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Biomedical subjects

J H James

Publications and source records attributed to J H James.

At least 19 recordsLinked to original sources
PubMed1999

Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis.

High blood lactate concentration (hyperlactacidaemia) in trauma or sepsis is thought to indicate tissue hypoxia and anaerobic glycolysis even when blood pressure, cardiac output, and urine output are within clinically acceptable ranges. However, mechanisms of lactate generation by well-oxygenated tissues have received little attention. Within cells, oxidative and glycolytic energy production can proceed in separate, independent compartments. In skeletal muscle and other tissues, aerobic glycolysis is linked to ATP provision for the Na+-K+ pump, the activity of which is stimulated by epinephrine. In injured patients, hypokalaemia may reflect increased Na+,K+-ATPase activity. We propose that increased blood lactate often reflects increased aerobic glycolysis in skeletal muscle secondary to epinephrine-stimulated Na+,K+-ATPase activity and not anaerobic glycolysis due to hypoperfusion. The hypothesis explains why hyperlactacidaemia often neither correlates with traditional indicators of perfusion nor diminishes with increased oxygen delivery. When other variables have returned to normal, continued attempts at resuscitation based on elevated blood lactate may lead to unnecessary use of blood transfusion and inotropic agents in an effort to increase oxygen delivery and lactate clearance.

Cell Hypoxia↗
PubMed1999

Adrenergic antagonists reduce lactic acidosis in response to hemorrhagic shock.

BACKGROUND: Hemorrhagic shock is associated with lactic acidosis and increased plasma catecholamines. Skeletal muscle increases lactate production under aerobic conditions in response to epinephrine, and this effect is blocked by ouabain, a specific inhibitor of the cell membrane Na+/K+ pump. In this study, we tested whether adrenergic antagonists can block lactate production during shock. METHODS: Male Sprague-Dawley rats (250-300 g) were pretreated with phenoxybenzamine (2 mg/kg, i.v.) and/or propranolol (0.5 mg/kg, i.p.) before hemorrhaging to a mean arterial pressure of 40 mm Hg for 1 hour. Skeletal muscle perfusion, plasma lactate, and catecholamines were measured at baseline, 55 minutes after shock, and 1 hour after resuscitation. In a separate study, extensor digitorum longus and soleus muscles were incubated in Krebs buffer (95:5, O2:CO2) with 10 mmol/L glucose. One of each muscle pair was incubated in the absence or presence of epinephrine and of one or both adrenergic blockers. Medium lactate concentration was then measured. RESULTS: The combination of alpha- and beta-blockers significantly reduced plasma lactate levels during hemorrhage. In contrast, beta-blockade alone was associated with a significant increase in plasma lactate and epinephrine. None of the blockers altered tissue perfusion. Epinephrine stimulation of muscle lactate production in vitro was completely blocked by propranolol. CONCLUSION: Epinephrine release in response to hypotension is a primary stimulus for muscle lactate production in this model of hemorrhagic shock. Hypoxia alone does not explain the increased lactate levels because tissue perfusion was not altered by the adrenergic antagonists. These observations challenge the rationale behind lactate clearance as an end point for resuscitation after hemorrhagic shock.

Acidosis, Lactic↗
PubMed1999

Stimulation of both aerobic glycolysis and Na(+)-K(+)-ATPase activity in skeletal muscle by epinephrine or amylin.

Epinephrine and amylin stimulate glycogenolysis, glycolysis, and Na(+)-K(+)-ATPase activity in skeletal muscle. However, it is not known whether these hormones stimulate glycolytic ATP production that is specifically coupled to ATP consumption by the Na(+)-K(+) pump. These studies correlated glycolysis with Na(+)-K(+)-ATPase activity in resting rat extensor digitorum longus and soleus muscles incubated at 30 degrees C in well-oxygenated medium. Lactate production rose three- to fourfold, and the intracellular Na(+)-to-K(+) ratio (Na(+)/K(+)) fell with increasing concentrations of epinephrine or amylin. In muscles exposed to epinephrine at high concentrations (5 x 10(-7) and 5 x 10(-6) M), ouabain significantly inhibited glycolysis by approximately 70% in either muscle and inhibited glycogenolysis by approximately 40 and approximately 75% in extensor digitorum longus and soleus, respectively. In the absence of ouabain, but not in its presence, statistically significant inverse correlations were observed between lactate production and intracellular Na(+)/K(+) for each hormone. Epinephrine had no significant effect on oxygen consumption or ATP content in either muscle. These results suggest for the first time that stimulation of glycolysis and glycogenolysis in resting skeletal muscle by epinephrine or amylin is closely linked to stimulation of active Na(+)-K(+) transport.

Adenosine Triphosphate↗
PubMed1998

Increased skeletal muscle Na+, K+-ATPase activity as a cause of increased lactate production after hemorrhagic shock.

BACKGROUND: Lactate production after hemorrhagic shock may be produced by aerobic glycolysis, which has been linked to activity of the Na+/K+ pump in smooth muscle and other tissues. We tested whether increased muscle Na+/K+ pump activity after shock was linked to increased lactate production. METHODS: Male Sprague-Dawley rats were subjected to 1 or 2 hours of hemorrhagic shock and then resuscitated with shed blood and normal saline. After 24 hours, pairs of extensor digitorum longus muscles were preincubated for 30 minutes in Krebs buffer (95:5, O2:CO2) with 10 mmol/L glucose. One muscle served as a control and was incubated in buffer alone; the other was incubated in buffer with 1 mmol/L ouabain, an inhibitor of the Na+, K+-ATPase. Lactate, ADP, ATP, glycogen, and creatinine-phosphate were determined. RESULTS: Under these well-oxygenated conditions, muscles from shocked rats produced about twice as much lactate as sham muscles. Inhibition of the Na+/K+ pump by ouabain significantly reduced lactate production. CONCLUSIONS: Hypoxia is unlikely to account for increased muscle lactate production after resuscitated hemorrhagic shock, because high lactate production persists under well-oxygenated incubation conditions. Inhibition of shock-induced lactate production by ouabain indicates energetic coupling of glycolysis to the Na+, K+-ATPase.

Animals↗
PubMed1997

Increased glutamine consumption in small intestine epithelial cells during sepsis in rats.

BACKGROUND: Previous reports have emphasized increased intestinal glutamine consumption during sepsis. This may be of clinical significance as glutamine is a (and perhaps the) physiologic fuel for the intestine. A problem remains, however, as glutaminase, the major enzyme for the degradation of glutamine, is decreased rather than increased in sepsis. This implies an alteration in the metabolic fate of glutamine in sepsis, which may be of clinical significance. METHODS: We determined the effect of sepsis on glutamine metabolism in mucosa of small intestine. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. After 16 hours, glutamine consumption was measured in isolated enterocytes, and glutaminase, glutamine synthetase, and glutamine transaminase activities and DNA synthesis were determined in mucosa. RESULTS: Glutamine consumption was increased during sepsis in enterocytes from the tips of the villi and was unchanged in enterocytes from the midportions of the villi and the crypts. As previously shown, mucosal glutaminase activity was reduced. However, glutamine synthetase and glutamine transaminase activities were stimulated in septic rats, suggesting an increase in metabolism of glutamine via alternate pathways. DNA synthesis was increased during sepsis, especially in crypt cells. CONCLUSIONS: Increased or unchanged glutamine consumption in enterocytes from septic rats, despite reduced glutaminase activity, appears to reflect increased activity of other enzyme systems and/or increased utilization of the amino acid for DNA and protein synthesis. Since other aspects of glutamine metabolism may also be deranged in sepsis, a continual enteral supply of glutamine to the intestinal lumen during sepsis may be clinically useful.

Animals↗
PubMed1997

Cytokines block the effects of insulin-like growth factor-I (IGF-I) on glucose uptake and lactate production in skeletal muscle but do not influence IGF-I-induced changes in protein turnover.

There is evidence that proinflammatory cytokines are involved in the regulation of muscle protein breakdown in various catabolic conditions but the mechanisms are not fully understood. Previous studies suggest that cytokines reduce circulating and tissue levels of insulin-like growth factor-I (IGF-I) and may block the anabolic effects of the hormone in certain cell types and tissues. We tested the hypothesis that a mixture of tumor necrosis factor alpha, interleukin-1 alpha, and interferon-gamma block the anabolic effects of IGF-I in skeletal muscle. Muscles from burned or unburned rats were incubated in the absence or presence of 1 microgram/mL of IGF-I with or without the addition of the cytokines. As expected, IGF-I stimulated protein synthesis and inhibited protein breakdown in incubated muscles. The cytokines did not influence protein turnover rates in muscles incubated with or without IGF-I. In additional experiments, the effects of IGF-I on glucose uptake and lactate production were tested. IGF-I increased glucose uptake approximately 2.5-fold and stimulated lactate production approximately 5-fold. These effects of the hormone were significantly inhibited by the cytokine mixture. The results suggest that cytokines do not induce protein catabolism by directly inhibiting the anabolic effects of IGF-I in muscle tissue. The inhibitory effects of the cytokines on IGF-I-stimulated glucose transport and lactate production suggest that the lack of effect of cytokines on protein metabolism was not due to a metabolic unresponsiveness of the incubated muscles to the cytokines.

Animals↗
PubMed1996

Linkage of aerobic glycolysis to sodium-potassium transport in rat skeletal muscle. Implications for increased muscle lactate production in sepsis.

Although a linkage between aerobic glycolysis and sodium-potassium transport has been demonstrated in diaphragm, vascular smooth muscle, and other cells, it is not known whether this linkage occurs in skeletal muscle generally. Metabolism of intact hind-leg muscles from young rats was studied in vitro under aerobic incubation conditions. When sodium influx into rat extensor digitorum longus (EDL) and soleus muscles was facilitated by the sodium ionophore monensin, muscle weight gain and production of lactate and alanine were markedly stimulated in a dose-dependent manner. Although lactate production rose in both muscles, it was more pronounced in EDL than in soleus. Monensin-induced lactate production was inhibited by ouabain or by incubation in sodium-free medium. Preincubation in potassium-free medium followed by potassium re-addition also stimulated ouabain-inhibitable lactate release. Replacement of glucose in the incubation medium with pyruvate abolished monensin-induced lactate production but exacerbated monensin-induced weight gain. Muscles from septic or endotoxin-treated rats exhibited an increased rate of lactate production in vitro that was partially inhibited by ouabain. Increases muscle lactate production in sepsis may reflect linked increases in activity of the Na+, K+-ATPase, consumption of ATP and stimulation of aerobic glycolysis.

Aerobiosis↗
PubMed1996

"Through-glass" injuries.

This prospective trial collected all cases where injuries had resulted from the hand passing through or striking glass and had been referred to a hand injury service during 1 year. Eighty-seven cases were referred and the factors relating to these injuries were examined. A record was made of the structures damaged, the surgery performed and prevailing socioeconomic factors. These injuries were very costly in terms of morbidity, surgical effort and time, with significant resource implications. The study appears to confirm other reports that current legislation on glazing safety was too long delayed and is inadequate now that it is in place.

Adolescent↗
PubMed1995

Nitric oxide inhibits LPS-induced IL-6 production in enterocytes.

In recent studies, production of interleukin-6 (IL-6) in cultured enterocytes was stimulated by lipolysaccharide (LPS). In other cell types, IL-6 production was inhibited by nitric oxide (NO). We tested the hypothesis that LPS-induced IL-6 production in the enterocyte is regulated, at least in part, by NO. IEC-6 cells (a rat intestinal epithelial cell line) were cultured for 3 days with different combinations of LPS (1-10 micrograms/ml), the NO synthase inhibitor N-omega-nitro-L-arginine (NNA, 3-300 microM), L-arginine (10 mM), the NO donor sodium nitroprusside (SNP, 0.5-1 microM), or medium alone as control. IL-6 levels in the culture medium were determined by the B9 murine hybridoma bioassay. Nitrite, a stable end product of NO metabolism, was measured by HPLC. PCR was performed to determine inducible NO synthase (iNOS) mRNA expression in the IEC-6 cells. Treatment of IEC-6 cells with LPS stimulated IL-6 production. LPS-induced IL-6 production was further increased by NNA in a dose-dependent fashion. This effect of NNA was abolished by the addition of L-arginine. SNP caused a dose-dependent decrease in IL-6 production. Nitrite production was increased in a dose-dependent fashion after LPS treatment. PCR revealed an increase in iNOS mRNA expression in IEC-6 cells after administration of 1 microgram/ml LPS. The results suggest that NO inhibits LPS-induced IL-6 production in the enterocyte. NO may be an important regulator of intestinal cytokine response during sepsis and endotoxemia.

Animals↗
PubMed1995

Anticatabolic effect of the beta 2-agonist cimaterol in vivo in tumor-bearing animals.

Loss of lean body mass occurs in cancer and may adversely affect outcome. The beta 2-agonist cimaterol increases muscle mass and protein content in tumor-bearing animals, in part by decreasing protein degradation, but the effect of the drug on protein synthesis remains uncertain. To determine the influence of cimaterol on protein synthesis, a methylcholanthrene sarcoma was transplanted sc into the dorsum of male Fischer-344 rats. After 3 weeks of tumor growth, tumor-bearing and control animals received daily sc injections of the beta 2-agonist cimaterol (0.15 mg/kg) for 5 days. Rate of protein synthesis was measured using iv [3H]-phenylalanine (25 microCi/100 g body wt) and cold phenylalanine (150 mumole/100 g body wt) in a flooding dose. Extensor digitorum longus muscles were harvested 10 min later, homogenized, and assayed for [3H]-phenylalanine uptake (bound) (dpm/mg muscle) and tissue-specific (free) radioactivity to determine protein synthesis rate (Ks: %/24 hr). There was a significant increase in protein synthesis rate in control and tumor-bearing animals receiving cimaterol compared to that in freely feeding, food-deprived, or matched-carcass-weight nontumor-bearing controls, as well as compared to that in tumor-bearing controls. We conclude that the anabolic effects of cimaterol are due to both decreased protein degradation and increased muscle protein synthesis. Therefore, beta 2-agonists may prove useful in prevention and/or treatment of cancer cachexia.

Adrenergic beta-Agonists↗
PubMed1994

Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle.

We tested the role of different intracellular proteolytic pathways in sepsis-induced muscle proteolysis. Sepsis was induced in rats by cecal ligation and puncture; controls were sham operated. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents NH4Cl, chloroquine, leupeptin, and methylamine. Ca(2+)-dependent proteolysis was determined in the absence or presence of Ca2+ or by blocking the Ca(2+)-dependent proteases calpain I and II. Energy-dependent proteolysis was determined in muscles depleted of ATP by 2-deoxyglucose and 2.4-dinitrophenol. Muscle ubiquitin mRNA and the concentrations of free and conjugated ubiquitin were determined by Northern and Western blots, respectively, to assess the role of the ATP-ubiquitin-dependent proteolytic pathway. Total and myofibrillar protein breakdown was increased during sepsis by 50 and 440%, respectively. Lysosomal and Ca(2+)-dependent proteolysis was similar in control and septic rats. In contrast, energy-dependent total and myofibrillar protein breakdown was increased by 172% and more than fourfold, respectively, in septic muscle. Ubiquitin mRNA was increased severalfold in septic muscle. The results suggest that the increase in muscle proteolysis during sepsis is due to an increase in nonlysosomal energy-dependent protein breakdown, which may involve the ubiquitin system.

Animals↗
PubMed1993

Intracellular glutamine concentration does not decrease in all muscles during sepsis.

The concentrations of glutamine and other amino acids were measured in plasma and intracellular fluid of soleus and extensor digitorum longus (EDL) muscles of rats 4, 8, and 16 hr after induction of sepsis by cecal ligation and puncture or after sham operation. Previous studies have shown that muscle protein breakdown is greatly increased in EDL, but not in soleus muscle, in this sepsis model. Corresponding to previous observations of protein breakdown in sepsis, muscle glutamine was markedly depleted (< 50%) in EDL by sepsis, while no significant fall in glutamine concentration in soleus was observed. Changes in muscle glutamine concentration in sepsis could not be attributed to changes in the precursor of glutamine, glutamic acid. Data were examined for changes consistent with hypothesized alterations in glutamine transport. Correlations among glutamine and other amino acids in muscle, histidine in particular, were consistent with a sepsis-induced alteration in activity of the sarcolemmal glutamine transporter, system Nm. These results thus strengthen the proposed connection between muscle glutamine content and muscle protein metabolism under catabolic conditions.

Amino Acids↗
PubMed1993

Evidence that inhibition of muscle amino acid uptake during endotoxemia is not mediated by glucocorticoids.

Sepsis and endotoxemia are associated with increased muscle protein breakdown and inhibited amino acid uptake. Glucocorticoids are important for the regulation of muscle protein breakdown in catabolic conditions; in contrast, the role of glucocorticoids in the regulation of muscle amino acid transport during sepsis or endotoxemia is not known. The present study was designed to test the role of glucocorticoids in the regulation of muscle amino acid uptake during endotoxemia. Amino acid transport, determined as uptake of 3H-alpha-aminoisobutyric acid (AIB) by incubated soleus muscles in vitro, was reduced by approximately 40% 2 hours after intraperitoneal (IP) injection of 10 micrograms/kg endotoxin in rats. Administration of 5 mg/kg of the glucocorticoid receptor antagonist RU 38486 2 hours before endotoxin injection did not affect the inhibition of amino acid uptake. In vitro addition of plasma from endotoxemic rats to incubated rat soleus muscles inhibited amino acid uptake by approximately 30%. This effect of endotoxic plasma also was noted when muscles were from rats that had been treated with RU 38486 and when RU 38486 was present in the incubation medium. Results confirm previous reports of reduced muscle amino acid transport during endotoxemia and of the presence of a circulating factor that inhibits muscle amino acid uptake in this condition. Data suggest that inhibited muscle amino acid transport during endotoxemia is not regulated by glucocorticoids.

Aminoisobutyric Acids↗
PubMed1992

Cancrum oris: functional and cosmetic reconstruction in patients with ankylosis of the jaws.

Advances in reconstructive surgery allow treatment of established cases of Cancrum oris with total ankylosis of the jaws to produce a satisfactory functional and cosmetic result. This is achieved by radical excision of scar tissue followed by two layered flap closure of the defect. It is recommended that a cervical flap is used for lining and a deltopectoral flap for cheek cover. Ten patients with Cancrum oris are presented to demonstrate the techniques used.

Adolescent↗
PubMed1991

Decreased myofibrillar protein breakdown following treatment with clenbuterol.

Daily treatment of Fischer-344 rats for 14 days with the beta 2-adrenergic agonist, clenbuterol, increased gastrocnemius muscle mass and protein content. Coadministration with the beta-adrenergic antagonist, nadolol, significantly reduced these anabolic effects of clenbuterol. Although clenbuterol treatment reduced food intake during the first 4 days, clenbuterol-treated rats were hyperphagic during the second week of drug administration. Nadolol treatment also blocked these effects of clenbuterol on feeding. In a second experiment, in vitro incubation of extensor digitorum longus muscles taken from post weaning food-deprived rats demonstrated decreased release of 3-methylhistidine by clenbuterol-treated rats, suggesting decreased breakdown of myofibrillar protein. Protein synthesis was not increased in vitro in the soleus muscles taken from these rats. These experiments demonstrate that the anabolic effect of clenbuterol is due in part to beta-adrenergic activity and may involve reduced myofibrillar protein degradation. These results appear to have direct application to nutrition and protein repletion in various catabolic diseases.

Adrenergic beta-Antagonists↗
PubMed1991

Factors influencing the concentrations of the large neutral amino acids in the brain and in the CSF of dogs after portacaval anastomosis.

Portal-systemic shunting of blood is associated with hyperammonemia, an increased glutamine concentration in brain, an altered plasma neutral amino acid pattern, and high levels of several of the large neutral amino acids in brain. Since some of these amino acids are precursors for neurotransmitters and for other potentially neuroactive substances, high CNS levels of these amino acids may contribute to the development of encephalopathy. In order to determine the relative importance of changes in brain glutamine levels and changes in competition among the neutral amino acids for blood-brain transport, we measured the concentrations of the large neutral amino acids in plasma, cisternal cerebrospinal fluid and in brain tissue from various regions of dogs after end-to-side portacaval shunt. Although the changes in CSF amino acid levels correlated partially with altered amino acid plasma competitor ratios, better correlations were observed with the elevation of CSF glutamine. These results suggest a model of blood-brain amino acid transport in which a high level of glutamine in brain extracellular fluid competes with other neutral amino acids for efflux from brain, thus raising brain amino acid levels after portal-systemic shunting.

Amino Acids, Essential↗
PubMed1990

Prostaglandin E2 does not regulate total or myofibrillar protein breakdown in incubated skeletal muscle from normal or septic rats.

The role of prostaglandins in the regulation of muscle protein breakdown is controversial. We examined the influence of arachidonic acid (5 microM), prostaglandin E2 (PGE2) (2.8 microM) and the prostaglandin-synthesis inhibitor indomethacin (3 microM) on total and myofibrillar protein breakdown in rat extensor digitorum longus and soleus muscles incubated under different conditions in vitro. In other experiments, the effects of indomethacin, administered in vivo to septic rats (3 mg/kg, injected subcutaneously twice after induction of sepsis by caecal ligation and puncture) on plasma levels and muscle release of PGE2 and on total and myofibrillar protein breakdown rates were determined. Total and myofibrillar proteolysis was assessed by measuring production by incubated muscles of tyrosine and 3-methylhistidine respectively. Arachidonic acid or PGE2 added during incubation of muscles from normal rats did not affect total or myofibrillar protein degradation under a variety of different conditions in vitro. Indomethacin inhibited muscle PGE2 production by incubated muscles from septic rats, but did not lower proteolytic rates. Administration in vivo of indomethacin did not affect total or myofibrillar muscle protein breakdown, despite effective plasma levels of indomethacin with decreased plasma PGE2 levels and inhibition of muscle PGE2 release. The present results suggest that protein breakdown in skeletal muscle of normal or septic rats is not regulated by PGE2 or other prostaglandins.

Animals↗