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Biomedical subjects

A Karasik

Publications and source records attributed to A Karasik.

At least 73 records · Page 4Linked to original sources

Genetically programmed selective islet beta-cell loss in diabetic subjects with Wolfram's syndrome.

Insulin-producing beta-cells were selectively absent from the islets of Langerhans in postmortem specimens from two patients with Wolfram's syndrome. In families with multiple cases of this syndrome, we found a very high concordance rate (r = .910, P less than .001) among siblings for age at onset of diabetes mellitus. Taken together with the lack of markers for an autoimmune process, these findings suggest that diabetes mellitus in this syndrome results from genetically programmed selective beta-cell death.

Adult↗

Insulin and epidermal growth factor stimulate phosphorylation of a 170-kDa protein in intact hepatocytes immunologically related to lipocortin 1.

Lipocortin 1 is a steroid-induced, calcium-regulated membrane binding protein (Mr = 39,000) which is a substrate for the epidermal growth factor receptor kinase in intact cells. Using a polyclonal antibody to human recombinant lipocortin 1, we have identified a 170-kDa phosphoprotein in freshly isolated rat hepatocytes which shares antigenic determinants with lipocortin 1. The protein was recognized by four different anti-lipocortin 1 antisera, and antibody binding was inhibited by a 100-fold molar excess of human recombinant lipocortin 1 over antibody. Based on Coomassie Blue staining, the 170-kDa lipocortin-related protein is abundant (approximately 100 ng/10(6) cells) in rat liver, while lipocortin 1 itself is found in very low amounts. Epidermal growth factor and insulin stimulated phosphorylation of this 170-kDa protein in intact rat hepatocytes. The increase in phosphorylation was more pronounced in hepatocytes from dexamethasone-treated animals. The phosphorylation occurred exclusively on serine residues and was maximal 30-60 min after hormone addition. The 170-kDa protein was localized in the cytoplasm in the absence of calcium, while increasing calcium concentration led to partial association with the membrane compartment in rat liver. This 170-kDa protein represents a new member of the class of proteins whose serine phosphorylation is regulated by insulin and EGF and may belong to the family of lipocortin-related molecules.

Amino Acids↗

Lipocortins 1 and 2 as substrates for the insulin receptor kinase in rat liver.

Lipocortins 1 and 2 are major substrates for the epidermal growth factor receptor and the pp60v-src tyrosine kinases in transformed cells. In the present study, we have characterized the phosphorylation of lipocortins 1 and 2 by the insulin receptor tyrosine kinase in vitro and in vivo. In vitro, the solubilized insulin receptor, partially purified from rat liver, catalyzed phosphorylation of human recombinant lipocortin 1 and purified bovine lipocortin 2. Phosphorylation of lipocortin 1 was increased 15-fold upon stimulation with 10(-7) M insulin. The apparent Km of the reaction was 3.3 microM and was not affected by insulin stimulation. Insulin stimulated phosphate incorporation into lipocortin 2 by 20-fold (apparent Km greater than 20 microM). Both lipocortins were phosphorylated exclusively on tyrosine residues as judged by phosphoamino acid analysis. Based upon peptide mapping, lipocortin 1 was phosphorylated on Tyr-21, a site phosphorylated by other tyrosine kinases. Polyclonal anti-phosphotyrosine antibodies recognized the tyrosine-phosphorylated lipocortin 2, but not lipocortin 1 in its phosphorylated form. In hepatocytes from normal and dexamethasone-treated rats, lipocortin 1 content was less than 50 ng/10(6) cells. Insulin-induced phosphorylation of lipocortin 1 was detected in intact hepatocytes from corticosteroid-treated animals but not in cells from normal rats. No phosphorylation of lipocortin 2 was found, although its content was approximately 100 ng/10(6) cells from normal animals and increased to approximately 1 microgram/10(6) cells following treatment of rats with dexamethasone for 4 days. Thus, although lipocortins 1 and 2 are in vitro substrates of the insulin receptor kinase, only lipocortin 1 is phosphorylated in an insulin-dependent manner in intact hepatocytes, and this is only observed after dexamethasone treatment of the rats.

