The role of PGC-1α and mitochondrial biogenesis in kidney diseases

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.Supported by ISCIII-FIS, FEDER funds, CP14/00133, PI16/02057, PI16/01900, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009, Sociedad Española de Nefrología, Fundacion Renal Iñigo Álvarez de Toledo (FRIAT), ISCIII Miguel Servet (A.B.S., M.D.S.-N.), ISCIII Sara Borrell (J.M.M.-M.), Comunidad de Madrid CIFRA2 B2017/BMD-3686 (M.F.-B. and D.M.-S.

Mitogen-Activated Protein Kinase 14 Promotes AKI

An improved understanding of pathogenic pathways may identify novel acute kidney injury (AKI) therapeutic approaches. Unbiased LC-MS/MS protein expression profiling combined with focused data mining identified MAP3K14 and non-canonical NFκB activation at the crossroads of the enriched pathways MAPK, ubiquitin-mediated proteolysis, chemokines, NFκB and apoptosis in the kidney cortex of experimental toxic AKI. In AKI the upstream kinase MAP3K14, the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, such as Ube2m and cullin1 were up-regulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in experimental and human AKI. In vivo evidence of MAP3K14 activation in experimental folic acid-induced AKI consisted of NFκB2 p100 processing to p52, nuclear location and DNA binding of RelB and NFκB2. MAP3K14 activity-deficient aly/aly mice were protected from kidney dysfunction, inflammation and apoptosis in AKI induced by folic acid and from lethality in cisplatin-induced AKI. MAP3K14 siRNA targeting in cultured tubular cells decreased inflammation and cell death. Bone marrow transplantation experiments where consistent with a protective effect of renal cell MAP3K14 targeting. Cell culture and in vivo studies identified chemokines MCP-1, RANTES and CXCL10 as MAP3K14 targets in tubular cells, thus identifying potential mediators of the deleterious effect of MAP3K14 in kidney injury. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target

TWEAK promotes peritoneal inflammation

Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14 expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with the number of peritoneal macrophages (r = 0.491, p = 0.002). Potential TWEAK targets that express the receptor Fn14 include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.This work was supported by FIS PS09/00447, PI08/1564, PI10/00234, MS12/03262, FEDER funds ISCIII-RETIC REDinREN/RD06/0016, RD12/0021, Comunidad de Madrid (Fibroteam S2010/BMD-2321, S2010/BMD-2378). Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laı´n-Entralgo/CM) to AO, Programa Estabilizacio´n Investigadores to LB-C, Miguel Servet to ABS, Sara Borrell to BS, MDSN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Cardiac Insulin Resistance in Subjects With Metabolic Syndrome Traits and Early Subclinical Atherosclerosis.

OBJECTIVE Experimental evidence suggests that metabolic syndrome (MetS) is associated with changes in cardiac metabolism. Whether this association occurs in humans is unknown. RESEARCH DESIGN AND METHODS 821 asymptomatic individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study (50.6 [46.9-53.6] years, 83.7% male) underwent two whole-body 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance (18F-FDG PET-MR) 4.8 ± 0.6 years apart. Presence of myocardial 18F-FDG uptake was evaluated qualitatively and quantitatively. No myocardial uptake was grade 0, while positive uptake was classified in grades 1-3 according to target-to-background ratio tertiles. RESULTS One hundred fifty-six participants (19.0%) showed no myocardial 18F-FDG uptake, and this was significantly associated with higher prevalence of MetS (29.0% vs. 13.9%, P < 0.001), hypertension (29.0% vs. 18.0%, P = 0.002), and diabetes (11.0% vs. 3.2%, P < 0.001), and with higher insulin resistance index (HOMA-IR, 1.64% vs. 1.23%, P < 0.001). Absence of myocardial uptake was associated with higher prevalence of early atherosclerosis (i.e., arterial 18F-FDG uptake, P = 0.004). On follow-up, the associations between myocardial 18F-FDG uptake and risk factors were replicated, and MetS was more frequent in the group without myocardial uptake. The increase in HOMA-IR was associated with a progressive decrease in myocardial uptake (P < 0.001). In 82% of subjects, the categorization according to presence/absence of myocardial 18F-FDG uptake did not change between baseline and follow-up. MetS regression on follow-up was associated with a significant (P < 0.001) increase in myocardial uptake. CONCLUSIONS Apparently healthy individuals without cardiac 18F-FDG uptake have higher HOMA-IR and higher prevalence of MetS traits, cardiovascular risk factors, and early atherosclerosis. An improvement in cardiometabolic profile is associated with the recovery of myocardial 18F-FDG uptake at follow-up.The PESA study is funded by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Santander Bank. B.I. is supported by the European Commission (grant numbers 819775 and 945118), by the Spanish Ministry of Science and Innovation (PID2019- 110369RB-I00), and by the Red Madrilena de ~ Nanomedicina en Imagen Molecular-Comunidad de Madrid (S2017/BMD-3867 RENIM-CM). A.D. is an Alfonso Martin Escudero fellow and is scientifically supported by La Caixa Foundation. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovacion (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/ 10.13039/501100011033).S

Effect of the Lights4Violence intervention on the sexism of adolescents in European countries

Background: Sexism results in a number of attitudes and behaviors that contribute to gender inequalities in social structure and interpersonal relationships. The objective of this study was to evaluate the effectiveness of Lights4Violence, an intervention program based on promoting health assets to reduce sexist attitudes in young European people. Methods: We carried out a quasi-experimental study in a non-probabilistic population of 1146 students, aged 12–17 years. The dependent variables were the difference in the wave 1 and wave 2 values in the subscales of the Ambivalent Sexism Inventory: benevolent sexism (BS) and hostile sexism (HS). The effect of the intervention was evaluated through linear regression analyses stratified by sex. The models were adjusted by baseline subscales scores, socio-demographic and psychological variables. Results: In girls, we observed a decrease in BS in the intervention group compared to the control group (β = − 0.101; p = 0.006). In the wave2,, BS decreased more in the intervention group compared to the control group in girls with mothers with a low level of education (β = − 0.338; p = 0.001), with a high level of social support (β = − 0.251; p < 0.001), with greater capacity for conflict resolution (β = − 0.201; p < 0.001) and lower levels of aggressiveness (β = − 0.232, p < 0.001). In boys, the mean levels of HS and BH decreased in wave 2 in both the control and intervention groups. The changes observed after the wave 2 were the same in the control group and in the intervention group. No significant differences were identified between both groups. Conclusions: The implementation of the Lights4Violence was associated with a significant reduction in BS in girls, which highlights the potential of interventions aimed at supporting the personal competencies and social support. It is necessary to reinforce the inclusion of educational contents that promote reflection among boys about the role of gender and the meaning of the attributes of masculinity. Trial registration: Clinicaltrials.gov : NCT03411564. Unique Protocol ID: 776905. Date registered: 26-01-2018.The project “Lights, Camera and Action against Dating Violence” (Ligts4Violence) was funded by the European Commission Directorate-General Justice and Consumers Rights, Equality and Citizen Violence Against Women Program 2016 for the period 2017–2019 to promote healthy dating relationship assets among secondary school students from different European countries, under grant agreement No. 776905. It was also co-supported by the CIBER of Epidemiology and Public Health of Spain for its aid to the Gender-based Violence and Youth Research Program

Aplikasi Herbisida 2,4-d Dan Penoxsulam Pada Pertumbuhan Dan Hasil Tanaman Padi Sawah (Oryza Sativa L.)

Salah satu teknik budidaya untuk meningkatkan produksi tanaman padi sawah yaitu dengan mengurangi persaingan antara tanaman dengan gulma. Pengendalian dengan kimiawi merupakan salah satu cara mengurangi pertumbuhan gulma di pertanaman padi. Cara kimiawi merupakan cara yang praktis, efektif dan efisien untuk mengendalikan gulma. Penelitian ini bertujuan untuk mempelajari pengaruh dari aplikasi herbisida 2,4-D dan penoxsulam dalam meningkatkan pertumbuhan dan hasil padi sawah serta menentukan dosis aplikasi herbisida 2,4-D dan penoxsulam baik secara tunggal maupun campuran dalam mengendalikan gulma pada tanaman padi sawah. Penelitian telah dilaksanakan pada bulan Maret-Juli 2014 di Desa Campurasri, Ngawi. Penelitian menggunakan Rancangan Acak Kelompok sederhana, dengan menempatkan 11 perlakuan yaitu H1 : kontrol herbisida 2,4-D; H2 : 2,4-D 11,25 kg ha-1; H3 : 2,4-D 22,5 kg ha-1; H4 : 2,4-D 33,75 kg ha-1; H5 : kontrol herbisida penoxsulam; H6 : penoxsulam 200 ml ha-1; H7 : penoxsulam 400 ml ha-1; H8 : penoxsulam 600 ml ha-1; H9 : 2,4-D 11,25 kg ha-1 dan penoxsulam 200 ml ha-1; H10 : 2,4-D 22,5 kg ha-1 dan penoxsulam 400 ml ha-1; H11 : 2,4-D 33,75 kg ha-1 dan penoxsulam 600 ml ha-1. Hasil penelitian menunjukkan bahwa perlakuan herbisida 2,4-D 11,25 kg ha-1 dan penoxsulam 200 ml menghasilkan bobot kering total tanaman dengan peningkatan sebesar 34,62 % dibandingkan dengan kontrol. Pada produksi tanaman padi peningkatan terjadi sebesar 29,77 % pada perlakuan herbisida 2,4-D 33,75 kg ha-1 dan penoxsulam 600 ml dibandingkan dengan kontrol

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection