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Biomedical subjects

U Heinrich

Publications and source records attributed to U Heinrich.

At least 55 records · Page 3Linked to original sources
PubMed1995

Deconvolution analysis of spontaneous nocturnal growth hormone secretion in prepubertal children with preterminal chronic renal failure and with end-stage renal disease.

We sought to determine whether elevated circulating growth hormone (GH) concentrations in uremic prepubertal children are due to an increase in GH secretory activity by the pituitary gland or a decrease in the metabolic clearance of GH consequent to reduced GFR. Deconvolution analysis was applied to the nighttime plasma GH profiles of 1) 11 children with preterminal chronic renal failure, 2) 12 children with end-stage renal disease (ESRD), and 3) a control group of matched children with idiopathic short stature (n = 12). Mean (+/- SEM) half-life of endogenous GH in children with ESRD (27.5 +/- 2.7 min) and preterminal chronic renal failure (23.1 +/- 2.1 min) was significantly higher than in controls (14.8 +/- 1.6 min; p < 0.001). GH half-life correlated inversely with GFR (r = -0.65, p < 0.001). The number of GH secretory bursts/10 h in ESRD (8.1 +/- 0.4) was amplified compared with preterminal chronic renal failure (6.4 +/- 0.5) and with controls (5.9 +/- 0.4; p < 0.005). GH production rate varied over a broad range in the three groups: It was highest in ESRD (202 +/- 56.6 microgm/L/10 h; range 36-683), mainly as a result of an increased number of GH secretory bursts, and not statistically different in preterminal chronic renal failure (66.2 +/- 11.4 microgm/L/10 h; range 25-168) and in controls (129 +/- 27.7 microgm/L/10 h; range 39-392). Increased GH half-life, in concert with an increased GH production in some individuals with ESRD, leads to a 2.5-fold increase in the mean plasma GH concentration in ESRD compared with the two other groups (p < 0.005) [corrected].(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Type A natriuretic peptides exhibit different bronchoprotective effects in rats.

The protective effect of 11.4, 22.8 or 45.6 pmol/kg/min cardiodilatin/atrial natriuretic peptide (CDD/ANP-(99-126)), urodilatin (CDD/ANP-(95-126)) or vehicle intravenously against acetylcholine-induced bronchoconstriction was compared in spontaneously breathing, halothane-anesthetized Wistar rats. The inhalation of acetylcholine induced significant alterations of the spontaneous breathing parameters evaluated by whole-body plethysmography without significant differences between the treatment groups. Forced parameters detect airflow changes with a greater sensitivity and were measured in hyperventilation-induced temporary apnoea after the challenge. The forced expiratory volume in 0.1 s revealed a significant protective effect of 11.4 pmol/kg/min urodilatin compared to the controls whereas the parameters of the forced expiratory flow-volume curve were significantly preserved by 11.4 and 22.8 pmol/kg/min urodilatin (P < 0.05). Urodilatin showed protective effects against an acetylcholine challenge whereas CDD/ANP-(99-126) was without significant influence.

Acetylcholine↗
PubMed1994

Estimation of a lifetime unit lung cancer risk for benzo(a)pyrene based on tumour rates in rats exposed to coal tar/pitch condensation aerosol.

Female Wistar rats were exposed to coal tar/pitch condensation (CTP) aerosol containing either 20 or 46 micrograms/m3 benzo(a)pyrene (BaP) among other polycyclic aromatic hydrocarbons (PAH) 17 h/day and 5 days/week for 10 or 20 months followed by a clean air period of up to 20 or 10 months, respectively. Based on the inhaled BaP, given as BaP exposure concentration multiplied by the total exposure time, the cumulative dose of inhaled BaP of the 4 exposure groups was 71, 142, 158 and 321 mg BaP/m3 x h and the corresponding lung tumour rates were 4.2, 33.3, 38.9 and 97.2%. There was no lung tumour in the control group. Using the US Environmental Protection Agency (EPA) linearized multistage model, the lifetime lung tumour risk for rats exposed to 1 microgram/m3 BaP as a constituent of a complex PAH mixture may be 2% or correspondingly 2 per 100,000 with a BaP concentration of 1 ng/m3. The estimation of the unit lung cancer risk for BaP based on epidemiological data from coking plants was 7-9%.

