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.

NIH disease funding levels and burden of disease.

BACKGROUND: An analysis of NIH funding in 1996 found that the strongest predictor of funding, disability-adjusted life-years (DALYs), explained only 39% of the variance in funding. In 1998, Congress requested that the Institute of Medicine (IOM) evaluate priority-setting criteria for NIH funding; the IOM recommended greater consideration of disease burden. We examined whether the association between current burden and funding has changed since that time. METHODS: We analyzed public data on 2006 NIH funding for 29 common conditions. Measures of US disease burden in 2004 were obtained from the World Health Organization's Global Burden of Disease study and national databases. We assessed the relationship between disease burden and NIH funding dollars in univariate and multivariable log-linear models that evaluated all measures of disease burden. Sensitivity analyses examined associations with future US burden, current and future measures of world disease burden, and a newly standardized NIH accounting method. RESULTS: In univariate and multivariable analyses, disease-specific NIH funding levels increased with burden of disease measured in DALYs (p = 0.001), which accounted for 33% of funding level variation. No other factor predicted funding in multivariable models. Conditions receiving the most funding greater than expected based on disease burden were AIDS ($2474 M), diabetes mellitus ($390 M), and perinatal conditions ($297 M). Depression ($719 M), injuries ($691 M), and chronic obstructive pulmonary disease ($613 M) were the most underfunded. Results were similar using estimates of future US burden, current and future world disease burden, and alternate NIH accounting methods. CONCLUSIONS: Current levels of NIH disease-specific research funding correlate modestly with US disease burden, and correlation has not improved in the last decade.

Heterogeneous patterns of tissue injury in NARP syndrome.

Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual-spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss.

An intervention to teach medical students ankle reflex examination skills.

BACKGROUND: Methods of teaching neurologic examination skills are understudied compared with general physical examination skills. Eliciting an ankle reflex is an important element of a screening neurologic examination and directly drives further patient evaluation, but many students and physicians perceive this skill to be difficult; as a result, ankle reflex testing is frequently incorrectly performed or omitted entirely. METHODS: Twenty-two medical student volunteers of various levels of training took part in a blinded, randomized study of a brief intervention used to teach how best to elicit ankle reflexes. Standardized patients were used with quantification of ankle reflexes using electrodiagnostic techniques, providing an objective gold standard. RESULTS: Both the control and intervention groups improved over the course of the trial with mean change scores for correctness (maximum = 6) significantly increasing from 2.68 +/- 1.5 to 4.23 +/- 1.2 (P = 0.003) before and after the training sessions. However, there was no difference in change scores between students receiving the intervention and those in the control group in the entire cohort (P = 1.0) or by year. In a multivariate model, no significant difference in change score was associated with the intervention teaching session. CONCLUSIONS: Compared with the control session, the ankle reflex teaching intervention did not lead to significantly greater improvement in students' ability to master this difficult neurologic examination skill. This study demonstrates the feasibility of using a rigorous trial design to investigate methods of teaching students the neurologic examination. Further research is needed to define how best to teach these important skills.

Adaptive optics scanning laser ophthalmoscopy images in a family with the mitochondrial DNA T8993C mutation.

PURPOSE: This study was designed to assess the effect of mitochondrial DNA (mtDNA) mutation T8993C on cone structure in a family expressing neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome. METHODS: Five family members were studied, using clinical examination, nerve conduction studies, perimetry, optical coherence tomography (OCT) measures of central retinal thickness, and electroretinography. High-resolution images of cone structure using adaptive optics scanning laser ophthalmoscopy (AOSLO) were obtained in four subjects with stable fixation. Cone spacing was compared to 18 age-similar normal subjects and converted to z-scores at each location where unambiguous cones were identified. Tissue levels of T8993C mutant heteroplasmy in blood and hair follicles were quantified using real-time allele-refractory mutations system (ARMS) quantitative polymerase chain reaction (qPCR). RESULTS: Subjects expressing the T8993C mutation showed varying levels of disease severity. The subject with the lowest mutant load (42%-54%) showed no neurologic or retinal abnormalities. The remaining four subjects with over 77% mutant load all expressed severe neurologic and/or retinal abnormalities. AOSLO images revealed three patterns of cone spacing: pattern 1, normal; pattern 2, increased cone spacing within a contiguous cone mosaic; and pattern 3, patchy cone loss with increased cone spacing. Visual function was most severely affected in pattern 3. CONCLUSIONS: High levels of T8993C mutant load were associated with severe neurologic or visual dysfunction, while lower levels caused no detectable abnormalities. Visual function was better in patients with a contiguous and regular cone mosaic. Patients expressing high levels of the mtDNA T8993C mutation show abnormal cone structure, suggesting normal mitochondrial DNA is necessary for normal waveguiding by cones.

Influence of physician specialty on outcomes after acute ischemic stroke.

BACKGROUND: Specialist care has been shown to improve outcomes for several complex medical conditions. For patients with ischemic stroke, prior studies have suggested that admission to the care of neurologists is associated with better outcomes, but these studies may have incompletely controlled for confounding prognostic differences. OBJECTIVE: The objective of this study was to evaluate whether admission to the care of a neurologist is associated with improvement in outcomes of stroke patients after controlling for initial prognostic differences. DESIGN: This was a retrospective cohort study. SETTING: Participating in the study were 113 U.S. academic hospitals. PATIENTS: Demographic and clinical data for all ischemic stroke patients admitted through emergency departments from 1997 to 1999 were collected from an administrative database. MEASUREMENTS: In traditional analyses, we evaluated attending physician specialty as a predictor of in-hospital mortality. In grouped-treatment (GT) analyses, a method based on the instrumental variable approach that bypasses selection bias, the hospital rate of stroke admission to neurologists was used as the predictor. We used generalized estimating equations for all analyses, adjusting for demographics, urgency, comorbid illness severity, and treatment volume. RESULTS: Of 26,925 ischemic stroke patients, 60% were admitted to the care of neurologists. In univariate analysis, risk of in-hospital mortality in cases admitted to neurologists (4.6%) was lower than that for those admitted to generalists (9.5%; P < .001). Adjustment for individual-level characteristics did not alter the association (0.60 OR, 95% CI, 0.50-0.72; P < .001). However, no advantage to neurologist admission was demonstrated in GT analysis, with mortality rates similar at hospitals admitting different proportions of ischemic stroke cases to neurologists (1.02 OR, 95% CI, 0.79-1.30; P = .90). CONCLUSIONS: Differences in ischemic stroke outcomes between neurologists and generalists may be a result of differences in initial prognosis because outcomes are no better at hospitals that admit patients to the care of neurologists more frequently.

Preparing fourth-year medical students to teach during internship.

Interns are expected to teach medical students, yet there is little formal training in medical school to prepare them for this role. To enhance the teaching skills of our graduating students we initiated a 4-hour "teaching to teach" course as part of the end of the fourth-year curriculum. Course evaluations demonstrate that students strongly support this program (overall ratings 2000 to 2005: mean=4.4 [scale 1 to 5], n=224). When 2004 course participants were surveyed during the last month of their internship, 84%"agree" or "strongly agree" with the statement: "The teaching to teach course helped prepare me for my role as a teacher during internship" (2005: mean 4.2 [scale 1 to 5], n=45, response rate 60%). A course preparing fourth-year students to teach during internship is both feasible and reproducible, with a minimal commitment of faculty and resident time. Participants identify it as an important addition to their education and as useful during internship.