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Biomedical subjects

T Klockgether

Publications and source records attributed to T Klockgether.

At least 55 records · Page 3Linked to original sources
PubMed2001

Patients with Multiple Sclerosis and concomitant uveitis/periphlebitis retinae are not distinct from those without intraocular inflammation.

Recent models of experimental autoimmune encephalomyelitis (EAE) have indicated that antigens co-expressed in the retina and uvea might be of pathogenetic relevance in Multiple Sclerosis (MS). We investigated the clinical spectrum and magnetic resonance imaging of 11 MS patients with concomitant uveitis, and determined the frequency of clinically silent intraocular inflammation in a prospective series of 50 patients. Two of the 11 patients had panuveitis, seven had anterior, and the remaining two had intermediate uveitis. The onset of uveitis preceded that of neurological symptoms by a mean of 8.5 years (range 1-20). None of the 50 MS patients studied prospectively by using slit lamp examinations and dilated funduscopy showed any evidence of uveitis but six patients had signs of retinal inflammation ("periphlebitis retinae"). Cranial MRI did not reveal "atypical" lesional distribution in MS patients with uveitis or periphlebitis retinae. No correlation between the type of MS and uveitis, or between the degree of neurological disability and the type of uveitis was found.

Adult↗
PubMed2001

Cricopharyngeal achalasia is a common cause of dysphagia in patients with mtDNA deletions.

To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry. Cricopharyngeal achalasia was documented in nine of 12 patients (75%), whereas deglutitive coordination problems were found in one patient. Cricopharyngeal myotomy may be an effective treatment in selected cases with severe cricopharyngeal obstruction.

Adult↗
PubMed2001

Overexpression of bcl-2 results in reduction of cytochrome c content and inhibition of complex I activity.

Bcl-2 has been shown to exert its antiapoptotic activity predominantly at the level of mitochondria by preventing cytochrome c release. Whether Bcl-2 is involved in the regulation of mitochondrial function prior to an apoptotic stimulus remains elusive. Using functional and spectrophotometric measurements in an inducible PC12-Tet-on-bcl-2 cell line we demonstrate that induction of Bcl-2 overexpression rapidly reduced cytochrome b and c levels as well as complex I activity. To confirm that these changes were specific for Bcl-2 we generated a bcl-2 antisense construct under the control of the tetracycline responsive promotor. Transient transfection with this antisense plasmid prevented both the decrease of cytochrome b and c levels and the loss of complex I activity. The decrease of cytochrome b levels was paralleled by a decrease of cytochrome b mRNA levels while Northern blot analysis of cytochrome c mRNA expression did not reveal any overt changes in Bcl-2 cells. We propose that the antiapoptotic properties of Bcl-2 are related to the reduction of mitochondrial complex I activity and lowered mitochondrial cytochrome b and c levels.

Animals↗
PubMed2001

Proton magnetic resonance spectroscopy of the motor cortex in 70 patients with amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate proton magnetic resonance spectroscopy for detection and monitoring of upper motoneuron degeneration in patients with amyotrophic lateral sclerosis. METHODS: Seventy patients with amyotrophic lateral sclerosis according to the El Escorial criteria were compared with 48 healthy control subjects. Single-volume proton magnetic resonance spectroscopy (echo time, 272 milliseconds; repetition time, 2000 milliseconds) was performed in both motor cortices for detection of N-acetylaspartate (NAA), phosphocreatine + creatine ([P]Cr), and choline-containing compounds (Cho) to calculate the metabolite ratios NAA/Cho, NAA/(P)Cr, and Cho/(P)Cr. In addition, absolute metabolite concentrations of NAA, (P)Cr, and Cho were obtained in 30 patients and 15 controls with the unsuppressed water signal used as an internal reference. RESULTS: Absolute concentrations of NAA (P<.001) and (P)Cr (P<.05) were reduced in motor cortices of patients, whereas Cho concentrations remained unchanged. The NAA/Cho and NAA/(P)Cr ratios were reduced in all El Escorial subgroups (P<.001). The Cho/(P)Cr ratio was elevated in patients with definite amyotrophic lateral sclerosis (P<.05). Metabolite ratio changes corresponded to the lateralization of clinical symptoms and were weakly correlated with disease duration and disease severity. In follow-up observations of 16 patients during a mean (+/-SD) of 12.1 +/- 8.7 months, NAA/Cho dropped by 9.1% (P<.01), and Cho/(P)Cr increased by 7.0% (P<.01). Changes of metabolite ratios were significantly correlated with progression of disease severity. CONCLUSIONS: Measurement of NAA concentrations and NAA/Cho ratios appear to be most suitable for detection of motor cortex degeneration by single-volume proton magnetic resonance spectroscopy. Reduced NAA/Cho ratios correspond to aspects of the clinical presentation and reflect disease progression in follow-up measurements.

Adult↗
PubMed2001

Molecular genetic alterations in glioblastomas with oligodendroglial component.

Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such "glioblastomas with oligodendroglial component", we investigated 13 of these tumors for genetic alterations and/or expression of the TP53, CDKN2A, PTEN, and EGFR genes. In addition, we performed microsatellite analyses for loss of heterozygosity (LOH) on chromosome arms 1p, 19q and 10q. None of tumors showed evidence for LOH on 10q. LOH on 1p was detected in 3 tumors, 1 of which additionally showed LOH on 19q. The 3 tumors with LOH on 1p showed neither TP53 mutations nor nuclear p53 accumulation. In contrast, 9 of 10 tumors without demonstrated losses on 1p showed nuclear p53 accumulation. TP53 mutations were identified in 3 of these cases. Further aberrations detected were epidermal growth factor receptor (EGFR) overexpression (3 of 13 tumors), homozygous CDKN2A deletion (2 of 11 tumors), and PTEN mutation (1 of 13 tumors). Taken together, our results indicate that "glioblastomas with oligodendroglial component" carry heterogeneous genetic alterations. LOH on 10q, PTEN mutation, and homozygous CDKN2A deletion appear to be less common in these tumors as compared to ordinary glioblastomas. Furthermore, a subset of these tumors demonstrates LOH on 1p, i.e., an alteration that has recently been linked to chemosensitivity and good prognosis in anaplastic oligodendrogliomas.

Adult↗
PubMed2001

Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3.

To identify the prevalence and determinants of restless legs syndrome (RLS) in spinocerebellar ataxia (SCA) we studied 58 patients with a molecular diagnosis of SCA1, SCA2 and SCA3. Data on the symptoms of RLS were collected by a standardized questionnaire, and RLS was diagnosed when patients met the four minimal criteria of the syndrome as recently defined by an international study group. In addition, we studied the relationship between RLS and age, age at ataxia onset, CAG repeat length, and nerve conduction and evoked potentials data. RLS was significantly more frequent in SCA patients than in controls (28% vs. 10%). Age at RLS onset in SCA was 49.0 +/- 10.9 years. There were no significant differences in nerve conduction or evoked potentials between RLS and non-RLS SCA patients. The probability of developing RLS increased with age but not with CAG repeat length or higher age of ataxia onset. The data provide evidence that patients with SCA1, SCA2 and SCA3 are per se more susceptible to RLS than non-affected individuals. The probability of developing RLS is related principally to the period over which the CAG repeat mutation exerts its effect and not to CAG repeat length or age of ataxia onset.

Adult↗
PubMed2001

Phenotype assignment in symptomatic female carriers of X-linked adrenoleukodystrophy.

However, only very few studies have systematically investigated the extent and distribution of nervous and endocrine system involvement in female carriers of X-ALD. To define the phenotype in symptomatic female carriers of X-ALD we performed a prospective study including eight symptomatic women who were followed for a mean period of 3.4+/-1.8 years (range 1-6) using standardized clinical examination protocols, magnetic resonance imaging and spectroscopy, evoked potential studies including visual, brainstem auditory, somatosensory and magnetic evoked potentials, neurographic recordings and endocrine studies. Spastic paraparesis and decreased vibration sense in the lower extremities were the most frequent clinical findings. Slightly hyperintense symmetric parieto-occipital white matter lesions on magnetic resonance imaging were detectable in two of seven cases, and the N-acetylaspartate/choline ratios on magnetic resonance spectroscopy were decreased in three of seven patients. P40 latencies were abnormal in all patients, and central motor conduction times to the lower extremities in seven of eight patients. Prolonged latencies of brainstem auditory evoked potential waves III-V or interpeak latencies of waves I-III, I-V and III-V were detectable in all patients. The degree of walking impairment was positively correlated with the duration of clinical disease (r=0.58, P < 0.05) and inversely correlated with the N-acetylaspartate/choline ratios (r=0.85; P < 0.05). Neurographic recordings revealed only subtle abnormalities, suggesting that nervous system involvement in symptomatic female carriers of X-ALD is confined mainly to the central nervous system. No evidence of adrenal insufficiency was detected in any of the patients.

Adrenal Insufficiency↗
PubMed2001

Sporadic cerebellar ataxia associated with gluten sensitivity.

A total of 104 patients with sporadic cerebellar ataxia were tested for antigliadin and antiendomysium antibodies. Twelve individuals (11.5%) with gluten sensitivity underwent duodenal biopsy and extensive clinical, electrophysiological, neuropsychological, radiological and laboratory investigations including human leucocyte antigen (HLA) typing. Two patients showed typical changes of gluten-sensitive enteropathy with crypt hyperplasia and mucosal flattening. In five patients, the intraepithelial lymphocyte count was elevated. Sporadic ataxia with gluten sensitivity was found to be tightly linked to the HLA DQB1*0201 haplotype (70%). Neurological symptoms were not related to hypovitaminosis or inflammatory CSF changes. The clinical syndrome was dominated by progressive cerebellar ataxia with ataxia of stance and gait (100%), dysarthria (100%) and limb ataxia (97%). Oculomotor abnormalities were gaze-evoked nystagmus (66.7%), spontaneous nystagmus (33.3%), saccade slowing (25%) and upward gaze palsy (16.7%). Extracerebellar features also included deep sensory loss (58.3%), bladder dysfunction (33.3%) and reduced ankle reflexes (33.3%). In accordance with clinical findings, electrophysiological investigations revealed prominent axonal neuropathy with reduced amplitudes (50%) and abnormal evoked potentials (58.3%). On neuropsychological testing, patients presented with moderate verbal memory and executive dysfunction. All patients had evidence of cerebellar atrophy on MRI. We conclude that sporadic ataxia may be associated with positive antibodies against gliadin. Nevertheless, mucosal pathology does not represent an obligatory condition of ataxia with gluten sensitivity. The fact that the disease is strongly associated with the same HLA haplotypes found in coeliac disease not only demonstrates coeliac disease and ataxia with gluten sensitivity to be part of the same disease entity but supports the hypothesis of an immunological pathogenesis of cerebellar degeneration.

Adult↗
PubMed2001

Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease.

The enzyme argininosuccinate synthetase (ASS) is the rate limiting enzyme in the metabolic pathway leading from L-citrulline to L-arginine, the physiological substrate of all isoforms of nitric oxide synthases (NOS). ASS and inducible NOS (iNOS) expression in neurons and glia was investigated by immunohistochemistry in brains of Alzheimer disease (AD) patients and nondemented, age-matched controls. In 3 areas examined (hippocampus, frontal, and entorhinal cortex), a marked increase in neuronal ASS and iNOS expression was observed in AD brains. GFAP-positive astrocytes expressing ASS were not increased in AD brains versus controls, whereas the number of iNOS expressing GFAP-positive astrocytes was significantly higher in AD brains. Density measurements revealed that ASS expression levels were significantly higher in glial cells of AD brains. Colocalization of ASS and iNOS immunoreactivity was detectable in neurons and glia. Occasionally, both ASS-and iNOS expression was detectable in CD 68-positive activated microglia cells in close proximity to senile plaques. These results suggest that neurons and astrocytes express ASS in human brain constitutively, whereas neuronal and glial ASS expression increases parallel to iNOS expression in AD. Because an adequate supply of L-arginine is indispensable for prolonged NO generation, coinduction of ASS enables cells to sustain NO generation during AD by replenishing necessary supply of L-arginine.

Aged↗
PubMed2001

Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study.

The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly efficient in PCNSL. Toxicity is manageable in patients younger than 70 years.

Adult↗
PubMed2001

Executive dysfunction in spinocerebellar ataxia type 1.

Fourteen patients with spinocerebellar ataxia 1 (SCA1) and 11 controls with similar mean age and IQ estimates were submitted to a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory as well as executive functions. Neuropsychological assessment yielded verbal memory and executive dysfunction while tests of visuospatial memory and attention were not significantly impaired in SCA1 as compared to controls. Test performance was neither related to the repeat length, the age of onset nor the disease duration. The profile of cognitive impairment in SCA1 with prominent executive dysfunction corresponds to the concept of "frontal-subcortical" dementia that is likely to be contingent upon disruption of a cerebrocerebellar circuitry that consists of afferent and efferent connections between the prefrontal cortex and the cerebellum.

Adult↗
PubMed2000

No association of serum levels of interleukin-6 and its soluble receptor components with a genetic variation in the 3'flanking region of the interleukin-6 gene in patients with multiple sclerosis.

Interleukin-6 (IL-6) plays an important role in the regulation of the inflammatory response in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous reports indicated that a variable number tandem repeat (vntr) polymorphism in the 3'flanking region of the IL-6 gene (C allele) is associated with altered activity of IL-6 in vivo. Therefore, we analyzed the frequency distribution of IL-6 gene C allele vntr poymorphism in 96 MS patients and 106 ethnically matched healthy controls. Moreover, possible correlations between genotypic differences of IL-6 gene and serum levels of IL-6, soluble IL-6 receptor (sIL6-R), soluble gp130 (sgp130), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were investigated. There were no differences in the allelic distribution of the IL-6 gene C allele between MS patients and healthy controls, and no association of the IL-6 gene C allele with serum levels of IL-6, sIL-6R, spg130, sICAM and sVCAM-1 was found.

Adolescent↗
PubMed2000

Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo.

Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells (CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and interferon gamma into rat cerebellum induced iNOS expression in CGCs and subsequent cell death assessed by staining for DNA fragmentation. Co-injection of three structurally distinct agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the prostanoid 15-deoxy-Delta(12,14) prostaglandin J(2), reduced both iNOS expression and cell death, whereas co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonstrate that PPARgamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the onset of AD, these results further suggest that NSAIDs provide therapeutic value by binding to PPARgamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.

Animals↗
PubMed2000

Primary non-Hodgkin's lymphoma of the spinal cord.

STUDY DESIGN: Case report. OBJECTIVE: To report a rare case of primary lymphoma of the spinal cord and to discuss therapeutic options. SUMMARY OF BACKGROUND DATA: Only few cases of primary spinal cord lymphomas are reported. Prognosis is often poor, and therapy is not yet established. METHODS: A primary lymphoplasmacytoid lymphoma of the thoracic cord in a 75-year-old woman was treated with focal radiotherapy (30 Gy) and three cycles of chemotherapy consisting of procarbazine, lomustine, and vincristine. RESULTS: Complete tumor response and partial recovery of neurologic symptoms were achieved. The patient was in complete remission at last follow-up (11 months after diagnosis). CONCLUSIONS: Primary spinal cord lymphomas should be considered in the differential diagnosis of spinal cord tumors, especially in older patients. Combination therapy with radiotherapy and chemotherapy may be superior to radiotherapy alone in these tumors. Rapid initiation of treatment is essential to achieve recovery of neurologic function.

Aged↗
PubMed2000

Flupirtine and retigabine prevent L-glutamate toxicity in rat pheochromocytoma PC 12 cells.

Flupirtine is an analgesic drug thought to have NMDA receptor antagonistic and antiapoptotic effects. We investigated the effects of Ethyl-2-amino-6-(4-(4-fluorbenzyl)amino)-pyridine-3-carbamamic+ ++ acid, maleate (flupirtine) and the related compound N-(2-amino-4-(4-fluorobenzylamino)-phenyl)-carbamic acid, ethyl ester) (retigabine) (Desaza-flupirtine) on the toxicity of L-glutamate and L-3,4-dihydroxyphenylalanine (L-DOPA) in rat pheochromocytoma PC 12 cells in vitro. Both drugs (10 microM) markedly decreased nonreceptor-mediated necrotic cell death in PC 12 cultures treated with L-glutamate (10 mM) for 72 h. In contrast, apoptosis induced by L-DOPA (250 microM) after 48 h was not affected by either substance. While L-DOPA elicited massive generation of reactive oxygen intermediates, L-glutamate-induced cell death was accompanied by only slightly increased levels of reactive oxygen intermediates. Flupirtine and retigabine exerted anti-oxidative effects in PC 12 cultures independent of their ability to prevent cell death. Further examination of the protective action of flupirtine and retigabine against L-glutamate toxicity showed that it had no influence on monoamine oxidase (monoamine: oxygen oxidoreductase (deaminating), EC 1.4.3.4., MAO) activity. Thus, flupirtine and retigabine provided protection against cystine deprivation and L-glutamate toxicity but did not protect against L-glutamate under cystine-free conditions indicating that both compounds are sufficiently effective to compensate the oxidative stress elicited by cystine deprivation but not excessive activity of monoamine oxidase after L-glutamate treatment.

Aminopyridines↗
PubMed2000

[Brain infarct from a paradoxical embolism following a varices operation].

HISTORY AND CLINICAL FINDINGS: A 70-year-old woman developed an acute right-sided hemiparesis and global aphasia 10 days after saphenous vein stripping of varicosities. Initially, she presented with somnolence, conjugated to the left, flexor synergism of the right extremities, exaggeration of knee and ankle jerks and extensor plantar responses on the right side. INVESTIGATIONS: The initial cranial computed tomography one hour after the onset of symptoms did not show reliable signs of cerebral ischaemia but a "dense artery sign" of the left middle cerebral artery. Repeat computed tomography then revealed a partial, mainly subcortical, infarction of the left middle cerebral artery territory. Doppler sonography revealed an occlusion of the left internal carotid artery. In duplex sonography there was no evidence of arteriosclerosis. Transesophageal echocardiography revealed a patent foramen ovale with right-to-left shunt. TREATMENT AND COURSE: Immediately after admission intravenous anticoagulation was initiated because of the suspected cardioembolic origin of the stroke. During hospitalization the global aphasia regressed and a continuing mobilization was achieved while the right-sided hemiparesis persisted. The neurological rehabilitation was initiated and continuous oral anticoagulation was planned. CONCLUSION: This case suggests a causal relationship between previously performed vein stripping and paradoxical embolism resulting in a stroke. For patients with patent foramen ovale, vein stripping may be associated with an increased stroke risk.

Aged↗