Administration, Inhalation↗
PubMed1994

Induction of squamous cell carcinomas in the mouse lung after long-term inhalation of polycyclic aromatic hydrocarbon-rich exhausts.

A 10-month inhalation study using newborn female mice was performed to determine pulmonary tumorigenicity of polycyclic aromatic hydrocarbon (PAH)-enriched exhausts. At two exhaust doses containing 50 micrograms/m3 (group II) and 90 micrograms/m3 benzo(a)pyrene (BaP) (group III) a significant increase of lung tumors was observed and the incidence of malignant lung tumors was dose-dependent. Bronchiolo-alveolar adenomas were observed in all mice of groups II and III (40/40 each) as compared to 5/40 in the control (group I). Bronchiolo-alveolar adenocarcinomas developed in 10/40 and in 33/40 mice of groups II and III, respectively, but were absent in group I. Single or multiple squamous cell carcinomas, which showed variable degrees of differentiation were observed exclusively in 6 mice of group III. One adenosquamous carcinoma was seen in an further animal of this group.

Animals↗
PubMed1994

Formation of DNA adducts in rat lung following chronic inhalation of diesel emissions, carbon black and titanium dioxide particles.

Exposure of rats to diesel emissions results in the development of lung tumors. The objective of this study was to determine whether the polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs or other polycyclic organic matter adsorbed to diesel particles induces the formation of DNA adducts in the lung when compared to particles with little or no adsorbed organic matter. Rats were exposed to diesel emissions containing particles with over 30% solvent-extractable adsorbed organic matter and to particles with < 0.1% adsorbed organic matter (carbon black particles and TiO2). Wistar rats were exposed to diesel emissions (7.5 mg/m3) for 2 months, 6 months and 2 years and for 2 years to carbon black (11.3 mg/m3) and TiO2 particles (10.4 mg/m3) to compare tumorigenic response and DNA adduct formation in the lung. Two versions of the 32P-postlabeling assay for the detection of DNA adducts were used to tentatively identify nitrated-amine or arylamine adducts formed relative to other nitro PAH based on the demonstrated sensitivity of these adducts to nuclease P1 treatment. Total adduct levels were determined for peripheral lung tissue DNA as detected in a diagonal radioactive zone. One major adduct which migrated outside this region (adduct 1) and a nuclease P1-sensitive adduct (adduct 2) were quantitated separately. Adduct 1 increased significantly over time in the filtered air exposed animals but decreased markedly at the 2 year time points regardless of particle type, presumably as a result of adduct dilution through de novo cell synthesis or cell proliferation invoked in response to particle loading and/or effect on the endogenous synthesis or degradation of DNA reactive moieties. The nuclease sensitive adduct (adduct 2), possibly resulting from exposure to nitro-PAHs, was detected in diesel-exposed rats but was not detected in the rats exposed to TiO2 and carbon black. No significant elevation in PAH-derived adducts, relative to the filtered air controls, was observed in the rodents exposed to diesel emission. Our data suggest that long-term contact with these particles may result in a cell proliferative response, enhanced degradation of I-compounds not related to cell proliferation, and/or synthesis of I-compounds, irrespective of the differences in organic content associated with the three particle types. This response may be an important factor in explaining the reported similarity in tumorigenic response in rodents exposed to diesel emissions, carbon black and TiO2 particles.

Administration, Inhalation↗
PubMed1994

Congenital adrenal hyperplasia caused by a novel homozygous frameshift mutation 273 delta AA in type II 3 beta-hydroxysteroid dehydrogenase gene (HSD3B2) in three male patients of Afghan/Pakistani origin.

Classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is an autosomal recessive form of congenital adrenal hyperplasia caused by mutations in the type II 3 beta-HSD (HSD3B2) gene. The sequence of the type II 3 beta-HSD gene was determined by direct sequencing of asymmetric PCR products in three male infants suffering from a severe salt-losing form of 3 beta-HSD deficiency and belonging to three families originating from Afghanistan and Pakistan. The three patients were homozygous for the frameshift mutation 273 delta AA resulting from deletion of two adenosines at codon 273, thus leading to a premature termination codon at position 279. This mutation was detected in the heterozygous state in all the relatives studied. The observation that all three patients share the same haplotype for HSD3B1A, HSD3B1C, HSD3B2A, and the microsatellite marker D1S252 indicates that a founder effect is responsible for the severe form of 3 beta-HSD deficiency found in these three families.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Morphology and histogenesis of squamous cell metaplasia of the rat lung after chronic exposure to a pyrolized pitch condensate and/or carbon black, or to combinations of pyrolized pitch condensate, carbon black and irritant gases.

Female Wistar rats were exposed to different concentrations of a pyrolized pitch condensate and/or carbon black particles and/or a combination of irritant gases for 18 hours/day, 5 days/week for 10 months, followed by a clean air period of up to 20 months. Bronchiolo-alveolar hyperplasia and squamous metaplasia were important components of the resulting lesions. Squamous metaplasia and associated hyperplasia was investigated by routine histology, scanning and transmission electron microscopy, and by immunohistochemical detection of various cytokeratins (CKs). Intensely CK positive squamous metaplasia lacking a distinct stratum spinosum was distinguishable from squamous metaplasia with a distinct stratum spinosum that reacted weakly CK positive or CK negative. The CK positive type was histologically characterized by narrow intercellular spaces, the weakly CK positive or CK negative type had markedly enlarged intercellular spaces. Differentiated hyperplastic epithelium and the normal lung parenchyma reacted CK negative. In poorly differentiated hyperplasia of the alveolar type associated with squamous metaplasia scattered cells with characteristics of squamous differentiation were detected. Ultrastructurally these cells showed increased amounts of filament bundles and immunohistochemically a positive reaction with the CK antibody. These cells were regarded as precursor stages of squamous metaplasia of the lung periphery in rats.

Animals↗
PubMed1993

Efficacy and safety of growth hormone treatment in short children with renal allografts: three year experience. Members of the German Study Group for Growth Hormone Treatment in Children with Renal Allografts.

The majority of children with renal allografts have diminished growth and reduced final height. Impaired allograft function and glucocorticoid treatment are the main contributing factors. Since recombinant human growth hormone (rhGH) treatment was able to counteract the growth depressing effects of glucocorticoids in experimental uremia, an open-labeled prospective study in 17 short children with renal allografts was designed to investigate the efficacy of rhGH therapy (30 IU/m2/week) with special emphasis on the safety regarding graft function and carbohydrate metabolism. Height velocity in prepubertal children (N = 10) increased from baseline median 2.2 cm/year to 7.9 cm/year after one year (P < 0.01), 7.2 cm/year after two years (P < 0.01), and 5.5 cm/year (P < 0.05) after three years of rhGH therapy. This resulted in a normalization of height in three out of seven patients after two years and in three out of five after three years of therapy. Growth stimulation in pubertal children was less consistent. Bone maturation paralleled chronological age. The effect of rhGH treatment on longitudinal growth may be partially attributable to the improved ratio between the serum concentration of the insulin-like growth factor (IGF)-I and its major binding protein (BP) IGFBP-3 leading to a normal IGF bioactivity. The incidence of acute rejection crises in the study group (corrected for time after grafting) did not differ from that of untreated retrospective "controls" (0.10 vs. 0.12 episodes per patient and year). No systematic effect of rhGH on glomerular filtration rate assessed by repeated inulin and creatinine clearances was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Pharmacokinetics of recombinant human insulin-like growth factor I given subcutaneously to healthy volunteers and to patients with growth hormone receptor deficiency.

The pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) were studied in healthy volunteers and in patients with growth hormone receptor deficiency (GHRD; Laron syndrome). Following single subcutaneous injections of rhIGF-I, 40 and 80 micrograms/kg, to healthy volunteers, the peptide was absorbed slowly, with a maximum concentration reached after about 7 hours. Following daily multiple subcutaneous injections of rhIGF-I, 40 micrograms/kg, trough concentrations of IGF-I were increased by 277 +/- 50 micrograms/l (mean +/- SD) from baseline. IGF-I was thus characterized as a low-clearance peptide, with a clearance and half-life estimated at about 0.20 ml/minute/kg and 20 hours, respectively, in healthy volunteers. The volume of distribution was low, about 0.20-0.36 litres/kg, the bioavailability of subcutaneously administered rhIGF-I was 100%, and the rate of production of IGF-I was estimated to be about 50 micrograms/kg/day (3.5 mg/day). Patients with GHRD had low baseline IGF-I concentrations (30-50 micrograms/l) and a much more rapid turnover of IGF-I compared with that in healthy volunteers. The clearance and half-life of IGF-I were estimated to be about 0.60 ml/minute/kg and 6 hours, respectively. The volume of distribution was about the same as in healthy subjects. Due to the rapid turnover of IGF-I, trough IGF-I concentrations were increased to just above baseline during subcutaneous injections of 40 micrograms/kg once daily for 7 days. The maximum increase in IGF-I levels was 111 +/- 12 micrograms/l and 150 +/- 3 micrograms/l following daily subcutaneous injections of 40 x 1 and 40 x 2 micrograms/kg for 7 days, respectively.

Adolescent↗
PubMed1993

Late-onset 3 beta-hydroxysteroid dehydrogenase deficiency with virilization induced by a large ovarian cyst.

A midpubertal girl presented with secondary amenorrhea and a rapidly progressive deepening of her voice as the only signs of virilization. Diagnostic work-up yielded an extremely elevated plasma testosterone (289 ng/dl), low estradiol (29 pg/ml) levels and a large solitary cyst of the right ovary, which was totally removed. Pathohistology was in keeping with a granulosa cyst with mild luteinization. Normalization of testosterone (to 27.3 ng/dl) and estradiol (to 62 pg/ml) and resumption of regular menses after 2 months clearly indicated an autonomous function of the cyst. A malignant tumor was unequivocally excluded. Basal and ACTH stimulated levels of adrenal androgens pointed to a late-onset 3 beta-hydroxysteroid dehydrogenase deficiency, which per se is known to induce polycystic ovarian changes, but to date has never been described to be accompanied with a large and autonomous follicular cyst.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Molecular basis of congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency.

Congenital adrenal hyperplasia is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to congenital adrenal hyperplasia due to 21-hydroxylase and 11 beta-hydroxylase deficiencies, which impair steroid formation in the adrenal cortex, exclusively, classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency affects steroid biosynthesis in the gonads as well as in the adrenals. The structures of the highly homologous type I and II 3 beta-HSD genes have been analyzed in three male pseudohermaphrodite 3 beta-HSD deficient patients from unrelated families in order to elucidate the molecular basis of classical 3 beta-HSD deficiency from patients exhibiting various degrees of severity of salt losing. The nucleotide sequence of DNA fragments generated by selective polymerase chain reaction amplification that span the four exons, the exon-intron boundaries, as well as the 5'-flanking region of each of the two 3 beta-HSD genes have been determined in the three male patients. The five point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene, predominantly expressed in the placenta and peripheral tissues. The two male patients suffering from severe salt-losing 3 beta-HSD deficiency are compound heterozygotes, one bearing the frame-shift mutation 186/insC/187 and the missense mutation Y253N, while the other bears the nonsense mutation W171X and the missense mutation E142K. The influence of the detected missense mutations on enzymatic activity was assessed by in vitro expression analysis of mutant recombinant enzymes generated by site-directed mutagenesis in heterologous mammalian cells. Recombinant mutant type II 3 beta-HSD enzymes carrying Y253N or E142K substitutions exhibit no detectable activity. On the other hand, the nonsalt-losing patient is homozygous for the missense mutation A245P. This mutation decreases 3 beta-HSD activity by approximately 90%. The present findings, describing the first missense mutations in the human type II 3 beta-HSD gene, provide unique information on the structure-activity relationships of the 3 beta-HSD superfamily. Moreover, the present findings provide a molecular explanation for the enzymatic heterogeneity responsible for the severe salt-losing form to the clinically inapparent salt-wasting form of classical 3 beta-HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Retinopathy and nephropathy in 772 insulin-treated diabetic patients in relation to the type of diabetes.

