Background—: Sarcoplasmic reticulum (SR) Ca ²⁺ leak through ryanodine receptor type 2 (RyR2) dysfunction is of major pathophysiological relevance in human heart failure (HF); however, mechanisms underlying progressive RyR2 dysregulation from cardiac hypertrophy to HF are still controversial. Methods and Results—: We investigated healthy control myocardium (n=5) and myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In hypertrophy, Ca ²⁺ /calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both phosphorylated RyR2 at levels that were not different from healthy myocardium. Accordingly, inhibitors of these kinases reduced the SR Ca ²⁺ leak. In HF, however, the SR Ca ²⁺ leak was nearly doubled compared with hypertrophy, which led to reduced systolic Ca ²⁺ transients, a depletion of SR Ca ²⁺ storage and elevated diastolic Ca ²⁺ levels. This was accompanied by a significantly increased CaMKII-dependent phosphorylation of RyR2. In contrast, PKA-dependent RyR2 phosphorylation was not increased in HF and was independent of previous β-blocker treatment. In HF, CaMKII inhibition but not inhibition of PKA yielded a reduction of the SR Ca ²⁺ leak. Moreover, PKA inhibition further reduced SR Ca ²⁺ load and systolic Ca ²⁺ transients. Conclusions—: In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca ²⁺ leak. In the transition from hypertrophy to HF, the diastolic Ca ²⁺ leak increases and disturbed Ca ²⁺ cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction.

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease. Over time, symptoms accumulate leading to increased disability of patients. The objective of this article is to analyze the prevalence of symptoms and symptomatic treatment patterns in a nationwide MS registry. Data sets from 35,755 patients were analyzed. More than two-thirds of patients were women with a mean age of 46.1 (±12.8) years. Median Expanded Disability Status Score (EDSS) was 3.0. The most frequently reported symptoms were fatigue, spasticity, and voiding disorders. In patients with short disease duration, fatigue was reported most frequently. Symptomatic treatment was most common for spasticity and depression, whereas fatigue was treated only in a third of affected patients. Almost a fifth of patients with EDSS ⩽ 3.5 and neuropsychological symptoms had retired from work. Whereas treatment for spasticity and depression is common in our cohort, sexual dysfunction, dysphagia, cognitive dysfunction, and fatigue are treated to a far lesser extent. The need for psychological support, physical, and occupational therapy has to be recognized as neuropsychological symptoms have a great impact on retirement at an early stage. Overall symptomatic treatment rates for the most common symptoms have increased over the last years (p < 0.001).

Objective: Study aims were to determine the frequency of highly active disease in pediatric multiple sclerosis (MS), the response to natalizumab (NTZ) and fingolimod (FTY) treatment, and the impact of current treatment modalities on the clinical course. Methods: Retrospective single-center study in the German Center for MS in Childhood and Adolescence. Results: Of 144 patients with first MS manifestation between 2011 and 2015, 41.6% fulfilled the criteria for highly active MS. In total, 55 patients treated with NTZ and 23 with FTY demonstrated a significant reduction in relapse rate (NTZ: 95.2%, FTY: 75%), new T2 lesions (NTZ: 97%, FTY: 81%), and contrast-enhancing lesions (NTZ: 97%, FTY: 93%). However, seven patients switched from NTZ to FTY experienced an increase in disease activity. Comparing pediatric MS patients treated in 2005 with those treated in 2015 showed a 46% reduction in relapse rate and a 44% reduction in mean Expanded Disability Status Scale (EDSS). Conclusion: The rate of highly active disease among pediatric MS patients is high; more than 40% in our cohort. Response to NTZ and FTY treatment is similar if not better than observed in adults. Current treatment modalities including earlier treatment initiation and the introduction of NTZ and FTY have significantly improved the clinical course of pediatric MS.

Quiz Ref ID Apheresis therapies, including plasma exchange (PLEX) and immunoadsorption (IA), are used to treat steroid-unresponsive multiple sclerosis (MS) relapses.¹ Although the percentage of steroid-unresponsive cases is fairly low at 5%, PLEX and IA are important rescue therapies with response rates of 40% to 90%.^2-6 The mechanism of action is assumed to be the removal of disease-causing agents such as antibodies and autoantibodies, immune complexes, and cytokines.^7-9 As apheresis therapies are associated with potentially severe risks such as infections,¹⁰ predictors of treatment response are needed.