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Biomedical subjects

N Sommer

Publications and source records attributed to N Sommer.

At least 19 recordsLinked to original sources
PubMed2006

CNS involvement in hereditary neuropathy with pressure palsies (HNPP).

We assessed seven patients with hereditary neuropathy with liability to pressure palsies (HNPP) with 16 electrophysiological tests and cranial MRI for CNS abnormalities. Mean latencies differed between patients with HNPP and controls for the blink reflex, the jaw-opening reflex, and acoustic evoked potentials. MRI abnormalities were observed in four patients. Our study suggests subclinical but functionally relevant CNS myelin damage in HNPP.

Adult↗
PubMed2004

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Clinical Trials as Topic↗
PubMed2004

Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease.

OBJECTIVE: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer's disease (AD). Recently, it has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Abeta. This study reports the results from a pilot study using IVIgG in patients with AD. METHODS: Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Abeta/Abeta(1-42) measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG. RESULTS: Following IVIgG, total Abeta levels in the CSF decreased by 30.1% (17.3-43.5%) compared to baseline (p<0.05). Total Abeta increased in the serum by 233% (p<0.05). No significant change was found in Abeta(1-42) levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7+/-2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline. CONCLUSION: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.

Alzheimer Disease↗
PubMed2003

CD45 isoform expression in autoimmune myasthenia gravis.

In myasthenia gravis (MG), humoral and cellular immune mechanisms are involved in the autoimmune pathogenesis. In this study, we investigated the role of the CD45 molecule in MG, having recently reported an association in multiple sclerosis. CD45, a protein-tyrosine phophatase receptor type C (PTPRC), is essential for both thymic selection and peripheral activation of T and B cells. Our aims were to determine (a) the prevalence of a functional mutation in the CD45 gene (exon 4 77C --> G; prevalence analysis), and (b) the distribution of memory (CD45RO+) and naive (CD45RA+) T cells in the peripheral blood (subset analysis). T cells from 78 patients with generalised MG were stained with monoclonal antibodies against CD45RO, CD45RA, CD4 and CD8 and quantified by four-colour flow cytometry. The control panel for the prevalence analysis (a) consisted of 303 healthy individuals. (b) From those, 67 age- and sex-matched probands were randomly selected as controls for the subset analysis. Patients were stratified according to their MG onset age, thymic pathology and immunosuppressive treatment. Statistical analysis was performed by Fisher's exact test, asymptotic chi2 test, the two-sided Mann-Whitney test and Spearman's correlation coefficient. As a result, the 77C --> G mutation in exon 4 of the CD45 gene was found in 1 of 78 patients versus none of the 303 controls. Thus, no association was detected with this single nucleotide polymorphism in MG patients overall. Surprisingly, however, ratios of CD45RO+ to CD45RA+ T cells were lower among CD8+ T cells from patients with late-onset MG (P = 0.023). Thymoma patients also showed a similar trend among CD4+ and CD8+ T-cells, as expected. These differences were not related to immunosuppressive drug treatment or thymectomy (in the 67 informative patients). Since there is no other evidence for increased thymopoiesis in late-onset MG, we propose an altered subset balance in the circulation.

CD4-Positive T-Lymphocytes↗
PubMed2002

Simultaneous measurement of local cortical blood flow and tissue oxygen saturation by Near infra-red Laser Doppler flowmetry and remission spectroscopy in the pig brain.

In the current study we evaluated the combined use of Near-infrared Laser-Doppler flowmetry (NiLDF) and Remission Spectroscopy (RS) for measurement of regional perfusion and oxygen saturation of the cerebral cortex. An epidural probe for combined measurements of NiLDF and RS was placed above the parietal or frontal cortex of nine anesthetized juvenile pigs. Cerebral perfusion pressure (CPP) was stepwise decreased by intracisternal infusion of artificial CSF at clamped arterial blood pressure (baseline, CPP50, CPP40, CPP30 mmHg, ischemia). Subsequent reperfusion was followed for 3 h. Regional cerebral blood flow (rCBF) was measured with colored microspheres (CMS) and compared with corresponding NiLDF values during CMS injection. Cerebral venous oxygen saturation was measured in blood samples withdrawn from the sagittal sinus and compared with simultaneous recordings of tissue oxygenation during blood withdrawal. Linear regression analysis resulted in a significant correlation (p < 0.001) for changes in regional perfusion during CPP decrease and reperfusion, as measured with CMS and NiLDF (r = 0.92, n = 39). A significant correlation was also found for tissue oxygen saturation--as measured with RS--and cerebral venous oxygen saturation (r = 0.85, n = 67). Although the problem of spatial variability remains to be solved, the combined use of NiLDF and RS allows continuous and non-invasive monitoring of changes of key parameters of oxygen metabolism within the cerebral cortex.

