[Nephropathia epidemica as the result of a Puumala virus infection in a pregnant patient]. / Nephropathia epidemica als Folge einer Puumala-Virus-Infektion bei einer schwangeren Patientin.

HISTORY AND ADMISSION FINDINGS: A 29-year-old woman in the early stage of pregnancy ( approximately 6 (th) week) presented in our hospital with influenza-like symptoms of fever, headache, aching limbs and tenderness over the costovertebral angle. Acute oliguric renal failure occurred within a few days. INVESTIGATIONS: Ultrasonography revealed symmetrically enlarged kidneys with a small amount of perirenal fluids. The blood count showed thrombocytopenia, and viral serology verified a recent infection with Puumala virus (species of Hantavirus). TREATMENT AND COURSE: Epidemic nephropathy was diagnosed. The patient underwent one session of hemodialysis and soon recovered without any residual renal damage. The pregnancy continued without any further complications. CONCLUSIONS: There are only few reports on infections with Puumala virus during pregnancy are. None of theses described any fetal abnormalities causes by the maternal infection, as in our patient. Hantavirus infections should be considered in differential diagnosis of acute renal failure in endemic regions.

Chlamydia pneumoniae IgA seropositivity is associated with increased risk for atherosclerotic vascular disease, myocardial infarction and stroke in dialysis patients.

BACKGROUND: Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with chronic renal failure undergoing dialysis therapy. Aim of the study was to evaluate whether there is a correlation between a past infection with Chlamydia pneumoniae inducing antibody production and the manifestation of symptomatic atherosclerotic disease in patients with chronic renal failure on hemodialysis. METHODS: A retrospective study was designed including 151 dialysis patients with a clinical apparent atherosclerotic disease (case subjects) and 116 dialysis patients without any symptomatic atherosclerotic manifestation (control group). An ELISA was used to measure seropositivity for IgA and IgG titers. RESULTS: Elevated IgA titers against Chlamydia pneumoniae were found in 67% of the case subjects, but only in 29% of the controls (OR 5.34, CI 2.98-9.56). Forty-five patients of the case subjects had a history of myocardial infarction (OR 5.14, CI 2.38-11.09). Prior stroke was found in 30 patients in case subjects (OR 4.37, CI 1.73-11.01). The follow-up after 3 years showed that only 20 patients died from cardiovascular disease in the control group in comparison to 57 patients in the case group (OR 2.51). IgG seropositivity revealed an OR of 1.02 (CI 1.0-2.1). CONCLUSION: These results indicate that IgA seropositivity is associated with an increased frequency of symptomatic atherosclerotic manifestations. Especially an increased number of patients was found with prior myocardial infarction or stroke when elevated IgA titers were detected. IgA positivity seems to be a separate prospective risk factor in patients with chronic renal failure and hemodialysis for premature cardiovascular death.

Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells.

OBJECTIVE: Secondary failure due to late restenosis continues to occur in 30-50% of individuals after PTCA. beta-Blockers play an important role in the treatment of CAD. The aim of this study was to investigate the effects of the new beta-blocker nebivolol on cell proliferation of human coronary smooth muscle cells (haCSMCs) and endothelial cells (haECs) in comparison to traditional beta-blockers. METHODS: The effect of nebivolol and other beta-blockers on proliferation of HaECs and HaCSMCs was analyzed by bromodeoxyuridine incorporation. Apoptosis was measured by determination of hypodiploid DNA in both cell types. Additionally, in HaECs NO formation, endothelin-1 transcription and secretion were determined. RESULTS: Incubation for 1, 2, 4, 7 or 14 days resulted in a concentration- and time-dependent reduction of proliferation up to 80% in HaECs and HaCSMCs. beta-Blockers such as propranolol, metoprolol or bisoprolol did not exert this effect. Nebivolol inhibited accelerated haCSMC proliferation even in the presence of growth factors such as TGFbeta(1) and PDGF-BB. Nebivolol concentration-dependently induced a moderate apoptosis (10(-5) mol/l: 23%) and a decrease of haCSMCs in the S-phase by 66%. HaECs showed comparable results. During nebivolol incubation NO formation of HaCEs increased, while endothelin-1 transcription and secretion were suppressed. CONCLUSION: Whereas classical beta-blockers do not affect cell growth, only nebivolol inhibits haCSMC or haEC proliferation and induces a moderate rate of apoptosis. Furthermore, in HaCEs NO formation increases and endothelin-1 secretion decreases suggesting that nebivolol may represent a beta-blocker with great promises in CAD therapy.

Chronically elevated endothelin-1 concentrations modulate the beta-adrenergic receptor system in vitro and in vivo.

