Familial occurrence of the May-Hegglin anomaly: is the accompanying renal failure part of a new subentity?

We present two cases of the May-Hegglin anomaly discovered in a patient and one of her two sons. The female patient was known to have proteinuria from the age of 14 and was hospitalized in 1980, at the age of 25 years, because of hypertension and proteinuria (1.5 g/day). Thrombocytopenia was found with an abundance of megakaryocytes in the bone marrow. Both steroid treatment and splenectomy failed to ameliorate the thrombocytopenia, thought to be due to idiopathic thrombocytopenic purpura. Progressive renal failure, secondary hyperparathyroidism and uremic osteodystrophy were diagnosed in 1995. In January 1996, when she was hospitalized because of high-grade fever, we saw giant platelets and prominent blue inclusion bodies in almost all granulocytes in the peripheral blood smear. Electron microscopy confirmed the diagnosis of May-Hegglin anomaly in this patient and one of her sons, who at that time showed thrombocytopenia but no renal disease. Three years later, however, at the age of 15, the affected son was found to develop proteinuria. Coexpression of the May-Hegglin anomaly and renal disease, reported previously in a few other patients, may in fact represent a new subentity.

p53 mutations in hairy cell leukemia.

We have studied the frequency of p53 mutations in genomic DNA extracted from peripheral blood or the spleen of 61 patients with hairy cell leukemia using PCR-SSCP and automated cycle sequencing. We identified exon 5-8 mutations in 17 cases, corresponding to a frequency of 28%. In four cases, mutations were localized in exon 5; one patient with atypical HCL had a mutation in exon 6 at the 3' boundary; five cases showed mutations in exon 7, while exon 8 was found to be mutated in seven cases. The mutations found could be divided into three major categories: structural (n=9), inactivating (n= 6), and neutral (n= 2) mutations. None of the three transitions found occurred at CpG dinucleotides. The rate of p53 mutations found in this large cohort of HCL patients is unexpectedly high as in other non-Hodgkin lymphomas p53 mutations predict for poor treatment outcome. The character of the mutations we have found is entirely different from that described in other hematologic malignancies.

[Possibilities of non-hormonal drug treatment of osteoporosis]. / Az osteoporosis nem hormonpótló gyógyszeres kezelési lehetöségei.

In many countries osteoporosis is the most common metabolic bone diseases. A great deal is known about the pathophysiology and the treatment of the disease. There is a lot of treatment possibilities and many new treatments are being tested. Therapeutic agents for osteoporosis are correspondingly classified as substances primarily inhibiting bone turnover (most of them are inhibitors of bone resorption as well) and agents that appear capable of restoring bone mass previously lost (stimulators of bone formation). From a didactic point of view the distinction of these to groups is generally accepted, but pharmacologically there is a considerable overlap between two. In this review the authors evaluate non-hormonal drugs, which are being used widely in the treatment of osteoporosis. The key points of the evaluation are the mechanism of action, the effects on bone mass, bone strength and fracture.

Pharmacokinetics and pharmacodynamics of mibefradil in hypertensive patients with varying degrees of renal insufficiency.

Mibefradil, the first member of the tetralol derivatives, a new class of calcium antagonists, is used for the treatment of hypertension and angina pectoris. This study was designed to investigate the effect of varying degrees of chronic renal impairment on mibefradil pharmacokinetics and pharmacodynamics. Neither pharmacokinetic nor pharmacodynamic parameters varied as a function of renal status. Additionally, hemodialysis removed only a relatively small fraction of drug from the body. It was concluded that the majority of renal-failure patients will not require a change in mibefradil dosage relative to patients with normal renal function. Following hemodialysis, supplemental mibefradil treatment should not be necessary.

Relationship between blood pressure variability and serum dehydroepiandrosterone sulfate levels.

Decreased diurnal blood pressure variability and low dehydroepiandrosterone sulfate (DHEAS) levels are important predictors of cardiovascular morbidity and mortality. The aim of the study was to determine the relationship between DHEAS levels and diurnal blood pressure variability in normotensive subjects and in patients with essential hypertension of both genders. An ambulatory blood pressure monitor (ABPM), Meditech O2 device and radioimmunoassay were used for ambulatory blood pressure monitoring and the determination of DHEAS levels, respectively. A close correlation (P < .001) was found between the diurnal indices and plasma DHEAS levels of the 387 subjects (86 normotensive and 301 hypertensive patients) participating in the study. Decreased plasma DHEAS levels were associated in both genders, and in both normotensive and hypertensive patients with significantly (P < .001) lower diurnal indices. There was a close correlation (P < .001) between the age-related decrease in plasma DHEAS levels and diurnal indices in both genders. Systolic and diastolic blood pressure variability changed parallel to plasma DHEAS levels in both genders, whether hypertension was present or not. Additional investigations are needed to find out whether reduced DHEAS levels play a role in decreased diurnal indices or whether both can be traced back to one and the same cause.

