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Biomedical subjects

I Raz

Publications and source records attributed to I Raz.

At least 37 records · Page 2Linked to original sources
PubMed2000

The association between two common mutations C677T and A1298C in human methylenetetrahydrofolate reductase gene and the risk for diabetic nephropathy in type II diabetic patients.

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes mellitus (DM). Both A1298C and C677T are highly prevalent in the diabetic population with allele frequencies of 0.35 and 0.36, respectively. The genotype frequency and allele frequency for these two polymorphisms in patients who are normoalbuminuric (n = 55) were compared with those of patients who had either micro- or macroalbuminuria (n = 43). For both polymorphisms, there were no significant differences in either the genotype distribution or allele frequency in patients with or without DN. However, in patients with serum folate <15.4 nmol/L, there was a greater incidence of DN in those patients who were homozygous or heterozygous for the C677T mutation. For the A1298C mutation, there is evidence suggesting that the homozygous state may be protective in patients with low-normal serum folate. Folate supplementation in diabetic patients with the C677T mutation and low-normal serum folate may prevent the onset or retard the progression of DN.

Aged↗
PubMed2000

Octreotide, a somatostatin analogue, fails to inhibit hypoxia-induced retinal neovascularization in the neonatal rat.

OBJECTIVE: Octreotide, a somatostatin analogue, has been shown to prevent angiogenesis in diverse in vitro models. We evaluated its effect on retinal neovascularization in vivo, using a neonatal rat retinopathy model. METHODS: We used, on alternating days, hypoxia (10% O2) and hyperoxia (50% O2) during the first 14 days of neonatal rats, to induce retinal neovascularization. Half of the rats were injected subcutaneously with octreotide 0.7 microg/g BW twice daily. At day 18 the eyes were evaluated for the presence of epiretinal and vitreal hemorrhage, neovascularization and epiretinal proliferation. Octreotide pharmacokinetics and its effect on serum growth hormone (GH) and insulin-like growth factor I (IGF-I) were examined in 28 rats. RESULTS: Serum octreotide levels were 667 microg/l two hours after injection, 26.4 microg/l after nine hours and 3.2 microg/l after 14 hours. GH levels were decreased by 40% (p = 0.002) two hours after injection but thereafter returned to baseline. IGF-I levels were unchanged two hours after injection and were elevated by 26% 14 hours after injection (p = 0.02). Epiretinal membranes were highly associated with epiretinal hemorrhages (p < 0.001), while retinal neovascularization was notably associated with vitreal hemorrhages (p < 0.001). CONCLUSIONS: Twice-daily injections of octreotide failed to produce sustained decrease in serum GH, but produced rebound elevation of serum IGF-I. Accordingly, no statistically significant effect of injections on retinal pathology was noted. This finding, however, does not contradict our assumption that GH suppression may decrease the severity of retinopathy.

Animals↗
PubMed1999

Characterization of the regulatory region of the human testis-specific form of the pyruvate dehydrogenase alpha-subunit (PDHA-2) gene.

The alpha-subunit of human pyruvate dehydrogenase (E(1)) is encoded by two separate genes. The gene located on chromosome X (PDHA-1) is expressed in somatic tissues, whereas the second gene (PDHA-2), located on chromosome 4, is expressed only in post-meiotic spermatogenic cells. A genomic fragment harboring the human gene encoding PDHA-2 has been isolated and approximately 800 nucleotides of the promoter region have been characterized. Functional studies of the promoter indicate the presence of both enhancer and repressor elements that are common to other genes that are only expressed in mature sperm.

Base Sequence↗
PubMed1999

T cell proliferative responses of type 1 diabetes patients and healthy individuals to human hsp60 and its peptides.

T cell responses to peptide epitopes of the 60 kDa heat shock protein (hsp60) have been shown to play a role in the pathogenesis of type 1 insulin-dependent diabetes mellitus (IDDM) in mice. To test whether hsp60 autoimmunity might be involved in human type 1 diabetes, we studied T cell proliferative responses (stimulation index; SI) to intact human hsp60, to hsp60 peptides and to a recall antigen (tetanus toxoid) in 25 newly diagnosed type 1 diabetes patients, in 22 type 2 (non-insulin-dependent diabetes mellitus, NIDDM) patients, and in 25 healthy blood donors. There were no significant differences between the T cell responses of the three groups to tetanus toxoid. However, the responses to hsp60 of the type 1 diabetes group (median SI=5) were significantly greater (P<0. 01) than those of the type 2 group (median SI=1.67) and of the blood donors (median SI=1.7). Epitope mapping revealed significant responses to at least seven different peptides, with prevalent responses to the p277 peptide previously mapped in NOD mice and to peptide p32. Thus, newly diagnosed type 1 diabetes patients, similar to prediabetic and newly diabetic NOD mice, show heightened autoimmunity to hsp60 and hsp60 peptides.

Adolescent↗
PubMed1999

Prevalence of diabetes mellitus among workers in Israel: a nation-wide study.

The prevalence of diabetes mellitus in Israel has been described in various populations and ranges from 4.1% to 8.9%. However, the large immigration wave in the late 1980s and early 1990s could have affected the previous estimates. Moreover, data from the United states and other countries report a significant proportion of undiagnosed diabetes. The main purpose of this study was to estimate the prevalence and the ratio of undiagnosed/diagnosed diabetes in a large sample of workers. The study involved interviews, anthropometric measurements at the work site, and blood glucose determinations (casual capillary, fasting, and when necessary, 2 h after a 75-gram oral glucose load). Diabetes and impaired glucose tolerance (IGT) were diagnosed according to WHO criteria. Five thousand four hundred sixteen workers participated in the study. Three hundred ten reported to be known diabetics (5.7%), 35 (0.7%) were diagnosed as diabetic during the survey, and an additional 93 (1.8%) were classified as IGT. The ratio undiagnosed/diagnosed diabetes was therefore 1:10. Extrapolation of these results produced an estimate of diabetes prevalence in Israel of 10% among people over age 40 years. It seems that in the Israeli health care system, based on universal health insurance and easy access to primary care, the proportion of undiagnosed diabetes is lower than that described in other countries.

Adult↗
PubMed1999

Time course of lipopolysaccharide-induced nitric oxide synthase mRNA expression in rat glomeruli.

The decrease in glomerular filtration rate that is characteristic of sepsis has been shown to result from the local glomerular inhibition of endothelial nitric oxide synthase (NOS) by nitric oxide (NO) generated from the inducible isoform of NOS (iNOS). iNOS activation depends on de novo synthesis of both RNA and protein. Therefore it is assumed that several hours are required for its full activation. Yet the renal hemodynamic response in sepsis has been documented as early as 60 minutes after lipopolysaccharide (LPS) administration. Experiments were designed to determine the time course of LPS-induced glomerular iNOS mRNA expression and activity in rats. Rats were treated with LPS (2 mg/kg body weight IP). Kidneys were removed after 1,2, 4, 6, and 16 hours. Glomeruli were isolated and incubated. Nitric oxide generation was measured with a Griess assay, and iNOS mRNA was studied by reverse transcriptase-polymerase chain reaction. Similar time course experiments were repeated in glomeruli isolated from normal rats and exposed to LPS in vitro. A significant increase in iNOS mRNA expression was evident as early as 60 minutes after both in vivo and in vitro administration of LPS. The quantity of iNOS mRNA reached its peak between 2 to 4 hours after administration and declined to baseline levels after 16 hours. Immunohistochemical studies were remarkable for a significant increase in the staining for iNOS in glomeruli 2 hours after the in vivo administration of LPS. Plasma nitric oxide concentration after the in vivo administration of LPS increased from a baseline level of 11.25 +/- 0.8 micromol/L to a peak level of 62.9 +/- 3.8 micromol/L (P < .05 vs baseline) at 4 hours and then decreased to 17.5 +/-1.9 micromol/L at 16 hours. Similar results were obtained when the glomerular generation of nitric oxide after in vivo administration of LPS was measured (2.6 +/- 0.8 pmol/h/microg tissue, 17.2 +/- 2.1 pmol/h/microg tissue (P < .05 vs baseline), and 0.4 +/- 0.65 pmol/h/microg tissue, respectively). These results provide evidence of the rapid activation of glomerular iNOS after in vivo and ex vivo administration of LPS and thus support the role of nitric oxide in the early renal hemodynamic response to LPS.

