Biomedical subjects

A Ziegler

Publications and source records attributed to A Ziegler.

405 records · Page 23Linked to original sources

PubMedDate not supplied

Sunburn and p53 in the onset of skin cancer.

Squamous cell carcinoma of the skin (SCC) can progress by stages: sun-damaged epidermis, with individual disordered keratinocytes; actinic keratosis (AK), spontaneously regressing keratinized patches having aberrant cell differentiation and proliferation; carcinoma in situ; SCC and metastasis. To understand how sunlight acts as a carcinogen, we determined the stage at which sunlight mutates the p53 tumour-suppressor gene and identified a function for p53 in skin. The p53 mutations induced by ultraviolet radiation and found in > 90% of human SCCs were present in AKs. Inactivating p53 in mouse skin reduced the appearance of sunburn cells, apoptotic keratinocytes generated by overexposure to ultraviolet. Skin thus appears to possess a p53-dependent 'guardian-of-the-tissue' response to DNA damage which aborts precancerous cells. If this response is reduced in a single cell by a prior p53 mutation, sunburn can select for clonal expansion of the p53-mutated cell into the AK. Sunlight can act twice: as tumour initiator and tumour promoter.

Animals↗

PubMedDate not supplied

A 6p22 reference map of leukocyte DNA: exclusion of rearrangement in four cases of atypical haemochromatosis.

We describe a 4 Mb reference map of the haemochromatosis gene region in leukocyte DNA from seven controls and four atypical haemochromatosis patients. Three patients had normal coding sequence for HFE, the candidate gene for genetic haemochromatosis (GH). The fourth patient had classical GH but was heterozygous for Cys282Tyr with otherwise normal coding sequence. The genomic DNA was mapped by pulsed-field gel electrophoresis (PFGE) using five rare-cutting enzymes. Seventeen probes including HFE were positioned on the map. Despite proximity to the highly polymorphic major histocompatibility complex (MHC), no polymorphism was observed in the control group with these telomeric probes. Furthermore, major rearrangement of the HFE region was excluded as a mutation contributing to iron overload in these atypical patients. Maps of cloned DNA are linked through genes and other probes to this reference map of the HFE region in uncloned genomic DNA.

Chromosomes, Human, Pair 6↗

PubMedDate not supplied

Time courses of carbachol-induced responses in guinea pig atria under the influence of ouabain, calcium, and rate of stimulation.

The response of isolated left atria of guinea pigs to carbachol was measured in the presence and during washout of the drug. The time courses of the negative inotropic effect and of the rate of shortening in action potential duration were compared. The initial rapid decline in force of contraction was followed by a slowly developing partial recovery (fading). After removal of the drug, a transient phase of hypercontractility was observed before the control level was reached again. In contrast to the mechanical effect, the drug-induced shortening of the action potential duration proceeded monophasically. The fading and hypercontractility phenomena shown by the mechanical response to the drug were influenced by the stimulation rate and by the presence of ouabain. From the dissociation of electrical and mechanical effects it is concluded that fading and hypercontractility are not due to changes of receptor sensitivity but reflect a change in cellular calcium distribution.

Animals↗

PubMedDate not supplied

Effects of carbachol on contractile force and action potentials of isolated atria at different rates of stimulation.

Dose-response curves for the negative inotropic effect and the shortening of the action potential duration induced by carbachol were established in isolated left atria of rats and guinea pigs. Various experimental conditions were chosen, including two different frequencies of stimulation (0.1 and 2 Hz) and the application of ouabain. Under all experimental conditions, very similar dose-response curves were obtained for the electrical activity. In contrast, the dose-response curves for the negative inotropic effect were markedly affected, since carbachol was less effective in depressing contractile force at 0.1 Hz and in the presence of ouabain. A lesser negative inotropic effect of carbachol could also be demonstrated after a single prolongation of the beat interval for various periods of time. It is suggested that the differences in the dose-response curves for the electrical and mechanical activities reflect changes in the efficacy of excitation-contraction coupling.

Action Potentials↗

PubMedDate not supplied

Comparison of the effects of nitroglycerin administered to rats by different routes.

