Effects of immunosuppression with tacrolimus and mycophenolate mofetil on renal histology and function in single kidney rats submitted to ischemia and reperfusion

To evaluate renal histological changes and renal function in single kidney rats submitted to renal ischemia-reperfusion and to immunosuppression with tacrolimus and mycophenolate-mofetil. Experimental study with 80 Wistar rats distributed into control, Sham and six other groups treated with immunosuppressive drugs. Animals undergoing surgery, right nephrectomy and left renal clamping, killed on the 14th day and analyzed for renal histology, urea and creatinine. The group receiving tacrolimus at higher doses (T3) showed renal histological lesions indicative of early nephrotoxicity, and significant increase in urea and creatinine. The group M (mycophenolate-mofetil alone) and the group M2 (mycophenolate-mofetil combined with half the usual dose of tacrolimus) presented a slight rise in serum urea. The groups using mycophenolate-mofetil alone or combined with tacrolimus showed creatinine levels similar to that of the group T3. Histologically, the association of injury by ischemia-reperfusion with the use of tacrolimus or mycophenolatemofetil alone demonstrated a higher rate of renal changes typical of early nephrotoxicity. In laboratory, the combination of injury by ischemia-reperfusion with tacrolimus at higher doses proved to be nephrotoxic30212713

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Immunohistochemical analysis of the effect of a purified collagen gel Coating on integration of polypropylene meshes in rats

Orientador: Cássio Luís Zanettini RiccettoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: INTRODUÇÃO: Telas sintéticas representam, na atualidade, o pilar do tratamento da incontinência urinária e de prolapsos vaginais, sendo o polipropileno monofilamentar o material sintético mais utilizado. Apesar de taxas de cura de até 90%, complicações relacionadas à integração, tais como exposição ou erosão das telas, não podem ser negligenciadas. O colágeno, por ser um material biologicamente compatível, pouco imunogênico e com propriedades moduladoras do processo inflamatório, pode ser utilizado como um importante agente cicatricial melhorando a integração das telas. OBJETIVO: Avaliar, por meio de técnicas imunohistoquímicas, o efeito do recobrimento de tela de polipropileno monofilamentar, implantada no subcutâneo de ratas, com gel purificado de colágeno bovino, do ponto de vista da resposta imuno-inflamatória, do metabolismo do colágeno, angiogênese e citotoxicidade. MATERIAIS E MÉTODOS: Após aprovação no Comite de Ética em Experimentação Animal, foram utilizadas 20 ratas fêmeas da raça Wistar, tendo sido implantadas, em cada animal, de um lado da parede abdominal, uma tela de polipropileno monofilamentar (PP) e, do outro lado, uma tela semelhante recoberta com gel purificado de colágeno (PPC). Os animais foram divididos em quatro sub-grupos contendo 5 animais cada e foram eutanasiados em 7, 14, 21 e 90 dias após o implante. Foram utilizados reagentes específicos para avaliação dos aspectos de interesse: a) Imunológicos (Interleucina 1 ¿ IL-1); b) Metabolismo do colágeno (Metaloproteinases de Matriz 2 e 3 ¿ MMP-2 e 3); c) Angiogênese (Antígeno de Superfície CD-31); d) Citotoxicidade (Receptor do Fator de Necrose Tumoral alfa ¿ TNF ¿?). A análise das imunorreatividades foi realizada com auxílio do software analisador de imagens AxioVisionTM. RESULTADOS: A análise comparativa das variáveis entre os 4 períodos definidos (7,14, 21 e 90 dias) e entre os 2 grupos (PP e PPC) apontou diferença significativa para: CD-31 com maior número de vasos no grupo PPC, no subgrupo 14 dias (p=0.002) em relação ao grupo PP, e diminuição após 90 dias (p=0.002) no grupo PPC; MMP-2 com redução na densidade média no grupo PPC (p=0.046) nos subgrupos 21 e 90 dias em relação ao grupo PP ; MMP-3 com maior estabilidade ao longo do tempo no grupo PPC, de modo que houve queda significativa da área percentual reativa no grupo PP após 14 e 90 dias (p=0.017), bem como redução da densidade média logo após 21 dias, mas apenas após 90 dias no grupo PPC (p<0.001). CONCLUSÃO: O recobrimento com gel purificado de colágeno bovino determinou alterações significantes na resposta tecidual das ratas às telas de polipropileno, do ponto de vista imunohistoquímico, quanto à angiogênese e atividade das metaloproteinases na área do implante, sem influência significativa sobre a resposta imuno-inflamatória local (expressas por meio da IL-1 e TNF¿?)Abstract: INTRODUCTION: The use of synthetic meshes, specially the polypropylene mesh, has become the standart treatment of urinary incontinence and vaginal prolapses. Even though presenting high cure rates, complications related to integration issues, such as exposure or erosion of the mesh, cannot be neglected. The collagen, well known as an important immunoinflammatory modulator, has been speculated to be a usefull tool in the healing process and possibly improving integration of meshes. OBJECTIVE The aim of this study is to evaluate, using immunohistochemical techniques, the effect of the use of a new purified collagen gel covering the monofilament polypropylene mesh implanted subcutaneously in rats, regarding immune-inflammatory response, collagen metabolism, angiogenesis and cytotoxicity. METHODS: After Ethics Committee on Animal Use¿s approval, in 20 female Wistar rats were implanted, at one side of abdominal wall, a monofilament polypropylene mesh (PP) and on the other side, the same mesh covered with a new developed purified collagen gel (PPC). The animals were divided into four sub-groups containing 5 animals each and were euthanized at 7, 14, 21 and 90 days after implantation. The immunohistochemical assessment of the samples was done by using specific reagents for the evaluation of points of interest: a) Immunologic (Interleukin 1 (IL-1)), b) Collagen metabolism (Metalloproteinases 2 and 3 (MMP-2 and 3)), c) Angiogenesis (surface antigen CD-31), d) Cytotoxicity (Tumor Necrosis Factor-alpha Receptor - TNF- ?). The objective analysis was performed using the image analysis software AxioVision TM. RESULTS: Comparative analysis of variables between the four periods defined (7, 14, 21 and 90 days) and between the 2 groups (PP and PPC) showed: higher vessel density in PPC group after 14 days (p=0.002) and decrease after 90 days (p=0.002); decrease of MMP-2 average density in PPC group after 21 and 90 days (p=0.046); more stability in MMP-3¿s behavior in PPC group along the periods with MMP-3 percent reactive area showing significant decrease just in PP group after 14 and 90 days (p=0.017) and also for MMP-3 average density, in which reduction was significant after 21 days in PP group, but just after 90 days in PPC (p<0.001).CONCLUSION: Highly purified collagen coating causes significant changes in angiogenesis and in metalloproteinase's immunohystochemical expression in meshes implants in rats, without significant influence on the local immuno-inflammatory response (expressed by IL-1 and TNF-?)MestradoFisiopatologia CirúrgicaMestre em Ciência