Dimethyl fumarate alters intracellular Ca2+ handling in immune cells by redox-mediated pleiotropic effects.

Dimethyl fumarate (DMF) is widely used to treat the human autoimmune diseases multiple sclerosis (MS) and psoriasis. DMF causes short-term oxidative stress and activates the antioxidant response via the transcription factor Nrf2 but its immunosuppressive effect is not well understood. Immune cell activation depends on calcium signaling which itself is influenced by the cellular redox state. We therefore measured calcium, reactive oxygen species levels and glutathione content in lymphocytes from immunized mice before onset of experimental autoimmune encephalomyelitis, in peripheral blood mononuclear cells from MS patients treated with DMF, and in mouse splenocytes treated ex vivo with DMF. This demonstrated altered redox states and increased lymphocytic calcium levels in all model systems. DMF caused an immediate influx of calcium from the extracellular space, long-term increased cytosolic calcium levels and reduced calcium stored in intracellular stores. The DMF-elicited current had the electrophysiological characteristics of a transient receptor potential channel and the intracellular calcium levels were normalized by antagonists of TRPA1. Interestingly, the sarco/endoplasmic reticulum Ca2+-ATPase SERCA2b was downregulated but more active due to glutathionylation of the redox-sensitive cysteine 674. DMF therefore causes pleiotropic changes in cellular calcium homeostasis which are likely caused by redox-sensitive post-translational modifications. These changes probably contribute to its immunosuppressive effects.

Moyamoya angiopathy: early postoperative course within 3 months after STA-MCA-bypass surgery in Europe-a retrospective analysis of 64 procedures.

BACKGROUND: Despite the consensus on the necessity of revascularizing surgery in Moyamoya angiopathy in Asia, the indication in Caucasian Moyamoya patients is discussed controversially. OBJECTIVE: The safety of revascularizing surgery in Europe should be clarified. METHODS: This study retrospectively analyzed the rate of complications as well as clinical symptoms within the first 3 months after bypass surgery between superficial temporal artery and middle cerebral artery (STA-MCA). RESULTS: 64 direct bypass procedures in 45 patients (95.5% Caucasians) were analyzed. The magnetic resonance imaging at day 6 showed subdural hematoma in 60.3%. The mean diameter of these hematomas on magnetic resonance imaging was 5.1 mm (SD 3.4 mm) and increased in 25% at follow-up. No difference was found between those patients with early (day 1) or late (day 7) restarts of antiplatelet therapy. Magnetic resonance imaging at day 6 revealed hyperperfusion syndrome after six of 64 procedures (9.3%). Three of these six had clinical symptoms; two-thirds were transient within seconds. Magnetic resonance imaging depicted stroke after seven procedures (10.9%). Five of these seven patients had no new symptoms. Altogether, after ten procedures (15%), patients complained about clinical symptoms. These were all transient. No new transient ischemic attacks occurred during the 3 month follow-up and no new lesions were detected in magnetic resonance imaging. Only two patients underwent surgery for asymptomatic subdural hematoma. All other subdural hematomas resolved spontaneously. CONCLUSION: Revasculating surgery is a safe procedure in Caucasian patients with Moyamoya angiopathy. The observed complications have a good prognosis.

Efficacy of STA-MCA bypass surgery in moyamoya angiopathy: long-term follow-up of the Caucasian Krupp Hospital cohort with 81 procedures.

BACKGROUND: Despite the consensus on the efficacy of revascularizing surgery in moyamoya angiopathy (MA) in Asia, the indication in Caucasian moyamoya patients is controversially discussed. OBJECTIVE: The efficacy of revascularizing surgery in adult European patients with MA should be clarified. METHODS: This study retrospectively analyzed the rate of further strokes and hemorrhages as well as MRI and Duplex ultrasound features during long-term follow up after STA-MCA bypass. RESULTS: Eighty-one STA-MCA bypass procedures in 54 patients with MA operated in one single German institution were analyzed. All 54 patients (100%) were Caucasians. After two diffusion restricted spots in MRI perioperatively (2.5%) and short-lasting symptoms directly after surgery, no patient experienced further new symptoms related to stroke or hemorrhages nor no new gliotic scars or microbleeds on MRI for 38.2 months. Duplex ultrasound 3 months after surgery documented bypass patency in 100% and sonographic sign for good relevance of the bypass in 96.2%. In addition, the diameter of the donor vessel had increased in 89.9% as an indicator for the relevance of the bypass. Semi-quantitative analysis of perfusion changes in the operated hemispheres demonstrated an increase in perfusion in the MCA territory in 56 of 74 (75.7%) hemispheres 36.7 months after surgery. In MRA images, a reduction of typical moyamoya collaterals was found in 65 of 79 hemispheres (82.3%) after a mean of 37.2 months. CONCLUSION: Direct STA-MCA bypass is an effective therapy in Caucasian patients with hemodynamically compromised MA.

Tonsillotomy versus tonsillectomy on young children: 2 year post surgery follow-up.

ObjectivesTo study the long-term effect of tonsillotomy and tonsillectomy in young children after two years in comparison to the results after six months.MethodChildren, age 4-5 with Sleep Disordered Breathing (SDB) and tonsil hyperplasia, were randomized to TE (32) or TT (35). TT was performed ad modum Hultcrantz with radiofrequency technique (Ellman). An adenoidectomy with cold steel was performed in the same session for 80% of cases. The patients were assessed prior to surgery, at six and 24 months postoperatively. Effects of surgery were evaluated clinically, through questionnaire (general health/snoring/ENT-infections), Quality of Life (QoL), survey of pediatric obstructive sleep apnea with OSA-18, and children¿s behavior with the Child Behavior Checklist.ResultsAfter two years there was still no difference between the groups with respect to snoring and frequency or severity of upper airway infections. Both TT and TE had resulted in large improvement in short and long term QoL and behavior. Three TT-children and one TE child had been re-operated due to recurrence of obstructive problems, the TE-child and one of the TT-children with adenoidectomy and two of the TT-children with tonsillectomy. Three of the TT-children had tonsil tissue protruding slightly out of the tonsil pouch and twelve TE-children had small tonsil remnants within the tonsil pouches, but with no need for surgery.ConclusionYounger children have a small risk of symptom-recurrence requiring re-surgery within two years after TT. For the majority, the positive effect on snoring, infections, behavior and quality of life remain and is similar to TE.

Oral motor dysfunction in children with adenotonsillar hypertrophy--effects of surgery.

Adenotonsillar hypertrophy is associated with a wide range of problems. The enlargement causes obstructive symptoms and affects different functions such as chewing, swallowing, articulation, and voice. The objective of this study was to assess oral motor function in children with adenotonsillar hypertrophy using Nordic Orofacial Test-Screening (NOT-S) before and 6 months after surgery consisting of adenoidectomy combined with total or partial tonsil removal. A total of 67 children were assigned to either tonsillectomy (n=33) or partial tonsillectomy, 'tonsillotomy' (n=34); 76 controls were assessed with NOT-S and divided into a younger and older age group to match pre- and post-operated children. Most children in the study groups had oral motor problems prior to surgery including snoring, open mouth position, drooling, masticatory, and swallowing problems. Post-surgery oral motor function was equal to controls. Improvement was independent of surgery method.

Pediatric tonsillotomy with radiofrequency technique: long-term follow-up.

OBJECTIVES: Compare the effects of partial tonsil resection using a radiofrequency technique, tonsillotomy (TT), with total tonsillectomy (TE, blunt dissection) after 1 and 3 years. Compare frequency of relapse in snoring or infections and possible long-term changes in behavior among TT children with those in TE children. METHOD: Ninety-two children (5-15 yr) randomized to TT (n = 49) or TE (n = 43) groups because of obstructive problems with or without recurrent tonsillitis. One year after surgery, general health, degree of obstruction, history of infections, and behavior were investigated using two questionnaires, the Qu1 and Child Behavior Checklist, as well as an ENT visit. After 3 years, two questionnaires, Qu2 and the Glasgow Children's Benefit Inventory, were answered by mail. RESULTS: : After 1 year, both groups were in good health. The effect on snoring and total behavior was the same for both groups, and the rate of recurrence of infections was not higher in the TT group. After 3 years, two children in the TT group were tonsillectomized (4%, 2/49), one because of peritonsillitis and another because of increased snoring. Otherwise, no differences existed between the groups in general health, snoring, or number of infections. CONCLUSION: Removing only the protruding parts of the tonsils has the same beneficial long-term effect on obstructive symptoms and recurrent throat infections as complete TE in the majority of cases. The need for re-operation is low; therefore, it appears inadvisable to follow the current common practice of routinely removing the whole tonsil given its higher morbidity and risk for serious complications.