IL-4 Signaling Drives a Unique Arginase\u3csup\u3e+\u3c/sup\u3e/IL-1β\u3csup\u3e+\u3c/sup\u3e Microglia Phenotype and Recruits Macrophages to the Inflammatory CNS: Consequences of Age-Related Deficits in IL-4Rα after Traumatic Spinal Cord Injury

Alternative activation of microglia/macrophages (M2a) by interleukin (IL)-4 is purported to support intrinsic growth and repair processes after CNS injury. Nonetheless, alternative activation of microglia is poorly understood in vivo, particularly in the context of inflammation, injury, and aging. Here, we show that aged mice (18-19 months) had reduced functional recovery after spinal cord injury (SCI) associated with impaired induction of IL-4 receptor α (IL-4Rα) on microglia. The failure to successfully promote an IL-4/IL-4Rα response in aged mice resulted in attenuated arginase (M2a associated), IL-1β, and chemokine ligand 2 (CCL2) expression, and diminished recruitment of IL-4Rα+ macrophages to the injured spinal cord. Furthermore, the link between reduced IL-4Rα expression and reduced arginase, IL-1β, and CCL2 expression was confirmed using adult IL-4Rα knock-out (IL-4RαKO) mice. To better understand IL-4Rα-mediated regulation of active microglia, a series of studies was completed in mice that were peripherally injected with lipopolysaccharide and later provided IL-4 by intracerebroventricular infusion. These immune-based studies demonstrate that inflammatory-induced IL-4Rα upregulation on microglia was required for the induction of arginase by IL-4. In addition, IL-4-mediated reprogramming of active microglia enhanced neurite growth ex vivo and increased inflammatory gene expression (i.e., IL-1β and CCL2) and the corresponding recruitment of CCR2+/IL-4Rα+/arginase+ myeloid cells in vivo. IL-4 reprogrammed active microglia to a unique and previously unreported phenotype (arginase+/IL-1β+) that augmented neurite growth and enhanced recruitment of peripheral IL-4Rα+ myeloid cells to the CNS. Moreover, this key signaling cascade was impaired with age corresponding with reduced functional recovery after SCI

Development of a collaborative model of low back pain: report from the 2017 NASS consensus meeting

Low back pain (LBP) is a multifactorial problem with complex interactions among many biological, psychological and social factors. It is difficult to fully appreciate this complexity because the knowledge necessary to do so is distributed over many areas of expertise that span the biopsychosocial domains.This study describes the collaborative modeling process, undertaken among a group of participants with diverse expertise in LBP, to build a model to enhance understanding and communicate the complexity of the LBP problem.The study involved generating individual models that represented participants' understanding of the LBP problem using fuzzy cognitive mapping (FCM), and 4 subsequent phases of consultation and consensus with the participants to characterize and refine the interpretation of the FCMs.The phases consisted of: proposal of Categories for clustering of model Components; preliminary evaluation of structure, composition and focal areas of participant's FCMs; refinement of Categories and Components with consensus meeting; generation of final structure and composition of individual participant's FCMs. Descriptive statistics were applied to the structural and composition metrics of individual FCMs to aid interpretation.From 38 invited contributors, 29 (76%) agreed to participate. They represented 9 disciplines and 8 countries. Participants' models included 729 Components, with an average of 25 (SD = 7) per model. After the final FCM refinement process (Components from separate FCMs that used similar terms were combined, and Components from an FCM that included multiple terms were separated), there were 147 Components allocated to ten Categories. Although individual models varied in their structure and composition, a common opinion emerged that psychological factors are particularly important in the presentation of LBP. Collectively, Components allocated to the "Psychology" Category were the most central in almost half (14/29) of the individual models.The collaborative modeling process outlined in this paper provides a foundation upon which to build a greater understanding and to communicate the complexity of the LBP problem. The next step is to aggregate individual FCMs into a metamodel and begin disentangling the interactions among its Components. This will lead to an improved understanding of the complexity of LBP, and hopefully to improved outcomes for those suffering from this condition

Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages

Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid macrophage reaction; however, only dectin-1 activation causes macrophage-mediated demyelination and axonal injury. Coactivating TLR2 reduced the injurious effects of dectin-1 activation. When injected into traumatically injured spinal cord, TLR2 agonists enhance the endogenous macrophage reaction while conferring neuroprotection. Indeed, dieback of axons was reduced, leading to smaller lesion volumes at the peak of the macrophage response. Moreover, the density of NG2+ cells expressing vimentin increased in and near lesions that were enriched with TLR2-activated macrophages. In dectin-1-null mutant (knock-out) mice, dieback of corticospinal tract axons also is reduced after SCI. Collectively, these data support the hypothesis that the ability of macrophages to create an axon growth-permissive microenvironment or cause neurotoxicity is receptor dependent and it may be possible to exploit this functional dichotomy to enhance CNS repair. SIGNIFICANCE STATEMENT: There is a growing appreciation that macrophages exert diverse functions in the injured and diseased CNS. Indeed, both macrophage-mediated repair and macrophage-mediated injury occur, and often these effector functions are elicited simultaneously. Understanding the mechanisms governing the reparative and pathological properties of activated macrophages is at the forefront of neuroscience research. In this report, using in vitro and in vivo models of relevance to traumatic spinal cord injury (SCI), new data indicate that stochastic activation of toll-like and c-type lectin receptors on macrophages causes neuroprotection or neurotoxicity, respectively. Although this manuscript focuses on SCI, these two innate immune receptor subtypes are also involved in developmental processes and become activated in macrophages that respond to various neurological diseases

Stress Increases Peripheral Axon Growth and Regeneration Through Glucocorticoid Receptor-Dependent Transcriptional Programs

Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M. musculus). In response to stress or GCs, adult DRG neurite growth increases through mechanisms involving GR-dependent gene transcription. In vivo, prior exposure to an acute systemic stress increases peripheral nerve regeneration. These data have broad clinical implications and highlight the importance of stress and GCs as novel behavioral and circulating modifiers of neuronal plasticity

Multicenter study of the impact of community-onset Clostridium difficile infection on surveillance for C. difficile infection

OBJECTIVE: To evaluate the influence of community-onset/healthcare facility-associated cases on Clostridium difficile infection (CDI) incidence and outbreak detection. DESIGN: Retrospective cohort. SETTING: Five acute-care healthcare facilities in the United States. METHODS: Positive stool C. difficile toxin assays from July 2000 through June 2006 and healthcare facility exposure information were collected. CDI cases were classified as hospital-onset (HO) if they were diagnosed > 48 hours after admission or community-onset/healthcare facility-associated if they were diagnosed ≤ 48 hours from admission and had recently been discharged from the healthcare facility. Four surveillance definitions were compared: HO cases only and HO plus community-onset/healthcare facility-associated cases diagnosed within 30 (HCFA-30), 60 (HCFA-60) and 90 (HCFA-90) days after discharge from the study hospital. Monthly CDI rates were compared. Control charts were used to identify potential CDI outbreaks. RESULTS: The HCFA-30 rate was significantly higher than the HO rate at two healthcare facilities (p<0.01). The HCFA-30 rate was not significantly different from the HCFA-60 or HCFA-90 rates at any healthcare facility. The correlations between each healthcare facility’s monthly rates of HO and HCFA-30 CDI were almost perfect (range, 0.94–0.99, p<0.001). Overall, 12 time points had a CDI rate >3 SD above the mean, including 11 by the HO definition and 9 by the HCFA-30 definition, with discordant results at 4 time points (κ = 0.794, p<0.001). CONCLUSIONS: Tracking community-onset/healthcare facility-associated cases in addition to HO cases captures significantly more CDI cases but surveillance of HO CDI alone is sufficient to detect an outbreak

SDF1 in the dorsal corticospinal tract promotes CXCR4+ cell migration after spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Stromal cell-derived factor-1 (SDF1) and its major signaling receptor, CXCR4, were initially described in the immune system; however, they are also expressed in the nervous system, including the spinal cord. After spinal cord injury, the blood brain barrier is compromised, opening the way for chemokine signaling between these two systems. These experiments clarified prior contradictory findings on normal expression of SDF1 and CXCR4 as well as examined the resulting spinal cord responses resulting from this signaling.</p> <p>Methods</p> <p>These experiments examined the expression and function of SDF1 and CXCR4 in the normal and injured adult mouse spinal cord primarily using CXCR4-EGFP and SDF1-EGFP transgenic reporter mice.</p> <p>Results</p> <p>In the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal. After spinal cord injury (SCI), the pattern of SDF1 expression did not change rostral to the lesion but it disappeared from the degenerating dCST caudally. By contrast, CXCR4 expression changed dramatically after SCI. In addition to the CXCR4+ cells in the ependymal layer, numerous CXCR4+ cells appeared in the peripheral white matter and in the dorsal white matter localized between the dorsal corticospinal tract and the gray matter rostral to the lesion site. The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier. One population of macrophages appeared to be migrating towards the dCST that contains SDF1 rostral to the injury but not towards the caudal dCST in which SDF1 is no longer present. A second population of the CXCR4+ macrophages was present near the SDF1-expressing meningeal cells.</p> <p>Conclusions</p> <p>These observations suggest that attraction of CXCR4+ macrophages is part of a programmed response to injury and that modulation of the SDF1 signaling system may be important for regulating the inflammatory response after SCI.</p