In atherosclerosis and heart failure chronically elevated endothelin-1 (ET-1) plasma concentrations have been found which correlate with an increased mortality. The aim of this study was to determine the effects of chronically elevated ET-1 concentrations in vitro on the expression of the beta-adrenergic receptor (betaAR), the alpha-subunit of the stimulatory guanine-nucleotide-binding protein (G(s alpha)), and to determine betaAR's ability to activate adenylyl cyclase. In order to elucidate the effects of elevated ET-1 concentrations in vivo, male rats were infused with ET-1 and betaAR density was measured. Smooth muscle cells were incubated with ET-1 (10(-7) mol/l) for 6 to 48 h. Densities of betaARs were determined by radioligand binding studies and the G(s alpha) was analyzed by Western blotting. Isoproterenol-mediated adenylyl cyclase activity was measured. Additionally male rats were infused with ET-1 for 3 weeks. In vitro the betaAR density increased by 52% (p < 0.05, n = 5). The G(s alpha) increased to 260%. The isoproterenol-stimulated adenylyl cyclase activity was increased to 228%. In vivo, the pulmonary and myocardial betaAR density was elevated by 43% and 97%, respectively. Chronic ET receptor activation induces a transregulation of betaARs in vitro and in vivo.

Endothelin-receptor antagonists in uremic cardiomyopathy.

Increased endothelin-1 (ET-1) levels were found in patients with chronic renal failure. These correlate with the severity of renal failure. Patients with elevated ET-1 concentrations show an increased cardiovascular mortality. The prevalence of severe left ventricular hypertrophy (LVH) is a very important factor for survival and morbidity in uremic patients The aim of this study was to assess the protective effect of ET-receptor antagonists in chronic uremia. Sprague Dawley rats were subtotally nephrectomized (SNX) and treated either with the endothelin-A- (ET(A)) receptor antagonist LU302146 or with the unselective ET(A)/ET(B)-receptor antagonist LU302872 (30 mg/kgbw/day both). After subtotal nephrectomy protein excretion SNX (130.0 +/- 22.5 mg/24 h) was increased in comparison to the ET(A)-group (446 +/- 103 mg/24 h) and the ET(AB)-group (23.2 +/- 37 mg/24 h) vs sham: 115 +/- 19 mg/24 h). Heart weight was decreased by the ET(A)/ET(B)-receptor antagonist LU302146. Left ventricular contractility was impaired in SNX by about 40%. Treatment with the ET-receptor antagonists prevented the impairment in left ventricular function. Our study results provide a possible therapeutic approach using ET receptor antagonists to reduce cardiac hypertrophy and renal proteinuria. Further human studies are needed to show whether this protection of the heart and kidney might influence the survival and life-expectancy of patients suffering from chronic renal failure.

Beta-blockers of the third generation inhibit endothelin-1 liberation, mRNA production and proliferation of human coronary smooth muscle and endothelial cells.

Endothelin-1 (ET-1) plays an important role in atherogenesis. The aim of the study reported here was to investigate the effects of the third generation beta-blockers nebivolol and carvedilol on ET-1 liberation, preproendothelin-1 production and on proliferation of human coronary cells. Human coronary endothelial (HEC) and smooth muscle cells (HCSMC) were grown with carvedilol or nebivolol (10(-7)-10(-5) mol/l). Incubation for 1, 2 or 7 days resulted in an 80% concentration- and time-dependent reduction in HCSMC proliferation. beta-blockers such as propranolol or metoprolol did not influence cell proliferation. Nebivolol (10(-7) mol/l) inhibited accelerated HCSMC proliferation in the presence of growth factors such as transforming growth factor-beta1 or platelet-derived growth factor BB. During incubation with nebivolol or carvedilol ET-1 secretion decreased. For nebivolol this is a result of a reduction in preproendothelin-1 mRNA levels. beta-blockers of the third generation that reduce the cell proliferation and ET-1 secretion may represent strategies with great promise for antiproliferative therapy of coronary heart disease.

Protective effects of endothelin antagonists in chronic renal failure.

The present study suggests that ET-1 is involved in the pathogenesis of uraemic cardiac hypertrophy and in the progression of renal failure in rats with subtotal nephrectomy examined after an intermediate period of 12 weeks of renal failure. Furthermore, proteinuria is reduced by the selective ETA receptor antagonist more than by the unselective ETAB receptor antagonist, without reducing the blood pressure. ET receptor blockade might preserve renal function by reduction of protein excretion. In addition, ET receptor antagonists influence the aldosterone system. In our animal studies, the medication was well tolerated. Our study results provide a possible therapeutic approach using ET receptor antagonists for cardiac hypertrophy and renal protein excretion by blockade of endogenous ET-1. Further human studies are needed to show whether this protection of the heart and kidney might influence the survival and life expectancy of patients suffering from chronic renal failure, of patients on dialysis or after kidney transplantation.

Dynamic regulation of beta-adrenergic receptors by endothelin-1 in smooth-muscle cells.

