To determine the efficacy and safety of cyclosporine (CyA) in a large national registry-based population of patients with steroid-refractory (SR) acute severe ulcerative colitis (ASUC) and to ...establish predictors of efficacy and adverse events.
Multicenter study of SR-ASUC treated with CyA, based on data from the ENEIDA registry. SR-ASUC patients treated with infliximab (IFX) or sequential rescue therapy (CyA-IFX or IFX-CyA) were used as comparators.
Of 740 SR-ASUC patients, 377 received CyA, 131 IFX and 63 sequential rescue therapy. The cumulative colectomy rate was higher in the CyA (24.1%) and sequential therapy (32.7%) than in the IFX group (14.5%; P=0.01) at 3 months and 5 years. There were no differences in early and late colectomy between CyA and IFX in patients treated after 2005. 62% of patients receiving CyA remained colectomy-free in the long term (median 71 months). There were no differences in mortality between CyA (2.4%), IFX (1.5%) and sequential therapy (0%; P=0.771). The proportion of patients with serious adverse events (SAEs) was lower in CyA (15.4%) than in IFX treated patients (26.5%) or sequential therapy (33.4%; P<0.001). This difference in favor of CyA was maintained when only patients treated after 2005 were analyzed.
Treatment with CyA showed a lower rate of SAE and a similar efficacy to that of IFX thereby supporting the use of either CyA or IFX in SR-ASUC. In addition, the risk-benefit of sequential CyA-IFX for CyA non-responders is acceptable.
MicroRNAs are implicated in the response to biotic stresses. Papaya meleira virus (PMeV) is the causal agent of sticky disease, a commercially important pathology in papaya for which there are ...currently no resistant varieties. PMeV has a number of unusual features, such as residence in the laticifers of infected plants, and the response of the papaya to PMeV infection is not well understood. The protein levels of 20S proteasome subunits increase during PMeV infection, suggesting that proteolysis could be an important aspect of the plant defense response mechanism. To date, 10,598 plant microRNAs have been identified in the Plant miRNAs Database, but only two, miR162 and miR403, are from papaya. In this study, known plant microRNA sequences were used to search for potential microRNAs in the papaya genome. A total of 462 microRNAs, representing 72 microRNA families, were identified. The expression of 11 microRNAs, whose targets are involved in 20S and 26S proteasomal degradation and in other stress response pathways, was compared by real-time PCR in healthy and infected papaya leaf tissue. We found that the expression of miRNAs involved in proteasomal degradation increased in response to very low levels of PMeV titre and decreased as the viral titre increased. In contrast, miRNAs implicated in the plant response to biotic stress decreased their expression at very low level of PMeV and increased at high PMeV levels. Corroborating with this results, analysed target genes for this miRNAs had their expression modulated in a dependent manner. This study represents a comprehensive identification of conserved miRNAs inpapaya. The data presented here might help to complement the available molecular and genomic tools for the study of papaya. The differential expression of some miRNAs and identifying their target genes will be helpful for understanding the regulation and interaction of PMeV and papaya.
In the literature, decision models and techniques for supplier selection do not often consider inventory management of the items being purchased as part of the analysis. In this article, two mixed ...integer nonlinear programming models are proposed to select the best set of suppliers and determine the proper allocation of order quantities while minimizing the annual ordering, inventory holding, and purchasing costs under suppliers’ capacity and quality constraints. The first model allows independent order quantities for each supplier while the second model restricts all order quantities to be of equal size, as it would be required in a multi-stage (supply chain) inventory model. Illustrative examples are used to highlight the advantages of the proposed models over a previous model introduced in the literature.
The arthropod-borne Mayaro virus (MAYV) causes "Mayaro fever," a disease of medical significance, primarily affecting individuals in permanent contact with forested areas in tropical South America. ...Recently, MAYV has attracted attention due to its likely urbanization. There are currently no licensed drugs against most mosquito-transmitted viruses. Punica granatum (pomegranate) fruits cultivated in Brazil have been subjected to phytochemical investigation for the identification and isolation of antiviral compounds. In the present study, we explored the antiviral activity of pomegranate extracts in Vero cells infected with Mayaro virus.
