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Biomedical subjects

H Dietrich

Publications and source records attributed to H Dietrich.

At least 91 records · Page 5Linked to original sources
PubMed1988

Malignant mesothelioma of the pleura. A prospective therapeutic study of 132 patients from 1981-1985.

Between March 1981 and February 1985, 93 out of 132 patients with a histologically confirmed diagnosis of malignant pleural mesothelioma were eligible for therapy and were prospectively assigned to receive either combined therapy or best supportive care, according to their personal preferences. Fifty-seven patients underwent multimodal therapy including surgical resection where possible, polychemotherapy, and radiation therapy in case of partial remission. Thirty-six patients received maximal supportive care only, as did 39 patients who were not eligible for treatment. The median survival was 13 months for treated patients compared to 7 for those receiving best supportive care and 5 for patients not amenable to treatment. Median progress-free survival was 6, 2, and 1 month respectively. Surgical resection did not prolong life expectancy within the treated group. In view of significant differences in the distribution of various cofactors over the two study groups, stepwise Cox model analyses were performed. Prognostic nontreatment variables related to prolonged survival were: good performance status, stage I and II, absence of chest pain, age below 50 years, and epithelial histology. Although in the Cox model analyses the survival improvement of patients being treated could be greatly attributed to other cofactors, multimodal treatment showed some prolongation of life expectancy.

Adult↗
PubMed1988

Genetic analysis of extrathyroidal features of Obese strain (OS) chickens with spontaneous autoimmune thyroiditis.

The Obese strain (OS) of chickens, which is afflicted with Hashimoto-like spontaneous autoimmune thyroiditis (SAT), displays elevated T cell proliferation, interleukin (IL)2 production and IL2 receptor expression upon mitogen stimulation, and defects in the neuroendocrine control of the immune system including elevated corticosteroid-binding globulin (CBG) and a deficient increase of serum corticosterone (CN) upon cytokine injection. Recently this strain has further been shown to harbor retrovirus-related sequences (endogenous virus no. 22, ev22) absent in healthy control strains. To determine the number of genes responsible for SAT-associated immunodysregulation and to unravel possible ev22 associations, we analyzed the above immune and endocrine parameters in F1 hybrids and backcrosses of the autoimmune OS B15B15 with healthy inbred CB B12B12 chickens. OS-like T cell hyperproliferation and IL2 hypersecretion in response to both concanavalin A and phytohemagglutinin were transmitted as autosomal dominant traits and co-segregated in backcross animals. In vivo hyporesponse of the OS to the corticosterone-inducing effect of cytokine preparations was inherited dominantly and the elevated CBG serum levels recessively. None of these traits appeared to be major histocompatibility complex (MHC) linked. However, while T cell abnormalities and elevated CBG serum levels were not associated with the autosomal ev22 locus, in vivo hyporesponsiveness to glucocortocoid-inducing cytokines co-segregated with this OS-specific provirus. These results add to the concept of SAT as a polyetiological and plurigenetic disease and do not support our previous hypothesis that T cell hyperreactivity and immunoendocrine dysfunction might be functionally related.

Animals↗
PubMed1988

The polarized UV-absorption spectra and the crystal structure of two different monoclinic crystal forms of the retinal homologue beta-8'-apocarotenal.

During the visual process, light absorption in the 11-cis retinylidene chromophore leads to a rapid cis-trans-isomerization which initiates the phototransduction step. Important spectroscopic properties of this chromophore can be derived from polarized UV-absorption spectra of crystalline 11-cis-retinal if a parallel X-ray structure analysis is performed. Several questions about the relation between molecular geometry and spectroscopic behavior could not be answered from these spectra. All crystal forms of 11-cis-retinal contain this molecule in its 6-s-cis-ring conformation. For the retinal homologue, beta-8'-apocarotenal (APC), however, two crystal forms with different ring conformation can be grown. The spectrum of alpha-APC (6-s-cis) shows a vibronic structure whereas that of beta-APC (6-s-trans) is diffuse but has a distinct shoulder on the low energy side of the main band. This S-band is typical for retinal spectra and has been ascribed to a transition into a 1Ag-*-state. The appearance of the S-band is not correlated with a 6-s-cis-conformation as suggested by the retinal spectra but is due to intermolecular interactions: beta-APC has a dense dimer packing and a strong electrostatic interaction between the pi-electron systems. This might cause the "forbidden" 1Ag-*-transition. On the other hand, this interaction is missing in the loose and polar packing of alpha-APC which favors vibration in the polyene chain. This finding is remarkable in view of the photodynamic behavior of the visual chromophore for which strong electrostatic interactions with the protein helices of its binding site have to be postulated.

Carotenoids↗
PubMed1988

Diminished glucocorticoid tonus in obese strain (OS) chickens with spontaneous autoimmune thyroiditis: increased plasma levels of a physicochemically unaltered corticosteroid-binding globulin but normal total corticosterone plasma concentration and normal glucocorticoid receptor contents in lymphoid tissues.

Obese strain (OS) chickens afflicted with spontaneous autoimmune thyroiditis (SAT) display several signs of a general immune dysbalance, some of which may be related to altered endocrine mechanisms such as the glucocorticoid tonus. The latter is the combined result of corticosterone (CN) production, metabolism as well as excretion, and the binding of CN to corticosteroid binding globulin (CBG) and glucocorticoid receptors (GR). The present study deals with the comparative investigation of these parameters in OS and normal White Leghorn (NWL) chickens. The results obtained with radioimmunoassay for CN and radioligand saturation assays for plasma CBG as well as GR in the thymus were as follows: (1) both OS and NWL have equal total CN levels; (2) however, OS chickens exhibit elevated CBG levels, whereas the physicochemical parameters (equilibrium affinity, specificity spectrum) of CBG were equal in OS and NWL; (3) the GR capacities and affinities were equal in both OS and NWL throughout development until thymic involution. Similarly, the specificity, affinity, and sedimentation behaviour were equal in OS and NWL. (4) Furthermore, no differences were found in the response of OS and NWL splenocytes to the suppressive effect of glucocorticoids in vitro, also excluding postreceptor alterations at the cellular level in the OS. From these findings we conclude that the increased CBG levels, which are not compensated for by either increased CN plasma levels or by increased receptor capacities or affinities in lymphatic organs, represent a diminished glucocorticoid tonus in OS chickens. This may have immunoregulatory consequences which, in turn, may contribute to the development of SAT.

Animals↗
PubMed1988

The role of testosterone in spontaneous autoimmune thyroiditis of Obese strain (OS) chickens.

We have recently reported a two-fold defect in glucocorticoid mediated immunoregulation in the Obese strain (OS) of chickens with spontaneous autoimmune thyroiditis (SAT): (i) a decreased basal corticosterone (CN) tonus due to an elevation of plasma corticosteroid-binding globulin (CBG) and (ii) an impaired CN rise in response to antigenic stimuli as well as lymphokines produced after mitogenic stimulation. The aim of the present study was to investigate the pathophysiological relevance of testosterone for the development of SAT. Compared to healthy normal White Leghorn chickens (NWL) the basal sex hormone tonus as well as androgen receptors of bursal tissue are not altered in the OS. Administration of sheep red blood cells (SRBC) or lymphokine containing conditioned media not only increased CN plasma levels but concomitantly modulated testosterone serum concentrations, although in an inverse direction and without significant difference between OS and healthy control chickens. These results suggest that, in contrast to the glucocorticoid system, androgen tonus as well as its modulation by immune signals are normal in the OS. The mode of action by which androgens exert their known beneficial effect on the development of SAT was also studied. According to our findings the capacity of testosterone to prevent SAT when administered during the posthatching period can be attributed to direct effects on bursal epithelial cells as well as indirect mechanisms, namely a fall in CBG levels leading to normalization of the CN tonus.

Animals↗
PubMed1987

Disturbed immune-endocrine communication in autoimmune disease. Lack of corticosterone response to immune signals in obese strain chickens with spontaneous autoimmune thyroiditis.

