Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of individuals currently diagnosed as having diabetes mellitus are asymptomatic. In order to provide rational therapy for this patient population, it is necessary to focus upon the differences between these patients and the classic prototypes with polyuria and weight loss, who require insulin for survival. Patients with asymptomatic diabetes do not need insulin for survival, and, by definition, they do not need it to alleviate symptoms. They tend to be middle-aged and overweight, but they can be young and thin. Their degree of hyperglycemia is moderate, often indistinguishable from that of normal individuals in their day-to-day existence. Indeed, they can often be differentiated from normal persons only on the basis of their blood glucose response to the stress of a large dextrose challenge; in this regard, the potential problem of over-diagnosing diabetes has been discussed. Since the major problem facing patients with asymptomatic diabetes is accelerated atherogenesis, the therapeutic approach must be based upon efforts to delay or prevent the onset of vascular disease. It has yet to be shown that any therapeutic intervention helps such patients, but an argument has been made in support of the following goals in subjects with asymptomatic diabetes whose fasting blood glucose level is less than 170 mg/100 ml: (1) stop smoking, (2) control hypertension, (3) attain ideal body weight, and (4) maintain blood triglyceride and cholesterol levels well within normal limits. Attempts to lower blood glucose with either insulin or oral agents do not seem indicated in the majority of patients within this defined diabetic population.
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PMID:Treatment of asymptomatic diabetes mellitus. 97 61

Hyperglycemia has been implicated in the development of retinal vascular disease. Consequently, the effects of excessive hexose concentration on cells of the vascular wall are receiving increasing attention. Techniques for isolating metabolically active microvessels from tissues such as those from the retina and cerebral cortex are providing new opportunities for the study of the uptake and metabolism of hexose by microvessels. Such studies indicate that hexose uptake by microvessels is not insulin dependent and that microvessels are capable of metabolizing hexose by pathways common to many diverse tissues, including anaerobic and aerobic glycolysis, pentose phosphate shunt, and glycogenogenesis. Microvessels isolated from diabetic animals metabolize glucose at a subnormal rate. Hexitol production and accumulation has been implicated in the pathogenesis of diabetic complications in a variety of tissues and might also play a role in the development of diabetic microvascular disease. We have quantitated hexitol-producing metabolic activity of retinal and cerebral microvessels isolated from dogs, a species known to develop a retinopathy similar to that seen in diabetic patients. Erythrocytes were removed by perfusion prior to microvessel isolation because they are known to have hexitol-producing activity. Both retinal and cerebral microvessels produce galactitol from galactose, and this activity is inhibited in the presence of the aldose reductase inhibitor sorbinil. The presence of hexitol-producing activity within microvessels is consistent with a possible role of polyol production in the etiology of diabetic microvascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Microvascular metabolism in diabetes. 308 6

In view of the similarity of cataracts and neuropathy in galactose-fed and diabetic rats, the present experiments were undertaken to determine whether consumption of galactose-enriched diets (10, 25, or 50% by weight) also increases collagen crosslinking and permeation of vessels by 125I-albumin analogous to that observed in diabetic rats. The observations in these experiments: demonstrate that consumption of galactose-enriched diets for 3 wk selectively increases 125I-albumin permeation of the same vascular beds affected in diabetic rats and by diabetic vascular disease in humans (i.e., the aorta and vessels in the eye, kidney, sciatic nerve, and new tissue formed in the diabetic milieu); demonstrate that the susceptibility of the vasculature to aldose reductase-linked injury (increased permeability) varies greatly in different tissues; indicate that collagen solubility (crosslinking) changes in galactose-fed rats differ sharply from those in diabetic rats; and provide new evidence that consumption of galactose-enriched diets induces a hypogonadal state in male rats.
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PMID:Galactose ingestion increases vascular permeability and collagen solubility in normal male rats. 310 May 75

