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Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications. Presently, no specific therapeutics for the HIV-1-related central nervous system (CNS) complications exists. Here we report that three newly-designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, -084-13, and -087-13, which contain P1-3,5-bis-fluorophenyl- or P1-para-monofluorophenyl-ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano (...) demonstrated that the bicyclic rings at the P2 moiety of the CNS-targeting PIs form strong hydrogen-bond interactions with HIV-1 protease (PR) active-site. Moreover, both the P1-3,5-bis-fluorophenyl- and P1-para-monofluorophenyl-rings sustain greater contact surfaces and form greater van der Waals contacts with PR than in the case of darunavir (DRV). The data suggest that the present CNS-targeting PIs have desirable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1s
CRACKCast E109 – CNSInfections CRACKCast E109 - CNSInfections - CanadiEM CRACKCast E109 – CNSInfections In by Adam Thomas September 14, 2017 This episode of CRACKCast covers Rosen’s Chapter 109, CNSInfections. This chapter covers a differential diagnosis for CNSinfections, including necessary workup and approaches to treatment. Shownotes – Key Points CNSinfection should be considered in all patients with headache, neck stiffness, fever, altered sensorium, or diffuse or focal neurological (...) findings. pneumoniae is one of the two leading causes of bacterial meningitis in adults. Mortality from S. pneumoniae is 30%. pay close attention to cranial nerves 2, 3, 4, and 6 Altered mental status in a patient with suspected meningitis can be a sign of increased ICP or encephalitis. You’ve got to get the LP! Only true way to assess for meningitis Early initiation of empirical antimicrobial therapy is recommended in cases of suspected acute CNSinfection. Antibiotic administration should
Randomized Controlled Trial Comparing Cerebral Perfusion Pressure-Targeted Therapy Versus Intracranial Pressure-Targeted Therapy for Raised Intracranial Pressure due to Acute CNSInfections in Children PEDSCCM.org Criteria abstracted from series in Review Posted: founded 1995 Questions or comments?
T cells establish and maintain CNS viral infection in HIV-infected humanized mice The human brain is an important site of HIV replication and persistence during antiretroviral therapy (ART). Direct evaluation of HIV infection in the brains of otherwise healthy individuals is not feasible; therefore, we performed a large-scale study of bone marrow/liver/thymus (BLT) humanized mice as an in vivo model to study HIV infection in the brain. Human immune cells, including CD4+ T cells and macrophages (...) , were present throughout the BLT mouse brain. HIV DNA, HIV RNA, and/or p24+ cells were observed in the brains of HIV-infected animals, regardless of the HIV isolate used. HIV infection resulted in decreased numbers of CD4+ T cells, increased numbers of CD8+ T cells, and a decreased CD4+/CD8+ T cell ratio in the brain. Using humanized T cell-only mice (ToM), we demonstrated that T cells establish and maintain HIV infection of the brain in the complete absence of human myeloid cells. HIV infection
Tolerability of high-dose ceftriaxone in CNSinfections: a prospective multicentre cohort study. Ceftriaxone is widely used to treat community-acquired CNS bacterial infections. French guidelines for meningitis in adults promote 75-100 mg/kg/day ceftriaxone without an upper limit for dosage, yet little is known about the pharmacology and tolerability of such regimens.A multicentre prospective cohort study was conducted in adult patients to assess the adverse drug reactions (ADRs) of high-dose (...) ceftriaxone (i.e. daily dosage ≥4 g or ≥75 mg/kg) in CNSinfections and to analyse their related factors. Drug causality was systematically assessed by an expert committee who reviewed the medical charts of all included patients.A total of 196 patients were enrolled over a 31 month period. Median dosage and duration of ceftriaxone were 96.4 mg/kg/day (7 g/day) and 8 days, respectively. Nineteen ceftriaxone-related ADRs (mainly neurological) occurred in 17 patients (8.7%), with only one case of treatment
Kynurenine is a cerebrospinal fluid biomarker for bacterial and viral CNSinfections. The tryptophan-kynurenine-NAD+ pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in CNSinfections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers.We measured (...) -barrier dysfunction) and were highly increased in bacterial and viral CNSinfections, but were low or undetectable in anti-NMDA-R encephalitis, multiple sclerosis, and controls. Trp was decreased mostly in viral CNSinfections and neuroborreliosis. Multiple logistic regression analysis revealed combinations of Kyn, Trp and Kyn/Trp ratio with leukocyte count or lactate as accurate classifiers for the clinically important differentiation between neuroborreliosis, viral CNSinfections, and autoimmune
