De rol van P-glycoproteïne en andere ABC-transporters in fysiologische en pathologische processen

P-glycoproteïne is een multi-drug resistentie eiwit dat behoort tot de familie van de ATP-binding cassette (ABC) transporter eiwitten en wordt traditioneel geassocieerd met resistentie van kankers tegenover chemotherapeutica. Tegenwoordig is echter gekend dat deze ABC eiwitten ook een centrale functie uitoefenen als transporter eiwitten in meerdere fysiologische en pathologische processen. Op een ATP- afhankelijke manier staan zij in voor het transmembranair transport van diverse endogene en exogene substraten. Bij de mens zijn er 48 ABC genen gekend die onderverdeeld worden in zeven subfamilies (ABCA-G). Voor verschillende genen zijn er mutaties beschreven die leiden tot genetische defecten en geassocieerd zijn met pathofysiologische processen zoals inflammatory bowel disease, atherosclerose, ziekte van Alzheimer, Parkinson, retinadegeneratie, dilatorische cardiomyopathie, keratinisatiedefecten, hyperbilirubinemie en diabetes mellitus. P-glycoproteïne oefent voornamelijk zijn functie uit ter hoogte van de bloed-weefsel barrières met de bedoeling het weefsel te beschermen tegenover schadelijke stoffen. Uit onderzoek in de humane geneeskunde en dierproeven bij muizen blijkt de belangrijke rol die P-glycoproteïne speelt. In de diergeneeskunde is hierover nog maar weinig bekend. Het best gekende is de mutatie in P-glycoproteïne bij collies met ivermectine-overgevoeligheid. In dit overzichtsartikel bespreken we de weefseldistributie, de fysiologische functie en de pathologische processen waarbij P-glycoproteine betrokken is

Kvaliteta uzorkovanja kod sustavnog praćenja goveđe spongiformne encefalopatije u Belgiji.

The bovine spongiform encephalopathy (BSE) epidemics have led to active surveillance in Europe. Detection methods are focused on the obex, where prions first accumulate in the central nervous system (CNS). Sampling is made with a calibrated syringe (from Bio-Rad or Idexx) that must sample a target area in the obex area. This study checked the precision of the sampling in Belgian routine laboratories in 2010 and 2011 (analysed obex: N = 184 and N = 368). For that purpose, the obex was divided into 130 identical square zones with 50 in the target area. The success of sampling the target area was identical when comparing the years (72.8%). The different laboratories obtained similar results. However, in 2011, one of the four laboratories had a lower number of zones inside the target area than the best laboratory. As a conclusion, obex sampling in Belgium is adequate, provided the technicians are well trained. This is especially true when confronted with atypical BSE, for which the obex is not the primary region of prion accumulation.Epidemije goveđe spongiformne encefalopatije nužno su dovele do donošenja mjera za njezin aktivni nadzor u Europi. Metode dokazivanja usmjerene su na obex u središnjem živčanom sustavu gdje se prioni najprije nakupljaju. Uzorci se uzimaju kalibriranom štrcaljkom (Bio-Rad ili Idexx) na ciljnom mjestu na području obeksa. U ovom istraživanju provjerena je točnost uzimanja uzoraka u rutinskim dijagnostičkim laboratorijima u Belgiji u 2010. i 2011. kada je bilo analizirano 184 odnosno 368 uzoraka tkiva obeksa. U tu je svrhu obex bio podijeljen na 130 identičnih kvadratičnih područja s 50 ciljnih mjesta. Uspješnost uzimanja uzoraka s ciljnog mjesta bila je identična na godišnjoj razini (72,8%). Različiti laboratoriji postigli su slične rezultate. Ipak, u 2011. jedan od četiri laboratorija imao je manji broj zona unutar ciljnog područja u usporedbi s rezultatima najboljeg laboratorija. Zaključuje se da je uzimanje uzoraka tkiva obeksa u Belgiji zadovoljavajuće i da je tehničko osoblje dobro educirano. To je osobito važno kad je riječ u atipičnoj goveđoj spongiformnoj encefalopatiji kod koje obex nije primarno područje nakupljanja priona

The [OIII] profiles of far-infrared active and non-active optically-selected green valley galaxies

We present a study of the $\rm{[OIII]\lambda\,5007}$ line profile in a sub-sample of 8 active galactic nuclei (AGN) and 6 non-AGN in the optically-selected green valley at $\rm{z\,<\,0.5}$ using long-slit spectroscopic observations with the 11 m Southern African Large Telescope. Gaussian decomposition of the line profile was performed to study its different components. We observe that the AGN profile is more complex than the non-AGN one. In particular, in most AGN (5/8) we detect a blue wing of the line. We derive the FWHM velocities of the wing and systemic component, and find that AGN show higher FWHM velocity than non-AGN in their core component. We also find that the AGN show blue wings with a median velocity width of approximately 600 $\rm{km\,s^{-1}}$, and a velocity offset from the core component in the range -90 to -350 $\rm{km\,s^{-1}}$, in contrast to the non-AGN galaxies, where we do not detect blue wings in any of their $\rm{[OIII]\lambda\,5007}$ line profiles. Using spatial information in our spectra, we show that at least three of the outflow candidate galaxies have centrally driven gas outflows extending across the whole galaxy. Moreover, these are also the galaxies which are located on the main sequence of star formation, raising the possibility that the AGN in our sample are influencing SF of their host galaxies (such as positive feedback). This is in agreement with our previous work where we studied SF, morphology, and stellar population properties of a sample of green valley AGN and non-AGN galaxies.Comment: 15 pages, 6 figures, accepted for publication in Ap

Trade-offs and synergies of carbon sequestration in global agricultural soils: a literature synthesis

Comunicación oral presentada en: EGU General Assembly 2023. Viena, Austria, 23-28 abril (2023)Agricultural management practices aimed at sequestering carbon (C) in soils can have synergies with many agroecosystem services, but may come at the cost of increased greenhouse gas (GHG) emissions and nutrient losses. We performed a systematic literature synthesis to review whether C sequestration practices show synergies with soil structure and soil biota, but generate trade-offs in terms of CO2 and N2O emissions or N and P losses worldwide. We also assessed whether the magnitude of trade-offs and synergies vary across climatic regions and over time. We performed systematic literature searches in the Web of Science for articles that: 1. experimentally assess the effect of minimising soil disturbance, diversifying agroecosystems, and/or increasing organic matter inputs versus standard practices, and 2. include measurements of C sequestration and at least another response variable related to synergies or trade-offs. We retrieved 771 publications, 537 of which were excluded based on i) the type of article (review, opinion papers), ii) a focus on non-soil habitats, forests or organic soils, or iii) experimental designs not matching our criteria. We included 234 studies that report 572 effects of sustainable practices on 228 sites located in 38 countries. Experiments averaged 10 years of monitoring and the majority reported effects of increasing organic matter inputs and minimising soil disturbance (88%) in temperate and continental climates (75%). Soil organic C increased without compromising crop yields considering all management practices together, i.e. positive effects of sustainable versus standard practices on C sequestration were more frequent than expected by chance. As expected, C sequestration promoted soil biota, but effects were more evident on biomass than on diversity. We also detected synergistic effects on soil aggregation, porosity, water retention and compaction. Negative effects of C retention practices were significant when considering GHG emissions and nutrient losses, particularly for CO2 emissions and mineral N accumulation. However, the magnitude of these trade-offs varied significantly depending on the metrics used to measure them, e.g. field versus lab GHG fluxes. We discuss how these effects vary across management practices, time and space, and review main knowledge gaps detected in the literature

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI &lt;18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For school&#x2;aged children and adolescents, we report thinness (BMI &lt;2 SD below the median of the WHO growth reference) and obesity (BMI &gt;2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe