Cardiac and Respiratory Complications of Necrotizing Autoimmune Myopathy.

OBJECTIVE: To characterize the cardiorespiratory abnormalities in patients with necrotizing autoimmune myopathy (NAM). PATIENTS AND METHODS: Cardiopulmonary features of patients with NAM evaluated in our neuromuscular clinic (January 1, 2004, to September 20, 2018) were reviewed retrospectively with respect to autoantibody status and history of cardiac disease. Clinical characteristics and laboratory findings were compared among patient subgroups. RESULTS: We identified 109 patients with NAM: 36 anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody (anti-HMGCR Ab)-positive, 18 anti-signal recognition particle antibody (anti-SRP Ab)-positive (3 dual anti-HMGCR/anti-SRP Ab-positive), and 58 seronegative. Median age at diagnosis was 60 years (range, 18-86 years). Forty-three patients had dyspnea at presentation and 32 patients had preexisting risk for cardiac disease (10 coronary artery disease and 28 hypertension). The electrocardiogram was abnormal in 55 of 86 patients (33 without cardiac risk factors), including prolonged corrected QT interval (QTc) (n=31), conduction blocks (n=19), and atrial or ventricular ectopic beats (n=10). Echocardiography was abnormal in 34 of 72 patients, including 19 of 45 without preexisting cardiac disease risks. Echocardiographic abnormalities included left ventricular diastolic dysfunction (n=31) and systolic dysfunction (n=8). The left ventricular diastolic dysfunction improved in 4 of 11 patients after treatment. Pulmonary function testing showed changes suggestive of neuromuscular respiratory muscle weakness in 51 of 66 patients and reduced carbon monoxide diffusing capacity in 11 of 35 patients. However, only 6 patients had radiographic evidence of interstitial lung disease (2 anti-HMGCR Ab-positive and 4 seronegative). Overnight oximetry revealed desaturations in 24 of 38 patients. Six patients required mechanical ventilation and 7 required noninvasive ventilatory support. CONCLUSION: Most patients with NAM exhibited cardiac and respiratory muscle dysfunction. Immunotherapy can improve echocardiographic abnormalities. Interstitial lung disease was rarely identified. Formal evaluation of cardiac and respiratory status should be integral in assessment of patients with NAM.

High Percentage of Evanescent Red Cell Antibodies in Patients with Sickle Cell Disease Highlights Need for a National Antibody Database.

OBJECTIVES: Alloantibody formation secondary to transfusion in patients with sickle cell disease (SCD) is a well-known phenomenon. Pretransfusion testing (eg, "antibody screening") protects patients from receiving incompatible red blood cell transfusions. Because alloantibodies have a tendency to evanesce (ie, become undetectable over time), however, this phenomenon puts patients at risk of a delayed hemolytic transfusion reaction or even acute hemolysis. METHODS: We evaluated the records of 71 patients with SCD with alloantibodies detected during a 2-year period to describe their most common specificities and their rate of evanescence. RESULTS: We found that 81% of patients had at least one antibody that was undetectable during the study period; therefore, if patients were transfused with antigen-positive units at a facility that was unaware of their antibody history, life-threatening hemolysis could develop. CONCLUSIONS: Evanescence is a real risk for patients with SCD, and national/regional databases of alloantibodies should be considered a priority.

DNA methylation regulates associative reward learning.

Reward-related memories are essential for adaptive behavior and evolutionary fitness, but they are also a core component of maladaptive brain diseases such as addiction. Reward learning requires dopamine neurons located in the ventral tegmental area (VTA), which encode relationships between predictive cues and future rewards. Recent evidence suggests that epigenetic mechanisms, including DNA methylation, are essential regulators of neuronal plasticity and experience-driven behavioral change. However, the role of epigenetic mechanisms in reward learning is poorly understood. Here we show that the formation of reward-related associative memories in rats upregulates key plasticity genes in the VTA, which are correlated with memory strength and associated with gene-specific changes in DNA methylation. Moreover, DNA methylation in the VTA is required for the formation of stimulus-reward associations. These results provide the first evidence that that activity-dependent methylation and demethylation of DNA is an essential substrate for the behavioral and neuronal plasticity driven by reward-related experiences.