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Biomedical subjects

A Lev-Ran

Publications and source records attributed to A Lev-Ran.

At least 19 recordsLinked to original sources
PubMed2000

Homogeneity of the age at diagnosis in sibs with Type 2 diabetes: implications for sib-pair analysis.

Homogeneity of the age at diagnosis of Type 2 diabetes was studied in 1,228 sibs in 300 unrelated families: 100 consecutive single-affected and 200 consecutive multiple-affected ones. There were 635 diabetic sibs. The mean and median age at diagnosis in all affected individuals was 50 years (range, 19-75 years). The mean age at diagnosis in the multiply affected families was 49 years (median 50); the between-sibs range of age at diagnosis within multiple-affected families was (mean and median) 17 years (range, 0-55), with 42% of these diagnosed within a 5-year age span, 66% within 10 years, and 90% within 13 years. When one parent had diabetes, it was more often the mother (79% P = 0.0023). In order to examine this apparent tendency toward homogeneity of age at diagnosis within families, with full regard for and parsimonious to right-censored data, we employed a Cox proportional-hazards survival analysis, with family as the explanatory variable. Deviance residuals resulting from that model were analyzed in a variance components, random effects model ANOVA which indicated a significant (P << 0.001) effect of family on age of diagnosis, with an intraclass correlation of 0.29. In many families the clustering of age at diagnosis appeared very tight, with single outliers, and in 20 families with the longest history, diabetes was diagnosed in 68 sibs within the span of 8 +/- 7 years, whereas 38 unaffected sibs remain free of diabetes 25 +/- 8 years later. The wide differences of the age at diagnosis between families and its intrafamilial homogeneity should be considered in planning genetic analysis of Type 2 diabetes.

Adult↗
PubMed1998

Mitogenic factors accelerate later-age diseases: insulin as a paradigm.

Some genes are expressed differently in earlier and later generations of most cell lines. Many diseases become clinically expressed only later in life, and show clustering of the age at onset in the affected siblings, which may be related to the changing expression with age of the genes involved. Because insulin and its receptor are extremely ancient and well preserved structures with almost universal mitogenic effects, insulin may serve a paradigm of this process. It is suggested that by stimulating cell proliferation, hyperinsulinemia speeds up the appearance of later generations of cells with different expression of the genes. Insulin resistance, accompanying any hyperinsulinemia and considered to be a pathogenetic factor of some common later-age diseases, involves only some biochemical, but not mitogenic effects of the hormone. In humans, high levels of insulin in blood are encountered both physiologically after meals and in many pathological conditions: insulin therapy inevitably causes peripheral hyperinsulinemia; in type 2 diabetes hyperinsulinemia precedes hyperglycemia by many years; hyperinsulinemia is an independent risk factor of atherosclerosis, of type 2 diabetes itself, of some forms of dementia and other diseases; obesity is an obligatory hyperinsulinemic condition. The opposite of hyperalimentation, i.e. calorie restriction (at least, in rodents) may exert its life-prolonging effects through decreasing insulinemia and therefore the rate of cell proliferation. Insulin is only one example, and different mitogens regulate proliferation of different cells. It is likely that growth factors in general accelerating the replication of cells, play a role in speeding up the appearance of later-age diseases involving these cells.

Age Factors↗
PubMed1998

In most poorly controlled glyburide-treated type 2 diabetic patients drug withdrawal causes further increase in glycemia not accompanied by changes in insulin secretion.

To find out whether the secondary failure of glyburide in type 2 diabetes is complete or partial, we studied 38 patients, age (M +/- SD) 69 +/- 9 years, suffering from diabetes from 13.5 +/- 8.4 years and treated with glyburide for 5-13 years, with poor glycemic control (glycohemoglobin 10.6 +/- 2.6%). Serum glucose, insulin and C-peptide were assayed before and 1 h and 2 h after a simulated meal load (355 Cal), after which the drug was replaced with placebo for 4 weeks, and the test repeated. After glyburide withdrawal, fasting glycemia increased from 10.3 +/- 3.3 to 15.1 +/- 4.4 mmol/L (p < 0.001), but in 3/38 patients, it even decreased and in five others the changes were less than +/- 2 mmol/L. These changes negatively but only weakly correlated with initial glycemia: r = 0.4123, p < 0.010. The mean post-meal glycemia at 1 h and 2 h increased respectively by 3.3 and 5.9 mmol/L (both p < 0.001). Neither the levels of glycemia nor its changes after the glyburide withdrawal correlated with the levels of, or changes in, insulin or C-peptide. We conclude that in most but not all type-2 diabetic patients, poorly controlled with glyburide, the drug still retains some limited therapeutic effectiveness, and therefore its withdrawal causes further deterioration of control with the almost equal increases in fasting and post-meal levels of glycemia. These changes are not accompanied by decrease in insulin secretion.

Adult↗
PubMed1997

Excretion of epidermal growth factor in human adult polycystic kidney disease.

In chronic renal failure, epidermal growth factor (EGF) excretion is decreased. In this study, asymptomatic adult polycystic kidney disease (APKD) patients with a relatively preserved glomerular filtration rate were examined. Excretion of EGF was studied in 6 patients with APKD (median age 42 years; serum creatinine [median] 95 [range-80-133] mumol/l) and compared with that of 28 healthy controls. EGF was determined in a spot morning urine by using a specific radioimmunoassay, and expressed in relation to creatinine excretion. Excretion of EGF in APKD was (median) 157 (range-13-359) and in the controls (median) 546 (range-238-1199) pmol/mmol creatinine (p < 0.001). Low excretion of EGF in APKD patients with preserved kidney function suggests a distal abnormality at an early stage of the disease, prior to the development of renal failure.

Adult↗
PubMed1995

Effect of low-dose prophylactic dopamine on high-dose cisplatin-induced electrolyte wasting, ototoxicity, and epidermal growth factor excretion: a randomized, placebo-controlled, double-blind trial.

PURPOSE: To evaluate the protective effect of low-dose dopamine given as continuous infusion in patients who undergo chemotherapy with the nephrotoxin cisplatin. PATIENTS AND METHODS: Forty-two patients who received high-dose cisplatin-containing chemotherapy entered a prospective, randomized, double-blind, placebo-controlled trial. Twenty-one patients received dopamine, and 21 received placebo. Patients were to receive either infusional dopamine 2 micrograms/kg/min over 48 hours or placebo. Cisplatin 125 mg/m2 was administered 12 hours after initiating dopamine (group D) or placebo (group P). This schedule was repeated twice, 1 week apart. Measurements of serum creatinine, urinary electrolytes and creatinine, urinary excretion of epidermal growth factor (EGF), ototoxicity, parameters of hematopoietic recovery, and duration of hospitalization were analyzed. RESULTS: We observed an increase in serum creatinine level to a peak of 1.9 mg/dL (range, 0.8 to 7.8) in the dopamine group, in comparison to 1.4 mg/dL (range, 0.9 to 3.3) in the placebo group (P = .04). Urinary magnesium excretion increased and EGF excretion decreased in both groups. Urinary sodium, chloride, and potassium excretion were increased in both groups, but more so in the placebo group. Dopamine had no measurable effect on hearing loss, duration of hospitalization, or hematopoietic recovery. CONCLUSION: The use of prophylactic dopamine increased peak serum creatinine levels relative to placebo and failed to prevent cisplatin-induced renal toxicity or ototoxicity. Determination of whether dopamine could reverse chemotherapy-induced renal damage would require a randomized prospective trial.

Adult↗
PubMed1995

Effects of enalapril and nitrendipine on the excretion of epidermal growth factor and albumin in hypertensive NIDDM patients.

