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Biomedical subjects

I Hernandez

Publications and source records attributed to I Hernandez.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy.

BACKGROUND/AIMS AND METHODS: The mechanism(s) behind the effects of ursodeoxycholic acid on serum steroid sulphate profiles in patients with intrahepatic cholestasis of pregnancy is not clear. Conjugated progesterone metabolites and bile acids have therefore been analysed in serum and urine of patients with intrahepatic cholestasis of pregnancy before and during treatment with ursodeoxycholic acid using chromatographic and mass spectrometric methods. RESULTS: The concentration of glycine-/taurine-conjugated bile acids decreased from 8.9+/-3 micromol/l (mean+/-SEM) before treatment to 1.8+/-0.6 micromol/l during treatment with ursodeoxycholic acid. The total bile acid excretion in urine decreased from 56+/-14 to 32+/-5.6 micromol/g creatinine. The proportion of cholic acid in serum and urine, and of 1beta-, 2beta- and 6alpha-hydroxylated cholic acids in urine decreased markedly during ursodeoxycholic acid while the percentages of 3alpha,12alpha-dihydroxy-3-oxo-4-cholenoic acid and chenodeoxycholic acid were unchanged. The levels in serum and excretion in urine of sulphated steroids decreased during ursodeoxycholic acid, by 45-49% for disulphates and 33-35% for monosulphates. The ratios of 3alpha- to 3beta-hydroxysteroid disulphates were lowered by ursodeoxycholic acid from 1.1 (mean) to 0.68 in serum, and from 1.2 to 0.70 in urine. The corresponding ratios for monosulphates before and during ursodeoxycholic acid were 6.9 and 4.5, respectively, in serum, and 21 and 5.2, respectively, in urine. The major monosulphates in urine, dominated by 5alpha-pregnane-3alpha, 20alpha-diol, were also conjugated with N-acetylglucosamine. The excretion of these double conjugates decreased from 27+/-8.4 to 15+/-5.3 micromol/g creatinine during ursodeoxycholic acid. In contrast to sulphated steroids, the concentrations of glucuronides were unchanged in serum and their excretion in urine tended to increase during ursodeoxycholic acid. The metabolism of ursodeoxycholic acid was similar to that described in nonpregnant subjects. In addition to metabolites hydroxylated in the 1beta-, 5beta-, 6alpha/beta and 22-positions, a 4-hydroxy-ursodeoxycholic acid was tentatively identified. This occurred predominantly as a double conjugate with glycine/taurine and glucuronic acid, as did other 4-hydroxylated bile acids of probable foetal origin. CONCLUSIONS: The results are compatible with the contention that ursodeoxycholic acid stimulates the biliary excretion of sulphated progesterone metabolites, particularly those with a 3alpha-hydroxy-5alpha(H) configuration and disulphates. The effect(s) appears to be independent of the stimulation of bile acid secretion. An effect of ursodeoxycholic acid on the reductive metabolism of progesterone cannot be excluded.

Bile Acids and Salts↗
PubMed1997

Profiles of bile acids and progesterone metabolites in the urine and serum of women with intrahepatic cholestasis of pregnancy.

BACKGROUND/AIMS AND METHODS: The etiology of intrahepatic cholestasis of pregnancy (JCP) is unknown. We have performed comprehensive chromatographic and mass spectrometric analyses of progesterone metabolites and bile acids in serum and urine of six patients in order to characterize changes that might be of importance for the development of the disease. RESULTS: Conjugated bile acids were increased in serum and urine of patients with ICP while the levels of unconjugated bile acids were similar in healthy pregnancies and ICP. Unconjugated and conjugated 7 alpha, 12 alpha-dihydroxy-3-oxo-4-cholenoic acid was excreted in urine both in healthy pregnancies and in ICP, possibly indicating a rate limitation of 3-oxo-delta 4-steroid 5 beta-reductase in pregnancy. The serum levels and urinary excretion of total sulfated progesterone metabolites were increased in ICP while the glucuronides were unchanged or low. Confirming previous results, the fraction of metabolites with 3 alpha-hydroxy-5 alpha(H) configuration was increased. The urinary excretion of 5 alpha-pregnane-3 alpha, 20 alpha-diol 3-sulfate, 20-N-acetylglucosaminide was greatly increased in ICP, as was that of 3 alpha-hydroxy-5 alpha-androstane-17 beta-carboxylic acid, assumed to be a progesterone metabolite. CONCLUSIONS: The combined results of this and previous studies are compatible with a primary change in the reductive metabolism of progesterone in ICP, resulting in increased formation of metabolites with a 3 alpha-hydroxy-5 alpha(H) configuration and a larger fraction of sulfates. There also seems to be a selective defect in the biliary secretion of sulfated metabolites, particularly disulfates.