Diabetic vascular disease is associated with a state of hypercoagulability and altered endothelial properties, leading to elevated plasma levels of endothelium-derived peptides and proteins, e.g. endothelin-1, von Willebrand factor or fibronectin. This study determined dynamic immunoreactive endothelin-1 secretion by human umbilical vein endothelial cells exposed to thrombin (5 x 10(6) mU/l) in the presence (40 mmol/l) and absence (5.5 mmol/l) of excessive glucose in the cell culture medium. Exposure to high glucose and thrombin concentrations was initiated after cell confluency and applied for 24 h for measurements of endothelin-1 and for 2 and 5 h for the determination of preproendothelin-1, von Willebrand factor and fibronectin messenger ribonucleic acid. Comparisons were made versus cells incubated with normal glucose concentrations or with high mannose or NaCl concentrations as osmotic control. Neither preproendothelin-1, fibronectin and von Willebrand factor messenger ribonucleic acid expression nor endothelin-1 release was affected by high concentrations of glucose, mannose or sodium chloride.
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PMID:Stimulation of endothelin-1 production by thrombin, but lack of interference by high ambient glucose in vitro. 815 1

Vascular disease is a prominent complication of diabetes mellitus, and hyperglycemia has been implicated as a risk factor for the development of these vascular complications. It has previously been suggested that down-regulation of glucose transport in response to hyperglycemia might serve a protective role by decreasing intracellular glucose concentrations. In the present study, regulation of glucose transport by extracellular glucose concentrations was investigated in cultured rat vascular smooth muscle cells (VSMCs). Confluent quiescent VSMCs were exposed to medium containing either normal (5 mmol/L) or elevated (20 mmol/L) extracellular glucose concentrations for 24 hours. VSMCs exposed to elevated extracellular glucose concentrations (with or without serum) for 24 hours exhibited significant decreases in 2-deoxyglucose (2-DG) and D-glucose uptake rates. This decreased glucose transport was associated with a decrease in the Vmax of D-glucose transport without a change in KM. In the absence of serum, a decrease in the quantity of GLUT-1 transport protein at the plasma membrane was noted in cells exposed to elevated extracellular glucose concentrations for 24 hours. Intracellular glucose concentrations were estimated by using two methods, and the results revealed significantly higher intracellular glucose concentrations in the cells exposed to elevated extracellular glucose concentrations for 24 hours. These results suggest that down-regulation of glucose transport in cultured VSMCs exposed to elevated extracellular glucose concentrations for 24 hours does not occur to an extent that normalizes intracellular glucose concentrations. This prolonged increase in intracellular glucose concentrations and the potential associated toxicity may explain the increased incidence of vascular complications in patients with diabetes mellitus.
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PMID:Down-regulation of glucose transport by elevated extracellular glucose concentrations in cultured rat aortic smooth muscle cells does not normalize intracellular glucose concentrations. 862 88

The histological lesions of diabetic micro-angiopathy have a long latency, but vascular cell function may be affected at early stages of the process. Rats with experimental galactosaemia develop a diabetic-like retinopathy in the absence of other metabolic abnormalities characteristic of diabetes mellitus; basement membrane thickening is measurable in their retinal vessels after 7 months of galactose feeding. To examine the course of biosynthetic changes relevant to the process, retinal expression of collagen IV and fibronectin were compared in rats fed a 30% galactose diet or a control diet for 5 or 9 weeks. Total retinal RNA was studied by reverse transcription-polymerase chain reaction; the fibronectin primers encompassed the alternatively spliced EIIIA exon. The levels of alpha 1 (IV) collagen and fibronectin mRNAs were measured relative to an internal standard (beta-actin mRNA). The proportion of EIIIA+ to EIIIA- fibronectin transcripts was similar in the retinas of control and galactose-fed rats, which, however, showed increased levels of both fibronectin and collagen IV mRNAs in the presence of unchanged beta-actin mRNA levels. An upward trend was detected by 5 weeks of galactose feeding; and after 9 weeks the fibronectin/actin ratio was 1.2 +/- 0.3 vs 0.8 +/- 0.2 in controls (p = 0.015) and the collagen IV/actin ratio was 1.3 +/- 0.3 vs 0.9 +/- 0.2 in controls (p = 0.04). Thus, hyperhexosaemia of a few weeks' duration is a perturbation sufficient to increase the synthesis of basement membrane components in the retina. The search for additional early biosynthetic changes should assist in reconstructing the pathogenesis of hexose-induced retinal microangiopathy.
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PMID:Early biosynthetic changes in the diabetic-like retinopathy of galactose-fed rats. 878 71

