Biomedical subjects
Publications and source records attributed to U Heinrich.
We compared the effect between ultra-high-streptoinase therapy and standard fibrinolysis in a prospective randomized multicenter study of deep vein thrombosis. Ultra-high doses group seems to be a better treatment including decreasing the side-effects, but without showing statistical significance.
Because patients with uremia have evidence for growth hormone resistance, we investigated whether this resistance can be overcome by administration of recombinant human growth hormone in supraphysiologic doses in children with severe uremia. Nine stunted children with end-stage renal disease (median age 5.8 years, median bone age 2.7 years) were treated with recombinant human growth hormone, 4 IU/m2/day subcutaneously, for a period of 1 year. Median height velocity was increased from 4.4 cm/yr before therapy to 8.0 cm/yr during treatment. Negative values for height velocity standard deviation scores for chronologic age were improved from a median of -2.6 to +1.5 without advancing bone age more than chronologic age. The growth hormone-insulin-like growth factor I resistance may be explained in part by the increased serum concentration of the high molecular weight insulin-like growth factor binding protein despite normal insulin-like growth factor I serum concentration. Treatment with recombinant human growth hormone improved the ratio between the serum concentrations of insulin-like growth factor I and its binding protein, and normalized the somatomedin bioactivity in the growth cartilage bioassay.
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In 8 healthy normotensive probands with normal glomerular filtration rate, the effect of recombinant human growth hormone (rhGH) on inulin clearance (Cin) was examined in an open study with intraindividual crossover with or without enalapril pretreatment (20 mg/day). rhGH was administered by subcutaneous injection (4.5 U twice daly) for 3 days. On the following day Cin was measured with an enzymatic steady state infusion technique. Systemic hemodynamics and potential metabolic effects of rhGH, i.e., inulin-like growth factors I and II, somatomedin-binding protein, glucagon, C peptide, amino acid pattern, etc., were monitored. On controlled dietary intake of protein, the median Cin rose 72 h after start of rhGh administration from 114 (range 91-158) to 135 (108-167) ml/min/1.73 m2 without enalapril pretreatment (p less than 0.01) and from 111 (88-153) to 131 (100-173 ml/min/1.73 m2 with enalapril pretreatment (p less than 0.02). The results confirm that (1) rhGH increases Cin to a similar extent as extractive GH and (2) further demonstrate that this action is not obliterated by blocking the circulating converting enzyme.
Animal experiments have shown that the carcinogenic activity of organic extracts of exhaust condensates is caused predominantly by PAHs containing 4-6 rings. The carcinogenic potency not only of PAH-containing extracts but also of the whole exhausts has often been estimated from their benzo[a]pyrene (BP) content. However, this simplified yardstick should not be applied for comparison of the carcinogenic potency of different types of PAH-containing exhausts. Epidemiological and experimental studies indicate that, for the induction of a certain tumour incidence, inhaled cigarette smoke contains about 100 times less BP and inhaled diesel exhaust contains about 1000 times less BP than the exhausts from coke ovens or heated tar pitch which yield the same results. This means that diesel exhaust and cigarette smoke contain--apart from PAHs--highly potent carcinogenic substances and/or they induce tumorigenic reactions which are very effective.
The urinary and faecal excretion of pyrene and 1-hydroxypyrene after oral (53.4%), intraperitoneal (3.1%), intratracheal (30-37%) and intrapulmonary application (0.003%) to rats has been determined by means of gas chromatography/mass spectrometry and the excretion rates were found to depend on the mode of application. With regard to the low urinary excretion rates, 1-hydroxypyrene seems not to be very suitable as a biological marker for PAH exposure to man.
