Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration.

We recently showed that the post-ischemic induction of matrix metalloproteinase-12 (MMP-12) in the brain degrades tight junction proteins, increases MMP-9 and TNFα expression, and contributes to the blood-brain barrier (BBB) disruption, apoptosis, demyelination, and infarct volume development. The objectives of this study were to (1) determine the effect of MMP-12 suppression by shRNA-mediated gene silencing on neurological/functional recovery, (2) establish the optimal timing of MMP-12shRNA treatment that provides maximum therapeutic benefit, (3) compare the effectiveness of acute versus chronic MMP-12 suppression, and (4) evaluate potential sex-related differences in treatment outcomes. Young male and female Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion. Cohorts of rats were administered either MMP-12shRNA or scrambled shRNA sequence (control) expressing plasmids (1 mg/kg; i.v.) formulated as nanoparticles. At designated time points after reperfusion, rats from various groups were subjected to a battery of neurological tests to assess their reflex, balance, sensory, and motor functions. Suppression of MMP-12 promoted the neurological recovery of stroke-induced male and female rats, although the effect was less apparent in females. Immediate treatment after reperfusion resulted in a better recovery of sensory and motor function than delayed treatments. Chronic MMP-12 suppression neither enhanced nor diminished the therapeutic effects of acute MMP-12 suppression, indicating that a single dose of plasmid may be sufficient. We conclude that suppressing MMP-12 after an ischemic stroke is a promising therapeutic strategy for promoting the recovery of neurological function.

Spine centers of excellence: a systematic review and single-institution description of a spine center of excellence.

Background: Centers of excellence (COEs) are interdisciplinary healthcare organizations created with the goal of improving health/economic outcomes in medical treatment for both individuals and health systems, compared to traditionally structured counterparts. Multiple studies have highlighted both societal/individual burdens associated with back pain, underscoring the importance of identifying new avenues for improving both cost/clinical outcomes for this patient population. Here, we utilize available literature to better characterize the features of a spine COE at a tertiary care center and determine the impact of COEs on patient satisfaction and outcomes. Methods: A systematic review describing spine COEs was performed. PubMed, OVID, Cochrane, Web of Science, and Scopus were utilized for electronic literature search. Data including institution, department, pathologies treated, patient satisfaction scores, patient outcomes, and descriptions of the COE, were extracted and analyzed by two reviewers per full-text article. Inclusion criteria consisted of literature describing the organization, purpose, or outcomes of a spine COE, all publication types (except technical/operative report), adult or pediatric patients, publication from inception through September 2021. Exclusion criteria consisted of articles that do not discuss spinal COEs, technical/operative reports, studies unavailable in English language, unavailable full text, or non-human subjects. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included studies. Results: Five hundred and sixty-seven unique publications were obtained from the literature search. Of these articles, 20 were included and 547 were excluded based on inclusion and exclusion criteria. Following full-text review of the 20 publications, 6 contained pertinent data. Quantitative data comparing COE versus non-COE was contradictory in comparing complication rates and episodic costs. Qualitative data included descriptions of spine COE features and cited improved patient care, technical advancements, and individualized care paths as positive aspects of the COE model. Mean risk of bias assessment was 3.67. Discussion: There is little evidence regarding if spine COEs provide an advantage over traditionally organized facilities. The current number and heterogeneity of publications, and lack of standardized metrics used to define a spinal COE are limiting factors. Spinal COE may offer higher value care, reduced complication rates and advancements in knowledge and technical skill.

Cerebral Aß deposition in an Aß-precursor protein-transgenic rhesus monkey.

With the ultimate goal of developing a more representative animal model of Alzheimer's disease (AD), two female amyloid-ß-(Aß) precursor protein-transgenic (APPtg) rhesus monkeys were generated by lentiviral transduction of the APP gene into rhesus oocytes, followed by in vitro fertilization and embryo transfer. The APP-transgene included the AD-associated Swedish K670N/M671L and Indiana V717F mutations (APPSWE/IND) regulated by the human polyubiquitin-C promoter. Overexpression of APP was confirmed in lymphocytes and brain tissue. Upon sacrifice at 10 years of age, one of the monkeys had developed Aß plaques and cerebral Aß-amyloid angiopathy in the occipital, parietal, and caudal temporal neocortices. The induction of Aß deposition more than a decade prior to its usual emergence in the rhesus monkey supports the feasibility of creating a transgenic nonhuman primate model for mechanistic analyses and preclinical testing of treatments for Alzheimer's disease and cerebrovascular amyloidosis.

Iron Deficiency in Heart Failure: Characteristics and Treatment.

Purpose of the Review: Iron deficiency in heart failure has been associated with impaired functional capacity and quality of life. The purpose of this paper is to review mechanisms of iron homeostasis and current clinical data exploring mechanisms of iron repletion in heart failure. Recent Finding: Multiple international societies now advise iron repletion for symptomatic heart failure patients with iron deficiency. Due to the chronic inflammation in heart failure, iron deficiency in heart failure is classically defined as ferritin < 100 µg/L or ferritin 100-300 µg/L and transferrin saturation < 20%. Multiple randomized clinical trials have demonstrated benefit from intravenous iron repletion, though studies have predominantly focused on functional capacity and quality of life. A recent study, AFFIRM-AHF, supports the treatment of iron deficiency identified during acute heart failure admissions, noting a reduction in future heart failure hospitalizations. Studies examining iron repletion in patients with heart failure with preserved ejection fraction are currently in process. Summary: Iron homeostasis is maintained predominantly through the regulation of iron absorption, keeping iron levels tightly controlled in the normal state regardless of iron intake. In chronic heart failure however, iron homeostasis becomes dysregulated with resulting iron deficiency in many patients, with and without associated anemia. Iron is a critical element not only for erythropoiesis and oxygen carrying, but also for energy production at the level of the mitochondria and in other cell processes. We thus propose a standardized approach be utilized to screen and treat heart failure patients with iron deficiency.

Protocol for AREST: Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation-A Randomized Controlled Trial of Early Anticoagulation After Acute Ischemic Stroke in Atrial Fibrillation.

Background: Optimal timing to initiate anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF) is currently unknown. Compared to other stroke etiologies, AF typically provokes larger infarct volumes and greater concern of hemorrhagic transformation, so seminal randomized trials waited weeks to months to begin anticoagulation after initial stroke. Subsequent data are limited and non-randomized. Guidelines suggest anticoagulation initiation windows between 3 and 14 days post-stroke, with Class IIa recommendations, and level of evidence B in the USA and C in Europe. Aims: This open-label, parallel-group, multi-center, randomized controlled trial AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) is designed to evaluate the safety and efficacy of early anticoagulation, based on stroke size, secondary prevention of ischemic stroke, and risks of subsequent hemorrhagic transformation. Methods: Subjects are randomly assigned in a 1:1 ratio to receive early apixaban at day 0-3 for transient ischemic attack (TIA), 3-5 for small-sized AIS (<1.5 cm), and 7-9 for medium-sized AIS (1.5 cm or greater but less than a full cortical territory), or warfarin at 1 week post-TIA or 2 weeks post-stroke. Large AISs are excluded. Study Outcomes: Primary: recurrent ischemic stroke, TIA, and fatal stroke; secondary: intracranial hemorrhage (ICH); hemorrhagic transformation (HT) of ischemic stroke; cerebral microbleeds (CMBs); neurologic disability [e.g., modified Rankin Scores (mRS), National Institutes of Health Stroke Scale (NIHSS), Stroke Specific Quality of Life scale (SS-QOL)]; and cardiac biomarkers [e.g., AF burden, transthoracic echo (TTE)/transesophageal echo (TEE) abnormalities]. Sample Size Estimates: Enrollment goal was 120 for 80% power (two-sided type I error rate of 0.05) to detect an absolute risk reduction of 16.5% postulated to occur with apixaban in the primary composite outcome of fatal stroke/recurrent ischemic stroke/TIA within 180 days. Enrollment was suspended at 91 subjects in 2019 after a focused guideline update recommended direct oral anticoagulants (DOACs) over warfarin in AF, excepting valvular disease (Class I, level of evidence A). Discussion: AREST will offer randomized controlled trial data about timeliness and safety of anticoagulation in AIS patients with AF. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02283294.

Disparities and Temporal Trends in Stroke Care Outcomes in Patients with Atrial Fibrillation: The FLiPER-AF Stroke Study.

BACKGROUND AND PURPOSE: Atrial Fibrillation (AF) is the most common cardiac cause of ischemic stroke. However, the relation between AF and stroke care outcomes in diverse populations is understudied. We aimed to evaluate sex and race-ethnic disparities associated with AF in hospital stroke outcomes utilizing data from the FLorida PuErto Rico Atrial Fibrillation (FLiPER-AF) Stroke Study. METHODS: The study included 104,308 ischemic stroke cases with available information on AF status enrolled in a state-wide stroke registry from 2010 to 2016. Multivariable logistic regression models were performed to evaluate the association between AF and stroke outcomes and the modification effects on the associations by sex and by race-ethnicity, adjusted for socio-demographic status, vascular risk factors and stroke severity. RESULTS: AF was present in 23% of ischemic stroke cases. AF was associated with worse disability at discharge (OR=1.11, 95% CI, 1.04-1.18), less discharge to home (OR=0.89, 0.85-0.92), and longer length of hospital stay (LOS>6 days, OR=1.53, 1.46-1.60). Interaction analyses showed that the association between AF and less discharge to home was stronger in women than men (p for interaction <0.001), as well as in FL-whites than in FL-blacks, FL-Hispanics or PR-Hispanics (p for interaction=0.002). The association between AF and prolonged LOS was more prominent in PR-Hispanics than in FL-blacks, FL-Hispanics, or FL-whites (p for interaction <0.001). From 2010 to 2016, the effects of AF on hospital length of stay attenuated (p for interaction<0.001). CONCLUSIONS: AF was associated with poor disability at discharge, less discharge to home, and prolonged hospital length of stay for acute stroke care. The effect of AF on length of stay attenuated over time. Sex and race-ethnic disparities were observed in the effect of AF on being less discharge to home and prolonged hospital stay. Further research is needed to identify and modify the biologic and systems of care contributors to these disparities.

Gender-Specific Differences for Risk of Disability and Death in Atrial Fibrillation-Related Stroke.

In the latest American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation (AF) guidelines, CHA2DS2-VASc replaced the CHADS2 stroke risk assessment to determine prophylactic anticoagulation, reflecting female gender's association with stroke incidence in AF. However, little investigation has been pursued of potential risk factors associated with worsened stroke severity. In this study, we examined patients with AF with ischemic stroke patient characteristics associated with increased stroke severity. Using the Get With The Guidelines-Stroke database, we retrospectively identified 221 consecutive patients with AF diagnosed with acute ischemic stroke and performed in depth chart review, evaluating demographics, labs, and co-morbidities. We analyzed the modified Rankin Scale (mRS) at discharge as a surrogate for stroke severity, defining severe stroke as fatal (mRS of 6) or disabling (mRS 4 to 5), requiring max assistance with ambulation or activities of daily living. Female gender, advanced age, and decreased body surface area were associated with disabling or fatal stroke (68.3% of patients with mRS 4 to 6 vs 50% with mRS 0 to 3, 78.4 vs 71.1 year, and 1.83 vs 1.92, respectively). Using a backward elimination approach revealed a logistic regression model with statistically significant odds ratios (ORs) for female gender (OR 1.99) and age (OR 1.04), and borderline significant for a history of coronary artery disease (OR 1.89). In conclusion, female gender is associated in the AF population with a twofold risk of severe disabling or fatal ischemic stroke, a finding that persists after controlling for potential confounders. This finding highlights the potential benefit from appropriate anticoagulation use for stroke prophylaxis in the AF population.

Testosterone modulates spatial recognition memory in male rats.

A growing body of research indicates that testosterone influences spatial cognition in male rats; however, the overwhelming majority of studies have been conducted on tasks motivated by either food deprivation or water escape. The hippocampus-dependent version of the Y-maze task, which characterizes spatial recognition memory, capitalizes on the propensity of rats to gravitate toward novel spatial environments and is not contingent upon either appetite or the stress associated with water escape, two factors also affected by testosterone. Accordingly, the aim of the current study was to examine the effects of orchidectomy and subsequent testosterone treatment on spatial recognition memory. Orchidectomy did not impact spatial recognition memory when the delay between the information and retention trials of the Y-maze task was 24h. Alternatively, on the second Y-maze task, which featured a 48-h delay between trials, orchidectomy reduced, and treatments that produced higher levels of testosterone restored, preference for the arm associated with the novel spatial environment. Importantly, there were no differences in activity levels as a function of orchidectomy or testosterone treatment on either of the two tasks. Consistent with previous findings, orchidectomy attenuated, and testosterone treatment restored, both body weight gain and the relative weight of the androgen-sensitive ischiocavernosus muscle, which confirmed the efficacy of orchidectomy and testosterone treatments on physiological outcomes. Therefore, testosterone influenced spatial cognition on a task that minimized the influence of non-mnemonic factors and took advantage of the innate preference of rodents to seek out novel spatial environments.

Anger on the internet: the perceived value of rant-sites.

Despite evidence that anger is routinely expressed over the Internet via weblogs, social networking Web sites, and other venues, no published research has explored the way in which anger is experienced and expressed online. Consequently, we know very little about how anger is experienced in such settings. Two studies were conducted to explore how people experience and express their anger on a particular type of Web site, known as a rant-site. Study 1 surveyed rant-site visitors to better understand the perceived value of the Web sites and found that while they become relaxed immediately after posting, they also experience more anger than most and express their anger in maladaptive ways. Study 2 explored the emotional impact of reading and writing rants and found that for most participants, reading and writing rants were associated with negative shifts in mood.

Prostaglandin E2 regulates AMPA receptor phosphorylation and promotes membrane insertion in preoptic area neurons and glia during sexual differentiation.

Sexual differentiation of the rodent brain is dependent upon the organizing actions of the steroid hormone, estradiol. In the preoptic area, a brain region critical for the expression of adult reproductive behavior, there are twice as many dendritic spine synapses per unit length on newborn male neurons compared to female neurons and this sex difference correlates with the expression of adult male copulatory behavior. The sex difference in the POA is achieved via estradiol's upregulation of the membrane-derived lipid signaling molecule prostaglandin E2 (PGE2); PGE2 is necessary and sufficient to masculinize both dendritic spine density and adult sexual behavior in rats. We have previously shown that PGE2 activates EP2 and EP4 receptors which increases protein kinase A (PKA) activity and that masculinized dendritic spine density and sex behavior are both dependent upon PKA as well as activation of AMPA type glutamate receptors. In the current experiments, we build upon this signaling cascade by determining that PGE2 induces phosphorylation of the AMPA receptor subunit, GluR1, which leads to increased AMPA receptor insertion at the membrane. Treating female pups on the day of birth with PGE2 induced the phosphorylation of GluR1 at the PKA-sensitive site within 2 hours of treatment, an effect that was blocked by co-administration of the PKA/AKAP inhibitor, HT31 with PGE2. Brief treatment of mixed neuronal/glial POA cultures with PGE2 or the cAMP/PKA stimulator, forskolin, increased membrane associated GluR1 in both neurons and glia. We speculate that PGE2 induced increases in AMPA receptor associated with the membrane underlies our previously observed increase in dendritic spine density and is a critical component in the masculinization of rodent sex behavior.

Driving anger, sensation seeking, impulsiveness, and boredom proneness in the prediction of unsafe driving.

The present study investigated the potential contribution of sensation seeking, impulsiveness, and boredom proneness to driving anger in the prediction of aggressive and risky driving. Two hundred and twenty-four college student participants completed measures of trait driving anger, aggressive and risky driving, driving anger expression, sensation seeking, impulsiveness, and boredom proneness. Findings provided additional support for the utility of the Driving Anger Scale (DAS; Deffenbacher, J.L., Oetting, E.R., Lynch, R.S., Development of a driving anger scale, Psychological Reports, 74, 1994, 83-91.) in predicting unsafe driving. In addition, hierarchical multiple regression analyses demonstrated that sensation seeking, impulsiveness, and boredom proneness provided incremental improvements beyond the DAS in the prediction of crash-related conditions, aggressive driving, risky driving, and driving anger expression. Results support the use of multiple predictors in understanding unsafe driving behavior.