Human immunodeficiency virus (HIV)-associated increase in monocyte adhesion and trafficking is exacerbated by cocaine abuse. The underlying mechanisms involve cocaine-mediated upregulation of adhesion molecules with subsequent disruption of the blood–brain barrier (BBB). Recently, a novel activated leukocyte cell adhesion molecule (ALCAM) has been implicated in leukocyte transmigration across the endothelium. We now show that upregulation of ALCAM in the brain endothelium seen in HIV+/cocaine drug abusers paralleled increased CD68 immunostaining compared with HIV+/no cocaine or uninfected controls, suggesting the important role of ALCAM in promoting leukocyte infiltration across the BBB. Furthermore, ALCAM expression was increased in cocaine-treated mice with concomitant increase in monocyte adhesion and transmigration in vivo , which was ameliorated by pretreating with the neutralizing antibody to ALCAM, lending additional support to the role of ALCAM. This new concept was further confirmed by in vitro experiments. Cocaine-mediated induction of ALCAM in human brain microvascular endothelial cells through the translocation of σ receptor to the plasma membrane, followed by phosphorylation of PDGF-β (platelet-derived growth factor-β) receptor. Downstream activation of mitogen-activated protein kinases, Akt, and NF-κB (nuclear factor-κB) pathways resulted in induced expression of ALCAM. Functional implication of upregulated ALCAM was confirmed using cell adhesion and transmigration assays. Neutralizing antibody to ALCAM ameliorated this effect. Together, these findings implicate cocaine-mediated induction of ALCAM as a mediator of increased monocyte adhesion/transmigration into the CNS.

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Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we com...

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About half the people infected with human immunodeficiency virus (HIV) have neurocognitive deficits that often include memory impairment and hippocampal deficits, which can be exacerbated by opioid abuse. To explore the effects of opioids and HIV on hippocampal CA1 pyramidal neuron structure and function, we induced HIV-1 transactivator of transcription (Tat) expression in transgenic mice for 14 d and co-administered time-release morphine or vehicle subcutaneous implants during the final 5 d (days 9–14) to establish steady-state morphine levels. Morphine was withheld from some ex vivo slices during recordings to begin to assess the initial pharmacokinetic consequences of opioid withdrawal. Tat expression reduced hippocampal CA1 pyramidal neuronal excitability at lower stimulating currents. Pyramidal cell firing rates were unaffected by continuous morphine exposure. Behaviorally, exposure to Tat or high dosages of morphine impaired spatial memory Exposure to Tat and steady-state levels of morphine appeared to have largely independent effects on pyramidal neuron structure and function, a response that is distinct from other vulnerable brain regions such as the striatum. By contrast, acutely withholding morphine (from morphine-tolerant ex vivo slices) revealed unique and selective neuroadaptive shifts in CA1 pyramidal neuronal excitability and dendritic plasticity, including some interactions with Tat. Collectively, the results show that opioid-HIV interactions in hippocampal area CA1 are more nuanced than previously assumed, and appear to vary depending on the outcome assessed and on the pharmacokinetics of morphine exposure.

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Drug intoxication and addiction can compromise judgment and decision-making and potentially lead to risky sexual behavior, including trading sex for drugs, and needle sharing. This increases a cocaine user’s risk for contracting infectious diseases such as HIV and hepatitis C (HCV).

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What is the aim of the DASH (2009) Risk Identification and Assessment Model? save and change lives through early identification, intervention and prevention identify risk and needs ensure an effective investigation create a common language across agencies to refer a case to risk management meetings such as MARAC enable information sharing inform decision making Who… Read more

Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare

Chronic distress and the vulnerable host: a new target for HIV treatment and prevention? Carlo Contoreggi,1 George P Chrousos,2 Michele Di Mascio3 1Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, MD, USA; 2Department of Pediatrics, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece; 3AIDS Imaging Research Section, Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA Abstract: Pathologic stress (distress) disturbs immune, cardiovascular, metabolic, and behavioral homeostasis. Individuals living with HIV and those at risk are vulnerable to stress disorders. Corticotropin-releasing hormone (CRH) is critical in neuroendocrine immune regulation. CRH, a neuropeptide, is distributed in the central and peripheral nervous systems and acts principally on CRH receptor type 1 (CRHR1). CRH in the brain modulates neuropsychiatric disorders. CRH and stress modulation of immunity is two-pronged; there is a direct action on hypothalamic–pituitary–adrenal secretion of glucocorticoids and through immune organ sympathetic innervation. CRH is a central and systemic proinflammatory cytokine. Glucocorticoids and their receptors have gene regulatory actions on viral replication and cause central and systemic immune suppression. CRH and stress activation contributes to central nervous system (CNS) viral entry important in HIV-associated neurocognitive disorders and HIV-associated dementia. CNS CRH overproduction short-circuits reward, executive, and emotional control, leading to addiction, cognitive impairment, and psychiatric comorbidity. CRHR1 is an important therapeutic target for medication development. CRHR1 antagonist clinical trials have focused on psychiatric disorders with little attention paid to neuroendocrine immune disorders. Studies of those with HIV and those at risk show that concurrent stress-related disorders contribute to higher morbidity and mortality; stress-related conditions, addiction, immune dysfunction, and comorbid psychiatric illness all increase HIV transmission. Neuropsychiatric disease, chronic inflammation, and substance abuse are endemic, and chronic distress is a pathologic factor. It is being understood that stress and CRH are fundamental to neuroendocrine immunity; therapeutic interventions with existing and novel agents hold promise for restoring homeostasis, reducing morbidity and mortality for those with HIV and possibly reducing future disease transmission. Keywords: corticotropin-releasing hormone, stress, neuroendocrine immunology, hypothalamic–pituitary–adrenal, cytokine, glucocorticoid resistance

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Companies are moving toward a DevSecOps approach to application development, but problems remain with security testing ownership and open-source code vulnerabilities.

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What is a risk assessment? Why is risk assessment important? What is the goal of risk assessment?

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