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  • 1
    Keywords: etiology, review
    Type of Publication: Journal article epub ahead of print
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  • 2
    Keywords: BLOOD ; Germany ; MODEL ; PERFUSION ; DIAGNOSIS ; IMAGES ; QUANTIFICATION ; VOLUME ; PATIENT ; BLOOD-FLOW ; blood flow ; FLOW ; MR ; MRI ; SIGNAL ; magnetic resonance imaging ; AGE ; WOMEN ; MEN ; MUSCLE ; PARAMETERS ; SKELETAL-MUSCLE ; ULTRASONOGRAPHY ; KINETICS ; sensitivity ; specificity ; BIOPSY ; ultrasound ; INCREASE ; replenishment kinetics ; analysis ; methods ; MYOPATHY ; muscle perfusion ; replenishment kinetics of microbubbles ; Sensitivity and Specificity ; EVALUATE ; UNIT ; myopathies ; MR-IMAGES ; contrast-enhanced ultrasound ; BIOPSIES ; DERMATOMYOSITIS ; INFLAMMATORY MYOPATHIES ; POLYMYOSITIS ; MYOSITIS ; SKELETAL-MUSCLE PERFUSION
    Abstract: Objective To evaluate prospectively contrast-enhanced ultrasound (CEUS) in patients suspected of having dermatomyositis or polymyositis. Methods In 35 patients (23 women, 12 men; mean age, 51 years +/- 16 years) who were suspected of having dermatomyositis or polymyositis, perfusion in clinically affected skeletal muscles was quantified with contrast-enhanced intermittent power Doppler ultrasound. By applying a modified model that analyzed the replenishment kinetics of microbubbles, the perfusion-related parameters blood flow, local blood volume and blood flow velocity were measured. Findings were compared with muscle biopsy appearances and with the results of MRI that was performed with a 1.5-Tesla unit. Receiver operating characteristic analysis was performed and optimum thresholds for diagnosis of myositis were determined. Results Eleven patients had histologically confirmed dermatomyositis or polymyositis and showed significantly higher blood flow velocity (P = .01 for dermato- and P 〈 .001 for polymyositis), blood flow (P 〈 .001 for dermato- and polymyositis), and blood volume (P = .007 for dermato- and P 〈 .001 for polymyositis) on contrast-enhanced ultrasound than those who did not have myositis. An increase in signal intensity on T2-weighted MR images was found in all patients with myositis. MRI had a sensitivity, specificity, positive (PPV), and negative predicting values (NPV) of 100%, 88%, 77%, and 100% for diagnosis of myositis, respectively. CEUS blood flow was the best ultrasound measure for diagnosis of dermato- or polymyositis with sensitivity, specificity, PPV, and NPV of 73%, 91%, 80%, and 88%, respectively. Conclusions Increased skeletal muscle perfusion measured by CEUS could serve as an additional measurer for the diagnosis of an inflammatory myopathy
    Type of Publication: Journal article published
    PubMed ID: 17219033
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  • 3
    Keywords: brain ; DISEASE ; GLUTAMIC-ACID DECARBOXYLASE ; antibodies ; antibody ; CYTOTOXICITY ; CYTOTOXIC T-CELLS ; quantitative ; COMPLEMENT ; cytotoxic T lymphocytes ; Neurological disorders ; ANTI-NMDAR ENCEPHALITIS ; AUTOIMMUNE LIMBIC ENCEPHALITIS ; encephalitis ; NEURONAL PROTEINS ; PARANEOPLASTIC ENCEPHALOMYELITIS ; pathogenic ; POTASSIUM CHANNEL ANTIBODY ; RASMUSSENS ENCEPHALITIS ; RECEPTOR ANTIBODIES
    Abstract: Classical paraneoplastic encephalitis syndromes with 'onconeural' antibodies directed to intracellular antigens, and the recently described paraneoplastic or non-paraneoplastic encephalitides and antibodies against both neural surface antigens (voltage-gated potassium channel-complexes, N-methyl-d-aspartate receptors) and intracellular antigens (glutamic acid decarboxylase-65), constitute an increasingly recognized group of immune-mediated brain diseases. Evidence for specific immune mechanisms, however, is scarce. Here, we report qualitative and quantitative immunopathology in brain tissue (biopsy or autopsy material) of 17 cases with encephalitis and antibodies to either intracellular (Hu, Ma2, glutamic acid decarboxylase) or surface antigenic targets (voltage-gated potassium channel-complex or N-methyl-d-aspartate receptors). We hypothesized that the encephalitides with antibodies against intracellular antigens (intracellular antigen-onconeural and intracellular antigen-glutamic acid decarboxylase groups) would show neurodegeneration mediated by T cell cytotoxicity and the encephalitides with antibodies against surface antigens would be antibody-mediated and would show less T cell involvement. We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B(+) cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases) compared to the patients with surface antigens (anti-N-methyl-d-aspartate receptors and anti-voltage-gated potassium channel complex cases). One of the glutamic acid decarboxylase antibody encephalitis cases (intracellular antigen-glutamic acid decarboxylase group) showed multiple appositions of GrB-positive T cells to neurons. Generally, however, the glutamic acid decarboxylase antibody cases showed less intense inflammation and also had relatively low CD8/CD3 ratios compared with the intracellular antigen-onconeural cases. Conversely, we found complement C9neo deposition on neurons associated with acute neuronal cell death in the surface antigen group only, specifically in the voltage-gated potassium channel-complex antibody patients. N-methyl-d-aspartate receptors-antibody cases showed no evidence of antibody and complement-mediated tissue injury and were distinguished from all other encephalitides by the absence of clear neuronal pathology and a low density of inflammatory cells. Although tissue samples varied in location and in the stage of disease, our findings strongly support a central role for T cell-mediated neuronal cytotoxicity in encephalitides with antibodies against intracellular antigens. In voltage-gated potassium channel-complex encephalitis, a subset of the surface antigen antibody encephalitides, an antibody- and complement-mediated immune response appears to be responsible for neuronal loss and cerebral atrophy; the apparent absence of these mechanisms in N-methyl-d-aspartate receptors antibody encephalitis is intriguing and requires further study.
    Type of Publication: Journal article published
    PubMed ID: 22539258
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  • 4
    Keywords: RISK ; TUMORS ; CANCER-PATIENTS ; CENTRAL-NERVOUS-SYSTEM ; MALIGNANT GLIOMAS ; ISCHEMIC-STROKE ; VENOUS THROMBOEMBOLISM ; intracranial hemorrhage ; ANGIOGENESIS INHIBITOR BEVACIZUMAB ; DIFFUSION RESTRICTION
    Abstract: Ischemic strokes, intracranial hemorrhages (ICH) and deep venous thromboembolism (DVT) are clinically important events in patients with gliomas. In this multicentre, noninterventional observational study, current data pertaining to frequency, contributing factors and outcomes of vascular events during times of anti-angiogenic therapy with the antibody against vascular endothelial growth factor, bevacizumab (BEV) was collected from the German Glioma Network. Among 3,889 glioma patients, 70 ischemic strokes (1.8 %) and 123 ICH (3.2 %) were recorded. 143 DVT (5.0 %) were recorded in 2,855 patients. Rates of DVT and ICH, but not of ischemic strokes, increased with the World Health Organization (WHO) grade of glioma. In 81 BEV-treated patients, five ischemic strokes (6.2 %), one ICH (1.2 %) and six DVT (7.4 %) were documented. Compared to patients that were not treated with BEV, ischemic stroke rate was significantly higher during treatment with BEV (p 〈 0.001). The rates of DVT (p = 0.123) or ICH (p = 0.571) in BEV-treated patients did not differ. On cerebral magnetic resonance imaging (MRI), BEV-related ischemic strokes appeared as diffusion-restricted sites next to contrast-enhancing tumor. 67 % of ICH, 61 % of ischemic strokes and 18 % of DVT occurred postoperatively (within 30 days after tumor resection). Outcome after postoperative ICH was significantly worse than after spontaneous ICH (p = 0.008). Ischemic stroke outcomes did not differ between postoperative and spontaneous occurrence (p = 0.401). Rate of pulmonary embolism did not differ significantly between postoperative and spontaneous DVT (p = 0.133). Relatively low rates of ICH and DVT might be partially due to a high proportion of low-grade gliomas in this patient cohort. The finding of a relevant number of symptomatic, therapy-associated intracerebral diffusion restrictions should be controlled in ongoing phase III studies.
    Type of Publication: Journal article published
    PubMed ID: 23104124
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  • 5
  • 6
    Keywords: Germany ; AIR ; STROKE ; ESOPHAGEAL-ATRIAL FISTULA ; GAS EMBOLISM
    Type of Publication: Journal article published
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  • 7
    Keywords: brain ; PEPTIDE ; RECEPTOR ; CELLS ; EXPRESSION ; BLOOD ; CELL ; Germany ; human ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; RNA ; PATIENT ; RISK-FACTORS ; NO ; PATTERNS ; gene expression ; DESIGN ; DIFFERENCE ; risk factors ; leukocyte ; PERIPHERAL-BLOOD ; HEALTHY ; ANTAGONIST ; INJURY ; HUMAN NEUTROPHILS ; ORDER ; genomics ; ISCHEMIC-STROKE ; INTERLEUKIN-1 ; SURVIVORS ; LEVEL ; analysis ; methods ; PROFILES ; TESTS ; SIGNATURE ; EXPRESSION PROFILES ; SYMPTOMS ; RISK-FACTOR ; WHOLE-BLOOD ; systemic ; comparison ; PROFILE ; VALUES ; acute ischemic stroke ; acute traumatic brain injury ; CONFERS RISK
    Abstract: Background and purpose Ischemic stroke provokes a systemic inflammatory response. The purpose of this study was to characterize this response on the gene expression level in circulating mononuclear leukocytes from acute ischemic stroke (AIS) patients. Methods RNA from peripheral blood mononuclear cells (PBMCs) of AIS patients (24 +/- 2 hours after onset of symptoms) was analyzed with Affymetrix U133A GeneChips using a pooled design. We compared the gene expression signature from AIS patients (n = 20), stroke survivors (n = 15), patients with acute traumatic brain injury (ATBI, n = 15) and healthy control subjects without vascular risk factors (n = 15). Results Expression levels of 9682 probe sets with present calls on each GeneChip were compared. Between AIS patients and stroke survivors or between AIS patients and ATBI patients there were no significant differences in expression values of single genes after correction for multiple testing. However, comparison of the PBMC expression profiles from AIS patients and healthy subjects revealed significantly different expression (p = 0.012) of a single probe set, specific for phosphodiesterase 4 D (PDE4D). In order to detect modest expression differences in multiple genes with a presumed cumulative effect we studied the gene expression of functional groups of genes by global statistical tests. Analysis of 11 gene groups revealed differential expression between AIS patients and healthy subjects for genes involved in the inflammatory response (GeneOntology GO:0006954). Genes encoding the N-formyl peptide receptor-like 1 (FPRL1), interleukin-1 receptor antagonist (IL1RN) and complement component 3a receptor 1 (C3AR1) contributed most to the observed difference. Conclusions This transcriptome analysis did not identify significant changes between circulating mononuclear cells from AIS patients 24 hours after stroke and closely matched stroke survivors. However, comparing AIS patients with healthy control subjects revealed measurable differences in PDE4D and in inflammatory response genes when considered as a set
    Type of Publication: Journal article published
    PubMed ID: 18465111
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  • 8
    Abstract: Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.
    Type of Publication: Journal article published
    PubMed ID: 19240962
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  • 9
    Keywords: ACCUMULATION ; MRI ; SKELETAL-MUSCLE ; WEAKNESS ; channelopathies ; NA+ OVERLOAD
    Abstract: To assess the presence and persistence of muscular edema and increased myoplasmic sodium (Na+) concentration in Duchenne muscular dystrophy (DMD). We examined eight DMD patients (mean age 9.5 +/- A 5.4 years) and eight volunteers (mean age 9.5 +/- A 3.2 years) with 3-tesla proton (H-1) and Na-23 density-adapted 3D-radial MR sequences. Seven DMD patients were re-examined about 7 months later without change of therapy. The eighth DMD patient was re-examined after 5 and 11 months under medication with eplerenone. We quantified muscle edema on STIR images with background noise as reference and fatty degeneration on T1-weighted images using subcutaneous fat as reference. Na+ was quantified by a muscular tissue Na+ concentration (TSC) sequence employing a reference containing 51.3 mM Na+ with 5 % agarose. With an inversion-recovery (IR) sequence, we determined mainly the myoplasmic Na+. The normalized muscular Na-23 IR signal intensity was higher in DMD than in volunteers (n = 8, 0.75 +/- A 0.07 vs. 0.50 +/- A 0.05, p 〈 0.001) and persisted at second measurement (n = 7, 1st 0.75 +/- A 0.07, 2nd 0.73 +/- A 0.06, p = 0.50). When compared to volunteers (25.6 +/- A 2.0 mmol/l), TSC was markedly increased in DMD (38.0 +/- A 5.9 mmol/l, p 〈 0.001) and remained constant (n = 7, 1st 37.9 +/- A 6.4 mmol/l, 2nd 37.0 +/- A 4.0 mmol/l, p = 0.49). Muscular edema (15.6 +/- A 3.5 vs. 6.9 +/- A 0.7, p 〈 0.001) and fat content (0.48 +/- A 0.08 vs. 0.38 +/- A 0.01, p = 0.003) were elevated in DMD when compared to volunteers. This could also be confirmed during follow-up (n = 7, p = 0.91, p = 0.12). Eplerenone slightly improved muscle strength and reduced muscular sodium and edema. The permanent muscular Na+ overload in all DMD patients is likely osmotically relevant and responsible for the persisting, mainly intracellular muscle edema that may contribute to the progressive muscle degeneration.
    Type of Publication: Journal article published
    PubMed ID: 22544297
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  • 10
    Abstract: We studied a two-generation family presenting with conditions that included progressive permanent weakness, myopathic myopathy, exercise-induced contracture before normokalaemic periodic paralysis or, if localized to the tibial anterior muscle group, transient compartment-like syndrome (painful acute oedema with neuronal compression and drop foot). 23Na and 1H magnetic resonance imaging displayed myoplasmic sodium overload, and oedema. We identified a novel familial Ca(v)1.1 calcium channel mutation, R1242G, localized to the third positive charge of the domain IV voltage sensor. Functional expression of R1242G in the muscular dysgenesis mouse cell line GLT revealed a 28% reduced central pore inward current and a -20 mV shift of the steady-state inactivation curve. Both changes may be at least partially explained by an outward omega (gating pore) current at positive potentials. Moreover, this outward omega current of 27.5 nS/nF may cause the reduction of the overshoot by 13 mV and slowing of the upstroke of action potentials by 36% that are associated with muscle hypoexcitability (permanent weakness and myopathic myopathy). In addition to the outward omega current, we identified an inward omega pore current of 95 nS/nF at negative membrane potentials after long depolarizing pulses that shifts the R1242G residue above the omega pore constriction. A simulation reveals that the inward current might depolarize the fibre sufficiently to trigger calcium release in the absence of an action potential and therefore cause an electrically silent depolarization-induced muscle contracture. Additionally, evidence of the inward current can be found in 23Na magnetic resonance imaging-detected sodium accumulation and 1H magnetic resonance imaging-detected oedema. We hypothesize that the episodes are normokalaemic because of depolarization-induced compensatory outward potassium flux through both delayed rectifiers and omega pore. We conclude that the position of the R1242G residue before elicitation of the omega current is decisive for its conductance: if the residue is located below the gating pore as in the resting state then outward currents are observed; if the residue is above the gating pore because of depolarization, as in the inactivated state, then inward currents are observed. This study shows for the first time that functional characterization of omega pore currents is possible using a cultured cell line expressing mutant Ca(v)1.1 channels. Likewise, it is the first calcium channel mutation for complicated normokalaemic periodic paralysis.
    Type of Publication: Journal article published
    PubMed ID: 24240197
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