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Prevalence of chronic kidney disease and comorbidities in isolated African descent communities (PREVRENAL): methodological design of a cohort study
No full textAbstract\ud
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Background\ud
Chronic kidney disease (CKD) is considered a serious public health problem, both in Brazil and worldwide, with an increasing number of cases observed inrecent years. Especially, CKD has been reported to be highly prevalent in those of African descent. However, Brazil lacks data from early-stage CKD population studies, and the prevalence of CKD is unknown for both the overall and African descent populations. Hence, the present study aimsto estimate the prevalence of early-stage CKD and its associated risk factors in African-Brazilians from isolated African-descent communities. Herein, the detailed methodology design of the study is described.\ud
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Methods\ud
This population-based, prospective, longitudinal, cohort study (PREVRENAL) is performed in three stages: first, clinical, nutritional, and anthropometric evaluations; measurements of serum and urinary markers; and examinations of comorbiditieswere performed. Second, repeated examinations of individuals with CKD, systemic arterial hypertension, and/or diabetes mellitus; image screening; and cardiac risk assessment were performed. Third, long-term monitoring of all selected individuals will be conducted (ongoing). Using probability sampling, 1539 individuals from 32 communities were selected. CKD was defined asaglomerular filtration rate (GFR) ≤60 mL/min/1.73m2 and albuminuria > 30 mg/day.\ud
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Discussion\ud
This study proposes to identify and monitor individuals with and without reduced GFR and high albuminuria in isolated populations of African descendants in Brazil. As there are currently no specific recommendations for detecting CKD in African descendants, four equations for estimating the GFR based on serum creatinine and cystatin C were used and will be retrospectively compared. The present report describes the characteristics of the target population, selection of individuals, and detection of a population at risk, along with the imaging, clinical, and laboratory methodologies used. The first and second stages have been concluded and the results will be published in the near future. The subsequent (third) stage is the long-term, continuous monitoring of individuals diagnosed with renal abnormalities or with CKD risk factors. The entire study population will be re-evaluated five years after the study initiation. The expectation is to obtain information about CKD evolution among this population, including the progression rate, complication development, and cardiovascular events.This study was funded by the Research Support Foundation of Maranhão (Fundação de Amparo a Pesquisa do Maranhão – FAPEMA)
The tyrosine kinase inhibitor nilotinib is more efficient than mitotane in decreasing cell viability in spheroids prepared from adrenocortical carcinoma cells
No full textAbstract\ud
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Background\ud
New drugs for adrenocortical carcinoma (ACC) are needed because most patients undergo rapid disease progression despite surgery and adjuvant therapy with mitotane. In this study, we aimed to investigate the in vitro effects of different chemotherapy drugs, alone or combined with mitotane, on the viability of adrenocortical carcinoma cells.\ud
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Methods\ud
Everolimus, sunitinib, zoledronic acid, imatinib and nilotinib cytotoxicity, alone or combined with mitotane were tested on ACC H295R cells in monolayer or spheroid cultures using MTS assays and confocal microscopy. Moreover, the nilotinib effects were investigated in spheroids cultured from patient tumor-derived ACC-T36 cells.\ud
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Results\ud
Morphological characterization of H295R cell spheroids using histochemistry was performed and showed that dense, homogenously sized, multicellular spheroids were obtained. We observed that sunitinib and nilotinib alone were equally effective in a monolayer preparation, whereas mitotane was the most effective even at a low dose. A combination of sunitinib and mitotane was the most effective treatment, with only 23.8% of cells in the monolayer remaining viable. Spheroid preparations showed resistance to different drugs, although the poor effect produced by mitotane alone was surprising, with a cell viability of 84.6% in comparison with 13.1% in monolayer cells. The most ineffective drugs in spheroid preparations were everolimus, zoledronic acid and imatinib. In both cell types, nilotinib, either alone or in combination with mitotane induced more significant cell viability inhibition in monolayer and spheroid preparations. In addition, the mechanism of nilotinib activity involves the ERK1/2 pathway.\ud
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Conclusion\ud
Taken together, our data identified nilotinib as a cytotoxic drug that combined with ERK inhibitors deserves to be tested as a novel therapy for adrenocortical carcinoma.This work was supported by FAPESP, the São Paulo State Research Foundation (nº 2011/07656-3 and 2015/014199-9). CFPL received funding from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and ES and IPC were recipients of scholarships from Capes (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior)
Endoplasmic reticulum stress activation in adipose tissue induces metabolic syndrome in individuals with familial partial lipodystrophy of the Dunnigan type
No full textAbstract\ud
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Background\ud
Familial partial lipodystrophy of the Dunnigan type is one of the most common inherited lipodystrophies variables. These individuals have important metabolic disorders that cause predisposition to various diseases. In this study we aimed to demonstrate the relation between the metabolic abnormalities, inflammatory profile and the expression of genes involved in the activation of the endoplasmic reticulum stress (ERS) in subjects with FPLD.\ud
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Methods\ud
We evaluated 14 female FPLD patients and compared with 13 female healthy individuals. The subjects were paired with their respective BMI and age and categorized into two groups: Familial partial lipodystrophy of the Dunnigan type (FPLD) and control. Patients were fasted for 12 h before blood collection for measurement of HbA1c, glucose, insulin, lipids and inflammatory markers. Subcutâneous adipose tissue was collected by puncture aspiration of submental region during ambulatorial surgical aesthetic procedure.\ud
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Results\ud
We demonstrate that patients with FPLD show increased HbA1c (p < 0.01), fasting glucose (p < 0.002) and triglycerides (p < 0.005) while HDL/cholesterol (p < 0.001) was lower when compared to healthy individuals. We found that 64.2% FPLD patients had metabolic syndrome according to International Diabetes Federation definition. We also observe increased AUC of glucose (p < 0.001) and insulin during oGTT, featuring a frame of hyperglycemia and hyperinsulinemia, suggesting insulin resistance. Also we found hyperactivation of several genes responsible for ERS such as ATF-4 (p < 0.01), ATF-6 (p < 0.01), EIF2α3K (p < 0.005), CCT4 (p < 0.001), CHOP (p < 0.01), CALR (p < 0.001) and CANX (p < 0.005), that corroborate the idea that diabetes mellitus and metabolic syndrome are associated with direct damage to the endoplasmic reticulum homeostasis. Ultimately, we note that individuals with lipodystrophy have an increase in serum interleukins, keys of the inflammatory process, as IL-1β, TNF-α and IL-6 (p < 0.05 all), compared with healthy individuals, which can be the trigger to insulin resistance in this population.\ud
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Conclusion\ud
Individuals with FPLD besides having typical dysfunctions of metabolic syndrome, show a hyperactivation of ERS associated with increased systemic inflammatory profile, which together may explain the complex clinical aspect of this diseases.\ud
Trial registration HCRP no 6711/2012FAEPA
Influences of weight, age, gender, genetics, diseases, and ethnicity on bitterness perception: a narrative review of current methodological aspects
No full textAbstract\ud
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Background\ud
Bitterness perception seems to be related to an enhanced intake of dietary fat and to a tendency to the development of diseases such as obesity. However, the exact factors for this possible contribution still need to be better investigated. So, gustatory perception of the bitter taste is a promising area of study because of its importance regarding food choices and consequently feeding behavior. Therefore, this short review focused on recent papers reporting correlations between bitter taste, anthropometric variables, obesity and other chronic diseases, age, gender, ethnicity, and genetics.\ud
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Methods\ud
A survey was performed in MEDLINE (PubMed) and Scielo from September 2015 to January 2017. Only review articles, observational studies and clinical trials published in English and Portuguese over the last 15 years which met the objectives of the present study were considered. A total of 40 papers were evaluated.\ud
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Results\ud
Two papers showed a positive correlation between bitter taste and obesity, one indicated that this correlation is influenced by the subject’s age, one suggested a negative correlation, and two found no association. Age seems to be negatively correlated with the bitterness perceived, and female gender was associated with a stronger perception of bitterness. Genetics, mostly due to differences in TAS2R38 expression, influences sensitivity to the bitter taste, feeding behavior and also alcohol intake. Ethnicity, not only the subject’s phenotypic or genotypic characteristics, seems to play a role in taste perception and nutritional diseases.\ud
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Conclusions\ud
Age, gender, genetics and ethnicity seem to play a role in bitterness perception. Data about associations between bitterness perception and anthropometrics are conflicting.AA received a scholarship from the São Paulo Research Foundation - FAPESP, process 2015/00403-3. SS received a scholarship from the National Council of Technological and Scientific Development - CNPq (PIBIC). JSM received a productivity scholarship from the National Council of Technological and Scientific Development – CNPq, process 304127/2009-4. The other authors have nothing to declare
Imatinib-induced fulminant liver failure in chronic myeloid leukemia: role of liver transplant and second-generation tyrosine kinase inhibitors: a case report
No full textAbstract\ud
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Background\ud
There is a worldwide problem of acute liver failure and mortality associated with remaining on the waiting for a liver transplant. In this study, we highlight results published in recent years by leading transplant centers in evaluating imatinib-induced acute liver failure in chronic myeloid leukemia and follow-up in liver transplantation.\ud
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Case presentation\ud
A 36-year-old brown-skinned woman (mixed Brazilian race) diagnosed 1 year earlier with chronic myeloid leukemia was started after delivery of a baby and continued for 6 months with imatinib mesylate (selective inhibitor of Bcr-Abl tyrosine kinase), which induced liver failure. We conducted a literature review using the PubMed database for articles published through September 2017, and we demonstrate a role of liver transplant in this situation for imatinib-induced liver failure. We report previously published results and a successful liver transplant after acute liver failure due to imatinib-induced in chronic myeloid leukemia treatment.\ud
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Conclusions\ud
We report a case of a successful liver transplant after acute liver failure resulting from imatinib-induced chronic myeloid leukemia treatment. The literature reveals the importance of prompt acute liver failure diagnosis and treatment with liver transplant in selected cases
Assessment of asymptomatic Plasmodium spp. infection by detection of parasite DNA in residents of an extra-Amazonian region of Brazil
No full textAbstract\ud
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Background\ud
The hypotheses put forward to explain the malaria transmission cycle in extra-Amazonian Brazil, an area of very low malaria incidence, are based on either a zoonotic scenario involving simian malaria, or a scenario in which asymptomatic carriers play an important role.\ud
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Objectives\ud
To determine the incidence of asymptomatic infection by detecting Plasmodium spp. DNA and its role in residual malaria transmission in a non-Amazonian region of Brazil.\ud
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Methods\ud
Upon the report of the first malaria case in 2010 in the Atlantic Forest region of the state of Espírito Santo, inhabitants within a 2 km radius were invited to participate in a follow-up study. After providing signed informed consent forms, inhabitants filled out a questionnaire and gave blood samples for PCR, and thick and thin smears. Follow-up visits were performed every 3 months over a 21 month period, when new samples were collected and information was updated.\ud
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Results\ud
Ninety-two individuals were initially included for follow-up. At the first collection, all of them were clearly asymptomatic. One individual was positive for Plasmodium vivax, one for Plasmodium malariae and one for both P. vivax and P. malariae, corresponding to a prevalence of 3.4% (2.3% for each species). During follow-up, four new PCR-positive cases (two for each species) were recorded, corresponding to an incidence of 2.5 infections per 100 person-years or 1.25 infections per 100 person-years for each species. A mathematical transmission model was applied, using a low frequency of human carriers and the vector density in the region, and calculated based on previous studies in the same locality whose results were subjected to a linear regression. This analysis suggests that the transmission chain is unlikely to be based solely on human carriers, regardless of whether they are symptomatic or not.\ud
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Conclusion\ud
The low incidence of cases and the low frequency of asymptomatic malaria carriers investigated make it unlikely that the transmission chain in the region is based solely on human hosts, as cases are isolated one from another by hundreds of kilometers and frequently by long periods of time, reinforcing instead the hypothesis of zoonotic transmission.This project was financed by the State of Espírito Santo Research Founda‑\ud
tion (FAPES) (Grant No. 45617600/2009) and the State of São Paulo Research\ud
Foundation (FAPESP) (Grant No. 10/50707-5)
Impact of diabetes mellitus on ischemic cardiomyopathy. Five-year follow-up. REVISION-DM trial
No full textAbstract\ud
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Background\ud
Patients with ischemic cardiomyopathy and severe left ventricular dysfunction have a worse survival prognosis than patients with preserved ventricular function. The role of diabetes in the long-term prognosis of this patient group is unknown. This study investigated whether the presence of diabetes has a long-term impact on left ventricular function.\ud
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Methods\ud
Patients with coronary artery disease who underwent coronary artery bypass graft surgery, percutaneous coronary intervention, or medical therapy alone were included. All patients had multivessel disease and left ventricular ejection fraction measurements. Overall mortality, nonfatal myocardial infarction, stroke, and additional interventions were investigated.\ud
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Results\ud
From January 2009 to January 2010, 918 consecutive patients were selected and followed until May 2015. They were separated into 4 groups: G1, 266 patients with diabetes and ventricular dysfunction; G2, 213 patients with diabetes without ventricular dysfunction; G3, 213 patients without diabetes and ventricular dysfunction; and G4, 226 patients without diabetes but with ventricular dysfunction. Groups 1, 2, 3, and 4, respectively, had a mortality rate of 21.6, 6.1, 4.2, and 10.6% (P < .001); nonfatal myocardial infarction of 5.3, .5, 7.0, and 2.6% (P < .001); stroke of .40, .45, .90, and .90% (P = NS); and additional intervention of 3.8, 11.7, 10.3, and 2.6% (P < .001).\ud
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Conclusion\ud
In this sample, regardless of the treatment previously received patients with or without diabetes and preserved ventricular function experienced similar outcomes. However, patients with ventricular dysfunction had a worse prognosis compared with those with normal ventricular function; patients with diabetes had greater mortality than patients without diabetes.\ud
Trial registration \ud
http://www.controlled-trials.com\ud
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. Registration Number: ISRCTN66068876Financial support for the present study was provided by the Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP) No 11-0169-11 and, in part, by a research grant from the Zerbini Foundation, São Paulo, Brazil. Medical writing support was provided by Ann Conti Morcos during the preparation of this paper, supported by the Zerbini Foundation
Palmitoleic acid (16:1n7) increases oxygen consumption, fatty acid oxidation and ATP content in white adipocytes
No full textAbstract\ud
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Background\ud
We have recently demonstrated that palmitoleic acid (16:1n7) increases lipolysis, glucose uptake and glucose utilization for energy production in white adipose cells. In the present study, we tested the hypothesis that palmitoleic acid modulates bioenergetic activity in white adipocytes.\ud
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Methods\ud
For this, 3 T3-L1 pre-adipocytes were differentiated into mature adipocytes in the presence (or absence) of palmitic (16:0) or palmitoleic (16:1n7) acid at 100 or 200 μM. The following parameters were evaluated: lipolysis, lipogenesis, fatty acid (FA) oxidation, ATP content, oxygen consumption, mitochondrial mass, citrate synthase activity and protein content of mitochondrial oxidative phosphorylation (OXPHOS) complexes.\ud
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Results\ud
Treatment with 16:1n7 during 9 days raised basal and isoproterenol-stimulated lipolysis, FA incorporation into triacylglycerol (TAG), FA oxidation, oxygen consumption, protein expression of subunits representing OXPHOS complex II, III, and V and intracellular ATP content. These effects were not observed in adipocytes treated with 16:0.\ud
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Conclusions\ud
