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Frank A. DeLano, Geert W. Schmid-Schönbein
PLoS One Infectious Diseases, 18.10.2024
Tilføjet 18.10.2024
by Frank A. DeLano, Geert W. Schmid-Schönbein The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract. Using immune-histochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage. These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion.
Læs mere Tjek på PubMedGarcia, Bruno; Ter Schiphorst, Benoit; Su, Fuhong; Picod, Adrien; Ikenna-Uba, Theo; Favory, Raphaël; Annoni, Filippo; Mebazaa, Alexandre; Vincent, Jean-Louis; Creteur, Jacques; Taccone, Fabio S.; Herpain, Antoine
Critical Care Explorations, 17.10.2024
Tilføjet 17.10.2024
OBJECTIVES: To analyze dynamic changes in the renin-angiotensin system (RAS) during septic shock, focusing on angiotensin-converting enzyme (ACE) activity and the balance between angiotensin peptides, using a mass spectrometry method. DESIGN: Experimental septic shock model induced by peritonitis in swine. SETTING: Experimental Laboratory, Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles. SUBJECTS: Forty time points from eight mechanically ventilated pigs. INTERVENTIONS: Septic shock was induced using intraperitoneal instillation of autologous feces, followed by standardized fluid resuscitation, norepinephrine infusion, antibiotic administration, and peritoneal lavage. MEASUREMENTS AND MAIN RESULTS: The induction of sepsis resulted in a significant increase in plasma renin activity and levels of angiotensin I and II, with a significant decrease in ACE activity observed from 4 hours post-resuscitation and a notable rise in the angiotensin I/angiotensin II ratio at 12 hours. Additionally, a shift toward the angiotensin-(1–7) axis was observed, evidenced by an increased angiotensin-(1–7)/angiotensin II ratio. CONCLUSIONS: The study highlighted dynamic shifts in the RAS during septic shock, characterized by reduced circulating ACE activity, elevated angiotensin I/II ratio, and a shift toward the angiotensin-(1–7) axis. These findings suggest an adaptive response within the RAS, potentially offering new insights into sepsis management and therapeutic targets.
Læs mere Tjek på PubMedChunyan Guo, Cuixiang Xu, Qing Feng, Xin Xie, Yan Li, Xiangrong Zhao, Jun Hu, Senbiao Fang, Lijun Shang
Journal of Medical Virology, 15.10.2024
Tilføjet 15.10.2024
Anne GreifenhagenHannes RuweVictoria ZimmerJana MesserschmidtDurga Prasad Naik BhukyaHawi Deressa KeneaAndreas SchallerThomas SpallekaDepartment of Plant Physiology and Biochemistry, University of Hohenheim, Stuttgart 70599, GermanybPlant Biotic Interactions Group, Albrecht-von-Haller Institute of Plant Sciences, Göttinger Zentrum für Molekulare Biowissenschaften (GZMB), University of Göttingen, Göttingen 37077, Germany
Proceedings of the National Academy of Sciences, 12.10.2024
Tilføjet 12.10.2024
Proceedings of the National Academy of Sciences, Volume 121, Issue 42, October 2024.
Læs mere Tjek på PubMedJournal of Infectious Diseases, 12.10.2024
Tilføjet 12.10.2024
Abstract Background Rising incidence of invasive beta-haemolytic streptococcal (iBHS) infections has prompted consideration of vaccination as a preventative strategy for at-risk populations. The benefits of a vaccine targeting Lancefield group A (Streptococcus pyogenes; Strep A) would increase if cross-species immunity against Lancefield groups C/G (Streptococcus dysgalactiae subspecies equisimilis; SDSE) and B (Streptococcus agalactiae; GBS) was demonstrated.Methods A prospective, observational study of adult patients with iBHS infections due to Strep A, SDSE or GBS. Antibody responses to six Strep A candidate antigens were assayed on acute and convalescent sera. A serological response was defined as an increase of >0.2log10 arbitrary units/mL (AU/mL).Results Sixty-seven participants were enrolled. Thirty-three participants were included in the final analysis (12, 11 and 10 with Strep A, SDSE and GBS, respectively). The median serological response for participants with Strep A was significant for all tested antigens (median >0.2log10 difference between acute and convalescent samples; P
Læs mere Tjek på PubMedOkegbe, Tishina; Bishop, Kristina Monroe; Rose, Jessica; Srivastava, Meena; Baptiste, Anne Jean
Journal of Acquired Immune Deficiency Syndromes, 10.10.2024
Tilføjet 10.10.2024
Introduction: Adolescents 10-19 years account for a growing proportion of people living with HIV (PLHIV). In 2023, 140,000 adolescents were diagnosed with HIV, yet knowledge of HIV status and uptake of testing services remain critically low. Index testing – offering testing to contacts of PLHIV – is an important case-finding strategy. In 2021, PEPFAR expanded guidance to explicitly include older adolescents 15 to 19 years. We reviewed index testing data to assess uptake and case-finding trends among biological adolescent-aged children and siblings of PLHIV 10-19 years. Methods: Routinely collected programmatic data from 27 USAID-supported PEPFAR country and regional programs were analyzed for fiscal years (FY) 2017 through FY2022 (October 2016 - September 2022). We compared the volume of index testing and subsequent new diagnoses across FYs and countries among biological adolescent-aged children and siblings of PLHIV, and disaggregated by age, 10-14 and 15-19 years, and sex. Results: Index testing among adolescents 10-19 years increased from FY17 to FY22, nearly doubling from 147,088 to 291,534. Similarly, new diagnoses among adolescents increased between FY17 and FY22 (3,721 vs 10,730). Overall, across FYs, index testing uptake and case-finding were higher among females than males, and the gap in testing uptake between sexes was larger for older than younger adolescents. Conclusion: Index testing uptake has increased substantially among adolescents over time, with rebounded gains for adolescents 15-19 years noted beginning in FY21. However, uptake across age and sex remained uneven, highlighting an opportunity to ensure targeted testing strategies are employed to reach adolescents 15-19 years and males. Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
Læs mere Tjek på PubMed