The O2 supply of the blood-free perfused brain cortex of the guinea pig was investigated by measuring polarographically the local distribution of tissue PO2 at 18 degrees C, 24 degrees C, and 37 degrees C. The perfusion was performed in situ, using a medium equilibrated by a gas mixture of 95% O2 and 5% CO2. Papaverine was added to prevent vasoconstriction during hypothermia. To avoid measuring artefacts thin micro electrodes with a small sharpened tip of ca. 4 microns in diameter were used and a special puncturing technique was applied. The experimental results indicate the presence of a large variation of local tissue PO2. Local mean PO2 increased up to a depth of 1000 microns, reached a plateau, and then decreased towards 3000 microns. This demonstrates that the O2 supply changes in dependence of the distance of the brain surface. This may partly be caused by the special vascularization pattern of the brain cortex. As it follows from the PO2 histograms, at 24 degrees C the tissue layer between 0-2000 microns (layer I) was well supplied with oxygen, whereas at the same time the layer between 2001-3000 microns (layer II) was hypoxic. At 37 degrees C, both layers were hypoxic, but layer III showed the more pronounced tissue hypoxia. To obtain a sufficient oxygen supply the temperature had to be reduced below 24 degrees C to sufficiently decrease tissue O2 consumption: at 18 degrees C, there was no sign of hypoxia any more. In comparison with the PO2 histogram of the tissue the PO2 histogram of the pial surface was shifted to higher PO2 values.(ABSTRACT TRUNCATED AT 250 WORDS)
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In this investigation rats were exposed to gasoline engine and diesel engine exhaust, respectively, and additionally treated with DPN in order to check the syncarcinogenic effects.
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The inhalation of cadmium chloride aerosols induced lung carcinomas in rats (3). Subsequently, CdCl2 was classified as probably carcinogenic in humans (2). Thus the Cd compounds CdCl2, CdSO4, CdS and CdO were investigated for their carcinogenic potencies in the lungs of hamsters and mice. The same experiment was conducted by GLASER et al. with rats (1).
Long-term inhalation of CdCl2 at concentrations as low as 12.6 micrograms Cd/m3 causes development of lung tumors in rats (4). No information, however, was available on the chronic carcinogenicity of CdO, CdS and CdSO4 which are especially relevant to the occupational area. In the present joint study of the Fh-ITA and the Fh-IUCT, rats and hamsters were exposed to CdCl2, CdSO4, CdO and CdS in a chronic inhalation carcinogenicity set-up (2, 3). The goal of the ultrastructural investigation was to compare inflammatory reactions and fibrotic lesions, as well as epithelial alterations occurring in the species under study. The present communication focusses especially on observations obtained from male and female hamsters and rats chronically exposed to CdO. In addition, we report preliminary results from a short-term inhalation study with CdO.
The laryngeal epithelium of Syrian golden hamsters (SGH) at 8, 12.5 and 17 months was studied by scanning electron microscopy (SEM) and light microscopy (LM). Stratified squamous epithelium, covered with shallow microvilli or microplicae, was observed covering the upper two-thirds of the laryngeal epiglottis, the false folds, the vocal cords and the luminal protrusions of the arytenoid cartilages. Pseudostratified respiratory epithelium, characterized by mucus producing cells with microvilli and ciliated cells, covered the base of the epiglottis and the entire subglottis. Transitional zones between squamous and respiratory epithelium were composed of stratified cuboidal epithelium. Towards the base of the epiglottis cuboidal cells with a relatively large surface area were present which displayed short surface microvilli, while cells with a small surface area were covered with long microvilli. Age related changes were not observed. Degenerative changes of submucosal glands or cartilages occurred in almost every animal, but no epithelial lesions were found. The findings confirm a low incidence of spontaneous metaplasia in the laryngeal epithelium of the SGH.
