摘要:

Abstract.11β‐hydroxy steroid dehydrogenase (11 β‐HSD) catalyzes the reversible conversion of physiological glucocorticoids (cortisol, corticosterone) to inactive products. The enzyme thus protects non‐selective renal mineralocorticoid receptors from circulating glucocorticoids (ensuring aldosterone‐selectivityin vivo), excludes maternal glucocorticoids from the foetal circulation and modulates glucocorticoid access to glucocorticoid receptors in other tissues. 11β‐HSD has been purified from rat liver, antisera raised, a cDNA isolated and its human homologue cloned. However, it is difficult to reconcile all of the actions of 11β‐HSD with a single enzyme. Here data are reviewed that demonstrate not only molecular heterogeneity of the ‘liver‐type’ 11β‐HSD, but also the existence of a novel high affinity isoform in the placenta and perhaps distal nephron. These data are discussed in the light of their potential physiological and pathological importance, with particular reference to the path

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00720.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.To determine the impact of an acute reduction of the circulating mass of apolipoprotein B (apo B) on apo B metabolism we studied six healthy male volunteers before (day 0), 1 day after (day 2), and 7 days after (day 8) an LDL apheresis treatment which reduced apo B mass by 59%. Appearance of newly synthesized apo B in plasma VLDL and LDL was studied using a primed‐constant infusion of [I‐13C]‐leucine. VLDL apo B pool size and fractional VLDL apo B production rate calculated using a one‐compartment model were similar on all 3 study days. Absolute VLDL apo B production was not statistically different throughout the study (19.7±12.3, 19.5 ± 7.5, 29.1 ± 17.7 mg kg‐1day‐1). LDL apo B fractional production rate was increased on day 2 (0.38 ± 0.17, 0.68±0.08, 0.37±0.06 pools day‐1on days 0, 2, and 8;P<0.01). Absolute LDL apo B production, however, remained constant throughout the study (10.8 ± 3.3, 11.0±1.9, 10.8 ± 3.1 mg kg‐1day‐1). We conclude that in healthy male volunteers acute reduction of the circulating apo B mass by LDL apheresis does not affect apo

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00721.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.Diabetes Mellitus in its early stages, is associated with kidney enlargement and increased glomerular filtration rate in humans and in rats. The present study was designed to clarify the direct effect of diabetes on serum and tissue angiotensin converting enzyme (ACE) activity in streptozotocin‐induced diabetic rats. Serum ACE activity, as determined using a radiometric assay, was significantly increased in the diabetic rats (n= 15) 14 days after induction of diabetes (670 ± 31 vs. 506±14 nmol ml‐1min‐1). Lung ACE activity, but not renal, was significantly elevated at 7 and 14 days by 29 and 46%, respectively. Plasma renin activity in the diabetic rats was decreased at 7 and 14 days by 41 and 78%, respectively. Incubations of lung slices in the presence of glucose at different concentrations did not affect in‐vitro release of the enzyme. Administration of insulin (8 units kg‐1) to diabetic rats (n= 6) on the 4th day for 11 days reduced ACE activity to values below control. Thus, serum and lung ACE activity is increased in the diabetic rat and reduced upon insuli

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00722.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.In most eukaryotic cells the regular alternation of chromosome reduplication and cell division is controlled by interdependent relationships which prevent progression to the next cell‐cycle phase unless the preceding phase has been completed. Megakaryo‐cytes become polyploid by allowing many rounds of DNA replication without completion of intervening mitoses. To assess the role of cell‐cycle dependencies in megakaryocytopoiesis we examined human cell lines which express megakaryocytic features for their ability to continue DNA synthesis and undergo polyploidization in the presence of mitotic poisons. Treatment of HEL cells with colcemid blocked cell division but not cellular DNA synthesis. DNA content distributions of cells treated with colcemid for 48 h showed a marked increase in the proportion of polyploid cells (57.6%± 9.9%,n= 16), an increase in cellular size and nuclear lobation. Identical effects were observed in HEL cells treated with colchicine, nocodazole or taxol but not with the inactive compound lumicolchicine. Induction of polyploidization by antimicrotubule agents was also observed in the megakaryoblastic cell lines MEG‐01, DAMI and UT‐7 but not in the T‐cell line MOLT‐4 or the promyelocytic cell line HL‐60. These results suggest that dependency of DNA replication on completion of the previous mitosis is suppressed in the megaka

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00723.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.In a survey of a healthy population (n =197), LDL cholesterol, plasma triglycerides and VLDL triglycerides were found to be substantially increased and plasma HDL cholesterol decreased in smokers. The lipid‐associated atherogenic risk in smokers as assessed by the LDL/HDL ratio was significantly higher [2.89 (SD 1.18,n= 63)] than in non‐smokers [2.38 (SD 0.98,n= 86)P<0.01]. The lower HDL level found in smokers was explained by a lower HDL‐2 subfraction as determined by analytical ultracentrifugation. HDL 2b, 2a and 3a, measured by gradient gel electrophoresis, were all lower in the smokers but this was only significant for HDL 2a. Smoking had no effect on Lp(a) levels. HDL cholesterol and HDL‐2 were strongly negatively correlated whereas LDL cholesterol and LDL/HDL ratio were strongly positively correlated with the plasma triglyceride concentration. There was a small but significant reduction in plasma CETP activity [non‐smokers 49%t/μl (SD 17,n= 90), smokers 43%t/μl (SD 17,n= 66) P<0.05] but CETP activity was not correlated with any measure of HDL in this population. Smoking was found to be an important independent contributor to the variation in plasma triglyceride, HDL, HDL‐2 and LDL/HDL ratio. After correcting for sex, age, BMI, alcohol consumption, oral contraceptive use and plasma triglycerides smoking was still found to be significantly associated with HDL and the LDL/HDL ratio. Upon adjustment for covariant factors the mean differences between smokers and non‐smokers for HDL cholesterol, HDL‐2 and LDL/HDL were 0.15 mM, 16 mg dl‐1and 0.39 respectively. There appeared to be important sex differences in the influence of smoking on plasma lipoproteins. In women the main impact of smoking was on triglyceride levels and they in turn affected LDL and HDL. In contrast, in men, smoking had little impact on triglycerides and affected HDL more directly. We conclude that smoking cigarettes has an important effect on plasma lipoprotein metabolism through

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00724.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.The mechanisms by which raw soya diets and CCK‐receptor antagonists increase postprandial plasma CCK concentrations are not fully understood. Therefore we examined the effects of different diets including raw soya, and the effect of the potent CCK antagonist devazepide in the fed and fasted state on CCK concentrations in plasma and in the duodenal mucosa and on the duodenal CCK: β‐tubulin mRNA ratio in rats. Diets which stimulated high plasma CCK levels, such as raw soya, also gave the highest CCK tissue and mRNA concentrations with a close correlation between plasma and tissue CCK concentrations within each group (r = 0.94,P= 0.018) and between tissue CCK concentrations and CCK: β‐tubulin mRNA ratios (r = 0.91,P =0.030). Animals fedad libitumand treated with devazepide (1 mg kg‐1) had higher CCK: β‐tubulin mRNA ratios, tissue CCK concentrations and plasma CCK concentrations than animals injected with vehicle. Fasted animals treated with devazepide for 28 h also had higher CCK mRNA:β‐tubulin mRNA ratios (1.86 ± 0.43 vs. 0.85 ± 0.15,P<0.05), and higher tissue CCK concentrations (0.99 ± 0.09 vs. 0.69 ± 0.04,P<0.01). However, despite these intracellular changes devazepide did not elevate plasma CCK concentrations in the fasted state. Therefore, devazepide increases tissue concentrations of CCK but requires an additional dietary stimulus to raise plasma concentrations. These findings indicate that devazepide produces a dissociation between synthesis and release of CC

