Schistosoma mansoni in IL-4-deficient mice

Immunopathology and Immune responses to Schistosoma mansoni were examined in IL-4 -/- mice. IL-5 and IL-10 production by lymphoid cells stimulated with soluble egg antigen (SEA), peripheral eosinophilla and serum levels of soluble IL-4 receptor but not IgE were all significantly elevated over background normal levels in IL-4 -/- mice as a result of infection. Additionally, IL-10 and IL-5 in addition to IL-2 and IFN-γ transcripts were equally evident in diseased liver tissue from infected IL-4 -/- and wild-type mice. Nevertheless, analysis of antigen-stimulated IL-2, IL-4, IL-5, IL-10 and IFN-γ production by lymphoid organ cells from infected or egg-injected IL-4 / mice revealed a more Th1 -like pattern of cytokine production (IFN-γ > IL-5) than In (wild-type) mice in which a stronger type 2 response to SEA was detectable (IL-4, IL-5 > IFN-γ). Despite this, at 8 and 16 weeks after infection, liver pathology, as indicated by the size, ceilularity, cellular composition and collagen content of granulomas, was similar in IL-4 / and wild-type animals. As in wild-type animals, granuloma size at week 16 was smaller than at week 8, Indicating that modulation had occurred in the absence of IL-4. Differences in pathology were seen only when eggs were experimentally embolized to the lungs, in which case IL-4 / mice made smaller granulomatous responses than did wild-type animals. These data clearly show that IL-4 Is not necessary for the hepatic granuloma formation which occurs during experimental schistosomiasi

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 \u3bcM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 \u3bcM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability

Making sense of big data in health research: Towards an EU action plan.

Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans

Prognostic impact of acute pulmonary triggers in patients with Takotsubo syndrome : new insights from the International Takotsubo Registry

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002). Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.C. T. has been supported by the H.H. Sheikh Khalifa binHamad Al-Thani Research Programme and the Swiss HeartFoundation. The InterTAK Registry is supported by the BissDavies Charitable Trust. L. S. M. has been supported by EUHORIZON 2020(SILICOFCM ID777204)info:eu-repo/semantics/publishedVersio

The Need for Global Protections Against Existential Risks

As bad as the social and economic impact of the new coronavirus is, it could be worse. It could kill everyone it infects. A scenario with such a fully fatal virus would be known as an existential risk because it would threaten all human life on the planet. Global nuclear war and climate change might also be other possible existential risks—although some contention still exists over the degree to which these would annihilate the entire planet. But almost no one disputes that a meteorite crashing into Earth could do so by suddenly and drastically altering the climate. Furthermore, experts also agree that still more deadly pathogens—viruses and bacteria—could pose such an existential risk. But what is currently missing in international law is an adequate mechanism to compel nations to cooperate to minimize or mitigate the harms from existential risks. In addition to efforts to strengthen national regulation of research and technology risks, countries also need to pursue the adoption of a multilateral agreement to address existential risks while separately working to insert existential risk clauses in existing international agreements. The fact that some human-made existential risks, and even natural existential risks, might be minimized by human action, makes prudent the development of new international law aimed at addressing those risks. Admittedly, some of these risks are more amenable to national policy than others. The consequences of existential risks are, however, by necessity global and therefore demand a global policy response. Hubs of such international coordination exist for some risks, such as the World Health Organization, the International Atomic Energy Agency, and the United Nations’s Office for Disarmament Affairs. Unfortunately, these international agencies often lack sufficient power and scope to respond effectively to existential risks. Governments around the world should give particular focus to developing stronger international policies on urgent existential risks. I define a risk as “urgent” if the cost of reducing the risk or strengthening resilience increases rapidly over time, or if the risk is about to become unmanageable altogether. One risk that fits that description is climate change, even though its character as existential risk has been contested. Given that current global institutions lack powers to address existential risks because real power continues to lie with the nation state, a different device is required to mobilize national power globally. Such a device should bridge the global policy approach and national enforcement on the ground. This device becomes necessary because—although states generally are well intentioned and are self-interested in protecting their own population—in practice, some of them might be slow or ineffective in their response, or they might coordinate insufficiently with their neighbors. Others will refuse international assistance for reasons of sovereignty or pride, while being unable to tackle the risk themselves. A new device becomes particularly important for biological existential risks, where insufficient action by a single state can massively increase the cost to others or even render tackling the existential risk impossible. I have identified two devices that could address this challenge. The first device is a multilateral agreement with enforcement clauses of unprecedented strength, aimed at minimizing and mitigating existential risk. This agreement should contain the following: The last two items conflict with the currently established order of international agreements. That is, under existing international law, nations could not lawfully take any action needed to compel reluctant signatory nations. Furthermore, a new agreement cannot overrule an earlier one unless all the contracting parties of the earlier agreement agree to do so. This difficulty will make a second device necessary to implement, even before a dedicated multilateral agreement on urgent existential risk can develop its full efficacy. This second device is what I call an “existential risk sanction clause.” Whenever a bilateral or multilateral agreement on any area of cooperation is amended, a special clause should be inserted that permits the suspension of the obligations to another signatory if that signatory fails to act against urgent existential risk. Important multilateral agreements should be revised with the express purpose of adding such a clause. In addition, should some signatories to the multilateral agreement refuse such a clause, the agreement should be rescinded and replaced by a new agreement, concluded by the remaining signatories. These modifications to existing agreements might deter states from failing to cooperate even before a multilateral agreement aimed at existential risk becomes effective. In other words, the existential risk sanction clause is also a device on its own. One major international player alone could push for the inclusion of the existential risk sanction clause in international agreements. With the spread of the existential risk sanction clause through multilateral and bilateral agreements on various areas of international cooperation by one major international player, the scope of potential sanctions could increase sharply. The cost of non-cooperation could also increase with the scope of potential sanctions and could compel uncooperative states to act. Existential risk would not, however, be eliminated by the multilateral agreement on urgent existential risk and existential risk sanction clauses. But these devices would provide a basis for global cooperation that would move substantially toward that goal. The two devices might be thought of as existential themselves—they will at some point become crucial for humanity’s collective survival