Investigating the NLRP3 inflammasome and its regulator miR-223-3p in multiple sclerosis and experimental demyelination.

Innate immune signaling pathways are essential mediators of inflammation and repair following myelin injury. Inflammasome activation has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models, although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not completely understood. Herein, we investigated the NLRP3 (NBD-, LRR- and pyrin domain-containing protein 3) inflammasome and its endogenous regulator microRNA-223-3p within the demyelinated CNS in both MS and an animal model of focal demyelination. We observed that NLRP3 inflammasome components and microRNA-223-3p were upregulated at sites of myelin injury within activated macrophages and microglia. Both microRNA-223-3p and a small-molecule NLRP3 inhibitor, MCC950, suppressed inflammasome activation in macrophages and microglia in vitro; compared with microglia, macrophages were more prone to inflammasome activation in vitro. Finally, systemic delivery of MCC950 to mice following lysolecithin-induced demyelination resulted in a significant reduction in axonal injury within demyelinated lesions. In conclusion, we demonstrate that NLRP3 inflammasome activity by macrophages and microglia is a critical component of the inflammatory microenvironment following demyelination and represents a potential therapeutic target for inflammatory-mediated demyelinating diseases, including MS. Cover Image for this issue: https://doi.org/10.1111/jnc.15422.

Research Priorities of the Australian Chiropractic Profession: A Cross-Sectional Survey of Academics and Practitioners.

OBJECTIVE: The purpose of this study was to explore the research priorities of Australian practicing chiropractors and academics across a set of research domains to determine the agreement or disagreement based on these domains. METHODS: We conducted a pilot-tested online survey focusing on the following 5 principal research domains: basic science, conditions (disorders chiropractors may encounter), patient subgroups, clinical interventions, and practice and public health/health services. Responses were sought regarding support for funding research scholarships, practice-based research networks, scientific conferences/symposia, journals, and existing research agendas. Data were collected (February 19 to May 24, 2019) from a sample of chiropractic academics (n1 = 33) representing 4 Australian programs and practicing chiropractors (n2 = 340). Collected data were ranked and analyzed to determine agreement across domains and items. RESULTS: There was agreement between the 2 groups across the majority (>90%) of domain items. The closest agreement and highest rankings were achieved for the "clinical interventions and practice" and "conditions" domains. Disagreement was observed within specific domain items, such as patient subgroups (infants), and for 1 intervention (chiropractic-specific techniques). Disagreement also occurred outside of the main domains, including research agenda support and funding. CONCLUSIONS: There was overall agreement between practicing chiropractors and academics across most research area domain items, which should help facilitate consensus-led development of any potential Australian Chiropractic research agenda. Disagreements across specific domain items, such as population subgroups, interventions, and funding require further investigation.

Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis.

BACKGROUND: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. OBJECTIVES: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. METHODS: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. RESULTS: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. CONCLUSIONS: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.

TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation.

TAAR1 is a neuroregulator with emerging evidence suggesting a role in immunomodulation. Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Here, we investigate TAAR1 expression in human primary monocytes, peripherally-derived macrophages, and MS brain tissue. RT-qPCR was used to assess TAAR1 levels in MS monocytes. Using a previously validated anti-human TAAR1 antibody and fluorescence microscopy, TAAR1 protein was visualized in lipopolysaccharide-stimulated or basal human macrophages, as well as macrophage/microglia populations surrounding, bordering, and within a mixed active/inactive MS lesion. In vivo, TAAR1 mRNA expression was significantly lower in MS monocytes compared to age- and sex-matched healthy controls. In vitro, TAAR1 protein showed a predominant nuclear localization in quiescent/control macrophages with a shift to a diffuse intracellular distribution following lipopolysaccharide-induced activation. In brain tissue, TAAR1 protein was predominantly expressed in macrophages/microglia within the border region of mixed active/inactive MS lesions. Considering that TAAR1-mediated anti-inflammatory effects have been previously reported, decreased mRNA in MS patients suggests possible pathophysiologic relevance. A shift in TAAR1 localization following pro-inflammatory activation suggests its function is altered in pro-inflammatory states, while TAAR1-expressing macrophages/microglia bordering an MS lesion supports TAAR1 as a novel pharmacological target in cells directly implicated in MS neuroinflammation.

Vigorous cool room treadmill training to improve walking ability in people with multiple sclerosis who use ambulatory assistive devices: a feasibility study.

BACKGROUND: Aerobic training has the potential to restore function, stimulate brain repair, and reduce inflammation in people with Multiple Sclerosis (MS). However, disability, fatigue, and heat sensitivity are major barriers to exercise for people with MS. We aimed to determine the feasibility of conducting vigorous harness-supported treadmill training in a room cooled to 16 °C (10 weeks; 3times/week) and examine the longer-term effects on markers of function, brain repair, and inflammation among those using ambulatory aids. METHODS: Ten participants (9 females) aged 29 to 74 years with an Expanded Disability Status Scale ranging from 6 to 7 underwent training (40 to 65% heart rate reserve) starting at 80% self-selected walking speed. Feasibility of conducting vigorous training was assessed using a checklist, which included attendance rates, number of missed appointments, reasons for not attending, adverse events, safety hazards during training, reasons for dropout, tolerance to training load, subjective reporting of symptom worsening during and after exercise, and physiological responses to exercise. Functional outcomes were assessed before, after, and 3 months after training. Walking ability was measured using Timed 25 Foot Walk test and on an instrumented walkway at both fast and self-selected speeds. Fatigue was measured using fatigue/energy/vitality sub-scale of 36-Item Short-Form (SF-36) Health Survey, Fatigue Severity Scale, modified Fatigue Impact Scale. Aerobic fitness (maximal oxygen consumption) was measured using maximal graded exercise test (GXT). Quality-of-life was measured using SF-36 Health Survey. Serum levels of neurotrophin (brain-derived neurotrophic factor) and cytokine (interleukin-6) were assessed before and after GXT. RESULTS: Eight of the ten participants completed training (attendance rates ≥ 80%). No adverse events were observed. Fast walking speed (cm/s), gait quality (double-support (%)) while walking at self-selected speed, fatigue (modified Fatigue Impact Scale), fitness (maximal workload achieved during GXT), and quality-of-life (physical functioning sub-scale of SF-36) improved significantly after training, and improvements were sustained after 3-months. Improvements in fitness (maximal respiratory exchange ratio and maximal oxygen consumption during GXT) were associated with increased brain-derived neurotrophic factor and decreased interleukin-6. CONCLUSION: Vigorous cool room training is feasible and can potentially improve walking, fatigue, fitness, and quality-of-life among people with moderate to severe MS-related disability. TRIAL REGISTRATION: The study was approved by the Newfoundland and Labrador Health Research Ethics Board (reference number: 2018.088) on 11/07/2018 prior to the enrollment of first participant (retrospectively registered at ClinicalTrials.gov: NCT04066972. Registered on 26 August 2019.

MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis.

Multiple sclerosis is a chronic inflammatory, demyelinating, and neurodegenerative disease affecting the brain, spinal cord and optic nerves. Neuronal damage is triggered by various harmful factors that engage diverse signalling cascades in neurons; thus, therapeutic approaches to protect neurons will need to focus on agents that can target multiple biological processes. We have therefore focused our attention on microRNAs: small non-coding RNAs that primarily function as post-transcriptional regulators that target messenger RNAs and repress their translation into proteins. A single microRNA can target many functionally related messenger RNAs making microRNAs powerful epigenetic regulators. Dysregulation of microRNAs has been described in many neurodegenerative diseases including multiple sclerosis. Here, we report that two microRNAs, miR-223-3p and miR-27a-3p, are upregulated in neurons in the experimental autoimmune encephalomyelitis mouse model of CNS inflammation and in grey matter-containing multiple sclerosis lesions. Prior work has shown peripheral blood mononuclear cell conditioned media causes sublethal degeneration of neurons in culture. We find overexpression of miR-27a-3p or miR-223-3p protects dissociated cortical neurons from condition media mediated degeneration. Introduction of miR-223-3p in vivo in mouse retinal ganglion cells protects their axons from degeneration in experimental autoimmune encephalomyelitis. In silico analysis revealed that messenger RNAs involved in glutamate receptor signalling are enriched as miR-27a-3p and miR-223-3p targets. We observe that antagonism of NMDA and AMPA type glutamate receptors protects neurons from condition media dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by targeting messenger RNAs involved in glutamate receptor signalling.

Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis.

Elucidation of distinct T-cell subsets involved in multiple sclerosis immune-pathophysiology continues to be of considerable interest since an ultimate goal is to more selectively target the aberrant immune response operating in individual patients. While abnormalities of both effector (Teff) and regulatory (Treg) T cells have been reported in patients with multiple sclerosis, prior studies have mostly assessed average abnormalities in either limb of the immune response, rather than both at the same time, which limits the ability to evaluate the balance between effectors and regulators operating in the same patient. Assessing both phenotypic and functional responses of Teffs and Tregs has also proven important. In studies of adults with multiple sclerosis, in whom biological disease onset likely started many years prior to the immune assessments, an added challenge for any reported abnormality is whether the abnormality indeed contributes to the disease (and hence of interest to target therapeutically) or merely develops consequent to inflammatory injury (in which case efforts to develop targeted therapies are unlikely to be beneficial). Paediatric-onset multiple sclerosis, though rare, offers a unique window into early disease mechanisms. Here, we carried out a comprehensive integrated study, simultaneously assessing phenotype and functional responses of both effector and regulatory T cells in the same children with multiple sclerosis, monophasic inflammatory CNS disorders, and healthy controls, recruited as part of the multicentre prospective Canadian Pediatric Demyelinating Disease Study (CPDDS). Stringent standard operating procedures were developed and uniformly applied to procure, process and subsequently analyse peripheral blood cells using rigorously applied multi-parametric flow cytometry panels and miniaturized functional assays validated for use with cryopreserved cells. We found abnormally increased frequencies and exaggerated pro-inflammatory responses of CD8+CD161highTCR-Vα7.2+ MAIT T cells and CD4+CCR2+CCR5+ Teffs in paediatric-onset multiple sclerosis, compared to both control groups. CD4+CD25hiCD127lowFOXP3+ Tregs of children with multiple sclerosis exhibited deficient suppressive capacity, including diminished capacity to suppress disease-implicated Teffs. In turn, the implicated Teffs of multiple sclerosis patients were relatively resistant to suppression by normal Tregs. An abnormal Teff/Treg ratio at the individual child level best distinguished multiple sclerosis children from controls. We implicate abnormalities in both frequencies and functional responses of distinct pro-inflammatory CD4 and CD8 T cell subsets, as well as Treg function, in paediatric-onset multiple sclerosis, and suggest that mechanisms contributing to early multiple sclerosis development differ across individuals, reflecting an excess abnormality in either Teff or Treg limbs of the T cell response, or a combination of lesser abnormalities in both limbs.

miR-223 promotes regenerative myeloid cell phenotype and function in the demyelinated central nervous system.

In the injured central nervous system, myeloid cells, including macrophages and microglia, are key contributors to both myelin injury and repair. This immense plasticity emphasizes the need to further understand the precise molecular mechanisms that contribute to the dynamic regulation of myeloid cell polarization and function. Herein, we demonstrate that miR-223 is upregulated in multiple sclerosis (MS) patient monocytes and the alternatively-activated and tissue-regenerating M2-polarized human macrophages and microglia. Using miR-223 knock-out mice, we observed that miR-223 is dispensable for maximal pro-inflammatory responses, but is required for efficient M2-associated phenotype and function, including phagocytosis. Using the lysolecithin animal model, we further demonstrate that miR-223 is required to efficiently clear myelin debris and promote remyelination. These results suggest miR-223 constrains neuroinflammation while also promoting repair, a finding of important pathophysiological relevance to MS as well as other neurodegenerative diseases.

The usefulness of large sample size patient dose audits for optimisation of CT automatic exposure control (AEC) settings.

The aim of this study was to demonstrate the usefulness of large sample size patient dose audits for optimisation of CT automatic exposure control (AEC) settings, even when the investigation is limited to only three scanners at a single institution. Pre-optimisation patient dose audits of common CT examinations (n > 200 for each protocol) on three CT scanners (two Philips Brilliance and one Toshiba Aquilion) using radiology information system (RIS) data were conducted showing sub-optimal CT AEC performance on the Toshiba scanner. Based on these results, an optimisation exercise was carried out on the non-optimally performing scanner by phantom measurement and investigation of system configuration. Post-optimisation patient dose audits were subsequently carried out to assess the success of the optimisation exercise demonstrating standardisation of doses; median dose-length-product values were reduced by up to 43% on the sub-optimal scanner without any adverse effect on clinical image quality. This study has demonstrated that large sample patient dose audits using RIS data can be instrumental in identifying and rectifying sub-optimal CT AEC performance, even when the investigation is limited to only three scanners at a single institution.

The roles of extracellular vesicle microRNAs in the central nervous system.