OBJECTIVE: To compare the effect of the antihypertensive drugs nitrendipine and enalapril on the excretion of epidermal growth factor (EGF) and albumin in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) subjects. RESEARCH DESIGN AND METHODS: After a 4-week washout period, mildly hypertensive (systolic blood pressure [sBP] > or = 140 mmHg and/or diastolic blood pressure [dBP] > or = 90 mmHg) NIDDM patients with albuminuria (15-200 micrograms/min) were randomized into an 8-month-long therapy with either nitrendipine (n = 11) or enalapril (n = 10). Blood pressure, EGF, and microalbumin excretion were measured at baseline and throughout the treatment period. RESULTS: A significant fall in sBP was noticed in the enalapril group and in dBP in the nitrendipine group. In the enalapril group, EGF excretion progressively increased from 188 to 214 nmol/mmol creatinine after 6 weeks and to 274 after 8 months of therapy (P = 0.03). There was a significant fall in albumin excretion while patients were on enalapril, but in the nitrendipine group, neither albuminuria nor EGF excretion changed significantly. There was no correlation of improved EGF excretion with a decrease in albuminuria or BP. CONCLUSIONS: The angiotensin-converting enzyme inhibitor enalapril has been effective in decreasing albumin and increasing EGF excretion. Measurement of urinary EGF may provide a new valuable index of renal function.

Adult↗
PubMed1993

C-peptide in NIDDM. Follow-up for 4-6 yr.

OBJECTIVE: To study whether fasting and 1-h postbreakfast C-peptide levels in NIDDM stabilize with time in individual patients. RESEARCH DESIGN AND METHODS: Within the period of 4-6 yr, 49 NIDDM patients had repeated tests of fasting and 1-h postprandial levels of plasma glucose and C-peptide with the aim of determining their individual qualitative patterns. Throughout the follow-up period, 13 patients were treated with insulin, 21 with oral sulfonylureas, and 15 were switched from oral drugs to insulin, with the tests done in both treatment periods. RESULTS: The group as a whole demonstrated no changes in mean fasting or postprandial C-peptide within 4-6 yr of observation, irrespective of the mode of therapy or its changes. Glycemic and C-peptide response to breakfast was qualitatively typical for each patient with the correlation between plasma glucose and C-peptide. However, the response was vastly different from patient to patient, and the cross-sectional data showed no correlation between postprandial changes in glycemia and C-peptide, nor between glycemic response to breakfast and fasting plasma glucose or C-peptide. In spite of high fasting glycemia, 25% of the patients showed remarkable tolerance to breakfast with only small increases in plasma glucose. In many other patients, however, in spite of similar increase in C-peptide, plasma glucose rose sharply after the meal. CONCLUSIONS: In our group, no deterioration of the insulin secretory function was observed within 4-6 yr of follow-up. Qualitative patterns of the glycemic and C-peptide responses to breakfast were typical for each patient but vastly different between patients. We see in NIDDM a syndrome with few common characteristics and recommend further work for its subclassification into forms with different pathogenesis.

Biomarkers↗
PubMed1992

Release of different fractions of epidermal growth factor from human platelets in vitro: preferential release of 140 kDa fraction.

Platelet-rich plasma in acidic-citrate-dextrose anticoagulant was kept for 5 days in an oxygen-permeable bag at 22 degrees C in an incubator/rotator. Platelet count remained stable throughout the experiment. On days 0, 3 and 5, aliquots were removed; platelets were isolated by centrifugation at 22 degrees C, 1500 g for 20 min, reconstituted to the original volume with PBS buffer, and the contents of alpha-granules were released by repeated freezing and thawing. Epidermal growth factor (EGF) and beta-thromboglobulin (beta-TG) in the platelet-poor plasma and platelet lysates were determined by radioimmunoassays. Results indicated that in platelet-free plasma, both total EGF and beta-TG increased 3-5-fold after 5 days; this amount represented 10-20% of the factors stored in the platelets. Correspondingly, the EGF and beta-TG contents of the platelet lysates exhibited accompanying decreases. HPLC fractionation showed that the main EGF fraction which progressively decreased in the lysates and increased in plasma had a molecular mass of 140 kDa. The contents of the 67 kDa and 6 kDa fractions did not change substantially. We conclude that under these conditions, the 140 kDa fraction was released preferentially. In view of these and previous experiments, it seems likely that different organs contribute to plasma EGF fractions.

