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Biomedical subjects

John W McDonald

Publications and source records attributed to John W McDonald.

At least 19 recordsLinked to original sources
PubMed2006

Delivery of neurotrophin-3 from fibrin enhances neuronal fiber sprouting after spinal cord injury.

Neurotrophins have been shown to promote axonal growth and regeneration after spinal cord injury. The therapeutic utility of neurotrophins may be enhanced by using a controlled delivery system to increase the duration of neurotrophin availability following injury. Such a delivery system can be incorporated into a bioactive scaffold to serve as a physical bridge for regeneration. This study assessed the effect of controlled delivery of neurotrophin-3 (NT-3) from fibrin scaffolds implanted in spinal cord lesions immediately following 2-mm ablation injury in adult rats. Nine days after injury, fibrin scaffolds containing the delivery system and NT-3 (1000 ng/mL) elicited more robust neuronal fiber growth into the lesion than did control scaffolds or saline (1.5- to 3-fold increase). Implantation of fibrin scaffolds resulted in a dramatic reduction of glial scar formation at the white matter border of the lesion. Hindlimb motor function of treated animals did not improve relative to controls at 12 weeks post-injury. Thus, controlled delivery of NT-3 from fibrin scaffolds enhanced the initial regenerative response by increasing neuronal fiber sprouting and cell migration into the lesion, while functional motor recovery was not observed in this model.

Animals↗
PubMed2006

Gap junctions and connexon hemichannels in human embryonic stem cells.

Intercellular communication via gap junctions is thought to play an important role in embryonic cell survival and differentiation. Classical studies demonstrated both dye and electrical coupling of cells in the inner cell mass of mouse embryos, as well as the development of restrictions against coupling between cells of the inner cell mass and surrounding trophectoderm. Here we demonstrate extensive gap junctional communication between human embryonic stem (ES) cells, the pluripotent cells isolated from the inner cell mass of preimplantation blastocysts. Human ES cells maintained in vitro expressed RNA for 18 of the 20 known connexins; only connexin 40.1 (Cx40.1) and Cx50 were not detected by reverse transcription-polymerase chain reaction. Cx40, Cx43, and Cx45 were visualized by immunofluorescence at points of contact between adjacent cells. Electron microscopy confirmed that neighboring cells formed zones of tight membrane apposition characteristic of gap junctions. Fluorescent dye injections demonstrated extensive coupling within human ES cell colonies growing on mouse embryonic fibroblast (MEF) feeder cells, whereas dye coupling between human ES cells and adjacent MEFs was extremely rare. Physiological recordings demonstrated electrical and dye coupling between human ES cells in feeder-free monolayers and between isolated human ES cell pairs. Octanol, 18-alpha-glycyrrhetinic acid, and arylaminobenzoates inhibited transjunctional currents. Dye uptake studies on human ES cell monolayers and recordings from solitary human ES cells gave evidence for the surface expression of connexon hemichannels. Human ES cells provide a unique system for the study of human connexin proteins and their potential functions in cellular differentiation and the maintenance of pluripotency.

Animals↗
PubMed2006

The prevalence of concern about weight loss and change in eating habits in people with advanced cancer.

Weight loss and anorexia are commonly reported symptoms in people with advanced cancer. Little is known about patient experience of these phenomena, in particular whether they find them of concern. In this study, the prevalence of weight loss and eating-related concern was evaluated in patients with advanced cancer receiving specialist palliative homecare. The survey was a component of a larger study exploring the potential for helping patients and their families live with weight loss and change in eating habits. Patients were under the care of two specialist palliative homecare teams in the south of England in 2003. The questionnaire was distributed to the total eligible caseload of 233 patients with advanced cancer. The response rate was 85%. More than three-quarters of the 199 patients who returned the questionnaires reported weight loss (79%) and/or eating less (76%). Excluding the 32 patients (16%) who had sought help from a family member or friend to complete the questionnaires, more than half (52%) reported concern about weight loss and/or eating. Concern about weight loss or eating was found irrespective of proximity to death. Weight loss and eating-related concerns are commonly experienced by people with advanced cancer receiving palliative homecare. Further work is needed to establish if concerns are amenable to interventions that translate into meaningful outcomes for patients and their families.

Adult↗
PubMed2005

Generating chimeric spinal cord: a novel model for transplantable oligodendrocyte progenitors derived from embryonic stem cells.

OBJECT: To identify and evaluate stem cell-derived oligodendrocytes obtained for cell transplantation therapies, the authors developed a novel model to examine single, adult oligodendrocytes in situ. METHODS: Green fluorescent protein-expressing, mouse embryonic stem cells (ESCs) were neural induced and additionally staged in an oligosphere preparatory step for high-yield derivation of oligodendrocyte progenitors. These transplantable, induced progenitors were injected into postnatal Day 2 rat pups, in which spinal cord sections were then examined at 3 and 9 weeks posttransplantation. CONCLUSIONS: Transplanted oligosphere ESCs survived and integrated anatomically into postnatal and adult white matter, generating targeted regions of chimeric spinal cord. A simple model for identifying adult oligodendrocytes in situ is presented, which is suitable for use in further studies examining functional myelination and derivation of oligodendrocytes from genetically engineered ESC lines, including human ESCs. Results from the model presented here demonstrate a unique method for examining transplantable oligodendrocyte progenitors derived from ESCs for repair of white matter disease.

Animals↗
PubMed2005

Significant difference in knowledge between English and Danish psychiatrists.

PURPOSE: The purpose of the study was to investigate if differences in levels of knowledge existed between Danish and English training and specialist psychiatrists. This is important in the context of the free (and growing) movement of the medical workforce across European Union (EU) countries' borders. METHODS: A complete balanced two-way factorial study design was used. Ten training and ten specialist psychiatrists were recruited in each country from reputable, university hospitals. They answered 50 multiple choice questions (MCQs), translated into the appropriate language, consisting of four subcategories of questions: psychology (15 MCQs), psychopharmacology (10 MCQs), neuroscience (five MCQs) and psychopathology (20 MCQs). No memory or other types of aids were allowed at the knowledge test. A two-way analysis of variance was used to analyse the total knowledge score (number of correct answers) and the component subscores. Levene's test of equality of error variances was used to test for variance homogeneity. RESULTS: There were significant differences in total knowledge and psychology knowledge by country and level of training. UK doctors scored 3.10 points higher than Danish doctors, with 95% confidence interval (0.97, 5.23). The knowledge of the specialists was also significantly superior to that of the training psychiatrists, with 2.30 higher score, 95% confidence interval (0.17, 4.43). In the sub-categories only the scores in the psychology section were significantly different. UK doctors scored 2.30 higher than Danish doctors, with 95% confidence interval (1.15, 3.45). Specialists scored 1.20 higher than non-specialists with 95% confidence interval (0.05, 2.35). CONCLUSIONS: The results indicate that there is a significant difference in level of knowledge between psychiatrists in these two EU-countries, England and Denmark. This difference seemed to be chiefly the result of different knowledge of psychology. The disparity could be a result of the fundamentally different post-graduate training system in psychiatry in the two countries. Surprisingly, the differences in total knowledge and psychology knowledge between countries were larger than the differences between levels of training. The difference in knowledge is worrying taking into consideration that there is free movement of the workforce, including doctors, across the EU. The results here need further confirmation in future studies with greater numbers, more countries involved and perhaps additional measurements to MCQs.

Culture↗
PubMed2005

Multi-germ layer lineage central nervous system repair: nerve and vascular cell generation by embryonic stem cells transplanted in the injured brain.

OBJECT: To restore proper function to a damaged central nervous system (CNS) through transplantation, it is necessary to replace both neural and nonneural elements that arise from different germ layers in the embryo. Mounting evidence indicates the importance of signals related to vasculogenesis in governing neural proliferation and differentiation in early CNS development. Here, the authors examined whether embryonic stem cell (ESC)-derived progenitors can selectively generate both neural and endothelial cells after transplantation in the damaged CNS. METHODS: Injections of 20 nmol N-methyl-D-aspartate created a unilateral striatal injury in 7-day-old rats. One week postinjury, murine ESCs, neural-induced with retinoic acid, were transplanted into the injured striatum. Histological staining, laser confocal microscopy, and transmission electron microscopy of grafted ESCs were performed 1 week posttransplantation. CONCLUSIONS: Transplanted ESCs differentiated into neural cells, which segregated into multiple pools and formed neurons that conformed to host cytoarchitecture. The ESCs also generated endothelial cells, which integrated with host cells to form chimeric vasculature. The combination of ESC pluripotentiality and multiple germ layer differentiation provides a new conceptual framework for CNS repair.