Animals↗
PubMed1999

Maggot therapy for the treatment of intractable wounds.

BACKGROUND: Fly maggots have been known for centuries to help debride and heal wounds. Maggot therapy was first introduced in the USA in 1931 and was routinely used there until the mid-1940s in over 300 hospitals. With the advent of antimicrobiols, maggot therapy became rare until the early 1990s, when it was re-introduced in the USA, UK, and Israel. The objective of this study was to assess the efficacy of maggot therapy for the treatment of intractable, chronic wounds and ulcers in long-term hospitalized patients in Israel. METHODS: Twenty-five patients, suffering mostly from chronic leg ulcers and pressure sores in the lower sacral area, were treated in an open study using maggots of the green bottle fly, Phaenicia sericata. The wounds had been present for 1-90 months before maggot therapy was applied. Thirty-five wounds were located on the foot or calf of the patients, one on the thumb, while the pressure sores were on the lower back. Sterile maggots (50-1000) were administered to the wound two to five times weekly and replaced every 1-2 days. Hospitalized patients were treated in five departments of the Hadassah Hospital, two geriatric hospitals, and one outpatient clinic in Jerusalem. The underlying diseases or the causes of the development of wounds were venous stasis (12), paraplegia (5), hemiplegia (2), Birger's disease (1), lymphostasis (1), thalassemia (1), polycythemia (1), dementia (1), and basal cell carcinoma (1). Subjects were examined daily or every second day until complete debridement of the wound was noted. RESULTS: Complete debridement was achieved in 38 wounds (88.4%); in three wounds (7%), the debridement was significant, in one (2.3%) partial, and one wound (2.3%) remained unchanged. In five patients who were referred for amputation of the leg, the extremities was salvaged after maggot therapy. CONCLUSIONS: Maggot therapy is a relatively rapid and effective treatment, particularly in large necrotic wounds requiring debridement and resistant to conventional treatment and conservative surgical intervention.

Adult↗
PubMed1999

Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon.

AIMS: To study changes in the expression of insulin-like growth factors (IGFs) and their receptors, as well as production of the IGF-I and IGF-II polypeptides, in adenocarcinoma of the colon. METHODS: Malignant tissue obtained at operation was used. Total RNA was extracted and specific IGF-I and IGF-II and their receptor mRNAs were measured by a solution hybridisation RNase protection assay. IGF-I and IGF-II polypeptides were measured by specific immunoassays. RESULTS: All normal tissues expressed IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate (Man-6-P) receptor. IGF-I mRNA could not be detected but the polypeptide was present in small but equal amounts in normal and malignant tissue. IGF-II was expressed 40 times more abundantly in colonic tumours than in adjacent normal tissue and the concentration of the corresponding polypeptide was twice as high in the malignant tissue. IGF-I receptor expression was increased by a factor of 2.5 and IGF-II/Man-6-P receptor by a factor of 4. CONCLUSIONS: This study confirms that in adenocarcinoma of the human colon there is increased expression of IGF-I receptor and IGF-II. Furthermore, IGF-II/Man-6-P receptor message is increased and the increase in IGF-II message is accompanied by a doubling of the IGF-II protein in the tumour tissue compared with the adjacent normal tissue. These findings suggest that the IGF-II/Man-6-P receptor may also be involved in development of adenocarcinoma of the colon. There is rapidly accumulating evidence implicating the IGF system in the development of malignancy of the large bowel.

