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Biomedical subjects

J Bosch

Publications and source records attributed to J Bosch.

At least 73 records · Page 4Linked to original sources
PubMed2000

Introduction of heteroatom-based substituents into 1,4-dihydropyridines by means of a halogen-mediated, oxidative protocol: diamination, sulfonylation, sulfinylation, bis-sulfanylation, and halo-phosphonylation processes

The natural tendency of 1,4-dihydropyridines to undergo "biomimetic" oxidation to afford pyridinium salts can be switched off and, through the use of reagents that interact electrophilically with the enamine moiety present in the heterocyclic system, it is possible to promote alternative oxidations. In this way, efficient regio- and stereocontrolled synthetic methods have been developed that lead to diversely substituted di- and tetrahydropyridines. These include iodoazidation, diamination, bis-sulfonamidation, sulfonylation, sulfinylation, thiocyanation, sulfanylation, bis-sulfanylation, and halo-phosphonylation processes.

Journal Article↗
PubMed2000

Synthesis and dopaminergic activity of heterocyclic analogues of 5,6-dihydroxy-2-aminotetralins.

The heterocyclic analogues of 5,6-dihydroxy-2-aminotetralins (6) were synthesized and their in vitro dopaminergic activity was compared to that of (-)-DP-5,6-ADTN and the novel potent agonist Z12571. The results show that changing the cathecol ring for a heterocycle decreases the D1-like activity of the target molecules 6. However, the D2-like activity of tetrahydroquinoline (6j) was comparable to that of (-)-DP-5,6-ADTN.

Acylation↗
PubMed2000

Enantioselective total synthesis of Wieland-Gumlich aldehyde and (-)-strychnine

A total synthesis of (-)-strychnine in 15 steps from 1,3-cyclohexanedione in 0.15% overall yield is described. The sequence followed in the assembling of rings is: E-->AE [2-(2-nitrophenyl)-1,3-cyclohexanedione]-->ACE (3a-aryloctahydroindol-4-one)-->ACDE (arylazatricyclic core)-->ABCDE (strychnan skeleton)-->ABCDEF (Wieland-Gumlich aldehyde)-->ABCDEFG (strychnine). The key steps of the synthesis are the enantioselective construction of the 3a-(2-nitrophenyl)-octahydroindol-4-one ring system and the closure of the piperidine ring by a reductive Heck cyclization to generate the pivotal intermediate (-)-14. In contrast, a Lewis acid promoted a-alkoxypropargylic silane-enone cyclization did not lead to synthetically useful azatricyclic ACDE intermediates. The introduction of C-17 and the closure of the indoline ring by reductive amination of the alpha-(2-nitrophenyl) ketone moiety complete the strychnan skeleton from which, via the Wieland-Gumlich aldehyde, the synthesis of (-)-strychnine is achieved.

Journal Article↗
PubMed2000

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.

BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. METHODS: A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper. RESULTS: A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03). CONCLUSIONS: Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Aged↗
PubMed2000

Vitamin E supplementation and cardiovascular events in high-risk patients.

BACKGROUND: Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis. METHODS: We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer. RESULTS: A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E. CONCLUSIONS: In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.

Aged↗
PubMed2000

Family functioning and psychosocial adjustment in overweight youngsters.

OBJECTIVE: To analyze the relationship between family functioning and psychosocial adjustment in Dutch overweight children and adolescents. METHOD: Seventy-three overweight (weight-for-height >P90) and 70 normal-weight youngsters between the ages of 10 and 16 years were recruited by school physicians during routine medical screening. The Family Dimension Scale, the Child Behavior Checklist, the Teacher Report Form, the Self-Perceived Competence Scale, and the Body-Esteem Scale were filled out, as well as a specific weight-related questionnaire. RESULTS: Both parents and teachers report more behavior problems in overweight children, particularly in the younger than 13 age group. Lower body-esteem was found in older overweight girls, whereas in older overweight boys higher levels of body-esteem were found. More significant relationships were found with the weight-related Parental Concern Scale than with the Family Dimension Scale. DISCUSSION: The results suggest that a developmental psychological approach reveals important age and sex differences. Weight-related instruments may be more useful than general questionnaires.

Adolescent↗
PubMed2000

The role of portal pressure in the severity of bleeding in portal hypertensive rats.

