The Pathological Activation of Microglia Is Modulated by Sexually Dimorphic Pathways.

Microglia are the primary immunocompetent cells of the central nervous system (CNS). Their ability to survey, assess and respond to perturbations in their local environment is critical in their role of maintaining CNS homeostasis in health and disease. Microglia also have the capability of functioning in a heterogeneous manner depending on the nature of their local cues, as they can become activated on a spectrum from pro-inflammatory neurotoxic responses to anti-inflammatory protective responses. This review seeks to define the developmental and environmental cues that support microglial polarization towards these phenotypes, as well as discuss sexually dimorphic factors that can influence this process. Further, we describe a variety of CNS disorders including autoimmune disease, infection, and cancer that demonstrate disparities in disease severity or diagnosis rates between males and females, and posit that microglial sexual dimorphism underlies these differences. Understanding the mechanism behind differential CNS disease outcomes between men and women is crucial in the development of more effective targeted therapies.

A prospective pilot study of predictors of acute stroke in emergency department patients with dizziness.

OBJECTIVE: To prospectively examine undifferentiated emergency department (ED) patients with dizziness to identify clinical features associated with acute stroke. PATIENTS AND METHODS: We conducted a pilot study from November 1, 2009, through October 30, 2010, of adult patients with dizziness presenting to 3 urban academic EDs. Data collected included demographic characteristics, medical history, presenting symptoms, examination findings, clinician pretest probability of stroke, and neuroimaging results. Logistic regression was used to identify variables with a significant association with acute stroke (P<.05). RESULTS: During the study period, we enrolled 473 patients (mean ± SD age, 56.7±19.3 years; 60% female; and 71% white). We found 30 acute, serious diagnoses (6.3%), including 14 ischemic strokes, 2 subarachnoid hemorrhages, 7 mass lesions, 2 demyelinating lesions, 2 severe vertebral artery stenoses, 2 acute coronary syndromes, and 1 case of hydrocephalus and meningitis). We identified 6 clinical variables associated with stroke: age (odds ratio [OR], 1.04; 95% CI, 1.0-1.07), hyperlipidemia (OR, 3.62; 95% CI, 1.24-10.6), hypertension (OR, 4.91; 95% CI, 1.46-16.5), coronary artery disease (OR, 3.33; 95% CI, 1.06-10.5), abnormal tandem gait test result (OR, 3.13; 95% CI, 1.10-8.89), and high or moderate physician pretest probability for acute stroke (OR, 18.8; 95% CI, 4.72-74.5). CONCLUSIONS: Most ED patients with dizziness do not have a serious cause of their symptoms. Although the small number of outcomes precluded development of a multivariate model, we identified several individual high-risk variables associated with acute ischemic stroke. Further study will be needed to validate the findings of this pilot investigation.

Preferences for resuscitation and intubation among patients with do-not-resuscitate/do-not-intubate orders.

OBJECTIVE: To determine the accuracy of do-not-resuscitate/do-not-intubate (DNR/DNI) orders in representing patient preferences regarding cardiopulmonary resuscitation (CPR) and intubation. PATIENTS AND METHODS: We conducted a prospective survey study of patients with documented DNR/DNI code status at an urban academic tertiary care center that serves approximately 250,000 patients per year. From October 1, 2010, to October 1, 2011, research staff enrolled a convenience sample of patients from the inpatient medical service, providing them with a series of emergency scenarios for which they related their treatment preference. We used the Kendall τ rank correlation coefficient to examine correlation between degree of illness reversibility and willingness to be resuscitated. Using bivariate statistical analysis and multivariate logistic regression analysis, we examined predictors of discrepancies between code status and patient preferences. Our main outcome measure was the percentage of patients with DNR/DNI orders wanting CPR and/or intubation in each scenario. We hypothesized that patients with DNR/DNI orders would frequently want CPR and/or intubation. RESULTS: We enrolled 100 patients (mean ± SD age, 78 ± 13.7 years). A total of 58% (95% CI, 48%-67%) wanted intubation for angioedema, 28% (95% CI, 20%-3.07%) wanted intubation for severe pneumonia, and 20% (95% CI, 13%-29%) wanted a trial resuscitation for cardiac arrest. The desire for intubation decreased as potential reversibility of the acute disease process decreased (Kendall τ correlation coefficient, 0.45; P<.0002). CONCLUSION: Most patients with DNR/DNI orders want CPR and/or intubation in hypothetical clinical scenarios, directly conflicting with their documented DNR/DNI status. Further research is needed to better understand the discrepancy and limitations of DNR/DNI orders.

