J. Gordon Boyd

Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury.

Over a half a century of research has confirmed that neurotrophic factors promote the survival and process outgrowth of isolated neurons in vitro. The mechanisms by which neurotrophic factors mediate these survival-promoting effects have also been well characterized. In vivo, peripheral neurons are critically dependent on limited amounts of neurotrophic factors during development. After peripheral nerve injury, the adult mammalian peripheral nervous system responds by making neurotrophic factors once again available, either by autocrine or paracrine sources. Three families of neurotrophic factors were compared, the neurotrophins, the GDNF family of neurotrophic factors, and the neuropoetic cytokines. Following a general overview of the mechanisms by which these neurotrophic factors mediate their effects, we reviewed the temporal pattern of expression of the neurotrophic factors and their receptors by axotomized motoneurons as well as in the distal nerve stump after peripheral nerve injury. We discussed recent experiments from our lab and others which have examined the role of neurotrophic factors in peripheral nerve injury. Although our understanding of the mechanisms by which neurotrophic factors mediate their effects in vivo are poorly understood, evidence is beginning to emerge that similar phenomena observed in vitro also apply to nerve regeneration in vivo.

Defining the role of olfactory ensheathing cells in facilitating axon remyelination following damage to the spinal cord

Olfactory ensheathing cells (OECs) are unique cells that are responsible for the successful regeneration of olfactory axons throughout the life of adult mammals. More than a decade of research has shown that implantation of OECs may be a promising therapy for damage to the nervous system, including spinal cord injury. Based on this research, several clinical trials worldwide have been initiated that use autologous transplantation of olfactory tissue containing OECs into the damaged spinal cord of humans. However, research from several laboratories has challenged the widely held belief that OECs are directly responsible for myelinating axons and promoting axon regeneration. The purpose of this review is to provide a working hypothesis that integrates several current ideas regarding the mechanisms of the beneficial effects of OECs. Specifically, OECs promote axon regeneration and functional recovery indirectly by augmenting the endogenous capacity of host Schwann cells to invade the damaged spinal cord. Together with Schwann cells, OECs create a 3‐dimensional matrix that provides a permissive microenvironment for successful axon regeneration in the adult mammalian central nervous system.—Boyd, J. G., Doucette, R., Kawaja, M. D. Defining the role of olfactory ensheathing cells in facilitating axon remyelination following damage to the spinal cord. FASEB J. 19, 694–703 (2005)

Proteomic evaluation reveals that olfactory ensheathing cells but not Schwann cells express calponin.

Human clinical trials have begun worldwide that use olfactory ensheathing cells (OECs) to ameliorate the functional deficits following spinal cord injury. These trials have been initiated largely because numerous studies have reported that OECs transform into Schwann Cell (SC)‐like cells that myelinate axons and support new growth in adult rats with spinal injury. This phenomenon is remarkable because OECs do not myelinate olfactory axons in their native environment. Furthermore, these myelinating OECs are morphologically identical to SCs, which can invade the spinal cord after injury. One factor that has contributed to a possible confusion in the identification of these cells is the lack of phenotypic markers to distinguish unequivocally between OECs and SCs. Such markers are required to first assess the degree of SC contamination in OEC cultures before intraspinal implantation, and then to accurately identify grafted OECs and invading SCs in the injured spinal cord. Using two‐dimensional gel electrophoresis, we have identified calponin, an actin binding protein, as the first definitive phenotypic marker that distinguishes between OECs and SCs in vitro and in vivo. We have also provided ultrastructural evidence that calponin‐immunopositive OECs do not transform into myelinating SC‐like cells after intraspinal implantation. Rather, the grafted OECs retain their morphological and neurochemical features. These data yield new insight into the phenotypic characteristics of OECs, which together with invading SCs can enhance regeneration of the injured spinal cord.

Technical Strategies to Isolate Olfactory Ensheathing Cells for Intraspinal Implantation

Over the past few years, the idea of using intraspinal implantations of olfactory ensheathing cells (OECs) as a therapeutic strategy to enhance recovery after spinal cord injury has quickly moved from experimentation with laboratory mammals to surgical approaches for paralyzed humans. Despite this progression, several important issues have yet to be thoroughly addressed: for instance, which of the many methods currently being used best yields enriched populations of OECs, and how such purity can be empirically tested and validated among different mammalian species, including humans. Here we offer an authoritative review of those methods used to isolate OECs from the olfactory mucosa and/or olfactory bulbs of rats, mice, dogs, pigs, non-human primates, and humans. As well, we assess which biomarkers are currently being utilized to determine the relative proportions of OECs and contaminating cells in these glial cultures. Although there have been numerous review articles regarding OECs in vitro, our review is unique in that it offers a critical assessment of the methods currently being used to generate cultures of mammalian OECs. More specifically, we examine the issue of culture contamination by phenotypically similar Schwann cells. This review is timely because recent clinical usage of OECs has come under intense criticism for a number of reasons, including the reliable identification of cultured human OECs. We believe that once these methodological issues of isolation and characterization of OECs have been resolved, this glial population will offer paralyzed individuals a truly viable cellular strategy for intraspinal therapy.

Olfactory ensheathing cells express smooth muscle α-actin in vitro and in vivo

One strategy for spinal cord repair after injury that has moved quickly from the research laboratory to the clinic is the implantation of olfactory ensheathing cells (OECs). These unique glial cells of the olfactory system have been associated with axonal remyelination and regeneration after grafting into spinalized animals. Despite these promising observations, there remains a lack of direct empirical evidence of the exact fate of OECs after intraspinal implantation, in large part because of a surprising paucity of defined biomarkers that unequivocally distinguish these cells from phenotypically similar Schwann cells. Here we provide direct neurochemical proof that OECs, both in vitro and in vivo, express smooth muscle α‐actin. That OECs synthesize this contractile protein (and a variety of actin‐binding proteins including caldesmon) provides compelling evidence that these cells are, in fact, quite different from Schwann cells. The identification of several smooth muscle‐related proteins in OECs points to a new appreciation of the structural and functional features of this population of olfactory glia. These biomarkers can now be used to elucidate the fate of OECs after intraspinal implantation, in particular assessing whether smooth muscle α‐actin‐expressing OECs are capable of facilitating axon remyelination and regeneration. J. Comp. Neurol. 503:209–223, 2007.

Temporal Lobe Epilepsy after Refractory Status Epilepticus: An Illustrative Case and Review of the Literature

New onset refractory status epilepticus (NORSE) is a relatively newly defined disease entity, where otherwise healthy individuals develop unrelenting seizures that do not respond to conventional anticonvulsant therapy and may require months of therapy with anesthetic drugs. We have described a case of NORSE who subsequently developed mesial temporal lobe sclerosis (MTS) and recurrent temporal lobe seizures. We discuss the possible pathophysiological mechanisms by which refractory seizures may contribute to the development of temporal lobe epilepsy (TLE).

Low brain tissue oxygenation contributes to the development of delirium in critically ill patients: A prospective observational study

Purpose: To test the hypothesis that poor brain tissue oxygenation (BtO2) during the first 24 h of critical illness correlates with the proportion of time spent delirious. We also sought to define the physiological determinants of BtO2. Materials and methods: Adult patients admitted to the ICU within the previous 24 h were considered eligible for enrollment if they required mechanical ventilation, and/or vasopressor support. BtO2 was measured using near‐infrared spectroscopy, for 24 h after enrollment. Hourly vital signs and clinically ordered arterial and central venous blood gases were collected throughout BtO2 monitoring. Patients were screened daily for delirium with the confusion assessment method for the intensive care unit (CAM‐ICU). Results: BtO2 and the proportion of time spent delirious did not result in a significant correlation (p = 0.168). However, critically ill patients who spent the majority of their ICU stay delirious had significantly lower mean BtO2 compared to non‐delirious patients, (p = 0.017). BtO2 correlated positively with central venous pO2 (p = 0.00003) and hemoglobin concentration (p = 0.001). Logistic regression indicated that lower BtO2, higher narcotic doses and a history of alcohol abuse were independent risk factors for delirium. Conclusions: Poor cerebral oxygenation during the first 24 hours of critical illness contributes to the development of delirium. Trial registration: This trial is registered on clinicaltrials.gov (Identifier: NCT02344043), retrospectively registered January 8, 2015. HIGHLIGHTSLow BtO2 is an independent risk factor for the subsequent development of delirium.BtO2 and the proportion of time spent delirious were not significantly correlated.BtO2 was positively associated with central vpO2 and hemoglobin concentration.Other delirium risk factors: higher narcotic doses and a history of alcohol abuse

Frailty measurement and outcomes in interventional studies: protocol for a systematic review of randomised control trials

Introduction Frailty is associated with reduced functional capacity, decreased resistance to stressors and is predictive of a range of adverse health outcomes, including dependency, hospitalisation and mortality. Early identification of frailty may prevent, reduce and postpone adverse health outcomes. However, there is a need for additional evidence to guide decision-making for the care of frail patients since frail persons are frequently excluded from studies, the differential impact of frailty is often not examined in clinical trials and few large-scale clinical trials examining frail cohorts have been conducted. Randomised control trials (RCTs) published to date have used a diverse range of definitions of frailty, as well as a variety of outcome measures. The objective of this systematic review is to comprehensively characterise the frail populations enrolled and the end points reported in frailty RCTs. Methods and analysis We will identify all RCTs reporting on the outcome of interventions in adult (age ≥18 years) frail populations as defined by authors, in all settings of care. Databases will include MEDLINE, CINAHL, EMBASE, PsycInfo, Global Health, the Joanna Briggs database and Cochrane Library. Two reviewers will independently determine trial eligibility. For each included trial, we will conduct duplicate independent data extraction, inter-rater reliability, risk of bias assessment and evaluation of the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. Ethics and dissemination This systematic review will comprehensively identify RCTs including frail patients to identify how frailty is measured and which outcomes are reported. The results of this systematic review may inform clinicians caring for persons with frailty, facilitate conduct of future RCTs and inform future efforts to develop common data elements and core outcomes for frailty studies. Our findings will be disseminated through conference presentation and publication in peer-reviewed journals. PROSPERO registration number CRD42017065233.

EEG utilization in Canadian intensive care units: A multicentre prospective observational study

PURPOSE We have previously shown that electroencephalography (EEG) may be an underutilized monitoring modality in a single general medical-surgical ICU, that does not have a specific neurocritical care consultation service or neurocritical care unit. The present study was designed to describe the pattern of EEG utilization across 3 academic ICUs in Ontario, Canada that use different models of neurocritical care. METHOD In this prospective multicentre observational study, ICU patients were screened weekly for 6 non-consecutive weeks to determine if they met the ESICMs recommendations or suggestions for EEG monitoring. If EEGs were performed, the results were recorded. Three models of neurocritical care provision were examined in 3 academic tertiary ICUs. Site 1 is an intensivist-led, medical-surgical ICU with no specific neurocritical care consultation service. The second site is also an intensivist led medical-surgical ICU, but with a formal neurocritical care consultation service. The third site is a virtual neurological and neurotrauma ICU within a medical-surgical ICU, staffed by rotating neurointensivists and general intensivists. RESULTS Of the 375 patients who were screened, 127 patients (34%) met at least one ESICM indication for EEG monitoring. Among the 127 patients, 46 patients (37%) had an EEG performed. Site 1 had the highest proportion of EEGs performed. The most common indication for EEG monitoring was for patients with unexplained altered level of consciousness, in the absence of primary brain injury. For the EEGs performed per ESICM indication, the majority of epileptiform abnormalities were found in patients admitted with status epilepticus. CONCLUSIONS EEG may be underutilized in Canadian ICUs. The impact on patient management and outcomes are unknown.

Quantifying Cognitive Dysfunction Across the Spectrum of End Stage Kidney Disease - A Systematic Review and Meta-Analysis: Cognitive Dysfunction Across the Spectrum of End Stage Kidney Disease

Cognitive dysfunction is reportedly highly prevalent among chronic kidney disease (CKD) patients. A variety of screening tools and neuropsychiatric batteries are used to quantify the magnitude and nature of this dysfunction. Our objective is to summarize the neurocognitive testing used, and determine what degree cognitive dysfunction is reported in CKD patients. All study designs published in English that contained participants who were either pre‐dialysis patients, haemodialysis (HD) or peritoneal dialysis (PD) patients or renal transplant recipients were considered. Reported comparative non‐CKD control data was also collected. All study designs were included. The search period encompassed articles from 1980 to May 2018. This review is registered with PROSPERO (CRD42018096568). Of the 1711 articles screened, 148 articles were relevant and used in the meta‐analysis. Commonly used assessments were The Mini–Mental State Examination (MMSE), The Modified Mini–Mental State Examination, the Trails Making Tests (TMT) forms A and B and components of the Wechsler Adult Intelligence Scale: Digit Span and Digit Symbol. Means for all assessments were adjusted using a random effects model to account for the differences in variance. Adjusted mean MMSE scores were significantly lower for both pre‐dialysis (26.08, n = 17 073) and HD (26.31, n = 3314) patients when compared to non‐CKD controls (28.21, n = 5226). PD (58.01 s, n = 859) and HD (56.04 s, n = 2344) patients also took significantly longer to complete the Trails Making Task A than non‐CKD controls (37.62 s, n = 4809). Patients with CKD, especially pre‐dialysis and those requiring dialysis, are likely to exhibit impairments in cognition that can be identified with specific screening neuropsychological assessments.