Pyruvate potentiates beta-adrenergic inotropism of stunned guinea-pig myocardium

This study tested the hypotheses that the sensitivity of stunned myocardium to beta-adrenergic stimulation is diminished, and that metabolic intervention with pyruvate can restore beta-adrenergic responsiveness to pre-ischemic levels. Isolated working guinea-pig hearts metabolizing 10 mM glucose were stunned by 45 min of low flow ischemia, and pyruvate and/or isoproterenol treatments were initiated 15 and 30 min after reperfusion, respectively. The dose: response for cardiac power from 0.1-100 nM isoproterenol was significantly shifted to the right in stunned hearts: EC50 (nm) increased from 0.3 +/- 0.06 to 5.2 +/- 1.86. Pyruvate (5 mM) largely restored isoproterenol responsiveness of stunned myocardium, lowering EC50 to 1.1 +/- 0.34 nM. Maximum power was similar in each group. Additional stunned hearts were treated with intermediate (2 nM) or high (30 nM) isoproterenol concentrations with or without pyruvate. Combining treatments produced a significant interaction at the low dose of isoproterenol, increasing cardiac power (mJ x min(-1) x g(-1)) to 149 +/- 20, twice the sum of the individual treatments (2 nM isoproterenol: 34 +/- 11; pyruvate: 33 +/- 8). Cyclic AMP content was unaltered by isoproterenol or pyruvate alone but was increased 41% by the combination. Power was maximized by 30 nM isoproterenol, which tripled cyclic AMP content; pyruvate did not augment these responses, but lessened the isoproterenol-induced decline in cytosolic phosphorylation potential. Conclusions: Beta-adrenergic inotropism is attenuated in stunned myocardium, although the maximal response is unchanged. Pyruvate potentiated the effects of sub-maximal doses of isoproterenol without depleting cellular energy reserves further, and attenuated energy depletion by high doses of isoproterenol. Pyruvate may allow restoration of contractile performance with lower, energetically less costly doses of beta-adrenergic agents.     

Fetal and maternal lipoprotein metabolism in human pregnancy complicated by type I diabetes mellitus

Serum lipid, apolipoprotein concentration, and lipoprotein composition were determined in maternal and umbilical venous cord blood at delivery by elective Cesarean section (CS) in 10 singleton, full-term pregnancies with maternal insulin-dependent diabetes mellitus (type I DM), which predated pregnancy, and in 22 nondiabetic pregnancies. The objectives of the study were to determine the influence of maternal type I DM, and hence potential fetal overnutrition on fetal lipid metabolism. There were no significant differences in gestational age, fetal weight, or fetal serum insulin concentration between the type I DM group and those with nondiabetic pregnancies, although fetal venous cord blood glucose was 3.4 mmol/L (3.0-4.5 mmol/L) (median and 25th-75th percentiles) and 2.9 mmol/L (2.0-3.4 mmol/L), respectively, and maternal Hemoglobin A1c [9.6% (8.2-10.7%) and 6.8% (6.3-7.8%), respectively], was significantly greater in the type I DM subjects (P < 0.02 and 0.002 respectively). Plasma nonesterified fatty acid (NEFA) concentrations were lower in the type I DM mothers [0.85 mmol/L (0.56-2.31 mmol/L) compared with 1.14 mmol/L (0.88-1.24 mmol/L] in nondiabetic pregnancies; P < 0.0001). Serum high-density lipoprotein phospholipids (HDL-PL) were increased in type I DM mothers because of elevated HDL2 phospholipid [0.39 mmol/L (0.27-0.48 mmol/L) compared with 0.12 mmol/L (0.06-0.21 mmol/L), respectively, P < 0.01). The maternal HDL cholesterol (C) concentration was not significantly different in the uncomplicated and type I DM pregnancies. However, in the umbilical venous cord blood, serum levels of NEFA [0.49 mmol/L (0.33-1.29 mmol/L) in type I DM compared with 0.13 mmol/L (0.06-0.33 mmol/L) in nondiabetics; P < 0.02)], total cholesterol (TC) [2.87 mmol/L (1.65-4.86 mmol/L) in type I DM compared with 1.65 mmol/L (1.46-1.87 mmol/L) in nondiabetics; P < 0.02]; free cholesterol (FC) [0.97 mmol/L (0.60-1.26 mmol/L) in type I DM compared with 0.62 mmol/L (0.37-0.75 mmol/L) in nondiabetics; P < 0.05), and cholesteryl ester (CE) [1.90 mmol/L (1.44-3.33 mmol/L) in type I DM compared with 1.01 mmol/L (0.83-1.24 mmol/L) in nondiabetics; P < 0.02), triglyceride (TG) (1.06 [0.50-1.91) mmol/L in type I DM compared with 0.29 [0.25-0.36] mmol/l in nondiabetics; P < 0.001), phospholipid (PL) (2.52 [1.73-3.03) mmol/L in type I DM compared with 1.34 [1.27-1.48] mmol/L in nondiabetics; P < 0.01], and the apolipoproteins A-I and B had significantly higher concentrations in type I DM. In umbilical venous cord blood, ratios of HDL-TC and HDL-PL to apo AI, reflecting the lipid content of HDL, were reduced when the mother had type I DM during pregnancy (P < 0.02 and P < 0.0001, respectively). These results indicate that maternal type I DM may lead to a fetal serum lipoprotein composition more closely resembling that seen in the adult. In type I DM, maternal TG and PL and fetal TC, TG, PL, CE, and FC were correlated to NEFA levels (P < 0.05), but not to glucose, insulin secretion, or maternal control of type I DM. These data suggest that the enhanced supply of NEFA to the fetus in type I DM pregnancies may drive the synthesis of cholesterol as well as TGs and PLs.     

Phosphodiesterase inhibitory properties of losartan. Design and synthesis of new lead compounds

In order to define more precisely the risk of hypoglycaemia in GH-deficient children and to clarify the role of growth hormone (GH) in glucose homeostasis, a 24-h fast was monitored in 10 GH-deficient children aged 1.1-6.5 y. Asymptomatic hypoglycaemia (blood glucose < or = 2.6 mmol/l) occurred in 9/10 children, 2 of whom prematurely interrupted the test. Blood glucose profile was not reproducible between children and had no correlation with age (p = 0.48). Gluconeogenesis was considered as non-altered as read from the normal plasma lactate and pyruvate concentrations throughout the test. Plasma ketone body concentrations increased during the test, but were lower than expected with respect to the decrease of blood glucose. This suggests insufficient ketogenesis which could exacerbate hypoglycaemia in GH-deficient children if brain glucose utilization were not alleviated by ketone body oxidization, as is normally the case. The positive glucose response after glucagon stimulation in 6/10 patients indicated normal hepatic glycogen content. However, these responses were unexpected following the prolonged fast and its concomitant hypoglycaemia, and would therefore tend to suggest a defect in glycogenolysis. These results confirm the tendency to hypoglycaemia, even after infancy, in GH-deficient children. These hypoglycaemias may occur by different types of malfunctioning, such as insufficient ketogenesis or a defect in glycogenolysis. These hypotheses require confirmation by a more systematic study of the metabolic and hormonal changes that occur during fasting in both GH-deficient and normal children.     

Age-related changes in blood lymphocyte subsets of Saudi Arabian healthy children

The age-related changes in absolute and percentage values of lymphocyte subsets in the peripheral blood of healthy children of different ages (1 month to 13 years) were studied by flow cytometry. The absolute and percentage values for most lymphocyte subpopulations differed substantially with age. Comparisons among age groups from infants through adults revealed progressive declines in the absolute numbers of leukocytes, total lymphocytes, and T, B, and natural killer (NK) cells. The percentages of T cells increased with age. Within the T-lymphocyte population, the CD8(+) subset increased but the CD4(+) subset decreased, resulting in a declining CD4(+)/CD8(+) ratio. The percentage of B cells declined, but that of NK cells remained unchanged. The percentage of HLA-DR+ T cells increased over time, but their number changed inconsistently. Our findings confirm and extend earlier reports on age-related changes in lymphocyte subpopulations. These data should be useful in the interpretation of disease-related changes, as well as therapy-dependent alterations, in lymphocyte subsets in children of different age groups.     

Myocardial contractility is not constant during spontaneous atrial fibrillation in patients

BACKGROUND: The variation in stroke volume and pulse pressure characteristic of atrial fibrillation is usually ascribed to time-dependent ventricular filling, implying a single positive relationship between end-systolic pressure and volume, which defines a single state of myocardial contractility. We tested the hypothesis that contractility also varies. METHODS AND RESULTS: We measured the left ventricular pressure and volume continuously with a conductance catheter with catheter-tip micromanometer introduced retrogradely into the left ventricle. The end-systolic pressure-volume relationship was determined in 6 patients in atrial fibrillation undergoing cardiac catheterization for diagnostic purposes and 4 control patients in sinus rhythm undergoing coronary artery bypass graft surgery. The normal positive relationship between end-systolic pressure and volume was found in the control patients, but no such positive relationship was found in any patient in atrial fibrillation. In the latter, the slopes of the linear regressions were either not significantly different from zero or significantly negative (r values <0.08), both results indicating a change in contractility from beat to beat. Significantly negative relationships were found between end-systolic volume and preceding R-R interval (-0.82相似文献   

Antro-pyloric canal values from early prematurity to full-term gestational age: an ultrasound study

PURPOSE: To evaluate antro-pyloric canal dimensions from early prematurity to full-term gestational age. MATERIALS AND METHODS: Ninety infants with no signs of regurgitation or vomiting were studied 3-5 days after birth. Their gestational ages ranged from 26 to 41 weeks (mean 33.7 weeks) and the body weight from 670 to 4150 g (mean 2067 g). Antro-pyloric muscle thickness, canal length and canal width were measured. RESULTS: A positive correlation between gestational age, muscle thickness (R = 0.71, P < 0.001), length (R = 0.63, P < 0.001) and width (R = 0.42, P < 0.001) was found. Furthermore, a positive correlation between body weight, muscle thickness (R = 0.82, P < 0.001) length, (R = 0.67, P < 0.001) and width (R = 0.55, P < 0.001) was observed. CONCLUSIONS: This study shows that antro-pyloric canal dimensions increase with gestational age. Moreover, it provides normal values for muscle thickness, canal length and canal width from the early gestation to full term.     

Infections due to sandfly fever virus serotype Toscana in Spain

Of the sandfly fever viruses known to be human pathogens (serotypes Toscana [TOS], Sicilian [SFS], and Naples [SFN]), only TOS has demonstrated neurotropic activity. Infections by TOS have been reported in Mediterranean countries, but the virus was previously isolated only in Italy and Portugal. We isolated 15 strains of TOS between 1988 and 1996 from the cerebrospinal fluid of patients with acute aseptic meningitis in Granada, Spain. This finding led us to study the presence of antibodies to TOS, SFS, and SFN in 1,181 adults and 87 children from different regions of Spain. We found that the prevalence of antibodies to these viruses was 26.2%, 2.2, and 11.9%, respectively; these rates imply that TOS infections are common in Spain.     

Dietary deficiency of cystine and methionine in rats alters thiol homeostasis required for cyanide detoxification

Nutritional status is an important factor in modulating the metabolic fate of xenobiotics. Sulfur amino acid (SAA) deficiency has been proposed as a risk factor for human neurological diseases among protein-poor populations subsisting on the cyanophoric plant cassava. Female Sprague-Dawley rats were used to develop and define a model of SAA deficiency for use in future studies examining cassava-related neurotoxicity. Rats were kept in metabolic cages for 7-21 d and fed a balanced diet (BD) of known composition or a comparable diet selectively deficient in methionine and cystine (SAA-free diet). Animals fed the SAA-free diet failed to thrive, lost body weight, excreted porphyrinic materials, and showed a steep and persistent reduction of urinary inorganic sulfate. In contrast, animals on the BD gained body weight and maintained baseline output of urinary inorganic sulfate. Urinary thiocyanate excretion did not differ between groups, but plasma thiocyanate concentrations reached double that in SAA-deficient rats. Increased plasma thiocyanate suggests mobilization of sulfur amino acids from endogenous sources. Liver glutathione and blood cyanide concentrations were similar in animals on the BD and the SAA-deficient diet. In summary, a diet free of methionine and cystine results in increased retention of inorganic sulfur as thiocyanate and a near absence of inorganic sulfur excretion in urine.     

Geographic distribution and clinical description of leishmaniasis cases in Peru

Asymmetric acetylcholinesterase (AChE) is anchored to the basal lamina (BL) of cholinergic synapses via its collagenic tail, yet the complement of matrix receptors involved in its attachment remains unknown. The development of a novel overlay technique has allowed us to identify two Torpedo BL components that bind asymmetric AChE: a polypeptide of approximately 140 kDa and a doublet of 195-215 kDa. These were found to stain metachromatically with Coomassie blue R-250, were solubilized by acetic acid, and were sensitive to collagenase treatment. Upon sequence analysis, the 140 kDa polypeptide yielded a characteristic collagenous motif. Another AChE-binding BL constituent, identified by overlay, corresponded to a heparan sulfate proteoglycan. Lastly, we established that this proteoglycan, but not the collagenous proteins, interacted with at least one heparin binding domain of the collagenic tail of AChE. Our results indicate that at least two BL receptors are likely to exist for asymmetric AChE in Torpedo electric organ.     

Comparative study of bone mineralization in children and adolescents with familial short stature and a control group

Within the past year there has been a dramatic increase in the number of molecular epidemiologic studies reported in the literature, particularly those evaluating gene-gene and gene-environment interactions. Molecular epidemiologic studies have become more sophisticated owing to collaborations between laboratory scientists and epidemiologists, and because these studies are now conducted on well-characterized populations with appropriate study design. Although there continue to be inconsistencies across some studies, it is clear that the evaluation of gene-gene and gene-environment interactions can delineate portions of the population who are particularly sensitive to certain carcinogenic exposures, based on polymorphisms in genes involved in preventing and controlling carcinogenesis. Identification of these subsets of susceptible individuals can result in the design of preventive strategies targeting the most "at risk" populations.