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Biomedical subjects

M Schmied

Publications and source records attributed to M Schmied.

At least 19 recordsLinked to original sources
PubMed2006

Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.

We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.

3' Untranslated Regions↗
PubMed2006

Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.

Mutations in the chloride channel gene CLCN2 have been reported in families with generalized and focal epilepsy syndromes. To evaluate the contribution of mutations in the CLCN2 gene to the etiology of epilepsies in our population, we screened 96 patients with different epilepsy syndromes and a putative genetic background. No definite mutations were found in our study population. We conclude that mutations in the CLCN2 gene are only a rare cause of idiopathic generalized epilepsy.

CLC-2 Chloride Channels↗
PubMed2003

In vitro evidence that subcutaneous administration of glatiramer acetate induces hyporesponsive T cells in patients with multiple sclerosis.

Glatiramer acetate (GA; Copaxone) is a random sequence polypeptide used in the treatment of relapsing remitting multiple sclerosis (RR MS). We have recently demonstrated that prior to treatment, GA induces proliferation of resting T cells and is not cross-reactive with myelin antigens. Daily GA injections induce a significant loss of this GA responsiveness, which is associated with the induction of highly cross-reactive Th2-type T cells potentially capable of suppressing inflammatory responses. The mechanism of action by which GA induces T cell nonresponsiveness leading to T cell receptor degeneracy in patients with RR MS is unknown. Here, we examined the effects of daily GA administration on the induction of T cell hyporesponsiveness. The frequency of GA-reactive T cells in peripheral blood of seven patients with RR MS was measured by limiting dilution analysis prior to and during 6 months of treatment. In addition, a model in which GA-reactive T cells were stimulated in vitro was developed to better characterize the selection of T cell populations over time. In vivo treatment with GA induced a decrease in GA-reactive T cell frequencies and hyporesponsiveness of CD4(+) T cell reactivity to GA in vitro that was only partially reversed by the addition of IL-2. These data suggest that T cell peripheral tolerance to GA was achieved in vivo during treatment. Thus, our in vitro data suggest that the underlying changes in GA-reactive CD4(+) T cell reactivity could be explained by the induction of T cell anergy and clonal elimination.

Adult↗
PubMed1999

Vaccinations and steroids in MS: effects on disease progression and mood.

OBJECTIVE: To investigate the effects of vaccinations and steroids on disease progression and mood in patients with multiple sclerosis (MS). MATERIAL AND METHODS: Twenty-three patients with clinically definite MS were questioned with respect to vaccination history and the cumulative dose of steroids given during their life-time. EDSS scores and MRI scans of the brain were obtained and used to quantify clinical and MRI disease progression. Mood was assessed by using a self-estimated adjective mood scale. RESULTS: The number of vaccinations showed no effect on disease progression or mood. High cumulative steroid doses were associated with rapid MRI disease progression and the number of supratentorial MRI lesions. The absence of band-like MRI lesions was correlated with rapid clinical and MRI disease progression. Self-estimated mood tended to be worse in patients with chronic-progressive MS compared to those with relapsing-remitting MS. CONCLUSION: Neither clinical nor MRI-documented disease progression nor mood are influenced by the total number of vaccinations whereas high cumulative steroid doses and the absence of band-like MRI lesions indicate rapidly progressive MS. Self-estimated mood tends to be worse in patients with chronic-progressive MS compared to patients with relapsing-remitting MS.

Adult↗
PubMed1997

[Accommodations for psychiatric patients. An empirical study of the Basel area canton].

The psychiatric services of the Swiss region of Basel-Landschaft observed an increasing deterioration and shortage of accommodation offers for mentally ill persons. At the same time, it grew temporarily more and more difficult to let single rooms in flat-sharing communities. Therefore a psychiatric services research project aimed at evaluating the wishes and needs of specialists in the housing sphere, and of about 600 in- and outpatients, as well as for their caregivers. The results showed, similar to other studies, on the one hand patients' predominant wish to live independently, whereas on the other hand there was a great difference between the views of patients and their caregivers. The latter view this aspiration for independence rather skeptically. The striking disagreement between patients and caregivers may be fruitful for the therapeutic process; however, this applies only if both partners are aware of this fact.

Activities of Daily Living↗
PubMed1996

Apoptosis of T cells and macrophages in the central nervous system of intact and adrenalectomized Lewis rats during experimental allergic encephalomyelitis.

The adrenocortical response is central to recovery from experimental allergic encephalomyelitis (EAE) in the Lewis rat, as reflected by the increased severity of the disease in adrenalectomized animals. The protection conferred by glucocorticoids is related to the immunosuppressive effects of the steroid, which may include apoptosis of immunocompetent cells. Here we describe T-cell infiltration and apoptosis in spinal cord lesions of intact (INT) and adrenalectomized (ADX) rats during the course of EAE. The normal disease course (peak clinical score 3) was induced following intra-peritoneal transfer of 4 x 10(7) myelin basic protein (MBP)-sensitized spleen lymphocytes to INT rats. Maximum apoptosis of infiltrating T cells (32%) was evident on day 7 and was associated with the expected increase in circulating corticosterone levels and the onset of disease remission. ADX rats, which have no corticosterone response, administered 4 x 10(7) cells displayed rapid and fatal EAE with only minimal signs of T-cell apoptosis (1.9-3.8%). In order to delay the onset and prolong the disease in ADX rats, a lower cell dose was used. In ADX rats injected with 1 x 10(6) cells, disease onset was comparable to INT 4 x 10(7) rats but disease progression was equally rapid and T-cell apoptosis (1.4-8.5%) was similarly low to that seen in ADX rats given the higher dose of cells. Transfer of the lower number of splenocytes (1 x 10(6) cells) to INT rats resulted in only mild EAE (clinical score 0.5-1) which was reflected both in low T cell apoptosis (1.7-16%) and circulating corticosterone levels. In all treatment groups very few apoptotic macrophages were detected ( < 1% of all macrophages) and no differences between groups were apparent. The results suggest that glucocorticoid-mediated T-cell apoptosis, whether initiated directly or indirectly, may contribute to the recovery phase of EAE in Lewis rats.

Adrenalectomy↗
PubMed1996

Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death. A model for T-cell apoptosis in vivo.

In this study we have characterized apoptotic cell death of autoreactive T cells resulting from their interaction with astrocytes and the modulatory effect of steroid hormones. Time kinetics of T-cell activation by interferon (IFN)-gamma-treated astrocytes from neonatal Lewis rats and by professional antigen presenting cells (APCs) from bulk suspensions of thymus or spleen were performed. [3H]Thymidine incorporation of neuritogenic P2- and encephalitogenic myelin basic protein (MBP)-specific T-cell lines declined after 48 h in culture with astrocytes. A similar suppressive effect was observed when T cells were cocultured with thymic APCs and astrocytes. This effect disappeared when astrocytes were separated by a transwell system. After 72 h of culture with astrocytes a mean of 17.5 +/- 12.4% T cells exhibited morphological signs of apoptosis. Apoptosis was identified by light microscopy, and confirmed by electron microscopy, by in situ tailing reaction and by agarose gel electrophoresis. Glucocorticosteroids and oestrogen specifically enhanced T-cell apoptosis within 8 h (69.8 +/- 23.1% and 69 +/- 17.1%, respectively) when added after 72 h to the astrocyte system, but not at earlier time points of T-cell activation or when thymic APCs were used. Glucocorticoid-mediated T-cell apoptosis was inhibited by the steroid-receptor antagonist RU 486. Pregnenolone, lipocortin-1, indomethacin and transforming growth factor-beta did not induce apoptosis in this system. The steroid effect was not associated with CD28, IL-2 receptor, or transferrin-receptor expression, which were equally upregulated on T cells activated by astrocytes or thymic APC as shown by fluorescence activated cell sorting (FACS) analysis. We conclude that astrocytes as CNS-specific APC may render T cells susceptible for induction of apoptotic cell death. Some steroid hormones can markedly enhance this process in vitro and may augment an additional effect of a systemic corticosteroid response in vivo during recovery from autoimmune encephalomyelitis.

Analysis of Variance↗
PubMed1996

MHC class I-mediated cytotoxicity does not induce apoptosis in muscle fibers nor in inflammatory T cells: studies in patients with polymyositis, dermatomyositis, and inclusion body myositis.

Apoptosis plays a crucial role in natural recovery from T cell-mediated autoimmune disorders of the nervous system. Whether apoptosis also occurs in human inflammatory myopathies is unclear. In this study we examined muscle biopsy specimens from untreated patients with polymyositis (n = 12), dermatomyositis (n = 12), and inclusion body myositis (n = 12) for the presence of apoptosis using morphological criteria and DNA fragmentation by in situ tailing. In all these disorders, only rare T cells exhibited signs of apoptosis by nuclear morphology and in situ labeling techniques. Although Fas-expression was upregulated in a few inflammatory cells, increased apoptosis of the surrounding T cells was not observed. Further, nuclei of degenerating muscle fibers did not show morphological signs of apoptosis and were not labeled by the tailing reaction. We conclude that in the inflammatory myopathies, T cell inflammation is not cleared by apoptosis and affected muscle fibers do not die by apoptosis. The observations are consistent with the non-self-limited nature of these disorders and suggest that, in contrast to the nervous system, the local microenvironment in muscle does not deliver pro-apoptotic stimuli.

Adult↗
PubMed1996

[Current therapy of multiple sclerosis].

There is no cure for multiple sclerosis (MS). Many therapeutic strategies are known. With exception of high dose corticosteroids for the treatment of acute exacerbations most of the concepts are not generally accepted. Reasons are the variable, often unpredictable natural course of MS, the incomplete understanding of the pathophysiology and the difficult trial design. Yet, new therapeutic agents give hope at least to slow the course of the disease.

Azathioprine↗
PubMed1995

[Increased residual urine volume after local injection of botulinum A toxin].

After major head trauma, a 28-year-old male patient developed tetraparesis with marked left-sided contractions of the leg adductors. Spasticity was resistant to antispastic drugs and intensive physiotherapy. Therefore, we injected 12.5 ng botulinum A toxin (Dysport) in the left adductor longus and adductor magnus. Eight measurements of the post-micturition residual urine of the bladder before botulinum-A-toxin administration gave no evidence for urinary retention. Between day 5 and 14 after injection we measured pathologically increased urinary volumes up to 130 ml at five different points of time. This case report indicates possible subclinical side effects on the autonomic nervous system of the urinary bladder.

Adult↗
PubMed1994

Oligodendrocytes in the early course of multiple sclerosis.

The neuropathology of demyelinating lesions in multiple sclerosis was studied in specimens obtained by diagnostic needle biopsy during early stages of the disease. The lesions were characterized by a chronic inflammatory reaction dominated by lymphocytes and macrophages, plaque-like demyelination, and astroglial sclerosis. Oligodendrocytes within the lesions were studied by immunocytochemistry using antibodies against various myelin and oligodendroglia components. The expression of messenger RNA for proteolipid protein was determined by in situ hybridization. Our studies revealed that myelin-oligodendrocyte glycoprotein is a sensitive and reliable marker for identification of oligodendrocytes in demyelinated plaques. The results suggest that in the early course of the disease in some patients, oligodendrocytes may largely be preserved, whereas in others oligodendroglial loss is pronounced. Loss of oligodendrocytes was only marginally related to the stage of demyelinating activity within the lesions. These findings indicate that the pathogenesis of demyelination may vary within different multiple sclerosis patients.

Adolescent↗
PubMed1994

[Therapeutic use of botulinum A toxin in neurology].

The highly potent neurotoxins produced by Clostridium botulinum lead to botulism when ingested in appreciable amounts. However, botulinum toxin injections delivered intramuscularly in very small quantities can produce a therapeutically intended focal paresis while producing only negligible local or systemic side effects. Over the past several years, various neurological disorders, especially those involving increased muscle tone and/or abnormal movements, have been successfully treated with local botulinum A toxin injections. The success of this method has led to a general change in the management of blepharospasm, torticollis spasmodicus, hemifacial spasm, and other disorders. Treatment is usually effective for 4 to 12 weeks; if symptoms recur, the injections can be repeated over a period of several years, usually with the same success. Side effects depend on the site of the injections, and are rare at the optimal dosage and always reversible. For optimum therapeutic results, this treatment must be restricted to specialized centers.

Botulinum Toxins↗
PubMed1994

Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques.

BACKGROUND: A number of enzymatic techniques have recently been developed to detect DNA fragmentation in apoptosis at the cellular level. However, since DNA fragmentation also occurs in cellular necrosis, we studied to which extent the use of DNA polymerase (nick translation) or terminal transferase (tailing) allows the differentiation between internucleosomal DNA degradation, typical for apoptosis, and the more random DNA destruction in necrosis. EXPERIMENTAL DESIGN: We compared these techniques on in vitro and in vivo models for apoptotic or necrotic cell death. Apoptosis of thymocytes in vitro was induced by gamma-irradiation, necrosis by the cytotoxic action of antibody and complement. Cell death in vivo was examined on paraffin-embedded tissue material from animals with autoimmune encephalomyelitis that served as a model for apoptosis, or in kainic acid-induced nerve cell degeneration as a model for necrosis. RESULTS: DNA fragmentation was visualized by the incorporation of labeled nucleotides into the nuclei of affected cells utilizing tailing or nick translation techniques. In the early stages of cell degeneration in vitro, cells undergoing apoptosis were preferentially labeled by tailing, whereas necrotic cells were identified by nick translation. Similarly, early stages of necrosis in vivo were preferentially detected by nick translation, whereas tailing was slightly more sensitive for the detection of apoptosis. Results obtained with these enzymatic techniques were in accord with the assessment of cell death by morphologic criteria. Both techniques could be applied in tissue samples even after prolonged fixation in paraformaldehyde if the sections were pretreated with proteinase K digestion. CONCLUSIONS: Our studies show that both in situ nick translation and in situ tailing are useful in detecting DNA fragmentation in cell suspensions and tissue sections. These techniques may help to define the molecular mechanisms leading to cell death in experimental conditions and eventually in human tissue.

Animals↗
PubMed1993

Inhibition of experimental autoimmune encephalomyelitis by an antibody to the intercellular adhesion molecule ICAM-1.

Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by active immunization with myelin from guinea pig spinal cord by the encephalitogenic myelin basic protein or by adoptive transfer using myelin basic protein-specific CD4-positive T cells. Treatment with purified monoclonal antibody (1A-29) to the intercellular adhesion molecule-1 and its F(ab')2 fragments efficiently suppressed active EAE. Control treatment with an irrelevant antibody or saline did not alter the course of the disease. Histological sections of the central nervous system showed a pronounced reduction of inflammatory infiltrates during treatment with antibody to intercellular adhesion molecule-1. In the adoptive transfer model of EAE, 1A-29 had only a minor effect. Proliferation assays on lymph node cells ex vivo from 1A-29- and saline-treated animals were performed. Administration of 1A-29 suppressed antigen-specific T-cell proliferation. The differential effects in EAE versus adoptive transfer EAE suggest that 1A-29 acts predominantly on the induction phase of the immune response and, to a lesser extent, on the transendothelial migration of T cells. We conclude that intercellular adhesion molecule-1-dependent pathways are critically involved in the pathogenesis of EAE and that antibodies to leukocyte adhesion molecules could be a novel therapeutic approach to autoimmune disease of the central nervous system.

Animals↗
PubMed1993

Bone marrow derived elements and resident microglia in brain inflammation.

Infection of the central nervous (CNS) system by the human immunodeficiency virus (HIV) depends on the migration of infected hematogenous cells into the brain. We thus used quantitative light and electron microscopic immunocytochemistry to study the homing and turnover of bone marrow derived cells in the CNS in radiation bone marrow chimeras under normal conditions and in experimental autoimmune encephalomyelitis (EAE) as an experimental model of brain inflammation. Our studies suggest the following conclusions. First, the central nervous system is continuously patrolled by a small number of T-lymphocytes and monocytes. Meningeal and perivascular monocytes are slowly replaced by hematogenous cells under normal conditions, and this turnover is accelerated in the course of inflammation. In contrast, resident microglia represent a very stable cell pool, which in adult animals is only exceptionally replaced by hematogenous cells, even after recovery from severe brain inflammation. Second, although in bone-marrow-chimeric animals resident microglia, astrocytes, and ependymal cells are not able to present antigen to Lewis T-lymphocytes, the inflammatory reaction in EAE is qualitatively and quantitatively similar in these animals compared to fully histocompatible Lewis rats. Finally, resident microglia express the macrophage activation antigen ED1. Thus, microglia cells appear to function as effector cells in EAE lesions.

Animals↗
PubMed1993

Detection of DNA fragmentation in apoptosis: application of in situ nick translation to cell culture systems and tissue sections.

Since DNA fragmentation is a key feature of programmed cell death (PCD) and also occurs in certain stages of necrosis, we have adapted the methodology of in situ nick-translation (ISNT) to detect DNA fragmentation on a single-cell level. We first established the technique for cell preparations. Apoptosis was induced by gamma-irradiation on freshly isolated rat thymocytes. After fixation procedures, ISNT was performed by overnight incubation either with fluorescein-12-dUTP or with digoxigenin-labeled 11-dUTP and DNA polymerase I. The enzymatic incorporation of labeled nucleotides at sites of DNA fragmentation was detected by flow cytometry either directly or indirectly with fluorescein-conjugated anti-digoxigenin. The quantitative results demonstrated close correlation with morphological essays for apoptosis, DNA gel electrophoresis, and ISNT. Proliferating cells determined by bromodeoxyuridine immunofluorescence were not labeled by ISNT. Immunocytochemistry for cell surface antigens in combination with ISNT allowed the identification of specific cell types undergoing PCD. Furthermore, the simultaneous application of photolabeling techniques with ethidium monoazide and ISNT led to the identification of DNA fragmentation in cells with still intact membranes. Extending ISNT to tissue sections of paraformaldehyde-fixed, paraffin-embedded material reliably revealed labeling of cells with typical morphological features of apoptosis. However, this technique was not useful in detecting early stages of necrotic cell death.

Animals↗