Adult hematopoietic progenitors are pluripotent in chimeric mice

18 pages, 7 figures.Embryonic stem cells (ESCs) and adult somatic cells, induced to pluripotency (iPSCs) by genetic manipulation, display high self-­‐renewal potential and the capacity to differentiate into multiple cell lineages. We asked whether there are in adult mammals natural stem cells that are pluripotent. We previously reported that normal adult mammalian bone marrow contains a sub-­‐population of CD34+ cells, that naturally expresses genes characteristic of ESCs and those required to generate iPSCs, but have a limited lifespan and do not form teratomas. In addition, these CD34+ cells spontaneously express, without genetic manipulation, genes characteristic of the three embryonic germ layers: i.e., ectodermal neural, mesodermal cardiac muscle, and endodermal pancreatic and intestinal lineage genes (Pessac, B, et al. 2011. Hematopoietic progenitors express embryonic stem cell and germ layer genes. Comptes Rendus Biologies 334: 300-­‐306). This suggested that these cells may be pluripotent. Here we have transplanted these CD34+ bone marrow stem cells from adult male C56Bl/6J ROSA mice, that carry two markers: the ß-­‐galactosidase gene and the male Y chromosome, into blastocysts of wildtype C57Bl/6J mice. These blastocysts develop normally and give rise to healthy adult chimeric mice. Each female ROSA chimeric mouse had a distinct pattern of male organs expressing ß-­‐galactosidase derived from each of the three embryonic germ layers: ectodermal brain, dorsal root ganglia and skin; mesodermal heart, bone and bone marrow; and endodermal pancreas, intestine, and liver. Thus, adult mammals still carry cells that appear to exhibit a developmental potential comparable to ESCs and iPSCs suggesting that CD34+ cells from adult bone marrow could be used for cell therapy

A Clinically Relevant Method of Analyzing Continuous Change in Robotic Upper Extremity Chronic Stroke Rehabilitation

Background. Robots designed for rehabilitation of the upper extremity after stroke facilitate high rates of repetition during practice of movements and record precise kinematic data, providing a method to investigate motor recovery profiles over time. Objective. To determine how motor recovery profiles during robotic interventions provide insight into improving clinical gains. Methods. A convenience sample (n = 22), from a larger randomized control trial, was taken of chronic stroke participants completing 12 sessions of arm therapy. One group received 60 minutes of robotic therapy (Robot only) and the other group received 45 minutes on the robot plus 15 minutes of translation-to-task practice (Robot + TTT). Movement time was assessed using the robot without powered assistance. Analyses (ANOVA, random coefficient modeling [RCM] with 2-term exponential function) were completed to investigate changes across the intervention, between sessions, and within a session. Results. Significant improvement (P < .05) in movement time across the intervention (pre vs post) was similar between the groups but there were group differences for changes between and within sessions (P < .05). The 2-term exponential function revealed a fast and slow component of learning that described performance across consecutive blocks. The RCM identified individuals who were above or below the marginal model. Conclusions. The expanded analyses indicated that changes across time can occur in different ways but achieve similar goals and may be influenced by individual factors such as initial movement time. These findings will guide decisions regarding treatment planning based on rates of motor relearning during upper extremity stroke robotic interventions

Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study

Background. Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin-oligodendrocyte-glycoprotein- (MOG-) 35–55 peptide. Analogues of RTL1000 induce T-cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic, C57BL/6, and SJL/J mice. Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS) subjects. Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2+ MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI) evaluations. Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2–60 mg doses of RTL1000. Doses ≥100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment. Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair

Quality indicators for multiple sclerosis

Determining whether persons with multiple sclerosis (MS) receive appropriate, comprehensive healthcare requires tools for measuring quality. The objective of this study was to develop quality indicators for the care of persons with MS. We used a modified version of the RAND/UCLA Appropriateness Method in a two-stage process to identify relevant MS care domains and to assess the validity of indicators within high-ranking care domains. Based on a literature review, interviews with persons with MS, and discussions with MS providers, 25 MS symptom domains and 14 general health domains of MS care were identified. A multidisciplinary panel of 15 stakeholders of MS care, including 4 persons with MS, rated these 39 domains in a two-round modified Delphi process. The research team performed an expanded literature review for 26 highly ranked domains to draft 86 MS care indicators. Through another two-round modified Delphi process, a second panel of 18 stakeholders rated these indicators using a nine-point response scale. Indicators with a median rating in the highest tertile were considered valid. Among the most highly rated MS care domains were appropriateness and timeliness of the diagnostic work-up, bladder dysfunction, cognition dysfunction, depression, disease-modifying agent usage, fatigue, integration of care, and spasticity. Of the 86 preliminary indicators, 76 were rated highly enough to meet predetermined thresholds for validity. Following a widely accepted methodology, we developed a comprehensive set of quality indicators for MS care that can be used to assess quality of care and guide the design of interventions to improve care among persons with MS