Interactions between ouabain, atrial natriuretic peptide, angiotensin-II and potassium: effects on rat zona glomerulosa aldosterone production.

The effects of ouabain, atrial natriuretic peptide, angiotensin-II and potassium on aldosterone production by collagenase dispersed rat zona glomerulosa cells were studied. A-II and 10(-4) M ouabain-induced increases in aldosterone production was inhibited by 10(-9) M ANP at all potassium concentrations examined. 10(-4) M ouabain inhibited the A-II induced increase in aldosterone production at all potassium concentrations. The degree of this inhibition was smaller at higher potassium levels. Ouabain enhanced the inhibitory effect of ANP on A-II-induced aldosterone synthesis at all potassium concentrations. Interactions between A-II, ANP, ouabain and potassium may be of physiological significance in the regulation of aldosterone secretion.

[The place of enalapril in the management of hypertension]. / Az enalapril helye a magasvérnyomás-betegség kezelésében.

In Hungary the use of angiotensin converting enzyme inhibitor enalapril has emerged as one of the most important drugs in the treatment of hypertension. The aim of our study was to evaluate the antihypertensive effect of enalapril of Hungarian production in combination therapy and alone, according to sexes, to the body mass index, among smokers and non smokers as well as non diabetic and in patients with diabetes (IDDM and NIDDM). The diurnal blood pressure values were registered by a 24 hour ambulatory blood pressure monitor. During the 6 weeks of the enalapril therapy (n = 28) both the daytime (141/84 vs. 135/80 mmHg) and the night-time (130/78 vs. 124/72 mmHg) blood pressure values decreased; the increase of diurnal indices during the therapy (SI/DI 6/8% vs. 8/10) reflect the 24 hour long lasting effect of the drug. The body mass index had no influence on the efficacy of treatment. Our results indicate that enalapril manufactured in Hungary is an effective antihypertensive drug both in monotherapy and in combination, in both sexes (especially in men), irrespective of the body weight, in non-smokers and especially in smokers, in insulin dependent and in non-insulin dependent diabetes mellitus alike.

[Current issues in the diagnosis and therapy of diabetic nephropathy]. / A diabeteses nephropathia diagnosztikájának és terápiajának aktuális kérdései.

Diabetic nephropathy is one of the most frequent causes of chronic renal failure worldwide. Altogether, 35% of patients with insulin-dependent diabetes mellitus and a somewhat smaller percentage of patients with non-insulin-dependent diabetes mellitus ultimately develop diabetic kidney disease. Early diagnosis is of utmost importance since the development of diabetic nephropathy affects the general health, the carbohydrate metabolism of the patient, moreover it aggravates hypertension and accelerates atherosclerosis. Microalbuminuria is a sensitive but relatively late marker of diabetic kidney disease. Still, screening of diabetic patients for microalbuminuria is of great importance since there is no other screening test capable of diagnosing diabetic nephropathy at an earlier stage. The description of the genetic substrate of susceptibility to diabetic kidney disease would revolutionize the diagnosis and prevention of diabetic nephropathy. Until then, compliance with therapeutic guidelines outlined in milestone clinical studies of the last years may significantly decrease morbidity, the progression of, and the mortality associated with diabetic kidney disease.

[Current questions concerning the pathomechanism of diabetic nephropathy]. / A diabeteses nephropathia patomechanizmusának aktuális kérdései.

Diabetic nephropathy has become, one of the most frequent causes of chronic renal failure in the industrialized countries. Basic and clinical research aimed at the clarification of the pathogenesis of diabetic kidney disease is of utmost importance. The role of non-enzymatic glycosylation, the polyol cycle, oxidative stress, various hormones and cytokines in the development of diabetic nephropathy is very likely. However, there is still no unifying concept about the relative importance and interaction of these factors. This paper reviews the most important directions and results of basic research centering on diabetic kidney disease. The coming years will likely bring the elaboration of a detailed theory of the pathogenesis and an even tighter coordination of basic and clinical research.

Production of ouabain by rat adrenocortical cells.

Our aim was to identify which adrenocortical cells produce ouabain and how it is regulated in vitro. With the help of an ouabain radioimmunoassay developed in our laboratory, we found that ouabain is produced both by zona glomerulosa and fasciculata cells. Our results were confirmed by reverse-phase HPLC. ACTH increased ouabain production in both cell types. Angiotensin-II, as well as changes in the potassium concentration of the incubation medium, affected ouabain production only in the zona glomerulosa.