Palmitoleic acid, by concerted action on lipolysis, FA esterification, mitochondrial FA oxidation, oxygen consumption and ATP content, does enhance white adipocyte energy expenditure and may act as local hormone.This work was supported by grants from FAPESP (2011/51627–8 and\ud
2011/51701–3)
Migration and tuberculosis transmission in a middle-income country: a cross-sectional study in a central area of São Paulo, Brazil
No full textAbstract\ud
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Background\ud
Little is known about the impact of growing migration on the pattern of tuberculosis (TB) transmission in middle-income countries. We estimated TB recent transmission and its associated factors and investigated the presence of cross-transmission between South American migrants and Brazilians.\ud
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Methods\ud
We studied a convenient sample of cases of people with pulmonary TB in a central area of São Paulo, Brazil, diagnosed between 2013 and 2014. Cases with similar restriction fragment length polymorphism (IS6110-RFLP) patterns of their Mycobacterium tuberculosis complex isolates were grouped in clusters (recent transmission). Clusters with both Brazilian and South American migrants were considered mixed (cross-transmission). Risk factors for recent transmission were studied using logistic regression.\ud
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Results\ud
Isolates from 347 cases were included, 76.7% from Brazilians and 23.3% from South American migrants. Fifty clusters were identified, which included 43% South American migrants and 60.2% Brazilians (odds ratio = 0.50, 95% confidence interval = 0.30–0.83). Twelve cross-transmission clusters were identified, involving 24.6% of all clustered cases and 13.8% of all genotyped cases, with migrants accounting for either an equal part or fewer cases in 11/12 mixed clusters.\ud
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Conclusions\ud
Our results suggest that TB disease following recent transmission is more common among Brazilians, especially among those belonging to high-risk groups, such as drug users. Cross-transmission between migrants and Brazilians was present, but we found limited contributions from migrants to Brazilians in central areas of São Paulo and vice versa.This work was supported by National Council for Scientific and Technological\ud
Development (CNPq) from Brazil (141998/2013-0, 202310/2015-9 to JMP and\ud
309647/2015-0 to EAW)
Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-δ/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity
No full textAbstract\ud
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Background\ud
Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis. In the present study, we investigated whether the chronic effects of Ang II via AT1 receptor (AT1R) would result in endoplasmic reticulum (ER) stress/PKC-delta/p38 MAPK stimulation, and consequently podocyte apoptosis.\ud
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Methods\ud
Wistar rats were treated with Ang II (200 ng·kg−1·min−1, 42 days) and or losartan (10 mg·kg−1·day−1, 14 days). Immortalized mouse podocyte were treated with 1 μM Ang II and/or losartan (1 μM) or SB203580 (0.1 μM) (AT1 receptor antagonist and p38 MAPK inhibitor) for 24 h. Kidney sections and cultured podocytes were used to evaluate protein expression by immunofluorescence and immunoblotting. Apoptosis was evaluated by flow cytometry and intracellular pH (pHi) was analyzed using microscopy combined with the fluorescent probe BCECF/AM.\ud
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Results\ud
Compared with controls, Ang II via AT1R increased chaperone GRP 78/Bip protein expression in rat glomeruli (p < 0.001) as well as in podocyte culture (p < 0.01); increased phosphorylated eIf2-α (p < 0.05), PKC-delta (p < 0.01) and p38 MAPK (p < 0.001) protein expression. Furthermore, Ang II induced p38 MAPK-mediated late apoptosis and increased the Bax/Bcl-2 ratio (p < 0.001). Simultaneously, Ang II via AT1R induced p38 MAPK-NHE1-mediated increase of pHi recovery rate after acid loading.\ud
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Conclusion\ud
Together, our results indicate that Ang II-induced podocyte apoptosis is associated with AT1R/ER stress/PKC-delta/p38 MAPK axis and enhanced NHE1-mediated pHi recovery rate.This work was supported by the Fundação de Amparo a Pesquisa do Estado\ud
de São Paulo (FAPESP) to Maria Oliveira-Souza (13/19569–3; 17/02020–0),\ud
Gerhard Malnic (13/23087–4), Vanessa Gerolde Cardoso (14/19154–0), Karina\ud
Thieme (14/17251–9), Fernando Augusto Malavazzi Casare (11/14022–0); by\ud
the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)\ud
to Mariana Charleaux de Ponte (14/151575–2) and Bruna Bezerra Lins\ud
(140141/2016–2); by Coordenação de Aperfeiçoamento de Pessoal de Nível\ud
Superior to Guilherme Lopes Gonçalves