Tempo and Pattern of Avian Brain Size Evolution

Relative brain sizes in birds can rival those of primates, but large-scale patterns and drivers of avian brain evolution remain elusive. Here, we explore the evolution of the fundamental brain-body scaling relationship across the origin and evolution of birds. Using a comprehensive dataset sampling> 2,000 modern birds, fossil birds, and theropod dinosaurs, we infer patterns of brain-body co-variation in deep time. Our study confirms that no significant increase in relative brain size accompanied the trend toward miniaturization or evolution of flight during the theropod-bird transition. Critically, however, theropods and basal birds show weaker integration between brain size and body size, allowing for rapid changes in the brain-body relationship that set the stage for dramatic shifts in early crown birds. We infer that major shifts occurred rapidly in the aftermath of the Cretaceous-Paleogene mass extinction within Neoaves, in which multiple clades achieved higher relative brain sizes because of a reduction in body size. Parrots and corvids achieved the largest brains observed in birds via markedly different patterns. Parrots primarily reduced their body size, whereas corvids increased body and brain size simultaneously (with rates of brain size evolution outpacing rates of body size evolution). Collectively, these patterns suggest that an early adaptive radiation in brain size laid the foundation for subsequent selection and stabilization

Practice improvement requires more than guidelines and quality measures.

Increasing emphasis on improving health care quality has led to a variety of programs that require neurologists to be familiar with the concept of systematic quality improvement. While they vary in extent, these quality improvement programs and their attendant costs now have implications for physician payment and certification. In response to these factors, the American Academy of Neurology is establishing a clinical quality data registry. This article reviews evidence demonstrating the ability of quality improvement initiatives to improve care, the role of clinical quality data registries in the identification and mitigation of gaps in care, and the principles to be considered in development of registry-based quality improvement programs. It addresses the key question: Is the effort worthwhile

Introducing the Axon Registry: An opportunity to improve quality of neurologic care.

Clinical quality data registries are increasingly popular tools used by providers to improve the quality of clinical care and satisfy growing numbers of regulatory and reporting requirements. Specialty societies use registries to provide value to their members and guide improvements in care at the population level. In this article, we outline the rationale, structure, function, and challenges related to the American Academy of Neurology\u27s development of its own clinical quality data registry: the Axon Registry

The effect of repeated measurements using an upper extremity robot on healthy adults

We are expanding the use of the MIT-MANUS robotics to persons with impairments due exclusively to orthopedic disorders, with no neurological deficits. To understand the reliability of repeated measurements of the robotic tasks and the potential for registering changes due to learning is critical. Purposes of this study were to assess the learning effect of repeated exposure to robotic evaluations and to demonstrate the ability to detect a change in protocol in outcome measurements. Ten healthy, unimpaired subjects (mean age = 54.1 +/- 6.4 years) performed six repeated evaluations consisting of unconstrained reaching movements to targets and circle drawing (with and without a visual template) on the MITMANUS. Reaching outcomes were aiming error, mean and peak speed, movement smoothness and duration. Outcomes for circle drawing were axis ratio metric and shoulder- elbow joint angles correlation metric (was based on a two-link model of the human arm and calculated hand path during the motions). Repeated-measures ANOVA (p &lt; or = .05) determined if difference existed between the sessions. Intraclass correlations (R) were calculated. All variables were reliable, without learning across testing sessions. Intraclass correlation values were good to high (reaching, R &gt; or =.80; circle drawing, R &gt; or =.90). Robotic measurement ability to differentiate between similar but distinct tasks was demonstrated as measured by axis ratio metric (p &lt; .001) and joint correlation metric (p = .001). Outcome measures of the MIT-MANUS proved to be reliable yet sensitive to change in healthy adults without motor learning over the course of repeated measurement

Determinants of 4-aminopyridine sensitivity in a human brain kv1.4 k(1) channel: phenylalanine substitutions in leucine heptad repeat region stabilize channel closed

ABSTRACT The biophysical and pharmacological effects of individual phenylalanine-for-leucine (Phe-for-Leu) substitutions in the leucine heptad repeat region located at the cytosolic surface of the channel pore, on whole-cell K ϩ currents, were studied in cloned and mutated human brain Kvl.4 K ϩ channels (hKvl.4) transiently transfected into HeLa cells. Although L2 and L5 are not considered part of the 4-aminopyridine (4-AP) binding site, unlike the L4 heptad leucine, Phe substitutions at L2 (L464) or L5 (L485) increase 4-AP sensitivity by 400-fold, as seen previously in the L4F mutant channel The leucine heptad repeat region, which is a highly conserved feature in K ϩ channels spanning the S4ϪS5 linker and adjacent ends of the S4 and S5 segments at the cytosolic mouth of the ion translocation pore, plays a significant role in modulating the stability of channel open and closed state conformations