Bile Acids and Salts↗
PubMed1997

Abnormal expression of serotonin transporter mRNA in the frontal and temporal cortex of schizophrenics.

Postmortem brain tissue was used to measure expression of serotonin transporter mRNA in the left frontal and left temporal cortex from schizophrenics (n = 24) and from normal control individuals with no history of psychiatric illness (n = 10). There was an approximately four-fold increase of serotonin transporter mRNA in Brodmann's area 9 and a two-fold decrease in Brodmann's areas 21 and 22. The changes in serotonin transporter mRNA were more prominent in schizophrenics who had received neuroleptic drugs within 1 week prior to death than in schizophrenics who were neuroleptic-free for more than 2 weeks prior to death, suggesting that the changes may be related to neuroleptic treatment. There was no correlation between serotonin transporter mRNA levels and the sex or age of schizophrenic and control cases or the postmortem delay intervals. These results support the hypothesis that region-specific changes in serotonin transporter expression occur in brains of some schizophrenics. Future studies are necessary to determine whether the changes in serotonin transporter expression are drug-related or are associated with the illness itself.

Aged↗
PubMed1997

Induction of guanosine triphosphate-cyclohydrolase by follicle-stimulating hormone enhances interleukin-1 beta-stimulated nitric oxide synthase activity in granulosa cells.

In cultured granulosa cells, interleukin-1 beta (IL-1 beta) induced a time-dependent (16-72 h) and dose-related (0.3-30 ng/ml) stimulation of nitric oxide (NO) synthase (NOS) activity, as determined by the catalytic conversion of [3H]arginine to [3H]citrulline and NO2- accumulation in the culture medium. Although FSH alone failed to stimulate NOS activity, concomitant treatment with the gonadotropin (200 ng/ ml) or the cell-permeant cAMP analog (Bu)2cAMP (0.5 mM) markedly enhanced IL-1 beta-induced NO generation in cultured granulosa cells. The effect of IL-1 beta on citrulline biosynthesis and NO2- accumulation was abrogated by the NOS inhibitor NG-methyl-L-arginine or the IL-1-receptor antagonist protein. In contrast bacterial endotoxin (lipopolysaccharide), interferon-gamma, or tumor necrosis factor-alpha, which are well known inducers of inducible NOS (iNOS) in a variety of immunocompetent and nonimmunocompetent cell types, failed to increase [3H]citrulline formation or NO2- accumulation in untreated or FSH-stimulated cells. As demonstrated by reverse transcriptase-PCR analysis, IL-1 beta-stimulated NO generation was accompanied by a time-dependent increase in messenger RNA levels for iNOS and GTP-cyclohydrolase (GTPCH), the rate-limiting step for de novo tetrahydrobiopterin (BH4) biosynthesis. Treatment with FSH augmented only GTPCH messenger RNA expression, and a more than additive GTPCH signal was observed when cells were simultaneously challenged with IL-1 beta and FSH. Treatment with the GTPCH inhibitor 2,4-diamino-6-hydroxypyrimidine prevented IL-1 beta-induced NOS activity in untreated or FSH-stimulated cells, and this inhibition was completely reversed by sepiapterin, a substrate for BH4 biosynthesis, via an alternative pterin salvage pathway present in many cell types. As BH4 is an essential cofactor for NOS catalytic activity, these observations strongly suggest that FSH-induced biosynthesis of endogenous BH4 is essential for full iNOS biosynthetic capacity in IL-1 beta-stimulated granulosa cells.

Animals↗
PubMed1996

Interleukin-1 beta stimulates sphingomyelin hydrolysis in cultured granulosa cells: evidence for a regulatory role of ceramide on progesterone and prostaglandin biosynthesis.

