Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. ...We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients.
We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization.
A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08).
Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.).
Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with ...amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.
We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks.
A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval CI, 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units CFU per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy.
Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).
Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson’s disease (PD) and dementia with LBs (DLB). Recent studies showed ...that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.
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•α-syn antibodies block uptake of misfolded α-syn seeds•α-syn antibodies inhibit cell-to-cell spread of α-syn pathology•α-syn antibody to misfolded α-syn reduces pathology spread in vivo•α-syn antibody to misfolded α-syn ameliorates neuron loss and motor dysfunction
Parkinson’s disease is characterized by the accumulation of misfolded α-synuclein as Lewy bodies. Through the use of in vitro and in vivo models expressing normal levels of endogenous α-synuclein that were induced to develop Lewy pathology by α-synuclein fibrils, Tran et al. show that α-synuclein immunotherapy prevents accumulation of pathologic α-synuclein and ameliorates neuron loss/motor dysfunction linked to α-synuclein pathology in part by blocking entry of pathologic α-synuclein into neurons. Thus, these studies support the therapeutic potential of α-synuclein immunotherapy.
Toll‐like receptors (TLR) are critical mediators of the immune response to pathogens and human polymorphisms in this gene family regulate inflammatory pathways and are associated with susceptibility ...to infection. Lipopeptides are present in a wide variety of microbes and stimulate immune responses through TLR1/2 or TLR2/6 heterodimers. It is not currently known whether polymorphisms in TLR1 regulate the innate immune response. We stimulated human whole blood with triacylated lipopeptide, a ligand for TLR1/2 heterodimers, and found substantial inter‐individual variation in the immune response. We sequenced the coding region of TLR1 and found a non‐synonymous polymorphism, I602S (base pair T1805G), that regulated signalling. In comparison to TLR1_602S, the 602I variant mediated substantially greater basal and lipopeptide‐induced NF‐κB signalling in transfected HEK293 cells. These signalling differences among TLR1 variants were also found with stimulation by extracts of Mycobacterium tuberculosis. Furthermore, individuals with the 602II genotype produced substantially more IL‐6 than those with the 602SS variant in a lipopeptide‐stimulated whole‐blood cytokine assay. Together, these observations demonstrate that variation in the inflammatory response to bacterial lipopeptides is regulated by a common TLR1 transmembrane domain polymorphism that could potentially impact the innate immune response and clinical susceptibility to a wide spectrum of pathogens.
See accompanying article: http://dx.doi.org/10.1002/eji.200737604
Summary
Objective To evaluate the existing WHO dengue classification across all age groups and a wide geographical range and to develop a revised evidence‐based classification that would better ...reflect clinical severity.
Methods We followed suspected dengue cases daily in seven countries across South‐east Asia and Latin America and then categorised them into one of three intervention groups describing disease severity according to the overall level of medical and nursing support required. Using a pre‐defined analysis plan, we explored the clinical and laboratory profiles characteristic of these intervention categories and presented the most promising options for a revised classification scheme to an independent group of WHO dengue experts for consideration. Potential warning signs were also evaluated by comparing contemporaneous data of patients who progressed to severe disease with the data of those who did not.
Results A total of 2259 patients were recruited during 2006–2007 and 230 (13%) of the 1734 laboratory‐confirmed patients required major intervention. Applying the existing WHO system, 47/210 (22%) of patients with shock did not fulfil all the criteria for dengue haemorrhagic fever. However, no three‐tier revision adequately described the different severity groups either. Inclusion of readily discernible complications (shock/severe vascular leakage and/or severe bleeding and/or severe organ dysfunction) was necessary to devise a system that identified patients requiring major intervention with sufficient sensitivity and specificity to be practically useful. Only a small number of subjects (5%) progressed to severe disease while under observation; several warning signs were identified, but much larger studies are necessary to fully characterize features associated with disease progression.
Conclusions Based on these results, a revised classification system comprised of two entities, ‘Dengue’ and ‘Severe Dengue’, was proposed and has now been incorporated into the new WHO guidelines.
Objectif: Evaluer la classification actuelle de l’OMS pour la dengue dans tous les groupes d’âge et sur une vaste étendue géographique et élaborer une classification révisée, fondée sur des preuves permettant de mieux tenir compte de la sévérité clinique.
Méthodes: Nous avons suivi quotidiennement des cas suspects de dengue dans 7 pays d’Asie du sud‐est et d’Amérique latine, puis les avons classé en trois groupes d’intervention décrivant la sévérité de la maladie en fonction du niveau général du soutien médical et infirmier nécessaire. En utilisant un plan d’analyse prédéfini, nous avons exploré les profils cliniques et de laboratoire, caractéristiques de ces catégories d’intervention et avons soumis pour avis, les options les plus prometteuses pour un système révisé de classification, à un groupe d’experts indépendants de l’OMS pour la dengue. Les signes avant‐coureurs potentiels ont également étéévalués en comparant les données contemporaines de patients qui ont évolué vers une maladie sévère avec les données de ceux qui n’ont pas évolué de cette façon.
Résultats: 2259 patients ont été recrutés en 2006–2007 et 230 (13%) des 1734 patients avec une confirmation de laboratoire ont nécessité une intervention majeure. En appliquant le système actuel de l’OMS, 47/210 (22%) patients atteints de choc ne remplissaient pas tous les critères de dengue hémorragique. Toutefois, aucune révision tertiaire non plus n’a pu décrire adéquatement les différents groupes de sévérité. L’inclusion de complications facilement reconnaissables (choc/pertes vasculaires sévères et/ou saignements sévères et/ou dysfonctionnement sévère d’un organe) a été nécessaire pour concevoir un système permettant d’identifier les patients nécessitant une intervention majeure, avec une sensibilité et une spécificité suffisantes pour être utiles dans la pratique. Seul un petit nombre de sujets (5%) a progressé vers une maladie sévère alors qu’ils étaient sous observation; plusieurs signes d’alerte ont été identifiés, mais beaucoup plus d’études sont nécessaires pour caractériser complètement les caractéristiques associées à la progression de la maladie.
Conclusions: Sur base de ces résultats, un système de classification révisé, composé de deux entités, “Dengue” et “ dengue sévère “, a été proposé et a été intégré dans les nouvelles directives de l’OMS.
Initially multiple independent Kelch mutations were observed,1 but in a recent sinister development, a single dominant artemisinin-resistant P falciparum C580Y mutant lineage has arisen in western ...Cambodia, outcompeted the other resistant malaria parasites, and subsequently acquired resistance to piperaquine.2 Cambodia had adopted dihydroartemisinin-piperaquine as first-line antimalarial treatment, but has now been forced to switch its first line artemisinin combination treatment back to artesunate-mefloquine as a consequence3. 1 EA Ashley, M Dhorda, RM Fairhurst, Plasmodium falciparum, malaria, N Engl J Med, Vol. 371, 2014, 411-423 2 M Imwong, K Suwannasin, C Kunasol, Plasmodium falciparum, in the Greater Mekong Subregion: a molecular epidemiology observational study, Lancet Infect Dis, Vol. 17, 2017, 491-497 3 World Health Organization, Status report on artemisinin and ACT resistance (April 2017), (accessed July 11, 2017).
In this study, activated carbon from corncobs was successfully synthesized by hydrothermal carbonization and hydrochemical activation at low temperatures, followed by pyrolysis. A developed method of ...hydrochemical activation of hydrochar that uses only small amounts of chemicals is a promising approach. After activation, the activator residues in the hydrothermal product can constantly act as a chemical activator during pyrolysis to form corncob-activated carbon (AHC-KOH), which had specific surface area of 965.028 m2/g and oxygenated functional groups of 0.3780 mmol/g, 31.67 and 4 times, respectively, of those of the inactivated sample. AHC-KOH was used to study the adsorption characteristics of methylene blue (MB). The MB adsorption efficiency of AHC-KOH was the highest at 489.560 mg/g, which was considerably higher than that of activated carbons produced from other biomasses. The isotherm equilibrium and adsorbent kinetics parameters of MB adsorption on AHC-KOH were also determined using the Langmuir isotherm model (R2 = 0.99) and pseudo-second-order kinetic model (R2 > 0.99). Thus, the results indicate that an inexpensive adsorbent produced from corncobs using the above method is a promising material for wastewater treatment.
