The Effect of Peripheral Pain on Spinal Circuits Following Spinal Cord Injury

Events soon after spinal cord trauma alter spinal cord function and drastically impact functional outcomes. Guided by our work in a transection model of spinal learning, we hypothesized that uncontrollable noxious input (C fiber activation) undermines spinal function by engaging a pro- inflammatory state (central sensitization). In a clinically relevant model of spinal cord injury (SCI), C fiber input exacerbates inflammatory processes within the lesion, increases cell death, and impairs functional outcomes. However, the mechanisms that underlie increased cell death and inflammation following C fiber activation have not been fully described. Specifically, the extent to which descending, brain-mediated processes are required is unknown. Here, we examined whether local spinal circuits, or descending brain-mediated processes, contribute to the increased inflammation associated with C fiber activation. In a contusion model of SCI, a spinal transection was used to isolate the spinal cord from the brain. Electrical stimulation of the tail provided C fiber activation. Examination of hemoglobin, IL-18, and IL-1β concentrations revealed that complete spinal transection reversed the detrimental effects of C fiber input. These results suggest that brain-mediated processes are required for the development of secondary injury cascades associated with C fiber activation following SCI

Buspirone Maintenance Does Not Alter the Reinforcing, Subjective, and Cardiovascular Effects of Intranasal Methamphetamine

Background—Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies. Experimental research using maintenance dosing, which models therapeutic use, is limited. This study evaluated the influence of buspirone maintenance on the reinforcing effects of methamphetamine using a self-administration procedure, which has predictive validity for clinical efficacy. The impact of buspirone maintenance on the subjective and cardiovascular response to methamphetamine was also determined. Methods—Eight research participants (1 female) reporting recent illicit stimulant use completed a placebo-controlled, crossover, double-blind protocol in which the pharmacodynamic effects of intranasal methamphetamine (0, 15, and 30 mg) were assessed after at least 6 days of buspirone (0 and 45 mg/day) maintenance. Results—Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like subjective (e.g., increased ratings of Good Effects and Like Drug) and cardiovascular (e.g., elevated blood pressure) effects. These effects of methamphetamine were similar under buspirone and placebo maintenance conditions. Maintenance on buspirone was well tolerated and devoid of effects when administered alone. Conclusions—These data suggest that buspirone is unlikely to be an effective pharmacotherapy for methamphetamine-use disorder. Given the central role of monoamines in methamphetamine-use disorder, it is reasonable for future studies to continue to target these systems

Hospital length of stay, do not resuscitate orders, and survival for post-cardiac arrest patients in Michigan: A study for the CARES Surveillance Group

OBJECTIVE: Current guidelines recommend deferring prognostic decisions for at least 72 h following admission after Out of Hospital cardiac arrest (OHCA). Most non-survivors experience withdrawal of life sustaining therapy (WLST), and early WLST may adversely impact survival. We sought to characterize the hospital length of stay (LOS) and timing of Do Not Resuscitate (DNR) orders (as surrogates for WLST), to assess their relationship to survival following cardiac arrest. DESIGN: We performed a retrospective cohort study of probabilistically linked cardiac arrest registries (Cardiac Arrest Registry to Enhance Survival (CARES) and Michigan Inpatient Database (MIDB) from 2014 to 2017. PATIENTS: Adult (≥18 years) patients admitted following OHCA were included. We considered LOS ≤ 3 days (short LOS) and written DNR order with LOS ≤ 3 days (Early DNR) as indicators of early WLST. Our primary outcome was survival to hospital discharge. We utilized multilevel logistic regression clustered by hospital to examine associations of these variables, patient characteristics and survival to hospital discharge. MEASUREMENT AND MAIN RESULTS: We included 3644 patients from 38 hospitals with \u3e30 patients. Patients mean age was 62.4 years and were predominately male (59.3%). LOS ≤ 3 days (OR(adj) = 0.11) and early DNR (OR(adj) = 0.02) were inversely associated with survival to discharge. There was a non-significant inverse association between hospital rates of LOS ≤ 3 days and survival (p = 0.11), and Early DNR and survival (p = 0.83). In the multilevel model, using median odd ratios to assess variation in LOS ≤ 3 days and survival, patient characteristics contributed more to variability in survival than between-hospital variation. However, between-hospital variation contributed more to variability than patient characteristics in the provision of early DNR orders. CONCLUSIONS: We observed that LOS ≤ 3 days for post-arrest patients was negatively-associated with survival, with both patient characteristics and between-hospital variation associated with outcomes. However, between-hospital variation appears to be more highly-associated with provision of early DNR orders than patient characteristics. Further work is needed to assess variation in early DNR orders and their impact on patient survival

Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The αvβ5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit αvβ5 in a rat model of renal IRI. Pretreatment with this anti-αvβ5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the αvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvβ5 antibody treatment. Immunostaining for αvβ5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for αvβ5 in modulating vascular leak. Additional studies showed αvβ5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvβ5 inhibition as a promising therapeutic strategy for AKI

Percutaneous mechanical circulatory support and survival in patients resuscitated from Out of Hospital cardiac arrest: A study from the CARES surveillance group

INTRODUCTION: Maintenance of cardiac function is required for successful outcome after out-of-hospital cardiac arrest (OHCA). Cardiac function can be augmented using a mechanical circulatory support (MCS) device, most commonly an intra-aortic balloon pump (IABP) or Impella®. OBJECTIVE: Our objective is to assess whether the use of a MCS is associated with improved survival in patients resuscitated from OHCA in Michigan. METHODS: We matched cardiac arrest cases during 2014-2017 from the Cardiac Arrest Registry to Enhance Survival (CARES) in Michigan and the Michigan Inpatient Database (MIDB) using probabilistic linkage. Multilevel logistic regression tested the association between MCS and the primary outcome of survival to hospital discharge. RESULTS: A total of 3790 CARES cases were matched with the MIDB and 1131 (29.8%) survived to hospital discharge. A small number were treated with MCS, an IABP (n = 183) or Impella® (n = 50). IABP use was associated with an improved outcome (unadjusted OR = 2.16, 95%CI [1.59, 2.93]), while use of Impella® approached significance (OR = 1.72, 95% CI [0.96, 3.06]). Use of MCS was associated with improved outcome (unadjusted OR = 2.07, 95% CI [1.55, 2.77]). In a multivariable model, MCS use was no longer independently associated with improved outcome (OR(adj) = 0.95, 95% CI [0.69, 1.31]). In the subset of subjects with cardiogenic shock (N = 725), MCS was associated with improved survival in univariate (unadjusted OR = 1.84, 95% CI [1.24, 2.73]) but not multi-variable modeling (OR(adj) = 1.14, 95% CI [0.74, 1.77]). CONCLUSION: Use of MCS was infrequent in patients resuscitated from OHCA and was not independently associated with improvement in post arrest survival after adjusting for covariates

The Radio Variability of the Gravitational Lens PMN J1838-3427

We present the results of a radio variability study of the gravitational lens PMN J1838-3427. Our motivation was to determine the Hubble constant by measuring the time delay between variations of the two quasar images. We monitored the system for 4 months (approximately 5 times longer than the expected delay) using the Australia Telescope Compact Array at 9 GHz. Although both images were variable on a time scale of a few days, no correlated intrinsic variability could be identified, and therefore no time delay could be measured. Notably, the fractional variation of the fainter image (8%) was greater than that of the brighter image (4%), whereas lensed images of a point source would have the same fractional variation. This effect can be explained, at least in part, as the refractive scintillation of both images due to the turbulent interstellar medium of the Galaxy.Comment: To appear in AJ (8 pages, including 4 figures

Detection of Viruses from Bioaerosols Using Anion Exchange Resin

This protocol demonstrates a customized bioaerosol sampling method for viruses. In this system, anion exchange resin is coupled with liquid impingement-based air sampling devices for efficacious concentration of negatively-charged viruses from bioaerosols. Thus, the resin serves as an additional concentration step in the bioaerosol sampling workflow. Nucleic acid extraction of the viral particles is then performed directly from the anion exchange resin, with the resulting sample suitable for molecular analyses. Further, this protocol describes a custom-built bioaerosol chamber capable of generating virus-laden bioaerosols under a variety of environmental conditions and allowing for continuous monitoring of environmental variables such as temperature, humidity, wind speed, and aerosol mass concentration. The main advantage of using this protocol is increased sensitivity of viral detection, as assessed via direct comparison to an unmodified conventional liquid impinger. Other advantages include the potential to concentrate diverse negatively-charged viruses, the low cost of anion exchange resin (~$0.14 per sample), and ease of use. Disadvantages include the inability of this protocol to assess infectivity of resin-adsorbed viral particles, and potentially the need for the optimization of the liquid sampling buffer used within the impinger