Animals↗
PubMed2004

Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury.

The goal of this work was to assess the feasibility of using affinity-based delivery systems to release neurotrophin-3 (NT-3) in a controlled manner from fibrin gels as a therapy for spinal cord injury. A heparin-based delivery system (HBDS) was used to immobilize NT-3 within fibrin gels via non-covalent interactions to slow diffusion-based release of NT-3, thus allowing cell-activated degradation of fibrin to mediate release. The HBDS consists of three components: immobilized linker peptide, heparin and NT-3. The linker peptide contained a Factor XIIIa substrate and was covalently cross-linked to fibrin during polymerization. This immobilized linker peptide sequesters heparin within fibrin gels, and sequestered heparin binds NT-3, preventing its diffusion. Mathematical modeling was performed to examine the effect of heparin concentration on the fraction of NT-3 initially bound to fibrin. In vitro release studies confirmed that heparin concentration modulates diffusion-based release of NT-3. Fibrin gels containing the HBDS and NT-3 stimulated neural outgrowth from chick dorsal root ganglia by up to 54% versus unmodified fibrin, demonstrating that the NT-3 released is biologically active. In a preliminary in vivo study, fibrin gels containing the HBDS and NT-3 showed increased neural fiber density in spinal cord lesions versus unmodified fibrin at 9 days.

Animals↗
PubMed2004

Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury.

A number of potential approaches aim to optimize functional recovery after spinal cord injury. They include minimizing the progression of secondary injury, manipulating the neuroinhibitory environment of the spinal cord, replacing lost tissue with transplanted cells or peripheral nerve grafts, remyelinating denuded axons, and maximizing the intrinsic regenerative potential of endogenous progenitor cells. We review the application of stem cell transplantation to the spinal cord, emphasizing the use of embryonic stem cells for remyelinating damaged axons. We speculate that harnessing the potential of endogenously born stem cells already present in the spinal cord represents an important therapeutic target. We also discuss the potential application of peripheral nervous system reconstruction to recovery from spinal cord injury. The principles of peripheral nerve regeneration and concepts of nerve grafting are reviewed. Particular attention is given to peripheral nerve allotransplantation for repairing extensively injured tissue when autologous donor nerve material is scarce. The potential role of nerve transfers for reconstructing the injured spinal cord, particularly the cauda equina and lumbosacral plexus, are also described.

Animals↗
PubMed2004

Repair of the injured spinal cord and the potential of embryonic stem cell transplantation.

Traditionally, treatment of spinal cord injury seemed frustrating and hopeless because of the remarkable morbidity and mortality, and restricted therapeutic options. Recent advances in neural injury and repair, and the progress towards development of neuroprotective and regenerative interventions are basis for increased optimism. Neural stem cells have opened a new arena of discovery for the field of regenerative science and medicine. Embryonic stem (ES) cells can give rise to all neural progenitors and they represent an important scientific tool for approaching neural repair. The growing number of dedicated regeneration centers worldwide exemplifies the changing perception towards the do-ability of spinal cord repair and this review was born from a presentation at one such leading center, the Kentucky Spinal Cord Injury Research Center. Current concepts of the pathophysiology, repair, and restoration of function in the damaged spinal cord are presented with an overlay of how neural stem cells, particularly ES cells, fit into the picture as important scientific tools and therapeutic targets. We focus on the use of genetically tagged and selectable ES cell lines for neural induction and transplantation. Unique features of ES cells, including indefinite replication, pluripotency, and genetic flexibility, provide strong tools to address questions of neural repair. Selective marker expression in transplanted ES cell derived neural cells is providing new insights into transplantation and repair not possible previously. These features of ES cells will produce a predictable and explosive growth in scientific tools that will translate into discoveries and rapid progress in neural repair.

Animals↗
PubMed2004

Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair.

PURPOSE OF REVIEW: In this review, we have documented some current research trends in rodent models of spinal cord injury. We have also catalogued the treatments used in studies published between October 2002 and November 2003, with special attention given to studies in which treatments were delayed for at least 4 days after injury. RECENT FINDINGS: Most spinal cord injury studies are performed with one of three general injury models: transection, compression, or contusion. Although most treatments are begun immediately after injury, a growing number of studies have used delayed interventions. Mice and the genetic tools they offer are gaining in popularity. Some researchers are setting their sights beyond locomotion, to issues more pressing for people with spinal cord injury (especially bladder function and pain). SUMMARY: Delayed treatment protocols may extend the window of opportunity for treatment of spinal cord injury, whereas continued progress in the prevention of secondary cell death will reduce the severity of new cases. The use of mice will hopefully accelerate progress towards useful regeneration in humans. Researchers must improve cross-study comparability to allow balanced decisions about potentially useful treatments.

Adult↗
PubMed2003

Enhanced oligodendrocyte survival after spinal cord injury in Bax-deficient mice and mice with delayed Wallerian degeneration.

Mechanisms of oligodendrocyte death after spinal cord injury (SCI) were evaluated by T9 cord level hemisection in wild-type mice (C57BL/6J and Bax+/+ mice), Wlds mice in which severed axons remain viable for 2 weeks, and mice deficient in the proapoptotic protein Bax (Bax-/-). In the lateral white-matter tracts, substantial oligodendrocyte death was evident in the ipsilateral white matter 3-7 mm rostral and caudal to the hemisection site 8 d after injury. Ultrastructural analysis and expression of anti-activated caspase-3 characterized the ongoing oligodendrocyte death at 8 d as primarily apoptotic. Oligodendrocytes were selectively preserved in Wlds mice compared with C57BL/6J mice at 8 d after injury, when severed axons remained viable as verified by antereograde labeling of the lateral vestibular spinal tract. However, 30 d after injury when the severed axons in Wlds animals were already degenerated, the oligodendrocytes preserved at 8 d were lost, and numbers were then equivalent to control C57BL/6J mice. In contrast, oligodendrocyte death was prevented at both time points in Bax-/- mice. When cultured oligodendrocytes were exposed to staurosporine or cyclosporin A, drugs known to stimulate apoptosis in oligodendrocytes, those from Bax-/- mice but not from Bax+/+ or Bax+/- mice were resistant to the apoptotic death. In contrast, the three groups were equally vulnerable to excitotoxic necrosis death induced by kainate. On the basis of these data, we hypothesize that the Wallerian degeneration of white matter axons that follows SCI removes axonal support and induces apoptotic death in oligodendrocytes by triggering Bax expression.

Animals↗
PubMed2003

AMPA receptors are the major mediators of excitotoxic death in mature oligodendrocytes.

Myelination of axons is important for central nervous system function, but oligodendrocytes, which constitute CNS myelin, are vulnerable to excitotoxic injury and death. Although mature oligodendrocytes express functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) and kainate-type glutamate receptors, the relative roles of these subtypes in excitotoxicity are not well understood. Using recently developed selective antagonists for subtypes of ionotropic non-NMDA receptors, we addressed this issue. By examining the pharmacological, biochemical, and morphologic features of kainite-induced excitotoxic death, we also determined whether it occurs by apoptosis, necrosis, or both. We conclude that when mature oligodendrocytes die after exposure to kainate: (1) AMPA receptors are the most important mediators, (2) kainate receptors play a smaller role, and (3) death occurs predominantly by necrosis, not apoptosis.

Animals↗
PubMed2003

Restoring function after spinal cord injury.

BACKGROUND: By affecting young people during the most productive period of their lives, spinal cord injury is a devastating problem for modern society. A decade ago, treating SCI seemed frustrating and hopeless because of the tremendous morbidity and mortality, life-shattering impact, and limited therapeutic options associated with the condition. Today, however, an understanding of the underlying pathophysiological mechanisms, the development of neuroprotective interventions, and progress toward regenerative interventions are increasing hope for functional restoration. REVIEW SUMMARY: This study addresses the present understanding of SCI, including the etiology, pathophysiology, treatment, and scientific advances. The discussion of treatment options includes a critical review of high-dose methylprednisolone and GM-1 ganglioside therapy. The concept that limited rebuilding can provide a disproportionate improvement in quality of life is emphasized throughout. CONCLUSIONS: New surgical procedures, pharmacologic treatments, and functional neuromuscular stimulation methods have evolved over the last decades that can improve functional outcomes after spinal cord injury, but limiting secondary injury remains the primary goal. Tissue replacement strategies, including the use of embryonic stem cells, become an important tool and can restore function in animal models. Controlled clinical trials are now required to confirm these observations. The ultimate goal is to harness the body's own potential to replace lost central nervous system cells by activation of endogenous progenitor cell repair mechanisms.