Animals↗
PubMed2001

[New approaches in research of therapy of multiple sclerosis].

BACKGROUND: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. With a prevalence of 0.1-0.15% in Germany multiple sclerosis is the most common cause of severe disability in young adults. PATHOGENESIS: Epidemiological and family studies demonstrate the role of environmental and genetic factors in the pathogenesis of multiple sclerosis. Based on those observations and findings in experimental animal models, it is believed that multiple sclerosis is caused by an autoimmune process. However, target antigens and mechanisms leading to tissue destruction are largely unknown. THERAPY: Since the efficacy of current immunomodulatory and immunosuppressive therapies (beta-interferons, glatiramer acetate, mitoxantrone) is limited, it is necessary to develop new strategies for the treatment of multiple sclerosis. To reach this goal, a much better understanding of disease pathogenesis is necessary which takes into account the clinical, paraclincial and histopathological heterogeneity of the disease. CONCLUSION: Only further intensive research activity on basic mechanisms of disease pathogenesis and a consequent development of resulting therapeutic strategies--from animal models to phase III studies--will result in significant improvement of the long-term course of multiple sclerosis.

Adjuvants, Immunologic↗
PubMed2001

No association of three polymorphisms in the alpha-2-macroglobulin and lipoprotein related receptor genes with multiple sclerosis.

Alpha-2-macroglobulin (A2M) is a proteinase inhibitor involved in deactivation of cytokines and modulation of antigen-mediated immune responses. Based on its role in inflammatory and neurodegenerative disorders, we investigated the role of A2M and its receptor low-density lipoprotein receptor-related protein (LRP) for the development of multiple sclerosis (MS). We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) gene in a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15. No association was found for any of the three polymorphism with MS. Furthermore, no differences in serum A2M levels were detected between MS patients and controls. The results do not suggest a contribution of A2M and LRP to the development of MS.

Alleles↗
PubMed2001

Ligand motif of the autoimmune disease-associated mouse MHC class II molecule H2-A(s).

The MHC class II molecule H2-A(s), expressed in the SJL mouse strain, is the principle restriction element of autoreactive CD4(+) T cells mediating experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. We deduced the H2-A(s) ligand motif from the analysis of naturally processed self peptides and from peptide binding studies. Major anchor residues were identified using various sets of substituted and truncated peptides, derived from natural peptide ligands and known H2-A(s) binders like myelin basic protein 81 - 99. The nine-residue H2-A(s) core binding motif comprises an arrangement of anchors in relative positions P1, P4, P6, P7, and P9. The P1 pocket is relatively unspecific and the P6 pocket favors hydrophobic-aliphatic side chains. The P1 pocket contributes little to peptide binding. Primary anchors were identified in P4, P7, and in particular in P9. The preferred anchor residues are Lys (P4), His/Arg (P7), and Pro (P9), respectively. Ala-polysubstituted peptides containing only one of these dominant anchor residues still retain the capacity to bind to H2-A(s). Thus, the presence of only one suitable anchor side chain in P4, P7, or P9 is sufficient for high-affinity peptide binding, at least in the absence of negatively charged side chains nearby. The identified ligand motif facilitates the analysis of immunogenic peptides interacting with H2-A(s) and will allow a better prediction of pathogenetically relevant peptide antigens in the autoimmune mouse model.

Amino Acid Motifs↗
PubMed2001

New approaches to dissect degeneracy and specificity in T cell antigen recognition.

The acquired immune system is a complex and very effective defense against invading pathogens such as bacteria and viruses. T cells are central to the acquired immune system by controlling B and T cell activation and induction of T cell effector functions. The key event for T cell activation is the recognition of a specific antigen by the T cell receptor. During the past decade antigen recognition of T cells has been investigated intensively leading to new insights into the molecular mechanisms of T cell activation. In addition to the resolution of the molecular structure of the trimolecular complex (T cell receptor, peptide, major histocompatibility complex) functional studies have demonstrated the flexibility of the T cell receptor interaction with its ligand. These observations have had strong implications for the understanding of T cell selection, maturation, and repertoire maintenance. In addition, the flexibility of the T cell receptor has provided the basis for novel methods to dissect antigen recognition and define the repertoire of ligands for a given receptor. Here, we summarize recent progress on T cell recognition and method innovations with respect to future studies in autoimmune diseases.

Animals↗
PubMed2001

Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis.

Multiple sclerosis is a chronic inflammatory and demyelinating disease of the CNS with, as yet, an unknown aetiology. Temporal profile, intensity and treatment responses are highly variable in multiple sclerosis suggesting pathogenetic heterogeneity. This hypothesis has been supported by histopathological studies disclosing at least four different subtypes of acute demyelinating lesions. Although stratification of multiple sclerosis patients into these categories would be extremely helpful for clinical studies, this approach is impractical as it requires brain biopsy. In this study we investigated CSF cytology from 60 multiple sclerosis patients by flow cytometry. We identified different patterns of CSF cytology, which were independent of immunological parameters in the peripheral blood. The most variable CSF parameter was the B cell to monocyte ratio, which remained stable during different phases of disease in selected patients. The ratio correlated with disease progression but not with disability or disease duration in a retrospective, consecutive analysis. A high ratio (predominance of B cells) was associated with more rapid disease progression, whereas a low ratio (predominance of monocytes) was found in patients with slower progression. Our study demonstrates the existence and potential clinical relevance of different CSF cytology patterns. We hypothesize that CSF cytology patterns may reflect the heterogeneity in the pathogenesis of multiple sclerosis.

Adolescent↗
PubMed2001

Immunosuppressive treatment of ocular myasthenia gravis.

Myasthenia gravis (MG) is caused by autoantibodies against proteins at the neuromuscular junction. This autoimmune process leads to abnormal fatiguability and weakness of striated muscle. Ptosis and diplopia are among the most common manifestations of MG. The term "ocular MG" (OMG) as opposed to "generalised MG" (GMG) is used to define the clinical subtype of MG with isolated eye muscle weakness. Although OMG may appear to cause only moderate disability, it can significantly impair the patient's activities of daily living and progress to generalised myasthenia. Therefore, a clear management plan should be installed early in these patients. Since prospective treatment trials have not been performed, basic management strategies for OMG have to be deduced from retrospective studies, trials in GMG, and generally accepted clinical experience. Cholinesterase inhibitors are used in all types of MG, but are often less helpful in OMG. In the absence of thymoma, thymectomy is usually not considered in OMG, although a few studies have described histological abnormalities in thymuses from patients with OMG. Corticosteroids are of great short term benefit in most patients with OMG but potential adverse effects limit their long term use. Azathioprine is needed to reduce long term corticosteroid adverse effects, but this agent requires about 6 months to be effective. In summary, OMG has a good prognosis in most patients, with corticosteroids and azathioprine being the major treatment options. The challenges for the clinician are to recognise the condition despite the large number of differential diagnoses, to minimise the patient's symptoms using the therapies available and to carefully limit potentially hazardous therapeutic efforts, especially in mild or even uncertain cases.

Adrenal Cortex Hormones↗
PubMed2000

Rapid identification of local T cell expansion in inflammatory organ diseases by flow cytometric T cell receptor Vbeta analysis.

Oligoclonal expansion of antigen-specific T cells occurs frequently during inflammatory diseases. These cells may persist for a long time at high frequency in the body and be enriched in the affected tissues. As a screening test for expanded cell T cell populations at sites of inflammation, we developed an optimized methodology for flow-cytometry-based quantification of T cell receptor Vbeta (TCRBV) expression. We first validated the specificity of a TCRBV-specific monoclonal antibody set by direct comparison with PCR-based analysis of mono- and polyclonal T cell samples. This monoclonal antibody (mAb) panel recognized approximately two thirds of the T cell receptor alpha/beta repertoire in a group of 64 healthy donors and allowed defining TCR usage in the CD4+ and CD8+ subsets. The reliable detection of expanded Vbeta gene families in T cell populations was confirmed in experiments on superantigen-stimulated T cells. Through differential TCR analysis on T cell subpopulations in cerebrospinal fluid and blood in patients with acute encephalitis, we were able to identify locally expanded CD8+ T cells. The power of this approach affords not only high-throughput comparative TCR analysis for immunological studies in vitro, but also rapid ex vivo identification of cell populations enriched in organ compartments during inflammatory diseases.

Acute Disease↗
PubMed2000

Degeneracy in T-cell antigen recognition - implications for the pathogenesis of autoimmune diseases.

T-cells recognize by their T-cell receptor (TCR) short peptides presented by major histocompatibility complex (MHC) molecules. Based on functional and structural data, it has become widely accepted that this interaction is highly flexible thus allowing a specific TCR to interact with a broad range of different peptide ligands. Although cross-reactivity is essential for selection and maintenance of the T-cell repertoire, it also carries the danger of inducing autoreactivity following protective immune responses. This hypothesis has been supported by a large number of findings in vitro and in vivo experimental systems. Here we discuss recent findings on cross-recognition of T-cells and provide a new experimental approach to address specificity and cross-reactivity in autoimmune disorders.

Antigen Presentation↗
PubMed2000

Treatment of arterial hypertension with diuretics, beta- and calcium channel blockers in old patients.

Hypertension increases in prevalence with age. Population based studies suggest that more than 50% of people over the age of 65 years may have chronic hypertension. Hypertension, especially systolic hypertension, is the single most common, powerful, however, treatable risk factor for cardiovascular morbidity and mortality in the elderly. In order to assess the effectiveness of antihypertensive drug therapy among the elderly, with diuretics, beta-blockers and calcium channel blockers, a literature search was performed at the Cochrane Library, Medline and Excerpta medica. The Cochrane Hypertension Group identified 14 randomised controlled trials of at least one year duration with 21,785 elderly subjects where diuretics, beta-blockers or calcium channel blockers were used in the treatment group as first line drugs. In their meta-analysis (including one small trial with a central acting antiadrenergic drug) there was a decrease in total mortality (111 vs 129 deaths) and cardiovascular morbidity and mortality (126 vs 177 events) within the treatment group. The three trials restricted to persons with isolated systolic hypertension indicated beneficial effects in the treatment group with regard to cardiovascular morbidity and mortality (104 vs 157 events). Trial data on adverse effects is limited. In three studies, where adverse effects were reported, no substantial differences between treatment and control groups in measures of physical, cognitive and emotional function were found. Cardiovascular benefits of treatment with low dose diuretics or beta-blockers are cleared for elderly subjects with either diastolic or isolated systolic hypertension. Treatment with a long-acting dihydropyridine calcium channel blocker shows beneficial effects in reducing cardiovascular morbidity and mortality for elderly people with isolated systolic hypertension. Due to inconsistent findings in a subgroup meta-analysis of antihypertensive drug treatment in very old people, the efficacy of antihypertensive treatment in these subjects still remains unclear.

Adrenergic beta-Antagonists↗
PubMed2000

A point mutation in PTPRC is associated with the development of multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis. Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown. Here we investigated the role of a point mutation in the gene (PTPRC) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families.

Base Sequence↗
PubMed1998

Myasthenia gravis and tumor necrosis factor beta polymorphisms: linkage disequilibrium but no association beyond HLA-B8.

Tumor necrosis factor (TNF) may contribute to the susceptibility for autoimmune diseases. We examined TNFbeta gene polymorphisms detected by AspHI and NcoI digestion of genomic DNA in patients with myasthenia gravis (n=105) and healthy controls (n=114). In both groups, the frequencies of TNFbeta alleles were not different. AspHI and NcoI polymorphisms of TNFbeta showed a strong association with HLA-B8 (p < 0.03 resp. p < 0.0001 for AspHI and Ncol) both in patients and controls. Our results imply linkage disequilibrium of TNFbeta alleles with HLA-B8 and in myasthenia gravis we were unable to show a stronger association beyond HLA-B8.

Adult↗