HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.

Utilizing Infantile Spasm Seizure Activity as a Baseline Vital in the Setting of Acute Pseudomonas aeruginosa Pneumonia.

The objective of this case report is to describe and document a decrease in seizure activity in a 16-year-old female with a past medical history of Aicardi syndrome (AS) and infantile spasms (IS) while being treated for acute Pseudomonas aeruginosa pneumonia with pleural effusion. This patient presented to the pediatric emergency department with a chief complaint of fever, tachycardia, increased nasal secretions, and oxygen requirement at home. She was admitted to the general pediatric medical floor for treatment of an adenovirus infection due to her having a complex medical history and her being medically unstable. On hospital admission day 1, she developed post-viral P. aeruginosa pneumonia. She subsequently had three days of complete clinical seizure cessation without changing her anti-epileptic medications. It was not until the symptomatology related to her pneumonia improved that her seizure activity returned to its baseline frequency. The treating team discovered that the decrease in her frequency of seizure activity related to periods of increased physiologic stress was not new. Her mother reported that she has used the relationship between her daughter's seizures and any acute illness to gauge how her daughter was "feeling" medically. Three weeks prior to this hospital admission, her mother reported that her daughter's seizures ceased for two days during a period in which it was determined that the patient was having renal colic and passed a renal stone. This phenomenon, the decrease in the frequency of seizure activity related to periods of increased physiologic stress, could help primary caretakers assess when significant, new comorbid conditions are present and could aid in the primary assessment of physical health in a particular patient population who are unable to verbalize their current medical status. Utilizing seizure activity as an at-home vital sign could help caretakers recognize when their patient is under an elevated physiologic stress condition. Recognizing the relationship between seizure frequency and acute illness could also help diagnostically, as ISs are difficult to both diagnose and manage. Also, future research on this possible association could explore more understanding of IS and pathophysiology of such phenomenon.

Transcranial Magnetic Stimulation in Bipolar II Disorder Treatment: A Case Report.

The objective of this case report is to describe and document the use of transcranial magnetic stimulation (TMS) to aid in the treatment of bipolar II disorder. A 35-year-old male with a past medical history of attention-deficit/hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), severe depression, and bipolar II disorder was presented to an outpatient psychiatric clinic 1.5 years after his initial TMS treatment for TMS maintenance therapy. He reported feeling depressed, brain fogginess, loss of concentration, fatigue, and constant changes in moods. He had tried multiple antidepressants and antipsychotics, seen several therapists, and underwent electroconvulsive therapy in 2014 with no improvement. In August 2021, he underwent the standard TMS protocol with 36 treatments and noticed significant improvement in his symptoms. He followed up with his psychiatrist who placed him on quetiapine 400 mg, lurasidone 120 mg, topiramate 100 mg, Adderall 20 mg, Wellbutrin 150 mg, propranolol 20 mg, and Klonopin 0.5 mg for management. However, after starting these medications, he noticed a loss of concentration, not being able to think straight, fatigue, depression, and a change in moods. In January 2023, the patient underwent maintenance TMS treatment with theta bursts (TBS). The treatment protocol consisted of 10 sessions for 3 ½ minutes each, 20 trains, 10 bursts, and eight seconds between intervals. He completed his treatment and reported feeling great and like himself again. Two weeks following treatment, he reported that his brain fog had resolved, hypomanic episodes had lessened, and depressive moods had been occurring less often. Due to improvement, topiramate and lurasidone were discontinued and the patient will continue with monthly follow-ups to monitor his progress. TMS appears to be a promising treatment option for bipolar disorder.

Sulforaphane prevents the reactivation of HIV-1 by suppressing NFκB signaling.

Despite more than 20 years of combination antiretroviral therapy (cART), complete eradication of HIV remains a daunting task. While cART has been very effective in limiting new cycles of infection and keeping viral load below detectable levels with partial restoration of immune functions, it cannot provide a cure. Evidently, the interruption of cART leads to a quick rebound of the viral load within a few weeks. These consistent observations have revealed HIV ability to persist as an undetectable latent reservoir in a variety of tissues that remain insensitive to antiretroviral therapies. The 'Block-and-Lock' approach to drive latent cells into deep latency has emerged as a viable strategy to achieve a functional cure. It entails the development of latency-promoting agents with anti-HIV functions. Recent reports have suggested sulforaphane (SFN), an inducer of NRF-2 (nuclear erythroid 2-related factor 2)-mediated antioxidative signaling, to possess anti-HIV properties by restricting HIV replication at the early stages. However, the effect of SFN on the expression of integrated provirus remains unexplored. We have hypothesized that SFN may promote latency and prevent reactivation. Our results indicate that SFN can render latently infected monocytes and CD4+ T cells resistant to reactivation. SFN treatments antagonized the effects of known latency reactivating agents, tumor necrosis pactor (TNF-α), and phorbol 12-myristate 13-acetate (PMA), and caused a significant reduction in HIV transcription, viral RNA copies, and p24 levels. Furthermore, this block of reactivation was found to be mediated by SFN-induced NRF-2 signaling that specifically decreased the activation of NFκB signaling and thus restricted the HIV-1 promoter (5'LTR) activity. Overall, our study provides compelling evidence to highlight the latency-promoting potential of SFN which could be used in the 'Block-and-Lock' approach to achieve an HIV cure.