18 research outputs found
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Brain and liver pathology, amyloid deposition, and interferon responses among older HIV-positive patients in the late HAART era
Background: HIV+ patients on highly active antiretroviral therapy (HAART) with suppressed viral loads have a low incidence of HIV-associated dementia, but increased prevalence of milder forms of HIV-associated neurocognitive disorders (HAND). These milder forms of HAND are often associated with minimal histological abnormalities, and their pathophysiology is unclear. Comorbidities, altered amyloid metabolism, accelerated brain aging, and activated interferon responses are suspected to play a role in HAND pathogenesis in HAART–treated persons. Methods: To investigate associations between liver disease, accelerated brain aging, and HAND in HIV+ patients in the late HAART era (2002–2015), we studied liver and brain autopsy tissues from 53 older subjects evaluated at UCLA and BWH using histopathological stains, a sensitive fluorescent amyloid stain (AmyloGlo), and targeted gene expression profiling (NanoString). Results: The majority of HIV+ subjects (median age 56) were on HAART (89.3%) with last pre-mortem plasma viral load <400 copies/mL (81.5%); 50% had CD4+ counts <200 cells/μL. Compared to HIV- controls (median age 65), HIV+ subjects had more cancer (p = 0.04), illicit drug use (p <0.00001), and HCV co-infection (p = 0.002), less cardiovascular disease (p = 0.03), and similar prevalence of cerebrovascular disease (~40%), hypertension, hyperlipidemia, and diabetes. Deep frontal white matter showed increased gliosis in HIV+ subjects vs. HIV- controls (p = 0.09), but no significant differences in myelin loss, blood vessel thickening, or inflammation. Liver showed more severe fibrosis/cirrhosis (p = 0.02) and less steatosis (p = 0.03) in HIV+ subjects, but no significant differences in inflammation, blood vessel thickness, or pigment deposition. There were no significant associations between liver and brain pathologies. AmyloGlo staining detected large amyloid deposits in only one HIV+ case (age 69 with Alzheimer’s disease pathology) and two HIV- controls (ages 66 and 74). White matter from HIV+ cases vs. HIV- seronegative controls showed a trend (p = 0.06) towards increased interferon response gene expression (ISG15, MX1, IFIT1, IFIT2, and IFITM1). Conclusions: Gliosis and cerebrovascular disease, but not accelerated amyloid deposition, are common brain pathologies among older HIV+ patients in the late HAART era. Although HIV+ subjects had more cirrhosis, liver pathology was not associated with any consistent pattern of brain pathology. Cerebrovascular disease, interferon responses, and neuroinflammation are likely factors contributing to brain aging and HAND in older HIV+ patients on current HAART regimens. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2246-7) contains supplementary material, which is available to authorized users
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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
Additional file 1: of Brain and liver pathology, amyloid deposition, and interferon responses among older HIV-positive patients in the late HAART era
Gene expression profiling of frontal lobe subcortical white matter. Table listing 24 genes profiled using the Nanostring nCounter platform to quantify mRNA transcripts. (DOCX 13 kb
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Outcome of pediatric pineoblastoma after surgery, radiation and chemotherapy
Introduction Pineoblastomas are a category of supratentorial primitive neuroectodermal tumors (sPNETs) occurring in the pineal gland; some studies support the impression that patients with pineoblastomas have a worse prognosis than those with other sPNETs. Methods We reviewed the medical records and tissue sections of all patients with the diagnosis of pineoblastoma that were treated at the Dana-Farber Cancer Institute/Children's Hospital Boston Pediatric Brain Tumor Program between 1986 and 2005. Results Thirteen patients with the pathologic diagnosis of pineoblastoma were treated at our Hospital; 11 of these cases had complete records suitable for study. The median age was 8 years 8 months (5 F, 6 M). Surgical, radiation and chemotherapeutic regimens varied from case to case. Three patients had gross total resection and are alive and free of disease, versus four of eight with subtotal resection or biopsy only. Patients who received CSI and multi-agent chemotherapy had improved overall survival. Conclusions Seven of eleven patients with pineoblastoma are currently alive and free of disease, reflecting an improved outcome and longer survival than previously appreciated. Gross total surgical resection appeared to correlate with improved survival, as did treatment with craniospinal irradiation and multi-agent chemotherapy. Further study of this group of patients as a distinct diagnostic entity will be necessary to determine optimal therapy
Expanding the Phenotype Associated With the NEFL
IMPORTANCE: Newer sequencing technologies in combination with traditional gene mapping techniques, such as linkage analysis, can help identify the genetic basis of disease for patients with rare disorders of uncertain etiology. This approach may expand the phenotypic spectrum of disease associated with those genetic mutations. OBJECTIVE: To elucidate the molecular cause of a neuromuscular disease among a family in which 4 members, a mother and her 3 sons, were affected. DESIGN, SETTING, AND PARTICIPANTS: Two of 4 affected members manifested nemaline myopathy, a common subtype of congenital myopathy, while the other 2 had a nonspecific myopathy. Single-nucleotide polymorphism–based linkage analysis was performed on DNA samples from the 4 affected family members, and whole-genome sequencing was performed in the proband. Real-time quantitative reverse transcription–polymerase chain reaction, immunofluorescence, and Western blot analysis were performed on muscle biopsy specimens. MAIN OUTCOMES AND MEASURES: Whole-genome sequencing and linkage analysis identified a variant in a gene that explains the phenotype. RESULTS: We identified a novel neurofilament light polypeptide (NEFL) nonsense mutation in all affected members. NEFL mutations have been previously linked to Charcot-Marie-Tooth disease in humans. This led us to reevaluate the diagnosis, and we recognized that several of the findings, especially those related to the muscle biopsy specimens and electromyography, were consistent with a neurogenic disease. CONCLUSIONS AND RELEVANCE: NEFL mutations are known to cause Charcot-Marie-Tooth disease in humans and motor neuron disease in mice. We report the identification of an NEFL mutation in a family clinically manifesting congenital myopathy. We also describe potential overlap between myopathic and neurogenic findings in this family. These findings expand the phenotypic spectrum of diseases associated with NEFL mutations. This study is an example of the power of genomic approaches to identify potentially pathogenic mutations in unsuspected genes responsible for heterogeneous neuromuscular diseases