prox1b Activity Is Essential in Zebrafish Lymphangiogenesis

BACKGROUND: The lymphatic vascular system, draining interstitial fluids from most tissues and organs, exerts crucial functions in several physiological and pathological processes. Lymphatic system development depends on Prox1, the first marker to be expressed in the endothelial cells of the cardinal vein from where lymph vessels originate. Prox1 ortholog in the optically clear, easily manipulated zebrafish model has been previously isolated and its contribution to lymphangiogenesis has been clarified. Because of a round of genome duplication occurred at the base of teleosts radiation, several zebrafish genes have been retained in duplicate through evolution. We investigated for the presence of additional prox1 genes and determined their role in zebrafish lymphangiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We isolated a second ortholog, named prox1b, and analyzed its expression during development by whole mount in situ hybridization (WISH). We detected strong prox1b expression in the endothelium of the posterior cardinal vein (PCV) from where lymphatic precursors originate. To analyze prox1b involvement in lymphangiogenesis we utilized the fli1:GFP transgenics and followed the formation of the toracic duct (TD), the primary lymph vessel in fish, after prox1b knockdown. Our findings clearly demonstrated that the absence of prox1b activity severely hampers the formation of the TD. CONCLUSIONS/SIGNIFICANCE: This work provides substantial progress toward the understanding of zebrafish lymphangiogenesis. In light of the features shared by the lymphatic systems of zebrafish and higher vertebrates, the establishment of such lymphatic model will provide a powerful tool to study, for instance, disorders of body fluid homeostasis, inflammation and cancer metastasis, and may ultimately contribute to novel therapies

Erythropoietin: Recent Developments in the Treatment of Spinal Cord Injury

Erythropoietin (EPO), originally identified for its critical function in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of cells and tissues. Here is presented the analysis of EPO effects on spinal cord injury (SCI), considering both animal experiments concerning to mechanisms of neurodegeneration in SCI and EPO as a neuroprotective agent, and some evidences coming from ongoing clinical trials. The evidences underling that EPO could be a promising therapeutic agent in a variety of neurological insults, including trauma, are mounting. In particular, it is highlighted that administration of EPO or other recently generated EPO analogues such as asialo-EPO and carbamylated-EPO demonstrate interesting preclinical and clinical characteristics, rendering the evaluation of these tissue-protective agents imperative in human clinical trials. Moreover the demonstration of rhEPO and its analogues' broad neuroprotective effects in animal models of cord lesion and in human trial like stroke, should encourage scientists and clinicians to design clinical trials assessing the efficacy of these pharmacological compounds on SCI

Type I IFN induces IL-10 production in an IL-27-independent manner and blocks responsiveness to IFN-gamma for production of IL-12 and bacterial killing in Mycobacterium tuberculosis-infected macrophages

Tuberculosis, caused by the intracellular bacterium Mycobacterium tuberculosis, currently causes ~1.4 million deaths per year, and it therefore remains a leading global health problem. The immune response during tuberculosis remains incompletely understood, particularly regarding immune factors that are harmful rather than protective to the host. Overproduction of the type I IFN family of cytokines is associated with exacerbated tuberculosis in both mouse models and in humans, although the mechanisms by which type I IFN promotes disease are not well understood. We have investigated the effect of type I IFN on M. tuberculosis-infected macrophages and found that production of host-protective cytokines such as TNF-a, IL-12, and IL-1ß is inhibited by exogenous type I IFN, whereas production of immunosuppressive IL-10 is promoted in an IL-27-independent manner. Furthermore, much of the ability of type I IFN to inhibit cytokine production was mediated by IL-10. Additionally, type I IFN compromised macrophage activation by the lymphoid immune response through severely disrupting responsiveness to IFN-?, including M. tuberculosis killing. These findings describe important mechanisms by which type I IFN inhibits the immune response during tuberculosis.This work was funded by Medical Research Council, U.K. Grant U117565642 and European Research Council Grant 294682-TB-PATH. M.S. and L.M.-T. were funded by the Fundacao para a Ciencia e Tecnologia, Portugal. M.S. is a Fundacao para a Ciencia e Tecnologia, Portugal investigator. L.M.T. was supported by Fundacao para a Ciencia e Tecnologia, Portugal Grant SFRH/BPD/77399/2011

