ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01508.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.Glucose tolerance deteriorates dramatically with advancing age. It is not known whether the underlying pathophysiology is different in older subjects. We employed a two step hyperinsulinaemic euglycaemic glucose clamp with [614C] glucose infusion to compare peripheral and hepatic insulin sensitivity in eight elderly (EAGT) with eight young (YAGT) subjects with abnormal (matched) glucose tolerance and nine elderly subjects with normal glucose tolerance (ENGT). There was no difference in basal HGO (EAGT 14.5 ±0.9, YAGT 15.3 ±1.1 μmol kg‐1min‐1). Glucose turnover was similar in both groups at step 1 (EAGT 13.2 ± 0.8, YAGT 13.4±0.8 μmol kg‐1‐min‐1) and step 2 (EAGT 25.1±3.1, YAGT 27.2 ± 2.7 μmol kg‐1min‐1). HGO was lower in the EAGT subjects at step 1 (2.3 ±0.4 vs. 4.3±0.6 μmol kg‐1min‐1P=0.01). Incremental serum insulin response to oral glucose was comparable (EAGT 66.8 ±11.6 YAGT 57.8±12.2 mU 1‐1, h). Compared to the ENGT group the EAGT group was insulin resistant with a lower MCR of glucose at step 1 (2.03 ±0.28 vs. 3.23±0.44 ml kg‐1minv‐1P=0.04) and at step 2 (6.18±0.83 vs. 9.64±0.38 ml kg‐1min‐1P=0.004) and had a lower early insulin response (AUC 0–30 min 5.9±1.1 vs. 9.8±± 1.4 mU 1‐1. hP=0.04). We conclude that elderly and young subjects with abnormal glucose tolerance have similar pathophysiology but in such older subjects insulin suppression of HGO is similar to that seen in normal older subjects. Compared to normal elderly subjects the EAGT subjects are insulin resistant and have reduced early insulin secretion and both of these factor

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01509.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.Hyperactive platelets contribute to angio‐pathic complications in diabetes mellitus. It is unclear whether the increased platelet function is a primary pathogenetic factor in diabetes or follows vascular injury. Increased platelet size and numbers of glyco‐protein receptors on diabetic platelets suggest that thrombopoiesis is altered in diabetes mellitus. For further support of this hypothesis we studied whether megakaryocytes are changed with regard to the DNA‐ploidy pattern and the GPIIB/IIIA expression in 10 acute diabetic (AD) and 24 insulin treated diabetic (ITD) BB rats in comparison with 22 diabetes resistant (ND) BB rats. In the AD group megakaryocyte size (P=0.035) and the modal DNA‐ploidy distribution dropped (P=0.0001) concomitant with increased TNF‐alpha activity (P=0.001). GPIIB/IIIA expression and the peripheral platelet status were unchanged. After 4 weeks of insulin substitution metabolic parameters (glucose, cholesterol, triglycer‐ides) were lowered, but remained still elevated. As compared to the AD group the modal DNA‐ploidy pattern reversed, but the relative percentage of 64n megakaryocytes increased 2.3‐fold and GPIIB/IIIA expression increased 1.6‐fold. Simultaneously, the peripheral platelet count and size increased. From these results we conclude that alterations of the megakaryocyte compartment occur at early onset of diabetes. These changes could reflect a response to increased systemic cytokine production during inflammatory islet cell destruction. The peripheral platelet thrombotic potency increased with insulin treatment. This was associated with an increase of 64n‐megakary‐ocytes with upregulated GPIIB/IIIA expression and could reflect a mitogenic effect of insulin upon the endomitotic cycle

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01510.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.A 60‐year‐old white male (KH) was diagnosed to suffer from severe type III hyperlipoproteinemia (HLP) and premature cardiovascular disease. Biochemical analysis revealed an unusual apolipoprotein (apo) E phenotype and genotype. All clinical characteristics of type III HLP were present in the patient. His very low density lipoprotein (VLDL) cholesterol to plasma triglyceride (TG) ratio was elevated at 0.97 without therapy which is unusually high (normal ratio about 0.18). By contrast his plasma apo E level was only moderately elevated (6.8 mg dl‐1). The patient's apo E migrated in the apo El position on isoelectric focusing gels. Chemical modification with cysteamine and treatment with neuraminidase confirmed the presence of two cysteine residues in the patient's apo E and a normal sialylation pattern. Pedigree analysis suggested that the patient was a compound heterozygote with one apo ε l allele and another allele whose product did not appear in the plasma compartment (‘null’ allele). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo E gene as well as restriction fragment length polymorphism (RFLP) analysis with the endo‐nuclease Taq I identified an adenosine for guanosine (G←A) exchange in the second base of codon 127 that is predictive for an Asp for Gly substitution in the encoded apo E amino acid sequence. This mutation is the structural basis for the apo E l isoform identified upon isoelectric focusing. Five other family members are also carriers of the mutant apo εl allele. Two of those were hyperlipidemic and exhibited biochemical characteristics of type III HLP. A second mutation, a deletion of a G in codon 31, is predictive for a reading frameshift that encodes for a premature stop in codon 60. Our inability to identify the product of a second apo E allele in the plasma of the patient and two other members of the KH family corresponds with the heterozygous presence of this mutation in the affected individuals. Both relatives (like the index case) had an increased VLDL cholesterol to plasma TG ratio, which indicates the presence of cholesterol‐enriched VLDL particles. We propose that the single base deletion in the apo E gene which is the cause of a nonfunctional ‘null’ allele in addition to a probably dominant apo El (Gly127→Asp, Arg158→Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to seve

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01511.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.To assess the validity of two techniques capable of identifying immediate changes in human cholesterol production, plasma mevalonic acid levels and the rate of uptake of deuterium into plasma free cholesterol were compared in 5 healthy individuals over 48 h. The free‐living subjects self‐selected three meals per day prior to and during study. At t = 0, deuterium oxide was administered orally. Blood samples were collected before and every 4 h after dosing. Total cholesterol and mevalonic acid levels were determined in plasma at each timepoint. Deuterium enrichment changes in plasma free cholesterol, relative to plasma water content, were used to calculate free cholesterol fractional synthetic rates (FSR) at each timepoint. Total plasma cholesterol levels remained constant, whereas significant circadian rhythmicity was observed in both plasma mevalonic acid and deuterium uptake methods, with nadir and peak formation rates indicated at 14.00 to 16.00 h and about midnight, respectively. It is suggested that plasma mevalonic acid levels and free cholesterol deuterium uptake rate techniques are both suitable techniques for short‐term measurement of human cholesterol synt

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01512.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.To investigate the role of muscarinic cholinergic mechanisms in mediating the pancreatic and pituitary hormonal responses to hypoglycaemia, six normal subjects were studied during acute insulin‐induced hypoglycaemia under control conditions, and during blockade with intravenous atropine. During atropine blockade the response of pancreatic polypep‐tide was suppressed while the maximum response of plasma glucagon was significantly higher. The increment in plasma vasopressin was also increased significantly during cholinergic blockade. During blockade with atropine the responses of plasma prolactin was reduced, with a slight but significant reduction in the growth hormone response, and although a similar maximum response of plasma ACTH was achieved, this rise was delayed. These results implicate involvement of a cholinergic muscarinic inhibitory and stimulatory mechanisms in regulating the responses of pancreatic and pituitary hormones to hypoglycae

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01513.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.The pulsatility index (PI) of blood flow velocities has been reported to vary with changes in peripheral vascular resistance. Since blood flow velocities can easily be detected with the Echo‐Color‐Doppler technique in interlobar arteries of normally positioned kidneys, we tried in six healthy volunteers to estimate pharmacological induced variations in renal plasma flow (RPF) and renovascular resistance (RVR) by means of PI measurements.In this study no significant correlation between the absolute values of PI and RVR was found. In order to correct PI for different blood pressure‐inputs to the renal artery, PI was divided by the pulsatility of the systemic arterial pressure, i.e. the ‘blood pressure index’ [BPI = (SAD‐DAP)/MAP)], resulting in the ‘velocity blood‐pressure index’ (VBI = PI/BPI), which was significantly correlated with RVR (r=0.54,P<0.01). The pharmacological induced changes of RPF and RVR (ΔRPF, ΔRVR) were also correlated to the respective changes of PI and VBI (ΔPI, ΔVBI), with the highest significance when ΔVBI was plotted against ARVR (r = 0.83,P<0.0001). VBI, i.e. the pulsatility index of blood flow velocities as corrected for the pulsatility of the driving force, may be a tool for non‐invasive assessment of changes in RVR and thereby of importance for the diagnosis and follow‐u

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01514.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.Lipid A is responsible for the activities of endotoxin and may cause circulatory failure and haemolysis. This study evaluated the effects of different lipid A concentrations on red blood cell (RBC) deformation (rheoscope), the aspiration pressure required to aspirate RBC into 3.3 μm pipettes, the membrane shear elastic modulus (i.e. membrane rigidity) and cellular geometry (micropipette system) after 15 min of incubation. Lipid A concentrations of 10 and 100 μg ml‐1of RBCs decreased RBC deformability by 26% and 39%, respectively. The aspiration pressure for RBCs into a 3.3 μm micropipette increased by 235% at a lipid A concentration of 10 μg ml‐1and by 586% at a concentration of 100 μg ml‐1. The elastic shear modulus almost doubled at a lipid A concentration of 10 μg ml‐1and tripled at 100 μg ml‐1. At a lipid A concentration of 100 μg ml‐1, 37% of RBCs showed spicules. These echinocytes were less deformable than discocytes. Mean corpuscular volume, RBC volume and surface area were not affected by lipid A. We conclude that lipid A causes marked reduction of RBC deformability due to increasin

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01515.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract.Colchicine has been used in diverse clinical settings such as gout, familial Mediterranean fever, liver cirrhosis, Behcet's disease and pericarditis. It also has an antimitotic potential hitherto unexplored due to its narrow therapeutic toxic ratio.The aim of the present study was to compare the effectiveness and the toxicity of colchicine and three analogues: thiocolchicine, 2,3 dimethyl‐colchicine and 3‐dimethylthiocolchicine in the blockage of amyloid synthesis in a murine model.3‐demethylthiocolchicine was equipotent to colchicine in the blockage of casein induced amyloidogenesis. However, it was markedly less toxic (LD50 11.3 mg kg‐1vs. 1.6 mg kg‐1). Thiocolchicine was toxic (LD50 1.0 mg kg‐1) and 2,3 didemethyl‐colchicine was far less effective.The effect of 3‐dimethylthiocolchicine on polymorphonuclear leukocytes was then compared to colchicine. The effect of this analogue on inhibition of chemotaxis was equivalent to that of colchicine whereas the latter was superior to the analogue in the suppression of phagocytosis (by a ratio of 2:1) and in the inhibition of bactericidal activity (by a ratio of 10:1).Since in therapeutic concentrations the only detectable effect of colchicine on PMNs is inhibition of chemotaxis, our data may point to 3‐demethylthiocolchicine as an optional, perhaps superior alternative to colchicine for some of its therap

ISSN:0014-2972    

DOI:10.1111/j.1365-2362.1992.tb01516.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY