The impact of COVID-19 on emergency department presentations for mental health disorders in Queensland, Australia: A time series analysis.

BACKGROUND: The COVID-19 pandemic has been associated with detrimental effects on mental health and psychological well-being. Although multiple studies have shown decreases in mental health-related Emergency Department (ED) presentations early in the COVID-19 pandemic, the medium-term effects on mental health-related ED presentations have remained less clear. This study aimed to evaluate the effect of the pandemic on mental health ED presentations by comparing observed presentation numbers to predictions from pre-pandemic data. METHODS: This retrospective cohort study tallied weekly ED presentations associated with mental health disorders from a state-wide minimum dataset. Three time periods were identified: Pre-Pandemic (January 1, 2018-March 8, 2020), Statewide Lockdown (March 9, 2020-June 28, 2020), and Restrictions Easing (June 29, 2020-June 27, 2021). Time series analysis was used to generate weekly presentation forecasts using pre-pandemic data. Observed presentation numbers were compared to these forecasts. RESULTS: Weekly presentation numbers were lower than predicted in 11 out of 16 weeks in the Statewide Lockdown period and 52 out of 52 weeks in the Restrictions Easing period. The largest decrease was seen for anxiety disorders (Statewide Lockdown: 76.8% of forecast; Restrictions Easing: 36.4% of forecast), while an increase was seen in presentations for eating disorders (Statewide Lockdown: 139.5% of forecast; Restrictions Easing: 194.4% of forecast). CONCLUSIONS: Overall weekly mental health-related presentations across Queensland public EDs were lower than expected for the first 16 months of the COVID-19 pandemic. These findings underline the limitations of emergency department provision of mental health care and the importance of alternate care modalities in the pandemic context.

T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity.

Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that NT-induced neurological reinstatement may require activation of mechanisms beyond motor axon reinnervation (our hypothesis). We previously reported that to enhance rat locomotion following T13-L1 hemisection, T12-L3 NT must be performed within timeframes optimal for sensory nerve regrowth. Here, T12-L3 NT was performed for adult female rats with subacute (7-9 days) or chronic (8 weeks) mild (SCImi: 10 g × 12.5 mm) or moderate (SCImo: 10 g × 25 mm) T13-L1 thoracolumbar contusion. For chronic injuries, T11-12 implantation of adult hMSCs (1-week before NT), post-NT intramuscular delivery of FGF2, and environmentally enriched/enlarged (EEE) housing were provided. NT, not control procedures, qualitatively improved locomotion in both SCImi groups and animals with subacute SCImo. However, delayed NT did not produce neurological scale upgrading conversion for SCImo rats. Ablation of the T12 ventral/motor or dorsal/sensory root determined that the T12-L3 sensory input played a key role in hindlimb reanimation. Pharmacological, electrophysiological, and trans-synaptic tracing assays revealed that NT strengthened integrity of the propriospinal network, serotonergic neuromodulation, and the neuromuscular junction. Besides key outcomes of thoracolumbar contusion modeling, the data provides the first evidence that mixed NT-induced locomotor efficacy may rely pivotally on sensory rerouting and pro-repair neuroplasticity to reactivate neurocircuits/central pattern generators. The finding describes a novel neurobiology mechanism underlying NT, which can be targeted for development of innovative neurotization therapies.

Direct Cell Reprogramming and Phenotypic Conversion: An Analysis of Experimental Attempts to Transform Astrocytes into Neurons in Adult Animals.

Central nervous system (CNS) repair after injury or disease remains an unresolved problem in neurobiology research and an unmet medical need. Directly reprogramming or converting astrocytes to neurons (AtN) in adult animals has been investigated as a potential strategy to facilitate brain and spinal cord recovery and advance fundamental biology. Conceptually, AtN strategies rely on forced expression or repression of lineage-specific transcription factors to make endogenous astrocytes become "induced neurons" (iNs), presumably without re-entering any pluripotent or multipotent states. The AtN-derived cells have been reported to manifest certain neuronal functions in vivo. However, this approach has raised many new questions and alternative explanations regarding the biological features of the end products (e.g., iNs versus neuron-like cells, neural functional changes, etc.), developmental biology underpinnings, and neurobiological essentials. For this paper per se, we proposed to draw an unconventional distinction between direct cell conversion and direct cell reprogramming, relative to somatic nuclear transfer, based on the experimental methods utilized to initiate the transformation process, aiming to promote a more in-depth mechanistic exploration. Moreover, we have summarized the current tactics employed for AtN induction, comparisons between the bench endeavors concerning outcome tangibility, and discussion of the issues of published AtN protocols. Lastly, the urgency to clearly define/devise the theoretical frameworks, cell biological bases, and bench specifics to experimentally validate primary data of AtN studies was highlighted.

