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Biomedical subjects

W Schmid

Publications and source records attributed to W Schmid.

At least 19 recordsLinked to original sources

Functionality or aesthetics? A pilot study of music therapy in the treatment of multiple sclerosis patients.

INTRODUCTION: Neuro-degenerative diseases are, and will remain, an enormous public health problem. Interventions that could delay disease onset even modestly will have a major public health impact. The aim of this study is to see which components of the illness are responsive to change when treated with music therapy in contrast to a group of patients receiving standard medical treatment alone. MATERIAL AND METHODS: Twenty multiple sclerosis patients (14 female, 6 male) were involved in the study, their ages ranging from 29 to 47 years. Ten participants formed the therapy group, and 10 the matched control group matched by age, gender and the standard neurological classification scheme Expanded Disability Status Scale (EDSS). Exclusion criteria were pregnancy and mental disorders requiring medication. Patients in the therapy group received three blocks of music therapy in single sessions over the course of the one-year project (8-10 sessions, respectively). Measurements were taken before therapy began (U1), and subsequently every three months (U2-U4) and within a 6-month follow-up without music therapy (U5) after the last consultation. Test battery included indicators of clinical depression and anxiety (Beck Depression Inventory and Hospital Anxiety and Depression Scale), a self-acceptance scale (SESA) and a life quality assessment (Hamburg Quality of Life Questionnaire in Multiple Sclerosis). In addition, data were collected on cognitive (MSFC) and functional (EDSS) parameters. RESULTS: There was no significant difference between the music-therapy treatment group and the control group. However, the effect size statistics comparing both groups show a medium effect size on the scales measuring self-esteem (d, 0.5423), depression HAD-D (d, 0.63) and anxiety HAD-A (d, 0.63). Significant improvements were found for the therapy group over time (U1-U4) in the scale values of self-esteem, depression and anxiety. In the follow-up, scale values for fatigue, anxiety and self-esteem worsen within the group treated with music therapy. DISCUSSION: A therapeutic concept for multiple sclerosis, which includes music therapy, brings an improvement in mood, fatigue and self-acceptance. When music therapy is removed, then scale scores worsen and this appears to intimate that music therapy has an influence.

Adult↗

[Stroke management on general medical departments. A multicenter study in Austria].

BACKGROUND AND OBJECTIVE: Despite the claimed superiority of Stroke Units a majority of patients with acute stroke is still treated on general medical departments in many countries. In Austria 90 % of 121 medical departments state that they take care of stroke patients routinely or at least sometimes. Therefore, our aim was to evaluate whether stroke management on medical wards meets up-to-date standards. PATIENTS AND METHODS: 55 medical departments all over Austria participated in a prospective multicenter registry documenting diagnostics, treatment and the in-hospital course of unselected patients admitted with an acute stroke according to a standardised protocol. RESULTS: 1100 patients, 56 % female, with a median age of 75 years were assessed. Median hospital stay was 14 days. In 96 % a cranial computer tomogram was performed. 81 % of cerebral lesions were ischemic, 10 % haemorrhagic. Only 10 % had no risk factor or accompanying medical disease. 31 % suffered at least one medical and 18 % one neurological complication (p = 0.00000003). In-hospital mortality was 17 %, functional outcome was poor in 27 % (Rankin scale [RS] 4 or 5) and good in 56 % (RS 0-3). 74 % of discharged patients could leave to their home, 13 % were transferred to a nursing home and 13 % to a rehabilitation center. 95 % of surviving patients left on either an antiplatelet or an anticoagulant medication and 73 % received antihypertensives. CONCLUSION: Outcome of stroke patients treated on general medical departments seems to be fairly comparable to that commonly reported by neurological Stroke Units. Further improvements may be obtained by implementation of integrated "mixed assessment" units into medical departments.

Aged↗

Short-term risk forecasts of heavy rainfall.

