Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole ...versus placebo in adult chronic indeterminate Chagas disease.
In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18–50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 and placebo arms, and assessors were masked to all treatment allocations. The primary efficacy endpoint was parasitological response to E1224 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were parasitological response to benznidazole at end of treatment, assessed by PCR; sustainability of parasitological response until 12 months; parasite clearance and changes in parasite load; incidence of conversion to negative response in conventional and non-conventional (antigen trypomastigote chemiluminescent ELISA AT CL-ELISA) serological response; changes in levels of biomarkers; and complete response. The primary analysis population consisted of all randomised patients by their assigned treatment arms. This trial is registered with ClinicalTrials.gov, number NCT01489228.
Between July 19, 2011, and July 26, 2012, we screened 560 participants with confirmed Chagas disease, of whom 231 were enrolled and assigned to high-dose E1224 (n=45), low-dose E1224 (n=48), short-dose E1224 (n=46), benznidazole (n=45), or placebo (n=47). Parasite clearance was observed with E1224 during the treatment phase, but no sustained response was seen with low-dose and short-dose regimens, whereas 13 patients (29%, 95% CI 16·4–44·3) had sustained response with the high-dose regimen compared with four (9%, 2·4–20·4) in the placebo group (p<0·0001). Benznidazole had a rapid and sustained effect on parasite clearance, with 37 patients (82%, 67·9–92·0) with sustained response at 12-month follow-up. After 1 week of treatment, mean quantitative PCR repeated measurements showed a significant reduction in parasite load in all treatment arms versus placebo. Parasite levels in the low-dose and short-dose E1224 groups gradually returned to placebo levels. Both treatments were well tolerated. Reversible, dose-dependent liver enzyme increases were seen with E1224 and benznidazole. 187 (81%) participants developed treatment-emergent adverse events and six (3%) developed treatment-emergent serious adverse events. Treatment-emergent adverse events were headaches, nausea, pruritus, peripheral neuropathy, and hypersensitivity.
E1224 is the first new chemical entity developed for Chagas disease in decades. E1224 displayed a transient, suppressive effect on parasite clearance, whereas benznidazole showed early and sustained efficacy until 12 months of follow-up. Despite PCR limitations, our results support increased diagnosis and access to benznidazole standard regimen, and provide a development roadmap for novel benznidazole regimens in monotherapy and in combinations with E1224.
Drugs for Neglected Diseases initiative.
The influence of the fermentative addition of Pedro Ximenez grape pomace (PXGP, white variety) on the phenolic composition and color of Syrah red wines from a warm climate was studied. Changes on ...phenolic composition (HPLC), copigmentation/polymerization (spectrophotometry), and color (tristimulus colorimetry) allowed differences among the maceration treatments to be established. PXGP additions at the rates studied increased the extraction of total phenolics, phenolic acids, and monomeric flavanols. However, the effect on the anthocyanins, copigmentation, and polymerization depended on the doses applied, with important consequences on the color. PXGP addition at 10% led to wines with higher polymerization, more stable colors, and bluish hues. in contrast, perceptibly lighter and less intense wines were obtained with PXGP addition at 20%. Thus, the use of white grape byproducts as wine additives at appropriate levels (10% w/w) could improve the phenolic potential of red young wines from a warm climate, contributing to preserve their color characteristic.
Pancreatic ductal adenocarcinoma is an aggressive form of pancreatic cancer and the fourth leading cause of cancer-related death. When possible, curative approaches are based on surgical resection, ...though not every patient is a candidate for surgery. There are clinical guidelines for the management of these patients that offer different treatment options depending on the clinical and pathologic characteristics. However, the survival rates seen in this kind of patients are still low. The CDSE1 gene is located upstream of NRAS and encodes an RNA-binding protein termed UNR. The aim of this study was to analyze UNR expression and its correlation with outcome in patients with resectable pancreatic ductal adenocarcinoma (PDAC). For this, samples from resectable PDAC patients who underwent duodenopancreatectomy were used to evaluate UNR protein expression by immunohistochemistry using a tissue microarray. Here, we observed that low UNR expression was significantly associated with shorter progression-free survival after surgery (P = 0.010). Moreover, this prognostic marker remained significant after Cox proportional hazards model (P = 0.036). We further studied the role of CDSE1 expression in patient's prognosis using data from public repositories (GEO and TGCA), confirming our results. Interestingly, CDSE1 expression correlated with that of genes characteristic of an immunogenic molecular subtype of pancreatic cancer. Based on these findings, UNR may be considered a potential prognostic biomarker for resectable PDAC and may serve to guide subsequent adjuvant treatment decisions.
Ni catalysts supported on silica as textural promoter prepared by different methods are studied as catalysts for the thermo catalytic decomposition (TCD) of methane to produce hydrogen and deposited ...carbon in a fixed-bed reactor at 700 deg C. The characterization of the fresh and used catalysts and the deposited carbon has been carried out by using different techniques like powder X-ray diffraction (XRD), Raman spectroscopy and scanning electron microscopy (SEM). The effect of copper addition and the type of copper precursor used (nitrate or oxide) on Ni activity as the catalyst of the TCD process has also been investigated. Whatever the preparation method used, all catalysts showed a high and almost constant methane conversion without apparent deactivation after 8h on stream, revealing the good catalyst performance in the TCD process. Copper as a nickel dopant increases the hydrogen production leading to hydrogen concentrations over 80vol% in the production gas, independent of the preparation method or the copper precursor used. All catalysts studied promote the formation of carbon nanofibers some micrometers long with different diameters, especially dependent on the presence or absence of copper. Ni-Si1 catalysts prepared by the fusion method promote the formation of small carbon fibers with a rather narrow diameter distribution, while Ni-Cu-Si catalysts lead to the formation of larger fibers with a broad diameter distribution.
Organophosphate flame retardants (OPFRs) are high-production volume chemicals widely present in environmental compartments. The presence of water-soluble OPFRs (tri-n-butyl phosphate (TnBP), ...tris(2-butoxyethyl) phosphate (TBEP), tris(2-chloroethyl) phosphate (TCEP), tris(2-chloroisopropyl) phosphate (TCPP), and triethyl phosphate (TEP)) in water compartments evidences the struggle of conventional wastewater treatment plants (WWTPs) to effectively eliminate these toxic compounds. This study reports for the first time the use of white-rot fungi as a promising alternative for the removal of these OPFRs. To accomplish this, a simple and cost-efficient quantification method for rapid monitoring of these contaminants’ concentrations by GC–MS while accounting for matrix effects was developed. The method proved to be valid and reliable for all the tested parameters. Sample stability was examined under various storage conditions, showing the original samples to be stable after 60 days of freezing, while post-extraction storage techniques were also effective. Finally, a screening of fungal degraders while assessing the influence of the glucose regime on OPFR removal was performed. Longer chain organophosphate flame retardants, TBP and TBEP, could be easily and completely removed by the fungus
Ganoderma lucidum
after only 4 days. This fungus also stood out as the sole organism capable of partially degrading TCEP (35% removal). The other chlorinated compound, TCPP, was more easily degraded and 70% of its main isomer was removed by
T. versicolor
. However, chlorinated compounds were only partially degraded under nutrient-limiting conditions. TEP was either not degraded or poorly degraded, and it is likely that it is a transformation product from another OPFR’s degradation. These results suggest that degradation of chlorinated compounds is dependent on the concentration of the main carbon source and that more polar OPFRs are less susceptible to degradation, given that they are less accessible to radical removal by fungi. Overall, the findings of the present study pave the way for further planned research and a potential application for the degradation of these contaminants in real wastewaters.
Graphical Abstract
Abstract
Objective:
A systematic review was conducted to analyze the tolerability of several oral iron supplements based on data obtained in available publications and to report the incidence of ...adverse effects (AEs) for each supplement both overall and gastrointestinal.
Methods:
Electronic databases - Medline, the Cochrane Library, and Embase were searched for studies published up to January 2009. Clinical or observational studies reporting data on the tolerability of oral iron supplements were included. Results were described statistically and a quasi-binomial logistic regression model was developed to evaluate and compare the tolerability of the supplements studied.
Results:
For this review 111 studies were included, with data on 10,695 patients. Ferrous sulfate with mucoproteose had the lowest incidence of AEs (4.1% for overall AEs, 3.7% for gastrointestinal AEs GAEs) and was used as the reference supplement in the regression model. Incidence rates of overall AEs for the other supplements were 7.3% for iron protein succinylate GAEs: 7%; OR for AE compared to the reference supplement, 1.96, 23.5% for ferrous glycine sulfate GAEs: 18.5%; OR: 5.90, 30.9% for ferrous gluconate GAEs: 29.9%; OR: 11.06, 32.3% for ferrous sulfate without mucoproteose GAEs: 30.2%; OR: 11.21, and 47.0% for ferrous fumarate GAEs: 43.4%; OR: 19.87.
The differences in incidence of AEs between extended-release ferrous sulfate with mucoproteose and all other supplements except iron protein succinylate were statistically significant at p < 0.001. These findings are subject to some limitations as the designs and methodologies of the studies included show heterogeneity among them that has partially been counteracted by the large sample size provided by the substantial number of trials, which is considered a strength in tolerability studies.
Conclusion:
Extended-release ferrous sulfate with mucoproteose appears to be the best tolerated of the different oral iron supplements evaluated.
Innate immunity recognizes bacterial molecules bearing pathogen-associated molecular patterns to launch inflammatory responses leading to the activation of adaptive immunity. However, the ...lipopolysaccharide (LPS) of the gram-negative bacterium Brucella lacks a marked pathogen-associated molecular pattern, and it has been postulated that this delays the development of immunity, creating a gap that is critical for the bacterium to reach the intracellular replicative niche. We found that a B. abortus mutant in the wadC gene displayed a disrupted LPS core while keeping both the LPS O-polysaccharide and lipid A. In mice, the wadC mutant induced proinflammatory responses and was attenuated. In addition, it was sensitive to killing by non-immune serum and bactericidal peptides and did not multiply in dendritic cells being targeted to lysosomal compartments. In contrast to wild type B. abortus, the wadC mutant induced dendritic cell maturation and secretion of pro-inflammatory cytokines. All these properties were reproduced by the wadC mutant purified LPS in a TLR4-dependent manner. Moreover, the core-mutated LPS displayed an increased binding to MD-2, the TLR4 co-receptor leading to subsequent increase in intracellular signaling. Here we show that Brucella escapes recognition in early stages of infection by expressing a shield against recognition by innate immunity in its LPS core and identify a novel virulence mechanism in intracellular pathogenic gram-negative bacteria. These results also encourage for an improvement in the generation of novel bacterial vaccines.
The brucellae are α-Proteobacteria facultative intracellular parasites that cause an important zoonosis. These bacteria escape early detection by innate immunity, an ability associated to the absence ...of marked pathogen-associated molecular patterns in the cell envelope lipopolysaccharide, lipoproteins and flagellin. We show here that, in contrast to the outer membrane ornithine lipids (OL) of other Gram negative bacteria, Brucella abortus OL lack a marked pathogen-associated molecular pattern activity. We identified two OL genes (olsB and olsA) and by generating the corresponding mutants found that olsB deficient B. abortus did not synthesize OL or their lyso-OL precursors. Liposomes constructed with B. abortus OL did not trigger IL-6 or TNF-α release by macrophages whereas those constructed with Bordetella pertussis OL and the olsB mutant lipids as carriers were highly active. The OL deficiency in the olsB mutant did not promote proinflammatory responses or generated attenuation in mice. In addition, OL deficiency did not increase sensitivity to polymyxins, normal serum or complement consumption, or alter the permeability to antibiotics and dyes. Taken together, these observations indicate that OL have become dispensable in the extant brucellae and are consistent within the trend observed in α-Proteobacteria animal pathogens to reduce and eventually eliminate the envelope components susceptible of recognition by innate immunity.
•A preliminary analysis of EJ in the two main Spanish cities, Madrid and Barcelona.•Proposal of a baseline methodology for EJ evaluation.•The goodness-of-fit test and an ‘EJ scale’ are effective ...tools for comparative assessment.•Elderly people and immigrants’ areas tend to bear an unequal level of NO2 burden.
The concept of environmental justice (EJ) has recently gained currency, both as a factor for and a goal of sustainable development. Its implementation in practice implies establishing current environmental injustice patterns and analysing planning policies, with the aim to reduce socio-demographic inequalities in the negative environmental impact borne by different population groups. This paper proposes a method to assess differential exposure to excessive pollution levels by socio-demographic groups in intra-urban spaces.
The approach developed in this paper is based upon GIS and quantitative spatial analysis techniques. It incorporates the idea of an ‘environmental justice weighting scale’ for policy-making, using normative pollution thresholds to measure inequalities more objectively and consistently. Spain’s two largest cities, Madrid and Barcelona, have been chosen as case-studies, taking nitrogen dioxide as the pollutant, and the geographic distribution of six vulnerable population groups (children, elderly people and international immigrants) in the year 2010. The results reveal that a large part of these groups suffer exposure to air pollution exceeding the maximum permitted levels disproportionately, which would imply a case of environmental injustice.
The lipopolysaccharide (LPS) O-polysaccharide (O-PS) is the main virulence factor in
Brucella
. After synthesis in the cytoplasmic membrane, O-PS is exported to the periplasm by the Wzm/Wzt system, ...where it is assembled into a LPS. This translocation also engages a bactoprenol carrier required for further biosynthesis pathways, such as cell wall biogenesis. Targeting O-PS export by blockage holds great potential for vaccine development, but little is known about the biological implications of each Wzm/Wzt moiety. To improve this knowledge and to elucidate its potential application as a vaccine, we constructed and studied
wzm
/
wzt
single- and double-deletion mutants, using the attenuated strain
Brucella melitensis
Rev1 as the parental strain. This allowed us to describe the composition of
Brucella
peptidoglycan for the first time. We observed that these mutants lack external O-PS yet trigger changes in genetic transcription and in phenotypic properties associated with the outer membrane and cell wall. The three mutants are highly attenuated; unexpectedly, Rev1Δ
wzm
also excels as an immunogenic and effective vaccine against
B. melitensis
and
Brucella ovis
in mice, revealing that low persistence is not at odds with efficacy. Rev1Δ
wzm
is attenuated in BeWo trophoblasts, does not infect mouse placentas, and is safe in pregnant ewes. Overall, these attributes and the minimal serological interference induced in sheep make Rev1Δ
wzm
a highly promising vaccine candidate.
PDF
