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Biomedical subjects

D O Jacobs

Publications and source records attributed to D O Jacobs.

At least 19 recordsLinked to original sources
PubMed1996

Glucocorticoid receptor antagonism by mifepristone alters phosphocreatine breakdown during sepsis.

OBJECTIVE: To determine the role of glucocorticoids in the regulation of myocellular energetics induced by sepsis by means of the glucocorticoid receptor antagonist mifepristone (RU 38486). DESIGN: Randomized controlled study. SETTING: University laboratories. PARTICIPANTS: Thirty-two adult male Wistar rats. METHODS: Animals were randomly assigned to 1 of 4 groups. In 2 groups, mifepristone (10 mg/kg) was administered by gavage feeding 2 hours before cecal ligation and single 18-gauge needle puncture or sham operation. The other 2 groups of animals received placebo gavage feedings 2 hours before their surgical procedures. Twenty-four hours after operation, high-energy phosphate ratios, intracellular pH, the forward rate constant for the creatine kinase reaction, and phosphocreatine breakdown rates were measured in the gastrocnemius muscle by in vivo phosphorus 31 magnetic resonance spectroscopy. Tissue and blood samples were collected to measure creatine and adenosine 5'-triphosphate concentrations, Na(+)-K+ adenosine triphosphatase activity, and circulating corticosterone levels. RESULTS: Circulating corticosterone levels were twice as high in septic animals as in sham-operation control rats (P < .01). Phosphocreatine breakdown rates and Na(+)-K+ adenosine triphosphatase activity were significantly higher (40% and 75%, respectively; P < .01) in placebo-treated septic rats than in sham-operation control rats. However, phosphocreatine breakdown rates and Na(+)-K+ adenosine triphosphatase activity in mifepristone-treated septic animals were not significantly elevated above control levels. CONCLUSION: Pretreatment with mifepristone reduces the demand for adenosine triphosphate production from phosphocreatine breakdown and downregulates Na(+)-K+ adenosine triphosphatase activity during sepsis.

Adenosine Triphosphate↗
PubMed1996

Use of bioelectrical impedance analysis measurements in the clinical management of critical illness.

I review the utility of bioelectrical impedance analysis (BIA) for assessing changes in body composition and content and distribution of body water in critically ill patients. Published studies suggest that resistance measurements provide a reasonable estimate of total body water but that the precision of the measurements is poor. Presently, BIA does not appear to be a useful clinical technique for measuring changes in body composition. Despite the limitations of current technology, the utility and efficacy of BIA merit evaluation in large, longitudinal studies if our understanding of the meaning of changes in the electrical properties of the body is to improve.

Body Composition↗
PubMed1995

The duration of infection modifies mitochondrial oxidative capacity in rat skeletal muscle.

Sepsis increases phosphocreatine (PCr) breakdown and reduces PCr stores in skeletal muscle. To determine if systemic infection impairs mitochondrial function, in vivo 13P magnetic resonance spectroscopy (31P MRS) studies of the gastrocnemius muscle were performed in virus-free male Wistar rats 24 or 48 hr after cecal ligation and 18-gauge needle single puncture (24 degrees CLP, n = 16; 48 degrees CLP, n = 15) or sham operation (24 degrees SHAM, n = 18; 48 degrees SHAM, n = 13). Physiologic saline (6 ml/100 g body wt) was injected intraperitoneally for fluid resuscitation. Water but no food was allowed in all animals. High resolution (8.45 Tesla) 31P MRS spectra, obtained at rest and during exercise using a 1.4-cm surface coil, were used to calculate PCr/ATP, PCr/P(i) ratios, and intracellular pH. Steady-state muscle exercise was induced by supramaximal sciatic nerve stimulation at 10 Hz for 10 min. Recovery of PCr/(PCr + P(i)) ratios after exercise was fitted to a monoexponential curve. The resultant function was used to calculate the half time for PCr recovery, the initial PCr resynthesis rate, and the maximal oxidative ATP synthesis rate, which reflect the rephosphorylation of ADP and are therefore measures of mitochondrial oxidative capacity. PCr/ATP ratios decreased by 12 and 11%, 24 and 48 hr after CLP, respectively. The PCr/P(i) ratios decreased incrementally (7% in 24 degrees CLP vs 23% in 48 degrees CLP animals). Twenty-four hours after operation the half time for PCr recovery was shortened while the initial PCr resynthesis rate and maximal oxidative ATP synthesis rate were accelerated in CLP animals compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1994

31P magnetic resonance spectroscopy demonstrates expansion of the extracellular space in the skeletal muscle of starved rats.

Starvation significantly alters the distribution of body water. To study the effects of starvation on cellular energetics and water distribution in skeletal muscle, a novel 31P magnetic resonance technique (31P MRS) was developed to measure water compartments. After 31P MRS-visible water space markers which distribute in total body water (dimethyl methylphosphonate, DMMP) and extracellular water (phenylphosphonate, PPA) were infused intravenously, 31P MRS spectra were obtained from the gastrocnemius muscle of male virus-free Wistar rats at baseline and after starvation or ad libitum feeding for 4 days. Muscle water spaces were also measured using the chloride method and Nernst's equation. Muscle water contents as determined by drying were equivalent in the two groups. In vivo measurements of changes in DMMP relative to all of the MRS visible phosphates also demonstrated that the total water space was similar in control and starved rats. However, starvation significantly increased the ratio of PPA/DMMP (0.67 +/- 0.05 vs 0.87 +/- 0.04, Control vs Starvation; P < 0.001), and therefore the ratio of extracellular water to total water in the gastrocnemius. Furthermore, because muscle water contents were comparable between the groups, this expansion of the extracellular space was accompanied by contraction of the intracellular compartment in starved animals. Equivalent changes were detected in vitro using the chloride method. Lastly, phosphocreatine/ATP ratios, which measured changes in high-energy phosphate stores, decreased after starvation (4.09 +/- 0.06 vs 3.61 +/- 0.06; P < 0.001) and were inversely related to changes in PPA/DMMP (r = -0.61; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1994

Does the route of feeding modify the inflammatory response?

OBJECTIVE: The authors compared the responses to endotoxin in enterally and parenterally fed human volunteers. BACKGROUND: Recent investigations have reported that the response to endotoxin in humans is greater in individuals who receive parenteral nutrition rather than enteral feeding. It was proposed that this difference was related to gut barrier dysfunction during intravenous nutrition. To evaluate this hypothesis, the authors analyzed the responses of human subjects to an intravenously administered bolus of endotoxin after enteral or parenteral nutrition. METHODS: Fifteen randomly selected healthy volunteers were studied during two separate investigations; ten studies were performed in ten subjects who received enteral nutrition, and nine studies were carried out in five additional subjects who received parenteral nutrition. After 2 days of enteral feedings or 7 days of parenteral feedings, endotoxin was administered by intravenous injection; temperature, symptom score, and duration then were measured serially. Blood samples were obtained for leukocyte and platelet count, and plasma concentrations of corticotrophin, cortisol, epinephrine, norepinephrine, tumor necrosis factor, and interleukin-6. Mononuclear cell response to phytohemagglutinin was determined at 0, 4, and 24 hours. RESULTS: In the parenteral group, a diminished response was observed in platelet count and plasma interleukin-6 levels compared with volunteers who received enteral nutrition. The duration of symptoms tended to be reduced in the parenterally fed group, although this did not achieve significance. Other responses were not significantly different between the two groups. CONCLUSION: The responses to endotoxin in human subjects who received parenteral nutrition were similar compared with subjects who received enteral nutrition, although platelet count and plasma interleukin-6 concentration were diminished.

Adrenocorticotropic Hormone↗
PubMed1993

Glutathione depletion in rats impairs T-cell and macrophage immune function.

Critical illness is associated with both immunosuppression and glutathione deficiency. We determined if in vivo depletion of glutathione would adversely affect immune status. Rats with normal glutathione levels and those with glutathione stores depleted by diethyl maleate underwent analysis of splenocyte function and mesenteric lymph node lymphocyte function. Lymphocytes of the spleen and mesenteric lymph nodes were tested for concanavalin A proliferative response and interleukin 2 production. Tumor necrosis factor and interleukin 6 secretion by splenic adherent cells was also measured. Glutathione-depleted animals had significantly decreased lymphocyte proliferation and decreased production of tumor necrosis factor and interleukin 6 but unaltered interleukin 2 production. These findings indicate that in vivo glutathione deficiency impairs macrophage and T-cell function. Because glutathione depletion may occur in sepsis, trauma, and shock, treatments that help maintain glutathione levels may enhance immunocompetence and thus improve the ability of patients to recover from critical illness.

Animals↗
PubMed1993

Effects of tumour necrosis factor on protein metabolism.

Increased skeletal muscle breakdown and negative nitrogen balance are features of sepsis that may be mediated by cytokines. The effects of tumour necrosis factor (TNF) on protein metabolism were studied. When administered to anaesthetized dogs (0.57 x 10(5) units per kg body-weight over 6h), TNF caused urinary nitrogen excretion to increase (mean(s.e.m.) 165(15) mg kg-1 for dogs that received TNF versus 113(8) mg kg-1 for control animals, P < 0.01). Amino acid nitrogen release from the hindlimbs showed no change over the study period, indicating that the additional urinary nitrogen was not derived from peripheral protein stores. In a second study the same dose of TNF or saline was infused after the intestine had been removed. The mean(s.e.m.) urinary nitrogen excretion in control dogs that had undergone enterectomy (101(7) mg kg-1) was similar to that of intact animals, and addition of TNF did not significantly increase nitrogen excretion (86(18) mg kg-1). The results suggest that nitrogen excreted in the urine during administration of TNF is derived, at least initially, from the intestinal tract.

Amino Acids↗
PubMed1993

The effects of tumor necrosis factor after removal of the gut.

Tumor necrosis factor (TNF) is thought to be an important mediator of the septic response; intravenous administration of this cytokine provokes a wide range of metabolic and hemodynamic effects which closely resemble those known to follow endotoxin administration. These effects include damage to gut mucosa. Since the gut constitutes an internal reservoir of endotoxin and bacteria it is possible that some of TNF's effects might be secondary to an increased absorption of these agents. To test this hypothesis TNF was given both to intact dogs and also to animals in which the gut had been removed, from duodenum to anus ("enterectomy"). The data indicates that the effects of TNF upon systemic pressure, white count, and cortisol and glucagon levels were not affected by prior removal of the gut. For most other parameters the findings were less clear but in general the changes in enterectomized dogs were qualitatively similar to those described in the intact animal. We conclude that the effects observed following TNF infusion in the dog are not dependent on the intestinal tract as a secondary source of bacteria or mediators.

Animals↗
PubMed1993

Glutathione depletion alters hepatocellular high-energy phosphate metabolism.

Oxygen free radicals have recently been implicated as a major cause of tissue injury in critically ill patients. Glutathione (GSH) is a potent endogenous antioxidant that may be important in minimizing oxidant-induced organ damage. However, this tripeptide is depleted during severe illness. In order to determine the effect of GSH depletion on hepatic high-energy phosphate metabolism, in vivo 31P magnetic resonance spectroscopy was used to measure phosphate ratios in male Wistar rats given 1 ml/kg of diethylmaleate (DEM), an agent that binds and thus depletes tissue GSH, or corn oil vehicle intraperitoneally. Spectra of the liver were obtained in noninjected animals (baseline, n = 15) and in rats 2 and 24 hr after the intraperitoneal injection of DEM (n = 20) or corn oil (control, n = 20). These spectra were used to measure hepatocellular pH, phosphomonoester to ATP (PME/ATP), and phosphodiester to ATP ratios, measures of hepatocellular damage; and the inorganic phosphate (Pi)/ATP ratio, a measure of energy status. In addition, tissue GSH, phosphofructokinase, citrate synthase, and beta-OH-acyl-Co-A dehydrogenase activities as well as hepatocellular ATP were measured in vitro in representative liver samples. Hepatic GSH levels were maximally depressed by 85% 2 hr after the injection of DEM (6.94 +/- 0.34 vs 0.94 +/- 0.22 microM/g wet wt, baseline vs 2 degrees DEM). This was associated with a marked increase in the PME/ATP and Pi/ATP ratios by 25 and 33%, respectively, and both ratios were significantly correlated with the severity of hepatic GSH depletion (r = 0.63, P < 0.001 and r = 0.42, P < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1992

Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study.

OBJECTIVE: To determine whether glutamine-supplemented parenteral nutrition improves nitrogen retention and reduces hospital morbidity compared with standard parenteral nutrition after bone marrow transplantation. DESIGN: Double-blind, randomized, controlled clinical trial. SETTING: University teaching hospital. PATIENTS: Forty-five adults receiving allogeneic bone marrow transplants for hematologic malignancies. INTERVENTION: Parenteral nutrition was initiated the day after bone marrow transplantation (day 1). The experimental solution was supplemented with L-glutamine (0.57 g/kg body weight per day) and provided estimated requirements for energy and protein. The control solution was a standard, glutamine-free, isonitrogenous, isocaloric formula. MEASUREMENTS: Nitrogen balance was determined between days 4 and 11 in the initial 23 patients. The incidence of clinical infection and microbial colonization, time until bone marrow engraftment, indices of clinical care, and other data related to hospital morbidity were recorded for all patients. RESULTS: The glutamine-supplemented patients (n = 24) were clinically similar to the controls (n = 21) at entry. Nutrient intake was similar in both groups; however, nitrogen balance was improved in the glutamine-supplemented patients relative to the controls (-1.4 +/- 0.5 g/d compared with -4.2 +/- 1.2; P = 0.002). Fewer experimental patients developed clinical infection (three compared with nine in the control group; P = 0.041), and the incidence of microbial colonization was also significantly reduced. Hospital stay was shortened in patients receiving glutamine supplementation (29 +/- 1 d compared with 36 +/- 2 d; P = 0.017). CONCLUSION: Patients receiving glutamine-supplemented parenteral nutrition after bone marrow transplantation had improved nitrogen balance, a diminished incidence of clinical infection, lower rates of microbial colonization, and shortened hospital stay compared with patients receiving standard parenteral nutrition. These effects occurred despite no differences between groups in the incidence of fever, antibiotic requirements, or time to neutrophil engraftment.

Adult↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1991

Sepsis alters skeletal muscle energetics and membrane function.

The effects of sepsis on skeletal muscle energetics and membrane function are poorly understood, and the time course of changes in energy metabolism are unclear. To clarify these relationships, high energy phosphate ratios, intracellular pH, and phosphocreatine breakdown rates were measured in vivo in the gastrocnemius muscle of adult male Wistar rats after cecal ligation and puncture or sham operation with 31P magnetic resonance spectroscopy. Adenosine triphosphate (ATP) concentration and Na(+)-K+ ATPase and creatine kinase activities were determined in vitro. Within 24 hours, Na(+)-K+ ATPase activity increased by 60% in rats with cecal ligation and puncture, all of which had positive bacterial cultures, as compared to none of the sham-operated controls. Phosphocreatine/ATP ratios decreased by 20% in association with a quantitatively similar increase in phosphocreatine breakdown (9.7 +/- 0.5 vs 11.9 +/- 0.5 mumoles/gm wet wt/sec; p = 0.01). ATP concentrations were maintained, and intracellular pH did not change significantly. In this model, changes in phosphocreatine breakdown were not related to total creatine kinase activity, which did not change significantly, or increases in adenosine 5'-diphosphate (ADP) concentration (62 +/- 8 vs 92 +/- 8 mumols/L; p = 0.02). Thus, in early sepsis before a measurable decrease in pH occurs, ATP is utilized at an increased rate to help maintain ionic balance and/or to support other metabolic processes. Phosphocreatine stores are used to buffer ATP concentrations.

Adenosine Diphosphate↗