Cathepsin S as a biomarker of low-grade inflammation, insulin resistance, and cardiometabolic disease risk

Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer.    The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations.    This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial.    In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol.    Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations. 

Water for life : the impact of the privatization of water services on child mortality

While most countries are committed to increasing access to safe water and thereby reducing child mortality, there is little consensus on how to actually improve water services. One important proposal under discussion is whether to privatize water provision. In the 1990s Argentina embarked on one of the largest privatization campaigns in the world including the privatization of local water companies covering approximately 30 percent of the country’s municipalities. Using the varia tion in ownership of water provision across time and space generated by the privatization process, we find that child mortality fell 8 percent in the areas that privatized their water services; and that the effect was largest (26 percent) in the poorest areas. We check the robustness of these estimates using cause specific mortality. While privatization is associated with significant reductions in deaths from infectious and parasitic diseases, it is uncorrelated with deaths from causes unrelated to water conditions.

Influência de fatores biopsicossociais sobre a mortalidade de idosos no município de Santa Cruz/RN: um estudo prospectivo

The aging process if characterizes for a complex events network, from multidimensional nature, that encloses biological, social, psychic and functional aspects. The alteration of one or more aspects can speed up the aging process, anticipating limitations and until the death in the aged. For an adjusted confrontation of this question is necessary an interdisciplinary vision, in which the some areas of the knowledge can interact and with this to intervenes of the best possible form. Then, information derived from studies of aspects related to incidence, morbidity-mortality and transition patterns, involved in the health-illness process can more accurately identify risk groups thereby establishing links between social factors, illness, incapacity and death. Thus, this study aimed to identify, by a multidimensional vision, the risk factors of mortality in a coorth of elderly in a city in the interior of the state of Rio Grande do Norte (RN), Brazil. A prospective study carried out in Santa Cruz RN, where 310 elderly were randomly selected to form a baseline. The follow-up was 53 months. The predictive variables were divided into sociodemographic, physical health, neuropsychiatric and functional capacity. The statistical analysis carried out by bivariate analysis, survival analysis, followed by binary logistic regression and Cox regression, in the multivariate analysis, considering significant levels p < 0.05 and confidence interval (CI) of 95%. A total of 60 (19.3%) elderly died during the follow-up, where cardiovascular disease was the main cause. The survival was approximately 24.8 months. The study of general survival showed, at 12, 24, 36, and 48 months of observation, a survival rate of 97%, 54%, 31%, and 5% respectively, with a statistical difference in survival only observed for the variables of cognitive function and Basic Activities of Daily Living. In the logistic regression analysis, the risk factors identified were cognitive deficits (OR = 8.74), poor perception of health (OR = 3.89) and dependence for Basic Activities of Daily Living (OR = 3.96). In the Cox analysis, as well as dependence for Basic Activities of Daily Living (HR = 3.17), cognitive deficit (HR = 4.30) and stroke (CVA) (HR = 3.49) continued as independent risk factors for death. The risk factors found in the study can be interpreted as the primary predictors for death among elderly members of the community. Therefore, improvements in health conditions, with actions towards sustaining an autonomous life with special attention for elderly with cognitive impairment, could mean additional healthy quality of life, resulting in the reduction of premature mortality in this population

Tabelas de vida de Orius insidiosus (Say, 1832) (Hemiptera: Anthocoridae) predando Aphis gossypii Glover, 1877 (Hemiptera: Aphididae) em diferentes cultivares de algodoeiro

The life table parameters were studied for Orius insidiosus on the three cotton plant cultivars Antares, CNPA7H and Acala 90 (respectively, without tricome, medium tricome density and high tricome density). This study showed that the type of cultivar can strongly influence the life-table parameters. The intrinsic rate (rm) was 0.088 (on Antares), 0.081 (CNPA7H) and 0.079 (on Acala 90), which was expected as these differences were also observed for development time, survival, fecundity and longevity on the cultivars. The reproductive rate (Ro) was 18.53 on the Antares cultivar, but showed less difference for CNPA7H (12.26) and Acala 90 (12.95). The development time was 33.9, 30.62 and 32.13 days for Antares, CNPA7H and Acala 90, respectively. The age-specific survival was similar until the 12th day. Maximum survival was 60 days on the Antares cultivar. Females usually began to oviposit after 16 days on the Antares cultivar and the after 19 days day on CNPA7H and Acala 90.

Prognostic significance of beta-2 adrenergic receptor in oral squamous cell carcinoma

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Human pulp response to resin cements used to bond inlay restorations

Objective. The aim of this study was to evaluate the pulp response following cementation of inlays using two different resin cements.Methods. Deep Class V cavities were prepared on the buccal surface of 34 sound human premolars. impressions were taken and inlays were prepared which were cemented with the following luting materials-Group 1: Rely X(TM) Unicem. (3M ESPE); Group 2: Variolink(R) II (Ivoclar Vivadent). in Group 3 (control), after lining the cavity floor with Dycal(R) (Dentsply Caulk) the inlays were cemented with Rely X(TM) Unicem. Four additional teeth were used as an intact control group. For Variolink(R) II, the adhesive system Excite was used as part of the cementation procedure. After 7 or 60 days, the teeth were extracted and processed for histological assessment.Results. At 7 days, Rely X(TM) Unicern and Variolink(R) II system triggered in two samples a mild and moderate inflammatory response, respectively. At 60 days, the pulpal response decreased for both groups. A discrete persistent inflammatory response occurred in Group 2 in which displacement of resin components across the dentin tubules was observed. In the control group, normal histological characteristics were observed. The inflammatory response and tissue disorganization were related to the remaining dentin thickness between the cavity floor and the pulp tissue.Significance. Techniques for inlay cementation using distinct luting cements may cause specific pulpal damage. Variolink(R) II associated with the adhesive system Excite cause more aggressive effects to the pulp-dentin complex than Rely X(TM) Unicern cement when both are used to cement inlay restorations. (C) 2005 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

ATM down-regulation is associated with poor prognosis in sporadic breast carcinomas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

ROCK1 as a novel prognostic marker in vulvar cancer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Análise da relevância clínica da classificação histológica dos carcinomas de mama de tipos lobular e ductal e sua relação com a classificação molecular

Pós-graduação em Patologia - FMB

Low serum potassium levels increase the infectious-caused mortality in peritoneal dialysis patients: a propensity-matched score study

Background and ObjectivesHypokalemia has been consistently associated with high mortality rate in peritoneal dialysis. However, studies investigating if hypokalemia is acting as a surrogate marker of comorbidities or has a direct effect in the risk for mortality have not been studied. Thus, the aim of this study was to analyze the effect of hypokalemia on overall and cause-specific mortality.Design, Setting, Participants and MeasurementsThis is an analysis of BRAZPD II, a nationwide prospective cohort study. All patients on PD for longer than 90 days with measured serum potassium levels were used to verify the association of hypokalemia with overall and cause-specific mortality using a propensity match score to reduce selection bias. In addition, competing risks were also taken into account for the analysis of cause-specific mortality.ResultsThere was a U-shaped relationship between time-averaged serum potassium and all-cause mortality of PD patients. Cardiovascular disease was the main cause of death in the normokalemic group with 133 events (41.8%) followed by PD-non related infections, n=105 (33.0%). Hypokalemia was associated with a 49% increased risk for CV mortality after adjustments for covariates and the presence of competing risks (SHR 1.49; CI95% 1.01-2.21). In contrast, in the group of patients with K < 3.5mEq/L, PD-non related infections were the main cause of death with 43 events (44.3%) followed by cardiovascular disease (n=36; 37.1%). For PD-non related infections the SHR was 2.19 (CI95% 1.52-3.14) while for peritonitis was SHR 1.09 (CI95% 0.47-2.49).ConclusionsHypokalemia had a significant impact on overall, cardiovascular and infectious mortality even after adjustments for competing risks. The causative nature of this association suggested by our study raises the need for intervention studies looking at the effect of potassium supplementation on clinical outcomes of PD patients.

Stage, Grade and Behavior of Bladder Urothelial Carcinoma Defined by the MicroRNA Expression Profile

Purpose: We identified miRNA expression profiles in urothelial carcinoma that are associated with grade, stage, and recurrence-free and disease specific survival. Materials and Methods: The expression of 14 miRNAs was evaluated by quantitative reverse transcriptase-polymerase chain reaction in surgical specimens from 30 patients with low grade, noninvasive (pTa) and 30 with high grade, invasive (pT2-3) urothelial carcinoma. Controls were normal bladder tissue from 5 patients who underwent surgical treatment for benign prostatic hyperplasia. Endogenous controls were RNU-43 and RNU-48. miRNA profiles were compared and Kaplan-Meier curves were constructed to analyze disease-free and disease specific survival. Results: miR-100 was under expressed in 100% of low grade pTa specimens (p <0.001) and miR-10a was over expressed in 73.3% (p <0.001). miR-21 and miR-205 were over expressed in high grade pT2-3 disease (p = 0.02 and <0.001, respectively). The other miRNAs were present at levels similar to those of normal bladder tissue or under expressed in each tumor group. miR-21 over expression (greater than 1.08) was related to shorter disease-free survival in patients with low grade pTa urothelial carcinoma. Higher miR-10a levels (greater than 2.30) were associated with shorter disease-free and disease specific survival in patients with high grade pT2-3 urothelial carcinoma. Conclusions: Four miRNAs were differentially expressed in the 2 urothelial carcinoma groups. miR-100 and miR-10a showed under expression and over expression, respectively, in low grade pTa tumors. miR-21 and miR-205 were over expressed in pT2-3 disease. In addition, miR-10a and miR-21 over expression was associated with shorter disease-free and disease specific survival. miRNAs could be incorporated into the urothelial carcinoma molecular pathway. These miRNAs could also serve as new diagnostic or prognostic markers and new target drugs.

Prognostic significance of NDRG1 expression in oral and oropharyngeal squamous cell carcinoma

Human N-myc downstream-regulated gene 1 (NDRG1) is a metastasis suppressor gene with several potential functions, including cell differentiation, cell cycle regulation and response to hormones, nickel and stress. The purpose of this study was to investigate the immunoexpression of NDRG1 in oral and oropharyngeal squamous cell carcinomas searching for its role in the clinical course of these tumors. We investigated immunohistochemical expression of NDRG1 protein in 412 tissue microarray cores of tumor samples from 103 patients with oral and oropharyngeal squamous cell carcinomas and in 110 paraffin-embedded surgical margin sections. The results showed NDRG1 up-regulation in 101/103 (98.1 %) tumor samples, but no expression in any normal tissue sample. Western blot assays confirmed the immunohistochemical findings, suggesting that lower levels of NDRG1 are associated with a high mortality rate. NDRG1 overexpression was related to long-term specific survival (HR = 0.38; p = 0.009), whereas the presence of lymph-node metastasis showed the opposite association with survival (HR = 2.45; p = 0.013). Our findings reinforce the idea that NDRG1 plays a metastasis suppressor role in oral and oropharyngeal squamous cell carcinomas and may be a useful marker for these tumors.

Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC)

Proteins of the lysyl oxidase (LOX) family are important modulators of the extracellular matrix. However, they have an important role in the tumour development as well as in tumour progression. To evaluate the diagnostic and prognostic value of the LOX protein in oral and oropharyngeal squamous cell carcinoma (OSCC) we performed QRT-PCR and immunohistochemical analysis on two tissue microarrays (622 tissue samples in total). Significantly higher LOX expression was detected in high grade dysplastic oral mucosa as well as in OSCC when compared to normal oral mucosa (P < 0.001). High LOX expression was correlated with clinical TNM stage (P = 0.020), lymph node metastases for the entire cohort (P < 0.001), as well as in the subgroup of small primary tumours (T1/T2, P < 0.001). Moreover, high LOX expression was correlated with poor overall survival (P = 0.004) and disease specific survival (P = 0.037). In a multivariate analysis, high LOX expression was an independent prognostic factor, predicting unfavourable overall survival. In summary, LOX expression is an independent prognostic biomarker and a predictor of lymph node metastasis in OSCC. Moreover, LOX overexpression may be an early phenomenon in the pathogenesis of OSCC and thus an attractive novel target for chemopreventive and therapeutic strategies.

Primary tumors of the submandibular glands: a retrospective study based on 41 cases

We report our experience on the diagnostic approach, treatment, and follow-up of primary submandibular gland tumors. Retrospective review. Tertiary referral center. Forty-one adult patients, 22 male and 19 female, with primary submandibular gland tumors, 20 benign and 21 malignant. Age, gender, clinical findings, cyto- and histopathology, treatment and outcome were analyzed. Most tumors presented as a painless submandibular mass. Thirty three patients underwent a fine needle aspiration, the sensitivity, specificity and accuracy of which--in detecting malignant tumors--were 79%, 100% and 88%, respectively. Preoperative radiological imaging was performed in 30 cases. Patients with benign tumors were treated with surgery. Most malignant tumors were treated with a combined modality, including neck dissection and radiation therapy. Five patients developed a postoperative complication. Recurrent disease was encountered in 5 malignant tumors. The 2, 5 and 10 year disease-specific survival of patients with malignancy were 84%, 75% and 41%, respectively. The preoperative assessment of the nature of submandibular gland tumors remains challenging. Aggressive treatment of patients with malignant disease may help to avoid poor prognosis.

Estimating loss to follow-up in HIV-infected patients on antiretroviral therapy: the effect of the competing risk of death in Zambia and Switzerland

Background Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. Methods and Findings HIV-infected patients aged ≥18 years who started ART 2004–2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. Conclusions In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings.