Twofold Elevation Research Articles

Hypoinsulinemia is not critical to glucose recovery from hypoglycemia in humans

To test the hypothesis that glucose recovery from hypoglycemia can occur in the absence of decrements in insulin below baseline, we studied nine normal humans on six occasions. In a control study, saline was infused. In five experimental studies, insulin (0.6 mU.kg-1.min-1) was infused from 0 to 80 min, to produce hypoglycemia (approximately 3.3 mM). Then, from 80 to 180 min, insulin was not infused or was infused in four different doses 0.1, 0.2, 0.4, and 0.6 mU.kg-1.min-1), and glucose recovery was assessed. In the recovery periods, approximately fourfold peripheral with approximately twofold portal insulin elevations prevented glucose recovery (glucose = 3.6 +/- 0.1 mM, counter-regulatory hormone levels elevated throughout). However, biological glucose recovery, documented by increments to 4.3 +/- 0.1 mM and decrements in all counterregulatory hormones (glucagon, epinephrine, growth hormone, and cortisol) to control levels, occurred despite nearly twofold peripheral hyperinsulinemia (54 +/- 4 vs. 32 +/- 4 pM, P less than 0.01) in the absence of portal hypoinsulinemia (58 +/- 4 vs. 68 +/- 8 pM). Thus we conclude that, although dissipation of insulin normally plays an important role in the correction of hypoglycemia, biological glucose recovery from hypoglycemia to glucose levels more than sufficient to disengage glucose counterregulatory systems and well above those required to produce symptoms of hypoglycemia can occur in the absence of decrements in portal insulin below baseline and despite mild peripheral hyperinsulinemia.

Binding of IgG containing immune complexes to human neutrophil Fc gamma RII and Fc gamma RIII induces actin polymerization by a pertussis toxin-insensitive transduction pathway.

The ability of a phagocytic stimulus, rabbit IgG anti-BSA/BSA immune complexes, to increase the F-actin content of human polymorphonuclear leukocytes was quantitated by flow cytometry following staining with nitrobenzoxadiazole-phallacidin. A significant rise in F-actin assembly was induced by addition of 5 micrograms/ml immune complex. Concentrations of immune complex of more than 200 micrograms/ml caused a maximal (approximately twofold) increase in F-actin content. After a delay of 5 s, the F-actin levels rose and reached maximum levels by 60 s after adding immune complexes. The twofold elevation in F-actin persisted for up to 60 min. Both anti-Fc gamma RII and anti-Fc gamma RIII mAb blocked immune complex stimulated actin polymerization. Exposure to pertussis toxin failed to affect the rate or extent of immune complex-induced actin polymerization. Cells incubated with immune complexes and then lysed with Triton had an increased number of sites able to nucleate actin polymerization. These findings suggest that immune complex binding to both polymorphonuclear leukocytes Fc gamma RII and Fc gamma RIII is required for actin filament assembly and that the induction of assembly occurs via transduction pathways that differ from those used by chemoattractants. As with adhesion this phagocytic stimulus induces actin assembly by a pertussis toxin insensitive pathway and produces a rise in actin filament content that persists for prolonged periods of time.

Neuropeptide Y and catecholamine synthesizing enzymes and their mRNAs in rat sympathetic neurons and adrenal glands: Studies on expression, synthesis and axonal transport after pharmacological and experimental manipulations using hybridization techniques and radioimmunoassay

The effects of reserpine treatment (10 mg/kg, i.p.) on the content of neuropeptide Y-like immunoreactivity and catecholamines were compared with the levels of mRNA coding for neuropeptide Y, tyrosine hydroxylase and phenylethanolamine N-methyltransferase in rat sympathetic neurons and adrenal gland. A reversible depletion of neuropeptide Y-like immunoreactivity was observed in the right atrium of the heart, kidney and masseter muscle, while the immunoreactive neuropeptide Y content in the stellate and lumbar sympathetic ganglia and its axonal transport in the sciatic nerve increased following reserpine. The increase in the stellate ganglion was maximal at 48 h and absent 9 days after reserpine treatment. The expression of neuropeptide Y mRNA and tyrosine hydroxylase mRNA in both the stellate and the superior cervical ganglion increased earlier than the neuropeptide Y content, with a clear cut two-fold elevation at 24 h after reserpine. The increase in both mRNAs in the superior cervical ganglion and the depletion of neuropeptide Y, but not of noradrenaline, in terminal areas was prevented after pretreatment both with a nicotinic receptor antagonist (chlorisondamine) and with surgical preganglionic denervation. A marked (75–90%) depletion of neuropeptide Y-like immunoreactivity and adrenaline in the adrenal gland, concomitant with 3–4-fold increases in neuropeptide Y mRNA and tyrosine hydroxylase mRNA expression, was present at 24 h after reserpine treatment. Also in the adrenal gland, there was a reversal of the reserpine-induced increase in neuropeptide Y mRNA and tyrosine hydroxylase mRNA and depletion of neuropeptide Y and adrenaline following splanchnic denervation. Pharmacological, ganglionic blockade prevented the depletion of neuropeptide Y and the increased expression of neuropeptide Y mRNA, but not fully, the tyrosine hydroxylase mRNA elevation. In addition, a marked decrease in phenylethanolamine N-methyltransferase mRNA levels was noted after reserpine. This decrease was reversed by denervation and by ganglionic blockade. Denervation alone led to a small but significant decrease in all mRNAs examined both in the superior cervical ganglion and the adrenal medulla. The present data suggest that the depletion of neuropeptide Y-like immunoreactivity in sympathetic nerves and in the adrenal gland after reserpine is associated with a compensatory increase in neuropeptide Y synthesis and axonal transport, most likely due to increased nicotinic receptor stimulation. Whereas the reserpine depletion of neuropeptide Y in both sympathetic nerves and adrenal gland is related to neuronal activation, adrenal but not nerve terminal depletion of catecholamines can be prevented by the ganglionic blocker chlorisondamine. The difference in effect of pharmacological ganglionic blockade on neuropeptide Y mRNA and tyrosine hydroxylase mRNA in the adrenal medulla suggests that other messengers than acetylcholine may be involved in regulation of tyrosine hydroxylase. Finally, tyrosine hydroxylase mRNA and phenylethanolamine N-methyltransferase mRNA appear to be regulated at least partly via separate neuronal mechanisms.

Cholinergic mechanisms involved in release and effect of prostaglandin E2 in HCI‐stimulated duodenal HCO‐3 secretion in the conscious rat

Using a proximal duodenal loop in conscious rats, we investigated interactions between prostaglandin E2 and nicotinic and muscarinic receptor mechanisms previously found to be involved in the duodenal HCO3- response to HCl. In previous studies using the same model, a 5-min perfusion of the duodenal loop with 150 mmol l-1 HCl produced a marked and sustained HCO3- response. In the present study, the identical challenge produced a rapid 20-fold increase in the luminal output of prostaglandin E2 during acid exposure, followed by a sustained more than twofold elevation above the basal level during the 45 min monitored. The prostaglandin synthesis inhibitor indomethacin (4 mg kg-1 i.p.) suppressed the output of prostaglandin E2 during the HCl challenge from 131 +/- 84 to 15.4 +/- 10.0 pmol cm-1 h-1, and in the post-stimulatory period from 17.3 +/- 9.1 to 4.4 +/- 2.2 pmol cm-1 h-1. The nicotinic receptor antagonist hexamethonium (20 mg kg-1 i.v.) had no effect on the output of prostaglandin E2. The muscarinic receptor antagonist atropine (0.5 mg kg-1 s.c.) had no effect on the output of prostaglandin E2 during HCl challenge, but reduced the post-stimulatory output to 7.7 +/- 4.1 pmol cm-1 h-1. Perfusion of the duodenal loop with 0.1 mmol l-1 prostaglandin E2 produced a HCO3- response that was abolished by hexamethonium (20 mg kg-1 i.v.), but not affected by atropine (0.5 mg kg-1 s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)

Rhizobium meliloti suhR suppresses the phenotype of an Escherichia coli RNA polymerase sigma 32 mutant

sigma 32, the product of the Escherichia coli rpoH locus, is an alternative RNA polymerase sigma factor utilized to express heat shock genes upon a sudden rise in temperature. E. coli K165 [rpoH165(Am) supC(Ts)] is temperature sensitive for growth and does not induce heat shock protein synthesis. We have isolated a locus from Rhizobium meliloti called suhR that allows E. coli K165 to grow at high temperature and induce heat shock protein synthesis. R. meliloti suhR mutants were viable and symbiotically effective. suhR was found to have no DNA or derived amino acid sequence similarity to the genes of previously sequenced sigma factors or other data base entries, although a helix-turn-helix DNA-binding protein motif is present. suhR did not restore the phenotypic defects of delta rpoH E. coli; suppression of the E. coli K165 phenotype is thus likely to involve E. coli sigma 32. Western immunoblots showed that suhR caused an approximately twofold elevation of sigma 32 levels in K165; RNA blots indicated that rpoH mRNA level and stability were not altered. Stabilization of sigma 32 protein and increased rpoH mRNA translation are thus the most probable mechanisms of suppression.

A 62-Dose, 6-Month Therapy for Pulmonary and Extrapulmonary Tuberculosis

To evaluate the efficacy and toxicity of a 62-dose, four-drug, 6-month, and directly observed regimen for treatment of pulmonary and extrapulmonary tuberculosis. An open, nonblinded clinical trial, with intended follow-up of patients for 36 months after the completion of therapy. A metropolitan tuberculosis clinic in a public health department. From March 1981 through April 1989, we enrolled 160 patients with suspected or known tuberculosis; 35 of these patients were excluded from the analysis. Isoniazid, rifampin, pyrazinamide, and streptomycin were administered daily for 2 weeks; these drugs were then given in higher doses twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 18 weeks. A total of 62 doses were administered, and all therapy was directly observed by a nurse or an outreach worker. Of the 125 evaluable patients, 101 (81%) had pulmonary tuberculosis, 7 (6%) had both pulmonary and extrapulmonary involvement, and 17 (13%) had extrapulmonary disease only. Seventy-one (57%) patients had a history of recent alcoholism. There were two relapses (1.6% +/- 2.2%), occurring 6 and 56 months after the completion of therapy. The time at which sputum samples became culture negative in pulmonary patients ranged from 1 to 19 weeks (median, 4.6 weeks); 40% +/- 9.6% of patients were culture-negative after 4 weeks of therapy, 75% +/- 8.5% after 8 weeks, 94% +/- 4.7% after 12 weeks, 97% +/- 3.3% after 16 weeks, and 100% after 20 weeks. Adverse drug reactions included hyperuricemia (greater than 178 mumol/L [3 mg/dL] above normal) secondary to pyrazinamide in 80 patients (64%), twofold or greater elevations of aspartate aminotransferase in 21 patients (17%), 1.5-fold or greater elevations of alkaline phosphatase in 33 patients (27%), cutaneous abnormalities in 8 patients (6%), nausea in five patients (4%), and dizziness in 1 patient (1%). This 62-dose, largely twice-weekly tuberculosis treatment regimen is efficacious and relatively nontoxic and is especially useful for patients in whom directly observed therapy is indicated.

Activities of pollutant metabolising and detoxication systems in the liver of the plaice, Pleuronectes platessa: Sex and seasonal variations in non-induced fish

1. The ability of immature plaice to perform a number of representative hepatic phase I and II biotransformations was examined. 2. Activities attributable to cytochrome P-450 1A1 and phenol UDP-glucuronosyltransferase activity were markedly higher in plaice than other fish or rats. Glucuronidation of sex hormones and bilirubin, conjugation of ethacrynic acid with glutathione and the sulphation of phenols was very much lower in plaice than in rats, indicating that these are minor pathways in this fish. 3. MFO activities in sexually mature female plaice were 20–25% of those in immature fish, whilst there were no significant differences in glutathione S-transferase or glutathione peroxidase activity. 4. Seasonal variations in activities were determined for use in biomonitoring studies. With the exception of microsomal GST, all enzymes and the liver somatic index showed a marked seasonal variation, activities were lower in summer and showed a gradual rise in autumn and winter with a peak in spring. This pattern appeared to be the inverse of the environmental temperature, indicative of a possible temperature-dependent effect; however, there was not direct proportionality and photoperiod, feeding behaviour, plasma corticosteroid and plasma glucose also show a similar cyclical variation. 5. Cytochrome P-450 dependent ethoxyresorufin O-deethylase and cytosolic glutathione S-transferase activities in immature male fish showed a two-fold elevation over those in immature females during late winter and spring in the period when gonadal regression might be occurring and may be due to elevated 11-ketotestosterone levels.

Circulating Interleukin-1 and Tumor Necrosis Factor in Septic Shock and Experimental Endotoxin Fever

Interleukins (IL) -1 beta and -1 alpha and tumor necrosis factor (TNF-alpha) were measured by radioimmunoassay in plasma samples from 44 healthy individuals, 15 patients in septic shock, and 6 volunteers infused with endotoxin. Plasma IL-1 alpha levels were low (40 pg/ml) or undetectable in all situations. In 67% of the healthy subjects, plasma IL-1 beta levels were less than 70 pg/ml. Septic patients had higher plasma IL-1 beta levels (120 +/- 17 pg/ml, P = .001); those of surviving patients were higher than those of patients who died (P = .05). Plasma TNF-alpha concentrations in septic individuals were elevated (119 +/- 30 pg/ml) and correlated with severity of illness (r = .73, P = .003), but no correlation was observed between plasma IL-1 beta and TNF-alpha concentrations in individual samples. Infusion of endotoxin caused a twofold elevation of IL-1 beta, from a baseline of 35 +/- 5 pg/ml to a maximum of 69 +/- 27 pg/ml at 180 min (P less than .05). Peak TNF-alpha levels after endotoxin infusion were 15 times higher than IL-1 beta levels, were attained more rapidly (90 min), and as with the septic patients, did not correlate with IL-1 beta levels. These data support the concept that plasma IL-1 beta and TNF-alpha concentrations are regulated independently and are associated with different clinical outcomes.

Interactions between Antral Peptides and Prostaglandin Biosynthesis in Gastric Acid Regulation in Man

The role of endogenous prostaglandins as modulators of antral hormone release and gastric acid secretion was studied in the intact human stomach. The subjects (n = 9) received indomethacin prior to gastric perfusion at pH greater than 7 or less than 2 and subsequent vagal stimulation. Indomethacin was also tested against parenteral somatostatin (n = 10) and pentagastrin (n = 8). The release of somatostatin into the circulation was biphasic after vagal stimulation, and the plasma levels were inversely proportional to those of plasma gastrin. Acidification of the gastric antrum from pH greater than 7 to less than 2 increased twofold the basal plasma levels of somatostatin (p less than 0.05) and suppressed basal and vagally stimulated gastrin release (p less than 0.05) and gastric acid secretion (p less than 0.05). Indomethacin prior to acidification had little effect in the basal state. Following stimulation the release of somatostatin increased, as indicated by a twofold elevation of somatostatinlike immunoreactivity in the gastric lumen (p less than 0.05), but there was less inhibition of plasma gastrin (p less than 0.05) and gastric acid secretion (p less than 0.05) as compared to acidification alone. During alkaline gastric perfusion, indomethacin increased circulating somatostatin (p less than 0.05) levels without affecting plasma gastrin or gastric acid. Indomethacin given against intravenously infused somatostatin (0.1 microgram.kg-1.h-1) partially reversed the inhibited gastrin response to vagal stimulation without affecting somatostatin-suppressed gastric acid secretion. The effects of indomethacin against pentagastrin were marginal. Gastric acidification in man stimulates plasma release of somatostatin in parallel to suppressing gastrin release and gastric acid secretion. Endogenous prostanoids participate to regulate antral hormone interactions and may have dual actions on antral somatostatin, as negative modulators of release and as mediators of somatostatin effects on the gastrin cell. It is suggested that an unrestricted release of antral somatostatin is reflected in the gastric lumen rather than in the circulation.

