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Biomedical subjects

T Klockgether

Publications and source records attributed to T Klockgether.

At least 37 records · Page 2Linked to original sources
PubMed2004

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma.

Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A>G (D919G) missense polymorphism among the patients (0.16 vs 0.42; odds ratio 0.26, CI(95%): 0.09-0.74; P=0.005), suggesting a protective function of the G allele. These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2004

Heparin-induced thrombocytopenia in neurologic disease treated with unfractionated heparin.

The risk for immune-mediated heparin-induced thrombocytopenia (HIT) in neurologic patients receiving unfractionated heparin (UFH) is not known. In a prospective study of 200 patients, the authors found a 2.5% rate of HIT and a 2% rate of HIT-associated thromboses, suggesting that neurologic patients treated with UFH are at considerable risk for development of HIT and its complications. Prevalence of heparin-induced antibodies was 20.5% and was dependent on heparin dose. It was higher in cerebrovascular than in noncerebrovascular (29.4% versus 11.2%, p < 0.01) patients.

Adult↗
PubMed2004

[Diagnostic value of mitochondrial DNA analysis in chronic progressive external ophthalmoplegia (CPEO)].

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial cytopathy presenting with ptosis and external ophthalmoparesis. Mitochondrial disorders are characterized by a broad clinical spectrum and genetic background with marked genotype/phenotype variability. The routine diagnostic work-up usually includes clinical and laboratory examinations as well as histological and histochemical analysis of skeletal muscle biopsy. In our case only an additional molecular biological examination allowed the diagnosis of CPEO. PATIENT AND METHODS: We report a 35-year-old woman with a 7-years history of slowly progressive diplopia due to impaired ocular motility and bilateral ptosis. We performed ophthalmological and neurological examinations, laboratory testing, lower limb skeletal muscle biopsy including histological and histochemical investigations, biochemical analysis of respiratory chain enzymes in skeletal muscle homogenate and molecular genetic testing of skeletal muscle DNA. RESULTS: Although clinical, laboratory, histological and biochemical analyses did not give any hints suggesting a mitochondrial cytopathy, molecular genetic testing of total DNA from skeletal muscle tissue by Southern blot analysis finally revealed a 3.8 kb mitochondrial DNA deletion with a degree of heteroplasmy of 45 %. CONCLUSIONS: In patients with unexplained binocular diplopia , oculomotor deficits and/or acquired ptosis, an underlying mitochondrial cytopathy should be considered. Even in the case of inconspicuous skeletal muscle histology and biochemistry, molecular genetic testing of skeletal muscle DNA is advisable in order to establish the diagnosis.

Adult↗
PubMed2004

Probable multiple system atrophy in a German family.

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown aetiology. A possible underlying genetic component has not yet been identified. A family is reported with phenotypic MSA and probable autosomal dominant inheritance. The patients presented initially with either parkinsonian or cerebellar signs, and developed severe autonomic failure and typical atrophy of the brain stem and cerebellum in the course of the disease.

Adult↗
PubMed2003

Prevalence of antigliadin antibodies in ataxia patients.

We determined antigliadin antibodies in 95 ataxia patients and 73 controls. Antibodies were positive in 8% of the controls, 19% of patients with sporadic ataxia, 8% of patients with recessive ataxia, and 15% of patients with dominant ataxia. Statistical comparison using chi(2) statistics did not reveal significant differences between the groups. Although we found a trend toward a higher prevalence of antigliadin antibodies in patients with sporadic ataxia and dominant ataxia, our data do not support an association of ataxia with antigliadin antibodies.

Adult↗
PubMed2003

Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3.

Cognitive impairment was studied in distinct types of spinocerebellar ataxia (SCA): eleven SCA1, 14 SCA2, and 11 SCA3 individuals and 8 age- and IQ- matched controls. All were submitted to a neuropsychological test battery that comprised tests for IQ, attention, executive function, verbal and visuospatial memory. Executive dysfunction was prominent in SCA1 as compared with controls and all other SCA types. Mild deficits of verbal memory were present in SCA1, SCA2 and SCA3. The neuropathological pattern in different SCA types suggests that these cognitive deficits are not likely to be contingent upon cerebellar degeneration but to result from disruption of a cerebrocerebellar circuitry presumably at the pontine level.

Age of Onset↗
PubMed2003

Inflammation in Parkinson's disease.

Several studies of Parkinson's disease (PD) patients and experimental models of PD indicate the presence of an inflammatory process in PD. Although the primary cellular mechanisms remain to be clarified, activation of resident microglia appears to aggravate or even maintain the disease process in PD. Modulation of inflammatory mechanisms could provide a new neuroprotective therapy in PD.

Animals↗
PubMed2002

Local intra-arterial thrombolysis in the carotid territory: does recanalization depend on the thromboembolus type?

Little is known about whether recanalization of carotid territory occlusions by local intra-arterial thrombolysis (LIT) depends on the type of the occluding thromboembolus. We retrospectively analysed the records of 62 patients with thromboembolic occlusions of the intracranial internal carotid artery (ICA) bifurcation or the middle cerebral artery who were undergoing LIT with urokinase within 6 h of symptom onset. We determined the influence of thromboembolus type (according to the TOAST criteria), thromboembolus location, leptomeningeal collaterals, time interval from onset of symptoms to onset of thrombolysis, and patient's age on recanalization. The thromboembolus type was atherosclerotic in six patients, cardioembolic in 29, of other determined etiology in four, and of undetermined etiology in 23 patients. Thirty-three (53%) thromboembolic occlusions were recanalized. The thromboembolus location but not the TOAST stroke type nor other parameters affected recanalization. In the TOAST group of patients with cardioembolic occlusions recanalization occurred significantly less frequently when transoesophageal echocardiography showed cardiac thrombus. The present study underlines the thromboembolus location as being the most important parameter affecting recanalization. The fact that thromboembolic occlusions originating from cardiac thrombi had a lower likelihood of being resolved by thrombolysis indicates the thromboembolus type as another parameter affecting recanalization.

Carotid Artery Thrombosis↗
PubMed2002

Identification of inhibitor-of-differentiation 2 (Id2) as a modulator of neuronal apoptosis.

Inhibitor-of-differentiation 2 (Id2) belongs to a family of transcriptional modulators that are characterized by a helix loop helix region but lack the basic amino acid domain. During development, Id2 antagonizes differentiation mediated by the retinoblastoma protein, probably by scavenging downstream E-box basic helix-loop-helix proteins. Here, using differential display RT-PCR, we identify Id2 as an induced gene during serum and potassium deprivation-induced apoptosis of cerebellar granule neurons. Consistent with a biological role for induced Id2 messenger RNA and protein expression in neuronal cell death, expression of Id2 antisense RNA, or targeted deletion of the Id2 gene in neurons from Id2 knock-out mice, protect from apoptosis. Further, gene transfer- mediated overexpression of Id2 induces neuronal cell death both in high potassium and low potassium conditions. Thus, the present study defines a role for Id2 in the modulation of neuronal apoptosis.

Animals↗
PubMed2002

The aetiology of sporadic adult-onset ataxia.

The nosology and aetiology of sporadic adult-onset ataxia are poorly understood. The aim of the present study was to answer the following questions: (i) How many sporadic ataxia patients have a genetic cause? (ii) How many sporadic ataxia patients suffer from multiple system atrophy (MSA)? (iii) Is there a specific association between sporadic ataxia and serum anti-glutamic acid decarboxylase (GAD) or antigliadin antibodies? and (iv) What are the clinical features of patients with unexplained sporadic ataxia? The study was performed in 112 patients who met the following inclusion criteria: (i) progressive ataxia; (ii) onset after 20 years; (iii) informative and negative family history (no similar disorders in first- and second-degree relatives; parents older than 50 years); and (iv) no established symptomatic cause. Thirty-two patients (29%) met the clinical criteria of possible (7%) or probable (22%) MSA. The Friedreich's ataxia mutation was found in five patients (4%), the spinocerebellar ataxia (SCA) 2 mutation in one (1%), the SCA3 mutation in two (2%) and the SCA6 mutation in seven (6%). The disease remained unexplained in 65 patients (58%). We did not detect anti-GAD antibodies in any of our patients. Antigliadin antibodies were present in 14 patients, 10 patients with unexplained ataxia (15%) and 4 patients with an established diagnosis (9%). Patients with unexplained sporadic ataxia had a median disease onset of 56.0 years. Decreased vibration sense (62%), decreased or absent ankle reflexes (40%), increased ankle reflexes (39%), dysphagia (38%) and extensor plantar responses and/or spasticity (34%) were the most frequent extracerebellar symptoms. Compared with MSA, disease progression was significantly slower.

