TLR9 activation dampens the early inflammatory response to paracoccidioides brasiliensis, Impacting host survival

Background: Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear.J.F. Menino was supported by a grant from Fundacao para a Ciencia e Tecnologia (FCT), Portugal (SFRH/BD/33446/2008). This work was supported by a grant from FCT (PTDC/BIA-MIC/108309/2008). M. Saraiva is a Ciencia 2007 fellow and M. Sturme is a Ciencia 2008 fellow. We would also like to thank FAPESP (Fundacao para Amparo a Pesquisa do Estado de Sao Paulo) and CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Trauma Severity and Not the Socio-Economic Variables Determine Survival after Penetrating Trauma in a Medium-Income Country

Survival after severe trauma is lower in low- and middle-income countries. Quality of pre-hospital care, lack of insurance, and differential access to trauma care are possible explanations. The aim of this study was to evaluate the effect of lack of insurance, pre-hospital times, and the nature of the hospital (public or private) in survival after violent penetrating trauma in a middle-income country

12-month Follow-up Analysis Of A Multicenter, Randomized, Prospective Trial In De Novo Liver Transplantation Recipients (lis2t) Comparing Cyclosporine Microemulsion (c2 Monitoring) And Tacrolimus

The LIS2T study was an open-label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA-ME) (Neural) (n = 250) (monitoring of blood concentration at 2 hours postdose) C2 or tacrolimus (n = 245) (monitoring of trough drug blood level[predose])Co to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA-ME patients and 86% o tacrolimus patients survived with a functioning grat (P not significant). Efficacy was similar in deceased-and living-donor recipients. Significantly fewer hepatitis C-positive patients died or lost their graft by 12 months with CsA-ME 95/ 88,6%) than with tacrolimus (14/85,16%) (P< 0.03). Recurrence of hepatitis C virus in liver grafts was similar in each group. Based on biopsies driven by clinical events, the mean time to histological diagnosis of hepatitis C virus recurrence was significantly longer with CsA-ME (100 ± 50 days) than with tacrolimus (70 ± 40 days) (P < 0.05). Median serum creatinine at 12 months was 106 μmol/L with CsA-ME and with tacrolimus. More patients who were nondiabetic at baseline received antihyperglycemic therapy in the tacrolimus group at 12 months was (13% vs. 5%, P< 0.01). Of patients who were diabetic at baseline, more tacrolimus-treated individuals required anti-diabetic treatment at 12 months ( 70% vs. 49%, P+ 0.02). Treatment for de novo or preexisting hypertension or hyperlipidemia was similar in both groups. In conclusion, the efficacy of CsA-ME monitored by blood concentration at 2 hours postdose and tacrolimus in liver transplant patients is equivalent to 12 months, and renal function is similar. More patients required antidiabetic therapy with tacrolimus regardless of diabetic status at baseline. © 2006 AASLD.121014641472United Network for Organ Sharing Data Report: Liver Kaplan-Meier Graft Survival Rates for Transplants Performed 1996-2001 (2004), http://www.optn.org, Available at: Accessed: February 2Vogt, D.P., Henderson, J.M., Carey, W.D., Barnes, D., The long-term survival and causes of death in patients who survive at least 1 year after liver transplantation (2002) Surgery, 132, pp. 775-780Johnston, S.D., Morris, J.K., Cramb, R., Gunson, B.K., Neuberger, J., Cardiovascular morbidity and mortality after orthotopic liver transplantation (2002) Transplantation, 73, pp. 901-906Neal, D.A., Tom, B.D., Luan, J., Wareham, N.J., Gimson, A.E., Delrivere, L.D., Is there disparity between risk and incidence of cardiovascular disease after liver transplant? (2004) Transplantation, 77, pp. 93-99O'Grady, J.G., Burroughs, Hardy, P., Elbourne, D., Truesdale, A., Tacrolimus versus microemulsified ciclosporin in liver transplantation: The TMC randomised controlled trial (2002) Lancet, 360, pp. 1119-1125Mühlbacher, F., Tacrolimus versus cyclosporin microemulsion in liver transplantation: Results of a 3-month study (2001) Transplant Proc, 33, pp. 1339-1340. , European Liver Transplantation Tacrolimus vs Cyclosporin Microemulsion Study GroupLevy, G., Villamil, F., Samuel, D., Sanjuan, F., Grazi, G.L., Wu, Y., Results of LIS2T, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring and tacrolimus with Co monitoring in de novo liver transplantation (2004) Transplantation, 77, pp. 1632-1638Levy, G., Burra, P., Cavallari, A., Duvoux, C., Lake, J., Mayer, A.D., Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2) (2002) Transplantation, 73, pp. 953-959Villamil, F., Pollard, S., C2 monitoring of cyclosporine in de novo liver transplant recipients: The clinician's perspective (2004) Liver Transpl, 10, pp. 577-583Yantorno, S.E., Varela, E.B., Raffa, S.R., Descalzi, V.I., Gomez Carretero, M.L., Pirola, D.A., How common is delayed cyclosporine absorption following liver transplantation? (2005) Liver TranspI, 11, pp. 167-173Watashi, K., Hijakata, M., Hosaka, M., Yamaji, M., Shimotohno, K., Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes (2003) Hepatology, 38, pp. 1282-1288Nakagawa, M., Sakamoto, N., Enomoto, N., Tanabe, Y., Kanazawa, N., Koyama, T., Specific inhibition of hepatitis C virus replication by cyclosporin A (2004) Biochem Biophys Res Commun, 313, pp. 42-47Manir̀e, T., Ethier, C., Raymond, V.A., Andre, A., Bilodeau, M., Evaluation of the effect of immunosuppressive agents on hepatitis C: Cyclosporine reduces viral replication in the replicon model (2004) Transplantation, 78 (SUPPL. 1), pp. 13-14. , [abstract]Sheiner, P.A., Schwartz, M.E., Mor, E., Schulager, L.K., Theise, N., Kishikawa, K., Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation (1995) Hepatology, 21, pp. 30-34Johnson, M.W., Washburn, W.K., Freeman, R.B., Fitzmaurice, S.E., Dienstag, J., Basgoz, N., Hepatitis C viral infection in liver transplantation (1996) Arch Surg, 131, pp. 284-291Paik, S.W., Tan, H.P., Klein, A.S., Boitnott, J.K., Thulavath, P.J., Outcome of orthotopic liver transplantation in patients with hepatitis C (2002) Dig Dis Sci, 47, pp. 450-455Duvoux, C., Mennecier, D., Pageaux, G., Conti, F., Roudot-Thoraval, F., Dhumeaux, D., Immunosuppression with tacrolimus an absence of antihypertensive therapy are associated with fibrosis progression after hepatitis C virus (HCV) graft reinfection (2002) Transplantation, 74 (SUPPL.). , International Society of Transplantation Congress 2002 [abstract 2652]Hunt, J., Gordon, F.D., Lewis, W.D., Histological recurrence and progression of hepatitis C after orthotopic liver transplantation: Influence of immunosuppressive regimens (2001) Liver Transpl, 7, pp. 1056-1063Berenguer, M., Prieto, M., San Juan, F., Rayon, J.M., Martinez, F., Carrasco, D., Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients (2002) Hepatology, 36, pp. 202-210Ghobrial, R.M., Farmer, D.G., Baquerizo, A., Orthotopic liver transplantation for hepatitis C: Outcome, effect of immunosuppression, and causes of retransplantation duringan 8-year single-center experience (1999) Ann Surg, 6, pp. 824-833Neumann, U.P., Berg, T., Bahra, M., Puhl, G., Guckelberger, O., Langrehr, J.M., Long-term outcome of liver transplants for chronic hepatitis C: A 10-year follow-up (2004) Transplantation, 77, pp. 226-231Ericzon, B., Groth, C., Bismuth, H., Calne, R., McMaster, P., Neuhaus, P., Glucose metabolism in liver transplant recipients treated with FK 506 or cyclosporin in the European multicentre study (1994) Transplant Int, 7 (SUPPL.), pp. Sll-S14Lohmann, T., List, C., Lamesch, P., Kohlhaw, K., Wenzke, M., Schwarz, C., Diabetes mellitus and islet cell specific autoimmunity as adverse effects of immunosuppressive therapy by FK506/tacrolimus (2000) Exp Clin Endocrinol Diabetes, 108, pp. 347-352Prasad, G.V., Kim, S.J., Huang, M., Kohlhaw, K., Zaltzman, J.S., Fenton, S.S., Reduced incidence of new-onset diabetes mellitus after renal transplantation with 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins) (2004) Am J Transplant, 4, pp. 1897-190