Emergency department presentations during the COVID-19 pandemic in Queensland (to June 2021): interrupted time series analysis.

OBJECTIVES: To assess emergency department (ED) presentation numbers in Queensland during the coronavirus disease 2019 (COVID-19) pandemic to mid-2021, a period of relatively low COVID-19 case numbers. DESIGN: Interrupted time series analysis. SETTING: All 105 Queensland public hospital EDs. MAIN OUTCOME MEASURES: Numbers of ED presentations during the COVID-19 lockdown period (11 March 2020 - 30 June 2020) and the period of easing restrictions (1 July 2020 - 30 June 2021), compared with pre-pandemic period (1 January 2018 - 10 March 2020), overall (daily numbers) and by Australasian Triage Scale (ATS; daily numbers) and selected diagnostic categories (cardiac, respiratory, mental health, injury-related conditions) and conditions (stroke, sepsis) (weekly numbers). RESULTS: During the lockdown period, the mean number of ED presentations was 19.4% lower (95% confidence interval, -20.9% to -17.9%) than during the pre-pandemic period (predicted mean number: 5935; actual number: 4786 presentations). The magnitudes of the decline and the time to return to predicted levels varied by ATS category and diagnostic group; changes in presentation numbers were least marked for ATS 1 and 2 (most urgent) presentations, and for presentations with cardiac conditions or stroke. Numbers remained below predicted levels during the 12-month post-lockdown period for ATS 5 (least urgent) presentations and presentations with mental health problems, respiratory conditions, or sepsis. CONCLUSIONS: The COVID-19 pandemic and related public restrictions were associated with profound changes in health care use. Pandemic plans should include advice about continuing to seek care for serious health conditions and health emergencies, and support alternative sources of care for less urgent health care needs.

Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain.

BACKGROUND: People with spinal cord injury (SCI) frequently develop neuropathic pain (NP) that worsens disability and diminishes rehabilitation efficacy. Chronic NP is presently incurable due to poor understanding of underlying mechanisms. We hypothesized that multilocus neuroinflammation (NIF) might be a driver of SCI NP, and tested it by investigating whether NP coexisted with central NIF, neurotransmission (NTM), neuromodulation (NML) and neuroplasticity (NPL) changes post-SCI. METHODS: Female Sprague-Dawley rats (230-250 g) with T10 compression or laminectomy were evaluated for physical conditions, coordinated hindlimb functions, neurological reflexes, and mechanical/thermal sensitivity thresholds at 1 day post-injury (p.i.) and weekly thereafter. Eight weeks p.i., central nervous system tissues were histochemically and immunohistochemically characterized for parameters/markers of histopathology and NIF/NTM/NML/NPL. Also analyzed was the correlative relationship between levels of selected biomarkers and thermosensitivity thresholds via statistical linear regression. RESULTS: SCI impaired sensorimotor functions, altered reflexes, and produced spontaneous pain signs and hypersensitivity to evoked nociceptive, mechanical, and thermal inputs. Only injured spinal cords exhibited neural lesion, microglia/astrocyte activation, and abnormal expression of proinflammatory cytokines, as well as NIF/NTM/NML/NPL markers. Brains of SCI animals displayed similar pathophysiological signs in the gracile and parabrachial nuclei (GrN and PBN: sensory relay), raphe magnus nucleus and periaqueduct gray (RMN and PAG: pain modulation), basolateral amygdala (BLA: emotional-affective dimension of pain), and hippocampus (HPC: memory/mood/neurogenesis). SCI augmented sensory NTM/NPL (GrN and PBN); increased GAD67 (PAG) level; reduced serotonin (RMN) and fear-off neuronal NTR2 (BLA) expressions; and perturbed neurogenesis (HPC). CONCLUSION: T10 compression caused chronic hyperalgesia that coexisted with NIF/NTM/NML/NPL responses at multilevel neuroaxis centers. The data have provided multidimensional biomarkers as new mechanistic leads to profile SCI NP for therapeutic/therapy development.

Effects of Magnetite Nanoparticles and Static Magnetic Field on Neural Differentiation of Pluripotent Stem Cells.

Neurodevelopmental processes of pluripotent cells, such as proliferation and differentiation, are influenced by external natural forces. Despite the presence of biogenic magnetite nanoparticles in the central nervous system and constant exposure to the Earth's magnetic fields and other sources, there is scant knowledge regarding the role of electromagnetic stimuli in neurogenesis. Moreover, emerging applications of electrical and magnetic stimulation to treat neurological disorders emphasize the relevance of understanding the impact and mechanisms behind these stimuli. Here, the effects of magnetic nanoparticles (MNPs) in polymeric coatings and the static external magnetic field (EMF) were investigated on neural induction of murine embryonic stem cells (mESCs) and human induced pluripotent stem cells (hiPSCs). The results show that the presence of 0.5% MNPs in collagen-based coatings facilitates the migration and neuronal maturation of mESCs and hiPSCs in vitro. Furthermore, the application of 0.4 Tesla EMF perpendicularly to the cell culture plane, discernibly stimulates proliferation and guide fate decisions of the pluripotent stem cells, depending on the origin of stem cells and their developmental stage. Mechanistic analysis reveals that modulation of ionic homeostasis and the expression of proteins involved in cytostructural, liposomal and cell cycle checkpoint functions provide a principal underpinning for the impact of electromagnetic stimuli on neural lineage specification and proliferation. These findings not only explore the potential of the magnetic stimuli as neural differentiation and function modulator but also highlight the risks that immoderate magnetic stimulation may affect more susceptible neurons, such as dopaminergic neurons.

Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges.

Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable "biological gas" (CO, H2 , H2 S, NO, O2 , O3 , and N2 O) or "noble gas" (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO-CO, HIF-1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF-1α/ERK activation. Primary findings also reveal that the need to utilize cutting-edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad-spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.

Prelude to the special issue on novel neurocircuit, cellular and molecular targets for developing functional rehabilitation therapies of neurotrauma.

The poor endogenous recovery capacity and other impediments to reinstating sensorimotor or autonomic function after adult neurotrauma have perplexed modern neuroscientists, bioengineers, and physicians for over a century. However, despite limited improvement in options to mitigate acute pathophysiological sequalae, the past 20 years have witnessed marked progresses in developing efficacious rehabilitation strategies for chronic spinal cord and brain injuries. The achievement is mainly attributable to research advancements in elucidating neuroplastic mechanisms for the potential to enhance clinical prognosis. Innovative cross-disciplinary studies have established novel therapeutic targets, theoretical frameworks, and regiments to attain treatment efficacy. This Special Issue contained eight papers that described experimental and human data along with literature reviews regarding the essential roles of the conventionally undervalued factors in neural repair: systemic inflammation, neural-respiratory inflammasome axis, modulation of glutamatergic and monoaminergic neurotransmission, neurogenesis, nerve transfer, recovery neurobiology components, and the spinal cord learning, respiration and central pattern generator neurocircuits. The focus of this work was on how to induce functional recovery from manipulating these underpinnings through their interactions with secondary injury events, peripheral and supraspinal inputs, neuromusculoskeletal network, and interventions (i.e., activity training, pharmacological adjuncts, electrical stimulation, and multimodal neuromechanical, brain-computer interface [BCI] and robotic assistance [RA] devices). The evidence suggested that if key neurocircuits are therapeutically reactivated, rebuilt, and/or modulated under proper sensory feedback, neurological function (e.g., cognition, respiration, limb movement, locomotion, etc.) will likely be reanimated after neurotrauma. The efficacy can be optimized by individualizing multimodal rehabilitation treatments via BCI/RA-integrated drug administration and neuromechanical protheses.

Non-invasive approaches to functional recovery after spinal cord injury: Therapeutic targets and multimodal device interventions.

This paper is an interdisciplinary narrative review of efficacious non-invasive therapies that are increasingly used to restore function in people with chronic spinal cord injuries (SCI). First presented are the secondary injury cascade set in motion by the primary lesion and highlights in therapeutic development for mitigating the acute pathophysiologic process. Then summarized are current pharmacological strategies for modulation of noradrenergic, serotonergic, and dopaminergic neurotransmission to enhance recovery in bench and clinical studies of subacute and chronic SCI. Last examined is how neuromechanical devices (i.e., electrical stimulation, robotic assistance, brain-computer interface, and augmented sensory feedback) could be comprehensively engineered to engage efferent and afferent motosensory pathways to induce neuroplasticity-based neural pattern generation. Emerging evidence shows that computational models of the human neuromusculoskeletal system (i.e., human digital twins) can serve as functionalized anchors to integrate different neuromechanical and pharmacological interventions into a single multimodal prothesis. The system, if appropriately built, may cybernetically optimize treatment outcomes via coordination of heterogeneous biosensory, system output, and control signals. Overall, these rehabilitation protocols involved neuromodulation to evoke beneficial adaptive changes within spared supraspinal, intracord, and peripheral neuromuscular circuits to elicit neurological improvement. Therefore, qualitatively advancing the theoretical understanding of spinal cord neurobiology and neuromechanics is pivotal to designing new ways to reinstate locomotion after SCI. Future research efforts should concentrate on personalizing combination therapies consisting of pharmacological adjuncts, targeted neurobiological and neuromuscular repairs, and brain-computer interfaces, which follow multimodal neuromechanical principles.

ATP and spontaneous calcium oscillations control neural stem cell fate determination in Huntington's disease: a novel approach for cell clock research.

Calcium, the most versatile second messenger, regulates essential biology including crucial cellular events in embryogenesis. We investigated impacts of calcium channels and purinoceptors on neuronal differentiation of normal mouse embryonic stem cells (ESCs), with outcomes being compared to those of in vitro models of Huntington's disease (HD). Intracellular calcium oscillations tracked via real-time fluorescence and luminescence microscopy revealed a significant correlation between calcium transient activity and rhythmic proneuronal transcription factor expression in ESCs stably expressing ASCL-1 or neurogenin-2 promoters fused to luciferase reporter genes. We uncovered that pharmacological manipulation of L-type voltage-gated calcium channels (VGCCs) and purinoceptors induced a two-step process of neuronal differentiation. Specifically, L-type calcium channel-mediated augmentation of spike-like calcium oscillations first promoted stable expression of ASCL-1 in differentiating ESCs, which following P2Y2 purinoceptor activation matured into GABAergic neurons. By contrast, there was neither spike-like calcium oscillations nor responsive P2Y2 receptors in HD-modeling stem cells in vitro. The data shed new light on mechanisms underlying neurogenesis of inhibitory neurons. Moreover, our approach may be tailored to identify pathogenic triggers of other developmental neurological disorders for devising targeted therapies.

A Combinatorial Approach with Cerebellar Tonsil Suspension to Treating Symptomatic Chiari Malformation Type I in Adults: A Retrospective Study.

BACKGROUND: Primary Chiari malformations (CMs) are congenital defects of the skull base and brain. Among the 4 CM types, type I (CM-I) occurs most frequently and may cause somatosensorimotor, autonomic and vision symptoms. Presently, posterior fossa decompression alone (PFD) or with duraplasty (PFDD) and cerebellar tonsil (CbT) shrinkage tactics are standard treatments, albeit inherent issues. There has been no report on devising CbT suspension (CTS) to manage CM-I. OBJECTIVES: 1) To design a CTS protocol that can be used with CbT coagulation (CTC) and PFDD; 2) to evaluate the regimen for feasibility, safety, and efficacy in a retrospective study; and 3) to obtain data for planning prospective studies to validate PFDD + CTC + CTS as a novel approach to treating adult CM-I. METHODS: PFDD + CTC + CTS (n = 17), PFDD + CTC (n = 13), and PFDD (n = 12) were performed for 42 adult patients (age range, 18-55 years; female:male = 27:15) following a balanced study design. Neck Disability Index (NDI), Chicago Chiari Outcome Scale (CCOS), and /magnetic resonance imaging/computed tomography were used to determine postsurgery outcomes for approximately 20 months. RESULTS: Comparing to PFDD + CTC or PFDD, patients receiving PFDD + CTC +CTS operation exhibited significantly improved group average NDI (10.72 ± 3.95%; P = 0.007), CbT elevation distance (7.06 ± 2.42 mm; P < 0.001, Kruskal-Wallis test; 55.7 ± 25.4% higher than the presurgery level; P < 0.001, analysis of variance), and syringomyelia syrinx retraction (P = 0.009, analysis of variance). CONCLUSIONS: The PFDD + CTC + CTS regimen appeared to be safe and potentially more efficacious in patients with CM-I evaluated for the period, relative to PFDD + CTC or PFDD treatment. Future prospective studies were warranted.