Antigenic challenge as well as injection of lymphokine-containing media lead to a transient increase of serum glucocorticoids, a phenomenon that has been implicated in the regulation of the specificity of immune responses. In the present study we examined the dialogue between the immune and the neuroendocrine systems in Obese strain (OS) chickens, an animal model for human Hashimoto thyroiditis. The following results were obtained: A) OS and normal White Leghorn (NWL) chickens, 5-mo-old, were immunized with sheep red blood cells followed by daily monitoring of corticosterone (CN) serum levels. Whereas in NWL animals CN serum levels markedly increase 3 to 4 days after immunization, OS animals did not respond with CN elevation. B) A single i.v. injection of conditioned medium (CM) from concanavalin A-stimulated spleen cells also led to a transient, dose-dependent peak in plasma CN (maximum after 30 min). This CN response to a given CM preparation was significantly lower in OS than in NWL animals. C) CM, whether obtained from OS or NWL splenocytes, were equally effective to stimulate CN production. D) A single i.v. injection of CM leads--concomitantly to the CN peak--to a decrease of the concanavalin A-mediated proliferative response of peripheral blood lymphocytes in both OS and NWL chickens. This suppression, however, was significantly more pronounced in NWL chickens. In summary, these data suggest a disturbance of the immune-neuroendocrine communication in OS chickens with spontaneous thyroid autoimmunity. The possible implications for the generation of "forbidden" autoimmune responses are discussed.

Animals↗
PubMed1987

Mechanisms of T cell hyperreactivity in obese strain (OS) chickens with spontaneous autoimmune thyroiditis: lack in nonspecific suppression is due to a primary adherent cell defect.

The disturbed homeostasis of the immune system in Obese strain (OS) chickens with spontaneous autoimmune thyroiditis consists in a general T cell hyperreactivity (concanavalin A hyperresponsiveness, interleukin 2 (IL 2) hypersecretion), particularly expressed by those lymphocytes which infiltrate the diseased thyroid gland. This abnormality has been attributed to a defective regulation of both IL 2 production and IL 2 function by low m.w. factors, which are present in serum and splenocyte culture supernatants of normal chickens, but deficient in the OS. In the present study we identified the cellular origin of IL 2 antagonistic activity as a nonlymphoid, adherent cell. Suppressor factor production in vitro was confined to the plastic adherent fraction of spleen cells and preincubation of splenocytes with nylon wool, silica particles, or carbonyl iron significantly reduced the nonspecific suppressive activity of the culture supernatant. Kinetic studies revealed the defect in nonspecific suppression to entail prolonged IL 2 production by concanavalin A-activated OS spleen cells. In vivo treatment of normal White Leghorn chickens with silica led to a decrease in suppressive serum activity down to the OS level, whereas neither neonatal thymectomy nor bursectomy had any effect. The defective suppressor factor production in autoimmune chickens appeared to be due to a functional, but not numeric defect of macrophages as revealed by phenol red staining. The possibility that this aberration in adherent cell function might be a secondary phenomenon to the recently described reduced corticosterone tonus in OS chickens was excluded by in vivo substitution with exogenous glucocorticoids which did not normalize the suppressor defect in serum or in conditioned medium. Finally, we present evidence that T lymphoblasts from OS animals are less susceptible to IL 2 antagonistic regulation than normal cells, which possibly further contributes to the T cell hyperfunction of this autoimmune strain.

Animals↗
PubMed1986

Sex steroid and glucocorticoid receptors in the bursa of Fabricius of obese strain chickens spontaneously developing autoimmune thyroiditis.

The female sex develops autoimmune disease far more often than the male. This is claimed to be due to differences in peripheral sex steroid levels. We have examined in the bursa of Fabricius of Obese strain (OS) chickens, which spontaneously develop autoimmune thyroiditis, as well as in their healthy counterparts androgen(AR)-, estrogen(ER)-, progestin(PR)- and glucocorticoid(GR)-receptors in an attempt to elucidate possible further pathomechanisms, namely at the target site of steroid hormones. The characterization (affinity, specificity, association- and dissociation-rate, sedimentation behaviour) of all four types of receptors revealed no difference between sex or strain. Furthermore, the ontogeny study of the receptor capacity and affinity from the 7th embryonic day (i.e. before lymphocyte settlement) until bursa involution, again showed no difference between OS and healthy chickens of either sex. Thus, it can be concluded that the principal sex dependency of the susceptibility to autoimmune disease results predominantly from differences in sex steroid levels per se, although alterations in mechanisms beyond the cytosolic receptor level can presently not be excluded.

Animals↗
PubMed1986

Genetic background of spontaneous autoimmune thyroiditis in the obese strain of chickens studied in hybrids with an inbred line.

To determine the number and function of genes which are responsible for spontaneous autoimmune thyroiditis (SAT) in the obese strain (OS) of chickens we crossed birds of this strain (B15/B15) with those of the inbred CB line (B12/B12). The progeny was analyzed for autoantibodies to thyroglobulin (TgAAb) and for histopathological changes in the thyroid glands. In F1 (OS X CB) hybrids only those animals which derived from CB mothers had circulating TgAAb, the progeny from the reverse combination female OS X male CB was negative. Since the disease is not inherited by OS males only, we conclude that maternal TgAAb, which are transferred from the egg yolk to the embryo, might prevent the immune system of the F1 chickens from TgAAb formation via blocking or eliminating the respective antigens. Those F1 hybrids which have high TgAAb levels in the serum show only little or no thyroiditis. Together with other observations, these data lead to the conclusion that the thyroid gland of the F1 hybrids is not susceptible to TgAAb. This supports previous findings that a genetically determined thyroid abnormality is a prerequisite for the full development of SAT. The low degree of SAT in backcross (F1 X OS) animals and F2 hybrids suggests that several genes are involved in the disease. MHC typing of these generations revealed that the B haplotype affects the time of SAT onset.

Animals↗
PubMed1986

Globular domain of basement membrane collagen induces autoimmune pulmonary lesions in mice resembling human Goodpasture disease.

A distinct circulating antibody response could be evoked in C57BL mice after immunization with the globular domain NC1 of basement membrane collagen IV obtained from the mouse Engelbreth-Holm-Swarm tumor when injected together with complete Freund's adjuvant. The antibodies reacted with various subunits of NC1, did not cross-react with other basement membrane proteins, and exhibited a tissue reactivity restricted to certain basement membranes. Tissue-bound antibodies could be detected by direct immunofluorescence and were distributed together with C3 in a linear pattern along glomerular and alveolar basement membranes. Pathological changes were mainly observed in lung and kidney and consisted of inflammatory infiltrates and massive hemorrhages with strong granulomatous fibrotic development in the lung. Kidney alterations were comparably weaker and of focal nature. A nephrotoxic serum model showed rapid binding of rabbit antibodies against mouse NC1 to lung, liver, and kidney basement membranes which was followed several weeks later by an autologous phase with anti-rabbit IgG antibodies bound to basement membranes as immune complexes. There was no fibrotic response but hemorrhagic and inflammatory lung and kidney changes similar to those after active immunization were observed after passive transfer. The experimental NC1 autoimmune model has several features such as anti-NC1 response, tissue restriction, lung hemorrhages, and glomerulonephritis in common with patients suffering from Goodpasture disease. The development of lung fibrosis appears to be unique for the animal model.

Animals↗
PubMed1985

Spontaneous autoimmune thyroiditis in obese strain chickens: a genetic analysis of target organ abnormalities.

In this study we investigated the genetic background of primary abnormalities found in the thyroid gland of Obese strain (OS) chickens with spontaneous autoimmune thyroiditis (SAT), i.e., susceptibility to passively transferred antibodies to thyroglobulin (TgAb) and incomplete suppression of iodine uptake by thyroxine (T4). Several crosses between the B15/B15 subline of OS chickens and the inbred CB line (B12/B12) were done and the progeny was analyzed for thyroiditis after injection of OS serum containing high titers of TgAb. It was found that passive transfer of TgAb increased the lymphoid infiltration in the thyroids of OS chickens, but had no effect on CB birds. A genetic analysis of backcrosses revealed that this trait is, in the case of simple Mendelian inheritance, encoded by at least three recessive genes. The thyroidal 131I uptake of these crosses under T4 was also determined and we found that this trait is most probably encoded by only one recessive gene.

Animals↗
PubMed1985

Antiarrhythmic and electrophysiological actions of flecainide, bepridil and amiodarone on isolated heart preparations during controlled hypoxia.

A model of arrhythmias based on the application of sinusoidal alternating current (ac) to isolated heart preparations has been employed to determine the effects of hypoxia (30 vol % O2 in the perfusion medium) on the threshold of arrhythmia and asystole. With this method three representatives of different classes of antiarrhythmic drugs, flecainide, bepridil and amiodarone, have been investigated in isolated papillary muscles and left atria from guinea-pigs. Hypoxia reduces both the threshold for ac-arrhythmia and the threshold for ac-asystole. Flecainide (3 and 10 mumol/l) elevates both thresholds under normoxia and has a protective effect against the hypoxia-induced reduction of threshold. Bepridil (10 mumol/l) is without effect on the threshold of ac-arrhythmia in papillary muscle, prevents the hypoxia-induced decline of the threshold of ac-arrhythmia in left atria and depresses the threshold of ac-asystole both in normoxia and hypoxia. amiodarone (10 mumol/l) elevates the threshold of ac-arrhythmia both during normoxia and hypoxia in papillary muscle but only during the second hour of hypoxia in left atria. The results may be interpreted with respect to the inhibitory action on Na+-channels (flecainide), Ca2+-channels (bepridil) or protective effects against hypoxia-induced changes in action potential duration (amiodarone, but also flecainide and bepridil) as shown by additional electrophysiological experiments.

Action Potentials↗
PubMed1984

Reaction of the Z isomer of 4-trans-(N,N-dimethylamino)cinnamaldoxime with the liver alcohol dehydrogenase-oxidized nicotinamide adenine dinucleotide complex.

The Z isomer of 4-trans-(N,N-dimethylamino)-cinnamaldoxime, (Z)-DMOX (lambda maxH2O 354 nm), forms a ternary complex with NAD+ and equine liver alcohol dehydrogenase. The 3-acetyl (3-acetyl-PdAD+), 3-thiocarboxamide (3-thio-NAD+), 3-iodo (io3PdAD+) and nicotinamide mononucleotide (NMN+) analogues of NAD+ also form ternary complexes with enzyme and (Z)-DMOX. These complexes are characterized by large red-shifts in the UV-visible spectrum of bound (Z)-DMOX (lambda max 428 nm for the NAD+ complex) and new spectral bands in the 280-340-nm region associated with the pyridine moieties of NAD+ and the NAD+ analogues. The ternary enzyme-NAD+-(Z)-DMOX complex is weakly fluorescent (lambda ex 430 nm; lambda em max 505 nm) and strongly quenches the residual tryptophan fluorescence of the enzyme-NAD+ binary complex. (Z)-DMOX binds with high affinity to the enzyme-NAD+ complex (Kd less than or equal to 4 X 10(-9) M at pH 8.75 and 25 degrees C), and similarly high affinities were found for the 3-acetyl-PdAD+, 3-thio-NAD+, and io3PdAD+ complexes. Binding is much weaker to the enzyme-NMN+ complex. The active site specifically substituted Co(II), Ni(II), Cu(II), and Cd(II) enzyme derivatives and the enzyme species lacking any metal ion at the active site (apoenzyme) also form ternary complexes with (Z)-DMOX in which the DMOX UV-visible spectrum is red-shifted (ranging from 43 to 83.5 nm). The complexes formed with the Zn(II) and Co(II) enzymes are characterized by relatively high affinities for (Z)-DMOX and by spectra that are independent of pH over the range 6-10. The affinity of the apoenzyme-NAD+ complex for (Z)-DMOX is much lower, and the spectrum of the complex is pH dependent with lambda max = 430 nm at pH 7 and lambda max = 397 nm at pH 10. The rate of (Z)-DMOX dissociation from the apoenzyme complex was found to be approximately 10(3)-fold greater than the rates observed for the metal ion substituted enzymes. The 280-340-nm spectral bands appear to result from the dihydropyridine moieties of covalent adducts formed between (Z)-DMOX and NAD+ and the NAD+ analogues. The large red-shifts of the (Z)-DMOX spectrum result from the bonding of the oxime nitrogen to a strong electrophilic center (either the active site zinc ion or the nicotinamide ring of NAD+.)(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Dehydrogenase↗
PubMed1984

Lack of correlation between serum cholesterol levels, lymphocyte plasma membrane fluidity and mitogen responsiveness in young and aged chickens.

Chickens were studied in an attempt to demonstrate correlations between serum lipid levels and peripheral blood lymphocyte (PBL) plasma membrane fluidity and mitogen responsiveness: (a) in the laying hen; (b) during aging; and (c) following dietary manipulation of serum cholesterol of young and aged chickens. The membrane fluidity of PBL from laying hens was significantly greater than that of immature birds. However, no direct correlation was found between serum lipid levels, nor the serum free cholesterol/phospholipid (FC/Pl) mole composition and PBL membrane fluidity in any of the age-groups tested. Likewise, no correlation was found either between serum FC/Pl mole ratio or membrane fluidity and mitogen responsiveness of PBL from birds up to 5 years of age nor was there any evidence for a decline in mitogen responsiveness up to this age. Supplementation of diets with 1% cholesterol induced hypercholesterolemia, mainly in the very low density lipoprotein (VLDL) fraction, but membrane fluidity and mitogen responsiveness remained unaffected.

Aging↗