In pentobarbital-anesthetized rats a comparison was undertaken of the blood pressure lowering effect of nitroglycerin (glyceryl trinitrate, GTN) administered by different routes: jugular vein (i.v.), portal vein (p.v.), peritoneal (i.p.), intrajejunal (i.j.), and sublingual (s.l.). The potency of GTN given by these routes was approximately i.v.:s.l.:i.p.:p.v.:i.j. = 100:20--10:10--5:5:5--2.5. Application of GTN to the visceral peritoneum (i.p.) caused a greater and more prolonged lowering of blood pressure than an injection into the portal vein. We conclude that the capacity of the liver to degrade the active agent during the first passage can be overcome and that a blood pressure response to enterally absorbed GTN could be caused by a prehepatic site of action, i.e., on the splanchnic venous system.

Animals↗

PubMedDate not supplied

Genetic susceptibility and severity of alopecia areata in human and animal models.

Alopecia areata (AA) is a non-scarring, inflammatory form of hair loss. Human and animal model observations suggest that AA is an autoimmune mediated disease. Genetic influence has been clearly demonstrated in many other autoimmune diseases and one would expect that AA is no exception. AA in rodent models involves genetic susceptibility and it is possible to cross breed the AA phenotype to unrelated rodent strains. Segregation analysis of rodent breeding programs suggests the involvement of several dominant and secondary genes. The increased frequency of AA in genetically related individuals, suggests that human AA expression also involves genetic susceptibility. Within the general population, AA does not segregate as a Mendelian, monogenic trait. AA is a continuous trait with varying degrees of hair loss within the affected population. This suggests that human AA expression involves a complex interaction of multiple genes. AA is most likely a polygenic disease where several, potentially identifiable, major genes affect disease susceptibility and minor severity modifying genes may further affect the phenotype. Here we review the literature on humans and animal models for AA to identify data in support of AA as a polygenic, multivariate penetrance disease with a threshold level for disease onset. Genome wide allelic association screening of animal models and genetically related human sibling pairs may be a suitable approach to identifying susceptibility and severity modifying genes for AA.

Alopecia Areata↗

PubMedDate not supplied

Treatment of alopecia areata in C3H/HeJ mice with the topical immunosuppressant FK506 (Tacrolimus).

Alopecia areata-like hair loss has been observed in C3H/HeJ mice and can be defined as a tissue-restricted T cell mediated disease of the hair follicle. Because FK506 has been described as suppressing T cell mediated autoimmune diseases, we addressed the question whether topical treatment of C3H/HeJ mice with FK506 has a beneficial effect on alopecia areata (AA). For this purpose six C3H/HeJ mice with AA were treated topically with 0.1% FK506 ointment, four mice received the vehicle only. Four of six FK506-treated mice showed complete hair regrowth, whereas 1/4 vehicle-treated mice regrew hair. Mice treated successfully with FK506 had reduced perifollicular infiltrates of CD4+ and CD8+ cells and a decreased expression of MHC class I and II and ICAM-1 on hair follicle epithelium, compared to control mice. We conclude that topical treatment with FK506 is able to induce hair regrowth in AA of C3H/HeJ mice, most likely by suppressing the T cell mediated immune response.

Administration, Cutaneous↗

PubMedDate not supplied

Differences in frequency dependence of quinidine effects on force, dV/dtmax and action potential duration.

In the left atria of the guinea-pig heart, quinidine produces a transient inotropic effect that is largest at low rates of stimulation; at high rates, the negative inotropic action of quinidine prevails. In contrast to the depression of the maximum rate of depolarization (dV/dtmax), the quinidine-induced prolongation in action potential duration was largest at low rates of stimulation. Recovery from block during rest was observed only for dV/dtmax; the prolongation in action potential duration, however, did not reverse but became most prominent after rest. The differences in frequency dependence of quinidine-induced decrease in dV/dtmax and prolongation of action potential duration can be explained if the drug interacts preferentially with the sodium channels while they are in an open or inactivated state, but with potassium channels while they are closed.

Action Potentials↗

PubMedDate not supplied

Identification of human spermatozoa antigens using monoclonal antibodies and the alkaline phosphatase anti-alkaline phosphatase-technique.

Both cytoplasmic and surface-membrane antigens of human spermatozoa were detected by means of monoclonal antibodies (MoAbs) and of the alkaline phosphatase anti-alkaline phosphatase- (APAAP-) technique. Several advantages of this technique for the identification of sperm could be demonstrated. The labeling of cytocentrifuge preparations from 16 ejaculates proved the presence of glycosphingolipids, nuclear and mitochondrial antigens of spermatozoa. However, there were no HLA-molecules and other leukocyte antigens on sperm cells.

Antibodies, Monoclonal↗