Neuromusculoskeletal Modeling-Based Prostheses for Recovery After Spinal Cord Injury.

Concurrent stimulation and reinforcement of motor and sensory pathways has been proposed as an effective approach to restoring function after developmental or acquired neurotrauma. This can be achieved by applying multimodal rehabilitation regimens, such as thought-controlled exoskeletons or epidural electrical stimulation to recover motor pattern generation in individuals with spinal cord injury (SCI). However, the human neuromusculoskeletal (NMS) system has often been oversimplified in designing rehabilitative and assistive devices. As a result, the neuromechanics of the muscles is seldom considered when modeling the relationship between electrical stimulation, mechanical assistance from exoskeletons, and final joint movement. A powerful way to enhance current neurorehabilitation is to develop the next generation prostheses incorporating personalized NMS models of patients. This strategy will enable an individual voluntary interfacing with multiple electromechanical rehabilitation devices targeting key afferent and efferent systems for functional improvement. This narrative review discusses how real-time NMS models can be integrated with finite element (FE) of musculoskeletal tissues and interface multiple assistive and robotic devices with individuals with SCI to promote neural restoration. In particular, the utility of NMS models for optimizing muscle stimulation patterns, tracking functional improvement, monitoring safety, and providing augmented feedback during exercise-based rehabilitation are discussed.

Physical impacts of PLGA scaffolding on hMSCs: Recovery neurobiology insight for implant design to treat spinal cord injury.

Our earlier work generated a powerful platform technology of polymeric scaffolding of stem cells to investigate and treat the injured or diseased central nervous system. However, the reciprocal sequelae between biophysical properties of the polymer and responses of the stem cell have not been examined in situ in lesioned spinal cords. We postulated that implantable synthetic scaffolds, acting through physical features, might affect donor cell behavior and host tissue remodeling. To test this hypothesis, poly(d,l-lactic-co-glycolic acid) (PLGA) in either low/soft or high/hard rigidity was fabricated for carrying adult human bone marrow mesenchymal stromal stem cells (hMSCs). The construct was transplanted into the epicenter of a rat model of acute T9-10 segmental hemisection to evaluate the effect of PLGA rigidity on the therapeutic potential and fate of hMSCs for neural repair. Compared to controls, only treatment with soft PLGA-scaffolded hMSCs significantly improved sensorimotor function via activation of recovery neurobiology mechanisms. The main benefits included inhibiting neuroinflammation and enhancing tissue protection. Also detected in the treated lesion region were expressions of neurotrophic and anti-inflammatory factors together with proliferation of endogenous neural stem cells, impacts likely derived from hMSCs' functional multipotency maintained by soft PLGA-scaffolding. Conversely, hard rigidity PLGA activated mechanotransduction and mesoderm lineage differentiation of hMSCs that ectopically produced bone, cartilage and muscle markers in neural parenchyma. The findings collectively suggested that the physical texture of polymeric scaffolds should be tailored for sustaining the stemness of hMSCs to constructively interact with the spinal cord for functional restoration.

Functional Multipotency of Stem Cells and Recovery Neurobiology of Injured Spinal Cords.

This invited concise review was written for the special issue of Cell Transplantation to celebrate the 25th anniversary of the American Society for Neural Therapy and Repair (ASNTR). I aimed to present a succinct summary of two interweaved lines of research work carried out by my team members and collaborators over the past decade. Since the middle of the 20th century, biomedical research has been driven overwhelmingly by molecular technology-based focal endeavors. Our investigative undertakings, however, were orchestrated to define and propose novel theoretical frameworks to enhance the field's ability to overcome complex neurological disorders. The effort has engendered two important academic concepts: Functional Multipotency of Stem Cells, and Recovery Neurobiology of Injured Spinal Cords. Establishing these theories was facilitated by academic insight gleaned from stem cell-based multimodal cross-examination studies using tactics of material science, systems neurobiology, glial biology, and neural oncology. It should be emphasized that the collegial environment cultivated by the mission of the ASNTR greatly promoted the efficacy of inter-laboratory collaborations. Notably, our findings have shed new light on fundamentals of stem cell biology and adult mammalian spinal cord neurobiology. Moreover, the novel academic leads have enabled determination of potential therapeutic targets to restore function for spinal cord injury and neurodegenerative diseases.

Functional multipotency of stem cells: Biological traits gleaned from neural progeny studies.

In this review, a stem cell concept, initially defined by the author more than 10 years ago focusing on neural stem cells, has been systematically refined and updated. Relative to the conventional view which touched principally on the totipotency, pluripotentcy and multipotency of cell lineage differentiation (e.g., the ability of neural stem cells to grow into all three types of neural cells), accumulated data obtained by other researchers and my own team promoted me and my colleagues to propose and establish a new biological concept: Functional Multipotency of Stem Cells. The goal is to recognize the biofunctional multipotency of the stem cell to mediate homeostasis during development and adulthood. Under this academic context, an enriched repertoire of signaling, epigenetic and genetic events has been revealed. Such insight has enabled appreciation of the wide range of molecular tactics the stem cell can use at each developmental or adult stage. The multifunctionality allows stem cells to properly migrate, differentiate, and integrate into as well as prepare, influence, and repair the neighboring cells to steer the micro- and macro-environment towards the formation and self-maintenance of a physiological organ and system. It has been demonstrated that embracing this concept of the stem cell's "functional multipotency" is pivotal for correctly, efficiently, and optimally investigating stem cells to advance fundamental biology and therapeutic translation.

Spinal cord astrocytomas: progresses in experimental and clinical investigations for developing recovery neurobiology-based novel therapies.

Spinal cord astrocytomas (SCAs) have discernibly unique signatures in regards to epidemiology, clinical oncological features, genetic markers, pathophysiology, and research and therapeutic challenges. Overall, there are presently very limited clinical management options for high grade SCAs despite progresses made in validating key molecular markers and standardizing tumor classification. The endeavors were aimed to improve diagnosis, therapy design and prognosis assessment, as well as to define more effective oncolytic targets. Efficacious treatment for high grade SCAs still remains an unmet medical demand. This review is therefore focused on research state updates that have been made upon analyzing clinical characteristics, diagnostic classification, genetic and molecular features, tumor initiation cell biology, and current management options for SCAs. Particular emphasis was given to basic and translational research endeavors targeting SCAs, including establishment of experimental models, exploration of unique profiles of SCA stem cell-like tumor survival cells, characterization of special requirements for effective therapeutic delivery into the spinal cord, and development of donor stem cell-based gene-directed enzyme prodrug therapy. We concluded that precise understanding of molecular oncology, tumor survival mechanisms (e.g., drug resistance, metastasis, and cancer stem cells/tumor survival cells), and principles of Recovery Neurobiology can help to create clinically meaningful experimental models of SCAs. Establishment of such systems will expedite the discovery of efficacious therapies that not only kill tumor cells but simultaneously preserve and improve residual neural function.

An ioMRI-assisted case of cervical intramedullary diffuse glioma resection.