The immediate and long-term effects of exercise and patient education on physical, functional, and quality-of-life outcome measures after single-level lumbar microdiscectomy: a randomized controlled trial protocol

BACKGROUND: Low back pain remains a costly quality-of-life-related health problem. Microdiscectomy is often the surgical procedure of choice for a symptomatic, single-level, lumbar disc herniation in younger and middle-aged adults. The question of whether a post-microdiscectomy exercise program enhances function, quality of life, and disability status has not been systematically explored. Thus, the overall purpose of this study is to assess immediate and long-term outcomes of an exercise program, developed at University of Southern California (USC), targeting the trunk and lower extremities (USC Spine Exercise Program) for persons who have undergone a single-level microdiscectomy for the first time. METHODS/DESIGN: One hundred individuals between the ages of 18 and 60 who consent to undergo lumbar microdiscectomy will be recruited to participate in this study. Subjects will be randomly assigned to one of two groups: 1) one session of back care education, or 2) a back care education session followed by the 12-week USC Spine Exercise Program. The outcome examiners (evaluators), as well as the data managers, will be blinded to group allocation. Education will consist of a one-hour "one-on-one" session with the intervention therapist, guided by an educational booklet specifically designed for post-microdiscectomy care. This session will occur four to six weeks after surgery. The USC Spine Exercise Program consists of two parts: back extensor strength and endurance, and mat and upright therapeutic exercises. This exercise program is goal-oriented, performance-based, and periodized. It will begin two to three days after the education session, and will occur three times a week for 12 weeks. Primary outcome measures include the Oswestry Disability Questionnaire, Roland-Morris Disability Questionnaire, SF-36(® )quality of life assessment, Subjective Quality of Life Scale, 50-foot Walk, Repeated Sit-to-Stand, and a modified Sorensen test. The outcome measures in the study will be assessed before and after the 12-week post-surgical intervention program. Long-term follow up assessments will occur every six months beginning one year after surgery and ending five years after surgery. Immediate and long-term effects will be assessed using repeated measures multivariate analysis of variance (MANOVA). If significant interactions are found, one-way ANOVAs will be performed followed by post-hoc testing to determine statistically significant pairwise comparisons. DISCUSSION: We have presented the rationale and design for a randomized controlled trial evaluating the effectiveness of a treatment regimen for people who have undergone a single-level lumbar microdiscectomy

The Influence of Hip Strength on Lower-Limb, Pelvis, and Trunk Kinematics and Coordination Patterns During Walking and Hopping in Healthy Women

Study Design Cross-sectional laboratory study. Objectives To compare peak lower-limb, pelvis, and trunk kinematics and interjoint and intersegmental coordination in women with strong and weak hip muscle performance. Background Persons with lower extremity musculoskeletal disorders often demonstrate a combination of weak hip musculature and altered kinematics during weight-bearing dynamic tasks. However, the association between hip strength and kinematics independent of pathology or pain is unclear. Methods Peak hip extensor and abductor torques were measured in 150 healthy young women. Of these, 10 fit the criteria for the strong group and 9 for the weak group, representing those with the strongest and weakest hip musculature, respectively, of the 150 screened individuals. Kinematics of the hip, knee, pelvis, and trunk were measured during the stance phases of walking and rate-controlled hopping. Hip/knee and pelvis/trunk coordination were calculated using the vector coding technique. Results There were no group differences in peak hip, knee, or pelvis kinematics. Participants in the weak group demonstrated greater trunk lateral bend toward the stance limb during hopping (P = .002, effect size [d] = 1.88). In the transverse plane, those in the weak group utilized less inphase coordination between the hip and the knee during walking (P = .036, d = 1.45) and more antiphase coordination between the hip and knee during hopping (P = .03, d = 1.47). Conclusion In the absence of pain or pathology, poor hip muscle performance does not affect peak hip or knee joint kinematics in young women, but is associated with significantly different lower-limb and trunk/pelvis coordination during weight-bearing dynamic tasks