Chronic Systemic Immune Dysfunction in African-Americans with Small Vessel-Type Ischemic Stroke

The incidence of small vessel-type (lacunar) ischemic strokes is greater in African-Americans compared to whites. The chronic inflammatory changes that result from lacunar stroke are poorly understood. To elucidate these changes, we measured serum inflammatory and thrombotic biomarkers in African-Americans at least 6 weeks post-stroke compared to control individuals. Cases were African-Americans with lacunar stroke (n = 30), and controls were age-matched African-Americans with no history of stroke or other major neurologic disease (n = 37). Blood was obtained \u3e 6 weeks post-stroke and was analyzed for inflammatory biomarkers. Freshly isolated peripheral blood mononuclear cells were stimulated with lipopolysaccharide (LPS) to assess immune responsiveness in a subset of cases (n = 5) and controls (n = 4). After adjustment for covariates, the pro-inflammatory biomarkers, soluble vascular cadherin adhesion molecule-1 (sVCAM-1) and thrombin anti-thrombin (TAT), were independently associated with lacunar stroke. Immune responsiveness to LPS challenge was abnormal in cases compared to controls. African-Americans with lacunar stroke had elevated blood levels of VCAM-1 and TAT and an abnormal response to acute immune challenge \u3e 6 weeks post-stroke, suggesting a chronically compromised systemic inflammatory response

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors

Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke

The abrupt hyperglycemic reperfusion following thrombectomy has been shown to harm the efficacy of the intervention in stroke patients with large vessel occlusion. Studies of ours and others have shown thioredoxin-interacting protein (TXNIP) is critically involved in hyperglycemic stroke injury. We recently found verapamil ameliorates cerebrovascular toxicity of tissue plasminogen activators in hyperglycemic stroke. The present study aims to answer if verapamil exerts direct neuroprotective effects and alleviates glucose toxicity following thrombectomy in a preclinical model of hyperglycemic stroke. Primary cortical neural (PCN) cultures were exposed to hyperglycemic reperfusion following oxygen-glucose deprivation (OGD), with or without verapamil treatment. In a mouse model of intraluminal stroke, animals were subjected to 4 h middle cerebral artery occlusion (MCAO) and intravenous glucose infusion. Glucose infusion lasted one more hour at reperfusion, along with intra-arterial (i.a.) verapamil infusion. Animals were subjected to sensorimotor function tests and histological analysis of microglial phenotype at 72 h post-stroke. According to our findings, glucose concentrations (2.5–20 mM) directly correlated with TXNIP expression in OGD-exposed PCN cultures. Verapamil (100 nM) effectively improved PCN cell neurite growth and reduced TXNIP expression as well as interaction with NOD-like receptor pyrin domain-containing-3 (NLRP3) inflammasome, as determined by immunoblotting and immunoprecipitation. In our mouse model of extended hyperglycemic MCAO, i.a. verapamil (0.5 mg/kg) could attenuate neurological deficits induced by hyperglycemic stroke. This was associated with reduced microglial pro-inflammatory transition. This finding encourages pertinent studies in hyperglycemic patients undergoing thrombectomy where the robust reperfusion may exacerbate glucose toxicity

Systemic Inhibition of Tissue-Nonspecific Alkaline Phosphatase Alters the Brain-Immune Axis in Experimental Sepsis

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25− and CD8 + Foxp3+ CD25− splenocyte T-cell populations compared to controls. Further evaluation of SBI-425’s effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis

SN 2019ehk: A Double-peaked Ca-rich Transient with Luminous X-Ray Emission and Shock-ionized Spectral Features

We present panchromatic observations and modeling of the Calcium-rich supernova (SN) 2019ehk in the star-forming galaxy M100 (d ≈ 16.2 Mpc) starting 10 hr after explosion and continuing for ~300 days. SN 2019ehk shows a double-peaked optical light curve peaking at t = 3 and 15 days. The first peak is coincident with luminous, rapidly decaying Swift-XRT–discovered X-ray emission (L_x ≈ 10⁴¹ erg s⁻¹ at 3 days; L_x ∝ t⁻³), and a Shane/Kast spectral detection of narrow Hα and He II emission lines (v ≈ 500 km s⁻¹) originating from pre-existent circumstellar material (CSM). We attribute this phenomenology to radiation from shock interaction with extended, dense material surrounding the progenitor star at r (0.1–1) × 10¹⁷ cm. The photometric and spectroscopic properties during the second light-curve peak are consistent with those of Ca-rich transients (rise-time of t_r = 13.4 ± 0.210 days and a peak B-band magnitude of M_B = −15.1 ± 0.200 mag). We find that SN 2019ehk synthesized (3.1 ± 0.11) × 10⁻² M_⊙ of ⁵⁶Ni and ejected M_(ej) = (0.72 ± 0.040) M⊙ total with a kinetic energy E_k = (1.8 ± 0.10) × 10⁵⁰ erg. Finally, deep HST pre-explosion imaging at the SN site constrains the parameter space of viable stellar progenitors to massive stars in the lowest mass bin (~10 M_⊙) in binaries that lost most of their He envelope or white dwarfs (WDs). The explosion and environment properties of SN 2019ehk further restrict the potential WD progenitor systems to low-mass hybrid HeCO WD+CO WD binaries

Consensus Recommendations for the Use of Automated Insulin Delivery (AID) Technologies in Clinical Practice

International audienceThe significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past six years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage

Opportunity for verbalization does not improve visual change detection performance:A state trace analysis

Evidence suggests that there is a tendency to verbally recode visually-presented information, and that in some cases verbal recoding can boost memory performance. According to multi-component models of working memory, memory performance is increased because task-relevant information is simultaneously maintained in two codes. The possibility of dual encoding is problematic if the goal is to measure capacity for visual information exclusively. To counteract this possibility, articulatory suppression is frequently used with visual change detection tasks specifically to prevent verbalization of visual stimuli. But is this precaution always necessary? There is little reason to believe that concurrent articulation affects performance in typical visual change detection tasks, suggesting that verbal recoding might not be likely to occur in this paradigm, and if not, precautionary articulatory suppression would not always be necessary. We present evidence confirming that articulatory suppression has no discernible effect on performance in a typical visual change-detection task in which abstract patterns are briefly presented. A comprehensive analysis using both descriptive statistics and Bayesian state-trace analysis revealed no evidence for any complex relationship between articulatory suppression and performance that would be consistent with a verbal recoding explanation. Instead, the evidence favors the simpler explanation that verbal strategies were either not deployed in the task or, if they were, were not effective in improving performance, and thus have no influence on visual working memory as measured during visual change detection. We conclude that in visual change detection experiments in which abstract visual stimuli are briefly presented, pre-cautionary articulatory suppression is unnecessary

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine