[Show abstract][Hide abstract] ABSTRACT: To determine the long-term health and function of transplanted dopamine neurons in Parkinson's disease (PD) patients, the expression of dopamine transporters (DATs) and mitochondrial morphology were examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate for at least 14 years after transplantation. The transplanted dopamine neurons showed a healthy and nonatrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and α-synuclein showed a typical cellular pathology in the patients' own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy for the long term in PD patients, consistent with clinical findings that fetal dopamine neuron transplants maintain function for up to 15-18 years in patients. These findings are critically important for the rational development of stem-cell-based dopamine neuronal replacement therapies for PD.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the feasibility of remote presence for improving the health of residents in a remote northern Inuit community.
A pilot study assessed patient's, nurse's and physician's satisfaction with and the use of the remote presence technology aiding delivery of health care to a remote community. A preliminary cost analysis of this technology was also performed.
This study deployed a remote presence RP-7 robot to the isolated Inuit community of Nain, Newfoundland and Labrador for 15 months. The RP-7 is wirelessly controlled by a laptop computer equipped with audiovisual capability and a joystick to maneuver the robot in real time to aid in the assessing and care of patients from a distant location. Qualitative data on physician's, patient's, caregiver's and staff's satisfaction were collected as well as information on its use and characteristics and the number of air transports required to the referral center and associated costs.
A total of 252 remote presence sessions occurred during the study period, with 89% of the sessions involving direct patient assessment or monitoring. Air transport was required in only 40% of the cases that would have been otherwise transported normally. Patients and their caregivers, nurses and physicians all expressed a high level of satisfaction with the remote presence technology and deemed it beneficial for improved patient care, workloads and job satisfaction.
These results show the feasibility of deploying a remote presence robot in a distant northern community and a high degree of satisfaction with the technology. Remote presence in the Canadian North has potential for delivering a cost-effective health care solution to underserviced communities reducing the need for the transport of patients and caregivers to distant referral centers.
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder that is characterized by progressive dementia, choreiform involuntary movements and emotional deterioration. Neuropathological features include the progressive degeneration of striatal γ-aminobutyric acid (GABA) neurons. New therapeutic approaches such as the transplantation of human neural precursor cells (hNPCs) to replace damaged or degenerated cells are currently being investigated. The aim of this study was to investigate the potential for utilizing telencephalic hNPCs expanded in suspension bioreactors for cell restorative therapy in a rodent model ofHD. hNPCs were expanded in a hydrodynamically controlled and homogeneous environment under serum free conditions. In vitro analysis revealed that the bioreactor-expanded telencephalic (BET)-hNPCs could be differentiated into a highly enriched population of GABAergic neurons. Behavioural assessments of unilateral striatal quinolinic acid lesioned rodents revealed a significant improvement in motor and memory deficits following transplantation with GABAergic cells differentiated from BET-hNPCs. Immunohistochemical analysis revealed that transplanted BET-hNPCs retained a GABAergic neuronal phenotype without aberrant transdifferentiation or tumour formation, indicating that BET-hNPCs are a safe source of cells for transplantation. This pre-clinical study has important implications as the transplantation of GABAergic cells derived from pre-differentiated BET-hNPCs may be a safe and feasible cell replacement strategy to promote behavioural recovery in HD.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:: The expansion of neuromodulation and its indications has resulted in hundreds of thousands of patients implanted with devices worldwide. As all patients require programming, this growth has created a heavy burden on neuromodulation centers and patients. Remote point-of-care programming may provide patients with real-time access to neuromodulation expertise in their communities. OBJECTIVE:: To test the feasibility of remotely programming a neuromodulation device using a remote presence robot, and to determine the ability of an expert programmer to telementor a non-expert in programming the device. METHODS:: A remote presence robot (RP-7, In Touch Health Inc., Santa Barbara, CA) was used for remote programming. Twenty patients were randomly assigned to either conventional programming or a robotic session. The expert remotely mentored ten nurses, with no previous experience, to program the devices of patients assigned to the remote presence sessions. Accuracy of programming, adverse events, and satisfaction scores for all participants were assessed. RESULTS:: There was no difference in the accuracy or clinical outcomes of programming between the standard and remote presence sessions. No adverse events occurred in any session. The patients, nurses, and the expert programmer expressed high satisfaction scores with the remote presence sessions. CONCLUSION:: This study establishes the proof-of-principle that remote programming of neuromodulation devices using telepresence and expert telementoring of an individual with no previous experience to accurately program a device is feasible. We envision a time in the future, where patients with implantation devices will have real-time access to neuromodulation expertise from the comfort of their own home.
[Show abstract][Hide abstract] ABSTRACT: Understanding initial cell growth, interactions associated with the process of expansion of human neural precursor cells (hNPCs), and cellular events pre- and postdifferentiation are important for developing bioprocessing protocols to reproducibly generate multipotent cells that can be used in basic research or the treatment of neurodegenerative disorders. Herein, we report the in vitro responses of telencephalon hNPCs grown in a serum-free growth medium using time-lapse live imaging as well as cell-surface marker, aggregate size, and immunocytochemical analyses. Time-lapse analysis of hNPC initial expansion indicated that cell-surface attachment in stationary culture and the frequency of cell-cell interaction in suspension conditions are important for subsequent aggregate formation and hNPC growth. In the absence of cell-surface attachment in low-attachment stationary culture, large aggregates of cells were formed and expansion was adversely affected. The majority of the telencephalon hNPCs expressed CD29, CD90, and CD44 (cell surface markers involved in cell-ECM and cell-cell interactions to regulate biological functions such as proliferation), suggesting that cell-surface attachment and cell-cell interactions play a significant role in the subsequent formation of cell aggregates and the expansion of hNPCs. Before differentiation, about 90% of the cells stained positive for nestin and expressed two neural precursor cells surface markers (CD133 and CD24). Upon withdrawal of growth cytokines, hNPCs first underwent cell division and then differentiated preferentially towards a neuronal rather than a glial phenotype. This study provides key information regarding human NPC behavior under different culture conditions and favorable culture conditions that are important in establishing reproducible hNPC expansion protocols.
[Show abstract][Hide abstract] ABSTRACT: Tissue-specific human neural precursor cells (hNPCs) can be isolated from various regions of the developing or adult central nervous system and may serve as a viable source of cells in cell replacement therapies for the treatment of neurodegenerative disorders. However, in order for cell replacement strategies to become a routine therapeutic option for the treatment of neurodegenerative disorders, hNPCs should be generated under standardized and controlled conditions. Studies over the last two decades have focused on developing cell growth media and cell handling protocols for expansion and differentiation of hNPCs in culture. Key studies have reported the development of serum-free growth media and large-scale computer-controlled suspension bioreactors that can support high cell proliferation rates (doubling times < 3 days), multipotentiality, and potential neurogenic differentiation (more than 60% neurons). Moreover, bioengineering studies have focused on controlling culture conditions in suspension bioreactors including inoculation, hydrodynamics of culture, oxygen and nutrients transfer to the cells, monitoring in situ physiological parameters using process control techniques, and expansion for extended periods of time. In addition, in vitro and in vivo characterization of hNPCs have been performed, providing information on stem/progenitor cell characteristics, cell surface analysis, and appropriate type of cells to use in transplantation studies.
Current Stem Cell Research & Therapy 04/2011; 6(3):229-54. DOI:10.2174/157488811796575378 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Postmortem analyses from clinical neural transplantation trials of several subjects with Parkinson's disease revealed surviving grafted dopaminergic neurons after more than a decade. A subset of these subjects displayed isolated dopaminergic neurons within the grafts that contained Lewy body-like structures. In this review, we discuss why this isolated cell damage is unlikely to affect the overall graft function and how we can use these observations to help us to understand age-related neurodegeneration and refine our future cell replacement therapies.
[Show abstract][Hide abstract] ABSTRACT: Tourette's syndrome (TS) is a neurological disorder characterized by motor and vocal tics that typically begin in childhood and often are accompanied by psychiatric comorbidities. Symptoms of TS may be socially disabling and cause secondary medical complications. Pharmacological therapies remain the mainstay of symptom management. For the subset of patients in whom TS symptoms are medically recalcitrant and do not dissipate by adulthood, neurosurgery may offer an alternative treatment strategy. Greater understanding of the neuroanatomic and pathophysiologic basis of TS has facilitated the development of surgical procedures that aim to ameliorate TS symptoms by lesions or deep brain stimulation of cerebral structures. Herein, the rationale for the surgical management of TS is discussed and neurosurgical experiences since the 1960s are reviewed. The necessity for neurosurgical strategies to be performed with appropriate ethical considerations is highlighted.
Neuropsychiatric Disease and Treatment 01/2009; 4(6):1111-28. · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human neural precursor cells (hNPCs), harvested from somatic tissue and grown in vitro, may serve as a source of cells for cell replacement strategies aimed at treating neurodegenerative disorders such as Parkinson's disease (PD), Huntington's disease (HD), and intractable spinal cord pain. A crucial element in a robust clinical production method for hNPCs is a serum-free growth medium that can support the rapid expansion of cells while retaining their multipotency. Here, we report the development of a cell growth medium (PPRF-h2) for the expansion of hNPCs, achieving an overall cell-fold expansion of 10(13) over a period of 140 days in stationary culture which is significantly greater than other literature results. More importantly, hNPC expansion could be scaled-up from stationary culture to suspension bioreactors using this medium. Serial subculturing of the cells in suspension bioreactors resulted in an overall cell-fold expansion of 7.8 x 10(13) after 140 days. These expanded cells maintained their multipotency including the capacity to generate large numbers of neurons (about 60%). In view of our previous studies regarding successful transplantation of the bioreactor-expanded hNPCs in animal models of neurological disorders, these results have demonstrated that PPRF-h2 (containing dehydroepiandrosterone, basic fibroblast growth factor and human leukemia inhibitory factor) can successfully facilitate the production of large quantities of hNPCs with potential to be used in the treatment of neurodegenerative disorders.
