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Biomedical subjects

K J Tracey

Publications and source records attributed to K J Tracey.

121 records · Page 7Linked to original sources
PubMed1987

Effect of hormonal and substrate backgrounds on cell membrane function in normal males.

Hormonal and substrate influences on in vivo cellular membrane function were evaluated in 15 healthy male volunteers. Each subject underwent serial evaluations of membrane function in the anterior tibialis muscle, as assessed by transcutaneous measurement of resting membrane potential (Em). Group A subjects (n = 9) underwent measurement of resting Em in the basal state and again during the 10th day of intravenous feeding (IVF). Group B subjects (n = 6) underwent measurement of resting Em in the basal state during epinephrine infusion and again during epinephrine infusion on the 7th day of IVF. Percutaneous needle biopsy of the vastus lateralis muscle permitted calculation of transmembrane electrolyte distribution from the Nernst equation, using the measured Em and the chloride space method. Hospitalization with intake of a defined-formula enteral diet for 3 days resulted in depolarization (P less than 0.05) of resting Em (-75.3 +/- 1.6 mV) compared with normal (-79.8 +/- 0.9 mV). Despite 10 days of subsequent IVF, further depolarization (P less than 0.05) of resting Em (-71.2 +/- 1.2 mV) was observed. In the dual presence of IVF and exogenous epinephrine infusion, there was an increase (P less than 0.05) in intracellular potassium concentration and repolarization of resting Em (-80.6 +/- 0.8 mV) to normal levels. These data indicate that hormonal background and substrate availability contribute to the in vivo modulation of cellular membrane function in human skeletal muscle, possibly through facilitation of sodium-dependent amino acid transport across the cell membrane.

Adult↗
PubMed1987

Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog.

Cachectin/tumor necrosis factor has been implicated as a mediator of lethal endotoxemia, but the metabolic and hemodynamic responses to this macrophage-derived peptide have been incompletely characterized. Cachectin was administered by intra-arterial infusion in two groups of beagle dogs at lethal (100 micrograms per kilogram) and sublethal (10 micrograms per kilogram) doses. The infusion produced serum cachectin levels (1 to 50 nanomoles per liter) similar to those achieved after experimental endotoxemia. The lethal response to cachectin was characterized by progressive hypotension, shock and death within three hours. Histopathologic findings included acute inflammation of the pulmonary interstitium, intravascular thrombosis with hemorrhagic necrosis, adrenal medullary necrosis and acute renal tubular necrosis. Cachectin infusion precipitated significant increases of plasma catecholamines, cortisol and glucagon in a dose response manner. Cachectin infused directly into the isolated hindlimb mediated reductions of skeletal muscle resting transmembrane potential and stimulated lactate efflux. Cachectin appears to occupy a crucial role in physiopathologic responses to infection, and likely participates in the mobilization of host energy stores, intravascular depletion and shock after lethal endotoxemia.

Animals↗
PubMed1987

Comparison of numerical and phenotypic leukocyte changes during constant hydrocortisone infusion in normal humans with those in thermally injured patients.

Twenty-four to 48 hours after thermal injury, percentages and number of T X mu or T4 lymphocytes decrease with little or no change in T X gamma or T8 cells. Additionally, the plasma hydrocortisone level is extremely elevated. Since administration of hydrocortisone to normal humans also produces a specific decrease in T X mu or T4 lymphocytes, it was hypothesized that burn induced elevations of hydrocortisone were responsible for the decrease in T X mu/T4 cells. In this study, normal humans were administered constant infusions of hydrocortisone for six hours, such that plasma levels were increased to an extent that mimics those 24 to 48 hours after thermal injury. Before, during and after infusion, percentages and numbers of lymphocytes, monocytes, granulocytes and T3, T4, T8, T11, HLA-DR and Leu7 lymphocytes were quantified by flow cytometry. Results were compared with those for patients with burns. The plasma hydrocortisone level rose to 49.0 micrograms per deciliter during infusion, similar to the mean of 47.5 micrograms per deciliter for patients with burns. Infused volunteers showed significant lymphopenia, monocytopenia and granulocytosis. Additionally, there were significant decreases in percentages of T3, T4 and T11 lymphocytes, no significant changes in percentages of T8 or HLA-DR and an increase in percentages of Leu7+ cells. These changes in lymphocyte subsets mimicked those of burn patients. Numbers of T3, T4 and T11 cells significantly decreased during hydrocortisone infusion while numbers of T8, HLA-DR and Leu7 lymphocytes did not change. Burn patients showed decreased numbers of T3 and T4 cells, but this T3/T4 lymphopenia was not as great as during hydrocortisone infusion. These results support the hypothesis that elevation of hydrocortisone is responsible for the lymphocyte phenotypic changes that occur in the early postburn period.

Adult↗
PubMed1986

Shock and tissue injury induced by recombinant human cachectin.

Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.

Animals↗
PubMed1986

Cachectin/tumor necrosis factor mediates changes of skeletal muscle plasma membrane potential.

Lethal infections are associated with cellular dysfunction as evidenced by a decrease in the resting transmembrane potential difference (Em) of skeletal muscle fibers. Endotoxin stimulation of macrophages evokes production of cachectin, a protein that has been implicated as a mediator of the lethal effects of endotoxemia. In the present study, rat skeletal muscle fiber Em decreased when incubated with recombinant human cachectin. The reduction of Em induced by cachectin occurred in a dose-related fashion and was inhibited by mAb against the monokine. Infusion of cachectin induced a decline of skeletal muscle Em in vivo, and suggests that cachectin may acutely mediate alterations of skeletal muscle membrane function after infection.

Animals↗
PubMed1986

Peripheral tissue metabolism in man with varied disease states and similar weight loss.

The purpose of this study was to identify the effects of tumor burden and benign inflammatory disease on peripheral tissue metabolism independent of antecedent weight loss. This was accomplished by comparing forearm substrate flux profiles in cachectic cancer and benign disease patients to those of normal subjects before and after 10 days of total protein calorie depletion. Tumor-bearing patients (CA), benign disease patients (BD), and starved (ST) normal volunteers had similar weight loss. Resting energy expenditure was not significantly different between the study populations. Efflux of total amino acids (TAA [nmole/100 ml tissue-min]) decreased significantly (P less than 0.05) in the normals after 10 days of starvation (-886 +/- 185 postabsorptive (PA) vs -278 +/- 60 (ST]. CA patients had TAA efflux of -428 +/- 52 which was significantly (P less than 0.05) less than PA normals. In contrast, BD patients had a significantly (P less than 0.05) elevated TAA efflux of -895 +/- 165 compared to ST normals. CA patients had a significantly (P less than 0.05) elevated glucose uptake and lactate efflux compared to ST normals (glucose: +1.12 +/- 0.21 (CA) vs +0.11 +/- 0.09 (ST), lactate: -0.84 +/- 0.13 (CA) vs -0.38 +/- 0.13 (ST) [mumole/100 ml tissue-min]). The data suggest that tumor-bearing patients are able to maintain their peripheral tissue protein sparing adaptation to nutritional depletion in the presence of accelerated glucose utilization. However, clinically stable patients with benign disease do not demonstrate this adaptation and may be at greater risk for lean tissue dissolution than previously appreciated.

Adult↗
PubMed1986

Extremity amino acid metabolism during starvation and intravenous refeeding in humans.

This study was designed to evaluate peripheral tissue amino acid metabolism in normal subjects who underwent starvation followed by intravenous administration of a nutritional repletion regimen with varying nonprotein caloric sources. Extremity amino acid (AA), arteriovenous differences, and blood flow were measured across forearm and/or leg of 12 healthy male subjects. Plasma AA flux [(arterial concentration - venous concentration) X flow X (1 - hematocrit); ml X min-1 X 100 ml tissue-1] was determined postabsorptively (PA), after 10 days of starvation (ST) and on the 10th day of intravenous feeding (IVF). There was a significant (P less than 0.05) decrease in efflux of total amino acids during the starvation study (-345 +/- 74) compared with the PA study (-1,463 +/- 263). Peripheral tissue AA uptake increased significantly (P less than 0.05) after 10 days of IVF (+276 +/- 79) compared with both PA and ST studies. There were no significant differences in extremity AA flux between those subjects who received 100% dextrose and those receiving 50% dextrose-50% lipid as a nonprotein caloric source. Linear relationships of AA infusion rate (IR) to AA flux (r = 0.845, P less than 0.001) and AA IR to [AA]art IVF (r = 0.842, p less than 0.001) were observed during IVF. Results of this study suggest that extremity flux determinations during IVF cannot be interpreted without correction for AA availability as reflected by AA infusion rate.