Impact of the SARS-CoV-2 pandemic on emergency surgery services—a multi-national survey among WSES members

Background: The SARS-CoV-2 pandemic is a major challenge for health care services worldwide. It’s impact on oncologic therapies and elective surgery has been described recently, and the literature provides guidelines regarding appropriate elective patient treatment during the pandemic. However, the impact of SARS-CoV-2 pandemic on emergency surgery services has been poorly investigated up to now. Methods: A 17-item web survey had been distributed to emergency surgeons in June 2020 around the world, investigating the impact of SARS-CoV-2 pandemic on patients and septic diseases both requiring emergency surgery and the time-to-intervention in emergency surgery routine, as well as experiences with surgery in COVID-19 patients. Results: Ninety-eight collaborators from 31 countries responded to the survey. The majority (65.3%) estimated the impact of the SARS-CoV-2 pandemic on emergency surgical patient care as being strong or very strong. Due to the pandemic, 87.8% reported a decrease in the total number of patients undergoing emergency surgery and approximately 25% estimated a delay of more than 2 h in the time-to-diagnosis and another 2 h in the time-to-intervention. Fifty percent make structural problems with in-hospital logistics (e.g. transport of patients, closed normal wards etc.) mainly responsible for delayed emergency surgery and the frequent need (56.1%) for a triage of emergency surgical patients. 56.1% of the collaborators observed more severe septic abdominal diseases during the pandemic, especially for perforated appendicitis and severe septic cholecystitis (41.8% and 40.2%, respectively). 62.2% had experiences with surgery in COVID-19-infected patients. Conclusions: The results of The WSES COVID-19 emergency surgery survey are alarming. The combination of an estimated decrease in numbers of emergency surgical patients and an observed increase in more severe septic diseases may be a result of the fear of patients from infection with COVID-19 and a consecutive delayed hospital admission and diagnosis. A critical delay in time-to-diagnosis and time-to-intervention may be a result of changes in in-hospital logistics and operating room as well as intensive care capacities. Both reflect the potentially harmful impact of SARS-CoV-2 pandemic on emergency surgery services