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Biomedical subjects

Robert H Miller

Publications and source records attributed to Robert H Miller.

At least 37 records · Page 2Linked to original sources

Netrin 1 mediates spinal cord oligodendrocyte precursor dispersal.

In spinal cord, oligodendrocyte precursors that give rise to myelin-forming cells originate in a restricted domain of the ventral ventricular zone. During development, these cells migrate widely throughout the spinal cord. Netrin 1 is expressed at the ventral ventricular zone during oligodendrocyte precursors emigration, and, in vitro, netrin 1 acts as chemorepellent and antagonizes platelet-derived growth factor (PDGF) chemoattraction. Oligodendrocyte precursors express the netrin receptors DCC and UNC5 and function-blocking anti-DCC antibody inhibits chemorepulsion of ventral spinal cord explants and netrin-secreting cells. In spinal cord slice preparations, addition of function-blocking anti-DCC antibody or netrin 1 dramatically inhibits oligodendrocyte precursor migration from the ventral ventricular zone. These data indicate the initial dispersal of oligodendrocyte precursors from their localized origin is guided by a chemorepellent response to netrin 1.

Animals↗

Sonic hedgehog-induced neural precursor proliferation after adult rodent spinal cord injury.

OBJECT: The glycoprotein molecule sonic hedgehog (Shh) has been shown to play a critical role in neuraxial development. To assess its role in the repair of demyelination following spinal cord injury (SCI), escalating doses of Shh were injected into demyelinated lesions in adult rat spinal cords. METHODS: Twenty-seven adult rats underwent thoracic laminectomy and chemical demyelination of the spinal cord dorsal columns without neurological deficit A subset of 20 rats was treated after 3 days by direct injection of Shh at two different doses. Rats were killed at 7 or 21 days after SCI, and tissue samples underwent immediate fixation or were placed into cell culture. Diffuse cellular proliferative responses throughout the gray and white matter were observed in up to 70% of Shh-treated rats. Proliferation around the central canal, believed to be derived from the ventricular ependyma consistent with neuronal stem cell induction, was demonstrated in up to 60% of the treated rats. No significant proliferation in these areas was detected in control rats. Dorsal areas of nestin-positive cells were also observed in 70% of rats treated with high doses of Shh, and these observations were reproduced in cell culture as well as in cultures of dorsal spinal cord explants. Cell counts revealed significant increases in the percentage of oligodendrocyte precursors and neurons in treated compared with control rats. CONCLUSIONS: Exogenous Shh administration promotes nestin-positive cell proliferation after SCI in adult rodents. These cells are believed to be derived from neural precursor cells. The populations of oligodendrocyte precursors and neurons were likewise increased in Shh-treated rats, suggesting that these cells may be derived from neural stem cells.

Animals↗

Electronic prescribing: ready for prime time?

Escalating drug expenditures and the prevalence of medication errors have prompted calls for drug cost control and quality improvement. E-prescribing promises to address these concerns. This study aims to describe the benefits and costs of eRx as assessed by key industry stakeholders, identify the components of a needed electronic prescribing infrastructure and the barriers to its completion, and identify potential public and private policies and initiatives that could encourage the development of an EPI and hasten eRx adoption among stakeholders.

Clinical Pharmacy Information Systems↗

Oligodendrogenesis is differentially regulated in gray and white matter of jimpy mice.

The factors that regulate oligodendrogenesis have been studied extensively in optic nerve, where oligodendrocyte production and myelination quickly follow colonization of the nerve by progenitor cells. In contrast, oligodendrocyte production in the cerebral cortex begins approximately 1 week after progenitor cell colonization and continues for 3-4 weeks. This and other observations raise the possibility that oligodendrogenesis is regulated by different mechanisms in white and gray matter. The present study examined oligodendrocyte production in the developing cerebral cortex of jimpy (jp) and jimpy(msd) (msd) mice, which exhibit hypomyelination and oligodendrocyte death due to mutations in and toxic accumulations of proteolipid protein, the major structural protein of CNS myelin. Proliferation of oligodendrocyte progenitors and production of myelinating oligodendrocytes was reduced in jp cerebral cortex when compared to wild-type (wt) and msd mice. The incidence of oligodendrocyte cell death was similar in jp and msd cortex, but total dying oligodendrocytes were greater in msd. We confirm previous reports of increased oligodendrocyte production in white matter of both jp and msd mice. The jp mutation, therefore, reduces oligodendrocyte production in cerebral cortex but not in white matter. These data provide additional evidence that oligodendrogenesis is differentially regulated in white matter and gray matter and implicate PLP/DM20 as a modulator of these differences.

Animals↗

The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration.

Spinal cord oligodendrocytes originate in the ventricular zone and subsequently migrate to white matter, stop, proliferate, and differentiate. Here we demonstrate a role for the chemokine CXCL1 and its receptor CXCR2 in patterning the developing spinal cord. Signaling through CXCR2, CXCL1 inhibited oligodendrocyte precursor migration. The migrational arrest was rapid, reversible, concentration dependent, and reflected enhanced cell/substrate interactions. White matter expression of CXCL1 was temporo-spatially regulated. Developing CXCR2 null spinal cords contained reduced oligodendrocytes, abnormally concentrated at the periphery. In slice preparations, CXCL1 inhibited embryonic oligodendrocyte precursor migration, and widespread dispersal of postnatal precursors occurred in the absence of CXCR2 signaling. These data suggest that population of presumptive white matter by oligodendrocyte precursors is dependent on localized expression of CXCL1.

Animals↗

Extracellular and intracellular regulation of oligodendrocyte development: roles of Sonic hedgehog and expression of E proteins.

Recent advances in understanding oligodendrocyte development have revealed the importance of both extra- and intracellular molecules in regulating the induction, survival, and proliferation of early oligodendrocyte progenitors. The signaling molecule Sonic hedgehog (Shh) is critical for normal development of oligodendrocytes, although the precise influences of Shh on cells of the oligodendrocyte lineage are unclear. The present study shows that Shh increased the number of oligodendrocyte precursors in both pure cultures of oligodendrocyte precursors and mixed cultures from embryonic rat spinal cord. In pure precursor cultures Shh increased cell survival. In mixed cultures, Shh increased both the survival and proliferation of oligodendrocyte precursors in a concentration dependent manner. One intracellular consequence of exposure to Shh is the activation of transcription factors in oligodendrocyte lineage cells, which are critical for oligodendrocyte development, helix-loop-helix (HLH) transcription factors, Olig1 and 2. In many cases, HLH proteins such as Olig1 and Olig2 heterodimerize with other HLH proteins, such as members of the E subfamily, which are critical regulators of cell proliferation and differentiation. Immature (A2B5(+)) and more mature (O4(+)) rat oligodendrocyte precursors in dissociated cell culture expressed Olig1 as well as E proteins, HEB and E2A. Similarly, cells bearing the morphology of oligodendrocyte precursors expressed both Olig1 and HEB or E2A. We propose that E2A and/or HEB, possibly in combination with Olig1 and 2, are critical components of oligodendrogenesis and may regulate cell survival, proliferation, and fate decisions in the oligodendrocyte lineage.

Animals↗

Glial cell migration directed by axon guidance cues.

Widespread myelination by oligodendrocytes is essential for the normal functioning of the vertebrate CNS. Oligodendrocyte precursors initially arise in restricted regions of the neuroepithelium and migrate relatively long distances to their final destinations. The signals that guide this migration have remained poorly understood, but recent studies suggest that glial precursors use similar molecular cues to those that guide axons through the complex terrain of the developing CNS. For example, in the developing optic nerve, glial-precursor migration from the brain towards the retina is guided by netrin-1 and semaphorin 3a. These studies suggest a novel mechanism governing glial precursor migration and provide new insights into development and the potential to direct CNS injury repair.

Animals↗

Regulation of oligodendrocyte development in the vertebrate CNS.

The vertebrate central nervous system (CNS) contains two major classes of macroglial cells, oligodendrocytes and astrocytes. Oligodendrocytes are responsible for the formation of myelin in the central nervous system, while the functions of astrocytes are more diverse and less well established. Recent studies have provided new insights into when, where and how these different classes of cell arise during CNS development. The founder cells of the oligodendrocyte lineage initially arise in distinct regions of the ventricular zone during early development as the result of local signals including sonic hedgehog. In the spinal cord, oligodendrocyte precursors appear to share a developmental lineage with motor neurons, although they may also develop from restricted glial precursors. Immature oligodendrocyte precursors are highly migratory. They migrate from their site of origin to developing white matter tracts using a variety of guidance cues including diffusible chemorepellents. The majority of oligodendrocyte precursor proliferation occurs in developing white matter as a result of the local expression of mitogenic signals. Oligodendrocyte precursor cell proliferation is regulated by a number of distinct growth factors that act at distinct stages in the lineage and whose activity is modulated by synergy with other molecules including chemokines. The final matching of oligodendrocyte and axon number is accomplished through a combination of local regulation of cell proliferation, differentiation and cell death. Not all oligodendrocyte precursors differentiate during development, and the adult CNS contains a significant population of precursors. Understanding the regulation of oligodendrogenesis will facilitate the use of these endogenous precursors to enhance repair in a variety of pathological conditions.

Animals↗

Efforts to improve patient safety in large, capitated medical groups: description and conceptual model.

Medical care should be safer. Inpatient problems and solutions have received the most attention; this outpatient qualitative case study addresses a gap in knowledge. We describe safety improvements among large physician groups, model the key influences on their behavior, and identify beneficial public and private policies. All groups were trying to reduce medical injury, which was part of the sample design. The most commonly targeted problems are those that are similar across groups: shortcomings in diagnosis, abnormal tests follow-up, scope of practice and referral patterns, and continuity of care. Medical group innovators vary greatly, however, in implementation of improvements, that is, in the extent to which they implement process changes that identify events/problems, analyze and track incidents, decide how to change clinical and administrative practices, and monitor impacts of the changes. Our conceptual model identifies key determinants: (1) demand for safety comes from external factors: legal, market, and professional; (2) organizational responses depend on internal factors: group size, scope, and integration; leadership and governance; professional culture; information-system assets; and financial and intellectual capital. Further, safety is an aspect of quality (the same tools, decision making, interventions, and monitoring apply), and safety management benefits from prior efficiency management (similar skills and culture of innovation). Observed variation in even simple safeguards shows that existing safety incentives are too weak. Our model suggests that the biggest improvement would come from boosting the demand for quality and safety from both private and public larger group purchasers. Current policy relies too much on litigation and discipline, which have sometimes helped, but not solved, problems because they are inefficient, tend to drive needed information underground, and complicate needed cultural change. Patients' safety demand is also weak for want of information and market power. Big purchasers' demands, however, quickly influence the internal environment of medical groups, helping managers advance quality safety toward the top of groups' congested decision-making "queues."

Ambulatory Care↗

Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cords of adult rats after contusion.

BACKGROUND CONTEXT: A substantial cause of neurological disability in spinal cord injury is oligodendrocyte death leading to demyelination and axonal degeneration. Rescuing oligodendrocytes and preserving myelin is expected to result in significant improvement in functional outcome after spinal cord injury. Although previous investigators have used cellular transplantation of xenografted pluripotent embryonic stem cells and observed improved functional outcome, these transplants have required steroid administration and only a minority of these cells develop into oligodendrocytes. PURPOSE: The objective of the present study was to determine whether allografts of oligodendrocyte precursors transplanted into an area of incomplete spinal cord contusion would improve behavioral and electrophysiological measures of spinal cord function. Additional treatment incorporated the use of the glycoprotein molecule Sonic hedgehog (Shh), which has been shown to play a critical role in oligodendroglial development and induce proliferation of endogenous neural precursors after spinal cord injury. SETTING: Laboratory study. METHODS: Moderate spinal cord contusion injury was produced in 39 adult rats at T9-T10. Ten animals died during the course of the study. Nine rats served as contusion controls (Group 1). Six rats were treated with oligodendrocyte precursor transplantation 5 days after injury (Group 2). The transplanted cells were isolated from newborn rat pups using immunopanning techniques. Another eight rats received an injection of recombinant Shh along with the oligodendrocyte precursors (Group 3), while six more rats were treated with Shh alone (Group 4). Eight additional rats received only T9 laminectomies to serve as noninjured controls (Group 0). Animals were followed for 28 days. RESULTS: After an initial complete hindlimb paralysis, rats of all groups receiving a contusive injury recovered substantial function within 1 week. By 28 days, rats in Groups 2 and 3 scored 4.7 and 5.8 points better on the Basso, Beattie, Bresnahan (BBB) open field locomotor score than rats in group 1 (Groups 2 and 3=18.2 and 19.4 points, respectively, after 28 days vs. Group 1=13.6 points; p=.015). Rats in Group 4 scored no better than those in Group 1 (BBB=16.4). Motor evoked potential (MEP) recordings revealed a strong trend towards significant improvement in latency measurements in all treatment groups compared with controls at 28 days, although three animals in Group 1 and two animals in Group 3 were not recordable. Histological examination demonstrated significantly more spared white matter in the same groups that correlated with the improvements in BBB scores and MEP latencies. Immunohistochemical analysis showed the survival, proliferation and migration of the transplanted cells, as well as the induction of proliferating endogenous neural precursor cells in animals treated with Shh. CONCLUSIONS: These findings suggest that the transplantation of oligodendrocyte precursors may improve axonal conduction and spinal cord function in the injured spinal cord. The benefits seem more pronounced with the addition of Shh, and the addition of Shh alone results in the proliferation of an endogenous population of neural precursor cells.