Methodologies for risk forecasts of severe weather hardly exist on the scale of nowcasting (0-3 hours). Here we discuss short-term risk forecasts of heavy precipitation associated with local thunderstorms. We use COTREC/RainCast: a procedure to extrapolate radar images into the near future. An error density function is defined using the estimated error of location of the extrapolated radar patterns. The radar forecast is folded ("smeared") with the density function, leading to a probability distribution of radar intensities. An algorithm to convert the radar intensities into values of precipitation intensity provides the desired probability (or risk) of heavy rainfall at any position within the considered window in space and time. We discuss, as an example, a flood event from summer 2000.

Disasters↗

The mineralocorticoid receptor expression in the mouse CNS is conserved during development.

Using a specific polyclonal antiserum raised in rabbit against amino acids 1-23 of the mouse mineralocorticoid receptor (MR) we investigated the developmental profile of MR expression in the murine CNS by immunocytochemistry. MR protein appeared first at embryonic day E16.5 in the limbic system, i.e. in the hippocampus and induseum griseum. During development and in adulthood, high levels of MR expression were observed in the limbic system, whereas expression levels detectable in layers II, III, V of the neocortex and in motoneurons of cranial nerves and spinal cord were lower. No MR staining was found in the hypothalamus. Developmental MR expression was restricted to neuronal populations that also express MR protein in the adult CNS, indicating that the MR may fulfill the same functions in neurons during development and in adulthood.

Animals↗

Na,K-ATPase expression in the mouse cochlea is not dependent on the mineralocorticoid receptor.

This study was performed in order to test the hypothesis that the mineralocorticoid hormone stimulates the expression of Na,K-ATPase in the cochlea of the mouse. Immunohistochemistry was used to investigate the distribution of the mineralocorticoid receptor (MR) in the cochlea of the C57Bl/J6 mouse at different ages between gestational day 19 and postnatal day 30, and the occurrence and distribution of Na,K-ATPase in the inner ear of a mouse with a null mutation of the MR. Adult patterns of staining for MR were found as early as on gestational day 19 in the cochlea, with small changes thereafter. MR was detected in the same structures in the cochlea as Na,K-ATPase in earlier studies, where the amount of Na,K-ATPase increased after postnatal day 4. Thus there is latency between the increase of MR and the increase of Na,K-ATPase. In the cochlea of the MR deficient mouse, antibody labelling of Na,K-ATPase showed no significant difference as compared to the control wild type mouse. The hypothesis that mineralocorticoid hormone alone via MR stimulates the formation of Na,K-ATPase in the inner ear could not be confirmed by this study, and other regulating mechanisms must be considered.

Animals↗

Synthesis and binding to plant lectins of sulfur-containing analogues of betaGal1,3 alphaGalNAc (T-antigen).

Analogues of the tumor-associated T-antigen (betaGal1,3 alphaGalNAc) containing 4,6-epidithio and 4,6-thietan modifications were synthesized from the alpha-allyl glycoside of betaGal alpha1,3GlcNAc via suitable thiocyanate derivatives. Binding to three leguminous lectins as model systems was investigated in an enzyme-linked lectin assay (ELLA) and IC50 values comparable to the corresponding natural disaccharides T-antigen, lactose and N-acetyllactosamine were found.

Antigens, Viral, Tumor↗

Stimulating effect of biologically modified low density lipoproteins on ADP-induced aggregation of washed platelets persists in absence of specific binding.

Oxidized low density lipoproteins are closely associated with atherosclerosis and also might be directly involved in thrombosis because they have been shown to mediate a stimulating effect on human platelets. In this work, we used biologically modified low density lipoproteins (i.e., low density lipoproteins sufficiently oxidized to show specificity for the macrophage scavenger receptor system) to examine if specific binding of the oxidized apolipoprotein moiety to the platelet surface is a prerequisite for the platelet-stimulating effects reported by other authors. We find that biologically modified low density lipoproteins show specific binding to human platelets (K(d)=5.83+/-0.4 microg/mL, 3850+/-620 sites/platelet) and strongly augment both ADP- and thrombin-induced aggregation of washed platelets. Maleylated albumin, an antagonist of oxidized low density lipoproteins binding to all currently classified scavenger receptors, is able to reduce platelet oxidized low density lipoproteins binding to background levels. Nevertheless, maleylated albumin is not able to exert any kind of normalizing effect on the augmented ADP-induced aggregation response observed in the presence of biologically modified low density lipoproteins. From these data, we conclude that specific binding of oxidatively modified apolipoprotein B to the platelet surface is not essential to the process of platelet stimulation. Therefore, we conclude that these stimulating effects may be mediated by unidentified compounds formed in the lipid phase of the lipoproteins.

Adenosine Diphosphate↗

Induction of an acute attack of calcium pyrophosphate dihydrate arthritis by intra-articular injection of hylan G-F 20 (Synvisc).

Little is known about the induction of acute calcium pyrophosphate dihydrate arthritis after the intra-articular injection of hylan G-F 20 (Synvisc). Two reports have documented this adverse effect after the intra-articular injection of hyaluronan. Our patient, a 60-year-old man with osteoarthritis in both knees, presented with a history of an arthroscopy with meniscus shaving 7 years previously. He was given an injection of hylan G-F 20 in the right knee joint. Two days after the second injection, pain and swelling of the knee occurred. There was a severe loss of physical function. Systemic inflammatory reactions such as fever were not observed. A microscopic investigation of the synovial fluid showed evidence of calcium pyrophosphate dihydrate crystals. Bacterial contamination was not detected. There was no indication for calcium pyrophosphate dihydrate in the history of the patient. Some days after receiving nonsteroidal anti-inflammatory drugs and an intra-articular injection of steroids, the symptoms disappeared.

Acute Disease↗

Mineralocorticoid receptor knockout mice: lessons on Na+ metabolism.

The mineralocorticoid receptor (MR) binds aldosterone and glucocorticoids with equal affinity. In aldosterone target tissues, like the epithelial cells of the distal colon and the principal cells of the collecting ducts in the kidney, the MR is protected from glucocorticoids by the action of the enzyme 11beta-hydroxysteroid-dehydrogenase type 2 (11betaOHSD2), allowing aldosterone to specifically activate the receptor. However, in MR-expressing cells, which lack 11betaOHSD2, like the neurons of the limbic system in the brain, MR is mainly activated by glucocorticoids. MR knockout mice die in the second week after birth, showing at day 8 symptoms of pseudohypoaldosteronism with hyponatremia, hyperkalemia, high renal salt wasting, and a strongly activated renin-angiotensin-aldosterone system (RAAS). The activity of the amiloride-sensitive epithelial Na+ channel (ENaC) is strongly reduced in colon and kidney, but there is no down-regulation of the mRNA abundance of the three ENaC subunits. Daily subcutaneous injections of isotonic NaCl solution until weaning and continued oral NaCl supply lead to survival of the MR knockout mice. The NaCl-rescued MR knockout mice display a strongly enhanced fractional renal excretion of Na+, hyperkalemia, and a persistently strongly activated RAAS. There is almost no renal ENaC activity. The renal mRNA abundance of alphaENaC is reduced by 30%, whereas betaENaC and gammaENaC are not altered.

Animals↗

Genetic disruption of mineralocorticoid receptor leads to impaired neurogenesis and granule cell degeneration in the hippocampus of adult mice.

To dissect the effects of corticosteroids mediated by the mineralocorticoid (MR) and the glucocorticoid receptor (GR) in the central nervous system, we compared MR-/- mice, whose salt loss syndrome was corrected by exogenous NaCI administration, with GR-/- mice having a brain-specific disruption of the GR gene generated by the Cre/loxP-recombination system. Neuropathological analyses revealed a decreased density of granule cells in the hippocampus of adult MR-/- mice but not in mice with disruption of GR. Furthermore, adult MR-/- mice exhibited a significant reduction of granule cell neurogenesis to 65% of control levels, possibly mediated by GR due to elevated corticosterone plasma levels. Neurogenesis was unaltered in adult mice with disruption of GR. Thus, we could attribute long-term trophic effects of adrenal steroids on dentate granule cells to MR. These MR-related alterations may participate in the pathogenesis of hippocampal changes observed in ageing, chronic stress and affective disorders.

Animals↗

The glucocorticoid receptor is essential for induction of cytochrome P-4502B by steroids but not for drug or steroid induction of CYP3A or P-450 reductase in mouse liver.

Cytochrome P-4503A, CYP2B, and P-450 reductase are induced by glucocorticoids, antiglucocorticoids such as pregnenolone 16alpha-carbonitrile, and drugs such as rifampin and phenobarbital. Although the pregnane X receptor is reported to mediate steroid and drug activation of CYP3A via a conserved cis-element in CYP3A genes, discrepancies exist between the induction of the endogenous CYP3A genes and the activation of the pregnane X receptor. It is a formal possibility that the glucocorticoid receptor may account for some of these discrepancies. To determine the requirement in vivo of the glucocorticoid receptor in expression of CYP3A and CYP2B, we compared the induction of these proteins in the livers of normal mice and mice with a targeted mutation in the glucocorticoid receptor. Mice lacking the glucocorticoid receptor show no difference in constitutive hepatic expression of CYP3A but show a decrease in the level of CYP2B. Glucocorticoid receptor-deficient mice challenged with either dexamethasone or pregnenolone 16alpha-carbonitrile failed to induce CYP2B proteins, whereas CYP2B was readily induced in (+/+) mice. In contrast, CYP3A and P-450 reductase proteins were induced by either inducer in wild-type and glucocorticoid receptor-null mice. Similarly, rifampin induced CYP3A in either wild-type or glucocorticoid receptor-null mice. Despite reports that rifampin is a nonsteroidal ligand for the human glucocorticoid receptor, rifampin failed to induce tyrosine aminotransferase in mice regardless of glucocorticoid receptor genotype, and rifampin did not compete for ligand binding to either mouse or human glucocorticoid receptor. Phenobarbital induced CYP3A, CYP2B, and P-450 reductase in all mice, but the amplitude of induction was diminished 37% in glucocorticoid receptor-null mice. Thus, there are distinctly different essential requirements of CYP3A, CYP2B, and P-450 reductase genes for the glucocorticoid receptor in their induction by steroids and drugs.

Aldosterone↗

Human platelets exclusively bind oxidized low density lipoprotein showing no specificity for acetylated low density lipoprotein.

The widely studied macrophage scavenger receptor system is known to bind both acetylated low density lipoprotein and oxidized low density lipoprotein. Although only the latter ligand has been shown to occur in vivo, acetylated low density lipoprotein is often used to evaluate the contribution of scavenger receptors to different (patho)physiologic processes, assuming that all existing subtypes of scavenger receptors recognise both lipoproteins. In the present work, we identify human platelets as the first natural cell type to bind oxidized low density lipoprotein without showing specificity for acetylated low density lipoprotein. Consequently, platelets possess exclusive receptor(s) for oxidized low density lipoprotein distinct from the 'classical' scavenger receptor AI/AII. From the data presented in this work, we conclude that the class B scavenger receptor CD36 (GPIV) is responsible for this exclusive oxidized low density lipoprotein binding.

Animals↗

Essential role of CREB family proteins during Xenopus embryogenesis.

The leucine zipper transcription factors cAMP response element binding protein (CREB), cAMP response element modulatory protein (CREM) and activating transcription factor 1 (ATF1) bind to the cAMP response element (CRE) with the palindromic consensus sequence TGACGTCA. Their transcriptional activities are dependent on serine phosphorylation induced by various extracellular signals such as hormones, growth factors and neurotransmitters. Here we show that CREB is the predominant CRE-binding protein in Xenopus embryos and that it plays an essential role during early development. The importance of CREB for morphogenetic processes was assessed by injection of RNA encoding a dominant-negative form of CREB that is fused to a truncated progesterone receptor ligand binding domain. In this fusion protein, a dominant-negative function can be induced by application of the synthetic steroid RU486 at given developmental stages. The inhibition of CREB at blastula and early gastrula stages leads to severe posterior defects of the embryos reflected by strong spina bifida, whereas the inhibition of CREB at the beginning of neurulation resulted in stunted embryos with microcephaly. In these embryos, initial induction of neural and mesodermal tissues is not dependent on CREB function, as genes such as Otx2, Krox20, Shh and MyoD are still expressed in injected embryos. But the expression domains of Otx2 and MyoD were found to be distorted reflecting the abnormal development in both neural and somitic derivatives. In summary, our data show that CREB is essential during several developmental stages of Xenopus embryogenesis.

Acetyltransferases↗

Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene argues against an essential role of glucocorticoid signalling for generating adrenal chromaffin cells.

Molecular mechanisms underlying the generation of distinct cell phenotypes is a key issue in developmental biology. A major paradigm of determination of neural cell fate concerns the development of sympathetic neurones and neuroendocrine chromaffin cells from a common sympathoadrenal (SA) progenitor cell. Two decades of in vitro experiments have suggested an essential role of glucocorticoid receptor (GR)-mediated signalling in generating chromaffin cells. Targeted mutation of the GR should consequently abolish chromaffin cells. The present analysis of mice lacking GR gene product demonstrates that animals have normal numbers of adrenal chromaffin cells. Moreover, there are no differences in terms of apoptosis and proliferation or in expression of several markers (e.g. GAP43, acetylcholinesterase, adhesion molecule L1) of chromaffin cells in GR-deficient and wild-type mice. However, GR mutant mice lack the adrenaline-synthesizing enzyme PNMT and secretogranin II. Chromaffin cells of GR-deficient mice exhibit the typical ultrastructural features of this cell phenotype, including the large chromaffin granules that distinguish them from sympathetic neurones. Peripherin, an intermediate filament of sympathetic neurones, is undetectable in chromaffin cells of GR mutants. Finally, when stimulated with nerve growth factor in vitro, identical proportions of chromaffin cells from GR-deficient and wild-type mice extend neuritic processes. We conclude that important phenotypic features of chromaffin cells that distinguish them from sympathetic neurones develop normally in the absence of GR-mediated signalling. Most importantly, chromaffin cells in GR-deficient mice do not convert to a neuronal phenotype. These data strongly suggest that the dogma of an essential role of glucocorticoid signalling for the development of chromaffin cells must be abandoned.

Adrenal Glands↗

Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism.

Mineralocorticoid receptor (MR)-deficient mice were generated by gene targeting. These animals had a normal prenatal development. During the first week of life, MR-deficient (-/-) mice developed symptoms of pseudohypoaldosteronism. They finally lost weight and eventually died at around day 10 after birth from dehydration by renal sodium and water loss. At day 8, -/- mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations. Methods were established to measure renal clearance and colonic transepithelial Na+ reabsorption in 8-day-old mice in vivo. The fractional renal Na+ excretion was elevated >8-fold. The glomerular filtration rate in -/- mice was not different from controls. The effect of amiloride on renal Na+ excretion and colonic transepithelial voltage reflects the function of amiloide-sensitive epithelial Na+ channels (ENaC). In -/- mice, it was reduced to 24% in the kidney and to 16% in the colon. There was, however, still significant residual ENaC-mediated Na+ reabsorption in both epithelia. RNase protection analysis of the subunits of ENaC and (Na++ K+)-ATPase did not reveal a decrease in -/- mice. The present data indicate that MR-deficient neonates die because they are not able to compensate renal Na+ loss. Regulation of Na+ reabsorption via MR is not achieved by transcriptional control of ENaC and (Na+ + K+)-ATPase in RNA abundance but by transcriptional control of other as yet unidentified genes. MR knockout mice will be a suitable tool for the search of these genes.

Amiloride↗