The objective of this review is to draw attention to those inherited metabolic traits which are potentially harmful also for the carrier, and to outline preventive measures, at least for obligate heterozygotes, i.e. parents of homozygous children. Concerning carriers of food-dependent abnormalities, early vascular disease in homocystinuria, hyperammonaemic episodes in ornithine transcarbamylase deficiency, presenile cataracts in galactosaemia as well as galactokinase deficiency, spastic paraparesis in X-linked adrenoleukodystrophy, and HELLP syndrome in mothers of babies with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have to be mentioned. In the group of food-independent disorders, clinical features in carriers may be paraesthesias and corneal dystrophy in Fabry disease, lens clouding in Lowe syndrome, lung and/or liver diseases in alpha 1-antitrypsin deficiency, and renal stones in cystinuria type II and III. Finally, two monogenic carrier states are known which in pregnant individuals could possibly afflict the developing fetus, i.e. heterozygosity for galactosaemia and for phenylketonuria. Elevated levels of galactose-1-phosphate have been found in red blood cells of infants heterozygous for galactosaemia born to heterozygous mothers. Aspartame in very high doses is reported to increase blood phenylalanine levels in heterozygotes for phenylketonuria, thus being a risk for the fetus of a heterozygous mother. For some of these carrier states preventive measures can be recommended, e.g. restriction of lactose in parents and heterozygous grandparents of children with galactosaemia and galactokinase deficiency as well as transiently in infants heterozygous for galactosaemia, dietary supplementation with monounsaturated fatty acids in symptomatic carriers for X-linked adrenoleukodystrophy, avoidance of smoking and alcohol in heterozygotes for alpha 1-antitrypsin deficiency, avoidance of episodes of dehydration in heterozygotes for cystinuria, and restriction of aspartame in pregnant women.
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PMID:Inherited metabolic diseases affecting the carrier. 906 62

Fabry disease is characterized by a deficiency of lysosomal alpha-galactosidase (alpha-Gal) and the accumulation of glycosphingolipid (e.g. predominantly globotriaosylceramide) in various tissues, mainly in lysosomes of the vascular endothelium. This disorder is currently classified into two clinical phenotypes; classical severe type and atypical variant type. Classical form patients, with clinical manifestations of generalized angiopathy of early onset, usually show no detectable alpha-Gal activity. Recently, there are also atypical form patients with residual alpha-Gal activity and late-onset cardiomyopathy without other systemic manifestations. So far, we identified a number of alpha-Gal gene mutations including partial gene deletions, splicing mutations, nonsense mutations and missense mutations. They were heterogeneous and more than half of them were missense mutations. To clarify the molecular mechanism causing the enzyme defect in the patient, various missense mutations were expressed in COS-1 cells. At least, two groups have been identified; one expressing a mutant enzyme without catalytic activity (non-functional type), and the other expressing catalytically active but unstable mutant enzyme (fragile type). The fragile type mutants were widely present in the different clinical phenotypes from classical severe type to atypical milder type including subclinical Fabry hemizygote, and the mutant enzymes were posttranslationally inactivated and degraded in the cells. The inactivation and degradation were prevented by the addition of substrate analogue; galactose or melibiose. These findings provided us with significant informations on the molecular pathology of the enzyme defect in Fabry disease, and suggested the possibility of a new therapeutic approach for this disease.
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PMID:[alpha-Galactosidase gene mutation and its expression product in Fabry disease (alpha-galactosidase deficiency)]. 912 Sep 96

A beta-galactosidase activity has recently been used as a histochemical marker of replicative senescence in human fibroblasts and keratinocytes. To establish whether this marker could be used to detect senescence of vascular cells, we have investigated its presence in cultures of serially passaged human umbilical vein endothelial cells and rabbit aortic smooth muscle cells. beta-Galactosidase activity was detected by light microscopy using the chromogenic substrate 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside. In endothelial cell cultures, lysosomal beta-galactosidase activity, which is detected at pH 4.0, was present in all cells regardless of their replicative age. In contrast, senescence-associated beta-galactosidase activity, which is detected at pH 6.0, was absent in the majority of cells in early passage cultures (<15 cumulative population doublings), but was present in a large proportion of cells (up to 62%) in late passage cultures (>30 cumulative population doublings); in intermediate passage cultures (15-30 cumulative population doublings) it was found in fewer than 15% of the cells. The increase in the percentage of senescence-associated beta-galactosidase-positive cells correlated with a decrease in the cell density at confluence and with a marked increase in cell size. Counterstaining with an antibody directed against the endothelial cell marker CD31 showed that senescent cells retained the expression of this antigen. Senescence-associated beta-galactosidase was also detected in serially passaged, but not in primary explant cultures of rabbit aortic vascular smooth muscle cells. The presence of senescence-associated beta-galactosidase in cultured vascular smooth muscle cells and endothelial cells suggests that this marker could be used to study the role of cellular senescence in vascular disease.
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PMID:Cytochemical detection of a senescence-associated beta-galactosidase in endothelial and smooth muscle cells from human and rabbit blood vessels. 963 72

A number of diseases alter the normal pathophysiology of the portohepatic vascular system. The impact of these changes depends on the severity of the disease and the involvement of the entrahepatic vasculature. Cirrhosis of the liver is not a vascular disease but the effects on the liver architecture result in severe disease often accompanied by hepatic vascular changes. Alcohol abuse and viral infections are the most common causes of cirrhosis. Portal hypertension (PHT) is one of the most frequently seen sequelae of liver cirrhosis. It results in the formation of porto-systemic collateral channels which may lead to varices and hemorrhage. Primary liver cancer is also strongly associated with liver cirrhosis. Hepatocellular carcinoma (HCC) is the most common liver cancer seen in patients with cirrhosis. There are four types of HCC based on its growth patterns: infiltrative, expansive, mixed and diffuse. Raised plasma levels of alpha-fetoprotein are a characteristic of HCC. However, this marker is unreliable in patients with smaller tumors. Ultrasound is an inexpensive, non-invasive and safe diagnostic technique used to detect portal vein changes in PHT and to identify HCC lesions in the liver. Grey scale ultrasound reveals the portal vein changes and the portal-systemic collaterals which typify PHT. The technique is most useful for diagnosis or confirmation of moderate to severe disease. HCC nodules have characteristic ultrasound patterns which help in differential diagnosis. Doppler ultrasound provides functional as well as anatomical information about blood flow in the liver and is especially useful in detecting HCC and the abnormal blood vessel architecture which surrounds a tumor. However, despite their usefulness, both imaging techniques have limitations which may be improved by the use of echo-enhancing agents. Levovist(R) is a galactose-based microbubble echo-enhancing agent which has an excellent safety profile and utility in enhancing ultrasound images of the liver. It markedly improves diagnostic confidence and reduces the percentage of non-diagnostic ultrasound scans in patients with abnormal liver pathologies. The use of echo-enhanced ultrasound to diagnose liver disease may obviate the need for more expensive and invasive diagnostic procedures.
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PMID:Portohepatic vascular pathology and liver disease: diagnosis and monitoring. 967 32


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