Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions

Elaine R Tavares1, Fatima R Freitas1, Jayme Diament1, Raul C Maranhão1,21Heart Institute of the Medical School Hospital (InCor), University of São Paulo, São Paulo, Brazil; 2Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, BrazilObjectives: Cholesterol-rich nanoemulsions (LDE) bind to low-density lipoprotein (LDL) receptors and after injection into the bloodstream concentrate in aortas of atherosclerotic rabbits. Association of paclitaxel with LDE markedly reduces the lesions. In previous studies, treatment of refractory cancer patients with etoposide associated with LDE had been shown devoid of toxicity. In this study, the ability of etoposide to reduce lesions and inflammatory factors in atherosclerotic rabbits was investigated.Methods: Eighteen New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30, nine animals were treated with four weekly intravenous injections of etoposide oleate (6 mg/kg) associated with LDE, and nine control animals were treated with saline solution injections.Results: LDE-etoposide reduced the lesion areas of cholesterol-fed animals by 85% and intima width by 50% and impaired macrophage and smooth muscle cell invasion of the intima. Treatment also markedly reduced the protein expression of lipoprotein receptors (LDL receptor, LDL-related protein-1, cluster of differentiation 36, and scavenger receptor class B member 1), inflammatory cytokines (interleukin-1β and tumor necrosis factor-α), matrix metallopeptidase-9, and cell proliferation markers (topoisomerase IIα and tubulin).Conclusion: The ability of LDE-etoposide to strongly reduce the lesion area and the inflammatory process warrants the great therapeutic potential of this novel preparation to target the inflammatory-proliferative basic mechanisms of the disease.Keywords: atherosclerosis treatment, drug delivery, LDL-receptor

Potential health impact of ultrafine particles under clean and polluted urban atmospheric conditions: a model-based study

The main goal of this study was to improve the knowledge of ultrafine particle number distributions in large urban areas and also to call the attention to the importance of these particles on assessing health risks. Measurements of aerosol size distributions were performed during 2 weeks, with distinct pollutant concentrations (polluted and clean periods), on the rooftop of a building located in downtown of the megacity of São Paulo, Brazil. CO, NO2, PM10, SO2, and O3 concentrations and meteorological variables were also used. Aerosol size distribution measurements showed that geometric mean diameters of the size spectra in the polluted period are on average considerably larger than those in the clean one. Besides the fact that total number of ultrafine particles did not show significant differences, during the polluted period, geometric mean diameter was larger than during the clean one. The results of a mathematical model of particle deposition on human respiratory tract indicated a more significant effect of smaller particles fraction of the spectra, which predominate under clean atmospheric conditions. The results also indicated that urban environmental conditions usually considered good for air quality, under the criteria of low mass concentration, do not properly serve as air quality standard to very small particles. In the size range of ultrafine particles, this traditional clean atmospheric condition can offer a strong risk to pulmonary hazards, since the cleansing of the atmosphere creates good conditions to increase the concentration of nucleation mode particles

Lipoprotein metabolism in patients with type 1 diabetes under intensive insulin treatment

Background\ud Type 1 diabetes (T1DM) is frequently accompanied by dyslipidemia related with insulin-dependent steps of the intravascular lipoprotein metabolism. T1DM dyslipidemia may predispose to precocious cardiovascular disease and the lipid status in T1DM under intensive insulin treatment has not been sufficiently explored. The aim was to investigate the plasma lipids and the metabolism of LDL and HDL in insulin-treated T1DM patients with high glycemic levels.\ud \ud Methods\ud Sixteen male patients with T1DM (26 ± 7 yrs) with glycated hemoglobin >7%, and 15 control subjects (28 ± 6 yrs) were injected with a lipid nanoemulsion (LDE) resembling LDL and labeled with 14C-cholesteryl ester and 3H-free-cholesterol for determination of fractional clearance rates (FCR, in h-1) and cholesterol esterification kinetics. Transfer of labeled lipids from LDE to HDL was assayed in vitro.\ud \ud Results\ud LDL-cholesterol (83 ± 15 vs 100 ± 29 mg/dl, p=0.08) tended to be lower in T1DM than in controls; HDL-cholesterol and triglycerides were equal. LDE marker 14C-cholesteryl ester was removed faster from plasma in T1DM patients than in controls (FCR=0.059 ± 0.022 vs 0.039 ± 0.022h-1, p=0.019), which may account for their lower LDL-cholesterol levels. Cholesterol esterification kinetics and transfer of non-esterified and esterified cholesterol, phospholipids and triglycerides from LDE to HDL were also equal.\ud \ud Conclusion\ud T1DM patients under intensive insulin treatment but with poor glycemic control had lower LDL-cholesterol with higher LDE plasma clearance, indicating that LDL plasma removal was even more efficient than in controls. Furthermore, HDL-cholesterol and triglycerides, cholesterol esterification and transfer of lipids to HDL, an important step in reverse cholesterol transport, were all normal. Coexistence of high glycemia levels with normal intravascular lipid metabolism may be related to differences in exogenous insulin bioavailabity and different insulin mechanisms of action on glucose and lipids. Those findings may have important implications for prevention of macrovascular disease by intensive insulin treatment.This study was supported by Fundação do Amparo à Pesquisa do Estado de São Paulo (FAPESP), São Paulo, Brazil. Dr. Maranhão has a Research Award from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Brasília, Brazil

Abnormal thyroid hormone status differentially affects bone mass accrual and bone strength in C3H/HeJ mice: a mouse model of type I deiodinase deficiency

C3H/HeJ (C3H) mice are deficient of type I deiodinase (D1), an enzyme that activates thyroid hormone (TH), converting thyroxine (T4) to triiodothyronine (T3). Nevertheless, C3H mice present normal serum T3 and a gross euthyroid phenotype. To investigate if a global D1 deficiency interferes in the TH effects on bone, we compared bone growth, bone mass accrual and bone strength of C3H and C57BL/6J (B6) mice under abnormal TH status. Four-week-old female mice of both strains were grouped as Euthyroid, Hypothyroid (pharmacologically-induced), 1xT4 and 10xT4 (hypothyroid animals receiving 1- or 10-fold the physiological dose of T4 /day/16 weeks). Hypothyroidism and TH excess similarly impaired body weight (BW) gain and body growth in both mice strains. In contrast, whereas hypothyroidism only slightly impaired bone mineral density (BMD) accrual in B6 mice, it severely impaired BMD accrual in C3H mice. No differences were observed in serum and bone concentrations of T3 between hypothyroid animals of both strains. Interestingly, treatment with 10xT4 was less deleterious to BMD accrual in C3H than in B6 mice and resulted in less elevated T3 serum levels in B6 than in C3H mice, which is probably explained by the lower D1 activity in C3H mice. In addition, hypothyroidism decreased bone strength only in C3H but not in B6 mice, while TH excess decreased this parameter in both strains. These findings indicate that D1 deficiency contributes to the TH excess-induced differences in bone mass accrual in C3H vs. B6 mice and suggest that deiodinase-unrelated genetic factors might account for the different skeleton responses to hypothyroidism between strains

A pesquisa participante e a intervenção comunitária no cotidiano do Pibid/CAPES

O artigo analisa as dimensões psicossociais do processo de participação e formação de um grupo de alunos da licenciatura de pedagogia, filosofia e ciências sociais, junto ao projeto Interdisciplinar-Pedagogia, no Programa Institucional de Bolsa de Iniciação à Docência (PIBID)/CAPES-UFPR. A atuação dos graduandos em duas escolas da rede pública de Curitiba-PR privilegiou a construção e a implementação conjunta de um plano de ação em direitos humanos e redes de solidariedade na comunidade. Os trabalhos de intervenção foram desenvolvidos apoiados na proposta de pesquisa participante de Orlando Fals Borda, nos aportes filosóficos da educação conscientizadora de Paulo Freire e na perspectiva teórico-metodológica da psicologia social comunitária latino-americana. Foram realizadas, com os participantes do projeto, reuniões e oficinas semanais de capacitação, grupos focais temáticos e conversações críticas avaliativas. As informações obtidas foram sistematizadas e submetidas à análise de conteúdo, nos seguintes eixos: razões para ingresso no projeto Pibid; atividades realizadas e metodologias para formação e sensibilização; e dificuldades sentidas nas atividades e geração dos produtos. O desenvolvimento das atividades contribuiu para um envolvimento e compromisso com a realidade educacional, colaborando para a quebra de mitos a respeito dessa realidade, com a diminuição de receios e eliminação de preconceitos sobre as escolas públicas. Observou-se que as práticas participativas, comunitárias e educacionais fortaleceram uma proximidade entre universidade e escola, colocando a docência como possível escolha futura desses estudantes e, consequentemente, colaborando para o reconhecimento social do trabalho do professor

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI

Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access Article under the CC BY 4.0 license. Background: Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods: The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings: Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation: Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI. Funding: Bill & Melinda Gates Foundation

Determinants of intensive insulin therapeutic regimens in patients with type 1 diabetes: data from a nationwide multicenter survey in Brazil

Background: To evaluate the determinants of intensive insulin regimens (ITs) in patients with type 1 diabetes (T1D).Methods: This multicenter study was conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 3,591 patients (56.0% female, 57.1% Caucasian). Insulin regimens were classified as follows: group 1, conventional therapy (CT) (intermediate human insulin, one to two injections daily); group 2 (three or more insulin injections of intermediate plus regular human insulin); group 3 (three or more insulin injections of intermediate human insulin plus short-acting insulin analogues); group 4, basal-bolus (one or two insulin injections of long-acting plus short-acting insulin analogues or regular insulin); and group 5, basal-bolus with continuous subcutaneous insulin infusion (CSII). Groups 2 to 5 were considered IT groups.Results: We obtained complete data from 2,961 patients. Combined intermediate plus regular human insulin was the most used therapeutic regimen. CSII was used by 37 (1.2%) patients and IT by 2,669 (90.2%) patients. More patients on IT performed self-monitoring of blood glucose and were treated at the tertiary care level compared to CT patients (p < 0.001). the majority of patients from all groups had HbA1c levels above the target. Overweight or obesity was not associated with insulin regimen. Logistic regression analysis showed that economic status, age, ethnicity, and level of care were associated with IT (p < 0.001).Conclusions: Given the prevalence of intensive treatment for T1D in Brazil, more effective therapeutic strategies are needed for long term-health benefits.Farmanguinhos/Fundacao Oswaldo Cruz/National Health MinistryBrazilian Diabetes SocietyFundacao do Amparo a Pesquisa do Estado do Rio de JaneiroConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Estado Rio de Janeiro, Unit Diabet, BR-20551030 Rio de Janeiro, BrazilBaurus Diabet Assoc, São Paulo, BrazilFed Univ São Paulo State, Diabet Unit, São Paulo, BrazilFed Univ Hosp Porto Alegre, Porto Alegre, BrazilUniv Hosp São Paulo, Diabet Unit, São Paulo, BrazilUniv Fed Rio de Janeiro, Rio de Janeiro, BrazilUniv Fed Ceara, Fortaleza, Ceara, BrazilSanta Casa Misericordia, Belo Horizonte, MG, BrazilSanta Casa Misericordia São Paulo, São Paulo, BrazilUniv Fed Amazonas, Manaus, Amazonas, BrazilHosp Geral de Bonsucesso, Rio de Janeiro, BrazilHosp Univ Clementino Fraga Filho IPPMG, Rio de Janeiro, BrazilUniv Hosp São Paulo, São Paulo, BrazilFac Ciencias Med Santa Casa São Paulo, São Paulo, BrazilUniv São Paulo, Inst Crianca, Hosp Clin, São Paulo, BrazilUniv São Paulo, Fac Med Ribeirao Preto, Hosp Clin, Ribeirao Preto, BrazilAmbulatorio Fac Estadual Med Sao Jose Rio Preto, Ribeirao Preto, BrazilEscola Paulista Med, Ctr Diabet, Ribeirao Preto, BrazilClin Endocrinol Santa Casa Belo Horizonte, Belo Horizonte, MG, BrazilUniv Estadual Londrina, Londrina, BrazilUniv Fed Parana, Hosp Clin, Porto Alegre, RS, BrazilInst Crianca Com Diabet Rio Grande Sul, Rio Grande Do Sul, RS, BrazilGrp Hosp Conceicao, Inst Crianca Com Diabet, Porto Alegre, RS, BrazilHosp Univ Santa Catarina, Florianopolis, SC, BrazilInst Diabet Endocrinol Joinville, Joinville, BrazilHosp Reg Taguatinga, Brasilia, DF, BrazilHosp Geral Goiania, Goiania, Go, BrazilCtr Diabet & Endocrinol Estado Bahia, Goiania, Go, BrazilUniv Fed Maranhao, Sao Luis, BrazilCtr Integrado Diabet & Hipertensao Ceara, Fortaleza, Ceara, BrazilUniv Fed Sergipe, Aracaju, BrazilHosp Univ Alcides Carneiro, Campina Grande, BrazilHosp Univ Joao de Barros Barreto, Belem, Para, BrazilFed Univ São Paulo State, Diabet Unit, São Paulo, BrazilUniv Hosp São Paulo, Diabet Unit, São Paulo, BrazilUniv Hosp São Paulo, São Paulo, BrazilEscola Paulista Med, Ctr Diabet, Ribeirao Preto, BrazilWeb of Scienc