In granulosa cells labeled to isotopic steady-state with [3H]serine, addition of interleukin-1 beta (IL1 beta) or bacterial sphingomyelinase (SMase) induced a rapid decrease (approximately 60% by 10 min) in cellular [3H]Sphingomyelin content and a prolonged generation (up to 60 min) of [3H]ceramide, the immediate lipid-moiety generated in response to sphingomyelin hydrolysis. In FSH-treated cells, IL1 beta (0.3-30 ng/ml) inhibited progesterone biosynthesis in a dose-dependent manner, an effect that was also observed in cells exposed to increasing concentrations of bacterial SMase (0.003-0.3 U/ml) or the membrane-permeable ceramide analogue N-hexanoylsphingosine (C6-cer:0.1-10 microM). Abrogation of progesterone biosynthesis was not a sole consequence of inadequate cAMP biosynthesis because cyclic nucleotide levels remained elevated (3- to 4-fold over untreated cultures) after addition of IL1 beta, SMase, or two different cell permeable ceramide analogues (C2-cer and C6-cer) to gonadotropin-stimulated granulosa cells. Moreover, taken into account that exogenous SMase or C6-cer partially abolished progesterone biosynthesis induced by But2cAMP (0.5 mM) or cholera toxin (CTX: 1 microgram/ml), the above mentioned results support the notion that activation of the sphingomyelin pathway exerts its inhibitory effects on granulosa cell steroidogenic activity at site(s) of action both proximal and distal to cAMP generation. As determined by RT-PCR analysis, the inhibitory effect of IL1 beta, SMase, or C6-cer on gonadotropin-stimulated steroidogenesis was accompanied by arrested transcription of the mitochondrial cholesterol side chain cleavage enzyme (P450scc) and 3 beta-hydroxysteroid dehydrogenase/delta 5-4isomerase, the two FSH-inducible steps involved in progesterone biosynthesis. Although bacterial SMase or the ceramide analogue C6-cer alone did not exactly reproduce the effect of IL1 beta on granulosa cell prostaglandin E2 (PGE2) biosynthesis, both agents augmented net PGE2 production and messenger RNA levels of the inducible prostaglandin endoperoxide synthase/cyclooxygenase (PGHS-2) in cytokine-treated cells. Although the effect on PGHS-2 messenger RNA may account for the facilitatory role of ceramide on IL1 beta-induced PGE2 biosynthesis, neither SMase nor the membrane-permeant ceramide analogue were able to augment prostaglandin accumulation in the presence of exogenously added arachidonate precursor. Collectively, whereas these results show that ceramide triggers a negative-effector pathway that is both necessary and sufficient to reproduce the inhibitory effect of IL1 beta on FSH-stimulated granulosa cell steroidogenesis, they also support the notion that sphingomyelin hydrolysis may be important for cytokine-induced PGHS-2 expression but not sufficient to reproduce IL1 beta-stimulated PGE2 biosynthesis.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

Hemodynamic and microcirculatory changes during development of renal hypertension.

To study the progression of vessel loss (rarefaction) during the development of hypertension, a plastic window was chronically implanted over the biceps femoralis muscle of reduced renal mass (RRM) and sham-operated control (SOC) rats on a low-salt diet (0.4%). Blood pressure was measured directly via a catheter implanted in the femoral artery, and tissue blood flow was measured by laser-Doppler flowmetry before and after local topical application of sodium nitroprusside. Measurements were made on the control day and after an increase in sodium intake (4.0%) in RRM rats on days 5, 10, 14, 21, and 28. SOC rats on a low-salt diet served as the control group. RRM rats became hypertensive (167 mmHg), and vascular resistance increased after a change in sodium intake. Resting tissue blood flow decreased by 19% by day 28 in RRM but did not change in SOC. Sodium nitroprusside administration reduced vascular resistance to the same level in both RRM and SOC during control and at day 10; however, on all other days, sodium nitroprusside was not able to fully dilate the RRM microcirculation compared with that of SOC. At the same time, microvascular density estimated by computer fluorescence microscopy was decreased by 25% in RRM rats. These studies indicate that the development of RRM hypertension is characterized by a transition from increased tone and vessel closure (functional rarefaction) to anatomic vessel loss (structural rarefaction).

Analysis of Variance↗
PubMed1995

Ceramide mediates tumor necrosis factor effects on P450-aromatase activity in cultured granulosa cells.