The ethanol extract and punicalagin of pomegranate were extracted solely from the shell and purified by chromatographic fractionation, and were chemically identified using spectroscopic techniques. The cytotoxicity of the purified compounds was measured by the dye uptake assay, while their antiviral activity was evaluated by a virus yield inhibition assay.
Pomegranate ethanol extract (CC
= 588.9, IC
= 12.3) and a fraction containing punicalagin as major compound (CC
= 441.5, IC
= 28.2) were shown to have antiviral activity (SI 49 and 16, respectively) against Mayaro virus, an alphavirus. Immunofluorescence analysis showed the virucidal effect of pomegranate extract, and transmission electron microscopy (TEM) revealed damage in viral particles treated with this extract.
The P. granatum extract is a promising source of antiviral compounds against the alphavirus MAYV and represents an excellent candidate for future studies with other enveloped RNA viruses.
Assessment of forest ecosystems and their services is seen as a key action for the advancement of biodiversity objectives, and to inform the development and implementation of related policies and ...planning. The Azorean forest is important for timber production, the protection of soil and water resources, and for its recreational and aesthetic value. However, its role in carbon accumulation has not been fully addressed. We assessed plant diversity, forest structure and carbon stocks in a gradient of three forest types (Natural Forest-NF; Exotic Woodland-EW and Production Forest-PF) in three of the Azores islands. We used biodiversity indices and found that NF harbored the highest plant diversity levels and PF the lowest. Diversity levels were lower for structural than for taxonomic data, particularly for PF. The highest tree carbon stock was found at EW in one of the islands, while PF consistently exhibited relatively high tree carbon stocks in the three islands. The largest soil carbon stocks were found at EW, while leaf litter carbon stocks were higher at PF. We concluded that NF play a fundamental role as plant diversity hotspots but have lower relevance as carbon stocks what might be associated with montane environmental conditions. PFs provide economic assets and act as carbon sinks, while EWs play a major role as carbon sinks in soil, but also at tree level in the oldest forests.
Shiga toxin-producing Escherichia coli-haemolytic uraemic syndrome (STEC-HUS) is considered a toxaemic disorder in which early intervention with neutralizing antibodies may have therapeutic benefits. ...INM004, composed of F (ab')
fragments from equine immunoglobulins, neutralizes Stx1/Stx2, potentially preventing the onset of HUS.
A single-centre, randomized, phase 1, single-blind, placebo-controlled clinical trial to evaluate INM004 safety, tolerance and pharmacokinetics (PK) in healthy adult volunteers, was conducted; in stage I, eight subjects were divided in two cohorts (n = 4) to receive a single INM004 dose of 2 or 4 mg kg
, or placebo (INM004:placebo ratio of 3:1). In stage II, six subjects received three INM004 doses of 4 mg kg
repeated every 24 h, or placebo (INM004:placebo ratio of 5:1).
Eight subjects (57.1%) experienced mild treatment-emergent adverse events (TEAEs); most frequent were rhinitis, headache and flushing, resolved within 24 h without changes in treatment or additional intervention. No serious AEs were reported. Peak concentrations of INM004 occurred within 2 h after infusion, with median C
values of 45.1 and 77.7 μg mL
for 2 and 4 mg kg
, respectively. The serum concentration of INM004 declined in a biphasic manner (t
range 30.7-52.9 h). Systemic exposures increased with each subsequent dose in a dose-proportional manner, exhibiting accumulation. Geometric median C
and AUC values were 149 and 10 300 μg h mL
, respectively, in the repeated dose regimen. Additionally, samples from subjects that received INM004 at 2 mg kg
showed neutralizing capacity against Stx1 and Stx2 in in vitro assays.
The results obtained in this first-in-human study support progression into the phase 2 trial in children with HUS.
The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have ...previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.