Adult↗
PubMed2002

Immunomodulatory effects of glatiramer acetate on superantigen- and mitogen-induced T-cell stimulation in vitro.

Glatiramer acetate (GA) interferes with antigen recognition and modulates cytokine secretion of T cells in an antigen-specific manner. Here we analysed the capacity of GA to modulate proliferative responses and cytokine secretion of peripheral blood mononuclear cells (PBMCs) in response to antigen-independent stimuli, i.e., phytohaemagglutinin (PHA) and staphylococcal enterotoxin B (SEB) stimulation in five healthy volunteers. A significant reduction of proliferative responses, as well as interferon-gamma (IFNalpha) and tumour necrosis factor-alpha (TNFalpha) secretion, was observed at concentrations of 200 microg/ml suggesting that GA may also exert immunomodulatory effects on mitogen- and superantigen-induced T-cell stimulation in vitro. However, since systemic GA concentrations of this magnitude are highly unlikely to occur in vivo the immunomodulatory effects observed here are not likely to contribute to the therapeutic mechanisms of action under physiological conditions.

Adult↗
PubMed2001

Proton magnetic resonance spectroscopy and transcranial magnetic stimulation for the detection of upper motor neuron degeneration in ALS patients.

Transcranial magnetic stimulation (TMS) was compared to proton magnetic resonance spectroscopy (1H-MRS) for the detection of upper motor neuron loss or dysfunction in 49 ALS patients classified according to the El Escorial criteria. Abnormal NAA/Cho ratios were detected in 53% of ALS patients. Abnormal TMS results (i.e. cortical inexcitability or prolonged CMCT's) were obtained in 63% of ALS patients. If one or both methods were considered for diagnosis of upper motor neuron degeneration/dysfunction, the percentage of abnormal findings was 77%, whilst in 39% of all patients both methods produced abnormal results. Compared to TMS, 1H-MRS detected more patients with upper motor neuron involvement in the suspected El Escorial subgroup (42% versus 25%), whereas TMS detected more patients with upper motor neuron involvement in the possible (81% versus 50%), probable (71% versus 57%) and definite El Escorial subgroup (71% versus 64%). We conclude that the combined use of 1H-MRS and TMS increases diagnostic accuracy for the detection of upper motor neuron involvement in ALS patients.

Adult↗
PubMed2001

Serum autoantibody responses to myelin oligodendrocyte glycoprotein and myelin basic protein in X-linked adrenoleukodystrophy and multiple sclerosis.

We analyzed the sera of 51 patients with various phenotypes of X-linked adrenoleukodystrophy (X-ALD), 20 patients with multiple sclerosis (MS) and 22 healthy volunteers for the presence of autoantibodies specific for the recombinant extracellular immunoglobulin-like domain of human myelin oligodendrocyte glycoprotein (rhMOG(Igd)) and myelin basic protein (MBP). Anti-rhMOG(Igd) autoantibodies were significantly more frequent in X-ALD and MS patients as opposed to healthy individuals (p<0.05). Anti-MBP autoantibodies were present in about one-fourth of X-ALD and MS patients but in less than 10% of healthy individuals. Anti-rhMOG(Igd) autoantibody responses were not accompanied by increased T cell reactivity against rhMOG(Igd). These findings may have important implications for the understanding of humoral anti-myelin immunoreactivity in demyelinating diseases of the central nervous system such as X-ALD and MS.

Adolescent↗
PubMed2001

Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCR-based cDNA subtractive hybridization in a cell culture model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1alpha (SDF1alpha). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid beta-protein (Abeta) in pontine neurons containing nuclear inclusions. In addition, extracellular Abeta-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1beta, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.

Amyloid beta-Protein Precursor↗