Temporal Changes in Carbohydrate Digestive Capacity and Growth Rate of Piglets in Response to Glucocorticoid Administration and Weaning Age

Two experiments were conducted that demonstrated that a single injection of hydrocortisone 21-acetate (HYD, 25 mg/kg BW) administered to 6-d-old nursing piglets resulted in a twofold elevation (P less than .02) of pancreatic amylase within 2 d; activity was unaffected by an injection of 15 IU adrenocorticotropic hormone (ACTH)/kg BW (P greater than .20). Intestinal sucrase and maltase activity tended to be elevated (P less than .20) 2 and 4 d postinjection with HYD but returned to normal (uninjected) levels by 14 d of age. The normal decline of intestinal lactase activity was delayed by at least 4 d in response to both hormones (P less than .10). Organ weights were not affected by either hormone. In a separate experiment, postweaning mortality was reduced (12 vs 27%) and growth rate was substantially improved by administration of HYD to piglets 4 and 2 d prior to weaning at 14 d of age. Hydrocortisone resulted in a faster rate of gain the 1st wk postweaning for pigs weaned at 21 or 28 d. Subsequent gain by control and HYD piglets weaned on d 21 was similar, but HYD subsequently impaired growth rate of piglets weaned at 28 d of age. Growth rates of control and ACTH piglets were similar at each postweaning period regardless of weaning age (weaning age [lin.] x week postweaning [quad.] x treatment, P less than .07). This differential treatment response of daily gain may be due in part to effects on feed intake (weaning age [lin.] x week postweaning [lin.] x treatment, P less than .10). We conclude that a single injection of HYD to 6-d-old piglets precociously induces pancreatic amylase and that the sensitivity of piglets to HYD is age-dependent.

Fatty acid modifies Ca 2+ -dependent potassium channel activity in smooth muscle cells from the human aorta

By using the patch-clamp technique the effect of 2-decenoic acid (DA) on Ca2+-activated potassium (K+) channels in the membrane of smooth muscle cells from the human aorta was studied. In the presence of 0.5 microM Ca2+ and 2 mM Mg2+ on the cytoplasmic side of the membrane, a more than tenfold elevation in the probability of the channels being open (po) was observed under the effect of DA. With divalent cation concentrations of less than 1 nM DA caused a more than twofold elevation in po. In the DA-treated membranes Mg2+ ions, which normally fail to activate the channels, brought about a nearly threefold increase in the channel activity when applied to the inner membrane surface. Channel sensitivity to the activating effect of cytoplasmic Ca2+ ions did not increase with the application of DA. Single-channel conductance was unchanged by DA exposure. We suggest that DA alters the Ca2+-binding mechanism of the channel, increasing its sensitivity to Mg2+ ions, presumably owing to membrane fluidization.

Chronic Epstein-Barr Virus Infection

A 37-year-old man had fever, weight loss, malaise, right upper quadrant pain, lymphadenopathy, and a twofold elevation of serum alkaline phosphatase, transaminases, and gamma glutamyl transpeptidase. Granulomas were found on liver biopsy after 2 1/2 months of illness. Treatment with isoniazid and rifampin for 2 months did not lead to improvement in fever or symptoms, but prednisone caused a prompt resolution. Positive IgM antibodies to the viral capsule antigen followed by marked elevation of the IgG fraction suggest chronic Epstein-Barr virus infection to be the etiology. The patient was asymptomatic without treatment 14 months after onset of the illness.

Relation of radon exposure and tobacco use to lung cancer among tin miners in Yunnan Province, China.

We studied the relation of radon exposure and tobacco use to lung cancer among tin miners in Yunnan Province in the People's Republic of China. Interviews were conducted in 1985 with 107 living tin miners with lung cancer and an equal number of age-matched controls from among tin miners without lung cancer to obtain information on lung cancer risk factors including a detailed history of employment and tobacco use. Occupational history was combined with extensive industrial hygiene data to estimate cumulative working level months (WLM) of radon daughter exposure. Similar data were also used to estimate arsenic exposure for control in the analysis. Results indicate an increased risk of lung cancer for water pipe smoking, a traditional form of tobacco use practiced in 91% of cases and 85% of controls. Ever use of water pipes was associated with a twofold elevation in risk when compared with tobacco abstainers, and a dose-response relation was observed with increasing categories of pipe-year (dose times duration) usage. Estimated WLM of radon exposure varied from 0 to 1,761 among subjects but averaged 515 in cases versus only 244 in controls. Analyses indicated that the persons in the highest quarter of the radon exposure distribution had an odds ratio (OR) = 9.5 (95% confidence interval = 2.7-33.1) compared to persons without radon exposure after controlling for arsenic exposure and other potential confounders. Examination of duration and rate of radon exposure indicated higher risk associated with long duration as opposed to high rate of exposure. Cross-categorizations of radon exposure and tobacco use suggest greater risk associated with radon exposure than tobacco in these workers.

Alteration of hemolymph polypeptides in Manduca sexta larvae parasitized by Cotesia congregata: A two‐dimensional electrophoretic analysis and comparison with major bacteria‐induced proteins

AbstractAnalyses using one‐dimensional sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) previously demonstrated that parasitization by the braconid wasp Cotesia congregata significantly alters the normal hemolymph polypeptide profile of host Manduca sexta larvae. In the present study two‐dimensional gel analyses corroborated our earlier findings and provided additional evidence that multiple parasitism‐specific polypeptides were induced, which varied according to the stage of development of the wasps. Parasitization additionally elicited changes in the total protein concentration detected in the blood. Initially an elevation was observed, with newly parasitized larvae exhibiting a twofold elevation in hemolymph protein concentration by 12–24 h postoviposition. In contrast, terminal‐stage hosts with second instar parasites had significantly less protein in the hemolymph, likely due to reduced growth and inhibition of arylphorin synthesis by the fat body during the final stages of parasitism. Comparison of the array of hemolymph polypeptides produced in unparasitized larvae injected with 106cells of the gram‐negative bacterium Enterobacter cloacae with those proteins induced by parasitization indicated the two classes are different. Our findings confirm that the hostresponse to parasitism is a specific one, and not mimicked by bacterial challenge. Duringshort‐term in vitro culture of wasp larvae dissected from the host hemocoel, several proteins were detected in the medium using SDS ‐ PAGE, with their appearance in vitro suggestive of secretion by the wasps in vivo. Moreover, hemolymph from the parasites had significant amounts of putative host proteins, including an arylphorin ‐ like polypeptide and a protein with a mobility similar to that of insecticyanin. Thus, a dynamic interchange of proteins may occur, with the parasites accumulating host proteins while simultaneously secreting a variety of factors into the host hemocoel.

Effect of insulin on myocardial contractility during canine endotoxin shock.

During endotoxin shock the heart becomes less responsive to the stimulatory effect of insulin on glucose uptake. In the present study we sought to determine if the heart was also less responsive to the positive inotropic effect of insulin during non-cardiogenic endotoxin shock. Responses of the heart to insulin were assessed under conditions of hyperinsulinaemic (4U.min-1), euglycaemic clamp (INS). Adult mongrel dogs, weighing 20-25 kg, were anaesthetised and instrumented to measure differences in substrate concentrations between arterial and coronary sinus blood, circumflex artery blood flow (using electromagnetic flow probe), haemodynamic variables, and left ventricular posterior wall thickness (using sonomicrometry). The first derivative of left ventricular pressure with respect to time was measured and its maximal value (LV dP/dtmax) used as an index of cardiac performance. Myocardial contractility was measured using the end systolic pressure-dimension relationship. Endotoxin shock was induced by Salmonella typhimurium (1 mg.kg-1 intravenously), and resulted in depression of myocardial performance but increased contractility. INS caused a twofold elevation in myocardial glucose uptake in control animals while in endotoxin shocked dogs it was unable to elevate glucose uptake above the pre-endotoxin level. In control animals INS caused both increased cardiac contractility and performance. In the endotoxin shock group INS was unable to increase LVdP/dtmax above the basal, pre-endotoxin level and did not cause any significant change in myocardial contractility. We suggest that the heart becomes less responsive to the positive inotropic as well as metabolic effects of insulin during endotoxin shock. Changes in LV dP/dtmax can be attributed to the changing loading conditions that occur during endotoxin shock.

Developmental changes in reperfusion injury: Comparison of intracellular ion accumulation in ischemic and cardioplegic arrest

Developmental differences in ischemic and potassium cardioplegic arrest were evaluated in newborn (birth to 7 day old) and adult (6 to 12 month old) New Zealand white rabbit hearts isolated and perfused by Langendorff's method. An extracellular space washout technique was used to measure intracellular sodium and calcium in the two age groups after ischemia alone, after normothermic and hypothermic cardioplegia, and after cardioplegia with reperfusion. Although the intracellular ionic contents of nonreperfused adult hearts after 30 and 40 minutes of ischemia were identical, there was a twofold elevation in intracellular sodium level after 40 minutes of ischemia in the newborn hearts. Adult hearts arrested by normothermic potassium cardioplegia demonstrated no alteration in the intracellular ionic content, whereas in the newborn hearts, potassium cardioplegia produced excess intracellular calcium loading before reperfusion, which was greater than that occurring with ischemia alone. When hypothermia (12 degrees C) was combined with cardioplegic arrest, a prereperfusion influx of sodium and calcium was not observed in the newborn hearts, and ionic reperfusion injury was blunted in both newborn and adult hearts. These studies demonstrate that the newborn heart is more susceptible than the adult to both ischemia and cardioplegia. This may be due to age-dependent differences in transmembrane passive diffusion, sodium/calcium exchange, or calcium slow channel properties and suggests alternative myocardial protective strategies for the newborn infant.

Increased neutrophil elastase activity in cigarette smokers.

We compared plasma levels of the neutrophil elastase-derived fibrinopeptide A-alpha-1-21 in healthy cigarette smokers with those in nonsmokers. The mean A-alpha-1-21 concentration was fivefold higher (95% confidence interval [CI], 3.0 to 9.6) in ten cigarette smokers than in 20 healthy nonsmokers (2.0 nmol/L compared with 0.4 nmol/L; p less than 0.0001). To evaluate the acute effect of smoking on enzyme activity, a second group of ten smokers was studied. After refraining from smoking for 12 hours, each person smoked three cigarettes. The mean A-alpha-1-21 level in the second group of smokers was not different from that in the first group of smokers (1.8 nmol/L compared with 2.0 nmol/L) but was fivefold higher (95% CI, 2.6 to 8.7) than that in the nonsmokers (1.8 nmol/L compared with 0.4 nmol/L; p less than 0.0001). After smoking three cigarettes, subjects had a twofold elevation (95% CI, 1.6 to 3.5) in the mean A-alpha-1-21 concentration (from 1.8 nmol/L to 4.1 nmol/L; p = 0.002). Our data show that cigarette smoking perturbs the in-vivo elastase-antielastase balance and thus may produce lung disease through this mechanism.

