Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. ...Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate β-oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD.
Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective ...and anti-inflammatory agents with therapeutic potential.
We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on ¹⁸F-fluoro-deoxyglucose (¹⁸FDG) uptake by positron emission tomography (PET).
Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased ¹⁸FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.
In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.
Abstract
Objectives
To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, ...2017–18) and Spain (SUPERIOR, 2016–17) surveillance studies.
Methods
P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS.
Results
Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance.
Conclusions
Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.
This study evaluates different fermentation strategies to produce 2,3-butanediol (2,3-BD) from banana industry waste, such as whole bananas (fruit + peels) and banana peels, selecting the most ...favorable from a technical and economic point of view. Both residues have enough free sugars (17.8 %–35.8 %), glucan (11.0 %–14.2 %) and hemicellulose (2.8 %–6.3 %), to be promising substrates for 2,3-BD fermentation. Saccharification was studied by comparing enzymatic hydrolysis, hydrothermal pretreatment, and hydrothermal pretreatment followed by enzymatic hydrolysis. Different fermentation scenarios were also compared regarding the 2,3-BD yield and productivity: Separate Hydrolysis and Fermentation (SHF), Simultaneous Saccharification and Fermentation (SSF), and direct fermentation without prior saccharification using Paenibacillus polymyxa DSM-365 as the fermenting microorganism. The results showed that the pretreatment step was not necessary to improve the release of fermentable sugars. Enzymatic hydrolysis was the most effective alternative for maximizing sugar recovery, reaching sugar concentrations of 18.1 g/L (recovery: 92.5 %) for banana peels and 33.3 g/L (recovery: ∼100 %) for whole bananas. The SSF strategy led to higher 2,3-BD concentrations of 15.0 g/L and 26.6 g/L for banana peels and whole bananas, respectively. The preliminary economic analysis indicated that SSF and direct fermentation could be the more cost-effective process alternatives for banana peels and whole bananas, respectively. Thus, it was demonstrated that banana waste is an interesting resource for the production of 2,3-BD. The bioprocess can be competitive when using a low-cost raw material and reducing the number of process steps compared to traditional technologies.
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•Valorizing Banana Wastes for Sustainable 2,3-Butanediol Production.•Comparison of three fermentation scenarios: SHF, SSF and direct fermentation.•Techno-economic comparison of three 2,3-Butanediol fermentation scenarios.•Enzymatic saccharification eliminates extensive pretreatment.•Maximum 2,3-Butanediol obtained of 26.6 g/L using whole banana in SSF.
Monkeypox is the most prevalent Orthopoxvirus zoonosis infection since the eradication of smallpox. The current multi-country outbreak involves five WHO regions affecting mainly Europe. Accurate ...clinical and virological aspects of the disease outside endemic areas are needed.
We performed an observational study of cases diagnosed in Madrid (Spain) (May/June 2022). Confirmation from vesicular lesions swabs, Orthopoxvirus real-time PCR, sequencing, phylogenetic analysis, and direct detection by Electron microscopy was performed. In addition, a structured epidemiological questionnaire was completed systematically to gather sociodemographic, clinical, and behavioral data from all confirmed cases.
We extracted data from 48 patients, all cisgender men. The median age was 35 years (IQR 29 - 44), and 87.5% were MSM. The most prevalent symptoms were the presence of vesicular-umbilicated and pseudo-pustular skin lesions (93.8%), asthenia (66.6%), and fever (52.1%). In addition, the location of the lesions in the genital or perianal area was related to the role in sexual intercourse (p<0.001). Sequencing analysis indicated the virus circulating in Spain belongs to the western African clade. Like the other European cases in the outbreak, the Spanish isolates are a direct descendant of viruses previously detected in Nigeria, the UK, Singapore, and Israel in 2017-2018.
Monkeypox is an emerging infectious disease in Europe where community transmission is reported, mainly in MSM. The first symptom was skin lesions instead of classical fever and rash. The disease follows a self-limited course, and there have been no cases with a serious presentation or severe complications.
One of the main focal points of aging research is the search for treatments that will prevent or ameliorate the learning and memory deficiencies associated with aging. Here we have examined the ...effects of maintaining mature mice on a long-term intermittent fasting diet (L-IFD). We found that L-IFD enhances learning and consolidation processes. We also assessed the long-term changes in synaptic efficiency in these animals. L-IFD mice showed an increase in low-theta-band oscillations, paired-pulse facilitation, and facilitation of long-term synaptic plasticity in the hippocampus with respect to mice fed ad libitum. In addition, we found an increase in the expression of the NMDA receptor subunit NR2B in some brain areas of L-IFD mice. Specific antagonism of this subunit in the hippocampus reversed the beneficial effects of L-IFD. These data provide a molecular and cellular mechanism by which L-IFD may enhance cognition, ameliorating some aging-associated cognitive deficits.
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•Patients achieve high SVR12 rates with sofosbuvir/velpatasvir/voxilaprevir after prior DAA failures.•Sofosbuvir/velpatasvir/voxilaprevir is a very safe and well tolerated ...combination.•GT3 cirrhotic patients with previous treatment with NS5A-inhibitors are poor responders.•GT3 is the only factor that impacts SVR12 rates in retreatment with sofosbuvir/velpatasvir/voxilaprevir.
Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting.
This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded.
A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific.
Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group.
Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.
Particle aggregation modifies sediment dynamics, which is a determining factor for morphodynamic and ecological processes in deltaic plains. Here, we investigated the link between intra-annual ...hydrodynamics variability and flocculation in the Grijalva-Usumacinta system. Monthly (2016–2017) and seasonal (2021–2022) river data was processed using analytical methods and the simplified sonar equation. Flocs were reformed and characterized in the laboratory, validating the in situ settling velocities (0.5–3.8 mm/s) and the existence of large low-density macro-flocs (>300 μm). We verified that flocculation prevailed, exhibiting seasonal patterns; (1) the highest aggregation rates matched the increase in total suspended solids at rising-flow (>100 mg/L), (2) periods of high-flow showed stable aggregation rates, and (3) an influence of marine conditions occurred at low-flow. Particulate phosphorous and organic fraction showed seasonal patterns linked to flocculation. Due to damming, the shear rates varied slightly (7–11 L/s) in the Grijalva, leading to high flocculation intensities affecting the diffusivity ratio. In the Usumacinta, aggregation was limited by shear rates that normally exceed 15 1/s. We found seasonal Rouse parameters representative of sediment dynamics.
Aims
Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre‐ and ...post‐capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre‐ and post‐capillary PH (CpcPH).
Methods and results
The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE‐HF) trial is a multicentre, randomized, parallel, placebo‐controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n = 39) or placebo (n = 41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo‐corrected mean difference of 0.62 Wood units, 95% confidence interval CI −0.38, 1.61, p = 0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo‐corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p = 0.026), without significant differences in other pre‐specified secondary outcomes.
Conclusions
SPHERE‐HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre‐specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.
Summary of the study outline, flowchart, and results of the primary and secondary outcomes. The β3 selective agonist mirabegron did not improve pulmonary haemodynamics in adult patients with combined pre‐ and post‐capillary pulmonary hypertension associated with symptomatic heart failure. On secondary outcomes, a significant improvement in right ventricular ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life. PP, per protocol population.
Foamed bitumen improves the properties of base layer, increasing the number of equivalent axles allowed, as result of this is a durable pavement. To achieve this, base layer’s design must count with ...an amount of filler, to increase the stony aggregate fraction. This research consists with two different types of filler, lime and cement, 1% in dosage respect to the stony aggregate weight. Has been discovered now, that the RAP (reclaimed asphalt pavement) aggregate in addition to mitigate environmental problems, has a significant impact value on the mechanic resistance of the mix.
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