Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Descriptive epidemiology and short-term outcomes of heart failure hospitalisation in rural Haiti.

OBJECTIVE: There is increasing attention to cardiovascular diseases in low-income countries. However, little is known about heart failure (HF) in rural areas, where most of the populations in low-income countries live. We studied HF epidemiology, care delivery and outcomes in rural Haiti. METHODS: Among adults admitted with HF to a rural Haitian tertiary care hospital during a 12-month period (2013-2014), we studied the clinical characteristics and short-term outcomes including length of stay, inhospital death and outpatient follow-up rates. RESULTS: HF accounted for 392/1049 (37%) admissions involving 311 individuals; over half (60%) were women. Mean age was 58.8 (SD 16.2) years for men and 48.3 (SD 18.8) years for women; 76 (41%) women were <40 years of age. Median length of stay was 10 days (first and second quartiles 7, 17), and inhospital mortality was 12% (n=37). Ninety nine (36%) of the 274 who survived their primary hospitalisation followed-up at the hospital's outpatient clinic, and 18 (6.6%) were readmitted to the same hospital within 30 days postdischarge. Decreased known follow-up (p<0.01) and readmissions (p=0.03) were associated with increased distance between patient residence and hospital. Among the one-quarter (81) patients with echocardiograms, causes of HF included: non-ischaemic cardiomyopathy (64%), right HF (12%), hypertensive heart disease (7%) and rheumatic heart disease (5%). One-half of the women with cardiomyopathy by echocardiogram had peripartum cardiomyopathy. CONCLUSIONS: HF is a common cause of hospitalisation in rural Haiti. Among diagnosed patients, HF is overwhelming due to non-atherosclerotic heart disease and particularly affects young adults. Implementing effective systems to improve HF diagnosis and linkage to essential outpatient care is needed to reduce long-term morbidity and mortality.