Posterior Fossa Progressive Multifocal Leukoencephalopathy Secondary to Rituximab.

Progressive multifocal leukoencephalopathy (PML) is a rare fatal central nervous system disorder characterized by infection-induced demyelination of white matter due to the opportunistic reactivation of John Cunningham virus in an immunocompromised patient. PML is associated with many immune-mediated diseases, lymphoproliferative conditions, and immunosuppressive agents. In this case report, we present a 79-year-old female patient diagnosed with rheumatoid arthritis who developed posterior fossa PML while on rituximab. She presented with subacute cerebellar ataxia, dysarthria, and nystagmus, and her brain MRI showed right pontine and pontocerebellar lesion with diffusion restriction and heterogenous enhancement highly characteristic of PML. Though many cases of PML with rituximab were reported in the literature, our case describes a rare type of PML affecting the posterior fossa in an HIV-negative patient on rituximab.

HIV-1 Tat-mediated microglial inflammation involves a novel miRNA-34a-NLRC5-NFκB signaling axis.

While the advent of combination antiretroviral therapy (cART) has dramatically increased the lifespan of people living with HIV-1 paradoxically, the prevalence of NeuroHIV in people treated with cART is on the rise. It has been well documented that despite the effectiveness of cART in suppressing viremia, CNS continues to harbor viral reservoirs with persistent low-level virus replication. This, in turn, leads to the presence and accumulation of early viral protein - HIV-1 Tat, that is a well-established cytotoxic agent. In the current study, we demonstrated that exposure of mouse microglia to HIV-1 Tat resulted both in a dose- and time-dependent upregulation of miRNA-34a, with concomitant downregulation of NLRC5 (a negative regulator of NFκB signaling) expression. Using bioinformatics analyses and Argonaute immunoprecipitation assay NLRC5 was identified as a novel target of miRNA-34a. Transfection of mouse primary microglia with miRNA-34a mimic significantly downregulated NLRC5 expression, resulting in increased expression of NFκB p65. In contrast, transfection of cells with miRNA-34a inhibitor upregulated NLRC5 levels. Using pharmacological approaches, our findings showed that HIV-1 Tat-mediated microglial activation involved miRNA-34a-mediated downregulation of NLRC5 with concomitant activation of NFκB signaling. Reciprocally, inhibition of miRNA-34a blocked HIV-1 Tat-mediated microglial activation. In summary, our findings identify yet another novel mechanism of HIV-1 Tat-mediated activation of microglia involving the miRNA-34a-NLRC5-NFκB axis. These in vitro findings were also validated in the medial prefrontal cortices of HIV-1 transgenic rats as well as in SIV-infected rhesus macaques. Overall, these findings reveal the involvement of miRNA-34a-NLRC5-NFκB signaling axis in HIV-1 Tat-mediated microglial inflammation.

Postpartum Invasive Group A Streptococcus Infection: Case Report and Mini-review.

The overall incidence of postpartum invasive group A streptococcal (GAS) disease is low in the United States. However, postpartum women are much more likely to develop GAS disease than nonpregnant women. Additionally, postpartum GAS has the potential to develop into a severe disease and a delay in diagnosis can have deadly consequences. This case describes a patient with invasive postpartum endometritis in the setting of diastases of the pubic symphysis. Sepsis secondary to the endometritis develops along with bilateral pneumonia. This case characterizes some of the typical and atypical symptoms a patient with invasive postpartum GAS can present with. Further, it outlines the timely identification of the disease and its appropriate treatment to prevent a potentially disastrous outcome.

Type 2M Von Willebrand Disease: A Case Report.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is divided into three types, namely type 1, type 2 (2A, 2B, 2M, 2N), and type 3. We report a case of a 24-year-old Caucasian woman with a rare variety of type 2M VWD. Her von Willebrand factor versus antigen ratio was 0.44 (normal ratio is greater than 0.7) . She was asymptomatic and hence not treated but followed up regularly. VWD is not life-threatening when treated timely.

HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy.

While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation. Our results demonstrated that exposure of mouse primary microglia to HIV-1 TAT resulted in cellular activation involving altered mitochondrial membrane potential that was accompanied by accumulation of damaged mitochondria. Exposure of microglia to HIV-1 TAT resulted in increased expression of mitophagy signaling proteins, such as PINK1, PRKN, and DNM1L, with a concomitant increase in the formation of autophagosomes, as evidenced by increased expression of BECN1 and MAP1LC3B-II. Intriguingly, exposure of cells to HIV-1 TAT also resulted in increased expression of SQSTM1, signifying thereby a possible blockade of the mitophagy flux, leading, in turn, to the accumulation of mitophagosomes. Interestingly, HIV-1 TAT-mediated activation of microglia was associated with decreased rate of extracellular acidification and mitochondrial oxygen consumption and increased expression of proinflammatory cytokines, such as Tnf, Il1b, and Il6. HIV-1 TAT-mediated defective mitophagy leading to microglial activation was further validated in vivo in the brains of HIV-1 transgenic rats. In conclusion, HIV-1 TAT activates microglia by increasing mitochondrial damage via defective mitophagy. ABBREVIATIONS: 3-MA: 3-methyladenine; Δψm: mitochondrial membrane potential; ACTB: actin, beta; AIF1: allograft inflammatory factor 1; ATP: adenosine triphosphate; BAF: bafilomycin A1; BECN1: beclin 1, autophagy related; cART: combined antiretroviral therapy; CNS: central nervous system; DNM1L: dynamin 1 like; DMEM: Dulbecco modified Eagle medium; DAPI: 4,6-diamidino-2-phenylindole ; ECAR: extracellular acidification rate; FBS: fetal bovine serum; FCCP: trifluoromethoxy carbonylcyanide phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAND: HIV-1-associated neurocognitive disorders; HIV-1 TAT: human immunodeficiency virus-1 transactivator of transcription; IL1B: interleukin 1, beta; IL6: interleukin 6; ITGAM: integrin subunit alpha M; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mPMs: mouse primary microglial cells; MRC: maximal respiratory capacity; mt-CO1: mitochondrially encoded cytochrome c oxidase; mt-ND6: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6; NFKB1: nuclear factor kappa B subunit 1; NLRP3: NLR family pyrin domain containing 3; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TNF: tumor necrosis factor.

Bilateral chorea/ballismus: detection and management of a rare complication of non-ketotic hyperglycaemia.

Non-ketotic hyperglycaemia (NKH) is the most common metabolic cause of hemichorea-hemiballismus (HC-HB) and an often-reversible condition. A 68-year-old man presented to the emergency department with a severe hyperglycaemic episode and altered mental status. He was treated appropriately and discharged home after his blood glucose levels were normal with an improvement of mental status. Four weeks after the discharge, he returned with flailing movements of bilateral upper and lower limbs. MRI of the brain revealed hyperintensities of the bilateral putamen on T1-weighted imaging. The patient's symptoms improved with a combination of amantadine, clonazepam and tetrabenazine. Several hypotheses involving gemistocytes, calcification and petechial haemorrhage were proposed in support of imaging abnormalities in the striatum. Dopamine-depleting agents and neuroleptics are used in the treatment of chorea. It is recommended to try a dose of tetrabenazine in patients with NKH-induced HC-HB if no improvement is appreciated with initial treatment of glycaemic control.

Rare Multidrug-Resistant Pulmonary Nocardiosis in AIDS.

Nocardiosis is an opportunistic infection in patients with depressed cell-mediated immunity. Inhalation is the primary route for exposure via dust particles. Patients with acquired immune deficiency syndrome (AIDS) are at increased risk of disseminated disease. A challenge in the diagnosis of pulmonary nocardiosis is that it can mimic other pulmonary diseases. Nocardia farcinica tends to be a more virulent, multidrug-resistant strain with an increased tendency to disseminate. This report describes a 64-year-old man with AIDS found to have pulmonary nocardiosis that did not respond to standard antibiotic therapy. Further evaluation revealed the virulent, multidrug-resistant Nocardia farcinica species. Targeted antibiotic therapy was initiated, after which the patient had an improvement in pulmonary symptoms. It is important to suspect pulmonary nocardiosis in immunocompromised patients who fail to respond to standard antimicrobial therapy. Susceptibilities should be obtained so that appropriate therapy can be promptly initiated as Nocardia farcinica is highly resistant to multiple antimicrobials.