Amino Acids↗
PubMed1984

Signet ring carcinoma of the pancreas, a rare variant with very high CEA values. Immunohistologic comparison with adenocarcinoma.

Signet ring carcinoma of the pancreas is rare. We report a case which was remarkable for (1) diffuse, infiltrating growth which suggested chronic pancreatitis at laparotomy, and (2) an associated very high circulating carcinoembryonic antigen (CEA) level of 6400 ng/ml. The case report and autopsy are presented. Twelve other cases of pancreatic adenocarcinoma (non-signet ring) are compared with the signet ring carcinoma with respect to CEA staining and circulating levels. We conclude immunocytochemical staining of biopsy tissue for CEA is a useful adjunct in the interpretation of circulating CEA levels in pancreatic carcinoma.

Adenocarcinoma↗
PubMed1983

Radioimmunoassay for methotrexate using hydroxyethylmethacrylate hydrogel.

A sensitive, rapid method for the measurement of methotrexate in biologic fluids has been developed using a solid-phase radioimmunoassay (RIA). Hydroxyethylmethacrylate monomer was polymerized in the presence of rabbit antimethotrexate antisera and the resultant gels lyophilized, ground to a fine powder, and aliquoted into 3-ml syringes fitted with a fritted filter disc. Control gels without incorporated antibodies did not bind radiolabeled methotrexate, whereas a dose-response curve expressing percent bound methotrexate against antiserum concentration could be readily constructed for appropriate gels. Drug concentrations of less than 1 ng/ml can be measured. The fate of a bolus IV injection of methotrexate (100 mg) into an adult female baboon was evaluated by the HEMA-RIA system and compared with a previously published enzyme assay for the drug. These studies describe a stable and efficient system for rapid separation of bound antigen by simple filtration.

Animals↗
PubMedDate not supplied

Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.

Bacterial infection of the mammalian bloodstream can lead to overwhelming sepsis, a potentially fatal syndrome of irreversible cardiovascular collapse (shock) and critical organ failure. Cachectin, also known as tumour necrosis factor, is a macrophage-derived peptide hormone released in response to bacterial lipopolysaccharide, and it has been implicated as a principal mediator of endotoxic shock, although its function in bacterial sepsis is not known. Anaesthetized baboons were passively immunized against endogenous cachectin and subsequently infused with an LD100 dose of live Escherichia coli. Control animals (not immunized against cachectin) developed hypotension followed by lethal renal and pulmonary failure. Neutralizing monoclonal anti-cachectin antibody fragments (F(ab')2) administered to baboons only one hour before bacterial challenge protected against shock, but did not prevent critical organ failure. Complete protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion. These results indicate that cachectin is a mediator of fatal bacteraemic shock, and suggest that antibodies against cachectin offer a potential therapy of life-threatening infection.

Animals↗
PubMedDate not supplied

Effect of starvation and total parenteral nutrition on electrolyte homeostasis in normal man.

Elemental balances, and skeletal muscle membrane potential (Em) and biopsy were utilized to evaluate electrolyte homeostasis and body composition in 11 healthy adult volunteers after 10 days of starvation. This controlled, acute malnutrition was followed by refeeding for 10 days with two different, commonly used, total parenteral nutrition (TPN) solutions. Six subjects were refed with crystalline amino acids and dextrose (dextrose group), while five subjects received amino acids, dextrose, and lipid (lipid group). During starvation, negative balances for potassium, phosphorous, magnesium, and nitrogen were observed in both groups. When compared to starvation, total parenteral nutrition produced statistically significant (p less than 0.05) equilibrium or positive electrolyte and nitrogen balances for both, the dextrose and lipid groups. During TPN, there was a significantly (p less than 0.001) positive chloride balance in the lipid group when compared to the dextrose group. At the conclusion of the 10-day period of TPN, there was a decrease (p less than 0.05) in skeletal muscle Em. This change, in concert with the electrolyte balance data obtained during parenteral repletion, lead us to postulate that restoration of lean tissue protein and cellular function does not occur at a rate which might be inferred from the positive nitrogen balance observed in this model. A persistent defect in cellular function which was evident after starvation, suggests that a brief period of TPN is insufficient to restore skeletal muscle integrity.

Adult↗