Longitudinal outcomes of high-risk human papillomavirus (HPV) infections as competing-risks events following cervical HPV test at baseline visit in the *NIS-LAMS** cohort

Background: The complex natural history of human papillomavirus (HPV) infections following a single HPV test can be modeled as competing-risks events (i.e., no-, transient- or persistent infection) in a longitudinal setting. The covariates associated with these compet ng events have not been previously assessed using competing-risks regression models. Objectives: To gain further insights in the outcomes of cervical HPV infections, we used univariate- and multivariate competing-risks regression models to assess the covariaies associated with these competing events. Study Design and Methods: Covariates associated with three competing outcomes (no-, transient- or persistent HR-HPV infection) were analysed in a sub-cohort of 1,865 women prospectively followed-up in the NIS (n = 3,187) and LAMS Study (n = 12,114). Results: In multivariate competing-risks models (with two other outcomes as competing events), permanently HR-HPV negative outcome was significantly predicted only by the clearance of ASCUS+Pap during FU, while three independent covariates predicted transient HR-HPV infections: i) number of recent (< 12 months) sexual partners (risk increased), ii) previous Pap screening history (protective), and history of previous CIN (increased risk). The two most powerful predictors of persistent HR-HPV infections were persistent ASCUS+Pap (risk increased), and previous Pap screening history (protective). In pair-wise comparisons, number of recent sexual partners and previous CIN history increase the probability of transient HR-HPV infection against the HR-HPV negative competing event, while previous Pap screening history is protective. Persistent ASCUS+Pap during FU and no previous Pap screening history are significantly associated with the persistent HR-HPV outcome (compared both with i) always negative, and ii) transient events), whereas multiparity is protective. Conclusions: Different covariates are associated with the three main outcomes of cervical HPV infections. The most significant covariates of each competing events are probably distinct enough to enable constructing of a risk-profile for each main outcome.

Incidence of adverse events associated with percutaneous muscular biopsy among healthy and diseased subjects

The development of the percutaneous muscle biopsy technique is recognized as one of the most important scientific contributions in advancing our understanding of skeletal muscle physiology. However, a concern that this procedure may be associated with adverse events still exists. We reported the incidence of adverse outcomes associated with percutaneous muscle biopsy in healthy and diseased subjects. Medical records of 274 volunteers (496 muscle biopsies) were reviewed. This included 168 healthy subjects (330 muscle biopsies) as well as 106 chronically ill patients (166 muscle biopsies). This latter group encompassed patients with type II diabetes (n=28), osteoarthritis (n=39), inclusion body myositis (n=4), polymyositis (n=4), and chronic heart failure (n=31). The most common occurrences were pain (1.27%), erythema (1.27%), and ecchymosis (1.27%). Panic episode, bleeding, and edema were also reported (0.21%, 0.42%, and 0.84%, respectively), while infection, hematoma, inflammation, denervation, numbness, atrophy, and abnormal scarring were not verified. The percent of incidents did not differ between healthy and ill individuals. In conclusion, the incidence of complications associated with percutaneous muscle biopsy is scarce and of minor clinical relevance. Additionally, the rate of adverse events is comparable between healthy and chronically ill subjects.

Identification and characterization of drought/wet events homogeneous environments based on regional climate simulations

The objective of this study was to identify and characterize homogeneous environments based on the probability of drought/wet occurrence in the central-northern Brazil, considering Rondonia, Mato Grosso, Goias and Tocantins States. The drought index denominated the moisture anomaly Z-index (Z-index) was used. The input climate data for the drought index was generated by the regional climate model RegCM3 for the period from 1975 to 1989. As result of cluster analysis, it was identified 13 homogeneous environments. These environments were characterized based on the probability of drought/wet, relative density of drought/wet occurrence, annual rainfall variability and probability of drought occurrence during the rainy season (October to March). The Mato Grosso State had the highest number of homogeneous environments and the environment 11, located at southwest of this State had the highest probability of drought occurrence, 9%. The environment 10, located at the extreme east of Goias State, showed the lowest median for the total annual rainfall. The climatic event with the highest probability of occurrence in the study area is close to normal or normality moisture.

