Mortalidade entre Idosos no Estado do Paraná e no município de Foz do Iguaçu

Trabalho de Conclusão da Residência apresentado ao Programa de Residência Multiprofissional em Saúde da Família da Universidade Federal da Integração Latino- Americana, como requisito parcial para obtenção do título de Especialista em Saúde da Família na modalidade de residência. Orientador: Walfrido Svoboda. (Prof. Dr. do Curso de Saúde Coletiva - UNILA) e Coorientadora: Carmen Justina Gamarra. (Profa. Dra. do Curso de Saúde Coletiva - UNILA)Objetivo: Analisar a tendência da mortalidade entre idosos residentes no estado do Paraná e no município de Foz do Iguaçu, no período de 2001 a 2012, e mortalidade proporcional por capítulos CID-10. Método: Trata-se de um estudo descritivo, ecológico de série temporal. Os dados dos óbitos e da população idosa de 60 anos ou mais foram obtidos por meio do Sistema de Informação de mortalidade SIM/DATASUS. Foram calculadas as taxas anuais de mortalidade bruta e padronizadas por sexo e faixa etária. Para os dados de mortalidade proporcional por capítulos CID-10 foram calculados os percentuais para os anos selecionados de 2001; 2006; 2011; 2016. As informações foram tabuladas em planilhas do Excel, sendo construídas tabelas e gráficos e analisados por meio de regressão linear simples. Resultados: Observou-se tendência declinante da mortalidade dos idosos no estado do Paraná e no município de Foz do Iguaçu. Ao longo do estudo verificou-se que as doenças do aparelho circulatório constituem-se como a primeira e principal causa de óbito, seguido das neoplasias e doenças do aparelho respiratório. Conclusão: No período analisado, a tendência da mortalidade padronizadas dos idosos obteve decréscimo tanto no Estado como no município, sendo observados maiores coeficientes de mortalidade entre os homens quando comparado às mulheres.Objective: To analyze the mortality trend among elderly people living in the state of Para- ná and in the municipality of Foz do Iguaçu, from 2001 to 2012, and proportional mortality by ICD-10 chapters. Method: This is a descriptive, ecological time series study. Data on deaths and the elderly population aged 60 years and over were obtained using the SIM / Datasus Mortality Infor- mation System. Gross annual mortality rates were standardized and standardized by gen- der and age group. The information was tabulated in Excel spreadsheets, and tables and graphs were constructed and analyzed using simple linear regression. Results: In general terms, a declining trend in mortality among the elderly was observed in the state of Paraná and in the city of Foz do Iguaçu. Throughout the study it was verified that diseases of the circulatory system constitute the first and main cause of death, fol- lowed by neoplasias and diseases of the respiratory system. Conclusion: In the period analyzed, the general trend of standardized mortality among the elderly decreased both in the state and in the municipality, with higher mortality rates among men when compared to womenObjetivo: Analizar la tendencia de la mortalidad entre ancianos residentes en el estado de Paraná y en el municipio de Foz do Iguaçu, en el período de 2001 a 2012, y mortali- dad proporcional por capítulos CID-10. Método: Se trata de un estudio descriptivo, eco- lógico de serie temporal. Los datos de mortalidad y de la población de la tercera edad (mayor de 60años) fueron obtenidos por medio del sistema de información de mortalidad SIM/DATASUS. Fueron calculadas las tasas anuales de mortalidad bruta y estandariza- das por sexo y edad. Las informaciones fueron tabuladas en planillas de cálculo Micro- soft Excel, siendo construidas tablas, gráficos e analizados por medio de regresión linear simple. Resultados: En términos generales fue observada la tendencia declinante de la mortali- dad en personas de la tercera edad en el Estado de Paraná y en el Municipio de Foz de Iguazú. A lo largo de este estudio, se verifico que las enfermedades del aparato circula- torio se consideran como la primera causa de muerte, seguido por Cáncer e enfermeda- des del Aparato Respiratorio. Conclusión: En el periodo analizado, la tendencia de la mortalidad estandarizada en personas de la tercera edad obtuvo decrecimos tanto en el Estado de Paraná como en el Municipio, siendo observados mayores coeficientes de mortalidad en hombres compara- do con mujere

Phenotypic Expression of ADAMTS13 in Glomerular Endothelial Cells

Background: ADAMTS13 is the physiological von Willebrand factor (VWF)-cleaving protease. The aim of this study was to examine ADAMTS13 expression in kidneys from ADAMTS13 wild-type (Adamts13+/+) and deficient (Adamts13-/-) mice and to investigate the expression pattern and bioactivity in human glomerular endothelial cells. Methodology/Principal Findings: Immunohistochemistry was performed on kidney sections from ADAMTS13 wild-type and ADAMTS13-deficient mice. Phenotypic differences were examined by ultramorphology. ADAMTS13 expression in human glomerular endothelial cells and dermal microvascular endothelial cells was investigated by real-time PCR, flow cytometry, immunofluorescence and immunoblotting. VWF cleavage was demonstrated by multimer structure analysis and immunoblotting. ADAMTS13 was demonstrated in glomerular endothelial cells in Adamts13+/+ mice but no staining was visible in tissue from Adamts13-/- mice. Thickening of glomerular capillaries with platelet deposition on the vessel wall was detected in Adamts13-/- mice. ADAMTS13 mRNA and protein were detected in both human endothelial cells and the protease was secreted. ADAMTS13 activity was demonstrated in glomerular endothelial cells as cleavage of VWF. Conclusions/Significance: Glomerular endothelial cells express and secrete ADAMTS13. The proteolytic activity could have a protective effect preventing deposition of platelets along capillary lumina under the conditions of high shear stress present in glomerular capillaries. © 2011 Tati et al.published_or_final_versio

ADAMTS13 phenotype in health and disease with special reference to thrombotic thrombocytopenic purpura

Von Willebrand factor (VWF) is synthesized and secreted by endothelial cells into the plasma as a series of multimers. VWF induces the formation of platelet plugs at sites of vascular injury and high shear stress. Biological activity is dependent on multimeric size, which is regulated in plasma by the VWF-cleaving protease ADAMTS13. Severe ADAMTS13 deficiency is associated with thrombotic thrombocytopenic purpura (TTP), a life threatening thrombotic microangiopathic disorder characterized by thrombocytopenia, hemolytic anemia, neurological and renal manifestations, and fever. Congenital TTP occurs due to ADAMTS13 mutations, while acquired TTP is associated with autoantibodies against the protease. Severe ADAMTS13 deficiency results in the accumulation of ultra-large (UL) VWF multimers, which induce the formation of disseminated thrombi in the microcirculation. The present study aimed to describe the ADAMTS13 phenotype in plasma and kidney (one of the main target organs in TTP) from normal controls and TTP patients. In addition, ADAMTS13 expression was studied in renal tissue and urine from patients with tubular damage. Patients with congenital TTP had undetectable ADAMTS13 antigen in the plasma as detected by immunoblotting. Patients with acquired TTP expressed the normal phenotype but the protease circulated in complex with inhibitory autoantibodies. In normal kidney expression was detected in glomeruli (podocytes, endothelial cells and the glomerular basement membrane) and tubuli. Patients with congenital TTP exhibited a similar staining pattern but with seemingly higher intensity, presumably due to impaired secretion resulting in intracellular accumulation. Podocytes and tubular cells were shown to synthesize biologically active ADAMTS13. Tubular damage altered the tubular expression pattern and resulted in detection of ADAMTS13 antigen in urine

Molecular basis of ADAMTS13 dysfunction in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathic disorder characterized by thrombocytopenia, hemolytic anemia, neurological and renal manifestations, and fever. It is associated with dysfunctional von Willebrand factor (VWF) proteolysis and the occurrence of VWF- and platelet-rich thrombi in the microcirculation of multiple organs, including the kidneys. Von Willebrand factor is a large glycoprotein that circulates in plasma as a series of multimers, and it plays a major role in primary hemostasis by inducing the formation of platelet plugs at sites of vascular injury and high-shear stress. Its activity is dependent on the sizes of the multimers, with ultra-large (UL) VWF multimers being biologically very potent. The ULVWF multimers are rapidly degraded upon their secretion from endothelial cells in normal individuals but not in the circulation of TTP patients, causing the formation of disseminated thrombi in the latter. The defective breakdown of VWF is attributed to a severely deficient activity of the VWF-cleaving protease ADAMTS13, a plasma metalloprotease synthesized in the liver, kidneys, and endothelium. This protease rapidly degrades VWF-platelet strings under flow by proteolytic cleavage of the VWF subunit, thereby regulating the size of the platelet thrombus. Congenital TTP occurs due to ADAMTS13 mutations, with the usual debut occurring during the first years of life, while acquired TTP is associated with auto-antibodies against ADAMTS13

Biologically active ADAMTS13 is expressed in renal tubular epithelial cells.

ADAMTS13 mRNA, which encodes the von Willebrand factor-cleaving protease, has been detected in a variety of tissues, including the kidney. The aim of our study was to characterize tubular expression and bioactivity of ADAMTS13. ADAMTS13 mRNA was detected in cultured primary human renal tubular epithelial cells (HRTEC) and in A498 cells, a human renal carcinoma cell line, by real-time PCR. Protein was detected using immunofluorescence and immunoblotting. Immunoblots demonstrated that the protein was secreted. The protease was proteolytically active in both cell lysates and cleaved the FRETS-VWF73 substrate. ADAMTS13 was demonstrated in situ in the renal cortex by immunohistochemistry. Protease was detected in both the proximal and distal renal tubules in normal renal tissue (n = 3) as well as in patients with tubular disorders (n = 3). Immunoblotting revealed that ADAMTS13 was present in the urine of patients with tubulopathy (n = 5) but not in normal urine. ADAMTS13 in urine had a molecular size similar to that in plasma, which indicates that the protease originates in the tubuli because such large proteins do not normally pass the glomerular filter. In conclusion, human renal tubular epithelial cells synthesize biologically active ADAMTS13 which may, after release from tubuli, regulate hemostasis in the local microenvironment

Neutrophil Protease Cleavage of Von Willebrand Factor in Glomeruli – An Anti-thrombotic Mechanism in the Kidney

Adequate cleavage of von Willebrand factor (VWF) prevents formation of thrombi. ADAMTS13 is the main VWF-cleaving protease and its deficiency results in development of thrombotic microangiopathy. Besides ADAMTS13 other proteases may also possess VWF-cleaving activity, but their physiological importance in preventing thrombus formation is unknown. This study investigated if, and which, proteases could cleave VWF in the glomerulus. The content of the glomerular basement membrane (GBM) was studied as a reflection of processes occurring in the subendothelial glomerular space. VWF was incubated with human GBMs and VWF cleavage was assessed by multimer structure analysis, immunoblotting and mass spectrometry. VWF was cleaved into the smallest multimers by the GBM, which contained ADAMTS13 as well as neutrophil proteases, elastase, proteinase 3 (PR3), cathepsin-G and matrix-metalloproteinase 9. The most potent components of the GBM capable of VWF cleavage were in the serine protease or metalloprotease category, but not ADAMTS13. Neutralization of neutrophil serine proteases inhibited GBM-mediated VWF-cleaving activity, demonstrating a marked contribution of elastase and/or PR3. VWF-platelet strings formed on the surface of primary glomerular endothelial cells, in a perfusion system, were cleaved by both elastase and the GBM, a process blocked by elastase inhibitor. Ultramorphological studies of the human kidney demonstrated neutrophils releasing elastase into the GBM. Neutrophil proteases may contribute to VWF cleavage within the subendothelium, adjacent to the GBM, and thus regulate thrombus size. This anti-thrombotic mechanism would protect the normal kidney during inflammation and could also explain why most patients with ADAMTS13 deficiency do not develop severe kidney failure

Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome.

Shiga toxin (Stx)-producing Escherichia coli (STEC) cause hemolytic uremic syndrome (HUS). This study investigated whether Stx2 induces hemolysis and whether complement is involved in the hemolytic process. RBCs and/or RBC-derived microvesicles from patients with STEC-HUS (n = 25) were investigated for the presence of C3 and C9 by flow cytometry. Patients exhibited increased C3 deposition on RBCs compared with controls (p < 0.001), as well as high levels of C3- and C9-bearing RBC-derived microvesicles during the acute phase, which decreased after recovery. Stx2 bound to P1 (k) and P2 (k) phenotype RBCs, expressing high levels of the P(k) Ag (globotriaosylceramide), the known Stx receptor. Stx2 induced the release of hemoglobin and lactate dehydrogenase in whole blood, indicating hemolysis. Stx2-induced hemolysis was not demonstrated in the absence of plasma and was inhibited by heat inactivation, as well as by the terminal complement pathway Ab eculizumab, the purinergic P2 receptor antagonist suramin, and EDTA. In the presence of whole blood or plasma/serum, Stx2 induced the release of RBC-derived microvesicles coated with C5b-9, a process that was inhibited by EDTA, in the absence of factor B, and by purinergic P2 receptor antagonists. Thus, complement-coated RBC-derived microvesicles are elevated in HUS patients and induced in vitro by incubation of RBCs with Stx2, which also induced hemolysis. The role of complement in Stx2-mediated hemolysis was demonstrated by its occurrence only in the presence of plasma and its abrogation by heat inactivation, EDTA, and eculizumab. Complement activation on RBCs could play a role in the hemolytic process occurring during STEC-HUS

Detection ofADAMTS13 in cultured endothelial cells by flow cytometry.

<p> ADAMTS13 protein was detected in CiGEnC (Panels A–D) using A10 monoclonal antibody (panel A) and SU19 polyclonal antibody (panel B). The control antibodies, mouse IgG_2b-κ (panel C) and rabbit IgG (panel D) did not bind to any cells. HMVEC showed similar results (Panels E–H). Reproducible results were obtained from two different experiments.</p