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Biomedical subjects

P Rieckmann

Publications and source records attributed to P Rieckmann.

At least 19 recordsLinked to original sources
PubMed2003

Modulation of cytokine mRNA expression by brain-derived neurotrophic factor and nerve growth factor in human immune cells.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) exert various effects on immune cells. Here we studied, whether they influence the cytokine expression pattern in peripheral blood mononuclear cells (PBMCs) or antigen specific T-cells. In PBMCs BDNF and NGF had interindividually variable effects on T helper cell type (Th)1- and Th2-cytokines. However, there was a high correlation between the modulating properties of these neurotrophins (r=0.97) concerning the expression of interleukin (IL) 4, transforming growth factor-beta and tumour necrosis factor-alpha mRNA at a concentration of 100 ng/ml. In myelin basic protein-specific T-cell lines BDNF and NGF increased interferon -gamma mRNA to a moderate extent, but not IL4. No major effects were detected at the cytokine protein level. In conclusion, our results suggest a partial effect of neurotrophins on immune cells, which may be modified by other signals.

Brain-Derived Neurotrophic Factor↗
PubMed2002

Serial analysis of cytokine mRNA profiles in whole blood samples from patients with early multiple sclerosis.

In this pilot study, we serially determined the cytokine messenger RNA (mRNA) expression pattern in whole blood samples from 12 patients with clinical isolated syndrome suggestive of early multiple sclerosis (MS) using a new sensitive quantitative polymerase chain reaction (PCR) method. Significantly higher levels of tumor necrosis factor-alpha (TNF-alpha; x 5.1), interferon-gamma (IFN-gamma; x 4.8) and interleukin-10 (IL-10; x 5.6) mRNA were detected in MS patients at the time of a relapse compared to healthy controls. Treatment with i.v. methylprednisolone (MP) led to an increase of IL-4 mRNA and a significant decrease of IFN-gamma and TNF-alpha mRNA expression. In this cohort of clinically stable patients, proinflammatory cytokines remained low during the 1-year follow-up period. As several indications point to a cytokine dysregulation in MS, quantitative analysis of cytokine mRNA profiles in whole blood samples by real time PCR may be a useful immunological marker to monitor disease activity in future therapeutic trials in MS.

Adult↗
PubMed2002

Human cerebral endothelial cells are a potential source for bioactive BDNF.

Inflammatory stimuli within the central nervous system may not only induce tissue damage but may also convey neuroprotection. It has been shown that brain derived neurotrophic factor (BDNF) is a neuroprotective candidate. Here we show that BDNF is constitutively expressed in cultured human cerebral endothelial cells (HCEC) and can further be upregulated under proinflammatory conditions. TNF-alpha treatment resulted in an increase in BDNF mRNA expression and protein levels were significantly elevated after 72 h (69+/-33%, P<0.01). Using functional assays it was demonstrated that BDNF produced by HCEC is bioactive and supports motoneuron survival. In contrast, BDNF expression was reduced by TNF-alpha in human umbilical vein endothelial cells (HUVEC). We conclude that HCEC likely to contribute to neuronal survival under physiological and inflammatory conditions.

Brain-Derived Neurotrophic Factor↗
PubMed2002

[Immunomodulatory staged therapy of multiple sclerosis. New aspects and practical applications, March 2002].

This update of the consensus on escalating immunotherapy in multiple sclerosis includes for the first time also important aspects of diagnosis, documentation, and cost of disease. The application of evidence-based therapeutic recommendations as described in the first two publications of the MSTKG has already improved the treatment situation for MS patients. It appears that the positive attitude towards a more active immunomodulatory therapy also helped to improve MS therapy in general. Due to the increasing use of standardized clinical documentation, individual recommendations for the application of innovative products are now clearer for patients as well as health care providers. The study on the cost of MS performed in several European countries demonstrated that medical treatment constitutes only a small part of the total cost of MS. It was demonstrated that MS-related costs correlate almost exponentially with increasing disability. Therefore, pharmacoeconomic reasons might also speak for early, individually adjusted, and escalating immunotherapy. This would also include a stringent therapy of individual relapses aimed at a complete resolution of clinical symptoms. Recent studies focus on a possible dose-effect relation for recombinant beta-interferons. The available data suggest a possible relation, but they have to be interpreted with caution, as important issues in the design of the studies (e.g., maintenance of blinding) were not adequately addressed. Up to now, there has been no general recommendation for a differential indication of the individual licensed substances, but the different available dose regimes and modes of application allow for an individual adjustment of therapy. In addition to immunomodulatory treatment, vaccinations and their effect on the disease course are important aspects in patient care. According to recent large epidemiological studies, the recommendations have changed as the relevant immunizations with split vaccines (e.g., influenza, tetanus) are now regarded as safe and without increased risk of relapse or disease progression.