Adenosine Triphosphate↗

Dexamethasone-induced changes in phosphorylation of the insulin and epidermal growth factor receptors and their substrates in intact rat hepatocytes.

Dexamethasone-induced changes in insulin and epidermal growth factor (EGF) receptor number, autophosphorylation, and kinase activity were studied in intact rat hepatocytes. Hepatocytes were freshly isolated from Sprague-Dawley rats treated with dexamethasone (1 mg/kg) for 4 days and from untreated littermates. Dexamethasone had no effect on insulin receptor number, while EGF receptor binding was slightly increased (21.3% vs. 17.2% binding/10(6) cells) after dexamethasone treatment. In hepatocytes from both control and dexamethasone-treated animals labeled with 32P, insulin induced tyrosine phosphorylation of the beta-subunit of the insulin receptor as well as of a 175K protein believed to be its endogenous substrate. The degree of phosphorylation of the insulin receptor was decreased 34% by dexamethasone treatment compared to the control value when studied in fasted animals. In contrast, phosphorylation was increased to a similar extent by dexamethasone treatment in fed animals. In addition, the beta-subunit of the insulin receptor extracted from dexamethasone-treated animals migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a slightly increased mobility compared to normal (89 +/- 1.2K vs. 92.5 +/- 0.4K). EGF induced tyrosine phosphorylation of its own receptor and of a 120K protein in intact hepatocytes. Their degree of phosphorylation was decreased by 30% as a result of dexamethasone treatment in the fasted animal and was unchanged in the fed animals. Our data indicate that glucocorticoids modulate insulin and EGF receptor kinase activity, but the nature of their effect depends on other factors, including the dietary state of the animal. These studies also suggest that postreceptor changes account for a major component of glucocorticoid-induced insulin resistance.

Animals↗

Elevated serum uric acid--a facet of hyperinsulinaemia.

In a representative sample of the adult Jewish population in Israel (n = 1016) excluding known diabetic patients and individuals on antihypertensive medications, serum uric acid showed a positive association with plasma insulin response (sum of 1- and 2-hour post glucose load levels) in both males (r = 0.316, p less than 0.001) and females (r = 0.236, p less than 0.001). This association remained statistically significant in both sexes (p less than 0.001) after accounting by multiple regression analysis for age and major correlates of serum uric acid i.e. body mass index, glucose response (sum of 1- and 2-hour post load levels), systolic blood pressure and total plasma triglycerides. The net portion of the variance of serum uric acid attributable to insulin response was 12% in males and 8% in females, the total variance accountable by all these variables being 17% and 19% respectively. We conclude that elevated serum uric acid is a feature of hyperinsulinaemia/insulin resistance.

Adult↗

Salbutamol versus atropine. Site of bronchodilatation in asthmatic patients.

The site of bronchodilatation produced by inhaled salbutamol (0.045 mg/kg) versus atropine (0.035 mg/kg) was investigated in 14 asthmatic young patients. No significant difference was found between the effects of the drugs on any of the large- or small-airway tests in those patients in whom bronchodilatation originated mainly in the large airways or when all patients were considered together. In those patients, however, in whom the small airways made the major contribution to the total airways resistance, atropine produced a higher increase in specific conductance, in maximal flow at all lung volumes and in density dependence of flow, but only the specific conductance showed a significant difference between the effects of the two drugs (p less than 0.01). It was concluded that in these patients atropine produced more bronchodilatation than salbutamol in both central and peripheral airways. These findings do not confirm previous studies which suggested that in asthmatic patients, as in normal subjects, atropine produces mainly central bronchodilatation, while salbutamol produces mainly peripheral bronchodilatation. The difference in doses, route of administration, time response and in the pretreatment severity and site of bronchodilatation could account for the disagreement between previous studies and the present one.

Adolescent↗

Effect of past and concurrent body mass index on prevalence of glucose intolerance and type 2 (non-insulin-dependent) diabetes and on insulin response. The Israel study of glucose intolerance, obesity and hypertension.