Adolescent↗
PubMed1992

Effects of platelet-contained growth factors (PDGF, EGF, IGF-I, and TGF-beta) on DNA synthesis in porcine aortic smooth muscle cells in culture.

Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and transforming growth factor-beta (TGF-beta) are potent mitogens present in human platelets. Since they are likely to be released simultaneously at the site of vessel injury, their combined effects on vascular smooth muscle cells are more relevant physiologically than their individual actions. Therefore, we added various concentrations of growth factors to quiescent porcine aortic smooth muscle cells cultured in low-serum (0.5%) medium and measured the amount of [3H]thymidine incorporated into DNA. Effect of TGF-beta alone was concentration-dependent: stimulatory (1.5-fold increase over the basal) at 0.025 ng/ml and inhibitory at greater than or equal to 0.1 ng/ml. Effects of the other three growth factors on DNA synthesis were only stimulatory; their maximally effective concentrations were 20 ng/ml for PDGF (eightfold over the basal), 40 ng/ml for EGF (six-fold increase), and 20 ng/ml for IGF-I (fourfold increase). When PDGF, EGF, and IGF-I were added at submaximally effective concentrations, their effects were additive. TGF-beta at 1 ng/ml inhibited at least 50% of the effects of 20 ng/ml EGF and of 10 ng/ml IGF-I, whereas inhibition of the effect of 10 ng/ml PDGF required 10 ng/ml of TGF-beta. The concentration of TGF-beta needed to inhibit 50% of the combined effect of EGF, IGF-1, and PDGF was 5 ng/ml. These results show complex interrelationships between the growth factors contained in the alpha-granules of human platelets in their effects on porcine aortic smooth muscle cells.

Animals↗
PubMed1992

Origin of urinary epidermal growth factor in humans: excretion of endogenous EGF and infused [131I]-human EGF and kidney histochemistry.

1. This study examined (i) whether blood-infused epidermal growth factor (EGF) can pass into urine; (ii) whether infused labelled EGF behaves like endogenous plasma immunoreactive EGF; and (iii) which parts of the human nephron show morphological evidence of EGF synthesis? 2. We infused human [131I]-EGF into a volunteer. After 6 min, only 66% of the plasma counts represented intact EGF. At the end of infusion, the T1/2 of EGF was calculated to be 1.6 min. The tail of the curve lasted for at least another 2 h. The total excretion of the labelled EGF was 2.45% of the infused dose and was proportional to the urine volume. 3. After a water load, the excretion of endogenous EGF was, on the contrary, inversely related to urine volume. 4. Immunohistochemically, human kidneys were not stained by monoclonal anti-EGF antibodies but showed positive in situ hybridization for EGF mRNA in the nuclei of glomerular mesangial cells, distal convoluted tubules and collecting tubules. 5. We conclude that human kidneys synthesize EGF and release it into urine. Plasma-derived EGF constitutes under normal conditions only a small part of the urinary EGF. Contrasting volume-dependency of the excretion of endogenous and [131I]-EGF requires further study and cautions against extrapolating results obtained with labelled EGF to physiological conditions.

Epidermal Growth Factor↗
PubMed1991

Trauma, especially of the submandibular glands, causes release of epidermal growth factor into bloodstream in mice.

Submandibular glands in mice were traumatized by handling and then removed. Immunoreactive epidermal growth factor (EGF) in serum increased after 5 min and continued to increase, reaching at 1 h a peak of 50-fold normal in males and twice normal in females. If after traumatization the glands were repositioned with their blood supply intact, maximal increase of serum EGF at 1 h was 190-fold control values in males and 2-fold in females. In male mice, incision of abdominal wall skin led to a 15-fold increase of EGF in the serum; this rise was absent 3 days after sialoadenoectomy. After traumatization, repositioned submandibular glands lost 80% of their EGF; after the abdominal wall incision, only 30%. Following removal of submandibular glands, decrease of EGF level in serum was very slow: to 60% of the initial value after 3 days and to 40% after 10 days. By the HPLC characteristics, immunoreactive EGF in control serum and at its peak were indistinguishable. Urinary excretion of EGF was significantly elevated only when its serum level was 190-fold normal. We conclude that traumatized submandibular glands discharge into circulation a large part of their stored EGF. A similar but much less pronounced process takes place after abdominal skin incision. The presence of EGF in serum after its slow decline in sialoadenoectomized mice shows that a fraction of circulating EGF may recirculate prolonging its apparent half-life.