Action Experience and Action Discovery in Medicated Individuals with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that markedly affects voluntary action. While regular dopamine treatment can help restore motor function, dopamine also influences cognitive portions of the action system. Previous studies have demonstrated that dopamine medication boosts action-effect associations, which are crucial for the discovery of new voluntary actions. In the present study, we investigated whether neural processes involved in the discovery of new actions are altered in PD participants on regular dopamine treatment, compared to healthy age-matched controls. We recorded brain electroencephalography (EEG) activity while PD patients and age-matched controls performed action discovery (AD) and action control tasks. We found that the novelty P3, a component normally present when there is uncertainty about the occurrence of the sensory effect, was enhanced in PD patients. However, AD was maintained in PD patients, and the novelty P3 demonstrated normal learning-related reductions. Crucially, we found that in PD patients the causal association between an action and its resulting sensory outcome did not modulate the amplitude of the feedback correct-related positivity (fCRP), an EEG component sensitive to the association between an action and its resulting effect. Collectively, these preliminary results suggest that the formation of long-term action-outcome representations may be maintained in PD patients on regular dopamine treatment, but the initial experience of action-effect association may be affected

Pain Input After Spinal Cord Injury (SCI) Undermines Long-Term Recovery and Engages Signal Pathways That Promote Cell Death

Pain (nociceptive) input caudal to a spinal contusion injury increases tissue loss and impairs long-term recovery. It was hypothesized that noxious stimulation has this effect because it engages unmyelinated pain (C) fibers that produce a state of over-excitation in central pathways. The present article explored this issue by assessing the effect of capsaicin, which activates C-fibers that express the transient receptor potential vanilloid receptor-1 (TRPV1). Rats received a lower thoracic (T11) contusion injury and capsaicin was applied to one hind paw the next day. For comparison, other animals received noxious electrical stimulation at an intensity that engages C fibers. Both forms of stimulation elicited similar levels of c-fos mRNA expression, a cellular marker of nociceptive activation, and impaired long-term behavioral recovery. Cellular assays were then performed to compare the acute effect of shock and capsaicin treatment. Both forms of noxious stimulation increased expression of tumor necrosis factor (TNF) and caspase-3, which promotes apoptotic cell death. Shock, but not capsaicin, enhanced expression of signals related to pyroptotic cell death [caspase-1, inteleukin-1 beta (IL-1ß)]. Pyroptosis has been linked to the activation of the P2X7 receptor and the outward flow of adenosine triphosphate (ATP) through the pannexin-1 channel. Blocking the P2X7 receptor with Brilliant Blue G (BBG) reduced the expression of signals related to pyroptotic cell death in contused rats that had received shock. Blocking the pannexin-1 channel with probenecid paradoxically had the opposite effect. BBG enhanced long-term recovery and lowered reactivity to mechanical stimulation applied to the girdle region (an index of chronic pain), but did not block the adverse effect of nociceptive stimulation. The results suggest that C-fiber input after injury impairs long-term recovery and that this effect may arise because it induces apoptotic cell death

Personality Predicts Mortality Risk: An Integrative Data Analysis of 15 International Longitudinal Studies

This study examined the Big Five personality traits as predictors of mortality risk, and smoking as a mediator of that association. Replication was built into the fabric of our design: we used a Coordinated Analysis with 15 international datasets, representing 44,094 participants. We found that high neuroticism and low conscientiousness, extraversion, and agreeableness were consistent predictors of mortality across studies. Smoking had a small mediating effect for neuroticism. Country and baseline age explained variation in effects: studies with older baseline age showed a pattern of protective effects (HR<1.00) for openness, and U.S. studies showed a pattern of protective effects for extraversion. This study demonstrated coordinated analysis as a powerful approach to enhance replicability and reproducibility, especially for aging-related longitudinal research.Funding support for this project was provided by the National Institute on Aging: P01-AG043362 (Integrative Analysis of Longitudinal Studies of Aging (IALSA), [Scott M. Hofer (PI)]), and Daniel K. Mroczek (CoInvestigator and Project Leader of the IALSA Personality & Health Project, as well as R01-AG018436 [Personality & Well-Being Trajectories in Adulthood, Daniel K. Mroczek, PI])