Elevated endothelin-1 (ET-1) levels are found in atherosclerosis, myocardial ischemia, and heart failure, and are correlated with increased mortality rates. Contrary to expectations, elevations of endogenous ET-1 levels in transgenic mice are not associated with increases in arterial blood pressure or with vasospasm, although these effects can be observed after i.v. ET-1 administration. The aim of this study was to determine the regulatory effects of ET-1 on the expression of vasodilator beta-adrenergic receptors and their ability to activate adenylyl cyclase. Smooth-muscle cells were incubated with ET-1 (10(-7) mol/L) for 3 days. The density of ET-1 or beta-adrenergic receptor binding sites was determined using a radioligand binding procedure. Adenylyl cyclase activity was measured to assess any functional changes in the beta-adrenergic receptor density. ET-1 incubation reduced ET-1 binding sites by 70%. In contrast, the beta-adrenergic receptor density increased from 354 +/- 35 to 538 +/- 50 fmol/mg protein (p < 0.01; n = 7) after 3 days. ET-1 increased beta-adrenergic receptors dose-dependently. Incubation with ET-1 for different periods of time showed an initial decrease of 30% after 6 h of ET-1 incubation. However, after 24 h ET-1 induced an increase of beta-adrenergic receptors, reaching a maximal amount after 48 h. An increased stimulation of beta-adrenergic receptor-activated adenylyl cyclase was observed after 3-day ET-1 incubation compared to controls. These data demonstrate that chronic ET receptor activation by ET-1 results in a functionally significant increase in beta-adrenergic receptor density and adenylyl cyclase activity.

Endothelin-1 and endothelin-3 levels in different types of glomerulonephritis.

There is evidence that an activated renal endothelin (ET) system is involved in development of glomerulosclerosis. However it is still unknown if different ETs are involved in the pathogenesis of various types of glomerulonephritis (GN). This study characterized ET-1 and ET-3 levels in patients suffering from chronic GN. We performed a prospective study to evaluate the ET-1 and ET-3 levels in 19 patients with biopsy-proven GN, including four minimal-change nephropathies (MCN), six perimembraneous GN (PM-GN), and nine mesangioproliferative GN (MP-GN). Twelve healthy subjects matched for age and sex served as controls. ET-1 and ET-3 were measured in plasma (p) and in urine [spontaneous urine (sp.urine) and urine over 24 h (24-h urine)] using a specific radioimmunoassay. Patients and controls were compared using the Wilcoxon rank-sum test. In MCN, ET-1 levels were enhanced in sp. urine (p = 0.03) and 24-h urine (p = 0.01), whereas ET-3 levels did not differ from controls. In comparison, in PM-GN we found an increased ET-3 level in 24-h urine (p = 0.004). In MP-GN, ET-3 levels were also elevated in p (p = 0.0002) and urine specimens (sp. urine p = 0.05; 24-h urine p = 0.03). No positive correlation to C3 or C4 complement fractions was found. Age, blood pressure or renal function did not correlate with ET-1 or ET-3 levels. In MP-GN and PM-GN, ET-3 is elevated whereas ET-1 is not. In contrast ET-1 is increased in MC-GN. These data indicate an important role for the ET-1 and ET-3 systems in the pathophysiology of different forms of GN. This is significant with regard to an early preservation of renal function at the onset of GN by the use of selective ET antagonists.

Influence of fitness on susceptibility to noise-induced temporary threshold shift.

PURPOSE: Two earlier reports indicated that cardiovascular fitness attenuates susceptibility to noise-induced temporary threshold shift (TTS) in hearing sensitivity; however, other parameters of fitness also may be related to this phenomenon. This study investigated the association of three different physical fitness indicators on TTS. METHODS: Maximal aerobic power (VO2max), body composition. and recent activity history were determined in 33 normal-hearing females of various fitness levels. Audiometric thresholds were obtained at 2000, 3000, 4000, and 6000 Hz before and immediately after 10 min of exposure to 108-dB SPL narrow-band noise centered at 2000 Hz. RESULTS: All postnoise measurements were significantly less than prenoise measurements (P < 0.0001) with the greatest TTS occurring at 3000 Hz. Similarly, the strongest Pearson-product correlations for VO2max, % fat, and recent activity history with TTS occurred at 3000 Hz (r = -0.68, 0.60, -0.59, respectively; P < 0.05). Canonical correlation analysis indicated a moderate correlation between physical fitness and TTS (Rc = 0.71: P < 0.01). Individually, VO2max, % fat, and recent activity history had correlations of -0.70, 0.62, and -0.63, respectively, to the TTS canonical variable. CONCLUSIONS: From these results, we concluded that there is a moderate association of physical fitness and diminished temporary hearing loss experienced after noise exposure.