A systematic review of clinical guidelines on the management of acute, community-acquired CNSinfections. The epidemiology of CNSinfections in Europe is dynamic, requiring that clinicians have access to up-to-date clinical management guidelines (CMGs) to aid identification of emerging infections and for improving quality and a degree of standardisation in diagnostic and clinical management practices. This paper presents a systematic review of CMGs for community-acquired CNSinfections (...) in Europe.A systematic review. Databases were searched from October 2004 to January 2019, supplemented by an electronic survey distributed to 115 clinicians in 33 European countries through the CLIN-Net clinical network of the COMBACTE-Net Innovative Medicines Initiative. Two reviewers screened records for inclusion, extracted data and assessed the quality using the AGREE II tool.Twenty-six CMGs were identified, 14 addressing bacterial, ten viral and two both bacterial and viral CNSinfections. Ten CMGs
An unexpectedly high occurrence of aciclovir-induced neuropsychiatric symptoms in patients treated for herpesvirus CNSinfection: a prospective observational study. Aciclovir is effective in herpesvirus infections of the CNS. Aciclovir-induced neuropsychiatric symptoms (AINS) have been reported and are associated with high CSF concentrations of aciclovir metabolite 9-carboxymethoxymethylguanine (CMMG). Risk factors except for renal failure have not been explored, and disruption of the blood (...) -brain barrier (BBB) in acute CNSinfection may be of interest.To investigate the impact of risk factors on aciclovir and CMMG concentrations, and to relate the results to AINS.We investigated 21 consecutively included, consenting patients treated with aciclovir or valaciclovir for herpesvirus CNSinfection. Regression models were constructed to study the impact of risk factors including BBB disruption, as measured with CSF:serum albumin ratio, on CSF aciclovir and CMMG concentrations. Medical
CNSinfections in Greenland: A nationwide register-based cohort study. Indigenous Arctic people suffer from high rates of infectious diseases. However, the burden of central nervous system (CNS) infections is poorly documented. This study aimed to estimate incidence rates and mortality of CNSinfections among Inuits and non-Inuits in Greenland and in Denmark.We conducted a nationwide cohort study using the populations of Greenland and Denmark 1990-2012. Information on CNSinfection (...) hospitalizations and pathogens was retrieved from national registries and laboratories. Incidence rates were estimated as cases per 100,000 person-years. Incidence rate ratios were calculated using log-linear Poisson-regression. Mortality was estimated using Kaplan-Meier curves and Log Rank test.The incidence rate of CNSinfections was twice as high in Greenland (35.6 per 100,000 person years) as in Denmark (17.7 per 100,000 person years), but equally high among Inuits in Greenland and Denmark (38.2 and 35.4
Advances in the diagnosis and treatment of fungal infections of the CNS. Fungal infections of the CNS are challenging to treat and their optimal management requires knowledge of their epidemiology, host characteristics, diagnostic criteria, and therapeutic options. Aspergillus and Cryptococcus species predominate among fungal infections of the CNS. Most of these fungi are ubiquitous, but some have restricted geographical distribution. Fungal infections of the CNS usually originate from primary (...) sites outside the CNS (eg, fungal pneumonia) or occur after inoculation (eg, invasive procedures). Most patients with these infections have immunodeficiencies, but immunocompetent individuals can also be infected through heavy exposure. The infecting fungi can be grouped into moulds, yeasts, and dimorphic fungi. Substantial progress has been made with new diagnostic approaches and the introduction of novel antifungal drugs, but fungal infections of the CNS are frequently lethal because of diagnostic
Generation of three-dimensional human neuronal cultures: application to modeling CNS viral infections A variety of neurological disorders including neurodegenerative diseases and infection by neurotropic viruses can cause structural and functional changes in the central nervous system (CNS), resulting in long-term neurological sequelae. An improved understanding of the pathogenesis of these disorders is important for developing efficacious interventions. Human induced pluripotent stem cells (...) (hiPSCs) offer an extraordinary window for modeling pathogen-CNS interactions, and other cellular interactions, in three-dimensional (3D) neuronal cultures that can recapitulate several aspects of in vivo brain tissue.Herein, we describe a prototype of scaffold-free hiPSC-based adherent 3D (A-3D) human neuronal cultures in 96-well plates. To test their suitability for drug screening, A-3D neuronal cultures were infected with herpes simplex virus type 1 (HSV-1) with or without acyclovir.The half
CNSInfections Effect on the Inner Ear CNSInfections Effect on the Inner Ear - Full Text View - ClinicalTrials.gov Hide glossary Glossary Study record managers: refer to the if submitting registration or results information. Search for terms x × Study Record Detail Saved Studies Save this study Warning You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. CNSInfections Effect on the Inner Ear The safety and scientific validity (...) by (Responsible Party): Elisa Skovgaard Jensen, Nordsjaellands Hospital Study Details Study Description Go to Brief Summary: Study on patients with CNSinfections. Condition or disease Intervention/treatment CNSInfection Inner Ear Hearing Loss Vestibular Abnormality Inner Ear Inflammation Hearing Loss, Sensorineural Diagnostic Test: Vestibular function Diagnostic Test: OAE/WBT Diagnostic Test: Biomarker Diagnostic Test: MOCA, eGOS Diagnostic Test: Audiometry Detailed Description: Aims and objectives
Association between Proton Pump Inhibitor Use and CNSInfection Risk: A Retrospective Cohort Study This study investigated the incidence of central nervous system (CNS) infection following the use of proton pump inhibitors (PPIs). A retrospective cohort study was conducted in Taiwan by using data from the National Health Insurance Research Database. We identified and enrolled 16,241 patients with CNSinfection who used PPIs (PPI users). The patients were individually propensity score matched (1 (...) :1) according to age, sex, hypertension, hyperlipidemia, Charlson comorbidity index (CCI), H2 blocker, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroid, and immunosuppressant use with 16,241 controls (PPI nonusers). A Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) for CNSinfection in the PPI users and nonusers. After adjustment for other confounding factors, the incidence of CNSinfection in the PPI users was 2.23-fold higher than that in the PPI
miR-1303 regulates BBB permeability and promotes CNS lesions following CA16 infections by directly targeting MMP9 Coxsackievirus A16 (CA16) is a member of the Picornaviridae family and causes mild and self-limiting hand, foot, and mouth disease (HFMD) in infants and young children. CA16 infection can also progress to central nervous system (CNS) complications; however, the underlying mechanism by which CA16 penetrates the blood-brain barrier (BBB) and then causes CNS damage remains unclear (...) , we used dual-luciferase, qRT-PCR, and western blot assays to provide evidence of MMP9 targeting by miR-1303. Further experiments revealed that CA16 infection promoted the degradation of junctional complexes (Claudin4, Claudin5, VE-Cadherin, and ZO-1), likely by downregulating miR-1303 and upregulating MMP9. Finally, EGFP-CA16 infection could enter the CNS by facilitating the degradation of junctional complexes, eventually causing neuroinflammation and injury to the CNS, which was confirmed using
CNSinfection and immune privilege. Classically, the CNS is described as displaying immune privilege, as it shows attenuated responses to challenge by alloantigen. However, the CNS does show local inflammation in response to infection. Although pathogen access to the brain parenchyma and retina is generally restricted by physiological and immunological barriers, certain pathogens may breach these barriers. In the CNS, such pathogens may either cause devastating inflammation or benefit from (...) immune privilege in the CNS, where they are largely protected from the peripheral immune system. Thus, some pathogens can persist as latent infections and later be reactivated. We review the consequences of immune privilege in the context of CNSinfections and ask whether immune privilege may provide protection for certain pathogens and promote their latency.
CSF extracellular vesicles and neurofilament light protein as biomarkers of CNS injury in HIV-infected patients on antiretroviral therapy. The relationship of cerebrospinal fluid (CSF) extracellular vesicles to neurocognitive impairment (NCI) in HIV-infected individuals is unclear. Here, we characterize CSF extracellular vesicles and their association with central nervous system (CNS) injury related biomarkers [neurofilament light (NFL), S100B, neopterin] and NCI in HIV-positive individuals (...) , suggesting potential applications as novel biomarkers of CNS injury.
PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection - Full Text View - ClinicalTrials.gov Hide glossary Glossary Study record managers: refer to the if submitting registration or results information. Search for terms x × Study Record Detail Saved Studies Save this study Warning You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. PD-1 Inhibition to Determine CNS (...) exhaustion against latent HIV. Study Design Go to Layout table for study information Study Type : Interventional (Clinical Trial) Estimated Enrollment : 20 participants Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Other Official Title: PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection Actual Study Start Date : April 9, 2018 Estimated Primary Completion Date : December 31, 2019 Estimated Study Completion Date : December 31, 2020 Resource links provided
CD11c-expressing cells affect Treg behavior in the meninges during CNSinfection Regulatory T cells (Tregs) play an important role in the CNS during multiple infections, as well as autoimmune inflammation, but the behavior of this cell type in the CNS has not been explored. In mice, infection with Toxoplasma gondii leads to a Th1-polarized parasite-specific effector T cell response in the brain. Similarly, Tregs in the CNS during T. gondii infection are Th1 polarized, as exemplified by their T (...) -bet, CXCR3, and IFN-γ expression. Unlike effector CD4+ T cells, an MHC class II tetramer reagent specific for T. gondii did not recognize Tregs isolated from the CNS. Likewise, TCR sequencing revealed minimal overlap in TCR sequence between effector T cells and Tregs in the CNS. Whereas effector T cells are found in the brain parenchyma where parasites are present, Tregs were restricted to the meninges and perivascular spaces. The use of intravital imaging revealed that activated CD4+ T cells