In [3H]serine-labelled granulosa cells treatment with TNF alpha (10 ng/ml) resulted in a transient decrease in cellular [3H]sphingomyelin and generation of [3H]ceramide that remained elevated 60 min later. In cells labelled with [methyl-14C]choline, TNF alpha induced a similar reduction in [14C]sphingomyelin content that was accompanied by a sustained elevation in [14C]phosphorylcholine levels. In FSH-primed cells, TNF alpha inhibited P450-AROM activity in a dose-dependent manner, an effect that was also observed in cells treated with bacterial sphingomyelinase (SMase 0.003-0.3 U/ml) or increasing concentrations (0.1-10 microM) of N-acetylsphingosine (C2-cer) a membrane-permeable analogue of ceramide. These results support the notion that sphingomyelin degradation to a bioeffector molecule ceramide, may be an early event involved in TNF alpha-induced signal transduction in granulosa cells.

Animals↗
PubMed1994

Bacterial pericarditis in infancy and childhood.

The authors report on a cooperative study of 43 cases of bacterial pericarditis observed in children. This disorder was suspected in patients with septicemia who developed symptoms and signs of pericarditis (precordial pain, muffled heart sounds, pericardial friction rub, cardiomegaly). Early diagnosis of this condition is now facilitated by echocardiography. A combination of medical and surgical treatments (appropriate antibiotic therapy after culture and sensitivity tests and early pericardial drainage) led to complete recovery in almost all of the cases (42 of 43). After long-term follow-up, no cases of constrictive pericarditis were observed.

Adolescent↗
PubMed1994

Clostridium difficile toxin A therapy for HCT 116 human colon cancer in nude mice.

Clostridium difficile toxin A was evaluated for an antitumor effect in vivo on HCT 116 human colon carcinoma cells growing subcutaneously in nude mice. A mean reduction in tumor volume of at least 65%, by measurement in three dimensions, was observed in mice who received two 9- to 13-day courses of daily intraperitoneal injections of toxin A as compared to mice receiving diluent alone. Reversible adverse effects of toxin A were noted in some animals, consisting primarily of liver toxicity and skin rash. HCT 116 cells in toxin A-treated mice grew as flattened tumors with ulcerated centers compared to rounded tumors without ulceration in controls. Histologic examination of tumors from representative mice revealed that two thirds of the tumor in a treated mouse was necrotic compared to only one third in a control, suggesting greater antitumor efficacy of toxin A than estimated by tumor measurements alone.

Animals↗
PubMed1994

Cardiovascular effects of angiotensin II and vasopressin in intact awake rats.

1. In this study we evaluated, in intact awake rats, the effects of angiotensin II (AII) and vasopressin (AVP) on venous tone to explain their different hemodynamic effects. 2. Cardiac index (CI) was measured by thermodilution. AII and AVP were infused at the doses adjusted to increase mean arterial pressure 25, 50 and 70% above baseline. Lower doses of AVP than AII were necessary to increase mean arterial pressure at the same levels. 3. To study whether the different effects of AII and AVP on CI may be explained by their different actions on the venous system, changes in venous tone were evaluated by measuring mean circulatory filling pressure (MCFP) and determining the pressure gradient for venous return (PGVR). 4. AVP induced a decrease in CI from 32.5 +/- 2.2 to 23.1 +/- 1.7 and 15.4 +/- 0.8 ml/min/100 g (P < 0.01) with the second and third level of increase in afterload respectively, whereas AII at the same levels of afterload decreased CI from 34.8 +/- 1.3 to 28.3 +/- 2.3 and 23.4 +/- 1.7 ml/min/100 g (P < 0.01). Furthermore, the rise in total peripheral resistances (TPR) was greater with AVP than with AII at the highest level of afterload (P < 0.05). Heart rate significantly decreased more in the animals infused with AVP than with AII. 5. There were no changes in MCFP and PGVR with either AII or AVP. 6. These results indicate that in intact awake rats the larger fall in CI induced by AVP can not be explained only by a greater decrease in HR since at highest levels of afterload AVP decreased SV.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1994

Mechanism of cholinergic stimulation of glucose oxidation in isolated gastric glands.

The mechanisms of cholinergic activation of carbohydrate metabolism were investigated in isolated rabbit gastric glands. Carbachol stimulated the rate of glucose oxidation in a dose-dependent fashion with a half-maximal effect occurring at approximately 9 microM. Atropine and omeprazole, but not cimetidine, completely blocked the stimulation induced by carbachol. Direct activation of the H(+)-K(+)-adenosinetriphosphatase by NH+4 caused a significant stimulation of glucose oxidation that was totally abolished by oligomycin and by the mitochondrial uncouplers dinitrophenol and carbonyl cyanide p-trifluoromethoxyphenylhydrazone. These latter agents did not abolish the stimulating effect of carbachol on glucose oxidation. Ionomycin increased the rate of glucose oxidation in a dose-dependent manner, and this effect was not blocked by oligomycin. The metabolic effect of ionomycin was reduced but not abolished by omeprazole. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester eliminated the carbachol-induced stimulation of glucose oxidation and partially inhibited the effect of NH+4. The mitochondrial enzymes pyruvate dehydrogenase and oxoglutarate dehydrogenase were activated by physiological concentrations of calcium in the isolated mitochondria. This effect was blocked by incubation with ruthenium red.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Reliability of the diagnosis of rheumatic conditions at the primary health care level.

