Nearly 30 years after the advent of antiretroviral therapy (ART), CNS opportunistic infections remain a major cause of morbidity and mortality in HIV-positive individuals. Unknown HIV-positive ...disease status, antiretroviral drug resistance, poor drug compliance, and recreational drug abuse are factors that continue to influence the morbidity and mortality of infections. The clinical and radiographic pattern of CNS opportunistic infections is unique in the setting of HIV infection: opportunistic infections in HIV-positive patients often have characteristic clinical and radiological presentations that can differ from the presentation of opportunistic infections in immunocompetent patients and are often sufficient to establish the diagnosis. ART in the setting of these opportunistic infections can lead to a paradoxical worsening caused by an immune reconstitution inflammatory syndrome (IRIS). In this Review, we discuss several of the most common CNS opportunistic infections: cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), tuberculous meningitis, cryptococcal meningitis and cytomegalovirus infection, with an emphasis on clinical pearls, pathological findings, MRI findings and treatment. Moreover, we discuss the risk factors, pathophysiology and management of IRIS. We also summarize the challenges that remain in management of CNS opportunistic infections, which includes the lack of phase II and III clinical trials, absence of antimicrobials for infections such as PML, and controversy regarding the use of corticosteroids for treatment of IRIS.
OBJECTIVE:To determine whether there is activation of human endogenous retrovirus K (HERV-K) in amyotrophic lateral sclerosis in HIV infection and whether it might respond to treatment with ...antiretroviral drugs.
METHODS:In this case series, we present 5 patients with HIV infection who subsequently developed motor neuron disease involving both upper and lower motor neurons. We monitored HERV-K levels in plasma of 4 of these patients.
RESULTS:Three patients who received antiretroviral therapy had reversal of symptoms within 6 months of onset of neurologic symptoms and the other 2 had slow neurologic progression over several years. Three patients in whom the levels were measured at onset of neurologic symptoms showed elevated HERV-K levels that responded to optimization of antiretroviral therapy for CNS penetration.
CONCLUSIONS:Thus, motor neuron disease in individuals with HIV infection may a treatable entity, but early treatment with CNS-penetrating antiretroviral therapy may be necessary. Monitoring of HERV-K levels may help guide treatment.
Corticobasal syndrome (CBS) is associated with asymmetrical rigidity as well as asymmetrical limb‐kinetic and ideomotor apraxia. Stiff person syndrome (SPS) is characterized by muscle stiffness and ...gait difficulties. Whereas patients with CBS have several forms of pathology, many patients with SPS have glutamic acid decarboxylase antibodies (GAD‐ab), but these 2 disorders have not been reported to coexist. We report 2 patients with GAD‐ab–positive SPS who also had signs suggestive of CBS, including asymmetrical limb rigidity associated with both asymmetrical limb‐kinetic and ideomotor apraxia. Future studies should evaluate patients with CBS for GAD‐ab and people with SPS for signs of CBS. ANN NEUROL 2015;77:173–176
BACKGROUND:Given the recent interest in blast injury spurred by returning soldiers from overseas conflicts, we sought to research the early historical descriptions of blast injuries and their ...treatments. Consideration was given to specific descriptions of survivors of closed head injury and their treatment.
METHODS:A review of the medical and nonmedical literature was undertaken, with particular emphasis on pre-1800 descriptions of volcanic eruptions and mining accidents. Compilations of accounts of the Etna eruptions dating from 126 BC were translated into English, and early mining texts from the 1600s and 1700s were reviewed.
RESULTS:Accumulations of flammable gases were recorded in many medieval sources and this knowledge of toxic gas which could lead to blast injury was known in the mining community by 1316. No direct attribution of injuries to blast forces was present in the historical record examined before the 1300s, although mining accounts in the 1600s detail deaths due to blast. No specific descriptions of survivors of a closed head injury were found in the mining and volcanic eruption literature.
CONCLUSIONS:Descriptions and warnings of blast forces were commonly written about in the medieval and Renaissance mining communities. Personal narratives as early as 1316 recognize the traumatic effects of blast injury. No mining or volcanic blast descriptions before 1800 detailed severe closed head injury survivors, suggesting greater mortality than morbidity from blast injury in the premodern era. This review also uncovered that there was no historical treatment or remedy recommended to survivors of blast injury. Blast explosions resulting in injury or death were frequently described, although in simplistic terminology.
Historians have suggested that MacArthur had Parkinson disease (PD), and that this may have influenced his military judgment. There is little evidence to support or to refute this suggestion.
We ...aimed in this article to review multiple cinematic images, as well as the personal writings of Douglas MacArthur to determine the likelihood that he had PD.
A complete review of the Western literature on Douglas MacArthur, including YouTube, Google Scholar/Google Images/Google Video, PubMed, and HighWirePress was undertaken. Over 200 minutes of film footage was analyzed, including such factors as MacArthur's facial profiles, facial expression, gait, posture, and movement. Handwriting samples from over 6 decades were compared for evidence of micrographia. Videos and handwriting samples were independently reviewed by 3 fellowship-trained movement disorders neurologists.
Examination of video footage showed evidence of progression of head tremors, postural action tremors, and voice tremors. There were no clear indications of a masked face, rigidity, bradykinesia, or a resting tremor on film footage recorded from 1906 to 1964. There was no evidence of micrographia in handwriting samples. Oral testimony and letters written by an attending gastroenterologist present at MacArthur's death in 1964 revealed no evidence of parkinsonian features.
We conclude that MacArthur had mild essential tremor that was more evident in his postmilitary career. There was no evidence to suggest that he had a clinical diagnosis of progressive PD.
In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements probably depend upon development of a broadly protective vaccine. To better ...understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory T (Trm) cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion, or depletion, which may be harnessed to control liver infections or autoimmunity.
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•CD8+ tissue-resident memory T cells (Trm cells) can be found in the murine liver•These liver Trm cells survey the liver from within the sinusoids•A prime-and-trap vaccination strategy efficiently induces liver Trm cells•Liver Trm cells are essential for protection against liver-stage malaria after vaccination
While various intervention strategies have reduced morbidity and mortality from malaria, further improvement is likely to depend on an effective vaccine. Fernandez-Ruiz et al. identify liver-resident memory CD8+ T cells as vital for liver-stage immunity and describe a protective vaccination strategy that drives their formation.
Though pharmaceuticals are increasingly observed in a variety of organisms from coastal and inland aquatic systems, trophic transfer of pharmaceuticals in aquatic food webs have not been reported. In ...this study, bioaccumulation of select pharmaceuticals was investigated in a lower order effluent-dependent stream in central Texas, USA, using isotope dilution liquid chromatography–tandem mass spectrometry (MS). A fish plasma model, initially developed from laboratory studies, was tested to examine observed versus predicted internal dose of select pharmaceuticals. Pharmaceuticals accumulated to higher concentrations in invertebrates relative to fish; elevated concentrations of the antidepressant sertraline and its primary metabolite desmethylsertraline were observed in the Asian clam, Corbicula fluminea, and two unionid mussel species. Trophic positions were determined from stable isotopes (δ15N and δ13C) collected by isotope ratio-MS; a Bayesian mixing model was then used to estimate diet contributions towards top fish predators. Because diphenhydramine and carbamazepine were the only target compounds detected in all species examined, trophic magnification factors (TMFs) were derived to evaluate potential trophic transfer of both compounds. TMFs for diphenhydramine (0.38) and carbamazepine (1.17) indicated neither compound experienced trophic magnification, which suggests that inhalational and not dietary exposure represented the primary route of uptake by fish in this effluent-dependent stream.
Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike ...receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.
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•RBD-NP enables dose-sparing and protects mice after only one dose•RBD-NP elicits diverse polyclonal antibody responses in non-human primates•RBD-NP and HexaPro confer similar resilience to antigenic drift•Mosaic and cocktail RBD-NPs protect against heterotypic SARS-CoV challenge
A clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine is protective in mice after a single immunization and elicits strong antibody responses across circulating mutants and some sarbecoviruses. Multivalent sarbecovirus RBD-NP vaccines elicit heterotypic protection against sarbecoviruses.
Liver-resident memory CD8+ T (TRM) cells remain in and constantly patrol the liver to elicit rapid immunity upon antigen encounter and can mediate efficient protection against liver-stage Plasmodium ...infection. This finding has prompted the development of immunization strategies where T cells are activated in the spleen and then trapped in the liver to form TRM cells. Here, we identify PbRPL6120-127, a H2-Kb-restricted epitope from the putative 60S ribosomal protein L6 (RPL6) of Plasmodium berghei ANKA, as an optimal antigen for endogenous liver TRM cell generation and protection against malaria. A single dose vaccination targeting RPL6 provided effective and prolonged sterilizing immunity against high dose sporozoite challenges. Expressed throughout the parasite life cycle, across Plasmodium species, and highly conserved, RPL6 exhibits strong translation potential as a vaccine candidate. This is further advocated by the identification of a broadly conserved, immunogenic HLA-A∗02:01-restricted epitope in P. falciparum RPL6.
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•The Plasmodium ribosomal protein RPL6 is expressed during liver-stage infection•RPL6 can be targeted by specific liver TRM cells for efficient parasite elimination•Prime-and-trap vaccination targeting RPL6 induces effective protection against malaria•RPL6 is highly conserved across global P. falciparum clinical isolates
Valencia-Hernandez et al. identify the ribosomal protein RPL6 as a liver-stage Plasmodium antigen that can be targeted by tissue-resident memory T cell-based vaccines for efficient protection against malaria. RPL6 is highly conserved across global isolates of P. falciparum, and is thus an ideal candidate for subunit vaccination against malaria.
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