The aim of this study was to investigate the role of portal hypertension determining the severity of bleeding in portal hypertensive rats. The effects of section of branches of the ileocolic vein were studied in sham-operated (SO), partial portal vein-ligated (PPVL), and common bile duct-ligated (CBDL) rats. The ensuing hemorrhage was compared with that caused by section of femoral vein, where the portal hypertensive factor is excluded. In PPVL rats, section of branches of increasing size (divided into fourth, third, second, and first order) resulted in increasingly severe bleeding (arterial pressure: / +/- 4%, / 6 +/- 12%, / /15 +/- 8%, and / 28 +/- 13%; P <.005; hematocrit / 4 +/- 2%, / 6 +/- 1%, / 7 +/- 2%, and / 10 +/- 4%; P <.005). Bleeding from first-order branches was mild in SO, moderate in PPVL, and severe in CBDL rats, as shown by increasing changes in arterial pressure (/ 3 +/- 3%, / 12 +/- 16% and, / 43 +/- 23%; P <.01), hematocrit (/ 4 +/- 1%, / 12 +/- 2%, and / 32 +/- 19%; P <.01), and mortality (0%, 0%, and 56%; P <.001). Greater blood loss in CBDL rats was associated with higher portal pressure (16.6 +/- 2.7 vs. 13. 1 +/- 1.1 mm Hg in PPVL; P <.01) and more prolonged bleeding time (70 +/- 4 vs. 35 +/- 3 seconds in PPVL; P <.001). Vessels were similarly dilated in CBDL and PPVL (0.7 +/- 0.2 and 0.7 +/- 0.1 vs. 0.4 +/- 0.1 mm in SO; P <.05). Section of femoral vein caused equal blood loss in SO, PPVL, and CBDL rats, assessed by falls in hematocrit (/ 8 +/- 2%, / 7 +/- 1%, / 8 +/- 1%, respectively; NS) and by the blood loss (3.6 +/- 0.7, 3.5 +/- 0.9, and 3.8 +/- 0.7 g; NS). The study shows that the degree of portal pressure elevation is a major determinant of the severity of portal hypertension-related bleeding in PPVL and CBDL rats.

Animals↗
PubMed2000

Ascites after liver transplantation.

Massive ascites after liver transplantation, although uncommon, usually represents a serious adverse event. The pathogenesis of this complication has not been adequately investigated. To determine the incidence, characteristics, and pathogenic factors of massive ascites after liver transplantation (ascitic fluid > 500 mL/d for >10 days), the charts of 378 liver transplant recipients were reviewed. Massive ascites occurred in 25 patients (7%). Mean ascitic fluid production was 960 mL/d (range, 625 to 2,350 mL/d), and the duration of ascites was 77 days (range, 15 to 223 days). The ascitic fluid had a high protein content (36 +/- 7 g/L; range, 25 to 50 g/L). When patients who did and did not develop massive ascites were compared, significant differences were found in receptor sex (men, 88% v 60%, respectively; P <.01) and surgical technique (inferior vena cava preservation with piggyback technique, 72% v 41%; P <.01). Significantly increased wedged and free hepatic venous pressures and gradients between hepatic vein and right atrial pressures were found in patients who developed ascites, suggesting a difficulty in graft blood outflow. Massive ascites was associated with renal impairment, increased incidence of abdominal infection, prolonged hospitalization, and a tendency toward reduced survival. In conclusion, massive ascites after liver transplantation is relatively uncommon but associated with increased morbidity and mortality and is predominantly related to difficulties of hepatic venous drainage. Measurement of hepatic vein and atrial pressures to detect a significant gradient and correct possible alterations in hepatic vein outflow should be the first approach in the management of these patients.

Adult↗
PubMed2000

Gene structure of the mouse leukocyte cell surface molecule Ly9.

