Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na-Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

Preservation of factor VIII activity in plasma by different freezing techniques, as determined with a chromogenic microtray assay.

The preservation of factor VIII activity in frozen plasma was studied using three different freezing techniques. Two were conventional methods, i.e. ethanol bath at -40 degrees C, and deep-frozen at -80 degrees C, and the third was a novel air-based -40 degrees C freezer with metal compartments and snugly fitting flat 750 ml plasma containers. No statistically significant difference in preservation of factor VIII was observed, irrespective of freezing technique, as determined with a chromogenic substrate assay.

Cholesterol screening of seven-year-old children. How to identify children at risk.

An inquiry was distributed to the parents of 1052 seven-year-old school beginners, concerning three issues, i.e. a known family history of myocardial infarction, angina pectoris before the age of 55 years and hyperlipidemia. A total of 147 children with a known family history were included in the study and compared with 148 classmates as control subjects. The proband children were subgrouped according to heredity factors and subjected to multivariate analysis at the 5% significance level for serum cholesterol fractions and triglycerides vs the control group. Statistically significant increased levels of total cholesterol and low density lipoprotein cholesterol, as well as an increased low density lipoprotein cholesterol and high density lipoprotein cholesterol ratio were found for all groups with hereditary for hyperlipidemia (p less than 0.001). However, no statistically significant difference was observed in the groups with heredity for myocardial infarction or angina pectoris exclusively. Also, there was no difference in any of the risk groups for high density lipoprotein cholesterol and triglycerides. The serum cholesterol levels in the present study were, to our knowledge, higher than those found elsewhere, except for Finland.

Vasoactive peptides in Bartter's syndrome.

Patients with Bartter's syndrome exhibit an increased vascular resistance to the pressor effects of angiotensin II and noradrenaline. Further, an increased production of vasodilating renal prostaglandins, perhaps mediating the vascular unresponsiveness, has been hypothesized in this syndrome based on high urinary prostaglandins. To determine whether different peptides might contribute to blood pressure control in this syndrome, the basal immunoreactive plasma levels of an array of vasoactive peptides and catecholamines were analysed in six patients with Bartter's syndrome. Among the vasoconstrictors analyzed, the mean plasma levels of noradrenaline (NA), adrenaline (A) and neuropeptide Y-like immunoreactivity (NPY-LI) were significantly increased as compared to healthy subjects (P = 0.030, 0.046 and 0.001, respectively). The plasma level of the vasodilator substance P (SP-LI) was also higher in these patients (P = 0.057). These results indicate that in Bartter's syndrome the vasoconstrictive effect of catecholamines and angiotensin II may be enhanced by concomitant NPY release. Whether a release of the vasodilator substance P is an independent mechanism or represents a reflex response to the increased secretion of angiotensin II, catecholamines and/or NPY remains to be established. However, the significance of these biochemical findings for blood pressure maintenance in Bartter's syndrome remains to be settled.

Cigarette smoking and glomerular filtration rate in insulin-treated diabetics without manifest nephropathy.

A sample of 120 insulin-treated diabetics, 20-40 years of age, with a glomerular filtration rate (GFR) exceeding -2 SD of the age-adjusted value and without albuminuria greater than 300 mg 24 h-1, and with a diastolic blood pressure not greater than 90 mmHg, were studied in order to evaluate the possible effect of smoking on glomerular filtration rate. The patients reported their smoking habits, use of oral snuff, use of alcohol, physical exercise and heredity for hypertension in a simple questionnaire. GFR was assessed with 51Cr-EDTA-clearance and glomerular hyperfiltration was defined as a value exceeding +2 SD of the age-adjusted normal value. We found a significantly higher prevalence of glomerular hyperfiltration in smokers than in non-smokers (41% vs. 18%), but no increased prevalence in users of oral snuff. In cigarette smokers a multivariate analysis revealed that GFR was positively related to body mass index (BMI), and negatively related to the number of cigarettes smoked per week and the mean blood pressure. In non-smokers GFR was dependent only on age. We conclude that in insulin-treated diabetics glomerular hyperfiltration is related to smoking, and that the GFR in smoking diabetics is directly dependent on the smoke doses. As glomerular hyperfiltration is regarded as a risk factor for diabetic nephropathy, our findings should be relevant to preventive measures in clinical work.

Protein intake and glomerular hyperfiltration in insulin--treated diabetics without manifest nephropathy.

Protein intake in relation to glomerular filtration rate (GFR) and urinary albumin excretion (UAE) has been studied in 96 insulin-treated diabetic patients, 20-40 years of age and without nephropathy. They had diastolic blood pressure (DBP) not exceeding 90 mmHg and a GFR exceeding -2 SD of the age-related value. They were without medications except for insulin. There were no significant differences in protein intake between diabetic patients with and without hyperfiltration (1.18 +/- 0.26 g/kg/d vs 1.21 +/- 0.42 g/kg/d, p = 0.75) or between diabetic patients with or without increased UAE (1.16 +/- 0.41 g/kg/d vs 1.24 +/- 0.37 g/kg/d, p = 0.37). No relations were found between protein intake and GFR or UAE in the whole sample, but a positive relation was found between UAE and protein intake in patients with increased UAE. Protein intake correlated with UAE in hyperfiltrators who use tobacco (n = 8, r = 0.85, p = 0.01), but not in non-users (n = 11, r = 0.24, p = 0.48). In conclusion our findings give no support for a relation between high protein intake and glomerular hyperfiltration in insulin-treated-diabetic patients. However, in contrast to non-users of tobacco, a positive relation was found between UAE and protein intake in tobacco users with hyperfiltration.

Plasma methylmalonic acid in relation to serum cobalamin and plasma homocysteine in a psychogeriatric population and the effect of cobalamin treatment.

Cobalamin deficiency seems to be a relatively common condition in psychogeriatric patients. To elucidate the diagnostic possibility of cobalamin deficiency we have in this study analysed three markers for cobalamin deficiency, plasma methylmalonic acid, plasma homocysteine and serum cobalamin, in 96 psychogeriatric patients. Patients were divided into four groups according to serum cobalamins above or below 150 pmol/l and normal (< 19.9 mumol/l) or increased plasma homocysteine. The upper reference limit (95th percentile) for plasma methylmalonic acid in 100 healthy subjects was established to 0.42 mumol/l. The mean value of methylmalonic acid was increased only in the group of patients with serum cobalamin below 150 pmol/l and increased plasma homocysteine compared to the other groups. In this group six (46%) out of 13 patients exhibited increased plasma methylmalonic acid, whereas in the other groups the frequency of increased plasma methylmalonic acid only varied from 10 to 13%. During cobalamin supplementation the most pronounced decrease of plasma methylmalonic acid also occurred in the group of patients with low serum cobalamin levels and increased plasma homocysteine. Only 39% of the initial mean value for plasma methylmalonic acid was noted after 7-10 days of cobalamin administration.