[Comparative study of 24-hour ambulatory blood pressure monitors with standard zero and random zero sphygmomanometers]. / 24 órás ambuláns vérnyomásmonitorozó készülék összehasonlító vizsgálata standard zéró és random zéró vérnyomásmérövel.

The aim of the study was to evaluate the accuracy of the most widespread 24-hour ambulatory blood pressure monitor in Hungary. The test was based on simultaneous measurement on the same arm with the test device and standard zero or random zero sphygmomanometer in 100 patients. The difference between the blood pressure values measured by the test device and by the standard device was calculated in each case, and a relationship between this difference and the actual blood pressure of the patient was analysed. Actual blood pressure was considered as the average of the blood pressure measured by the test and that by the standard device. Regarding the diastolic values, the mean difference between the values obtained by the test device and the standard zero sphygmomanometer was -3.8 +/- 7.55 mm Hg (p > 0.05), and that between the test device and the random zero sphygmomanometer was -0.1 +/- 6.05 mm Hg (p > 0.05). This differences did not reach statistical significance. Regarding the systolic values, the difference showed significant positive correlation with the actual blood pressure level of the patient, meaning that at higher blood pressure values the difference between the data gained by the test and standard device is greater than at lower actual blood pressure levels. Finally, according to the criteria of the British Hypertension Society, our device could be graded "C" both for diastolic and systolic values against the standard zero sphygmomanometer, and "C" for systolic and "B" for diastolic blood pressure against the random zero sphygmomanometer.

Atrial natriuretic peptide (ANP) responsiveness in patients with hypothyroidism.

Hypothyroidism is known to be associated with abnormalities of kidney function; recently, low atrial natriuretic peptide (ANP) plasma levels have been reported. Aim of the study was to asses ANP, sodium and water responsiveness to an acute saline load. Twelve patients with established primary hypothyroidism and 9 control subjects were studied. ANP was determined in plasma by RIA with extraction, prior to and after the infusion of saline, 500 ml/h for 4 hours. On a similar albeit liberal sodium diet hypothyroid patients excreted less sodium and water (74 +/- 33 (SD) mumol/min and 0.69 +/- 0.15 ml/min, respectively) than control subjects (110 +/- 52 mumol/min; P < 0.05 and 1.06 +/- 0.53 ml/min; P < 0.025, respectively). However, the infusion of saline resulted in a 3-fold increase of sodium output and more than 2-fold increase in urine flow. The exaggerated responsiveness in sodium excretion in patients with hypothyroidism was associated with significantly decreased pre-infusion ANP plasma levels (16.1 +/- 11.1 pg/ml vs. 44.4 +/- 14.4 pg/ml; P < 0.001) and also with sluggish response to the volume expansion (+24% vs. +48%). A significant correlation was found between serum T4 levels and plasma ANP concentrations in 8 patients (r = 0.689; P < 0.05). Although hypothyroid patients tend to retain sodium on a liberal salt diet, their kidney is capable of vigorously eliminating excess sodium when challenged with an acute saline load. This exaggerated responsiveness of sodium excretion can be demonstrated in spite of a sluggish response in ANP. Subnormal ANP levels in hypothyroidism are probably the result of thyroid deficiency.

Body sodium, atrial natriuretic peptide and blood pressure in diabetes mellitus.

Diabetes mellitus (DM) is frequently associated with hypertension for which an independent pathomechanism has been suggested. We studied 26 patients with insulin-dependent (IDDM) and 18 patients with non-insulin-dependent (NIDDM) uncomplicated DM; all patients were in metabolic balance and none of them had hypertension. Exchangeable body sodium (NaE was estimated by isotope dilution, using appr. 1.1 Mbq 24NA. In a subset of 8 IDDM and 8 NIDDM patients atrial natriuretic peptide (ANP) plasma concentration was determined prior to and after the infusion of 2000 ml physiological saline over 2 hr. NaE was significantly increased both in IDDM and NIDDM patients (104.4 +/- 11.4% and 109.9 +/- 8.0% of the normal value for healthy subjects of identical body surface area; p < 0.05 and < 0.001 resp.). Mean blood pressure (MBP) correlated significantly with NaE in both groups (r = 0.364 and r = 0.520; p < 0.05 and < 0.025, resp.) but not in healthy control subjects (r = 0.112; N.S.). Resting ANP levels were not significantly different in IDDM (34.9 +/- 11.3 pg/ml), NIDDM (42.6 +/- 11.7 pg/ml) or control subjects (40.9 +/- 17.2 pg/ml) however the infusion of saline resulted in a significantly greater increase of plasma ANP in the NIDDM patients (to 82.9 +/- 43.2 pg/ml; P < 0.01) than in the controls (55.6 +/- 23.7 pg/ml; P < 0.01) which was associated with a significantly less increase in sodium excretion (UNAV) in the NIDDM patients (+86% vs. 3170%; P < 0.02) indicating down-regulation of ANP receptors in the kidney of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between exchangeable body sodium and urinary 6-keto-prostaglandin F1 alpha excretion in normal man.