Animals↗
PubMed1991

Immunoreactive epidermal growth factor in serum, plasma, platelets, and urine in patients on chronic dialysis.

In 25 patients with chronic renal failure undergoing hemodialysis the level of epidermal growth factor (EGF) was significantly increased in plasma (61 +/- 10 vs. 36 +/- 12 pM in 23 aged-matched controls; p less than 0.0001) and serum (189 +/- 51 vs. 138 +/- 69 pM, p less than 0.006) and slightly increased in platelets (391 +/- 134 vs. 308 +/- 87 aM/10(6) platelets in controls; p less than 0.0582). In those 15 patients who produced urine, EGF was absent or close to the low limit of the sensitivity of the method (17 pM). Thus, kidneys are not delivering EGF to blood but their role in EGF removal is possible. Urinary EGF virtually disappears in severe chronic renal failure.

Aged↗
PubMed1990

Excretion of epidermal growth factor (EGF) in diabetes.

Excretion of epidermal growth factor (EGF) is decreased in renal failure. We assayed it in diabetes mellitus in an attempt to relate it to clinical parameters, esp. those of diabetic nephropathy. EGF excretion declined with age but in all age groups of diabetic patients was below the first percentile for controls. In 26 control and 34 prepubertal diabetic children excretion was correspondingly 1126 +/- 442 and 932 +/- 489 pmol/mmol creatinine (P = 0.087); in 26 control and 42 diabetic adolescents below age 18, 778 +/- 222 and 676 +/- 335 (P = 0.023) and in 81 control and 83 diabetic adults, 371 +/- 153 and 235 +/- 140 (P less than 0.0001). Decreased excretion of EGF was seen in some patients without any diabetic complications. Excretion of EGF was independently and inversely correlated with age and duration of diabetes but not with type of diabetes, treatment, body built, C-peptide, plasma glucose, glycohemoglobin or retinopathy. A positive correlation was seen with creatinine clearance and a negative correlation, with albuminuria, but the strongest and the only independent correlation found by stepwise multiple variable selection was with serum creatinine (r -0.711, P less than 0.0001). EGF excretion was not elevated in patients with hyperfiltration. We conclude that EGF excretion is abnormal in many patients with diabetes and that this abnormality reflects a kidney function different from glomerular filtration or glomerular permeability.

Adolescent↗
PubMed1990

Infusion of epidermal growth factor in mice: organ distribution and urinary excretion.

Anesthetized mice were infused into the tail vein with 7.5% mannitol in saline (0.1 ml/min for 60 min) alone or with EGF at 0.5 microgram/min. Urine was collected every 10 min starting 20 min after the beginning of the infusion and ending 20 min after its termination. EGF concentration in the serum of mice infused with EGF increased from the baseline level of 0.6 +/- 0.4 to 70.7 +/- 16.0 ng/ml at 80 min. Total excretion of EGF for 80 min was 117 +/- 49 ng with mannitol alone and 1916 +/- 420 ng (6.4% of the EGF infused) after mannitol with EGF. Serum and urine EGF was indistinguishable from the native mouse EGF by its radioimmunoassay and HPLC characteristics. Intact labeled EGF was also found in urine when mice were infused with 125I-EGF (1 x 10(6) cpm/ml) in mannitol. After 5 min infusion with 125I-EGF (6 x 10(6) cpm/ml in saline), more than 80% of the label was found in the liver and kidneys and more than 90% of it was intact EGF. However, 30 min after infusion more than 95% of the labeled EGF was degraded. We conclude that at least part of the urinary EGF in mice originates in blood and that liver and kidneys are the main organs of EGF degradation.

Animals↗