The Ly9 glycoprotein is a member of the immunoglobulin (Ig) superfamily, which is expressed on the cell surface of B and T lymphocytes. With two alleles (Ly9.1 and Ly9.2), it was first described as an alloantigenic marker of lymphocyte differentiation. Ly9 consists of four Ig-like domains with the structural features of the CD2 subfamily, which includes CD2, CD48, CD58, 2B4, CD84, and CDw15O (SLAM). Here, we report the isolation and characterization of the Ly9 gene, which encompasses at least 19 kb and contains ten separated exons, with sizes ranging from 54 to 355 bp. Each Ig-like domain is encoded by an individual exon. Sequence analysis of a 1.5-kb fragment upstream from the start translational codon revealed the absence of appropriately located TATA and CAAT boxes. However, potential binding sites for the transcription factors PU.1, Ikaros, AP-1, GATA-2, NF-GMa, NFAT-1, and Oct-2, which are involved in the early development and maturation of lymphocytes, were found. To further characterize the two allotypes of Ly9, cDNA of Balb/C and C57BL/6 mouse strains were sequenced and the predicted polypeptides compared. Nine discrepancies were found, four of them in the first Ig-like domain. The characterization of the genomic organization of Ly9 presented in this paper may improve understanding of the molecular mechanisms that regulate Ly9 expression, and the production of a construct to disrupt the Ly9 gene in ES cells in order to produce deficient mice.

5' Untranslated Regions↗
PubMed2000

Angiotensin II induces contraction and proliferation of human hepatic stellate cells.

BACKGROUND & AIMS: Circulating levels of angiotensin II (ANGII), a powerful vasoconstrictor factor, are frequently increased in chronic liver diseases. In these conditions, hepatic stellate cells (HSCs) proliferate and acquire contractile properties. This study investigated the presence of receptors for ANGII and the effects of ANGII in human HSCs activated in culture. METHODS: The presence of ANGII receptors was assessed by binding studies. The effects of ANGII on intracellular calcium concentration ([Ca(2+)](i)), cell contraction, and cell proliferation were also assessed. RESULTS: Binding studies showed the presence of ANGII receptors of the AT1 subtype. ANGII elicited a marked dose-dependent increase in [Ca(2+)](i) and cell contraction. Moreover, ANGII stimulated DNA synthesis and increased cell number. All these effects were totally blocked by losartan and reduced by nitric oxide donors or prostaglandin E(2). The effects of ANGII were barely detectable in quiescent cells (2 days in culture), suggesting that phenotypic transformation of HSCs is associated with a marked increase in the effects of ANGII. CONCLUSIONS: ANGII induces contraction and is mitogenic for human-activated HSCs by acting through AT1 receptors. These results suggest that activated HSCs are targets of the vasoconstrictor action of ANGII in the intrahepatic circulation.

Angiotensin II↗
PubMed2000

Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension.

BACKGROUND/AIMS: Septic shock is a systemic response to infection, and it causes a high mortality rate in cirrhotic patients. The mechanisms responsible for this susceptibility in cirrhosis are poorly understood. The aim of this study was to investigate whether monocyte activation and hepatic function are altered in portal hypertension after endotoxin administration. METHODS: Portal-hypertensive and sham-operated rats were used. Plasma levels of tumor necrosis factor-alpha after lipopolysaccharide stimulation (both in vivo and in vitro) were measured by ELISA. CD11b/CD18 integrin expression on leukocyte membrane was measured by flow cytometry. Plasma transaminase activities were also determined. RESULTS: The levels of tumor necrosis factor-alpha in plasma and the expression of CD11b/CD18 on leukocytes in portal-hypertensive rats was similar to that in sham-operated rats. Injection of 150 microg/kg of lipopolysaccharide produced a 9-fold increase in plasma levels of tumor necrosis factor-alpha in portal-hypertensive compared with sham-operated rats, together with a significant up-regulation of CD11b/CD18 expression on monocytes and an elevation in plasma transaminase activity. Blood leukocytes incubated in vitro with lipopolysaccharide (0.5 microg/ml) induced a hypersecretion of tumor necrosis factor-alpha in portal-hypertensive rats, as compared to sham-operated rats. CONCLUSIONS: This study shows that monocytes from portal-hypertensive rats have an enhanced response to endotoxin, leading to hepatotoxicity.

Alanine Transaminase↗
PubMed2000

Complications of cirrhosis. I. Portal hypertension.

Increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension, and is mainly determined by the morphological changes occurring in chronic liver diseases. This is aggravated by a dynamic component, due to the active-reversible- contraction of different elements of the porto-hepatic bed. A decreased synthesis of NO in the intrahepatic circulation is the main determinant of this dynamic component. This provides a rationale for the use of vasodilators to reduce intrahepatic resistance and portal pressure. Another factor contributing to aggravate the portal hypertension is a significant increase in portal blood flow, caused by arteriolar splanchnic vasodilation and hyperkinetic circulation. Splanchnic arteriolar vasodilation is a multifactorial phenomenon, which may involve local (endothelial) mechanisms as well as neurogenic and humoral pathways. Most pharmacological treatments have been aimed at correcting the increased portal blood inflow by the use of splanchnic vasoconstrictors, such as beta-blockers, vasopressin derivatives and somatostatin. Several studies have demonstrated that changes in the hepatic venous pressure gradient (HVPG) during maintenance therapy are useful to identify those patients who are going to have a variceal bleeding or rebleeding. The wide individual variation in the HVPG response to pharmacological treatment makes it desirable to schedule follow-up measurements of HVPG during pharmacological therapy. A priority for research in the forthcoming years is to develop accurate non-invasive methods to assess prognosis, which can be used to substitute or as surrogate indicators of the HVPG response. In the clinical management of portal hypertension, beta-blockers are at present the only accepted treatment for the prevention of variceal bleeding. Whether the association of isosorbide-5-mononitrate will improve the high efficacy of beta-blockers is questionable. The efficacy of more aggressive techniques, such as endoscopic band ligation, should be further tested against beta-blockers in patients with a high risk of bleeding. In the treatment of acute variceal bleeding, administration of somatostatin or terlipressin is an established therapy. It may be used alone or, preferably, as an initial treatment before sclerotherapy or endoscopic band ligation. No more than two sessions of endoscopic treatment should be used to control the bleeding. If the bleeding is not easily controlled, other alternatives such as transjugular intrahepatic portosystemic shunts (TIPS) or derivative surgery should be considered, the former being the best in patients with poor liver function. Recent studies suggest that early measurement of HVPG during variceal bleeding may be used as a guide for therapeutic decisions in the treatment of patients with acute variceal bleeding. Those patients with a high HVPG have a high risk of poor evolution, and may be candidates for more intensive and aggressive therapy, such as surgery or TIPS. Those with lower HVPG have a very high probability of an uneventful evolution, and may thus be managed more conservatively using medical and endoscopic treatments. Pharmacological agents (propranolol or nadolol), endoscopic treatment (preferably banding ligation) or surgery can be used to prevent rebleeding. A pending task for the new millennium is to assess whether the early treatment of asymptomatic, compensated cirrhotic patients with portal pressure reducing agents can prevent the development of esophageal varices and of other complications of portal hypertension.

Animals↗
PubMed2000

Production and characterization of monoclonal antibodies against conserved epitopes of P-selectin (CD62P).

P-selectin (CD62P) is an adhesion molecule expressed on the activated endothelium and activated platelets that is involved in the initial attachment of leukocytes to inflamed vascular endothelium. Blocking monoclonal antibodies (mAbs) and P-selectin-deficient mice have shown that P-selectin is a potential target in anti-inflammatory therapy. Most mAbs against P-selectin do not bind to conserved epitopes, including the ligand-binding region, since P-selectin from mammalian species shares high amino acid sequence homology. The aim of this study was to generate a novel panel of anti-P-selectin mAbs against the conserved epitopes present in several animal species. To produce these mAbs, P-selectin-deficient mice were immunized with a pre-B-cell line transfected with human P-selectin cDNA. Twelve mouse mAbs that recognize human P-selectin were obtained. Individual mAbs that bound to human, rat, mouse, rabbit and pig activated platelets were characterized by flow-cytometry, immunohistochemistry, adhesion assays and immunoprecipitation. Four of these mAbs (P-sel.KO.2.3, P-sel.KO.2.4, P-sel.KO.2.7 and P-sel.KO.2.12) cross-reacted with human, rat and mouse P-selectin. Another three mAbs (P-sel.KO.2.2, P-sel.KO.2.11 and P-sel.KO.2.12) blocked the attachment of HL60 cells to P-selectin-transfected COS cells, demonstrating that these mAbs inhibit P-selectin-mediated adhesion. MAb cross-blocking experiments showed that these three mAbs bind to very close and overlapping epitopes. An ELISA assay using mAbs P-sel.KO.2.3 and P-sel.KO.2.12 was designed to measure soluble rat, mouse and human P-selectin. These anti-P-selectin mAbs are unique since they recognize common epitopes conserved during mammalian evolution and they may be useful for studying P-selectin function in inflammatory models in various species.

