Shibani S. Mukerji

Activin is a Neuronal Survival Factor that is Rapidly Increased after Transient Cerebral Ischemia and Hypoxia in Mice

One approach for developing targeted stroke therapies is to identify the neuronal protective and destructive signaling pathways and gene expression that follow ischemic insult. In some neural injury models, the transforming growth factor-beta family member activin can provide neuroprotective effects in vivo and promote neuronal survival. This study tests if activin supports cortical neurons after ischemic challenge in vitro and if signals after cerebral ischemia involve activin in vivo. In a defined cell culture model that uses hydrogen peroxide (H2O2)-free radical stress, activin addition maintained neuronal survival. H2O2 treatment increased activin mRNA twofold in surviving cortical neurons, and inhibition of activin with neutralizing antibodies caused neuronal death. These data identify activin gene changes as a rapid response to oxidative stress, and indicate that endogenous activin acts as a protective factor for cortical neurons in vitro. Similarly, after transient focal cerebral ischemia in adult mice, activin mRNA increased at 1 and 4 h ipsilateral to the infarct but returned to control values at 24 h after reperfusion. Intracellular activated smad signals were detected in neurons adjacent to the infarct. Activin was also increased after 2 h of 11% hypoxia. Activin mRNA increased at 1 h but not 4 or 24 h after hypoxia, similar to the time course of erythropoietin and vascular endothelial growth factor induction. These findings identify activin as an early-regulated gene response to transient ischemia and hypoxia, and its function in cortical neuron survival during oxidative challenge provides a basis to test activin as a potential therapeutic in stroke injury.

Delayed activin A administration attenuates tissue death after transient focal cerebral ischemia and is associated with decreased stress-responsive kinase activation

Focal cerebral ischemia and reperfusion initiates complex cellular and molecular interactions that lead to either cell repair or destruction. In earlier work, we found that activin A is an early gene response to cerebral ischemia and supports cortical neuron survival in vitro. In this study, the ability of exogenous activin A to attenuate injury from transient middle cerebral artery occlusion was tested in adult mice. Intracerebroventricular administration of activin A prior to middle cerebral artery occlusion reduced infarct volume apparent 1 day after experimental stroke. A single activin A administration at 6 h following ischemia/reperfusion reduced lesion volumes at 1 and 3 days and led to improved neurobehavior. Moreover, activin A treatment spared neurons within the ischemic hemisphere and led to a concomitant reduction in microglial activation. Activation of the stress‐responsive kinases p38 and c‐jun N‐terminal kinase implicated in neuronal apoptosis after stroke was reduced following activin A treatment. Together these findings suggest that activin A promotes tissue survival after focal cerebral ischemia/reperfusion with an extended therapeutic window.

Lipid Profiles and APOE4 Allele Impact Midlife Cognitive Decline in HIV-Infected Men on Antiretroviral Therapy

Elevated cholesterol and APOE ε4 genotype were independent risk factors for cognitive decline in antiretroviral therapy–adherent human immunodeficiency virus (HIV)-infected men aged 50–65 years, whereas higher high-density lipoprotein attenuated cognitive decline. Treatment of dyslipidemia may reduce midlife cognitive decline among HIV-infected individuals.

Temporal Patterns and Drug Resistance in CSF Viral Escape Among ART-Experienced HIV-1 Infected Adults

