adipose tissue (BAT), we measured GDP binding to mitochondria from interscapular brown adipose tissue (BAT) in db/db and ob/ob mice and their lean controls after adrenalectomy, with and without corticosterone replacement. Both the vehicle treated and corticosterone treated db/db and ob/ob mice had lower body weights than the sham-operated mice GDP binding to mitochondria from IBAT was significantly lower in both the db/db and ob/ob mice than in their lean controls. Adrenalectomy significantly increased GDP binding in all mice compared to the respective sham-operated mice, but, the percentage increase was always greater in the db/db and ob/ob mice. Corticosterone treatment of adrenalectomized db/db, ob/ob or lean mice lowered GDP binding to sham levels. Our data confirm previous findings that adrenalectomy results in increased GDP binding to mitochondria from IBAT. Injections of corticosterone into adrenalectomized mice results in a decrease in GDP binding to values which are similar to values in sham-operated mice. Thus adrenalectomy may inhibit the development of obesity by increasing the thermic activity in IBAT.

Adipose Tissue↗

PubMed1989

Adrenalectomy and response to corticosterone and MSH in the genetically obese yellow mouse.

Animals with the viable yellow (Avy/a) gene and their corresponding lean control black mice (a/a) were adrenalectomized or sham adrenalectomized, and changes in body weight, body composition, corticosterone, and GDP-binding to mitochondria isolated from interscapular brown adipose tissue (IBAT) were measured. Adrenalectomy slowed the weight gain of both the yellow obese mice and the black lean mice, but the reduction was greater in the yellow mice. Food intake was significantly reduced in the yellow mice. Adrenalectomy in the yellow mouse was associated with an increase in lean mass and a significant decrease in weights of fat depots. Blood glucose concentrations of the adrenalectomized yellow mice were reduced to levels similar to those of lean mice, but insulin levels, although lower than sham-adrenalectomized yellow mice, remained significantly higher than in lean animals. GDP binding to IBAT mitochondria increased after adrenalectomy in both phenotypes to values that were similar. Corticosterone replacement in adrenalectomized yellow mice produced a dose-dependent increase in body weight that was associated with a decrease in muscle weight and an increase in adipose tissue weight. Both desacetyl-melanocyte-stimulating hormone (MSH) and alpha-MSH interacted with corticosterone to increase body weight gain of adrenalectomized yellow mice. Desacetyl-MSH was more effective than alpha-MSH on increasing adipose tissue and liver weights. The effects of desacetyl-MSH on food intake, weight gain, and tissue weights were independent of the adrenal gland or of corticosterone.

Adipose Tissue, Brown↗

PubMed1989

Effects of intraventricular infusion of corticotropin-releasing factor on VMH-lesioned obese rats.

Corticotropin-releasing factor (CRF) has been administered into the third ventricle of sham-operated and ventromedial hypothalamic (VMH)-lesioned rats in acute and chronic experiments. After a single 5-microgram injection of CRF, there was an acute reduction of food intake in both sham-operated and VMH-lesioned rats that persisted for 3 h. The effect was still present in the VMH-lesioned rats between 3 and 6 h but had dissipated in the sham-operated controls. Guanosine 5'-diphosphate (GDP) binding to mitochondria from interscapular brown adipose tissue was used as an index of thermogenic activity in this tissue. In 21-h food-deprived rats, GDP binding was significantly lower in VMH-lesioned than in sham-operated animals. Although the mean increase in sham-operated animals was increased, this was not significantly different from saline-injected controls. In the VMH-lesioned rats, however, CRF acutely increased GDP binding to values not different than those of the sham-operated controls. Serum corticosterone was significantly lower in the VMH-lesioned rats, but both groups showed a significant stimulation by CRF during a 7-day infusion of CRF (4.8 micrograms/day) into the third ventricle. Food intake was significantly depressed in the VMH-lesioned animals that received CRF, from values of 35 g/day to approximately 25 g/day. Body weight showed a slow steady decrease, having fallen by nearly 15 g at the end of the 7-day infusion period. In contrast the mean value in the VMH-lesioned controls had significantly higher in CRF-infused animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗

PubMed1989

Effects of dexamethasone on glucose transport by skeletal muscles of obese (ob/ob) mice.

Adrenalectomy normalized basal and insulin-stimulated glucose transport in the perfused hindquarter of the obese (ob/ob) mouse. Dexamethasone treatment of adrenalectomized obese mice for 9 days significantly reduced both the basal and insulin-stimulated uptake of (3H)-2-deoxy-D-glucose in hindlimbs of adrenalectomized mice to levels similar to those of intact ob/ob mice. Five hours after injection of dexamethasone in vivo and following 5 hours of perfusion in vitro there was a 10 percent reduction in basal 2-deoxy-D-glucose uptake in both groups. In muscles perfused with dexamethasone in vitro, the stimulation of 2-deoxy-D-glucose uptake by insulin was greater than in those muscles perfused with vehicle alone. Five hours of treatment in vivo also resulted in a significant increase in liver tyrosine aminotransferase activity, and a decrease in muscle glycogen synthetase activity ratio. These data suggest that the effect of glucocorticoids on lowering glucose transport in the skeletal muscle of obese ob/ob mice is a direct one.

Adrenalectomy↗

PubMed1988

Regulation of glycogen synthase in muscle and adipose tissue during fasting and refeeding.

Using immunoblot analysis, we examined the electrophoretic mobility of glycogen synthase from rat skeletal muscle and adipose tissue. Extracts from muscle freeze clamped in situ contained at least three forms of synthase with different electrophoretic mobilities. Extracts from adipose tissue also contained multiple forms but lacked the form with greatest mobility found in the muscle extracts. Phosphorylation at multiple sites of glycogen synthase is known to deactivate the enzyme and retard its electrophoretic mobility in sodium dodecyl sulfate gels. These results suggest that there is very little or no dephosphorylated glycogen synthase in adipose tissue and that phosphorylated forms of glycogen synthase synthesize adipose tissue glycogen. Relative to control, it is known that fasting decreases and refeeding increases glucose incorporation into glycogen in rat epididymal adipose tissue but not skeletal muscle incubated in vitro in the presence of insulin. Fasting did not change the electrophoretic pattern of muscle synthase but decreased the relative amount of adipose tissue forms with greater mobility. Refeeding increased above control the relative amount of adipose tissue synthase with greater mobility. These results indicate that changes in the phosphorylations that retard mobility contribute to the effects of fasting and refeeding on adipose tissue glycogen metabolism.

Adipose Tissue↗

PubMed1988

Intracerebroventricular infusions of 3-OHB and insulin in a rat model of dietary obesity.

We examined the effect of dietary fat on the response to 3-hydroxybutyrate (3-OHB) and insulin infused chronically into the third ventricle in three strains of rats with differing susceptibility to obesity induced by a high-fat diet: Osborne-Mendel rats are most susceptible; Sprague-Dawley-rats are intermediate; and S 5B/Pl rats are most resistant. Ten days after implantation of cannulas into the third ventricle, rats were fed either a low-fat diet or a high-fat diet for 14 days. On day 7, osmotic minipumps were attached to the ventricular cannulas. 3-OHB infusions (3.6 mumol/24 h) reduced food intake and body weight in Sprague-Dawley and Osborne-Mendel rats eating either diet. The dietary fat-resistant S 5B/Pl rats did not respond to the intracerebroventricular infusion of 3-OHB. The infusion of insulin (10 mU/24 h) lowered food intake and body weight in animals eating the low-fat (high-carbohydrate) diet but not in animals eating the high-fat diet. Diet profoundly affects the response to intracerebroventricular infusions of insulin but is without effect on the response to 3-OHB.

3-Hydroxybutyric Acid↗

PubMed1987

Normal levels of serum corticosterone and hepatic glucocorticoid receptors in obese (fa/fa) rats.

In an attempt to understand the hyper-responsiveness to glucocorticoids that is characteristic of genetically obese fa/fa rats, we have measured the levels of free corticosterone in serum from lean and obese rats as well as the number of "cytosolic" and "nuclear" binding sites in livers of these rats. Both the lean and obese rats had similar amounts of free corticosterone available for biological activity at 4 weeks and 10 weeks of age. Measurement of glucocorticoid binding to hepatic glucocorticoid receptors failed to show any differences between genotypes leading to the suggestion that the abnormal glucocorticoid response in obese rats may be due either to post-receptor defects or to a permissive action of the steroid in the expression of the fa/fa genotype.

Adrenalectomy↗

PubMed1987

Reproductive defects in the male diabetic athymic nude mouse.

We have previously reported spontaneous hyperglycemia and impaired glucose tolerance in male athymic nude Balb/c mice. This colony also demonstrates impaired fertility. Previous studies in both athymic nude and diabetic obese (ob/ob) mice have shown reproductive abnormalities. It was the purpose of this investigation to further elucidate the endocrine abnormalities which might contribute to the reduced fertility observed in this model. Fasting plasma glucose was measured on each nude mouse to ensure that a diabetic state existed. Testes were removed and intratesticular testosterone and LH receptors were measured. Testosterone levels in diabetic, athymic nude Balb/c (DAN) mice were significantly decreased to 46.5% of control Balb/c mice. LH receptors in DAN mice were significantly elevated by 23.6% when compared to control animals. These results demonstrate that the impaired fertility observed in the DAN mouse may result from decreased testosterone production. The increased LH receptor levels seen in the DAN mouse might reflect a regulatory event in response to the decreased intratesticular testosterone levels.

Animals↗

PubMed1986

Stimulation of tyrosine-specific protein phosphorylation in the rat liver plasma membrane by oxygen radicals.

Incorporation of 32P from [gamma-32P]ATP into endogenous proteins, added histone and the copolymers Glu 80 Tyr 20 by rat liver plasma membranes was markedly increased by several naphthoquinones, including menadione. This stimulation was most marked with Glu 80 Tyr 20, has an absolute requirement for either dithiothreitol or reduced glutathione, and was inhibited by superoxide dismutase, catalase, and desferrioxamine to varying degrees depending on the quinones used. Their effectiveness in stimulating the apparent tyrosine-specific protein phosphorylation correlated with the rates of DTT-dependent redox cycling measured by oxygen consumption. Increased protein phosphorylation was also seen with particulate fractions isolated from hepatocytes incubated with quinones. A free radical-mediated mechanism is suggested for the quinone stimulation of protein phosphorylation.

Adenosine Triphosphate↗

PubMed1986

Impaired insulin receptor phosphorylation in skeletal muscle membranes of db/db mice: the use of a novel skeletal muscle plasma membrane preparation to compare insulin binding and stimulation of receptor phosphorylation.

A method has been developed to isolate skeletal muscle plasma membranes from mice in good yield without harsh extraction procedures. The method involves perfusion of mouse hindquarters with a calcium-deficient buffer containing collagenase and hyaluronidase. This is followed by gentle disruption, filtration, and differential centrifugations. The entire procedure takes about six hours and the yield is approximately 4 mg. protein from 10 g. equivalent of hindquarter muscle. The preparation contained predominantly plasma membranes based on specific activities of marker enzymes, electron microscopic data, and specific binding sites for insulin and a -adrenergic ligand. Studies using such preparations from lean, 4-5 week old and 12-20 week old db/db mice showed marked reduction in the phosphorylation of the 95 kDa subunit of the insulin receptor of the obese mice with no change in insulin binding. In addition, there was a progressive reduction in insulin sensitivity in stimulating receptor phosphorylation in the db/db mice.

Animals↗