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00725.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.In a strictly controlled 6‐week trial with 47 healthy volunteers we have determined the effect of replacement of polyunsaturated by saturated fatty acids on the fecal steroid excretion and on the rate of whole body cholesterol synthesis, as measured both by the sterol balance method and by the concentration of the cholesterol precursor lathosterol in serum. Subjects were fed mixed natural diets, of which the total fat content was kept constant at 45% energy. Consumption of polyunsaturated fatty acids, mainly linoleic acid, was 21 % energy for the first 3‐week period (P: S ratio 1.9), and 5% of energy (P: S ratio 0.2) for the next 3‐week period, or vice versa. Cholesterol intake as determined by analysis of duplicate diets was 41 mg MJ‐1(about 500 mg day‐1) during both periods. Feces were collected for 5 days at the end of both periods. The steroid composition of the feces was not affected by the change of diets. The fecal excretion of neutral steroids was significantly higher on the low P: S high‐saturated‐fat (2.25 ± 0.68 mmol day‐1) than on the high P:S high‐linoleic‐acid diet (2.00 ± 0.69 mmol day‐1;P<0.01). The excretion of bile acids was similar (0.77 ± 0.40 and 0.79 ± 0.41 mmol day‐1, respectively). The cholesterol balance and the rate of cholesterol synthesis were higher during the low P:S (1.86 ± 0.83 mmol day‐1) than during the high P:S period (1.55 ± 0.85 mmol day‐1;P<0.01). The ratio of lathosterol to cholesterol in serum was 0.86 ± 0.33 μmol mmol‐1on the high‐and 1.07 ± 0.39 μmol mmol‐1on the low P: S diet (P<0.01). Thus, both the balance and the cholesterol precursor method suggested that saturated fatty acids

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00726.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.The effects of daily intranasal instillation of liposomal dexamethasone and free dexamethasone phosphate were compared in a murine model of hypersensitivity pneumonitis induced bySaccharopolyspora rectivirgula(formally known asMicropolyspora faeni). After 3 weeks of antigen and liposome instillations, lung response was evaluated by bronchoalveolar lavage cell counts, lung index and histopathology. Systemic absorption was evaluated by measuring plasma adrenocorticotropic hormone (ACTH) level. Free dexamethasone phosphate induced a dose‐dependent response with the maximal effect reached at 1 mgkg‐1. At 0.1 mgkg‐1, liposomal dexamethasone had a greater effect than free dexamethasone phosphate on bronchoalveolar cells ml‐1: 3.01 × 105± 0.35× 105compared to 4.70×105± 0.34 × 105, and lung index: 1.22 ±0.10 compared to 1.86 ± 0.07. Effect on histopathology was similar. Plasma ACTH levels (pg ml‐1) were: 75.1 ± 14.0 for animals receiving antigen and free dexamethasone phosphate (0.2 mg kg‐1), and 149.7 ± 12.0 for animals receiving antigen and liposomal dexamethasone (0.2 mg kg‐1). In conclusion, liposome‐incorporated dexamethasone is efficient in the treatment of experimental hypersensitivity pneumonitis and, contrarily to free dexamethasone phosphate, does n

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00727.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract.To determine whether vasodilator prostaglandins are involved in the peripheral hyperperfusion observed in patients with short‐term insulin‐dependent diabetes mellitus (IDDM), forearm and skin blood flow were studied before and after cyclooxygenase inhibition. Skin nutritive (CBV: capillary bloodcell velocity) and thermoregulatory (LDF: laserDoppler fluxmetry), and forearm (muscle) blood flow (FBF) were measured before and after 500 mg acetylsalicylic acid (ASA) infused intravenously in 14 short‐term IDDM patients and 22 healthy control subjects. In the IDDM patients, baseline LDF (median: 27 (19–35); interquartile range) vs. 17 (15–23) pu) and FBF (3.4 (2.5–4.1) vs. 2.6 (2.2–2.9) ml 100 ml‐1min‐1) were increased, while CBV (0.70 (0.40–1.33) vs. 069 (0.41–0.96) mm s‐1) was unchanged compared to healthy controls. ASA infusion had similar effects on baseline CBV, LDF, and FBF in patients and controls. In eight of the control subjects the role of prostaglandins in the regulation of basal peripheral blood flow was studied before and after ASA and placebo infusion. The changes in baseline CBV, LDF, and FBF were similar after ASA and placebo infusion in healthy controls. In conclusion, in short‐term IDDM patients, increased skin thermoregulatory and forearm (muscle) blood flow are probably not related to vasodilator prostaglandins. Furthermore, prostaglandins are not likely to be involved in regulating basal peripheral

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1993.tb00728.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY