Investigating the role of Angiotensin 1-9 in cardiomyocytes hypertrophy

The renin-angiotensin system (RAS) regulates blood pressure, and homeostasis through angiotensin II (AngII). Angiotensin converting enzyme 2 (ACE2), a homologue of ACE, metabolizes AngII to Ang1-7. Ang1-7 antagonizes AngII via the receptor MAS. ACE2 also converts AngI to Ang1-9. Very little is known about Ang1-9 although it is thought to be a substrate for Ang1-7 generation via ACE. We investigated Ang1-9 and Ang1-7 function in cardiomyocyte hypertrophy in rat neonatal and primary adult rabbit left ventricular cardiomyocytes. We have shown that Ang1-7 and Ang1-9 blocked AngII-induced hypertrophy. Furthermore, we demonstrated an independent role of Ang1-9 in cardiac hypertrophy and generated evidence that Ang1-9 signals via the angiotensin type 2 receptor. In vivo we delivered Ang1-9 via osmotic minipumps for 4 weeks into stroke-prone spontaneously hypertensive rats. Delivery of Ang1-9 reduced cardiac fibrosis and improved endothelial function compared to control animals. These findings have implications for our understanding of RAS function

Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin Type 2 receptor

The counter-regulatory axis of the renin angiotensin system peptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a potential therapeutic target in cardiac remodelling, acting via the mas receptor. Furthermore, we recently reported that an alternative peptide, Ang-(1-9) also counteracts cardiac remodelling via the angiotensin type 2 receptor (AT(2)R). Here, we have engineered adenoviral vectors expressing fusion proteins which release Ang-(1-7) [RAdAng-(1-7)] or Ang-(1-9) [RAdAng-(1-9)] and compared their effects on cardiomyocyte hypertrophy in rat H9c2 cardiomyocytes or primary adult rabbit cardiomyocytes, stimulated with angiotensin II, isoproterenol or arg-vasopressin. RAdAng-(1-7) and RAdAng-(1-9) efficiently transduced cardiomyocytes, expressed fusion proteins and secreted peptides, as demonstrated by western immunoblotting and conditioned media assays. Furthermore, secreted Ang-(1-7) and Ang-(1-9) inhibited cardiomyocyte hypertrophy (Control = 168.7±8.4 µm; AngII = 232.1±10.7 µm; AngII+RAdAng-(1-7) = 186±9.1 µm, RAdAng-(1-9) = 180.5±9 µm; P<0.05) and these effects were selectively reversed by inhibitors of their cognate receptors, the mas antagonist A779 for RAdAng-(1-7) and the AT(2)R antagonist PD123,319 for RAdAng-(1-9). Thus gene transfer of Ang-(1-7) and Ang-(1-9) produces receptor-specific effects equivalent to those observed with addition of exogenous peptides. These data highlight that Ang-(1-7) and Ang-(1-9) can be expressed via gene transfer and inhibit cardiomyocyte hypertrophy via their respective receptors. This supports applications for this approach for sustained peptide delivery to study molecular effects and potential gene therapeutic actions

A mutual regulatory loop between miR-155 and SOCS1 influences renal inflammation and diabetic kidney disease

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, a global health issue. Hyperglycemia, in concert with cytokines, activates the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway to induce inflammation and oxidative stress contributing to renal damage. There is evidence of microRNA-155 (miR-155) involvement in diabetes complications, but the underlying mechanisms are unclear. In this study, gain- and loss-of-function experiments were conducted to investigate the interplay between miR-155-5p and suppressor of cytokine signaling 1 (SOCS1) in the regulation of the JAK/STAT pathway during renal inflammation and DKD. In experimental models of mesangial injury and diabetes, miR-155-5p expression correlated inversely with SOCS1 and positively with albuminuria and expression levels of cytokines and prooxidant genes. In renal cells, miR-155-5p mimic downregulated SOCS1 and promoted STAT1/3 activation, cytokine expression, and cell proliferation and migration. Conversely, both miR-155-5p antagonism and SOCS1 overexpression protected cells from inflammation and hyperglycemia damage. In vivo, SOCS1 gene delivery decreased miR-155-5p and kidney injury in diabetic mice. Moreover, therapeutic inhibition of miR-155- 5p suppressed STAT1/3 activation and alleviated albuminuria, mesangial damage, and renal expression of inflammatory and fibrotic genes. In conclusion, modulation of the miR-155/ SOCS1 axis protects kidneys against diabetic damage, thus highlighting its potential as therapeutic target for DKDThis research was funded by grants from Spanish Ministry of Science and Innovation (RTI2018-098788-B-I00 and PID2021-127741OBI00) to C.G.-G., Instituto de Salud Carlos III (PI20/00487) to J.E, CIBERDEM (postdoctoral contract) to I.P., and Conacyt-Mexico (CB-2015-01 256639 and FOP02-2022-02 321869) to O.L.-F. The authors thank Ana Melgar and Patricia Saperas (IIS-FJD, Madrid) for technical support in mouse sample processing and histology, and Carmen Liliana Peña for technical assistant with in vitro experiment

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Estudio de biocontrol de endófitos y rizobacterias sobre hongos endófitos cultivables de semillas de Pinus chiapensis

"En esta tesis se trabajaron con hongos de los géneros Trichoderma, Penicillum, Cladosporium, Diaporthe y bacterias del género Bacillus y Paraburkholderia previamente aisladas de la semilla y la rizosfera de P. chiapensis. Se hicieron ensayos de antagonismo de bacterias contra hongos en donde el género Bacillus inhibió el crecimiento de los hongos, principalmente a Diaporthe y Cladosporium. En el caso particular del aislado Bacillus E presentó el mayor espectro de acción antagónica ya que también disminuyó el crecimiento no solo de los antes mencionados, sino también de los hongos Penicillum y cinco aislados identificados como Trichoderma sp. Por otra parte, aislamientos pertenecientes al género Paraburkholderia, por el contrario, el efecto antagónico fue nulo sobre aislados de los géneros Penicillum y Cladosporium. Así mismo, se llevaron a cabo co-inoculaciones, de todas las bacterias, en donde la dinámica bacteriana que se da en co-cultivo o juntando las bacterias inhiben de manera similar el crecimiento de los hongos. Dentro de las bacterias que se trabajaron, Bacillus E presento el mayor biocontrol sobre los hongos por lo que se estudió algunos de los probables mecanismos de biocontrol, dando positivo a producción de metabolitos secundarios, producción de compuestos volátiles, lipopéptidos, proteasas, celulasas, lipasas y glucanasas.

Implementation of strategies for tourism development of the municipality of Tlaxco, Tlaxcala. Mexico

In 2015, the municipality of Tlaxco is named Pueblo Mágico, although it is true that it has tourist wealth, according to the Annual Report on the Poverty Situation 60.22% of the population is in a state of poverty, therefore, the objective is to make tourism activity the engine of growth of the municipality through a planning of products and services that meet the needs of the tourist and those of the destination, based on a previously made diagnosis of the tourist inventory. For this, an instrument was designed whose sample was taken contemplating 118 companies that are directly linked to tourism, 36 surveys being applied. According to the results, 100% of respondents believe that Tlaxco can reach a more visited destination and although 66.7% have a high level of satisfaction residing in Tlaxco, 88.9% believe that although tourism has increased, public services have not improved. However, although 72.2% consider that the influx of tourists has increased, 58.3% consider that the tourist activity of the town is limited. Of the development plans that have been implemented, 44.5% of respondents have heard those plans but have no total knowledge of them. Therefore, it is essential that the opinion of the residents be taken into account, so that new activities and attractions for visitors are implemented in this way.En el año 2015 el municipio de Tlaxco es nombrado Pueblo Mágico, si bien es cierto que posee riquezas turísticas, de acuerdo al Informe Anual sobre la Situación de Pobreza (2018) el 60.22% de la población se encuentra en estado de pobreza, por ello, el objetivo es lograr que la actividad turística sea el motor de crecimiento del municipio a través de una planificación de productos y servicios que satisfagan las necesidades del turista y las del destino, a partir de un diagnóstico previamente realizado del inventario turístico. Para ello, se diseñó un instrumento cuya muestra fue tomada contemplando 118 empresas que se encuentran vinculadas directamente con el turismo, siendo aplicadas 36 encuestas. De acuerdo a los resultados, el 100% de los encuestados consideran que Tlaxco puede llegar a ser un destino más visitado y a pesar de que el 66.7% tiene un nivel alto de satisfacción al residir en Tlaxco, el 88.9% considera que, aunque el turismo ha aumentado, los servicios públicos no han mejorado. Sin embargo, aunque el 72.2% considera que ha aumentado la afluencia de turistas, el 58.3% considera que la actividad turística del pueblo se encuentra limitada. De los planes de desarrollo que han sido implementados, el 44.5% de los encuestados conocen dichos planes, pero no tienen total conocimiento de estos. Por tanto, es indispensable que se tome más en cuenta la opinión de los residentes, para que de esta manera se implementen actividades y atractivos nuevos para los visitantes