Glutathione deficiency and HIV infection.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
D W Wilmore
Publications and source records attributed to D W Wilmore.
Hyperphospholipasemia A2 in human volunteers challenged with intravenous endotoxin.
Phospholipase A2 (PLA2) activity was measured in the serum of 23 individuals infused intravenously with endotoxin (EN) at a dose of 4 ng/kg body weight. A marked increase in PLA2 was noted 3 h after EN challenge (mean 828 +/- 513 units/ml), reached its maximum at 24 h after the challenge (mean 2667 +/- 2442 units/ml), and was still evident at 48 h (mean 763 +/- 366 units/ml). In contrast, TNF levels were maximal (mean 712 +/- 375 pg/ml) 90 min after the EN challenge and subsided to very low values (5 +/- 5 pg/ml) 5 h after the challenge. There was a positive correlation between the maximum response of TNF and that of PLA2 (r = 0.82, P < 0.01). Administration of ibuprofen or pentoxifylline did not alter the PLA2 response. EN challenge did not affect serum pancreatic PLA2 concentration or that of the lysosomal cationic enzyme, lysozyme. Neutralizing antibody against human recombinant (synovial type) PLA2 completely abolished PLA2 activity in the sera tested. We conclude that EN infusions cause marked intravascular release of nonpancreatic secretory PLA2 and that the magnitude of this response seems to be related to the prior generation of TNF.
Endotoxins↗
Glutamine preserves liver glutathione after lethal hepatic injury.
Glutathione (GSH) is a major antioxidant that protects tissues from free radical injury. Glutamine augments host defenses and may be important in GSH synthesis. Acetaminophen toxicity causes hepatic GSH depletion and hepatic necrosis. The authors hypothesized that glutamine-supplemented nutrition would enhance liver GSH stores and diminish hepatic injury and death after acetaminophen overdose. Wistar rats received either a standard total parenteral nutrition (TPN) solution (STD) or an isocaloric, isonitrogenous glutamine-supplemented solution (GLN). On the 5th day of feeding, animals were given acetaminophen (400 mg/kg intraperitoneally) and then killed at various time points. Standard TPN solution animals had a rapid depletion of hepatic glutathione, whereas GLN animals were resistant to this drop and rapidly repleted hepatic GSH stores. Glutamine-supplemented animals maintained higher plasma glutamine concentrations, had lesser elevations in hepatic enzymes, and sustained significantly fewer complications compared with STD animals. The authors conclude that glutamine-supplemented nutrition preserves hepatic glutathione, protects the liver, and improves survival during acetaminophen toxicity. Glutamine may augment host defenses by enhancing antioxidant protection.
Acetaminophen↗
Identifying body fluid distribution by measuring electrical impedance.
The effects of critical illness on extracellular water (ECW) and total body water (TBW) were measured using (1) a multiple dilutional technique, and (2) whole body and regional bioelectrical impedance analysis (BIA) in a group of stable patients. Total body water and body resistance (R) were similar in patients when compared with normal healthy subjects (TBW: 45.1 +/- 4.5 vs. 46.2 +/- 3.4 L, p = 0.85; R: 518 +/- 42 vs. 500 +/- 22 omega, p = 0.70), and a significant relationship was present between these measurements (r = -0.87, p < 0.001). However, patients demonstrated an increase in ECW compared with controls (ECW: 18.6 +/- 1.3 vs. 14.7 +/- 1.1 L, p < 0.05). Expanded ECW values were associated with diminished electrical reactance (Xc) values (38 +/- 6 vs. 70 +/- 4 omega, p < 0.001) and these values were correlated (r = -0.67, p < 0.005). The ratio of Xc to R determined across the body and each of the segments was significantly lower in patients compared with controls (at least p < 0.005) and this ratio measured across a leg was the most sensitive predictor of health (Xc/R > or = 0.137) and disease (Xc/R < or = 0.101). Bioelectrical impedance analysis is a noninvasive and simple bedside technique that can be used to predict TBW and identify altered fluid distribution following critical illness.
Adult↗
The effect of insulin-induced hypoglycemia on gene expression in the hypothalamic-pituitary-adrenal axis of the rat.