OBJECTIVE: To assess the reliability of the diagnosis given to rheumatic disease patients at the primary care level, the clinical records of 612 patients at the outpatient clinic of rheumatology of the main General Hospital in Alicante (Spain) were studied. METHODS: The accuracy indices (sensitivity, specificity), the predictive values of tentative diagnosis made by the referring physicians and the degree of agreement (Kappa statistics) with the final diagnoses made by rheumatologists at the outpatient clinic of rheumatology were calculated. RESULTS: There were differences in diagnosis agreement depending on the age of the referring doctor, with a greater degree of concordance among younger ones. More than 50% of the referral diagnoses were modified at the rheumatology outpatient clinic. In the most frequent diagnoses (inflammatory rheumatic diseases, osteoarthritis, soft tissue rheumatism) the level of concordance and the predictive values were low. CONCLUSION: Our results highlight the need for upgrading courses in rheumatology for primary care physicians who have not been exposed to systematic training in rheumatology during their undergraduate studies. The epidemiological studies on rheumatic diseases based on primary care data should be interpreted with caution.

Adult↗
PubMed1992

Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy.

The efficacy and safety of ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy was investigated in an open pilot study. Five patients received 1 gm/day of ursodeoxycholic acid during 20 days and another three patients received two identical periods of treatment separated by a 14-day interval free of the drug. Pruritus and serum levels of total bile salts and glutamic-pyruvic transaminase improved significantly during treatment with ursodeoxycholic acid. In the three patients who received two periods of treatment with ursodeoxycholic acid, pruritus and the laboratory alterations relapsed in the second week after the drug was discontinued, but they improved again when ursodeoxycholic acid was readministered. No adverse reactions were detected in the mothers or in their babies. All newborns were thriving normally during a follow-up period that lasted 5 mo after delivery. It is concluded that UDCA appears to be safe when administered in late pregnancy; its promising efficacy in the treatment of intrahepatic cholestasis of pregnancy should now be confirmed in controlled clinical trials.

Adult↗
PubMed1992

Increased total vascular capacity in conscious cirrhotic rats.

The purpose of the present study was to determine the role of the systemic venous circulation in the hemodynamic alterations of the cirrhotic disease. Cardiac output (thermodilution; n = 8), mean circulatory filling pressure (balloon technique; n = 6), and blood volume (Evans blue dye; n = 7) were investigated in a rat model of liver cirrhosis without ascites induced by a 12-week individualized CCl4/phenobarbital treatment. Compared with control rats, conscious cirrhotic rats showed a hyperdynamic circulation characterized by normotension, high cardiac output (51 +/- 4.8 vs. 28.6 +/- 1.3 mL.min-1.100 g-1; P less than 0.01), and expanded blood volume (6.5 +/- 0.15 vs. 5.4 +/- 0.22 mL.100 g-1; P less than 0.05). There were no significant differences between control and cirrhotic rats in mean circulatory filling pressure (6.40 +/- 0.27 vs. 5.99 +/- 0.22 mm Hg, respectively) or in the pressure gradient for venous return (6.17 +/- 0.19 vs. 5.8 +/- 0.21 mm Hg, respectively). To further examine the venous tone, effective vascular compliance was estimated with the vascular filling-blood volume relationship by measuring the vascular filling before and after rapid changes in volume (+/- 8 mL.kg-1). Compliance was similar in both control and cirrhotic rats (3.15 +/- 0.26 and 3.41 +/- 0.21 mL.mm Hg-1), but the vascular filling-total blood volume relationship of the cirrhotic rats was displaced toward the volume axis. In conclusion, the increase in blood volume without changes in mean circulatory filling pressure (or venous tone) of the cirrhotic rats indicates a situation with venodilation and elevated total venous capacity; this is likely to be an important mechanism that could explain the hyperdynamic circulation of the cirrhotic disease.

Animals↗