Using the register of the centralized Diabetes Care system in former GDR as run until 1989, the frequency of diabetic retinopathy and nephropathy and related factors were investigated in insulin-treated diabetic patients. Retinopathy was diagnosed by ophthalmoscopy, nephropathy was evaluated on the estimation of macroproteinuria. Out of the total of 1058 insulin-treated patients, 772 subjects (286 males, 486 females) who had undergone ophthalmoscopic examination during the previous year were selected for this study. According to clinical criteria, there were 238 patients with Type 1 and 534 patients with Type 2 diabetes. Their mean age was 43.3 and 64.5 years, respectively, and duration of diabetes was 13.2 and 14.0 years. Essential results: (1) Retinopathy was diagnosed in 52.5% of Type 1 and in 50.3% of insulin-treated Type 2 diabetic patients. There were no differences in the degree of retinopathy between the two groups. (2) The Type 1 diabetic patients with retinopathy were significantly older than those without retinopathy (49 vs. 37 years), but no such difference could be ascertained in Type 2 diabetes (64 vs. 65 years). (3) Duration of diabetes was longer in patients with retinopathy both in Type 1 (18 vs. 8 years) and in Type 2 diabetes (16 vs. 12 years). (4) Subjects of either group with retinopathy exhibited significantly higher systolic blood pressure values. (5) There was no difference in postprandial blood sugar or in applied insulin doses between the patients with or without retinopathy. (6) Clinical nephropathy was more frequent in Type 2 (22%) than in Type 1 diabetes (16.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of photocorrosion on cadmium sulfide suspensions applied in animal inhalation studies with CdS particles.

Cadmium sulfide aerosol (90 micrograms Cd/m3) was generated from an aqueous suspension for 12 weeks and the ratio of Cd++/Cdtotal in the suspension and the resulting aerosol was determined. After 4 weeks the concentration of Cd++ in the suspension and the aerosol leveled off at 43.5 +/- 11.4% and 35.8 +/- 6.8%, respectively. Therefore, lung tumors in rats observed after inhalation exposure to such CdS aerosols (Glaser et al. 1990) may have been caused not only by the effect of CdS but also by the influence of inhaled Cd++ or CdSO4. The contribution of CdS particles to the observed lung tumor rate depends on the bioavailability of CdS retained in the lungs. The photochemical decay of CdS in aqueous suspensions only occurred when exposed to light and adjusting the suspension up to pH 3 did not increase the decomposition rate of CdS. Ethanolic suspensions of CdS are much more stable than aqueous ones and experiments with suspensions kept under shield gases showed that the decay of CdS is not dependent on oxygen.

Administration, Inhalation↗
PubMed1992

Growth hormone treatment in children with preterminal chronic renal failure: no adverse effect on glomerular filtration rate.

Impaired growth and stunting remains a major therapeutic problem in children with chronic renal failure (CRF). Recombinant human growth hormone (rhGH) treatment may be beneficial, but concern has been raised about possible side-effects, i.e. deterioration of renal function and glucose intolerance. We have treated 10 prepubertal children with CRF (median age 7.5 [1.7-10.0] years) with 4 IU rhGH/m2 per day s.c. over a period of 1 year. Height velocity increased significantly (P less than 0.03) from basal 4.6 (2.0-14.0) cm/year to 9.7 (6.8-17.6) cm/year. Height velocity SDS for chronological age and for bone age increased in all children from basal median -2.3 to +3.8 (P less than 0.005). Median glomerular filtration rate (GFR) measured by single injection inulin clearance at onset was 18 (11-66) ml/min per 1.73 m2 and did not change significantly during the treatment year. The loss of GFR as estimated by creatinine clearance was similar during the treatment year (median loss 1.3 ml/min per 1.73 m2) compared to the year before treatment (median loss 3.7 ml/min per 1.73 m2). Serum glucose levels during an oral glucose tolerance test did not change, but fasting as well as stimulated insulin levels increased significantly with time during the study period. It is concluded that the rhGH regimen employed was remarkably effective in improving growth velocity in children with CRF without adversely affecting GFR. Glucose homeostasis remained stable, but at the expense of increased serum insulin levels.

