FADD is upregulated in relapsing remitting multiple sclerosis.

OBJECTIVE: To elucidate the role of tumor necrosis factor (TNF) receptor signal transduction in multiple sclerosis (MS). METHODS: We performed a cross-sectional analysis of the gene expression of TNF receptor-associated death domain protein (TRADD) and Fas-associated death domain protein (FADD) in peripheral blood leukocytes of 23 relapsing remitting (RR), 19 secondary progressive (SP) and 12 primary progressive (PP) MS patients, as well as of 29 healthy controls by quantitative RT-PCR. Additionally, we monitored a subgroup of 15 RR MS patients longitudinally every 3 months over the time period of 9 months. RESULTS: FADD expression was significantly elevated in RR MS patients compared to the other disease courses (p < 0.048). The median of FADD expression was elevated in the RR MS patient groups compared to the healthy group, but this was not significant (p < 0.053). The median of TRADD expression was elevated in the patient groups compared to the healthy group, but this was not significant (p < 0.14). Neither variable changed significantly over the time course of 9 months. CONCLUSION: FADD elevation in leukocytes might be interpreted as the molecular equivalent of an elevated general inflammatory activity in RR MS patients compared to other disease courses. FADD elevation in RR MS reinforces the concept that different pathophysiological and immunological processes sustain RR MS and SP or PP MS.

TRAF2 is upregulated in relapsing-remitting multiple sclerosis.

OBJECTIVE: To elucidate the role of tumor necrosis factor (TNF) receptor signal transduction in multiple sclerosis (MS). METHODS: We performed a cross-sectional analysis of the gene expression of TRAF2 (TNF receptor-associated factor 2) and RIP (receptor-interacting protein) in peripheral blood leukocytes of 23 relapsing-remitting (RR), 19 secondary progressive (SP) and 12 primary progressive (PP) MS patients as well as of 29 healthy controls by quantitative RT-PCR. Additionally, we monitored a subgroup of 15 RRMS patients longitudinally every 3 months over a 9-month time period. RESULTS: TRAF2 expression was significantly elevated in RRMS patients compared to the other disease courses (p<0.005, respectively) and the control group (p<0.009). RIP expression was significantly elevated in the patient groups compared to the healthy group (phealthy-RR<0.002; phealthy-PP<0.003; phealthy-SP<0.06). Neither variable changed over the 9-month time course. CONCLUSION: TRAF2 and RIP1 elevation in leukocytes might be interpreted as the molecular equivalent of an elevated general inflammatory activity in MS patients compared to healthy control persons. TRAF2 elevation in RRMS reinforces the concept that different pathophysiological and immunological processes sustain RRMS and SPMS or PPMS.

Biomarkers of inflammation and endothelial dysfunction in stroke with and without sleep apnea.

OBJECTIVE: Although sleep apnea (SA) is a risk factor for ischemic stroke and an important prognostic factor in affected patients, the exact pathophysiological link between SA and stroke is unknown. We investigated whether the plasma concentration of biomarkers of inflammation and endothelial dysfunction, including soluble tumor necrosis factor receptor-1 and -2 (sTNF-R1 and sTNF-R2), tumor necrosis factor-ß (TNF-ß), soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) are increased in patients with acute stroke and SA compared with stroke patients without SA. DESIGN/METHODS: In total, 76 patients with ischemic stroke admitted to the stroke unit were included in this study. Plasma concentrations of biomarkers were determined after CT scans on admission. All patients received cardiorespiratory polygraphy within the first 72 h after admission. In all patients, demographic data, National Institutes of Health Stroke Scale scores and cerebrovascular risk factors were assessed. RESULTS: An apnea-hypopnea index (AHI) ≥10/h was found in 37 of our patients (48.7%). In these patients with SA, sTNF-R1 and sTNF-R2 levels were significantly higher than in patients with an AHI lower than 10/h. TNF-ß, however, showed no significant difference between both groups, just like the soluble intercellular and vascular cell adhesion molecules sICAM-1 and sVCAM-1. CONCLUSIONS/RELEVANCE: SA is associated with raised levels of sTNF-R1 and sTNF-R2 in patients with acute ischemic stroke. Taking into account the established impact of these two markers on the causation and course of cerebrovascular disease, these proteins may be part of the pathophysiological pathway linking SA to stroke.

Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients.

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

Torticollis under cyclobenzaprine.

The muscle-relaxing 5-HT(2) receptor antagonist cyclobenzaprine is structurally closely related to amitriptyline. It is widely used to treat patients presenting with back pain and fibromyalgia. Very rarely cyclobenzaprine toxicity can result in extrapyramidal symptoms, but occurrence of torticollis has not been reported so far. We report on a patient presenting with torticollis and myoclonic movements after treatment with cyclobenzaprine, who was successfully treated with intravenous biperiden. This case might be additional evidence for the necessity of appropriate dosage in case of liver impairment. Secondly there are possibly consequences as regards the therapy of motor side effects.

Interferon beta-1a induces tumor necrosis factor receptor 1 but decreases tumor necrosis factor receptor 2 leukocyte mRNA levels in relapsing-remitting multiple sclerosis.

OBJECTIVE: Members of the tumor necrosis factor (TNF) receptor superfamily play a major role in the pathogenesis of multiple sclerosis. To elucidate the role of TNF receptors, in 53 relapsing-remitting multiple sclerosis patients, we measured the TNF receptor 1 and receptor 2 (TNF-R1 and TNF-R2) mRNA levels in peripheral blood leukocytes in natural history (n = 27) and during administration of interferon (IFN) beta-1a (n = 26). METHODS: Every 3 months for the duration of 1 year peripheral blood leukocytes were investigated by quantitative reverse transcription polymerase chain reaction. Every 6 months, MRI scans of the brain were analyzed semiquantitatively. RESULTS: At baseline, clinical expanded disability status scale score and TNF-R1 mRNA level were correlated. In the therapy group, the difference between T2 lesion load at baseline and after 12 months correlated negatively with the difference between TNF-R1 mRNA level at baseline and after 12 months. Subcutaneously applied IFN beta increased the amount of TNF-R1 mRNA, but partly decreased the amount of TNF-R2 mRNA in clinically and subclinically defined responders to therapy after 1 year compared to baseline. CONCLUSION: This result might support the notion that due to different signal transduction properties of both receptors in the natural course of multiple sclerosis, TNF-alpha signaling in leukocytes via TNF-R1 might be beneficial, but detrimental via proinflammatory TNF-R2: part of the therapeutic efficacy of current first-line standard therapy with IFN might be due to the modulation of signal transduction pathways.

The expression of the carboxyl ester lipase gene in pancreas and pancreatic adenocarcinomas.

Since pancreatic cancer is an aggressive and often incurable malignancy, we investigated if the carboxyl ester lipase gene (CEL) is specifically expressed in pancreatic tissues and its promoter can be used for a specific suicide gene approach. Twenty-five tumor samples, 24 samples of normal pancreatic tissue and control tissues from other organs were examined by radioactive in situ hybridization (ISH) to localize CEL mRNA. Two carcinoma samples and 6 permanent cell lines were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). By ISH, we verified a strong CEL gene expression in acinar cells of the normal pancreas. A minor expression was noted in a single sample of acinar cell carcinoma and adenocarcinomas did not show any expression. By RT-PCR, no specific expression in both tested adenocarcinomas was observed. In summary, these results show that, contrary to notable expression of carboxyl ester lipase in acinar cells of normal pancreatic tissue, this lipase is not significantly active in pancreatic adenocarcinomas and thus not an apt genetic marker for diagnostic or therapeutic approaches.