Adjuvants, Immunologic↗
PubMed2002

Expression of tumor necrosis factor-alpha and interferon-gamma mRNA in blood cells correlates with depression scores during an acute attack in patients with multiple sclerosis.

Depression is a common problem in multiple sclerosis (MS) and affects about 50% of MS patients. Since a dysregulation of cytokine levels has been implicated in the pathogenesis of MS and alterations in cytokine serum levels have been found in depressive illness, we examined the relationship between depressive symptoms, cytokine mRNA expression levels of Th1-type and Th2-type cytokines and neurological disability among early diagnosed MS patients in a prospective study. Sixteen patients with clinically or laboratory supported MS were assessed using the Beck Depression Inventory (BDI) and the Kurtzke Expanded Disability Status Scale (EDSS). Cytokine mRNA in whole blood was serially determined by a new quantitative polymerase chain reaction (PCR) method. BDI sum scores (2,9 fold) and the expression levels of tumor necrosis factor-alpha (TNF-alpha; 4 fold), interferon-gamma (IFN-gamma; 4,6 fold) and interleukin-10 (IL-10; 6,1 fold) mRNA were increased in MS patients during an acute attack compared to age and sex matched healthy controls. We detected a significant positive correlation between TNF-alpha (r=0.55) and interferon-gamma (r=0.54) mRNA expression and the BDI sum scores during an acute attack in MS patients. At follow-up after 3-6 months, only TNF-alpha mRNA expression was correlated with BDI sum scores (r=0.62 resp. r=0.31). No correlation of the BDI sum scores with Th2-type cytokine mRNA expression for interleukin-4 (IL-4) and interleukin-10 (IL-10) or with the extent of neurological disability was observed. The possible contribution of Th1-type cytokines to the development of depression in MS is discussed.

Adult↗
PubMed2002

Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters.

OBJECTIVES: Fatigue is one of the most common, yet poorly defined, disabling symptoms in patients with multiple sclerosis (MS). To delineate more clearly the frequency and type of fatigue, we first compared four widely used fatigue scales in consecutive MS patients. Secondly, to further clarify the nature of fatigue, we investigated its relation to physical disability, course of the disease, immunotherapy, and depression. PATIENTS AND METHODS: Between February and September 2000, 151 consecutive MS patients entering our outpatient clinic (94 relapsing-remitting, 50 secondary progressive, and 7 primary progressive patients; mean age 29.0 +/- 7.3 years, mean disease duration 9.9 +/- 6.7 years, median EDSS 3.5) filled in a standardized questionnaire induding four fatigue scales--Fatigue Severity Scale (FSS), MS-specific FSS (MFSS), Modified Fatigue Impact Scale (MFIS), and Visual Analogue Scale (VAS). Patients were included in the 'MS-related fatigue group' (MS-F) when they stated in the questionnaire that fatigue: 1) is one of their three most disabling symptoms; 2) occurs daily or on most of the days; and 3) limits their activities at home or at work Patients fulfilling none of these criteria were classified as 'MS-related nonfatigue group' (MS-NF). Depression was measured by Beck's Depression Inventory (BDI). RESULTS: Although all scales showed significant differences between MS-F and MS-NF, correlation between these scales was, at best moderate (correlation coeffcients ranging from 0.06 to 0.56). The most discriminative scales were FSS and MFIS, showing no overlap of the 10th and 90th percentiles for the MS-F and MS-NF groups, with cut-off values of 4.6 and 38, respectively. Depression (BDI > or = 18) was present in 24 of 148 patients who filled in the BDI (16%). FSS was significantly correlated with physical disability (r=0.33, p<0.0001) and BDI (r=0.41, p<0.0001), but not with age, disease duration, clinical activity, and treatment with interferon-beta. In multivariate analysis, however, only BDI independently predicted fatigue. CONCLUSIONS: The association of fatigue and depression suggests that there might be either common underlying mechanisms or interdependence by a cause-and-effect relationship that requires further investigation. The weak correlation within various fatigue scales is best explained by the fact that fatigue is a multidimensional symptom and, therefore, the available tests measure and weight different aspects of fatigue. Our findings underline the necessity for a more exact definition of fatigue and the development of more valid tools if these are to be used to evaluate treatments.

Adult↗
PubMed2001

[Early multiple sclerosis therapy in the effects of public health economics].

BACKGROUND: Meanwhile, a number of drugs are available for the course-modifying therapy of multiple sclerosis. Their use depends on the individual indication as well as on the patient's compliance, but also increasingly on the economic considerations of the public health system. For years, the costs of multiple sclerosis and the critically evaluated cost-benefit analyses were based on estimated figures. PATIENTS AND METHODS: For better transparency of the actual costs of the disease, a cross-sectional study of multiple sclerosis patients was performed for the first time in Germany, where the patients answered questionnaires as to their financial resources and quality of life. Within this representative framework of questionnaires, data of 737 patients were evaluated. RESULTS: This study came up with a total cost of DM 65,400.-per patient and year. The complete costs of multiple sclerosis, based on an estimated number of 120,000 patients, thus run up to 7.85 bio. DM a year. Only a small percentage is caused by medication (7%), including the use of new extremely expensive drugs. There is a positive correlation between the severity of the disease and the underlying costs of treatment. CONCLUSION: Due to these results, concrete health-economic goals in the treatment of patients with multiple sclerosis should aim at stabilization on a low disability level at an early stage of the disease.

Cost of Illness↗
PubMed2001

[Ciguatera: clinical relevance of a marine neurotoxin].

HISTORY AND CLINICAL FINDINGS: A 45-year-old woman complained of gastrointestinal symptoms followed by paraesthesiae of the mouth, face, hands, feet, and trunk after she had eaten fish while she was on a journey to the red sea. Additionally, she suffered from headaches and muscle aches, weakness of the arms and legs, instability of gait as well as troubles of vision, taste, speech, and swallowing. Neurological examination revealed a cerebellar syndromE with mild dysarthria, multifocal dysaesthesiae, paresis of the arms and legs, generalized hyporeflexia, bilaterally reduced vision, and ataxic gait. INVESTIGATIONS: Laboratory work-up provided no diagnostic clues. Cranial and spinal magnetic resonance imaging were normal. The cerebrospinal fluid showed a normal cell count and a moderately impaired barrier function. Electrophysiological evaluation suggested a sensory and motor axonal neuropathy. DIAGNOSIS, TREATMENT AND COURSE: Based on the history and the characteristic clinical findings we made a diagnosis of ciguatera, a marine food poisoning caused by the ingestion of fish contaminated with ciguatoxin. Symptomatic treatment with mannitol, amitriptyline, carbamazepine, and corticosteroids started 3 weeks after the onset of symptoms proved inefficient, however, during the 21 months of follow-up there was a marked spontaneous clinical and electrophysiological reversal of symptoms. CONCLUSIONS: In the age of growing foreign tourism marine food intoxications have to be considered in the differential diagnosis of the frequently occurring travellers-diarrhea. The diagnosis of ciguatera is based on the typical history of a fishmeal followed by characteristic clinical findings with predominant neurological symptoms, often including dysaesthesiae, besides gastrointestinal disturbances. In the early phase of the disease intravenous therapy with mannitol has emerged as an efficient treatment.

Animals↗
PubMed2001

Influenza vaccination in MS: absence of T-cell response against white matter proteins.

BACKGROUND: Natural infections bear the risk of triggering MS bouts, whereas epidemiologic studies have not delineated an increased risk for disease activity after influenza virus vaccination. OBJECTIVE: To examine influenza A virus-specific and myelin protein-reactive T-cell frequencies by interferon gamma (IFNgamma)-enzyme-linked immunospot and the response of these cells by IFNgamma-reverse transcription (RT) PCR after immunization and any incidental upper respiratory tract infection (URI) in 12 patients with MS (seven with a relapsing-remitting course; five with a secondary progressive course; Kurtzke Expanded Disability Status Scale [EDSS] score from 1.0 to 6.5, without immunosuppressive treatment) and 28 healthy volunteers. RESULTS: A cellular immune response against influenza A virus was mounted in both populations at 2 weeks after vaccination. Patients with MS showed a higher relative increase (p = 0.008) than controls with respect to the number of influenza-specific T cells. Mean antibody responses against influenza A virus were increased in both populations after 2 weeks (p < 0.01). Despite these virus-specific reactions, no increase in T-cell frequencies responsive to human myelin basic protein (MBP) or recombinant human myelin oligodendrocyte protein (MOG) was observed after immunization, arguing against a general immune stimulation by influenza vaccination. In contrast, MBP-specific T-cell responses became detectable in several individuals after febrile infection. CONCLUSION: These data support the clinical observations that influenza vaccination is effective and safe in patients with MS with respect to cellular immunoreactivity against two main CNS myelin proteins.

Adult↗
PubMed2001

Analysis of interleukin-4 receptor alpha chain variants in multiple sclerosis.

A recent candidate gene study employing microsatellite markers suggested a possible linkage of multiple sclerosis (MS) with the interleukin-4 receptor (IL4R) gene. Consequently, we investigated the association of different IL4R variants with MS in 341 German MS patients and 305 healthy controls. Analysis of the first 100 MS patients for six IL4R variants showed an increased frequency of the R551 variant in MS patients versus healthy controls and carriage of the same IL4R variant was weakly associated with myelin oligodendrocyte glycoprotein (MOG) autoantibody production. However, further analysis of all 341 MS patients did not confirm the finding that this IL4R variant represents a general genetic risk factor for MS but revealed an increased frequency of the R551 variant in MS patients with primary progressive MS (PPMS, n=48) as compared to patients with relapsing remitting MS or secondary progressive MS (RR/SPMS n=284; P=0.005 for genotype differences) and to 305 healthy controls (P=0.001 for genotype differences). This association was statistically independent of the presence of the well-known MS susceptibility allele HLA-DRB1*15. After correction for multiple comparisons only the genotype differences between PPMS patients and healthy controls remained statistically significant. These results indicate, that the IL4R variant R551 may influence the genetic predisposition for PPMS but does not represent a general genetic risk factor for MS.

Adult↗
PubMed2001

Characterization of early immunological responses in primary cultures of differentially activated human peripheral mononuclear cells.

Specific immune cell activation is a hallmark of infections and autoimmune disorders. Quantification of proliferative cell responses by (3)H-thymidine incorporation is a slow process and describes only one type of cellular reaction. We here investigated early immunological responses of purified human peripheral blood mononuclear cells to the direct stimulus alpha CD3 and antigen specific stimulation (human myelin basic protein (hMBP), tetanus toxoid, and influenza vaccine) and compared them to polyclonal LPS stimulation. Cytokine mRNA levels were quantified using real-time quantitative reverse transcriptase polymerase chain reaction (RT PCR) 4 h, 16 h, and 48 h after activation. Proliferation was measured 96 h after initiation of the cultures. Antigen specific responses were detected as early as 4 h after stimulation and followed different kinetics depending on the mode of activation. We demonstrated significant correlations of cytokine mRNA and protein expression for TNF alpha, IL10, and IFN gamma. Expression of IL2 mRNA at 16 h was correlated with proliferation indices at 96 h whereas IL4 mRNA levels were negatively correlated. Early cytokine mRNA expression in stimulated immune cells provides important functional data and is a powerful tool with which to study immunological reactions.

Cell Division↗
PubMed2001

[Treatment of relapsing-remitting multiple sclerosis with recombinant interferon-beta preparations].

Three recombinant interferon-beta preparations, Betaferon (IFN beta-1b) and Avonex and Rebif (INF beta-1a) have been approved for the therapy of relapsing-remitting multiple sclerosis (MS). The results from pharmacokinetic and pharmacodynamic studies with different interferon-beta preparations reflect only in part the mechanisms of action of this substance, because standard assays primarily measure antiviral bioactivity. These studies are often overinterpreted in relation to the therapy of MS. In this article, we critically evaluate the results of pharmacologic studies with respect to the dose-dependent efficacy of different interferon-beta preparations.

Adjuvants, Immunologic↗
PubMed2001

Genetic polymorphism of the tumor necrosis factor (TNF)-alpha promoter region in families with localized early-onset periodontitis.

Tumor necrosis factor (TNF)-alpha is a potent proinflammatory cytokine that is able to induce tissue destruction and bone resorption. A G-to-A polymorphism at the -308 position of the TNF-alpha promoter region was suggested to influence TNF-alpha production. We had previously shown that monocytes of patients with localized early-onset periodontitis (EOP) secrete high levels of TNF-alpha compared to matched controls. The aim of the present study was to investigate the possible link between the -308 polymorphism in the TNF-alpha gene and EOP. Genomic DNA was extracted from the blood of 64 individuals from 11 nuclear families with EOP. The TNF-alpha polymorphism at -308 was assessed using allele-specific polymerase chain reaction. 77% of the tested adolescents were found to have the G/G genotype, and 23% had the A/G genotype. In the diseased subjects, 81% were with G/G genotype and 19% with A/G genotype. The healthy children had 74% G/G genotype, while 26% had A/G genotype. The differences between the disease group and the healthy group were not statistically significant. In summary, the present results could not demonstrate any link between EOP and genetic polymorphism in the -308 position of the TNF-alpha promoter.

Adenine↗
PubMed2001

Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions.

Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family and modulates inflammatory responses. Here we investigated the role of OSM as an immunoregulatory factor for human cerebral endothelial cells (HCEC). Using RT-PCR we detected transcripts of the receptor components involved in OSM signaling, gp130, OSM receptor (OSMR)-beta, and leukemia inhibitory factor receptor (LIFR), in HCEC. A parallel FACS analysis revealed surface expression of gp130 and OSMR-beta, but not of LIFR on these cells. Functionally, OSM upregulated intercellular adhesion molecule-1, but did not induce vascular cell adhesion molecule-1 in HCEC. Further, OSM upregulated IL-6 and monocyte chemoattractant protein (MCP)-1, whereas IL-8 was unaffected. Combined application of tumor necrosis factor (TNF)-alpha and OSM synergistically enhanced IL-6 and MCP-1 production, but downregulated TNF-alpha-induced IL-8. As OSM regulated molecules relevant in inflammatory brain diseases, we investigated its expression in normal and pathological human brains. OSM was detected by immunohistochemistry in brains from multiple sclerosis patients in microglia, reactive astrocytes, and infiltrating leukocytes, whereas in normal brains and noninflammatory neurological diseases. immunoreactivity was absent from the parenchyma. These data suggest that immunoregulatory functions in human cerebral endothelial cells may be a mechanism by which OSM participates in the pathophysiology of inflammatory brain disease.

Adult↗
PubMed2001

Production of MMPs in human cerebral endothelial cells and their role in shedding adhesion molecules.

Matrix metalloproteinases (MMPs) are Zn2+-endopeptidases that seem to play an important role in chronic inflammatory diseases of the central nervous system by disrupting the blood-brain barrier (BBB) and mediating the destruction of myelin components. We therefore investigated the influence of the pro-inflammatory cytokine TNF-alpha. on the expression and activation of several MMPs in human cerebral endothelial cells (HCEC). HCEC constitutively express MMP-2 and MMP-3 mRNA, but only MMP-3 is upregulated on mRNA and protein level after TNF-alpha stimulation. MMP-9 and MMP-12 mRNA could only be detected under inflammatory conditions. Furthermore, MMPs are involved in shedding of cell surface molecules. We therefore investigated the influence of MMPs on the release of soluble adhesion molecules using marimastat, a specific broad-spectrum MMP inhibitor and other protease inhibitors like aprotinin or leupeptin. Only marimastat inhibited the TNF-alpha mediated release of sVCAM-1 in the supernatants of HCEC. Western blot results of culture supernatants supported the time dependent release of the complete extracellular portion of the VCAM-1 molecule. These data suggest that MMPs produced by HCEC are actively involved in the shedding of soluble adhesion molecules at the BBB.

Alternative Splicing↗