Blood Glucose↗
PubMed1992

Pulmonary carcinogenicity of cadmium by inhalation in animals.

Although, the tumorigenic effect of cadmium after subcutaneous and intramuscular injection has been known since 1961, lung tumours after inhalation exposure were reported only more than 20 years later by Takenaka et al. (1983), using cadmium chloride aerosols. Based on these results, aerosols of cadmium sulfate, cadmium oxide and cadmium sulfide pigment were investigated for carcinogenic effects after inhalation exposure in rats, hamsters and mice. All the cadmium compounds tested appeared to have a very similar carcinogenic potency in the rat lung, whereas no exposure-related tumours occurred in hamsters and in mice only cadmium oxide seemed to increase the lung tumour rate. Subsequent analytical investigations of the aqueous suspension of cadmium sulfide used to generate the aerosol showed that it was soluble in water to some extent as a result of photo-oxidation. The exposure atmosphere therefore actually consisted of a mixture of sulfide and sulfate, and the observed lung tumour rate must be attributed to a combined action of the two compounds. For this reason, a clear-cut carcinogenic effect of cadmium sulfide could not be proved by this inhalation study, but because of the high carcinogenic potency of cadmium ions in the rat lung and because cadmium sulfide retained in the lung is bioavailable to a certain extent, aerosols of this compound should be regarded as a probable human carcinogen.

Administration, Inhalation↗
PubMed1991

How safe is the treatment of uraemic children with recombinant human growth hormone?

Exogenous growth hormone (GH) treatment for growth failure in uraemic children is effective over a period of up to 3 years. The safety of this new treatment modality is remarkably high, at least for this short period of time. Despite a reduced renal metabolic clearance rate of GH in uraemia, exogenous GH does not accumulate in the serum. In a dose range of 28 units/m2 per week, GH does not impair glucose tolerance but increases serum insulin levels, indicating that euglycaemia is maintained at the expense of increased insulin secretion. No alterations of lipid metabolism, mineral metabolism, pituitary-thyroid axis and blood pressure were observed. The GH-induced glomerular hyperfiltration in healthy subjects seems to be obliterated in chronic renal failure. Accordingly, no accelerated progression of renal disease was observed under GH treatment. However, potential side effects during long-term treatment, especially regarding carbohydrate metabolism and malignancy in children under immunosuppression, are not yet excluded.

Child↗
PubMed1991

Quantification of vascular stenosis with color Doppler flow imaging: in vitro investigations.

The accuracy of quantifying the degree of vascular stenosis with color Doppler flow imaging (7.5-MHz, linear array system) was determined in an experimental study carried out on six concentric and five eccentric model stenoses (cross-sectional area reduction, 13.4%-93.8%). The measurements were made with use of pulsatile flow at four different flow rates (70.8-339.0 mL/min). The degree of stenosis was calculated from the ratio of prestenotic to intrastenotic flow velocity. The most exact measurement of the degree of stenosis could be achieved with Doppler spectral analysis by determining the maximum peak systolic velocity (r = .994, y = 0.98x - 3.2). With the velocity values derived only from the color-coded image, it was also possible to find the most exact degree of stenosis (r = .995, y = 0.99x - 2.9). For quantification of stenosis, pre- and intrastenotic Doppler spectral analysis is no longer necessary if the stenosis can be imaged sufficiently with color Doppler.

Blood Flow Velocity↗