Down-regulation of ANAPC13 and CLTCL1: Early Events in the Progression of Preinvasive Ductal Carcinoma of the Breast

Alterations in the gene expression profile in epithelial cells during breast ductal carcinoma (DC) progression have been shown to occur mainly between pure ductal carcinoma in situ (DCIS) to the in situ component of a lesion with coexisting invasive ductal carcinoma (DCIS-IDC) implying that the molecular program for invasion is already established in the preinvasive lesion. For assessing early molecular alterations in epithelial cells that trigger tumorigenesis and testing them as prognostic markers for breast ductal carcinoma progression, we analyzed, by reverse transcription-quantitative polymerase chain reaction, eight genes previously identified as differentially expressed between epithelial tumor cells populations captured from preinvasive lesions with distinct malignant potential, pure DCIS and the in situ component of DCIS-IDC. ANAPC13 and CLTCL1 down-regulation revealed to be early events of DC progression that anticipated the invasiveness manifestation. Further down-regulation of ANAPC13 also occurred after invasion appearance and the presence of the protein in invasive tumor samples was associated with higher rates of overall and disease-free survival in breast cancer patients. Furthermore, tumors with low levels of ANAPC13 displayed increased copy number alterations, with significant gains at 1q (1q23.1-1q32.1), 8q, and 17q (17q24.2), regions that display common imbalances in breast tumors, suggesting that down-regulation of ANAPC13 contributes to genomic instability in this disease.

Adverse Drug Events Leading Children to Hospital Emergency Care

To determine the incidence of adverse drug events (ADE) that resulted in the need for children's emergency care, a total of 23,286 pediatric emergency case notes were analyzed. They were selected on the basis of the ICD code indicating a possible ADE. ADEs were found in 13 case notes (0.06%), predominantly among girls and mainly in the 1 to 5 year age group. About half of the observed events occurred as a result of accidental ingestion, 27.3% were suicide attempts, and 27.3% arose due to the discontinuation of treatment. Antiepileptic drugs were those most often involved. Three (23%) were serious. The results suggest that children have easy access to medications and are involved in the majority of accidental occurrences. Using drugs involves risks, and drawing attention to such risks while prescribing and dispensing them fosters the sharing of responsibility and the empowerment of the users, measures necessary to health promotion.

Long-Term Prospective Study of the Influence of Estrone Levels on Events in Postmenopausal Women with or at High Risk for Coronary Artery Disease

Background. The link between endogenous estrogen, coronary artery disease (CAD), and death in postmenopausal women is uncertain. We analyzed the association between death and blood levels of estrone in postmenopausal women with known coronary artery disease (CAD) or with a high-risk factor score for CAD. Methods. 251 postmenopausal women age 50-90 years not on estrogen therapy. Fasting blood for estrone and heart disease risk factors were collected at baseline. Women were grouped according to their estrone levels (<15 and >= 15 pg/mL). Fatal events were recorded after 5.8 perpendicular to 1.4 years of followup. Results. The Kaplan-Meier survival curve showed a significant trend (P = 0.039) of greater all-cause mortality in women with low estrone levels (< 15 pg/mL). Cox multivariate regression analysis model adjusted for body mass index, diabetes, dyslipidemia, family history, and estrone showed estrone (OR = 0.45; P = 0.038) as the only independent variable for all-cause mortality. Multivariate regression model adjusted for age, body mass index, hypertension, diabetes, dyslipidemia, family history, and estrone showed that only age (OR = 1.06; P = 0.017) was an independent predictor of all-cause mortality. Conclusions. Postmenopausal women with known CAD or with a high-risk factor score for CAD and low estrone levels (< 15 pg/mL) had increased all-cause mortality.