The respiratory epithelium of 8, 12.5 and 17.5-month-old Syrian golden hamsters was investigated by scanning electron microscopy (SEM) and routine light microscopy (LM) of paraplast sections. In selected cases, SEM-specimens were embedded in Epon after SEM evaluation. The samples were cut in semithin sections and examined by light microscopy. The density of ciliated cells in the respiratory epithelium differs from hamster to hamster. Care must, therefore, be taken when diagnosing simple metaplasia by SEM alone unless a sufficient number of damaged cilia are present. Only 1 animal (8 months old) exhibited squamous metaplasia of the tracheal mucosa. However, surface polymorphism resembling squamous metaplasia was seen in almost every specimen. The polymorphism was caused by either submucosal calcifications or by cystic changes of hypertrophic submucosal glands. In addition, variously formed aggregations of mucus were seen protruding from duct openings of hypertrophic submucosal glands. To avoid false positive or negative diagnosis which can occur when screening is done by SEM alone, light-microscopical examination of sections cut from SEM identified lesions appears necessary.
Syrian golden hamsters (480 males and 480 females) allocated into 24 groups were exposed 19 hours per day and 5 days per week for 6, 10.5, 15, or 18 months to total diesel exhaust, diesel exhaust without particles, a mixture of nitrogen dioxide (5 parts per million [ppm]2) and sulfur dioxide (10 ppm), or clean air. Two exposure groups from each test atmosphere were also treated by a single subcutaneous injection of either 3 mg or 6 mg of diethylnitrosamine/kg of body weight to evaluate an enhancing effect of diethylnitrosamine on exposure-related changes. Morphological evaluation was done by histopathology. Minor changes of the larynx and trachea were investigated by scanning electron microscopy, which showed a loss of ciliated cells in all exhaust-exposed groups. After exposure to diesel exhaust with or without particles, focal metaplasia and dysplasia of the respiratory epithelium were seen in the oldest animals by scanning electron microscopy. In the same specimens, attached mucous droplets indicated changes in mucous cells and mucous viscosity. Only the exposure to total diesel exhaust significantly increased the tumor rate in the upper respiratory tract of male hamsters treated with 6 mg of diethylnitrosamine per kg of body weight. At the lower diethylnitrosamine dose, no exposure-related effects on the tumor rates could be observed. The results from this study and from our other inhalation experiments appear to be insufficiently conclusive to demonstrate that diesel-engine exhaust should be classified as a cocarcinogen or enhancer for the test system used.
Recombinant human growth hormone (rhGH) has become available for treatment of growth failure in uremic children. Since GH raises the glomerular filtration rate (GFR) in healthy individuals, there has been concern that treatment with rhGH, by its action on glomerular hemodynamics, may adversely affect the progression of renal failure. To further address this issue, inulin clearance (enzymatic steady-state infusion technique) was measured in 7 healthy normotensive adult volunteers and 7 patients with chronic renal failure from glomerular or non-glomerular causes. Subjects were given 4.5 U bid of rhGH by s.c. injection for 3 days. In volunteers, a significant increase in Cin was noted 72 h after start of rhGH administration from 120 ml/min/1.73 m2 (range 91-158) to 133 (108-167) (p less than 0.02). In contrast, no significant increase in Cin was noted in patients with chronic renal failure (baseline Cin 21 ml/min/1.73 m2, 15-32; after rhGH 22 ml/min/1.73 m2, 15-32) despite pronounced effects of GH on S-cholesterol and urea excretion rate. The results show that stimulation of GFR by short-term administration of rhGH is obliterated in chronic renal failure.
Nine stunted prepubertal children with end-stage renal failure were treated by rhGH in supraphysiological doses (4 U/m2/day s.c.) for a period of six to nine months. The six-month data from these children indicated that exogenous rhGH significantly improved the growth rate in all children (mean height velocity SDS before therapy, -2.8; during the treatment period, +2.5). This effect was accompanied by a significant increase in serum somatomedin bioactivity. Low normal basal serum IGF I concentrations were increased by rhGH. Elevated basal serum IGF II concentrations were further increased by rhGH treatment. The pharmacokinetic profile of rhGH in uremia resembles that of the non-uremic state; no accumulation was seen after 14 days of treatment. Glucose tolerance did not change, and insulin levels remained stable throughout the six-month observation period. No rhGH antibodies were detected. Although these short-term results are very encouraging, the effects of rhGH on the prognosis for final height need to be assessed over a longer period of time.
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