From syndemic lesson after COVID-19 pandemic to a “systemic clinical risk management” proposal in the perspective of the ethics of job well done

The syndemic framework proposed by the 2021–2030 World Health Organization (WHO) action plan for patient safety and the introduction of enabling technologies in health services involve a more effective interpretation of the data to understand causation. Based on the Systemic Theory, this communication proposes the “Systemic Clinical Risk Management” (SCRM) to improve the Quality of Care and Patient Safety. This is a new Clinical Risk Management model capable of developing the ability to observe and synthesize different elements in ways that lead to in-depth interventions to achieve solutions aligned with the sustainable development of health services. In order to avoid uncontrolled decision-making related to the use of enabling technologies, we devised an internal Learning Algorithm Risk Management (LARM) level based on a Bayesian approach. Moreover, according to the ethics of Job Well Done, the SCRM, instead of giving an opinion on events that have already occurred, proposes a bioethical co-working because it suggests the best way to act from a scientific point of view

Ethical Criteria for the Admission and Management of Patients in the ICU Under Conditions of Limited Medical Resources: A Shared International Proposal in View of the COVID-19 Pandemic

Introduction The present pandemic has exposed us to unprecedented challenges that need to be addressed not just for the current state, but also for possible future similar occurrences. It is worth pointing out that discussions on the allocation of medical resources may not necessarily refer to an exception, but, unfortunately, to a regular condition for a large part of humanity (1). The criteria for admission to an Intensive Care Unit (ICU) setting generally take into account multiple factors. There must be a diagnostic and prognostic basis for the decisions made, considering both biological factors and patient values and wishes. Furthermore, the decision-making process should, whenever possible, respect the patient's advance directives as well as the relationship with the patient's family or attorney. Therapeutic neglect should be avoided. Having applied standard clinical evaluation criteria for the appropriate treatment of patients with COVID-19, including consideration of prognosis, if a hospital then finds itself unable to provide optimal treatment (e.g., due to a disproportion between the number of patients and the availability of beds, healthcare providers, ventilators, and drugs in the ICU), it becomes necessary to evaluate, case by case, how to achieve justice and the best possible good for the greatest number of patients. It is therefore mandatory to explore alternative solutions; these include increasing available beds and healthcare providers, implementing alternative, though suboptimal, approaches (where appropriate), transferring patients to other clinical units, etc. Making these decisions properly also involves the recovery of the political role of medicine and science (2). If the imbalance between needs and resources reaches a critical level, an emergency triage protocol, following the operational and ethical indications of “disaster medicine,” should be activated. These have been deployed in major and serious natural (earthquakes or tsunamis for example) and technological (factory explosions, public transport accidents for example) disasters, as well as following terrorist attacks (3, 4). The question of the feasibility of developing a clinical evaluation algorithm to support the decision-making of the triage team remains open, though many such protocols have been written. According to the above, we propose the following five ethical criteria for the triage of patients in conditions of limited resources, such as the COVID pandemic. They are the result of an interdisciplinary and intercultural dialogue between specialists from different disciplines. Several of the authors are working in the main epicenters of the crisis and currently are playing a central role in the bioethical, clinical, social and legal aspects of the management of the COVID-19 pandemic

Lake isotope records of the 8200-year cooling event in western Ireland: Comparison with model simulations

The early Holocene cooling, which occurred around 8200 calendar years before present, was a prominent abrupt event around the north Atlantic region. Here, we investigate the timing, duration, magnitude and regional coherence of the event as expressed in carbonate oxygen-isotope records from three lakes on northwest Europe's Atlantic margin in western Ireland, namely Loch Avolla, Loch Gealáin and Lough Corrib. An abrupt negative oxygen-isotope excursion lasted about 200 years. Comparison of records from three sites suggests that the excursion was primarily the result of a reduction of the oxygen-isotope values of precipitation, which was likely caused by lowered air temperatures, possibly coupled with a change in atmospheric circulation. Comparison of records from two of the lakes (Loch Avolla and Loch Gealáin), which have differing bathymetries, further suggests a reduction in evaporative loss of lake water during the cooling episode. Comparison of climate model experiments with lake-sediment isotope data indicates that effective moisture may have increased along this part of the northeast Atlantic seaboard during the 8200-year climatic event, as lower evaporation compensated for reduced precipitation

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