Search PubMed⌕ Search

Biomedical subjects

G Fischer

Publications and source records attributed to G Fischer.

At least 379 records · Page 21Linked to original sources

Regulation of divergent transcription of the genes coding for basement membrane type IV collagen.

The genes coding for the two polypeptide chains, alpha 1(IV) and alpha 2(IV), which form together the molecule of the basement membrane type IV collagen, were found to have a special and unusual genomic arrangement. The two genes are very closely linked, they are transcribed in opposite directions, and they apparently use a common and bidirectional promoter with a length of 127 bp. This region is characterized by a symmetrical arrangement of typical elements and by the palindromic structure of the sequence. In accordance with the symmetry of the promoter itself, a symmetrical organization of sequence motifs (SP1, CCAAT) was also observed in flanking regions. For the promoter and the flanking regions we could detect specific binding of nuclear factors that indicates their involvement in transcriptional activation. This suggests that the intrinsic symmetry of the type IV collagen promoter and its flanking regions may be a structural prerequisite for its bidirectional function. In transient gene expression systems no significant activity of the type IV collagen promoter was observed in either direction. This implies that additional enhancing elements are essential for the efficient and tissue-specific transcription of both type IV collagen genes. The screening for such controlling elements within the alpha 1(IV) and the alpha 2(IV) gene led to the observation that the transcription in direction of the alpha 2(IV) gene is activated by an element located in the first intron of the alpha 2 gene. Its enhancing effect is strictly dependent on the intact genomic structure of this region. Alternation of orientation and distance to the promoter destroys its activity completely. This element, located about 100-600 bp downstream from the start site of alpha 2(IV) transcription, seems to form a synergistically acting unit with the common promoter, essential for transcriptional activity in alpha 2 direction. We have not found additional enhancing elements in other regions of both genes. Explanations for the discrepancy with previous data, which define an enhancing element within the first intron of the alpha 1(IV) gene of mouse, are only speculative at present.

Base Sequence↗

Esmolol: effects on isoprenaline- and exercise-induced cardiovascular stimulation in conscious dogs.

Esmolol, a recently developed ultra-short acting beta-adrenoceptor blocking agent, was evaluated in 12 conscious chronically instrumented dogs with intact autonomic reflexes. The significance of its beta 1-adrenoceptor selectivity was examined at various cardiovascular activation levels established by either incremental isoprenaline infusion or graded treadmill exercise. The observed parameters were heart rate, systolic and diastolic arterial blood pressure, left ventricular dp/dtmax, and left ventricular end-diastolic pressure. Intravenous infusion of esmolol (25 and 250 micrograms.kg-1.min-1) led to a dose-dependent reduction of the isoprenaline-induced increase in positive dp/dtmax. The concomitant increase in heart rate was suppressed to a lesser extent. Characteristically of a beta 1-selective agent, esmolol had only a slight effect on the isoprenaline-induced reduction in diastolic blood pressure. The impact of esmolol on exercise-induced hemodynamic activation was much smaller. Exercise-induced increase in positive dp/dtmax was more sensitive to beta-adrenoceptor blockade than the concomitant increase in heart rate. Diastolic blood pressure was not influenced significantly. beta-Adrenoceptor blockade was virtually reversed within 20 min of discontinuation of esmolol infusion.

Adrenergic beta-Antagonists↗

Magnesium-deficient diet aggravates anaphylactic shock and promotes cardiac myolysis in guinea pigs.

Actively sensitized guinea pigs were rendered Mg(2+)-deficient for 2-3 weeks and then subjected to immune stress. No differences could be seen between treated and control groups prior to immune challenge. 1-2 h after antigen challenge, 95% of the Mg(2+)-deficient animals were observed to be anaphylactic, i.e. apathetic, dyspneic, and they had a rapid pulse rate. Only 4% of the control animals showed signs of anaphylaxis. Serum magnesium concentration, [Mg2+], fell from 1.32 +/- 0.07 mM in control guinea pigs to 0.56 +/- 0.04 mM in those fed an Mg(2+)-deficient diet. Cardiomyolysis (CM) developed in 19% of the anaphylactic animals and in 3% of the controls. We conclude that Mg(2+)-deficient animals continue to function, provided conditions are normal, but they are unable to withstand stress. The heart, however, appears to be better equipped to defend itself against Mg2+ deficiency and low serum [Mg2+], a supposition supported by the fact that heart [Mg2+] is not significantly reduced in hypomagnesemic guinea pigs (0.864 +/- 0.021 microgram/mg dry weight in control, and 0.834 +/- 0.062 microgram/mg dry weight in magnesium-deficient animals). The data indicate that hypomagnesemia heightens the intensity of the immune response, thereby exacerbating both anaphylactic shock (AS) and CM. A normal serum [Mg2+] would thus seem essential for protection against immune stress.

Anaphylaxis↗

[Clinical anatomy of the digital connective tissue cord of the ulnar side of the little finger].