Does primary omental pregnancy exist?

Omental pregnancy is a rare form of abdominal pregnancy. In the 5 previously reported cases, primary implantation of the embryo to the omentum has been proposed as its etiology. We present a new case of omental pregnancy in a 31-year-old woman presenting with symptoms of ectopic pregnancy. After careful review of our case and the published literature in view of the accepted definition of primary abdominal pregnancy, we conclude that all reported instances of omental pregnancy are secondary and probably follow tubal or ovarian pregnancy abortion.

Does L-arginine alter proteinuria and renal hemodynamics in patients with chronic glomerulonephritis and hypertension?

Endogenous nitric oxide (EDRF) plays an important role in the regulation of systemic and renal blood pressure by an alteration of vascular tone. To assess the effect of L-arginine (160 mumol/min i.v. for 3 hours), the precursor of EDRF, on blood pressure, protein-excretion and renal function (GFR = glomerular filtration rate, RPF = renal plasma flow) we performed a prospective, double blind, placebo controlled study. 18 patients with chronic glomerulonephritis (51.3 +/- 11.5 years), renal insufficiency (GFR < 65 ml/min) and hypertension were investigated for changes in GFR and RPF by continuous inulin- and PAH-clearances and for changes in permselectivity by determination of protein-excretion. L-arginine infusion results in a reduction of proteinuria (p < 0.05, t-test). There is no significant effect on renal hemodynamics and mean arterial pressure (MAP). Comparing the excretion of the endogenous proteins, only albuminuria is decreased significantly (p < 0.01), whereas IgG-excretion is reduced slightly (p < 0.05). This can be considered as an indicator of a special influence on the mesangial cells or the basement membrane of the glomerulum itself by EDRF. In conclusion L-arginine reduces protein-excretion without significant alterations in renal hemodynamics and so might prevent a decline in renal failure.

Measurement of terminal deoxynucleotidyl transferase mRNA in clinical samples: a new parameter in analysis of leukemia cells.

A 1750 base pair cDNA to human terminal deoxynucleotidyl transferase (TdT) has been cloned. This cDNA detects a dominant 2200 base pair messenger RNA species in normal and leukemic cells synthesizing the enzyme. A quantitative dot blot assay was utilized to survey a number of clinical samples from patients with TdT positive and negative leukemias as well as cells from normal volunteers. A linear relationship was detected between the amount of TdT mRNA and the amount of enzyme activity in bone marrow cells. The assay is sensitive enough to detect normal TdT levels in bone marrow, and distinguish these levels from the lack of such mRNA in peripheral blood and bone marrow of patients with myeloid leukemia. Elevated levels of mRNA were found in two cases of patients in clinical remission. The prognostic significance of these observations must await further study.

Cloning of terminal transferase cDNA by antibody screening.

A cDNA library was prepared from a terminal deoxynucleotidyltransferase-containing thymoma in the lambda phage vector lambda gt11. By screening plaques with anti-terminal transferase antibody, positive clones were identified of which some had beta-galactosidase-cDNA fusion proteins identifiable after electrophoretic fractionation by immunoblotting with anti-terminal transferase antibody. The predominant class of cross-hybridizing clones was determined to represent cDNA for terminal transferase by showing that one representative clone hybridized to a 2200-nucleotide mRNA in close-matched enzyme-positive but not to enzyme-negative cells and that the cDNA selected a mRNA that translated to give a protein of the size and antigenic characteristics of terminal transferase. Only a small amount of genomic DNA hybridized to the longest available clone, indicating that the sequence is virtually unique in the mouse genome.

Cell-free translation of the messenger RNA for calf terminal deoxynucleotidyltransferase.

Poly(A)-rich RNA has been isolated from calf thymus and translated in vitro in a rabbit reticulocyte translation system. Three peptides with Mr = 58,000, 33,000, and 13,000 were specifically immunoprecipitated from the translation products with calf terminal deoxynucleotidyltransferase antiserum. An oligo(dT)-purified preparation of calf terminal transferase competed with only the Mr = 58,000 peptide in the immunoprecipitation reaction. The anti-terminal transferase serum did not precipitate a Mr = 58,000 peptide from translation products of spleen or liver mRNA, but it did precipitate the Mr = 33,000 and 13,000 peptides from products of spleen mRNA and a Mr = 13,000 peptide from products of liver mRNA. In addition, when an affinity-purified antibody to calf terminal transferase was used, only a Mr = 58,000 peptide was immunoprecipitated from the translation products of calf thymus mRNA, and none was immunoprecipitated from spleen or liver mRNA products. This antibody also precipitated a Mr = 58,000 peptide from the cell lysates of calf thymocytes labeled in vitro with [35S]methionine. These results demonstrate that calf terminal transferase is biosynthesized as a Mr = 58,000 peptide.