Modelos de sobrevivência com fração de cura e erro de medida nas covariáveis

In this work, we study the survival cure rate model proposed by Yakovlev et al. (1993), based on a competing risks structure concurring to cause the event of interest, and the approach proposed by Chen et al. (1999), where covariates are introduced to model the risk amount. We focus the measurement error covariates topics, considering the use of corrected score method in order to obtain consistent estimators. A simulation study is done to evaluate the behavior of the estimators obtained by this method for finite samples. The simulation aims to identify not only the impact on the regression coefficients of the covariates measured with error (Mizoi et al. 2007) but also on the coefficients of covariates measured without error. We also verify the adequacy of the piecewise exponential distribution to the cure rate model with measurement error. At the end, model applications involving real data are made

Modelos de sobrevivência com fração de cura e omissão nas covariáveis

In this work we study the survival cure rate model proposed by Yakovlev (1993) that are considered in a competing risk setting. Covariates are introduced for modeling the cure rate and we allow some covariates to have missing values. We consider only the cases by which the missing covariates are categorical and implement the EM algorithm via the method of weights for maximum likelihood estimation. We present a Monte Carlo simulation experiment to compare the properties of the estimators based on this method with those estimators under the complete case scenario. We also evaluate, in this experiment, the impact in the parameter estimates when we increase the proportion of immune and censored individuals among the not immune one. We demonstrate the proposed methodology with a real data set involving the time until the graduation for the undergraduate course of Statistics of the Universidade Federal do Rio Grande do Norte

Estimação em modelos de tempo de falha acelerado para dados de sobrevivência correlacionados

We presented in this work two methods of estimation for accelerated failure time models with random e_ects to process grouped survival data. The _rst method, which is implemented in software SAS, by NLMIXED procedure, uses an adapted Gauss-Hermite quadrature to determine marginalized likelihood. The second method, implemented in the free software R, is based on the method of penalized likelihood to estimate the parameters of the model. In the _rst case we describe the main theoretical aspects and, in the second, we briey presented the approach adopted with a simulation study to investigate the performance of the method. We realized implement the models using actual data on the time of operation of oil wells from the Potiguar Basin (RN / CE).

Resposta celular Th1 /Th2 na doença periodontal experimental, em ratos: um estudo imuno-histoquímico

Host response plays a major role in the pathogenesis of periodontal disease. Mediators such as inflammatory cytokines which are secreted during the immune response to bacterial challenges have ambiguous functions that may or may not lead to protection of the attacked tissue. In this context, experimental evidence suggests that T-helper 1 (Th-1) and T-helper 2 (Th-2) mediated responses are potentially important during the disease process. The aims of this study therefore were to further clarify the role played by Th2 cells during different time points of the active phase of periodontal disease, as well as, to investigate whether there was any evidence of a Th1 response in the periodontal disease microenvironment. Experimental periodontitis was induced in 30 Wistar male rats by placing cotton ligatures around the mandibular first molars. The rats were then randomly divided into two groups. Group1 (G1=15) and Group 2 (G2=15). In G1 the ligatures were maintained for 2 days, whereas in G2 the ligatures were left for 15 days, a time point that corresponds to the advanced stage of periodontal disease The contra-lateral teeth served as controls (no ligatures). Immunohistochemical investigation for the presence in gingival tissue of Th2 specific transcription factor (GATA3) and the subunit of the IFN-γ receptor was carried out after the disease induction period. Light microscopy analysis revealed a decrease in the expression of GATA-3 as bone loss progressed. On the other hand, although IFN-γ R1 was detected at an early stage of the active phase of disease its expression remained unaltered during the remaining period of the study. These results indicate that the Th2 response have a protective role during the pathogenesis of periodontal disease and that the progression of the periodontal disease is related with the unbalance of the responses Th1/Th2

Estudo da detecção do DNA do papiloma vírus humano (HPV) e da expressão imuno-histoquímica de proteína do ciclo celular no carcinoma epidermóide oral

Oral squamous cell carcinoma (OSCC) is the most common malignancy in oral cavity and human papillomavirus (HPV) may have an important role in its development. The aim of this experiment was to investigate the HPV DNA and viral types in 90 cases of OSCC. Moreover, a comparative analysis between the cases of OSSC with and without HPV DNA was performed by using cell cycle markers p21 and pRb in order to detect a possible correlation of these proteins and HPV infection. DNA was extracted from paraffin embedded tissue and amplified by PCR (polymerase chain reaction) with primers PCO3+ e PCO4+ for a fragment of human β-globin gene. After this procedure, PCR for HPV DNA detection was realized using a pair of generic primers GP5+ e GP6+. Immunohistochemical study was performed by streptoavidin-biotin technique and antibodies against p21 and pRb proteins were employed. Eighty-eight cases were positive for human β-globin gene and HPV DNA was found in 26 (29.5%) of then. It could not be detected significant correlation between HPV and age, sex and anatomical sites of the lesion. The most prevalent viral type was HPV 18 (80.8%). Regarding the immunohistochemical analysis, it was detected significant association between HPV presence and pRb immunoexpression (p=0,044), nevertheless, the same was not observed in relation to p21 protein (p =0,416). It can be concluded that the low detection of HPV DNA in OSCC by the present experiment suggests a possible role of the virus in the development and progression in just a subset of this disease

Estimação de parâmetros genéticos para resistência à infecção por IMNV em camarões Litopenaeus vannamei por meio de análise de sobrevivência

The main specie of marine shrimp raised at Brazil and in the world is Litopenaeus vannamei, which had arrived in Brazil in the `80s. However, the entry of infectious myonecrosis virus (IMNV), causing the infectious myonecrosis disease in marine shrimps, brought economic losses to the national shrimp farming, with up to 70% of mortality in the shrimp production. In this way, the objective was to evaluate the survival of shrimps Litopenaeus vannamei infected with IMNV using the non parametric estimator of Kaplan-Meier and a model of frailty for grouped data. It were conducted three tests of viral challenges lasting 20 days each, at different periods of the year, keeping the parameters of pH, temperature, oxygen and ammonia monitored daily. It was evaluated 60 full-sib families of L. vannamei infected by IMNV in each viral challenge. The confirmation of the infection by IMNV was performed using the technique of PCR in real time through Sybr Green dye. Using the Kaplan-Meier estimator it was possible to detect significant differences (p <0.0001) between the survival curves of families and tanks and also in the joint analysis between viral challenges. It were estimated in each challenge, genetic parameters such as genetic value of family, it`s respective rate risk (frailty), and heritability in the logarithmic scale through the frailty model for grouped data. The heritability estimates were respectively 0.59; 0.36; and 0.59 in the viral challenges 1; 2; and 3, and it was also possible to identify families that have lower and higher rates of risk for the disease. These results can be used for selecting families more resistant to the IMNV infection and to include characteristic of disease resistance in L. vannamei into the genetic improvement programs

Avaliação genética da eficiência reprodutiva em vacas pardo-suíças por meio da análise de sobrevivência

Among the traits of economic importance to dairy cattle livestock those related to sexual precocity and longevity of the herd are essential to the success of the activity, because the stayability time of a cow in a herd is determined by their productive and reproductive lives. In Brazil, there are few studies about the reproductive efficiency of Swiss-Brown cows and no study was found using the methodology of survival analysis applied to this breed. Thus, in the first chapter of this study, the age at first calving from Swiss-Brown heifers was analyzed as the time until the event by the nonparametric method of Kaplan-Meier and the gamma shared frailty model, under the survival analysis methodology. Survival and hazard rate curves associated with this event were estimated and identified the influence of covariates on such time. The mean and median times at the first calving were 987.77 and 1,003 days, respectively, and significant covariates by the Log-Rank test, through Kaplan-Meier analysis, were birth season, calving year, sire (cow s father) and calving season. In the analysis by frailty model, the breeding values and the frailties of the sires (fathers) for the calving were predicted modeling the risk function of each cow as a function of the birth season as fixed covariate and sire as random covariate. The frailty followed the gamma distribution. Sires with high and positive breeding values possess high frailties, what means shorter survival time of their daughters to the event, i.e., reduction in the age at first calving of them. The second chapter aimed to evaluate the longevity of dairy cows using the nonparametric Kaplan-Meier and the Cox and Weibull proportional hazards models. It were simulated 10,000 records of the longevity trait from Brown-Swiss cows involving their respective times until the occurrence of five consecutive calvings (event), considered here as typical of a long-lived cow. The covariates considered in the database were age at first calving, herd and sire (cow s father). All covariates had influence on the longevity of cows by Log-Rank and Wilcoxon tests. The mean and median times to the occurrence of the event were 2,436.285 and 2,437 days, respectively. Sires that have higher breeding values also have a greater risk of that their daughters reach the five consecutive calvings until 84 months

Caracaterização do núcleo pré-geniculado do sagüi (Callithrix jacchus) :projeção retiniana, neuroquímica e atividade celular (expressão de FOS)

In rodents, the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) are the main components of the circadian system. The SCN is considerate the site of an endogenous biological clock because can to generate rhythm and to synchronize to the environmental cues (zeitgebers) and IGL has been related as one of the main areas that modulate the action of SCN. Both receive projections of ganglion cells of retina and this projection to SCN is called retinohypothalamic tract (RHT). Moreover, the IGL is connected with SCN through of geniculohypothalamic tract (GHT). In primates (include humans) was not still demonstrated the presence of a homologous structure to the IGL. It is believed that the pregeniculate nucleus (PGN) can be the answer, but nothing it was still proven. Trying to answer that question, the objective of our study is to do a comparative analysis among PGN and IGL through of techniques immunohystochemicals, neural tracers and FOS expression after dark pulses. For this, we used as experimental model a primate of the new world, the common marmoset (Callithrix jacchus). Ours results may contribute to the elucidation of this lacuna in the circadian system once that the IGL is responsible for the transmission of nonphotic information to SCN and participate in the integration between photic and nonphotic stimulus to adjust the function of the SCN. In this way to find a same structure in primates represent an important achieve in the understanding of the biological rhythms in those animals

Testes de hipóteses em modelos de sobrevivência com Fração de cura

Survival models deals with the modeling of time to event data. However in some situations part of the population may be no longer subject to the event. Models that take this fact into account are called cure rate models. There are few studies about hypothesis tests in cure rate models. Recently a new test statistic, the gradient statistic, has been proposed. It shares the same asymptotic properties with the classic large sample tests, the likelihood ratio, score and Wald tests. Some simulation studies have been carried out to explore the behavior of the gradient statistic in fi nite samples and compare it with the classic statistics in diff erent models. The main objective of this work is to study and compare the performance of gradient test and likelihood ratio test in cure rate models. We first describe the models and present the main asymptotic properties of the tests. We perform a simulation study based on the promotion time model with Weibull distribution to assess the performance of the tests in finite samples. An application is presented to illustrate the studied concepts

A distribuição F generalizada para selecionar modelos de sobrevivência com fração de cura

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Os efeitos das queimadas na Amazônia em nível celular e molecular

The Amazon holds over half of the planet's remaining tropical forests and comprises the largest biodiversity in the world, accounting for approximately 60 % of the Brazilian territory. However, deforestation fires in the region causes serious problems to exposed human. The aim of this study was to evaluate the chemical compounds as well as the cellular and molecular effects after exposure to organic material extracted from particulate matter less than 10 µm (PM10) in the Amazon region. As for the chemical composition, n-alkanes analysis showed a prevalence of anthropogenic influence during the fires in the region. In addition, there was a predominance of monosaccharides from biomass burning markers. Also, the Polycyclic Aromatic Hydrocarbons (PAH) and their derivatives have also been identified in samples collected in the Amazon. By using the PAH concentrations was possible to calculate the BaP-equivalent and it was found that the dibenz(a) anthracene contributes with 83% to potential carcinogenic risk. As for the potential mutagenic risk, the benzo (a) pyrene is the HPA that has a major contribution in this analysis. It may be noted that the retene was the most abundant PAH. This compound was genotoxic and cause death by necrosis in the human lung cells. In biological tests, the data showed that organic PM10 is capable of causing genetic damage in both plant cells and in human lung cells. This damage cause an arrest in the G1 phase of the cell cycle exposed, increasing the expression of p53 and p21. Additionally, the PM10 caused cell death by apoptosis, increasing the foci of histone - H2AX. Given these results, it is important to emphasize the reduction and better control of biomass burning in the Amazon region thus improving the quality of health of the population being exposed. As clearly stated recently by the World Health Organization, the reduction of air pollution could save millions of lives annually.

Conservação de material genético de espécies silvestres do bioma caatinga utilizando a manipulação oócitos inclusos em folículos ovarianos pré antrais (MOIFOPA)

The objective of the present thesis was to use the manipulation of oocytes enclosed in preantral follicles (MOEPF) as a tool for the female gametes rescue and optimization, from wild species of Caatinga biome. The thesis was divided into 4 experiments. At first experiment, it was performed the estimative and description of the agouti (Dasyprocta leporina) preantral follicles (PF) histologic and ultrastructural features, in which it was estimated 4419.8 ± 532.26 and 5397.52 ± 574.91 follicles for the right and left ovary, respectively, and the majority (86,63%) belonged to the primordial follicles category (P<0.05). Most of the population consists of morphologically normal follicles (70.78%), presenting a large and central nuclei and uniform cytoplasm. At ultrastructural evaluation it was verified the presence of a great number of round mitochondrias associated to lipid droplets. In the second experiment, it was performed the estimative and description of yellow-toothed cavies (Galea spixii) PF characteristics, also, the evaluation of the effect of solid surface vitrification (SSV) on the in situ PF morphology. The total of 416.0 ± 342.8 PF was estimated for the ovary pair and the presence of a large quantity of primary follicles (P<0.05) was evidenced. Most of the PF was morphologically normal (94.6%), in which the oocyte nuclei presented condensed granules of heterochromatin. Round or elongated shaped mitochondria constituted the most abundant organelles. In regard of the SSV, the protocol using the dimethylsulfoxide (DMSO) 3M possibility the preservation of 69.5% of morphologically normal PF, which was evidenced by the light and transmission electronic microscopy. At third experiment, the evaluation of the SSV procedure on the morphology and viability in situ PF form collared peccaries (Pecari tajacu) was performed. No differences were observed among treatments, in which the use of DMSO, ethylene glycol (EG) and dimethylformamide (DMF) as cryoprotectants, regardless its concentration, promoted the morphology preservation of much than 70% of PF. Concerning the PF viability, the DMSO and EG promoted the best preservation. The fourth experiment aimed to evaluate the effect of α MEM+ or TCM199 associated or not to 50 ng of FSHr on the morphology, activation and growth of collared peccaries PF, in vitro cultured (IVC) during 1 or 7 days and the effect on the extracellular matrix (ECM). After 7 days of IVC only the use of TCM199/FSH maintained the proportion of intact PF, similar to day 1(63.2%), however, no differences were observed among treatments (P>0.05). Also, an improvement of the proportion of intact growing PF was verified (P>0.05). By the Ag-NOR analysis it was observed that only the treatment using TCM199/FSH promoted the maintenance of cell proliferation similar to day 1 (P>0.05). The picrosirius red stain revealed that ECM remained intact in all treatments (P>0.05). Thus, as the general conclusion, the use of MOEPF in the refereed species allowed the knowledge of aspects related to its reproductive morphology and physiology, enabling the germplasm conservation, with the possibility of germplasm bank formation, as the elucidation of mechanisms related to the PF survive and in vitro development.