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•AHC-KOH prepared by hydrothermal carbonization of corncob biomass.•The specific surface area of AHC-KOH was approximately 965.028 m2/g.•Methylene blue adsorption on AHC-KOH was high at 489.560 mg/g.•The Langmuir isotherm model suited methylene blue adsorption on AHC-KOH.•Methylene blue adsorption on AHC-KOH followed pseudo-second-order kinetic model.
CRISPR/Cas9 gene editing is now revolutionizing the ability to effectively modify plant genomes in the absence of efficient homologous recombination mechanisms that exist in other organisms. However, ...soybean is allotetraploid and is commonly viewed as difficult and inefficient to transform. In this study, we demonstrate the utility of CRISPR/Cas9 gene editing in soybean at relatively high efficiency. This was shown by specifically targeting the Fatty Acid Desaturase 2 (GmFAD2) that converts the monounsaturated oleic acid (C18:1) to the polyunsaturated linoleic acid (C18:2), therefore, regulating the content of monounsaturated fats in soybean seeds.
We designed two gRNAs to guide Cas9 to simultaneously cleave two sites, spaced 1Kb apart, within the second exons of GmFAD2-1A and GmFAD2-1B. In order to test whether the Cas9 and gRNAs would perform properly in transgenic soybean plants, we first tested the CRISPR construct we developed by transient hairy root transformation using Agrobacterium rhizogenesis strain K599. Once confirmed, we performed stable soybean transformation and characterized ten, randomly selected T0 events. Genotyping of CRISPR/Cas9 T0 transgenic lines detected a variety of mutations including large and small DNA deletions, insertions and inversions in the GmFAD2 genes. We detected CRISPR- edited DNA in all the tested T0 plants and 77.8% of the events transmitted the GmFAD2 mutant alleles to T1 progenies. More importantly, null mutants for both GmFAD2 genes were obtained in 40% of the T0 plants we genotyped. The fatty acid profile analysis of T1 seeds derived from CRISPR-edited plants homozygous for both GmFAD2 genes showed dramatic increases in oleic acid content to over 80%, whereas linoleic acid decreased to 1.3-1.7%. In addition, transgene-free high oleic soybean homozygous genotypes were created as early as the T1 generation.
Overall, our data showed that dual gRNA CRISPR/Cas9 system offers a rapid and highly efficient method to simultaneously edit homeologous soybean genes, which can greatly facilitate breeding and gene discovery in this important crop plant.
Distance-aware quality adaptation is a potential approach to reduce the resource requirement for the transmission and rendering of textured 3D meshes. In this paper, we carry out a subjective ...experiment to investigate the effects of the distance from the camera on the perceptual quality of textured 3D meshes. Besides, we evaluate the effectiveness of eight image-based objective quality metrics in representing the user's perceptual quality. Our study found that the perceptual quality in terms of mean opinion score increases as the distance from the camera increases. In addition, it is shown that normalized mutual information (NMI), a full-reference objective quality metric, is highly correlated with subjective scores.
Adjunctive dexamethasone reduces mortality from tuberculous meningitis, but how it produces this effect is not known. Matrix metalloproteinases (MMPs) are important in the immunopathology of many ...inflammatory CNS diseases thus we hypothesized that that their secretion is important in TBM and might be influenced by dexamethasone.
The kinetics of cerebrospinal fluid (CSF) MMP and tissue inhibitors of MMPs (TIMPs) concentrations were studied in a subset of HIV uninfected adults (n = 37) with TBM recruited to a randomized, placebo-controlled trial of adjuvant dexamethasone. Analysis followed a pre-defined plan. Dexamethasone significantly reduced CSF MMP-9 concentrations in early follow up samples (median 5 days (range 3-8) of treatment), but had no significant influence on other MMPs/TIMPs. Additionally CSF MMP-9 concentration was strongly correlated to concomitant CSF neutrophil count.
Dexamethasone decreased CSF MMP-9 concentrations early in treatment and this may represent one mechanism by which corticosteroids improve outcome in TBM. The strong correlation between CSF MMP-9 and neutrophil count suggests that polymorphonuclear leukocytes may play a central role in the early pathogenesis of TBM.
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