Background: Cerebrospinal fluid (CSF) viral escape is an increasingly recognized clinical event among HIV-1-infected adults. We analyzed longitudinal data and drug-resistance mutations to characterize profiles of HIV-1-infected patients on antiretroviral therapy with discordant CSF and plasma HIV-1 RNA levels. Methods: Forty-one cases of CSF escape defined as detectable CSF HIV-1 RNA when plasma levels were undetectable, or HIV-1 RNA >0.5-log higher in CSF than plasma were identified from Boston Hospitals and National NeuroAIDS Tissue Consortium (NNTC) from 2005 to 2016. Results: Estimated prevalence of CSF escape in Boston and NNTC cohorts was 6.0% and 6.8%, respectively; median age was 50, duration of HIV-1 infection 17 years, CD4 count 329 cells/mm3 and CD4 nadir 21 cells/mm3. Neurological symptoms were present in 30 cases; 4 had repeat episodes of CSF escape. Cases were classified into subtypes based plasma HIV-1 RNA levels in the preceding 24 months: high-level viremia (1000 copies/mL), low-level viremia (LLV: 51–999 copies/mL), and plasma suppression with CSF blip or escape (CSF RNA <200 or ≥200 copies/mL). High-level viremia cases reported more substance abuse, whereas LLV or plasma suppression cases were more neurosymptomatic (81% vs. 53%); 75% of repeat CSF escape cases were classified LLV. M184V/I mutations were identified in 74% of CSF samples when plasma levels were ⩽50 copies per milliliter. Conclusions: Characteristics frequently observed in CSF escape include HIV-1 infection >15 years, previous LLV, and M184V/I mutations in CSF. Classification based on preceding plasma HIV RNA levels provides a useful conceptual framework to identify causal factors and test therapeutics.

Reversible cerebral vasoconstriction syndrome with reversible renal artery stenosis

A 41-year-old woman presented with thunderclap headaches, cortical blindness, generalized seizures, and severe hypertension. Brain imaging (figure) showed features of reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome.1 Her neurologic examination improved, but severe hypertension persisted. Abdomen CT angiography showed right renal artery narrowing with possible dissection, initially attributed to fibromuscular dysplasia (FMD). Renal angioplasty was considered; however, she was discharged on multiple antihypertensive agents. Her blood pressure normalized, and parenchymal lesions and vertebral/renal artery abnormalities showed complete resolution on follow-up at 7 months. This case emphasizes that RCVS can affect the extracerebral systemic arteries,2 and can be misinterpreted as FMD.

Propionibacterium acnes brain abscess in a patient with HIV-1 infection.

Propionibacterium acnes is a rod-shaped, gram-positive anaerobe that commonly colonizes skin crypts. Although an established, albeit rare, causative organism of intracerebral abscess, it most commonly occurs in the setting of prior surgery or trauma. There have been rare reports of P. acnes infections in the setting of HIV, but none of intracerebral abscess (El Karoui et al. 2007; Kronish et al. 1996; Cambanis et al. 2006). We describe the case of an HIVpositive patient on stable combination antiretroviral therapy (cART) who was diagnosed with P. acnes brain abscess in the absence of established risk factors.

Rapid Detection of Powassan Virus in a Patient With Encephalitis by Metagenomic Sequencing

Abstract We describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States.

Fatal Eastern Equine Encephalitis in a Patient on Maintenance Rituximab: A Case Report

Abstract A 63-year-old woman on rituximab maintenance for follicular lymphoma presented with headaches, vomiting, and fever, and was diagnosed with eastern equine encephalomyelitis by cerebrospinal fluid polymerase chain reaction. Eastern equine encephalomyelitis immunoglobulin (Ig)G/IgM remained negative due to rituximab treatment, and magnetic resonance imaging showed minimal abnormalities, making this a diagnostically challenging case. Despite therapy with intravenous Ig, the patient rapidly declined and died on hospital day 12. Autopsy revealed perivascular and parenchymal chronic inflammation, with an absence of B lymphocytes, and virally infected neurons throughout the central nervous system.

Marijuana Use Impacts Midlife Cardiovascular Events in HIV-Infected Men

Summary Long-term, heavy marijuana use was associated with increased cardiovascular events in human immunodeficiency virus (HIV)–infected men aged 40–60 independent of tobacco smoking, viral load, and other risk factors, while there was no significant association with HIV disease markers, progression to AIDS, or mortality.

Eastern Equine Encephalitis Treated With Intravenous Immunoglobulins

We report the case of a 68-year-old man from southeastern Massachusetts presenting with encephalitis due to eastern equine encephalitis (EEE) virus. Despite the high morbidity and mortality rate of EEE, the patient made a near complete recovery in the setting of receiving early intravenous immunoglobulins.