Moléculas coestimulatórias na leishmaniose visceral

Visceral leishmaniasis (VL) is endemic in many countries, including Brazil. The protozoan Leishmania infantum, is the etiological agent of VL, and is transmitted by the bite of female sandflies during the blood meal. The majority of subjects when exposed to the parasite do not develop the disease, because of development of Th1 cellular responses. Those who have develop signs of VL such as fever, weight loss, hepatosplenomegaly, have impairment of the cellular immune response, specific to the Leishmania antigens. We evaluated whether the specififc anergy during symptomatic VL, may be associated with changes in T cells costimulatory molecules or their ligands in CD14+ monocytes. There is an increase in CTLA-4 porcentage on CD4+ T lymphocytes (p=0.001) and ICOS on CD4+ and CD8+ T cells (p=0.002 to CD4+ and p=0.003 to CD8+), after stimulation by soluble Leishmania antigen (SLA) during active visceral leishmaniasis, and that there is a higher percentage of these molecules ex vivo, when comparing symptomatic to recovered individuals (p=0.04 to CTLA-4 in CD4+, and p=0.001 to ICOS in CD4+ and p=0.026 to CD8+). Moreover, we found a high gene expression of CTLA-4, OX-40 and ICOS during active VL. CD40, CD80, CD86, HLA-DR and ICOSL molecules do not suffer changes during disease. There is IFN-γ production by the peripheral blood cells, after SLA stimulation, by peripheral blood cells in symptomatic subjects; however, there is a decrease of the ratio IFN-γ/IL-10, which is reversed after clinical recovery. The impairment of some costimulatory molecules pathways during symptomatic VL could inhibit the ability of phagocytes to kill Leishmania and could facilitate their survival and the proliferation inside macrophages.

Avaliação do efeito da inibição do reparo de sítios abásicos na resposta inflamatória celular

Base excision repair (BER) proteins has been associated with functions beyond DNA repair. Apurynic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein involved in a plethora of cellular activities, such as redox activation of transcription factors, RNA processing and DNA repair. Some studies have described the action of the protein 8-oxoguanine (OGG1) in correcting oxidized lesions in promoters as a step in the transcription of pro-inflammatory cytokines. Despite being especially important in redox activation of transcription factors such as nuclear factor κB (NF-κB) and AP- 1, the repair activity of APE1 has not yet been associated with the inflammatory response. In this study, experimental and bioinformatic analysis approaches have been used to investigate the relationship between inhibition of the repair of abasic sites in DNA by MX, a synthetic molecule designed to inhibt the repair activity of APE1, and the modulation of the inflammatory response. The results showed that treatment of monocytes with lipopolysaccharide (LPS) and MX reduced the expression of cytokines, chemokines and toll-like receptors, and negatively regulated biological immune processes, as macrophages activation, and NF-κB and tumor necrosis factor (TNF-α) and interferon pathways, without inducing cell death. The transcriptomic analysis suggests that LPS/MX treatment induces mitochondrial dysfunction, endoplasmic reticulum stress and activation of autophagy pathways, probably activated by impairment of cellular energy and/or the accumulation of nuclear and mitochondria DNA damage. Additionally, it is proposed that the repair activity of APE1 is required for transcription of inflammatory genes by interaction with abasic sites at specific promoters and recruitment of transcriptional complexes during inflammatory signaling. This work presents a new perspective on the interactions between the BER activity and the modulation of inflammatory response, and suggests a new activity for APE1 protein as modulator of the immune response in a redox-independent manner.

“Acham que brotamos das fontes dessa cidade?”: uma etnografia sobre o cotidiano de sobrevivência de pessoas em situação de rua em Nata/RN

Through participant observation, held in the administrative region east of Natal / RN, this research aimed to understand about the daily life of men and women living on the streets in the city. How they relate to the space where they live? In this relationship, which uses and survival strategies triggered by this social segment? These were some of the questions that guided this research, in order to highlight the specificities of this way of life and the possible consequences that such a situation could reverberate. In this sense, there was an effort to keep up with people on the streets, their itineraries and seize their narratives. Along the search path - which took place intermittently between the years 2011-2015 - attended spaces of occupation and traffic of this population group in the street, as well as insert me and got involved in events, forums, seminars, meetings and subject of joints on the streets as a political movement (MNPR / RN). They are considered in this study as people on the street to those who occupy the street as their main space of survival and ordering of daily life: in the streets sleep, feed themselves, meet the physiological and hygienic needs, and is where draw sustenance. The street is taken in this research in its broadest sense, including all possible places relatively protected from the cold, rain and exposure to violence, thus includes both open and public spaces: as squares and parks; but also closed and private places: hostels, abandoned warehouses, prisons, etc. It was observed that in none of these spaces guys on the street are established in a fixed manner, in contrast, they experience the roaming, which in part is due to urban systems - which tends to stigmatize them and delete them places - and the very need to survive, because while living in the street differentiated practices are triggered, and these differ from the dominant mode of sedentary life.