MicroRNAs (miRNAs) are small, highly conserved non-coding RNA molecules that post-transcriptionally regulate protein expression and most biological processes. Mature miRNAs are recruited to the RNA-induced silencing complex (RISC) and target mRNAs via complementary base-pairing, thus resulting in translational inhibition and/or transcript degradation. Here, we present evidence implicating miRNAs within extracellular vesicles (EVs), including microvesicles and exosomes, as mediators of central nervous system (CNS) development, homeostasis, and injury. EVs are extracellular vesicles that are secreted by all cells and represent a novel method of intercellular communication. In glial cells, the transfer of miRNAs via EVs can alter the function of recipient cells and significantly impacts cellular mechanisms involved in both injury and repair. This review discusses the value of information to be gained by studying miRNAs within EVs in the context of CNS diseases and their potential use in the development of novel disease biomarkers and therapeutic strategies.

Differential transcriptional response profiles in human myeloid cell populations.

This study examines the transcriptional profiles of human adult brain-derived microglia in response to in vitro activating conditions previously used to polarize systemic myeloid cells into M1 and M2 phenotypes. A comparative study is done with monocyte-derived macrophages (MDMs), a myeloid cell type that also participates in disease relevant tissue injury and repair processes in the CNS. Current markers used to distinguish microglia and MDMs have been defined under homeostatic conditions. We observe that gene expression profiles of M1 microglia and MDMs overlap with an overrepresentation of immune-related pathways. M2 microglia and MDMs have distinct transcriptional signatures. Upregulated genes in M2 microglia favor neural-related pathways whereas upregulated genes in M2 MDMs are mostly involved in antigen presentation. Our microarray screen identifies candidate molecules that can potentially distinguish microglia and MDMs under all activation conditions. To be determined is how our observations made using conventional in vitro polarization translate into cellular responses to the complex combination of signals encountered in neurologic disease states.

Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis.

BACKGROUND: The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated. METHODS: We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells. RESULTS: Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease. CONCLUSIONS: Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.

The management of common recurrent headaches by chiropractors: a descriptive analysis of a nationally representative survey.

BACKGROUND: Headache management is common within chiropractic clinical settings; however, little is yet known about how this provider group manage headache sufferers. The aim of this study is to report on the prevalence of headache patients found within routine chiropractic practice and to assess how chiropractors approach key aspects of headache management applicable to primary care settings. METHODS: A 31-item cross-sectional survey was distributed to a national sample of chiropractors (n = 1050) to report on practitioner approach to headache diagnosis, interdisciplinary collaboration, treatment and outcome assessment of headache patients who present with recurrent headache disorders. RESULTS: The survey attracted a response rate of 36% (n = 381). One in five new patients present to chiropractors with a chief complaint of headache. The majority of chiropractors provide headache diagnosis for common primary (84.6%) and secondary (90.4%) headaches using formal headache classification criteria. Interdisciplinary referral for headache management was most often with CAM providers followed by GPs. Advice on headache triggers, stress management, spinal manipulation, soft tissue therapies and prescriptive neck exercises were the most common therapeutic approaches to headache management. CONCLUSION: Headache patients make up a substantial proportion of chiropractic caseload. The majority of chiropractors managing headache engage in headache diagnosis and interdisciplinary patient management. More research information is needed to understand the headache types and level of headache chronicity and disability common to chiropractic patient populations to further assess the healthcare needs of this patient population.

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells.

Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-ß compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-ß-treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-ß-treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte-derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti-inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair.

A critical review of manual therapy use for headache disorders: prevalence, profiles, motivations, communication and self-reported effectiveness.

BACKGROUND: Despite the expansion of conventional medical treatments for headache, many sufferers of common recurrent headache disorders seek help outside of medical settings. The aim of this paper is to evaluate research studies on the prevalence of patient use of manual therapies for the treatment of headache and the key factors associated with this patient population. METHODS: This critical review of the peer-reviewed literature identified 35 papers reporting findings from new empirical research regarding the prevalence, profiles, motivations, communication and self-reported effectiveness of manual therapy use amongst those with headache disorders. RESULTS: While available data was limited and studies had considerable methodological limitations, the use of manual therapy appears to be the most common non-medical treatment utilized for the management of common recurrent headaches. The most common reason for choosing this type of treatment was seeking pain relief. While a high percentage of these patients likely continue with concurrent medical care, around half may not be disclosing the use of this treatment to their medical doctor. CONCLUSIONS: There is a need for more rigorous public health and health services research in order to assess the role, safety, utilization and financial costs associated with manual therapy treatment for headache. Primary healthcare providers should be mindful of the use of this highly popular approach to headache management in order to help facilitate safe, effective and coordinated care.

Complementary and Alternative Medicine Use Among US Adults With Headache or Migraine: Results from the 2012 National Health Interview Survey.

BACKGROUND: Given the safety concerns regarding pharmacological agents, and the considerable impact of headache and migraine on the sufferer's quality of life, many people seek other treatment options beyond conventional medication and care to address their symptoms; this includes complementary and alternative medicine (CAM). Some CAM interventions have shown promising results in clinical trials of headache and migraine management. Nonetheless, there has been little research exploring the reasons for using CAM, and the types of CAM used, among this population. OBJECTIVE: The study aimed to answer the following questions: (1) Which CAM modalities are used most frequently among migraine/headache sufferers? and (2) What are the self-reported reasons for CAM use among migraine/headache sufferers? METHODS: This secondary analysis of data from the 2012 U.S. NHIS (a national cross-sectional survey) examined the use of CAM among migraine/headache sufferers, including the main reasons related to CAM use. Data were weighted and analyzed using STATA 14.0. RESULTS: The sample of 34,525 adults included 6558 (18.7%) headache/migraine sufferers. Of the headache/migraine sufferers, a substantial proportion (37.6%, n = 2427) used CAM for various conditions; however, CAM use specifically for headache/migraine was much less prevalent (3.3%, n = 216). Of those who used CAM for headache/migraine, about half used CAM in conjunction with prescription (47.8%, n = 100) or over-the-counter medication (55.1%, n = 113). As severity of headache/migraine increased so did the likelihood of using CAM (severe migraine odds ratio [OR] = 2.32; 95% confidence interval [CI]: 1.41, 3.82; both recurring headache/severe migraine OR = 3.36; 95% CI: 2.08, 5.43; when compared to those with recurring headache only). The most frequently used CAM modality among all headache/migraine sufferers (N = 6558) was manipulative therapy (22.0%, n = 1317), herbal supplementation (21.7%, n = 1389) and mind-body therapy (17.9%, n = 1100). The top 3 reasons for using CAM for headache were general wellness (28.7%, n = 60/209), improving overall health (26.8%, n = 56/209), and reducing stress (16.7%, n = 35/209). CONCLUSIONS: Although CAM is used by many sufferers of headache/migraine, the use of CAM specifically for the treatment of headache/migraine is relatively low in the United States. The study also assesses the key differences of CAM use among headache/migraine sufferers in NHIS 2012 compared with those in NHIS 2007, and identifies shortfalls in the evidence-base of several CAM modalities used by U.S. adults for headache/migraine. This information may assist health providers and consumers in making informed decisions about the safest and most appropriate approach to managing headache/migraine.

Direct and indirect effects of immune and central nervous system-resident cells on human oligodendrocyte progenitor cell differentiation.

In multiple sclerosis, successful remyelination within the injured CNS is largely dependent on the survival and differentiation of oligodendrocyte progenitor cells. During inflammatory injury, oligodendrocytes and oligodendrocyte progenitor cells within lesion sites are exposed to secreted products derived from both infiltrating immune cell subsets and CNS-resident cells. Such products may be considered either proinflammatory or anti-inflammatory and have the potential to contribute to both injury and repair processes. Within the CNS, astrocytes also contribute significantly to oligodendrocyte biology during development and following inflammatory injury. The overall objective of the current study was to determine how functionally distinct proinflammatory and anti-inflammatory human immune cell subsets, implicated in multiple sclerosis, can directly and/or indirectly (via astrocytes) impact human oligodendrocyte progenitor cell survival and differentiation. Proinflammatory T cell (Th1/Th17) and M1-polarized myeloid cell supernatants had a direct cytotoxic effect on human A2B5(+) neural progenitors, resulting in decreased O4(+) and GalC(+) oligodendrocyte lineage cells. Astrocyte-conditioned media collected from astrocytes pre-exposed to the same proinflammatory supernatants also resulted in decreased oligodendrocyte progenitor cell differentiation without an apparent increase in cell death and was mediated through astrocyte-derived CXCL10, yet this decrease in differentiation was not observed in the more differentiated oligodendrocytes. Th2 and M2 macrophage or microglia supernatants had neither a direct nor an indirect impact on oligodendrocyte progenitor cell differentiation. We conclude that proinflammatory immune cell responses can directly and indirectly (through astrocytes) impact the fate of immature oligodendrocyte-lineage cells, with oligodendrocyte progenitor cells more vulnerable to injury compared with mature oligodendrocytes.

The Interface of Clinical Decision-Making With Study Protocols for Knowledge Translation From a Walking Recovery Trial.

BACKGROUND AND PURPOSE: Despite efforts to translate knowledge into clinical practice, barriers often arise in adapting the strict protocols of a randomized, controlled trial (RCT) to the individual patient. The Locomotor Experience Applied Post-Stroke (LEAPS) RCT demonstrated equal effectiveness of 2 intervention protocols for walking recovery poststroke; both protocols were more effective than usual care physical therapy. The purpose of this article was to provide knowledge-translation tools to facilitate implementation of the LEAPS RCT protocols into clinical practice. METHODS: Participants from 2 of the trial's intervention arms: (1) early Locomotor Training Program (LTP) and (2) Home Exercise Program (HEP) were chosen for case presentation. The two cases illustrate how the protocols are used in synergy with individual patient presentations and clinical expertise. Decision algorithms and guidelines for progression represent the interface between implementation of an RCT standardized intervention protocol and clinical decision-making. OUTCOMES: In each case, the participant presents with a distinct clinical challenge that the therapist addresses by integrating the participant's unique presentation with the therapist's expertise while maintaining fidelity to the LEAPS protocol. Both participants progressed through an increasingly challenging intervention despite their own unique presentation. SUMMARY: Decision algorithms and exercise progression for the LTP and HEP protocols facilitate translation of the RCT protocol to the real world of clinical practice. The two case examples to facilitate translation of the LEAPS RCT into clinical practice by enhancing understanding of the protocols, their progression, and their application to individual participants.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A147).

The treatment of migraine patients within chiropractic: analysis of a nationally representative survey of 1869 chiropractors.

BACKGROUND: While the clinical role of manual therapies in migraine management is unclear, the use of chiropractors for this condition is considerable. The aim of this study is to evaluate the prevalence and characteristics of chiropractors who frequently manage patients with migraine. METHODS: A national cross-sectional survey of chiropractors collected information on practitioner characteristics, clinical management characteristics and practice settings. A secondary analysis was conducted on 1869 respondents who reported on their migraine caseload to determine the predictors associated with the frequent management of patients with migraine. RESULTS: A large proportion of chiropractors report having a high migraine caseload (HMC) (n = 990; 53.0%). The strongest factors predicting a chiropractor having a HMC include the frequent treatment of patients with axial neck pain (OR = 2.89; 95%CI: 1.18, 7.07), thoracic pain (referred/radicular) (OR = 2.52; 95%CI: 1.58, 3.21) and non-musculoskeletal disorders (OR = 3.06; 95%CI: 2.13, 4.39). CONCLUSIONS: Several practice-setting and clinical management characteristics are associated with chiropractors managing a HMC. These findings raise key questions about the therapeutic approach to chiropractic migraine management that deserves further examination. There is a need for more primary research to assess the approach to headache and migraine management provided by chiropractors and to understand the prevalence, burden and comorbidities associated with migraine found within chiropractic patient populations. This information is vital in helping to inform safe, effective and coordinated care for migraine sufferers within the wider health system.

A workforce survey of Australian chiropractic: the profile and practice features of a nationally representative sample of 2,005 chiropractors.

BACKGROUND: This paper reports the profile of the Australian chiropractic workforce and characteristics of chiropractic care from a large nationally-representative sample of practitioners. METHODS: A 21-item questionnaire examining practitioner, practice and clinical management characteristics was distributed to all registered chiropractors (n = 4,684) in Australia in 2015 via both online and hard copy mail out. RESULTS: The survey attracted a response rate of 43% (n = 2,005), and the sample is largely representative of the national chiropractic workforce on a number of key indicators. The average age of the chiropractors was 42.1 years, nearly two-thirds are male, and the vast majority hold a bachelor degree or higher qualification. Australian chiropractors are focused upon treating people across a wide age range who mainly present with musculoskeletal conditions. Australian chiropractors have referral relationships with a range of conventional, allied health and complementary medicine (CAM) providers. CONCLUSION: The chiropractic profession represents a substantial component of the contemporary Australian health care system with chiropractors managing an estimated 21.3 million patient visits per year. While the Australian chiropractic workforce is well educated, research engagement and research capacity remains sub-optimal and there is much room for further capacity building to help chiropractic reach full potential as a key integrated profession within an evidence-based health care system. Further rich, in-depth research is warranted to improve our understanding of the role of chiropractic within the Australian health care system.