Humans↗
PubMed2003

Spinal cord injury: promising interventions and realistic goals.

Long regarded as impossible, spinal cord repair is approaching the realm of reality as efforts to bridge the gap between bench and bedside point to novel approaches to treatment. It is important to recognize that the research playing field is rapidly changing and that new mechanisms of resource development are required to effectively make the transition from basic science discoveries to effective clinical treatments. This article reviews recent laboratory studies and phase 1 clinical trials in neural and nonneural cell transplantation, stressing that the transition from basic science to clinical applications requires a parallel rather than serial approach, with continuous, two-way feedback to most efficiently translate basic science findings, through evaluation and optimization, to clinical treatments. An example of mobilizing endogenous stem cells for repair is reviewed, with emphasis on the rapid application of basic science to clinical therapy. Successful and efficient transition from basic science to clinical applications requires (1) a parallel rather than a serial approach; (2) development of centers that integrate three spheres of science, translational, transitional, and clinical trials; and (3) development of novel resources to fund the most critically limited step of transitional to clinical trials.

Animals↗
PubMed2003

Joint regression and association modeling of longitudinal ordinal data.

We propose models for longitudinal, or otherwise clustered, ordinal data. The association between subunit responses is characterized by dependence ratios (Ekholm, Smith, and McDonald, 1995, Biometrika 82, 847-854), which are extended from the binary to the multicategory case. The joint probabilities of the subunit responses are expressed as explicit functions of the marginal means and the dependence ratios of all orders, obtaining a computational advantage for likelihood-based inference. Equal emphasis is put on finding regression models for the univariate cumulative probabilities, and on deriving the dependence ratios from meaningful association-generating mechanisms. A data set on the effects of treatment with Fluvoxamine, which has been analyzed in parts before (Molenberghs, Kenward, and Lesaffre, 1997, Biometrika 84, 33-44), is analyzed in its entirety. Selection models are used for studying the sensitivity of the results to drop-out.

Analysis of Variance↗
PubMed2002

Functional reorganization and stability of somatosensory-motor cortical topography in a tetraplegic subject with late recovery.

The functional organization of somatosensory and motor cortex was investigated in an individual with a high cervical spinal cord injury, a 5-year absence of nearly all sensorymotor function at and below the shoulders, and rare recovery of some function in years 6-8 after intense and sustained rehabilitation therapies. We used functional magnetic resonance imaging to study brain activity to vibratory stimulation and voluntary movements of body parts above and below the lesion. No response to vibratory stimulation of the hand was observed in the primary somatosensory cortex (SI) hand area, which was conversely recruited during tongue movements that normally evoke responses only in the more lateral face area. This result suggests SI reorganization analogous to previously reported neuroplasticity changes after peripheral lesions in animals and humans. In striking contradistinction, vibratory stimulation of the foot evoked topographically appropriate responses in SI and second somatosensory cortex (SII). Motor cortex responses, tied to a visuomotor tracking task, displayed a near-typical topography, although they were more widespread in premotor regions. These findings suggest possible preservation of motor and some somatosensory cortical representations in the absence of overt movements or conscious sensations for several years after spinal cord injury and have implications for future rehabilitation and neural-repair therapies.

Adult↗
PubMed2002

Spinal-cord injury.

More than a decade ago, spinal-cord injury meant confinement to a wheelchair and a lifetime of medical comorbidity. The physician's armamentarium of treatments was very limited, and provision of care for individuals with spinal-cord injury was usually met with frustration. Advances in the neurosciences have drawn attention to research into spinal-cord injury. Nowadays, advanced interventions provide high hope for regeneration and functional restoration. As scientific advances become more frequent, scepticism is giving way to the ideas that spinal-cord injury will eventually be repairable and that strategies to restore function are within our grasp. We address the present understanding of spinal-cord injury, its cause, pathophysiology, diagnosis, and treatment, and look at promising research avenues. We also discuss new treatment options, including functional electric stimulation and part-weight-supported walking.

Adolescent↗