Biotechnology and Bioengineering 01/2009; 105(4):823-33. DOI:10.1002/bit.22590 · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress leading to lipid peroxidation is a major cause of secondary injury following spinal cord injury (SCI). The objectives of this study were to determine the duration of lipid peroxidation following acute SCI and the efficacy of short-and long-term administration of methylprednisolone on decreasing lipid peroxidation.
A total of 226 female Wistar rats underwent clip-compression induced SCI. In the first part of the study, spinal cords of untreated rats were assayed colorimetrically for malondialdehyde (MDA) to determine lipid peroxidation levels at various time points between 0 and 10 days. In the second part of the study, animals were treated with methylprednisolone for either 24 hours or 7 days. Control animals received equal volumes of normal saline. Treated and control rats were killed at various time points between 0 and 7 days.
The MDA levels initially peaked 4 hours postinjury. By 12 hours, the MDA levels returned to baseline. A second increase was observed from 24 hours to 5 days. Both peak values differed statistically from the trough values (p < 0.008). The methylprednisolone reduced MDA levels (p < 0.04) within 12 hours of injury. No effect was seen at 24 hours or later.
The results of this study indicate that oxidative stress persists for 5 days following SCI in rats, and although methylprednisolone reduces MDA levels within the first 12 hours, it has no effect on the second lipid peroxidation peak.
[Show abstract][Hide abstract] ABSTRACT: With an increase in the aging population, the incidence of Parkinson's disease (PD), a disabling neurodegenerative disorder mainly affecting motor function, will inevitably present a challenge to an already overburdened healthcare system. Current medical and surgical therapies offer symptomatic relief but do not provide a cure. Experimental studies suggest that GDNF has the ability to protect degenerating dopamine neurons in PD as well as promote regeneration of the nigrostriatal dopamine system. However, clinical trials of GDNF infusion to date remain inconclusive. This review will examine the experimental and clinical evidence of GDNF use in PD with particular focus on its potential as an effective therapy in the treatment of PD.
[Show abstract][Hide abstract] ABSTRACT: Postmortem analysis of five subjects with Parkinson's disease 9-14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.
Nature medicine 06/2008; 14(5):507-9. DOI:10.1038/nm1752 · 28.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The transplantation of in vitro expanded human neural precursor cells (hNPCs) represents a potential new treatment alternative for individuals suffering from incurable neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). However, in order for cell restorative therapy to have widespread therapeutic significance, it will be necessary to generate unlimited quantities of clinical grade hNPCs in a standardized method. We report here that we have developed a serum-free medium and scale-up protocols that allow for the generation of clinical quantities of human telencephalon-derived hNPCs in 500-mL computer-controlled suspension bioreactors. The average hNPC aggregate diameter in the bioreactors was maintained below a target value of 500 microm by controlling the liquid shear field. The human cells, which were inoculated at 10(5) cells/mL, exhibited a doubling time of 84 h, underwent a 36-fold expansion over the course of 18 days, and maintained an average viability of over 90%. The bioreactor-derived hNPCs retained their nestin expression following expansion and were able to differentiate into glial and neuronal phenotypes under defined conditions. It has also been demonstrated that these hNPCs differentiated to a GABAergic phenotype that has recently been shown to be able to restore functional behavior in rat models of HD and neuropathic pain (Mukhida, K. et al. Stem Cells 2007; DOI 10.1634/stemcells.2007-0326). This study demonstrates that clinical quantities of hNPCs can be successfully and reproducibly generated under standardized conditions in computer-controlled suspension bioreactors.
[Show abstract][Hide abstract] ABSTRACT: Fetal tissue transplantation for Parkinson disease (PD) has demonstrated promising results in experimental and clinical studies. However, the widespread clinical application of this therapeutic approach is limited by a lack of fetal tissue. Human neural precursor cells (HNPCs) are attractive candidates for transplantation because of their long-term proliferation activity. Furthermore, these cells can be reproducibly expanded in a standardized fashion in suspension bioreactors. In this study the authors sought to determine whether the survival, differentiation, and migration of HNPCs after transplantation depended on the region of precursor cell origin, intracerebral site of transplantation, and duration of their expansion.
Human neural precursor cells were isolated from the telencephalon, brainstem, ventral mesencephalon, and spinal cord of human fetuses 8-10 weeks of gestational age, and their differentiation potential characterized in vitro. After expansion in suspension bioreactors, the HNPCs were transplanted into the striatum and substantia nigra of parkinsonian rats. Histological analyses were performed 7 weeks posttransplantation.
The HNPCs isolated from various regions of the neuraxis demonstrated diverse propensities to differentiate into astrocytes and neurons and could all successfully expand under standardized conditions in suspension bioreactors. At 7 weeks posttransplantation, survival and migration were significantly greater for HNPCs obtained from the more rostral brain regions. The HNPCs differentiated predominantly into astrocytes after transplantation into the striatum or substantia nigra regions, and thus no behavioral improvement was observed.
Understanding the regional differences in HNPC properties is prerequisite to their application for PD cell restoration strategies.
[Show abstract][Hide abstract] ABSTRACT: The origins of neurosurgical services in Atlantic Canada are tied to the individual efforts of William D. Stevenson. Born in Hamilton, Ontario, Stevenson completed his senior matriculation in Dunnville, Ontario, before studying medicine at the University of Toronto. He completed the Gallie surgical course in Toronto and then spent 1 year training with Edward Archibald at McGill University. After working for 2 years with the Canadian Mobile Neurosurgical Unit in Europe during the Second World War, Stevenson undertook formal neurosurgical training with Kenneth G. McKenzie, Canada's first neurosurgeon. Stevenson was thereafter recruited to Halifax to start the neurosurgical service at the Victoria General Hospital in January 1948, and he remained head of the division for the next 26 years. His pioneering work laid the foundations for the establishment of a major academic neurosurgical service at Dalhousie University and was crucial for the establishment of neurosurgery in Atlantic Canada. After his retirement, Stevenson moved back to Ontario and began his second career, transferring his passion for neurosurgery to oil painting. His legacy to neurosurgery in Atlantic Canada will be remembered in perpetuity with the annual Neurosurgery Resident Research Award at Dalhousie University, established and named in his honour. This paper focuses on Stevenson's life and work in neurosurgery as Atlantic Canada's first neurosurgeon.
Canadian journal of surgery. Journal canadien de chirurgie 01/2008; 50(6):485-9. · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Injury to the spinal cord or peripheral nerves can lead to the development of allodynia due to the loss of inhibitory tone involved in spinal sensory function. The potential of intraspinal transplants of GABAergic cells to restore inhibitory tone and thus decrease pain behaviors in a rat model of neuropathic pain was investigated. Allodynia of the left hind paw was induced in rats by unilateral L5- 6 spinal nerve root ligation. Mechanical sensitivity was assessed using von Frey filaments. Postinjury, transgenic fetal green fluorescent protein mouse GABAergic cells or human neural precursor cells (HNPCs) expanded in suspension bioreactors and differentiated into a GABAergic phenotype were transplanted into the spinal cord. Control rats received undifferentiated HNPCs or cell suspension medium only. Animals that received either fetal mouse GABAergic cell or differentiated GABAergic HNPC intraspinal transplants demonstrated a significant increase in paw withdrawal thresholds at 1 week post-transplantation that was sustained for 6 weeks. Transplanted fetal mouse GABAergic cells demonstrated immunoreactivity for glutamic acid decarboxylase and GABA that colocalized with green fluorescent protein. Intraspinally transplanted differentiated GABAergic HNPCs demonstrated immunoreactivity for GABA and beta-III tubulin. In contrast, intraspinal transplantation of undifferentiated HNPCs, which predominantly differentiated into astrocytes, or cell suspension medium did not affect any behavioral recovery. Intraspinally transplanted GABAergic cells can reduce allodynia in a rat model of neuropathic pain. In addition, HNPCs expanded in a standardized fashion in suspension bioreactors and differentiated into a GABAergic phenotype may be an alternative to fetal cells for cell-based therapies to treat chronic pain syndromes.
[Show abstract][Hide abstract] ABSTRACT: We describe the unusual clinical course of a patient with cranial dystonia (i.e., Meige syndrome) and additional upper limb involvement, who developed sustained relief of motor symptoms following cessation of a prolonged course of bilateral pallidal deep brain stimulation (DBS). Early response to therapy proved titratable and reversible; however, the patient gained independence from DBS in the fifth postoperative year and has since been more than a year without treatment or exacerbation of motor symptoms. Among the potential explanations for these neurological benefits lies the intriguing possibility that DBS therapy may have the capacity to induce plastic change that lessens or obviates the need for further treatment in susceptible patients.
Movement Disorders 10/2007; 22(13):1958-62. DOI:10.1002/mds.21616 · 5.63 Impact Factor