Adenocarcinoma↗
PubMed1998

Comparison of factors associated with 30-day mortality after coronary artery bypass grafting in patients with versus without diabetes mellitus. Israeli Coronary Artery Bypass (ISCAB) Study Consortium.

The purpose of this study was to identify factors associated with 30-day mortality after coronary artery bypass graft surgery (CABG) among diabetic patients, and to compare them with risk factors among nondiabetics. A subanalysis of a prospective national cohort study was performed which included patients who underwent CABG in 14 medical centers in Israel during 1994. Data including patient demographic and historical information, comorbidity, and cardiac catheterization results were collected by trained nurses. Data were derived from direct patient interviews, charts, catheterization reports, surgical reports, and national vital records. Multivariate logistic regression analysis was used to identify factors associated with a 30-day mortality in diabetic and nondiabetic patient populations. The results showed that crude mortality was 5.0% among diabetic patients (n = 1,034) and 2.5% among nondiabetics (n = 3,350; p < 0.001). The risk profile in diabetics was found to be worse. Multivariate logistic regression analysis identified female gender, 3-vessel disease, and left main disease as independent risk factors for 30-day, past-CABG mortality unique to diabetic patients. Left ventricular dysfunction was found to effect a greater risk among diabetic patients, whereas chronic renal failure was associated with greater risk among nondiabetics. In conclusion, we found differences in patterns of risk factors for post-CABG mortality between diabetics and nondiabetics. These findings may help physicians to identify patients at high risk for CABG mortality.

Aged↗
PubMed1998

Gene expression of insulin-like growth factor-I, its receptor and binding proteins in retina under hypoxic conditions.

Hypoxia is the main stimulus for neovascularization in the retina. Insulin-like growth factor-I (IGF-I) is thought to be one of the mediators of this process. Severe persistent hypoxia, as occurs in central retinal artery occlusion, is associated with less retinal neovascularization than relative hypoxia. To study the influence of different types of hypoxia on the IGF system, we used a model of neonatal rat retina that responds with neovascularization to a relative hypoxic stimulus produced by alternating oxygen concentrations in the respired air. We studied the influence of 24-hour hypoxia (10% oxygen), 48-hour hyperoxia (75% oxygen), and relative hypoxia (shifting from 48 hours in 75% oxygen to 24 hours in room air) on the gene expression of IGF-I, IGF-I receptor (IGF-IR), and IGF binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 in retina using a solution hybridization RNase protection assay. Hypoxia induced a significant increase in retinal IGF-IR (178%), IGFBP-2 (227%), and IGFBP-3 (317%) mRNA; however, retinal IGF-I mRNA was reduced, as well as serum growth hormone (GH). Relative hypoxia caused a similar but less pronounced trend in the gene expression of IGF-IR and the binding proteins, whereas retinal IGF-I mRNA was unchanged and serum GH was elevated. Both hypoxia and relative hypoxia may cause IGF system stimulation in the retina through upregulation of IGF-IR and IGFBPs. This stimulation may result in neovascularization. However, during hypoxia, low levels of tissue oxygenation and reduced local production of IGF-I may impede the neovascularization process.

Animals↗
PubMed1998

Hypoglycaemia following pancreatic allograft transplantation.

Pancreatic transplantation is an established treatment for patients with insulin-dependent diabetes mellitus. Side-effects are mainly related to surgical complications, immunosuppressive therapy and graft rejection. We report on two patients having recurrent hypoglycaemic events following pancreatic transplantation. The cause of hypoglycaemia in our patients remained obscure. Hypoglycaemia following pancreatic transplantation has been described. Hypoglycaemic events may appear years after transplantation. In the article we review three possible mechanisms of hypoglycaemia: hyperinsulinaemia, secondary to systemic drainage (due to loss of first pass hepatic insulin clearance), presence of anti-insulin antibodies and persistence of counter-regulatory abnormalities. Physicians and patients should be aware of possible hypoglycaemia events following transplantation.

Adult↗
PubMed1998

The effect of the mode of administration on the hypolipidaemic activity of niacin: continuous gastrointestinal administration of low-dose niacin improves lipid-lowering efficacy in experimentally-induced hyperlipidaemic rats.

The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia-Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg(-1)). Continuous administration of niacin into the duodenum at 1.66 mg h(-1) (total dose 40 mg kg(-1) day(-1)) for up to 7 days (Model A) or at 2.22 mg h(-1) over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15-25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg(-1)) has a greater lipid-lowering effect than a higher dose (200 mg kg(-1)) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.

Animals↗
PubMed1998

The endogenous insulin-like growth factor system in radiocontrast nephropathy.

The response of insulin-like growth factor (IGF) I in acute renal failure was evaluated in a model of radiocontrast nephropathy associated with selective necrosis of medullary thick ascending limbs. In brief, rats were administered radiocontrast medium or vehicle injections for controls after combined inhibition of prostanoids and nitric oxide. Twenty-four hours after the insult, tissue mRNAs for IGF-I, the IGF-I receptor, and IGF-binding proteins (IGFBP) 1 and 3 were assayed in cortex, medulla, and liver by solution hybridization-RNase protection assay, and IGFBPs were measured in serum and tissue by Western ligand blotting. Cortical IGF-1 increased, whereas medullary IGF-I mRNA decreased. Renal IGFBPs decreased, whereas IGFBP-1 mRNA increased. The IGF system in the liver was unchanged. We conclude that general changes in renal IGFBPs in this experimental model of acute renal failure might increase the level of cortical IGF-I in a way that could modulate medullary recovery.

Acute Kidney Injury↗
PubMed1998

Diffuse narrowing of coronary arteries in diabetic patients: the earliest phase of coronary artery disease.

Coronary arteries in diabetic patients appear to be narrower than in normal subjects, but this has not been examined systematically. To investigate this hypothesis we reviewed the data of 711 consecutive patients with angiographically 'normal coronary arteries'. Excluded were patients with valvular, myocardial or pericardial disease, and patients with hypertension or hyperlipidemia. Thirteen diabetic patients (10 men) and 22 nondiabetic persons (8 men) constituted the study and control groups, respectively. The diameters of the coronary arteries and their branches were measured and adjusted for body surface area. The sum of the proximal left anterior descending (LAD), circumflex and right coronary arteries (RCA) was calculated and defined as total coronary diameter (TCD). The sum of the distal LAD, first diagonal, first marginal and distal RCA was calculated and defined as total distal coronary diameter (dTCD). The clinical data of both groups were comparable. Adjusted TCD for body surface area was 5.4 +/- 1.1 and 6.5 +/- 1.1 mm/m2 (p < 0.05) in diabetics and nondiabetics, respectively, and adjusted dTCD was 4.9 +/- 1.2 and 6.1 +/- 1.2 mm/m2 (p = 0.01) in diabetics and normal subjects, respectively. Specific arteries and branches that were significantly smaller in diabetics included: left main coronary artery, distal LAD, first diagonal, proximal RCA, distal RCA, right ventricular branch, and posterolateral and posterior descending artery of RCA origin. Gender was not a confounding factor since the control group had a larger proportion of women and still larger arteries than the diabetic group. In conclusion, coronary arteries and their branches in diabetic patients have smaller diameters than normal subjects. This may be due to increased coronary tone, diffuse mild atherosclerosis or both.

Coronary Angiography↗
PubMed1998

The effect of low dose octreotide administration on renal function and on gene expression of IGF-I axis components in experimental diabetes mellitus.

The present study was undertaken to assess the chronic effects of low dose octreotide (Oc) administration in rats with experimental diabetes mellitus (DM). Metabolic and clearance studies were performed in control normal rats, in rats with streptozotocin-induced DM of 1 week duration and in similar DM rats treated with Oc, 10-20 microg/day. Gene expression of IGF-I, IGF-I receptor (IGF-I R) and IGF-binding protein-1 (IGFBP-1) was examined in renal tissue from normal DM animals and DM animals treated with Oc 10, 20 and 100 microg/day. Seven days of Oc administration, 10 microg/day, in rats with experimental DM, was associated with enhanced hyperglycemia, increased glomerular filtration rate and urinary sodium excretion as compared with untreated DM animals. After a higher Oc dose, 20 microg/day, however, there were no significant changes in renal function and in glycemic control. Significant increases in kidney weight and kidney weight/body weight ratio were seen in DM rats as compared with control intact animals. These changes were not affected by Oc therapy in various doses. Induction of DM was associated with a marked increase in renal IGFBP-1 mRNA expression. There were no significant changes in the expression of IGF-I or IGF-I R mRNA. Oc therapy in a low or high dose did not affect gene expression of IGF-I, IGF-I R or IGFBP-1. Thus, the response to chronic low dose Oc administration of DM rats may vary from enhanced hyperglycemia and hyperfiltration to a lack of change in renal function or in glycemic control. Low dose Oc therapy was not associated with significant variations in renal mass or in the gene expression of IGF-I axis components. These findings are at variance with previously published studies which show a suppressive effect of Oc on renal function and growth in experimental diabetes. This apparent discrepancy may be related to the duration of treatment or to a biphasic physiological effect of Oc when used in different doses.

Animals↗
PubMed1998

Octreotide prevents the early increase in renal insulin-like growth factor binding protein 1 in streptozotocin diabetic rats.

The early renal growth in streptozotocin (STZ)-induced diabetic rats is preceded by a transient rise in renal tissue insulin-like growth factor (IGF)-I concentration. Administration of the long-acting somatostatin analog octreotide to STZ diabetic rats inhibits the early increase in kidney IGF-I and the increase in kidney size without affecting metabolic control. We studied the effects of octreotide treatment on the intrarenal IGF axis at 2 and at 7 days after the induction of STZ diabetes. Two days after induction of diabetes, kidney IGF-I was increased from 850 +/- 43 ng/g tissue in controls to 1,648 +/- 165 ng/g tissue (P < 0.001) in diabetic animals. The diabetes-associated increase in renal IGF-I 48 h after STZ injection was totally prevented by octreotide (IGF = 780 +/- 57 ng/g tissue). However, 7 days after the induction of diabetes, kidney IGF-I was similar to that of control and was not affected by octreotide. No difference in serum IGF-I was observed between controls and diabetic rats after 2 days of diabetes; however, octreotide treatment resulted in a significant decrease of serum IGF-I after 2 days when compared with control rats (P < 0.05). Renal IGF-I mRNA was significantly decreased to the same extent in both diabetic groups 2 and 7 days after the induction of diabetes, while renal IGF-I receptor (IGF-IR) mRNA was unchanged in rats from either group. Two days after induction of diabetes, renal insulin-like growth factor binding protein (IGFBP)-1 mRNA and 30-kDa IGFBPs (containing IGFBP-1) increased by 186 and 192%, respectively, in untreated diabetic animals compared with controls. Octreotide treatment prevented the diabetes-associated rise in renal IGFBP-1 mRNA and protein. However, 7 days after the induction of diabetes, renal IGFBP-1 mRNA and protein were similarly increased in both octreotide-treated or untreated diabetic rats. Renal IGFBP-3 gene expression and protein and IGFPB-5 mRNA remained unchanged after 2 and 7 days of diabetes when treated or untreated with octreotide. We conclude that the well-known inhibitory effect of octreotide on the early increase in renal IGF-I concentration and renal size in diabetes may be mediated through a direct effect on renal IGFBP-1 levels.

Animals↗