Animals↗

Control of astrocyte migration in the developing cerebral cortex.

Development of the vertebrate central nervous system is characterized by significant long distance cell migration. While the radial migration of neuronal precursors to their final location is well established the migration of glial cells and their precursors is less well understood. To define the pathways of migration and dissect the cell and molecular mechanisms mediating such migration requires the development of appropriate models. Here we show that purified neonatal astrocytes injected into organotypic slice cultures of developing cerebral cortex migrate in defined patterns depending on where they are placed within the tissue. Injection into gray matter resulted in radially oriented migration either towards the pial or ventricular surface. By contrast injection into developing white matter resulted in largely longitudinal migration along developing axon tracts. While the cytoarchitecture of the tissue influenced the pattern of migration, the extent of migration appeared to be regulated primarily by the age of the host tissue. Homochronic injections performed prior to postnatal day 4 resulted in extensive migration while after day 7 migration was relatively limited. Heterochronic injections indicated that while astrocytes within the 1st postnatal week retained the capacity to migrate extensively, older tissue failed to support extensive migration of either young or old astrocytes. These data suggest the existence of distinct migrational cues in the CNS and that environmental, not cell intrinsic properties primarily regulate astrocyte migration through the developing cortex.

Aging↗

HMO plan performance update: an analysis of the literature, 1997-2001.

This paper synthesizes results from peer-reviewed literature published from 1997 to mid-2001, on various dimensions of health maintenance organization (HMO) plan performance. Results from seventy-nine studies suggest that both types of plans provide roughly comparable quality of care, while HMOs lower use of hospital and other expensive resources somewhat. At the same time, HMO enrollees report worse results on many measures of access to care and lower levels of satisfaction, compared with non-HMO enrollees. Quality-of-care results in particular are heterogeneous, which suggests that quality is not uniform--that it varies widely among providers, plans (HMO and non-HMO), and geographic areas.

Cost Control↗

Physicians' use of electronic medical records: barriers and solutions.

The electronic medical record (EMR) is an enabling technology that allows physician practices to pursue more powerful quality improvement programs than is possible with paper-based records. However, achieving quality improvement through EMR use is neither low-cost nor easy. Based on a qualitative study of physician practices that had implemented an EMR, we found that quality improvement depends heavily on physicians' use of the EMR-and not paper-for most of their daily tasks. We identified key barriers to physicians' use of EMRs. We then suggest policy interventions to overcome these barriers, including providing work/practice support systems, improving electronic clinical data exchange, and providing financial rewards for quality improvement.

Attitude to Computers↗

The value of electronic health records in solo or small group practices.

We conducted case studies of fourteen solo or small-group primary care practices using electronic health record (EHR) software from two vendors. Initial EHR costs averaged $44,000 per full-time-equivalent (FTE) provider, and ongoing costs averaged $8,500 per provider per year. The average practice paid for its EHR costs in 2.5 years and profited handsomely after that; however, some practices could not cover costs quickly, most providers spent more time at work initially, and some practices experienced substantial financial risks. Policies should be designed to provide incentives and support services to help practices improve the quality of their care by using EHRs.

Cost-Benefit Analysis↗

The value of electronic health records in community health centers: policy implications.

This paper analyzes the costs and benefits of electronic health records (EHRs) in six community health centers (CHCs) that serve disadvantaged patients. EHR-related benefits for most study CHCs did not pay for ongoing EHR costs, yet quality improvement (QI) was substantial. Compared to private practices, CHCs cannot use EHRs to increase visit coding levels and revenues, yet they likely use EHRs more aggressively for QI, which raises equity questions. The evidence suggests that policies are needed that help CHCs to afford EHRs and produce more EHR-related QI gains, including through grants and QI performance rewards.

Ambulatory Care Information Systems↗