PURPOSE: To date, application of intraoperative magnetic resonance imaging (ioMRI) to enhance surgical quality for spinal intramedullary neoplastic lesions has been rarely reported. Moreover, in developing countries or regions, ioMRI accessibility remains very limited. This report describes a technology design of high-field ioMRI accessible for multioperation rooms via a case presentation of an imaging-assisted surgical excision of human cervical spinal cord diffuse glioma. PATIENT AND METHODS: The patient was a 44-year-old woman with symptomatic and progressive C2-5 intramedullary diffuse glioma (IDG). Our ioMRI system was designed and arranged with accessibility to multiple operation rooms, which was used to assure more complete spinal cord or brain tumor removal. The intraoperational diagnostic aspects and the system setup technical details are presented for future applications of the system in hospitals where a designated ioMRI suite is not available. RESULTS: After a conventionally defined complete removal of C2-C5 IDG using a well-established surgical approach, ioMRI examination was able to detect residual tumor tissues that were indistinguishable under the surgical microscope. The IDG clusters were subsequently excised. The operation regimen resulted in a gross total elimination of the tumor, which enabled the patient to show very satisfactory postsurgery recovery and prognosis. CONCLUSION: ioMRI-assisted surgical removal of cervical spinal cord diffuse glioma should be systematically developed and applied to enhance therapeutic efficacy. The reported logistic flow of operating room tasks and imaging technical management are innovative for performing the tumor removal procedures in hospitals where designated ioMRI surgical suites do not exist. Critically, we emphasize implementation of stringent quality control measures for patient transportation safety and contamination prevention in establishing and maintaining such a system.

Updates on Human Neural Stem Cells: From Generation, Maintenance, and Differentiation to Applications in Spinal Cord Injury Research.

Human neural stem cells (hNSCs) and human induced pluripotent stem cells (hiPSCs) have been the primary focuses in basic science and translational research as well as in investigative clinical applications. Therefore, the capability to perform reliable derivation, effective expansion, and long-term maintenance of uncommitted hNSCs and hiPSCs and their targeted phenotypic differentiations through applying chemically and biologically defined medium in vitro is essential for expanding and enriching the fundamental and technological capacities of stem cell biology and regenerative medicine. In this chapter, we systematically summarized a set of protocols and unique procedures that have been developed in the laboratories of Prof. Teng and his collaborators. These regimens have been, over the years, reproducibly and productively used to derive, propagate, maintain, and differentiate hNSCs, including those derived from hiPSCs. We emphasize the multimodal methodologies that were pioneered and established in our laboratories for characterizing functional multipotency of stem cells and its value in basic science as well as translational biomedical studies.

Cancer Stem Cells or Tumor Survival Cells?

Research endeavors originally generated stem cell definitions for the purpose of describing normally sustainable developmental and tissue turnover processes in various species, including humans. The notion of investigating cells that possess a vague capacity of "stamm (phylum)" can be traced back to the late 19th century, mainly concentrating on cells that could produce the germline or the entire blood system. Lately, such undertakings have been recapitulated for oncogenesis, tumor growth, and cancer cell resistance to oncolytic therapies. However, due to the complexity and basic life-origin mechanisms comprising the genetic and epigenetic repertoire of the stemness in every developing or growing cell, presently there are ongoing debates regarding the biological essentials of the stem cell-like tumor initiation cells (ie, cancer stem cells; CSCs). This conceptual analysis focuses on the potential pitfalls of extrapolating that CSCs bear major traits of stemness. We propose a novel nomenclature of Tumor Survival Cells (TSCs) to further define tumor cells behaving like CSCs, based on the ruthless and detrimental features of Cancer Cell Survivology that appears fundamentally different from stem cell biology. Hence, precise academic separation of TSCs from all the stem cell-related labels applied to these unique tumor cells may help to improve scientific reasoning and strategies to decode the desperado-like survival behaviors of TSCs to eventually overcome cancer.

Establishing an Organotypic System for Investigating Multimodal Neural Repair Effects of Human Mesenchymal Stromal Stem Cells.

Human mesenchymal stromal stem cells (hMSCs) hold regenerative medicine potential due to their availability, in vitro expansion readiness, and autologous feasibility. For neural repair, hMSCs show translational value in research on stroke, spinal cord injury (SCI), and traumatic brain injury. It is pivotal to establish multimodal in vitro systems to investigate molecular mechanisms underlying neural actions of hMSCs. Here, we describe a platform protocol on how to set up organotypic co-cultures of hMSCs (alone or polymer-scaffolded) with explanted adult rat dorsal root ganglia (DRGs) to determine neural injury and recovery events for designing implants to counteract neurotrauma sequelae. We emphasize in vitro hMSC propagation, polymer scaffolding, hMSC stemness maintenance, hMSC-DRG interaction profiling, and analytical formulas of neuroinflammation, trophic factor expression, DRG neurite outgrowth and tropic tracking, and in vivo verification of tailored implants in rodent models of SCI. © 2018 by John Wiley & Sons, Inc.