This study has examined the effects of insulin-induced hypoglycemia on expression of the CRH, arginine vasopressin, and POMC genes and corresponding peptides in freely moving, unanesthetized, male Sprague-Dawley rats. Animals were infused with 150 mM NaCl for 3 days before the experimental day and were then administered insulin (4 U/kg) or saline iv. In one experiment animals were killed 0, 30, 60, or 90 min after insulin or saline, and RNA was isolated from anterior pituitary, cerebral cortex, and punches of the hypothalamic paraventricular and supraoptic nuclei. In a second experiment, animals were killed 90 min after insulin or saline treatment, and RNA was isolated from whole hypothalami. RNA was analyzed by Northern blot. Plasma glucose fell from 106 +/- 5 to 38 +/- 2 mg/dl after insulin administration and remained low for the duration of the experiment. Plasma levels of ACTH, corticosterone, and vasopressin were 10-, 6-, and 4-fold higher, respectively, in the insulin-treated vs. control animals (by analysis of variance, P less than 0.0001 in all cases), while plasma CRH was unchanged. During hypoglycemia POMC mRNA levels were 1.8-fold higher in the insulin-treated group (by analysis of variance, P less than 0.025). In contrast, paraventricular nucleus, whole hypothalamic, and parietal cortex CRH mRNA and vasopressin mRNA were unchanged. These data support previous studies which indicated that POMC gene expression is increased by hypoglycemia. However, we found no evidence for an increase in paraventricular nucleus or cerebral cortex CRH mRNA expression during hypoglycemia-associated stimulation of the hypothalamic-pituitary-adrenal axis, suggesting that another factor(s) may mediate the observed increase in POMC gene expression.
Adrenocorticotropic Hormone↗
Recombinant human growth hormone enhances the metabolic efficacy of parenteral nutrition: a double-blind, randomized controlled study.
This multicenter, randomized, double-blind study was performed to investigate whether recombinant GH improves the efficacy of total parenteral nutrition (TPN). Fifteen stable patients requiring parenteral feeding due to gastrointestinal/pancreatic disease were studied. Constant maintenance TPN providing approximately 30 kcal/kg day and approximately 1.6 g protein/kg.day was administered during an initial 7-day baseline period. After randomization, daily sc injections of saline (control, n = 9) or GH (10 mg/day, n = 6) were administered a 14-day treatment period as nutrient intake remained constant. Elemental balances for nitrogen (N), potassium (K), phosphorus (P), and sodium (Na) were determined daily and serial blood indices, vital signs, and other clinical parameters were monitored. Nutrient balances approached equilibrium during the baseline week in both groups. With GH administration, a significant increase in N, K, and P balance occurred; in contrast, nutrient balances did not change significantly from baseline values in control patients. The cumulative change (delta) in nutrient balances from the baseline week was also significantly greater in the GH-treated patients (delta N: control+2 +/- 7 g vs. GH+36 +/- 6. g, P less than 0.005; delta K:+57 +/- 45 mmol vs.+199 +/- 19 mmol, P less than 0.03; delta P: -27 +/- 30 mmol vs. +91 +/- 69 mmol, P less than 0.02). Plasma insulin-like growth factor-I concentrations rose 5-fold and serum cholesterol rose slightly with GH; no other significant change in group mean blood values occurred. One patient receiving GH and chronic prednisone therapy developed moderate hyperglycemia and mild peripheral edema; no other deleterious effects attributable to GH were observed. GH was well tolerated and significantly enhanced nutrient retention compared to standard parenteral feeding alone. GH improves the efficacy of parenteral nutrient utilization in patients requiring TPN.
Adolescent↗
O-side chain of Escherichia coli endotoxin 0111:B4 is transported across the intestinal epithelium in the rat: evidence for increased transport during total parenteral nutrition.
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Animals↗
Glutathione deficiency increases organ dysfunction after hemorrhagic shock.
BACKGROUND: Reactive oxygen metabolites contribute to tissue destruction in a wide variety of diseases. Glutathione, a potent endogenous antioxidant, neutralizes the destructive potential of free radicals, but this tripeptide may be depleted during illness. We hypothesized that glutathione deficiency would amplify organ dysfunction after shock in rats. METHODS: Rats received either diethyl maleate to deplete tissue glutathione or a control solution intraperitoneally. The animals were subsequently bled to and maintained at a mean arterial pressure of 40 mm Hg for 30 minutes and then fully resuscitated. Sham animals underwent blood pressure monitoring only. Tissue glutathione, liver and renal function tests, organ bacterial content, and mortality rates were determined 4 and 24 hours after shock. RESULTS: Normal rats subjected to shock and sham animals had similar laboratory chemistry results, organ culture results, and mortality rates. However, glutathione-depleted animals subjected to shock had elevated liver and renal function tests, increased organ bacteria, and a dramatic increase in mortality rates compared with control shock and sham animals. CONCLUSIONS: We conclude that glutathione deficiency predisposes animals to organ failure and death after an otherwise nonlethal period of hypotension. Because glutathione deficiency is associated with severe injury and sepsis, treatment strategies that maintain glutathione stores may decrease the incidence of multisystem organ failure.
Animals↗
Growth hormone attenuates the abnormal distribution of body water in critically ill surgical patients.
BACKGROUND: Catabolic illness is associated with fluid retention and extracellular space expansion. To determine the effect of human growth hormone (GH) on body water compartments, critically ill surgical patients were studied for a 2-week period during which they either continued to receive standard intensive care unit support, or in addition, received GH, 10 mg/day. METHODS: Body water compartments were measured at the beginning and end of the period by the indicator dilution technique with sodium bromide and heavy water used as the indicators of extracellular (ECW) and total body water (TBW), respectively; intracellular water (ICW) was calculated by subtraction. RESULTS: Neither group lost significant amounts of weight or TBW. A marked ECW expansion and disturbance of the ECW/TBW ratio occurred in the patients receiving standard care, which was associated with a dramatic reduction in ICW, a critical component of the body cell mass (BCM). In contrast, GH-treated patients maintained ECW and ICW, indicating a preservation of BCM, and their ECW/TBW ratio normalized. CONCLUSIONS: GH administration prevents ECW retention and stabilizes or normalizes fluid distribution during critical illness. Taken together with its known anabolic effects under these conditions, the maintenance of ICW demonstrates that GH can be used to preserve BCM in complex surgical patients.
Body Water↗
Production of interleukin-1-receptor antagonist during experimental endotoxaemia.
Interleukin-1 (IL-1) has been implicated in the pathogenesis of sepsis. IL-1-receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 activity that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We induced endotoxaemia in 9 healthy human volunteers by injection of Escherichia coli endotoxin, and measured plasma concentrations of IL-1 and IL-1ra by radioimmunoassay during the next 24 h. Peak plasma concentrations of IL-1ra were about a hundred-fold greater than those of IL-1 beta. No IL-1 or IL-1ra were detectable in the plasma of 4 volunteers injected with saline. Our results suggest that the predominant natural response to endotoxin in man is the production of antagonist rather than agonist.
Adolescent↗
Catabolic illness. Strategies for enhancing recovery.
After injury, infection, extensive chemotherapy, and other critical illnesses, both protein and fat are lost from the body. Although minor alterations in body composition are probably of little clinical importance, losses of body protein of 10 percent or more contribute to morbidity and debility. This catabolic response can be modified and recovery can be accelerated by a variety of approaches. First, the inflammatory response can be reduced; second, specific nutrients can be provided to support the patient's tissue requirements during catabolic illness; and third, growth factors can be used to enhance protein synthesis and tissue repair. These approaches, whether used alone or in combination, will reduce the loss of body protein, which should accelerate recovery, shorten the length of hospitalization, and reduce convalescence.
Adipose Tissue↗
Tumour necrosis factor increases hepatic cell mass.
The effect of tumour necrosis factor (TNF) on hepatic cellularity was investigated in male Wistar rats maintained on total parenteral nutrition. Twenty-eight rats were infused with TNF (2 x 10(5) units TNF-alpha kg-1 24 h-1) or saline (controls) for 6 days. Wet and dry liver weights and nitrogen content were significantly increased by TNF (P less than 0.001), indicating an increase in liver mass. A further 81 rats were infused with TNF (2 or 4 x 10(5) units kg-1 24 h-1) or saline over 1, 3 and 6 days. Total liver DNA and protein content and counts of hepatocyte mitosis were determined. Liver DNA and protein increased with dose of TNF and time (P less than 0.001), suggesting that TNF increased hepatic cellularity. Histological examination demonstrated no significant inflammatory infiltrate to account for the increased cell mass. However, the number of hepatocyte mitoses increased with dose of TNF and time (P less than 0.05), indicating that the increase in liver cellularity was due to increased hepatocyte cell number. TNF-induced hepatic hyperplasia appears to be an additional feature of the integrated host response to injury and infection.
Animals↗
Alterations in body fluid content can be detected by bioelectrical impedance analysis.
The electrical resistance across the whole body and its segments to the conduction of a weak alternating current was determined in human subjects under three different conditions: (1) during bed rest, (2) during infusion of 1 liter of saline, and (3) during donation of 1 unit of blood. During bed rest, extracellular and total body water were measured by dilution of bromide and heavy water, respectively. Electrical resistance obtained from electrodes placed on proximal portions of extremities ("proximal resistance") accounted for less than 50% of that determined by electrodes positioned on routinely used portions of a hand and foot ("whole body resistance"). Following saline infusion, resistance determined from the whole body and all its segments fell (P less than 0.001); the magnitude of the drop in both proximal and whole body resistance was inversely related to the volume of total body water (TBW) (r = -0.82, P less than 0.002, and r = -0.73, P less than 0.01, respectively). In contrast, blood donation was associated with significantly increased resistance at both measurement sites. TBW predicted from anthropometrics was inversely related to both proximal (r = -0.90, P less than 0.001) and whole body resistance (r = -0.75, P less than 0.001). Bioelectrical impedance analysis is a simple technique which may be useful in monitoring minimal alterations in TBW. Furthermore, altered fluid status may be predicted more accurately by changes in proximal resistance compared to changes in traditionally used whole body resistance.
Bed Rest↗
Insulin-like growth factor-I response is comparable following intravenous and subcutaneous administration of growth hormone.
Subcutaneous (sq) administration of recombinant human growth hormone (r-hgh) has an anabolic effect and increases systemic insulin-like growth factor (IGF-I) in surgical patients. IGF-I is a mediator of growth hormone (gh) anabolic effects. To determine the effect of intravenous (iv) administration of r-hgh on systemic IGF-I, 11 patients were given 14 1-week courses of daily 8-hr infusions of r-hgh (10 mg in 500 ml D5W). Serum gh and IGF-I levels were measured. To compare routes of administration, iv r-hgh patients were matched to comparable sq r-hgh patients and IGF-I responses were examined. Illness severity effect on IGF-I response to r-hgh was assessed by dividing 16 burn patients who received either iv or sq r-hgh into two groups on the basis of severity scores. Analysis of the data showed that IGF-I levels increased significantly after iv r-hgh, IGF-I response to iv r-hgh (1.14 +/- 0.18 U/ml to 4.12 +/- 0.65 U/ml) was not different from IGF-I response to sq r-hgh (1.04 +/- 0.36 U/ml to 4.96 +/- 1.09 U/ml). Increasing illness severity attenuated the IGF-I response in the more severely injured group (0.91 +/- 17 U/ml to 2.40 +/- 0.38 U/ml) relative to the less severely injured group (1.37 +/- 0.22 U/ml to 5.53 +/- 0.78 U/ml) despite a significant increase in IGF-I after gh in both groups. In summary, IGF-I increased significantly after iv r-hgh and the increases were similar to those seen after sq r-hgh in comparable patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Glutamine-enriched intravenous feedings attenuate extracellular fluid expansion after a standard stress.
A double-blind, randomized controlled trial was performed to determine the effect of glutamine (GLN)-enriched intravenous feedings on the volume and distribution of body fluids in catabolic patients. Subjects with hematologic malignancies in remission underwent a standard treatment of high-dose chemotherapy and total body irradiation before bone marrow transplantation. After completion of this regimen, they were randomized to receive either standard parenteral nutrition (STD, n = 10) or an isocaloric, isonitrogenous nutrient solution enriched with crystalline L-glutamine (0.57 g/kg/day, GLN, n = 10). Extracellular water (ECW) and total body water (TBW), determined by bromide and heavy water dilution techniques, were measured before the conditioning treatment and after termination of the intravenous feedings that were administered for 27 +/- 1 days. In addition electrical resistance (R, in ohms, omega) and reactance (Xc, omega) of the body to a weak alternating current were measured at these time points. Both study groups were comparable for age, weight, height, sex, and diagnosis. Initial TBW was highly related to electrical resistance (r = -0.93, p less than 0.001). After conditioning therapy, bone marrow infusion, and intravenous feedings, a 20% expansion in ECW was observed in the STD group (ECW: 18.0 +/- 1.1 L vs. 14.9 +/- 1.0, p = 0.012), and this fluid retention was associated with a marked decrease in electrical resistance (R: 514 +/- 28 omega vs. 558 +/- 26, p less than 0.05). In contrast the extracellular fluid compartment in patients receiving GLN-supplementation did not change (ECW: 15.8 +/- 0.9 L vs. 15.4 +/- 0.8, p = 0.49), and the body's resistance was maintained (R: 552 +/- 27 omega vs. 565 +/- 23, p = 0.42). Expansion of ECW could not be related to differences in fluid or sodium intake, or to the use of diuretics or steroids. Patients receiving the STD solution, however, exhibited a greater number of positive microbial cultures (p less than 0.01) and a higher rate of clinical infection compared with the GLN patients (5/10 vs. 0/10, p less than 0.05); the fluid expansion in infected STD patients was greater compared with uninfected individuals (delta ECW: + 5.0 +/- 1.4 vs. 0.7 +/- 0.5, p = 0.007). In this model of catabolic stress, fluid retention and expansion of the extracellular fluid compartment commonly observed after standard total parenteral nutrition can be attenuated by administering glutamine-supplemented intravenous feedings, possibly by protecting the host from microbial invasion and associated infection.
Adult↗
Effects of growth hormone administration on dehydroepiandrosterone sulphate, androstenedione, testosterone and cortisol metabolism during nutritional repletion.
This study evaluated whether pharmacological doses of recombinant human growth hormone (hGH) influences androgen or cortisol metabolism during nutritional repletion following prolonged illness. Stable hospitalized adults (three males, seven female) receiving constant calorie and protein intake were studied. An initial control week was followed by a treatment period during which hGH (10 mg/day s.c.) was administered daily. Prior to hGH treatment, serum and 24-h urinary concentrations of dehydroepiandrosterone sulphate (DS) were below the normal range; serum androstenedione and testosterone concentrations were within the lower limit of normal. In contrast, serum cortisol (F) and 24-h urinary F excretion were normal. During hGH treatment, nitrogen balance became positive and plasma insulin-like growth factor I (IGF-I) concentrations rose five to seven-fold. However, serum DS, androstenedione, testosterone and F, and urinary F excretion did not change, while 24-h urinary DS excretion fell significantly. Growth hormone administration markedly stimulated protein anabolism but did not increase the low concentrations of circulating androgens or alter the disassociation between adrenal androgen and F release in stable hospitalized males and females. Thus, hGH does not appear to function as a cortical adrenal androgen stimulating hormone (CASH) or regulate adrenal cortisol or gonadal androgen release in this clinical setting.
Adrenal Cortex↗
Impedance electrodes positioned on proximal portions of limbs quantify fluid compartments in dogs.
Body resistance and reactance to the conduction of an alternating electrical current were measured using electrodes attached to distal and proximal portions of limbs in anesthetized dogs. Body impedance was calculated from these measurements obtained at 30-min time intervals during a control period and after intravenous administration of 0.9% saline. Extracellular (ECW) and total body water (TBW) were determined by bromide and heavy water dilution techniques, respectively. Baseline impedance obtained from proximal electrodes was related to ECW (r = 0.95, P less than 0.001) and TBW (r = 0.80, P less than 0.02). After saline infusion, proximal electrodes detected a significant fall in impedance (P less than 0.001), whereas distal electrodes did not (P = 0.06). Furthermore, ECW and TBW could be estimated from the drop of proximal impedance after this bolus infusion (r = 0.82, P less than 0.02, and r = 0.86, P less than 0.01, respectively), but not from distal impedance measurements. Proximally placed impedance electrodes are superior to traditionally used distal electrodes for assessment of body fluid changes in the dog.
Animals↗
Effects of recombinant human growth hormone in adults receiving maintenance hemodialysis.
Administration of recombinant human growth hormone stimulates protein synthesis, decreases urea generation, and improves nitrogen balance in individuals with normal renal function. However, little information is available concerning the effects of growth hormone in patients with renal disease. This pilot study evaluated urea kinetics and clinical/metabolic responses to short-term growth hormone administration in five clinically stable adult patients requiring maintenance hemodialysis for end-stage renal failure. The dialysis prescription, medications, and oral calorie and protein intake of each patient remained constant during an initial control week and a subsequent 2-wk growth hormone treatment period. During treatment, growth hormone (5 or 10 mg) was administered s.c. immediately after each dialysis session. Protein and calorie intake, vital signs, body weight, and other clinical parameters remained stable throughout the 3-wk study. BUN values fell significantly (approximately 20 to 25%) during growth hormone administration compared with control week values. Similarly, urea kinetic modeling demonstrated a significant reduction in urea generation and the protein catabolic rate during each week of growth hormone treatment. Plasma insulin-like growth factor I levels rose significantly, and serum phosphorus and intact parathyroid hormone levels fell significantly during growth hormone administration. Serum glucose and other blood values remained stable. This preliminary study suggests that growth hormone administration reduces urea generation and improves the efficiency of dietary protein utilization in stable adult hemodialysis patients. Growth hormone may be a useful adjunctive therapy to diminish body protein catabolism in this patient population.
Adult↗