A representative sample (n = 2140) of the Israeli Jewish population aged 40-70 (excluding known diabetic patients), whose body mass index had been measured 10 years earlier, underwent an oral glucose tolerance test and redetermination of body mass index. Irrespective of weight changes, high concurrent and high past body mass index values (greater than or equal to 27) were associated with similarly increased rates of glucose intolerance as compared with body mass index values less than 27 at both time-points (rate ratio 1.76, 90% confidence limits 1.56-1.99). Glucose intolerance here includes borderline and impaired tolerance as well as Type 2 diabetes. The rate of Type 2 diabetes increased only with increasing past body mass index, while concurrent body mass index had no effect [rate ratios: 2.36 (1.48-3.75) and 1.99 (1.48-2.68) respectively for the medium-(23-26.9) versus-low (less than 23) and high- (greater than or equal to 27) versus-medium past body-mass-index categories]. Weight reduction was associated with only slightly reduced rate of glucose intolerance and had no effect on the rate of diabetes. Mean sum insulin (summed 1 and 2 h levels, mU/l) increased significantly with increasing concurrent body mass index (123, 150 and 190 in the low, medium and high categories) with no effect of past body mass index. It also increased significantly (p less than 0.001) in all concurrent body mass index categories from normal tolerance through borderline to impaired tolerance, and decreased significantly (p less than 0.001) in diabetes relative to impaired tolerance, although it remained above normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effectiveness of glycosylated hemoglobin, fasting plasma glucose, and a single post load plasma glucose level in population screening for glucose intolerance.

Five shortcut methods of population screening for glucose intolerance (impaired glucose tolerance and non-insulin-dependent diabetes mellitus) were assessed for effectiveness: 1) glycosylated hemoglobin concentration (HbA1), 2) fasting plasma glucose level, 3) combinations of fasting plasma glucose and HbA1, 4) plasma glucose one hour post oral glucose load, and 5) plasma glucose two hour post oral glucose load. In a sample of the Israeli Jewish population aged 40-70 years, 2040 participants in the Israel Study of Glucose Intolerance, Obesity and Hypertension, who were not known to be diabetic, underwent an oral glucose tolerance test based on three blood samples (fasting, one hour, and two hour post oral glucose load). In 1058 of the subjects, HbA1 was also measured, and was found to increase significantly (P less than 0.001) with increasing glucose intolerance, but with extensive overlap of ranges, even between normals and newly found diabetics. Fasting plasma glucose was more effective than HbA1 in screening for both impaired glucose tolerance and diabetes by its higher specificity and predictive value of a positive test at comparable sensitivity levels. Combinations of HbA1 and fasting plasma glucose did not improve prediction over fasting plasma glucose alone. As observed in other studies, the screening effectiveness of fasting plasma glucose was also unsatisfactory, either post load glucose level being more effective. Plasma glucose level two hour post load was better for detection of diabetes alone. Plasma glucose level one hour post load was more effective at detecting the total group of glucose intolerance, but did not discriminate well between impaired tolerance and diabetes. A cost-risk-benefit evaluation suggests that a full three-sample oral glucose tolerance test is the best method in screening for both intolerance categories.

Adult↗

Increased risk of lung cancer in patients with chondromatous hamartoma.

Fifty-two patients with chondromatous hamartoma of the lung (CHL) operated upon in one medical center in Israel during the years 1960 to 1975 were followed through the end of 1976 for occurrence of malignancy. In 51 patients, the operation followed the finding of a coin lesion in a routine chest x-ray film (32 cases) or an x-ray film taken due to symptoms related to the chest (19 cases). In one case, it followed a cytologic diagnosis of bronchogenic carcinoma. Four cases of carcinoma of the lung were observed in this group, three of them 2 to 10 years after the CHL was first observed; in the fourth the CHL was found during an operation for lung cancer. All four lung cancers were located in the same lobe as and in proximity to the CHL. Since hamartomas were randomly distributed among the lobes, this spatial association is highly significant (p = 0.0016). The risk of lung cancer in CHL patients was estimated to be 6.3 times higher than the age-sex-ethnic adjusted rate expected for the general Israeli population. No increased risk for malignancies of other sites was found.

Adult↗

Echocardiographic left ventricular function in mitral stenosis.

Left ventricular function was measured by echocardiography in 22 patients with pure mitral stenosis. Thirteen patients underwent closed transventricular mitral valvulotomy and nine underwent open mitral valvulotomy using cardiopulmonary bypass. Preoperative left ventricular function was normal in most patients but was depressed in older subjects (P less than 0.05) and in those undergoing a second operation on the mitral valve (P less than 0.001). The decrease in left ventricular function was probably related to the duration of mitral valve disease, with fibrosis and rigidity of the subvalvar apparatus and posterobasal left ventricular wall. There was no change in ventricular dimensions or in left ventricular function as measured by percentage shortening of the left ventricular diameter and ejection fraction 7 to 12 days after open or closed mitral valvulotomy.

Adult↗

Echocardiographic left ventricular function in aortic and mitral incompetence and the effect of valve replacement.

Left ventricular (LV) function was studied by echocardiography in 28 patients with volume overload of the LV before and after valve replacement. Of the 28 subjects, 19 had mitral valve disease (eight with mitral incompetence and 11 with mitral incompetence and stenosis) and nine patients had aortic incompetence. Patients with chronic mitral and aortic incompetence had marked LV enlargement with normal or slightly depressed systolic function; in those with acute mitral incompetence the degree of cardiomegaly was less and the state of LV function depended on the underlying cause of valvular incompetence. Valve replacement was followed by a decrease in LV end-diastolic volume and this occurred in the first week after operation. There was a gradual improvement in LV function in some patients, as measured by normalized mean velocity of posterior LV wall motion. Paradoxical septal motion occurred in many patients after operation but improved in the late postoperative period.

Adolescent↗

Thyroid function in attention deficit and hyperactivity disorder.

In view of the recent conflicting findings regarding the causative role of thyroid abnormalities in attention deficit hyperactivity disorder (ADHD), we performed a replication study to clarify the issue and establish clinical guidelines. Thyroid tests were performed in 43 ADHD children and 28 age- and gender-matched controls. Sixteen ADHD children showed total triiodothyronine (TT3) levels which were slightly above the upper limit of normal, but no significant difference in TT3 values was noted between the ADHD and the control groups. Moreover, none of the ADHD subjects had abnormal levels of total thyroxine, free thyroxine, thyroid stimulating hormone or total triiodothyronine reuptake. The present study supplies additional evidence for the lack of an association between thyroid function and ADHD, and counters the suggestion that thyroid function be routinely screened for in ADHD children.

Adolescent↗

Senile cataract and glucose intolerance: the Israel Study of glucose Intolerance Obesity and Hypertension (The Israel GOH Study).

Association of "senile" cataract (SC) with glucose intolerance (impaired tolerance and diabetes) was assessed by sex and age in a random population sample comprising 930 individuals aged 40-70 yr, who underwent concurrent oral glucose tolerance test and ophthalmoscopy. The eye examination was performed without knowledge of the glucose tolerance status. SC was defined as lens opacification preventing visualization of the eyeground or as surgical aphakia due to SC. To assess the independent effect of hyperglycemia, glycosylated hemoglobin (HbA1) was determined in 769 participants. In men, no association was found between SC, glucose intolerance, and HbA1. In women of all ages, glucose intolerance was associated with an SC risk ratio of 6.1 (95% confidence limits 3.3-11.1; P less than 0.001). Furthermore, SC was associated in women with increased HbA1 independently of the effect of glucose intolerance (P less than 0.01). These findings confirm the reported association of SC with diabetes (although unlike the Framingham and HANES population studies, the association was confined in women), indicate its presence at all degrees of glucose intolerance, and suggest a possible independent role of nonenzymatic glycosylation in its pathogenesis.

Adult↗