The renal prostaglandins are involved in the regulation of sodium balance. In the present study exchangeable body sodium (NaE) and the urinary excretion of the stable metabolite of prostacyclin, 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) were determined simultaneously in 10 hospitalized healthy individuals. NaE was 1461 +/- 107 mmol/m2 body surface area, or 98.5 +/- 6.9% when expressed as percent of the normal value assessed on the basis of measurements in 54 control subjects. The excretion of 6-k-PGF1 alpha amounted to 68.3 +/- 39.2 ng/4 hr. Statistical evaluation revealed significant correlation between NaE and PGF1 alpha excretion (r = 0.642; p less than 0.05) and between the serum Na concentration and the urinary excretion of 6-k-PGF1 alpha (r = 0.865; p less than 0.001). The obtained results indicate that urinary 6-k-PGF1 alpha excretion, hence the renal synthesis of prostacyclin, are regulated, among other factors, by body sodium stores. The increased production of prostacyclin with expanding sodium space might be regarded as a compensatory response contributing to the renal elimination of excess sodium from the body. The signal to this response could be the serum Na concentration.

Atrial natriuretic peptide (ANP) in patients with chronic renal failure on maintenance haemodialysis.

Atrial natriuretic peptide (ANP), a recently discovered cardiac hormone, is an important regulator of body fluid homeostasis. Twenty patients with established chronic renal failure and on maintenance haemodialysis were studied before and after dialysis with capillary dialysers. ANP was determined by RIA after extraction. Mean (+/- SD) pre-dialysis ANP concentration was 146 +/- 51 pg/ml and decreased significantly during dialysis to 68 +/- 38 pg/ml (p less than 0.001). Per cent and absolute changes in plasma ANP level correlated significantly with concomitant changes in body weight (r = 0.764; p less than 0.001 and r = 0.558; p less than 0.01, resp.) but not with changes in serum creatinine, blood pressure or serum electrolytes. The obtained results indicate that ANP levels in patients with chronic renal failure are elevated mainly due to fluid overload, and the rapid fall in ANP concentration observed during haemodialysis is caused by the removal of excess fluid from the body.

[The role of exchangeable sodium content of the body in cases of hypertension of various etiology]. / A szervezet kicserélhetö nátrium-tartalmának szerepe különbözö aetiológiájú hypertoniákban.

Measurement of exchangeable sodium by isotope dilution is a relatively simple, reliable method for the determination of body sodium contents, which can be used in the clinical practice without significant health hazard to the patient. When computed to body surface area, the values for exchangeable sodium can be compared in patients of different body build. Exchangeable sodium may be variably increased in different clinical conditions associated with hypertension, thus increased sodium contents of the body is of major importance in the pathogenesis of hypertension caused by all forms of mineralocorticoid excess, and in the majority of patients with chronic renal insufficiency. In several endocrine disorders, e. g., acromegaly, hypothyroidism, increased sodium space does not play any significant part in the pathogenesis of hypertension. In diabetes mellitus, exchangeable sodium may be increased already prior to the development of hypertension, however it is still a matter of debate whether this abnormality is involved in the pathogenesis of hypertension in these patients. It seems now beyond any doubt that body sodium is normal in patients with essential hypertension, including those with the low renin form of the disease; nevertheless, some data indicate that blood pressure may be volume dependent in elderly patients with essential hypertension.

Exchangeable body sodium in normal man: analysis of various frames of reference.

Exchangeable sodium is a reliable measure of body sodium contents. Since fat tissue contains significantly less sodium per unit of weight than other tissues, leanness of an individual may considerably affect exchangeable body sodium. Thus, subjects of different body size can be compared only when body build is considered. To evaluate various frames of reference, we analysed the relationship between exchangeable sodium as determined by isotope dilution and various parameters of body size. Body weight, body height, body surface area, and leanness index correlated significantly with exchangeable sodium, the closest relationship having been obtained with body surface area (r = 0.790; p less than 0.001). When analysing males and females separately (n = 18 and 36, resp.), best parallelism of regression lines was also obtained with body surface area. It is concluded that exchangeable sodium should be referred to unit of body surface area, expressing each individual's value as percent of the normal predicted value calculated from the regression equations y = 1388x + 370 and y = 1554x - 196 for males and females, respectively.