Multicenter observational study of the development of progressive organ dysfunction and therapeutic interventions in normotensive sepsis patients in the emergency department.

OBJECTIVES: Progressive organ dysfunction is the leading cause of sepsis-associated mortality; however, its incidence and management are incompletely understood. Sepsis patients with moderately impaired perfusion (serum lactate 2.0 to 3.9 mmol/L) who are not in hemodynamic shock ("preshock" sepsis patients) may be at increased risk for progressive organ dysfunction and increased mortality. The objectives of this study were to: 1) quantify the occurrence of progressive organ dysfunction among preshock sepsis patients, 2) examine if there were baseline differences in demographic and physiologic parameters between preshock sepsis patients who experienced progressive organ dysfunction and those who did not, and 3) examine if intravenous (IV) fluid administered in the emergency department (ED) differed between these two groups of patients. METHODS: This was a prospective, observational study in four urban EDs targeting the preshock sepsis population, defined as adults (18 years or older) with suspected infection, serum lactate between 2.0 and 3.9 mmol/L, and without hypotension (systolic blood pressure [sBP] < 90 mm Hg or mean arterial pressure [MAP] < 70 mm Hg) or requiring mechanical ventilation at ED presentation. The primary composite outcome was progressive organ dysfunction, defined as a rise in the Sequential Organ Failure Assessment (SOFA) score of ≥1, vasopressor use, mechanical ventilation use within 72 hours after ED presentation, or in-hospital death. The secondary outcomes were any intensive care unit (ICU) admission, and total ICU and hospital lengths of stay (LOS). RESULTS: Among 94 preshock sepsis patients, the primary composite outcome occurred in 24 of 94 (26%). In patients with the primary outcome, 22 of 24 (92%) experienced a rise in SOFA score of ≥1, five of 24 (21%) received vasopressor agents, and seven of 24 (30%) required mechanical ventilation. There were no baseline demographic or physiologic parameter differences between patients who met the primary outcome versus those who did not, while patients with the primary outcome had a higher average SOFA score at admission (2.4 vs. 1.3, p = 0.011) and at all subsequent time points. Median IV fluid volume administered to all preshock sepsis patients during their ED stay was 1,225 mL (interquartile range [IQR] = 712 to 2,000 mL) and did not differ significantly between patients with (1,150 mL, IQR = 469 to 2,000 mL) or without (1,250 mL, IQR = 750 to 2,000 mL) the primary outcome (p = 0.73). Patients with progressive organ dysfunction or death were more likely to be admitted to an ICU (50% vs. 20%, p < 0.01) and have an increased median hospital LOS (6 days vs. 3 days, p = 0.005), compared to those without progressive organ dysfunction. CONCLUSIONS: Over one-quarter of preshock sepsis patients developed progressive organ dysfunction with associated increased resource use. Demographic and physiologic parameters were unable to differentiate patients with progressive organ dysfunction, while the initial SOFA score was increased in patients meeting the outcome. Overall, these patients received relatively little IV fluid therapy during their ED stays. Further research to determine if more aggressive therapy can prevent progressive organ dysfunction in this population is warranted.

Effects of training and testosterone on muscle fiber types and locomotor performance in male six-lined racerunners (Aspidoscelis sexlineata).

Testosterone (T) is thought to affect a variety of traits important for fitness, including coloration, the size of sexual ornaments, aggression, and locomotor performance. Here, we investigated the effects of experimentally elevated T and locomotor training on muscle physiology and running performance in a nonterritorial male lizard species (Aspidoscelis sexlineata). Additionally, several morphological attributes were quantified to examine other characters that are likely affected by T and/or a training regimen. Neither training alone nor training with T supplementation resulted in increased locomotor performance. Instead, we found that T and training resulted in a decrease in each of three locomotor performance variables as well as in hematocrit, ventral coloration, and testis size. Strikingly, neither the size nor the fiber composition of the iliofibularis or gastrocnemius muscles was different among the two treatments or a group of untrained control animals. Hence, the relationships among T, training, and associated characters are not clear. Our results offer important insights for those hoping to conduct laboratory manipulations on nonmodel organisms and highlight the challenges of studying both training effects and the effects of steroid hormones on locomotor performance.