Animals↗
PubMed2000

Medical treatment of portal hypertension.

In this chapter we give a quick review of the rationale for treatment of portal hypertension. The different scenarios for treatment of variceal bleeding will be discussed-that is, primary and secondary prophylaxis of variceal bleeding as well as the treatment of the acute bleeding episode. The role of the pharmacological, endoscopic and derivative treatments in each one of these scenarios will be discussed. Particular attention will be devoted to the potential role of the combination therapy of beta-blockers with isosorbide-5-mononitrate for preventing re-bleeding and to the best approach to patients with intolerance or contraindications to beta-blockers. We also give a rational review of the data comparing sclerotherapy against ligation as well as the potential role of the latter on primary prophylaxis.

Combined Modality Therapy↗
PubMed2000

Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension.

Noninvasive measurements of variceal pressure adequately reflect the hemodynamic effects of propranolol on portal hypertension. However, the prognostic value of variceal pressure responses during continued propranolol therapy has not been evaluated, and it is unclear whether this may substitute invasive measurements of portal pressure response. Fifty-five portal hypertensive patients with cirrhosis were studied before and at 4 months of continued propranolol therapy. Variceal pressure was measured using an endoscopic pressure gauge. Portal pressure was evaluated as the hepatic venous pressure gradient (HVPG). Over a 28 +/- 11 month follow-up, 16 patients experienced variceal bleeding. Baseline characteristics were similar in bleeders and nonbleeders. At 4 months, reduction in variceal pressure was less marked in bleeders than in nonbleeders (5% +/- 20% vs. -15% +/- 24%; P =.03). A fall in variceal pressure 20% or greater of baseline was an independent predictor of absence of variceal bleeding; which occurred in 5% of patients with a 20% or greater fall in variceal pressure versus 42% of patients with less than a 20% reduction (P =.004). The HVPG response had similar independent prognostic value (decrease > or =20%: 6% bleeding; decrease <20%: 45% bleeding; P =.004) but identified different patients. Achieving a 20% decrease in either variceal pressure or HVPG was highly sensitive (85%) and specific (93%) identifying patients not bleeding on follow-up. Endoscopic measurements of variceal pressure response to continued pharmacotherapy provide useful prognostic information on the risk of variceal bleeding. As with HVPG response, a fall in variceal pressure of 20% or greater is associated with a very low risk of variceal bleeding. The combination of both parameters allows almost optimal prognostication.

Adult↗
PubMed2000

Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study.

Failure to control bleeding and early rebleeding account for the high mortality associated with variceal hemorrhage in cirrhosis. We compared endoscopic sclerotherapy to terlipressin, a drug that effectively controls acute bleeding while reducing in-hospital mortality. This multicenter randomized controlled trial included 219 cirrhotic patients admitted for endoscopy-proven acute variceal bleeding and randomized to receive repeated injections of terlipressin during 6 days (n = 105) or emergency sclerotherapy (n = 114). Success was defined as obtaining control of bleeding (24-hour bleeding-free period during the first 48 hours) and lack of early rebleeding (any further bleeding from initial control to 5 days later) and survival during the study. Both groups were similar at inclusion. Failure rate for terlipressin was 33% and 32% for sclerotherapy (not significant [NS]). Early rebleeding was responsible for 43% and 44% of failures, respectively. This high efficacy was observed in both Child-Pugh class A + B and Child-Pugh class C patients. Both treatments were similar regarding transfusion requirements, in-hospital stay, and 6-week mortality (26 vs. 19 patients). Side effects appeared in 20% of patients receiving terlipressin and in 30% of those on sclerotherapy (P =.06); being serious in 4% and 7%, respectively (NS). In conclusion, terlipressin and sclerotherapy are equally highly effective therapies achieving the initial control of variceal bleeding and preventing early rebleeding. Both treatments are safe, but terlipressin is better tolerated. Therefore, terlipressin may represent a first-line treatment in acute variceal bleeding until the administration of elective therapy, especially in hospitals where a skilled endoscopist is not available 24 hours a day.

Acute Disease↗