Effects of glucose infusion on surfactant and glycogen regulation in fetal lamb lung.

To investigate the increased incidence of respiratory distress syndrome (RDS) that occurs in infants of diabetic mothers (IDM) with poor maternal glucose homeostasis, we infused glucose intravenously at a rate of 14 +/- 2 (SD) mg.kg-1.min-1 into eight twin and four singleton chronically catheterized fetal lambs from 112 days (0.77) gestation onward. Twelve catheterized and seven uncatheterized fetuses served as controls, including the eight twins of the glucose-treated fetuses. Glucose infusion resulted in a twofold elevation in fetal serum glucose levels and a 2.2-fold elevation in fetal serum insulin levels. Before 113 days (0.9) gestation, pulmonary disaturated phosphatidylcholine (DSPC) content was 1.5-fold higher in the glucose-infused fetuses than in the controls. However, after 0.9 gestation, pulmonary DSPC content increased 2.2-fold in the controls but did not increase significantly in the glucose-infused fetuses. In addition, the DSPC content of lung lavage was 5.0-fold higher in the controls and lung stability to air inflation was 2.0-fold greater and to deflation was 2.2-fold greater than in the glucose-infused fetuses. Pulmonary adenosine 3',5'-cyclic monophosphate-dependent protein kinase activity was also 1.5-fold higher, and pulmonary protein kinase C activity was 1.3-fold higher in the controls than in the glucose-infused fetuses. In contrast, glucose infusion was associated with a 1.8-fold increase in pulmonary glycogen content and with increased activities of glycogen phosphorylase kinase and glycogen phosphorylase. We conclude that the effects of chronic glucose infusion on fetal lamb lung DSPC and lung stability are compatible with a predisposition of the fetus to develop RDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidural capsaicin produces prolonged segmental analgesia in the rat

The effect of epidural capsaicin injections on the thermal nociceptive threshold of unrestrained freely moving adult rats was examined. Capsaicin solution (1% 0.05 ml, 0.1 ml) was injected in a single dose or in two consecutive doses through an indwelling lumbar epidural catheter. Effects were compared with 1 ml 1% capsaicin injected intraperitoneally. Twelve rats served as sham-treated and vehicle controls. Nociceptive thermal stimuli were brief pulses of CO 2 laser radiation directed at three body areas, hind limb, forelimb, and pinna. Capsaicin caused prolonged, segmental thermal analgesia. Maximal nociceptive threshold values in the hind limbs, attained within 24 h of epidural injection, were 2.5 ( P ≤ 0.006) and 5.3 ( P ≤ 0.0005) time control values for the 0.05-ml and 0.1-ml doses, respectively. Response thresholds in the forelimbs and pinna were uneffected. Two-stage epidural injection of capsaicin led to a roughly twofold elevation of threshold, as well as prolongation of the analgesia to about 14 days. Intraperitoneal injection of capsaicin resulted in elevation of nociceptive threshold which included all body areas tested. These results indicate that epidural application of capsaicin at the lumbar spinal level produced a profound and long-lasting segmental analgesia.

Pentagastrin as a stimulator of immunogenesis

It has been shown that subcutaneous injection of pentagastrin to mice in doses 0.01-5 micrograms per animal during 10 days resulted in a considerable stimulation of the immune response to sheep red blood cells (SRBC). Pentagastrin in doses of 5 and 1 micrograms per animal was demonstrated to have the highest immunostimulating effect. These doses increased the production of IGM-antibody-forming cells 2.2-2.7-fold and produced a twofold elevation of the antibody titer. Pentagastrin did not influence the immune response to thymus independent Vi-antigen. The in vitro treatment of mouse bone marrow cells with pentagastrin (0.1 or 0.01 microgram/ml) increased the number of Thy-1 positive cells from 0 to 16-17%. Pentagastrin at a dose of 0.001 microgram/ml was not effective.