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Biomedical subjects

M Reindl

Publications and source records attributed to M Reindl.

At least 19 recordsLinked to original sources
PubMed2006

Interferon-beta antibodies have a higher affinity in patients with neutralizing antibodies compared to patients with non-neutralizing antibodies.

In this study, we investigated the affinity, determined by a relative affinity assay, using increasing concentrations of sodium-isothiocyanate to disrupt the antigen antibody binding of neutralizing and non-neutralizing antibodies against interferon-beta (IFNbeta)-1a and -1b in 73 serum samples of MS patients treated with IFNbeta-1a or -1b. Relative affinity values were significantly higher in NAB-positive compared to NAB-negative samples and in samples of IFNbeta-1a-treated patients compared to IFNbeta-1b. A significant positive correlation between relative affinity values and therapy duration indicates affinity maturation as another qualitative factor in IFNbeta neutralization.

Analysis of Variance↗
PubMed2006

[Treatment of the combined pelvic and thoracic trauma in the emergency room].

Priorities in the diagnosis and treatment of a multiple trauma with injuries to the thorax and pelvis are usually determined by the pattern and the severity of the injury sustained. In this case a haemodynamically unstable patient with severest pelvic trauma and a moderate thoracic trauma developed progressive haemodynamic instability during an intervention to the pelvis, resulting in a lethal outcome for the patient. The cause only became obvious when computed tomography of the thorax (CTT) was performed which was able to demonstrate venous pulmonary bleeding compressing the left atrium. In haemodynamically unstable patients with a major pelvic trauma combined with a moderate thoracic trauma, early CTT should therefore be a main priority in the initial management of such patients in the resuscitation room. The time spent on such a diagnostic procedure seems to be worth the information gained, which can significantly influence the initial choices and priorities in treatment.

Accidents, Traffic↗
PubMed2006

Antimyelin antibodies and the risk of relapse in patients with a primary demyelinating event.

AIM: To investigate whether the presence of serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome (CIS) predicts the interval to develop more frequently and earlier a first relapse (clinically definite multiple sclerosis: CDMS) than seronegative patients. METHODS: Sera from 45 patients with a CIS and positive intrathecal IgG-synthesis were retrospectively tested for the presence of IgM antibodies against both MOG and MBP. Antibodies were detected by immunoblot using recombinant MOG (1-125) and human MBP antigen preparations. Clinical follow ups were performed retrospectively by telephone interviews and documented neurological examination. RESULTS: Using the Cox proportional hazards model there was no significant increased risk for developing CDMS in anti-MOG and anti-MBP positive patients compared with negative. However regarding the median of the time span between CIS and CDMS over the whole follow up, antibody positive patients (MOG/MBP +/+) developed significantly earlier relapses (median 5.5 months (range 3-20)) than the antibody negative ones (median 25.0 months (range 7-43); p<0.006). On testing sera from 56 apparently healthy students, quite high frequencies of anti-MOG and anti-MBP antibodies (21% and 28% respectively) were detected. This limited specificity of anti-MOG and anti-MBP antibodies has been seen earlier and restricts their diagnostic relevance in MS despite their role as a predictor of relapses after a CIS. CONCLUSIONS: This study confirms previous data only in a subanalysis indicating that patients with positive anti-MOG/MBP antibodies develop earlier relapses than patients who are antibody negative. However, the authors could not verify that the presence of these antibodies anticipates the overall risk of developing CDMS-according to study criteria-after a first demyelinating event within the study period of 21-106 months (mean 60 (SD 25)).

Adolescent↗
PubMed2005

Anti-myelin antibodies do not allow earlier diagnosis of multiple sclerosis.

This study investigates whether the presence of serum and plasma anti-myelin oligodendrocyte glycoprotein (MOG) and anti-myelin basic protein (MBP) in patients presenting with a clinically isolated syndrome compatible with demyelination (CIS) predicts early conversion to multiple sclerosis (MS). Forty-seven patients with CIS (46 with optic neuritis) had anti-MOG and anti-MBP antibodies analysed at baseline, and clinical and magnetic resonance imaging assessments. There was no evidence that the MS status based on either the McDonald or Poser criteria relates to the antibody status.

Adult↗
PubMed2004

Genetic variants in the tumor necrosis factor receptor II gene in patients with multiple sclerosis.

Common genetic variants have been shown to influence disease susceptibility, disease course, or both in multiple sclerosis (MS). Several studies have suggested a role for tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of MS. Recently, it has been reported that the TNF receptor (TNFR) II plays an essential role in the pathology and progression of experimental autoimmune encephalomyelitis, an animal model of MS. To investigate whether TNFR II polymorphisms influence susceptibility and/or clinical progression of MS, genomic DNA of 321 samples of the Austrian Genetics in MS study group and DNA of 174 platelet donors, who served as healthy controls, were genotyped for five polymorphic sites in the TNFR II gene: exon 6 nucleotide (nt) 676*T-->G, exon 6 nt 783*G-->A (both are associated with non-conserved amino acid substitution), exon 10 nt 1663*G-->A, exon 10 nt 1668*T-->G, and exon 10 nt 1690*T-->C (all of which are located in the 3' non-coding region of the gene). We found a significant association between exon 10 nt 1668*T-->G polymorphism and susceptibility to MS. The other investigated nucleotide substitutions were not associated with susceptibility to or clinical parameters in MS.

Adult↗
PubMed2004

Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to NAb negativity.

BACKGROUND: It has been reported that in some patients with MS who develop neutralizing antibodies (NAbs) against interferon beta (IFNbeta), antibody levels can initially increase and then decrease thereafter even when treatment is continued. OBJECTIVE: To determine whether NAb titre correlates with time to reversion to NAb negativity in patients with multiple sclerosis (MS). METHODS: Twenty-eight patients with MS who were NAb-positive during treatment with one of the currently available IFNbetas were included in this retrospective study. NAb titres were determined by the myxovirus resistance protein A induction assay. Patients were considered NAb-positive if they had at least two consecutive samples with titres of > or = 20 neutralizing units (NU). Reversion to NAb-negative status was defined as two consecutive negative samples (NAb titre of < 20 NU) after NAb positivity. RESULTS: When measured two years after treatment initiation, a NAb titre of < 75 NU had a 91.7% sensitivity and a 87.5% specificity for reversion to NAb negativity in the following two years (after a total of four years of treatment). In addition, somewhat surprisingly, patients whose serum converted to NAb-negative generally developed peak NAb titres earlier than patients who remained NAb-positive (mean time of first detection was 21 versus 38 months, respectively). CONCLUSION: The NAb titre might support treatment decisions in patients with MS whose test results are positive for NAbs.

Adjuvants, Immunologic↗
PubMed2004

Increased frequencies of serum antibodies to neurofilament light in patients with primary chronic progressive multiple sclerosis.

We investigated whether serum and cerebrospinal fluid (CSF) antibodies to the light subunit of the NF protein (NF-L), a main component of the axonal cytoskeleton, may serve as biological markers for axonal pathology and/or disease progression in multiple sclerosis (MS). IgG to NF-L was measured in sera and CSF of MS patients, patients with inflammatory demyelinating diseases of the PNS, with acute inflammatory neurological diseases (including bacterial and viral meningitis), with neurodegenerative diseases, with acute noninflammatory neurological diseases (including stroke, headache and backache) and healthy controls by enzyme-linked immunosorbent assay. We found that serum anti-NF-L IgG antibodies were significantly elevated in MS patients with primary progressive disease course and we provide evidence for an intrathecal production of these antibodies. Our findings support the use of serum antibodies to NF-L as a marker for axonal destruction.

Adult↗
PubMed2003

Mutations in the gene for toll-like receptor 4 and multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with heterogeneous pathological features, disease courses and genetical backgrounds. In this study we determined whether genetic variants of toll-like receptor (TLR) 4, which confer substantial differences in the inflammation elicited by bacterial lipopolysaccharide, are related to the development of MS. We found no differences in the frequencies of the cosegregating TLR4 Asp299Gly and Thr399Ile polymorphisms between Austrian MS patients (11.6%) and age-matched controls (13.7%). Furthermore, we could not detect any influence of these mutations on clinical parameters and serum levels of soluble adhesion molecules of MS patients. Our data indicate that these TLR4 polymorphisms have no influence on the incidence, progression and inflammatory parameters of MS.

Alleles↗
PubMed2003

A novel and rapid assay for the detection of neutralizing antibodies against interferon-beta.

There is evidence that neutralizing antibodies (NAB) have a negative influence on the clinical and magnetic resonance imaging effects of interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. The current methods for NAB detection are restricted to specialized laboratories because they require a cell culture and sometimes a viral culture. Results are typically obtained after several weeks. Therefore, the development of a simple and rapid assay for the detection of NAB was sought. Whole blood samples from 28 NAB-positive patients and 110 NAB-negative patients (52 with IFNbeta and 58 without IFNbeta therapy) were incubated with IFNbeta 976 IU/mL for 24 hours. MxA protein levels--a specific marker of class I IFN bioactivity--were measured in paired samples with and without IFNbeta incubation and the difference in MxA levels was calculated. The mean increase of MxA levels after stimulation with IFNbeta in the NAB-positive group was 8 ng/mL (range 0-44 ng/mL) and in the NAB-negative group was 84 ng/mL (range 0-302 ng/mL). Using an increase of 22.5 ng/mL as cut-off) the specificity of the MxA stimulation assay was 81.2% and the sensitivity was 96.4%. The whole blood MxA stimulation assay is virtually as sensitive as the conventional NAB assay but somewhat less specific. However, this is outweighed by the procedural advantage of the assay, which is simpler, quicker and much less expensive.

Adjuvants, Immunologic↗
PubMed2002

Ultrastructure of alpha-synuclein-positive aggregations in U373 astrocytoma and rat primary glial cells.

Abnormal alpha-synuclein-positive glial cytoplasmic inclusions are found in Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. We have recently developed an in vitro model of alpha-synuclein-immunoreactive aggregations in U373 astrocytoma cells. We have additionally overexpressed wild-type and a C-terminally truncated form of alpha-synuclein in primary rat glial cells. Astrocytes and oligodendrocytes were found to form alpha-synuclein-positive aggregations in vitro perinuclearly or in the processes of the cells. The morphological studies presented here demonstrate that the aggregations we have observed in vitro are not limited by a membrane but have unclear borders. They have an amorphous dense core that is intensely alpha-synuclein-immunopositive and a predominantly filamentous halo around. Mainly filamentous structures at the border area between the halo and the core are alpha-synuclein-immunoreactive. We conclude that this in vitro model of alpha-synuclein-positive glial aggregations mimics the morphology of the abnormal glial inclusions described in neurodegenerative disorders and could be a suitable model for studying their role in the pathogenesis of these diseases.

Animals↗
PubMed2001

Increased intrathecal production of apolipoprotein D in multiple sclerosis.

Apolipoprotein D (apoD) is a small glycoprotein responsible for the local transport of small hydrophobic ligands. Within the nervous system, apoD may be an acute phase protein that is upregulated in a variety of neuropathological conditions and is involved in the removal of lipids during nerve cell degeneration and provision of lipids during the regenerative phase. In this study, we measured cerebrospinal fluid (CSF) and serum apoD levels in patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré Syndrome (GBS), infectious inflammatory neurological diseases (IND) and non-inflammatory neurological diseases (NND). We found that mean CSF apoD levels are significantly increased in patients with CIDP/GBS reflecting an acute blood-nerve barrier leakage. In contrast, MS is characterized by an increased intrathecal apoD release as measured by the apoD index. Thus, the results of our study provide the first evidence of an increased intrathecal production of apoD in MS. Moreover, we demonstrate that mean apoD indices are highest in MS patients at the time of their first clinical exacerbation. CSF apoD levels and apoD indices correlate with MS disease duration but not with disability or age. Finally, we found that corticosteroid treatment resulted in significantly elevated CSF apoD levels.

Adrenal Cortex Hormones↗
PubMed2001

Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis.

OBJECTIVE: The apolipoprotein E (APOE) polymorphism is known to impact on various neurologic disorders and has differential effects on the immune system and on CNS repair. Previous findings concerning a possible modulation of the clinical course of MS have been inconsistent, however. METHODS: In a cross-sectional study, the authors investigated 374 patients with clinically definite MS and a disease duration of at least 3 years and related their clinical and demographic findings to the allelic polymorphism of the APOE gene. The genotype distribution of patients with MS was compared with a cohort of 389 asymptomatic, randomly selected elderly volunteers. RESULTS: The authors found no significant differences in the distribution of genotypes between patients with MS and controls. However, patients with MS with the epsilon4 allele (n = 85) had a significantly higher progression index of disability (0.46 +/- 0.4 versus 0.33 +/- 0.26; p < 0.004) and a worse ranked MS severity score (5.1 +/- 1.9 versus 5.7 +/- 1.7; p = 0.05) than their non-epsilon4 counterparts, despite significantly more frequent long-term immunotherapy in epsilon4 carriers (74% versus 58%; p < 0.007). The annual relapse rate in epsilon4 carriers (0.87 +/- 0.56) was significantly higher than in patients with MS without an epsilon4 allele (0.71 +/- 0.47; p = 0.03). CONCLUSIONS: These results suggest no effect of the APOE genotype on susceptibility to MS, but indicate an association of the APOE epsilon4 allele with a more severe course of the disease.

Adult↗
PubMed2001

Glial cell death induced by overexpression of alpha-synuclein.

alpha-Synuclein is present in intracellular protein aggregates that are hallmarks of common neurodegenerative disorders including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. alpha-Synuclein is localized in neurons and presynaptic terminals. Under pathological conditions, however, it is also found in glia. The role of alpha-synuclein in glial cells and its relevance to the molecular pathology of neurodegenerative diseases is presently unclear. To investigate the consequence of alpha-synuclein overexpression in glia, we transfected U373 astrocytoma cells with vectors encoding wild-type human alpha-synuclein or C-terminally truncated synuclein fused to red fluorescent protein. alpha-synuclein immunocytochemistry of transfected astroglial cells revealed diffuse cytoplasmic labeling associated with discrete inclusions both within cell bodies and processes. Susceptibility to oxidative stress was increased in astroglial cells overexpressing alpha-synuclein, particularly in the presence of cytoplasmic inclusions. Furthermore, overexpression of alpha-synuclein induced apoptotic death of astroglial cells as shown by TUNEL staining. Our in vitro model is the first to replicate salient features of the glial pathology associated with alpha-synucleinopathies. It provides a simple testbed to further explore the cascade of events that leads to apoptotic glial cell death in some of these disorders; it may also be useful to assess the effects of therapeutic interventions including antioxidative and antiapoptotic strategies.

Apoptosis↗
PubMed2001

The fine specificity of the myelin oligodendrocyte glycoprotein autoantibody response in patients with multiple sclerosis and normal healthy controls.

Antibodies directed against the extracellular immunoglobulin (Ig)-like domain of the myelin oligodendrocyte glycoprotein (MOG(Igd)) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) and are implicated in the immunopathogenesis of multiple sclerosis (MS). In this study we investigated the epitope specificity of MOG(Igd)-specific autoantibodies immunopurified from MS patients (n=17) and normal healthy controls (HD; n=9). ELISA, using a panel of synthetic MOG(Igd) peptides, revealed that the epitope specificity of this response was heterogeneous in both groups. The most frequently recognised epitopes were located in amino acid sequences (a.a.) 1-26 (13/17) and 63-87 (15/17) in MS patients, and 14-39 (6/9) and 63-87 (6/9) in HDs, but there was no association between MS and any particular peptide specificity. We therefore investigated the ability of the immunopurified antibodies to recognise native MOG(Igd) expressed on at the membrane surface by FACS. Unexpectedly, antibodies fulfilling this essential criterion for a demyelinating antibody response were detected only in one of the MS samples. These results indicate that the epitope specificity of the human B cell response to MOG is not only heterogeneous, but may only mediate demyelination in a limited subset of MS patients.

Adolescent↗
PubMed2001

Immunoglobulin subclasses in patients with neutralizing and nonneutralizing antibodies against IFN-beta1b.

Treatment of multiple sclerosis (MS) with interferon-beta1b (IFN-beta1b) induces the production of antibodies in some patients. A proportion of these antibodies can reduce the biologic activity of IFN-beta, and they are, therefore, referred to as neutralizing antibodies (NAB). The remaining antibodies do not interfere with the biologic activity of IFN-beta and are referred to as nonneutralizing antibodies (NNAB) in this paper. Immunoglobulin (Ig) subtyping of these antibodies was carried out, and Ig subclass patterns in 20 patients with NAB were compared with those of NNAB in 39 patients. In patients with NAB, IgG2 and IgG4 were found to occur more frequently than in patients with NNAB (30% vs. 3%, p = 0.05, and 55% vs. 18%, p = 0.003, respectively) The NAB titer correlated strongly with the IgG4 titer (r = 0.53, p = 0.02). Median total IgG, IgG1, and IgG4 titers were significantly higher in NAB than in NNAB patients (respectively, 8000 vs. 3200, p = 0.01; 1600 vs. 400, p = 0.0004; 200 vs. 0, p = 0.004). It is concluded that the development of NAB is related to both the quantity and the quality of the antibodies against IFN-beta1b.

Adult↗
PubMed2001

Anti-MOG and anti-MBP antibody subclasses in multiple sclerosis.

In a subset of multiple sclerosis (MS) patients antibodies against myelin antigens seem to be important in the demyelinating process. In this study we investigated IgM, IgA and IgG serum antibodies against the myelin oligodendrocyte glycoprotein (MOG) and the myelin basic protein (MBP) in 261 MS patients. Seventy-two per cent had anti-MOG antibodies, 59% were anti-MBP seropositive. The dominating antibody was anti-MOG IgM. A significant relationship between IgA and a progressive disease course was found. The predominance of IgGI together with the significantly associated occurrence of IgG3 against MOG corresponds to the prevailing IgGI and IgG3 isotypes in other autoimmune diseases. Patients who actually suffered from a relapse were significant more often anti-MOG and anti-MBP IgG3 seropositive than those in remission. However, patients treated either with intravenous immunoglobulins or interferon-beta showed a significant reduction of anti-MOG IgG3 antibodies.

Adult↗
PubMed2000

A comparative study of the relative bioavailability of different interferon beta preparations.

BACKGROUND: Three different recombinant interferon beta (IFNbeta) preparations are currently available for the treatment of MS, two IFNbeta-1a products (Rebif and Avonex) and one IFNbeta-1b product (Betaferon). These products differ with respect to the recommended dose, the dosage regimen, and the injection route. This study compared the relative biologic activity of these three products in vitro and in vivo. METHODS: Blood samples were collected from 237 patients with MS (170 on IFNbeta therapy and 67 control subjects receiving no therapy). Samples with neutralizing antibodies were excluded. Levels of the antiviral protein MxA and soluble vascular cell adhesion molecule-1 (sVCAM) in the four groups were measured by ELISA. In the in vitro investigation, untreated blood was incubated for 24 hours with increasing concentrations of the three IFNs from a dose of 1 IU/mL to 1000 IU/mL, after which levels of MxA were measured. RESULTS: A difference between the groups was observed in vitro, with a significant change from baseline in MxA levels being observed at 10 IU for Betaferon compared with 100 IU for Rebif and Avonex. However, this might be due to the different methods used for the determination of IU by the manufacturers. At the single-dose level there were no significant differences between IFNbeta preparations. In vivo, there were significantly different levels of MxA in the four groups. In the Betaferon group, the median value for MxA was 2.29 ng/105 peripheral blood leukocytes (PBL), compared with 1.00 ng/105 PBL for Rebif, 0.57 ng/105 PBL for Avonex, and 0.14 ng/105 PBL for the control group. Some significant differences between the groups were also apparent with respect to levels of sVCAM, which were higher with Betaferon than with Rebif. CONCLUSION: IFNbeta-1b induces higher levels of the above markers of IFNbeta bioactivity than either of the two IFNbeta-1a preparations. Moreover, there is a less striking difference between the two IFNbeta-1a preparations in favor of subcutaneous IFNbeta-1a.

Adjuvants, Immunologic↗