Ceramides are an important group of sphingolipids that modulate several cellular events. The mechanisms underlying biological actions of ceramides are not fully known, but evidence suggests that ...ceramides can act through regulation of the biophysical properties of the membrane. However, ceramide-induced changes on membrane properties are complex and depend on several factors. To gain further insight into this subject, we characterized the biophysical impact of very-long acyl chain C24-ceramide in a fluid model membrane under thermodynamic equilibrium and non-equilibrium conditions. Our results show that C24-ceramide readily forms two types of gel domains with distinct properties, likely corresponding to different interdigitated metastable gel phases. Upon reaching thermodynamic equilibrium, only partially interdigitated gel phase coexists with the fluid phase. In addition, C24-ceramide promotes strong changes in the shape of the vesicles, including domains with sharp edges and tubule-like structures. The results suggest that the formation of very long acyl chain ceramides in response to stress stimuli will initially induce a multitude of changes in the organization and fluidity of biological membranes that might be responsible for the activation of different cellular processes.
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•C24-Cer induces time-dependent changes in membrane properties.•C24-Cer forms multiple interdigitated gel phases.•C24-Cer causes strong morphological alterations, including tubule formation.•C24-Cer-induced membrane reorganization might govern its biological action.
RadioLab is an Italian project, addressed to school-age people, and designed for the dissemination of scientific culture on the theme of environmental radioactivity, with particular regards to the ...importance of knowledge of radon gas exposure. The project is a nationwide initiative promoted by the National Institute of Nuclear Physics- INFN. First tool used by the project, and of immediate impact to assess the public awareness on radon, is the administration of the survey "do you know the radon gas?". In the survey, together with the knowledge of radon and of its sources, information on personal, cultural and territorial details regarding the interviewees are also taken. Reasonably, the survey invests not only young people, but also their relatives, school workers and, gradually, the public. The survey is administrated during exhibitions or outreach events devoted to schools, but also open to the public. The survey is in dual form: printed and online. The online mode clearly leads RadioLab project even outside the school environment. Based on the results of the survey, several statistical analyses have been performed and many conclusions are drawn about the knowledge of the population on the radon risk. The RadioLab benefit and the requirement to carry on the project goals, spreading awareness of environmental radioactivity from radon, emerge. The dataset involves all twenty Italian regions and consists of 28,612 entries covering the 5-year period 2018-2022.
To evaluate the visual outcomes for intravitreal ranibizumab administered on an as-needed basis for exudative age-related macular degeneration (AMD) and to investigate the relationship between ...injection frequency and visual outcome in this setting.
Retrospective, interventional case series.
A total of 131 eyes with treatment-naïve, exudative AMD undergoing ranibizumab monotherapy.
Intravitreal ranibizumab was administered on an as-needed basis guided by clinical examination and optical coherence tomography (OCT). The OCT scans were evaluated by the treating physicians for the presence of intraretinal fluid, subretinal fluid, intraretinal cysts, or increasing pigment epithelial detachment size. Clinical data including visual acuity (VA), choroidal neovascularization lesion morphology, and treatment course were collected retrospectively for analysis.
Mean change in best-corrected Snellen VA.
The mean age was 81.3 years, mean follow-up was 12+/-4.3 months (minimum 6 months, median 12 months), and mean number of injections was 5.2+/-2.8. Mean baseline Snellen VA for the entire population was 20/110 and significantly improved at 6 months (20/80; P = 0.0002) and at last follow-up (20/90; P = 0.0066). At 6 months, 31% of eyes had gained at least 3 lines of VA and 90.5% had avoided loss of 3 lines. On average, it took 3.0 injections and 3.5 months to achieve a "dry" or "flat" macula on OCT after initiating treatment. Resolution of intra- and subretinal fluid on OCT did not correlate with the degree of vision improvement. Eyes receiving more frequent injections (defined as <2 months mean inter-injection interval) gained more vision (+2.3 lines at 6 months) than eyes receiving injections less frequently (+0.46 lines at 6 months; P = 0.012). At 6 months, 3.1% of those in the more frequent injection group lost >3 lines of vision compared with 15.9% in the >2 months interval group (P = 0.011).
In a population receiving as-needed injections of ranibizumab for exudative AMD, visual improvement was related to the frequency of injections received but not to the resolution of fluid by OCT. Treatment with ranibizumab on a strictly as-needed basis may result in undertreatment and significantly less visual gain.
Proprietary or commercial disclosure may be found after the references.
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