A fibrous cord with a length of nearly 60 mm and a width of 3 mm consistency starts near the insertion of the abductor digiti minimi muscle at the ulnar border of the little finger. The fibers pass parallel to the longitudinal direction of the little finger and at the level of the osseous ridges on the palmar side of the flexion-extension axis of the finger joints. Proximally the cord receives fibers from the periosteum at the base of the proximal phalanx, from the ulnar end of the natatory ligament, and from the pretendinous fibers of the A1 pulley. Distally the digital cord has connections to the cutaneous ligaments of Grayson and Cleland. The cord also joins the flexor tendon sheath, the neurovascular bundles, and the skin. Sometimes these cords are involved in Dupuytren's contracture.

Adult↗

[Nitrate and nitrite concentrations in gastric juice with regard to the physiologic condition of the gastric mucosa].

In a random sample comprising 101 test persons (35 without and 66 with gastric disorders) nitrate and nitrite concentrations in gastric juice were determined. It was shown that parameters like pH, physiological stage of gastric mucosa, concentrations of bacteria and fungi in gastric juice or nitrate and nitrite concentrations, fungi and bacteria in saliva do not sufficiently characterize the dynamics of nitrate and nitrite in human stomach.

Adolescent↗

Determination of the partial benzodiazepine receptor agonist Ro 16-6028 in plasma by capillary gas chromatography with nitrogen-selective detection after conversion into the ethyl ester derivative.

A highly sensitive capillary gas chromatographic method was developed to determine plasma levels of a novel partial benzodiazepine receptor agonist in man following the very low therapeutic doses required for anxiolysis. The compound was isolated from plasma by liquid-liquid extraction at basic pH, converted into the ethyl ester analogue by a two-step procedure, separated from plasma constituents by capillary gas chromatography and quantified by means of nitrogen-selective detection. Because of the thermolabile tert.-butyl ester function, the agonist could not be gas chromatographed without degradation. Formation of the far more stable ethyl ester analogue was achieved by treatment with hydrogen chloride in ethanol, followed by an ethylation step with diazoethane. The high sensitivity of the new method (about 100 pg/ml, using 1-ml plasma specimens) allowed the monitoring of plasma levels of the agonist for up to 8 h (about three elimination half-lives) after a single 0.1-mg oral dose to human volunteers. The practicability of the procedure was demonstrated by the analysis of more than 600 plasma samples from clinical studies performed with human volunteers.

Anti-Anxiety Agents↗

Kinetic beta-deuterium isotope effects suggest a covalent mechanism for the protein folding enzyme peptidylprolyl cis/trans-isomerase.

The cis/trans interconversion of Glt-Ala-Ala-Pro-Phe-4-nitroanilide and Glt-Ala-Gly-Pro-Phe-4-nitroanilide was studied both enzymatically and nonenzymatically by measuring kinetic beta-deuterium isotope effects. The hydrogen atom at the alpha-carbon atom of the Xaa residue within the Xaa-Pro moiety was substituted by deuterium. In the nonenzymatic case the transition state of rotation is reflected by kH/kD greater than 1. When catalysed by 17 kDa PPIase the same bond rotation is characterized by kH/kD less than 1. This suggests a covalent mechanism of catalysis which involves an approximately tetravalent carbon of the prolyl imidic bond for the transition state of reaction.

Amino Acid Isomerases↗

[Nitrate and nitrite content of the saliva, urine, blood and cerebrospinal fluid in patients at an infection clinic].

In 254 patients of a ward for infectious diseases the authors demonstrated that inflammatory diseases are frequently accompanied by an increase in nitrate content of the blood, urine and saliva. This effect is especially evident in gastrointestinal disorders. Correlations of nitrate with indicators of the inflammatory process are, if at all, very weak. The endogenous synthesis of nitrate may be of importance for the total nitrate load to the organism especially in children or patients with long-lasting inflammatory disease.

Adult↗

Cardiac and hemodynamic effects of the selective bradycardic agent KC 8857 during exercise-induced myocardial ischemia.

The effects of an in vitro bradycardic agent without negative inotropism, KC 8857 (3,7-di-(cyclopropylmethyl)-9,9-tetramethylene-3,7-diazabicyclo-[3.3.1]- nonane dihydrochloride), were tested in chronically instrumented dogs in a model of exercise-induced myocardial ischemia. KC 8857 was i.v. infused during critical stenosis of the circumflex branch of the left coronary artery which led to exercise-induced myocardial dysfunction. KC 8857 caused a decrease in heart rate, left ventricular dp/dtmax and calculated myocardial oxygen demand at rest and during exercise. Since positive dp/dtmax values at a given heart rate were not altered by KC 8857 it may be assumed that myocardial function was restored mainly by the decrease in heart rate.

Animals↗

Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins.

The enzyme peptidyl-prolyl cis-trans isomerase (PPIase) was recently discovered in mammalian tissues and purified from porcine kidney. It catalyses the slow cis-trans isomerization of proline peptide (Xaa-Pro) bonds in oligopeptides and accelerates slow, rate-limiting steps in the folding of several proteins. Here, we report the N-terminal sequence of PPIase together with further chemical and enzymatic properties. The results indicate that this enzyme is probably identical to cyclophilin, a recently discovered mammalian protein which binds tightly to cyclosporin A (CsA). Cyclophilin is thought to be linked to the immunosuppressive action of CsA. The first 38 amino-acid residues of porcine PPIase and of bovine cyclophilin are identical and the two proteins both have a relative molecular mass of about 17,000 (ref. 7). The catalysis of prolyl isomerization in oligopeptides and of protein folding by PPIase are strongly inhibited in the presence of low levels of CsA. The activities of both PPIase and cyclophilin depend on a single sulphydryl group. At present it is unknown whether the inhibition of prolyl isomerase activity is related with the immunosuppressive action of CsA.

Amino Acid Isomerases↗

Tumor-promoting activity and cytotoxicity of 3,4,3',4'-tetrachlorobiphenyl on N-nitrosomorpholine-induced murine liver foci.

Effects of 3,4,3',4'-tetrachlorobiphenyl (TCB) on glucose-6-phosphatase (G6Pase)-altered hepatic foci of N-nitrosomorpholine (NNM)-treated B6C3F1 mice were investigated. TCB was chosen as a selective 3-methylcholanthrene-type inducer and tumor promoter. To initiate hepatocarcinogenesis, mice were treated with NNM (160 mg/l, in drinking water for 7 weeks), as in previous studies with the rat model. After a treatment-free interval of 22 weeks, TCB was administered (5 x 50 mg/kg, every 3 days), and liver foci were analysed 10 weeks after the start of TCB treatment. Unexpectedly, the number of G6Pase-negative and -positive foci per liver was markedly diminished following TCB treatment (to 32% and 57%, respectively). On the other hand, the mean volume of the remaining G6Pase-altered foci was enhanced, owing to an increase in the percentage of foci of large size (greater than 0.5 mm2). Throughout the experimental period of 39 weeks prolonged liver injury due to NNM and TCB treatment was demonstrated by histology and by elevated serum levels of glutamate-oxaloacetate transaminase. The results suggest that (in contrast to the rat system) TCB exhibited opposing effects on liver foci in the mouse model: (a) moderate tumor-promoting effects and (b) cytotoxic effects in NNM-injured liver, leading to decreased numbers of liver foci.

Adenoma, Bile Duct↗

Heterogeneous alterations of UDP-glucuronosyltransferases in mouse hepatic foci.

UDP-glucuronosyltransferase (UDPGT) was studied immunohistochemically in hepatic foci and nodules of N-nitrosomorpholine-treated mice. Serial sections were stained for glucose-6-phosphatase (G6Pase). It was found that a high percentage of G6Pase-negative liver foci and nodules were also UDPGT-negative (34%). In addition, G6Pase-negative foci without altered UDPGT phenotype (30%) and UDPGT-negative foci without altered G6Pase phenotype (8%) were detected. G6Pase-positive foci were also present (24%). Interestingly, most G6Pase-positive foci were UDPGT-positive (16%). Some G6Pase-positive lesions without altered UDPGT phenotype were also found (8%). The major phenotype observed in rat hepatocarcinogenesis models (UDPGT-positive/G6Pase-negative foci) was not detectable in the mouse model. These results demonstrate heterogeneous alterations of UDPGTs in mouse hepatic foci. They furthermore suggest marked differences between the mouse and the rat in the regulation of UDPGTs in similarly induced rat hepatic foci.

Animals↗

Small inhibitory cerebellar interneurons grow in a perpendicular orientation to granule cell neurites in culture.

When explants or reaggregates of small neurons from early postnatal mouse cerebella are plated on a mixture of laminin and poly-D-lysine, one observes small cells with an orientation of processes largely perpendicular to the direction of granule cell neurites after several days. These cells first have a bipolar morphology and then elaborate a rich dendritic arbor-like structure opposite a long, thin axon-like process. Several lines of evidence suggest that these cells are the small inhibitory interneurons of the cerebellar cortex: They take up GABA, express high levels of the embryonic form of N-CAM, do not express L1, the oligodendrocyte marker O4, or the glial marker vimentin, and display ultrastructural features reminiscent of stellate and/or basket cells in vivo. These observations suggest that the elaboration of directional positioning of small inhibitory interneurons can be studied in culture, thus offering the possibility to elucidate the cellular and molecular mechanisms underlying the orientation of particular neural cells with regard to others.

Animals↗

Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine.

Rolipram improves signal transmission in central noradrenergic neurones at a pre- and postsynaptic level, and is thus a novel approach in antidepressant therapy. In order to prove efficacy, tolerance, and safety, several controlled studies are underway. Results of a randomized double-blind comparative trial versus imipramine involving 64 in-patients with Major Depressive Disorder (DSM III) in six independent centers will be presented and discussed. The chosen biometric model provided evidence that towards the end of the study imipramine was superior to Rolipram. The particular clinical relevance of this difference is discussed. As regards tolerance, nausea emerged as the typical side-effect of Rolipram, whereas imipramine precipitated mainly anticholinergic side-effects.

Adult↗