Comparative analysis of the pathological events involved in immune and non-immune TRALI models

Background and Objectives Transfusion-related acute lung injury (TRALI) is characterized by leukocyte transmigration and alveolar capillary leakage shortly after transfusion. TRALI pathogenesis has not been fully elucidated. In some cases, the infusion of alloantibodies (immune model), whereas in others the combination of neutrophil priming by proinflammatory molecules with the subsequent infusion of biological response modifiers (BRMs) in the hemocomponent (non-immune model) have been implicated. Our aim was to compare the pathological events involved in TRALI induced by antibodies or BRMs using murine models. Materials and Methods In the immune model, human HNA-2+ neutrophils were incubated in vitro with a monoclonal antibody (anti-CD177, clone 7D8) directed against the HNA-2 antigen and injected i.v. in NOD/SCID mice. In the non-immune model, BALB/c mice were treated with low doses of lipopolysaccharide (LPS) followed by platelet-activating factor (PAF) infusion 2 h later. Forty minutes after PAF administration, or 6 h after neutrophil injection, lungs were isolated and histological analysis, determination of a variety of cytokines and chemokines including keratinocyte-derived chemokine (KC), MIP-2, the interleukins IL-1 beta, IL-6, IL-8 as well as TNFa, cell influx and alveolar capillary leakage were performed. Results In both models, characteristic histological findings of TRALI and an increase in KC and MIP-2 levels were detected. In contrast to the immune model, in the non-immune model, there was a dramatic increase in IL-1 beta and TNFa. However, capillary leakage was only detected if PAF was administrated. Conclusions Regardless of the triggering event(s), KC, MIP-2 and integrins participate in TRALI pathogenesis, whereas PAF is essential for capillary leakage when two events are involved.

Immunolocalization of bone morphogenetic protein 2 during the early healing events after guided bone regeneration

Objective. The objective of this study was to evaluate the immunolocalization of bone morphogenetic protein 2 (BMP-2) after autogenous block grafting covered or not with an e-PTFE membrane. Study Design. Forty-eight rats were divided into 2 groups, autogenous block graft (B) and autogenous block graft + e-PTFE membrane (MB), and were evaluated by immunohistochemistry at baseline and 3, 7, 14, 21, and 45 days. Results. The largest number of positive cells in the recipient bed was observed after 3 days in both groups. At the graft border, the largest number of positive cells was seen after 7 days in group B and after 14 days in group MB. The highest proportion of staining in the graft was observed after 3 days in group B and after 21 days in group MB. Conclusions. High proportions of stain were related to intense revascularization and osteogenesis. Except for the interface, BMP-2 staining occurred later in group MB than in group B in all structures analyzed. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:533-541)

Giant magnetofossils and hyperthermal events

Magnetotactic bacteria biomineralize magnetic minerals with precisely controlled size, morphology, and stoichiometry. These cosmopolitan bacteria are widely observed in aquatic environments. If preserved after burial, the inorganic remains of magnetotactic bacteria act as magnetofossils that record ancient geomagnetic field variations. They also have potential to provide paleoenvironmental information. In contrast to conventional magnetofossils, giant magnetofossils (most likely produced by eukaryotic organisms) have only been reported once before from Paleocene-Eocene Thermal Maximum (PETM; 55.8 Ma) sediments on the New Jersey coastal plain. Here, using transmission electron microscopic observations, we present evidence for abundant giant magnetofossils, including previously reported elongated prisms and spindles, and new giant bullet-shaped magnetite crystals, in the Southern Ocean near Antarctica, not only during the PETM, but also shortly before and after the PETM. Moreover, we have discovered giant bullet-shaped magnetite crystals from the equatorial Indian Ocean during the Mid-Eocene Climatic Optimum (similar to 40 Ma). Our results indicate a more widespread geographic, environmental, and temporal distribution of giant magnetofossils in the geological record with a link to "hyperthermal" events. Enhanced global weathering during hyperthermals, and expanded suboxic diagenetic environments, probably provided more bioavailable iron that enabled biomineralization of giant magnetofossils. Our micromagnetic modelling indicates the presence of magnetic multi-domain (i.e., not ideal for navigation) and single domain (i.e., ideal for navigation) structures in the giant magnetite particles depending on their size, morphology and spatial arrangement. Different giant magnetite crystal morphologies appear to have had different biological functions, including magnetotaxis and other non-navigational purposes. Our observations suggest that hyperthermals provided ideal conditions for giant magnetofossils, and that these organisms were globally distributed. Much more work is needed to understand the interplay between magnetofossil morphology, climate, nutrient availability, and environmental variability.

Local inflammatory events induced by Bothrops atrox snake venom and the release of distinct classes of inflammatory mediators

Bothrops atrox is responsible for most accidents involving snakes in the Brazilian Amazon and its venom induces serious systemic and local effects. The local effects are not neutralized effectively by commercial antivenoms, resulting in serious sequelae in individuals bitten by this species. This study investigates the local inflammatory events induced in mice by B. atrox venom (Bay), such as vascular permeability, leukocyte influx and the release of important inflammatory mediators such as cytokines, eicosanoids and the chemokine CCL-2, at the injection site. The effect of Bay on cyclooxygenase (COX-1 and COX-2) expression was also investigated. The results showed that intraperitoneal (i.p.) injection of BaV promoted a rapid and significant increase in vascular permeability, which reached a peak 1 h after venom administration. Furthermore, BaV caused leukocyte infiltration into the peritoneal cavity between 1 and 8 h after i.p. injection, with mononuclear leukocytes (MNs) predominating in the first 4 h, and polymorphonuclear leukocytes (PMNs) in the last 4 h. Increased protein expression of COX-2, but not of COX-1, was detected in leukocytes recruited in the first and fourth hours after injection of BaV. The venom caused the release of eicosanoids PGD(2), PGE(2), TXA(2) and LTB4, cytokines TNF-alpha, IL-6, IL-10 and IL-12p70, but not IFN-gamma, and chemokine CCL-2 at different times. The results show that Bay is able to induce an early increase in vascular permeability and a leukocyte influx to the injection site consisting mainly of MNs initially and PMNs during the later stages. These phenomena are associated with the production of cytokines, the chemokine CCL-2 and eicosanoids derived from COX-1 and COX-2. (c) 2012 Elsevier Ltd. All rights reserved.

Signaling Events During Cyclic Guanosine Monophosphate-Regulated Pigment Aggregation in Freshwater Shrimp Chromatophores

Crustacean color change results partly from granule aggregation induced by red pigment concentrating hormone (RPCH). In shrimp chromatophores, both the cyclic GMP (3', 5'-guanosine monophosphate) and Ca2+ cascades mediate pigment aggregation. However, the signaling elements upstream and downstream from cGMP synthesis by GC-S (cytosolic guanylyl cyclase) remain obscure. We investigate post-RPCH binding events in perfused red ovarian chromatophores to disclose the steps modulating cGMP concentration, which regulates granule translocation. The inhibition of calcium/calmodulin complex (Ca2+/CaM) by N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W7) induces spontaneous aggregation but inhibits RPCH-triggered aggregation, suggesting a role in pigment aggregation and dispersion. Nitric oxide synthase inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) strongly diminishes RPCH-induced aggregation; protein kinase G inhibition (by rp-cGMPs-triethylamine) reduces RPCH-triggered aggregation and provokes spontaneous dispersion, disclosing NO/PKG participation in aggregation signaling. Myosin light chain phosphatase inhibition (by cantharidin) accelerates RPCH-triggered aggregation, whereas Rho-associated protein kinase inhibition (by Y-27632, H-11522) reduces RPCH-induced aggregation and accelerates dispersion. MLCP (myosin light chain kinase) and ROCK (Rho-associated protein kinase) may antagonistically regulate myosin light chain (MLC) dephosphorylation/phosphorylation during pigment dispersion/aggregation. We propose the following general hypothesis for the cGMP/Ca2+ cascades that regulate pigment aggregation in crustacean chromatophores: RPCH binding increases Ca2+ (int), activating the Ca2+/CaM complex, releasing NOS-produced nitric oxide, and causing GC-S to synthesize cGMP that activates PKG, which phosphorylates an MLC activation site. Myosin motor activity is initiated by phosphorylation of an MLC regulatory site by ROCK activity and terminated by MLCP-mediated dephosphorylation. Qualitative comparison reveals that this signaling pathway is conserved in vertebrate and invertebrate chromatophores alike.

Effects of high-energy astrophysical events on habitable planets

With the possible exception of meteor impacts, high-energy astrophysical events such as supernovae, gamma-ray bursts (GRB) and flares are usually not taken into account for biological and evolutionary studies due to their low rates of occurrence. We show that a class of these events may occur at distances and time scales in which their biological effects are non-negligible, maybe more frequent than the impacts of large asteroids. We review the effects of four transient astrophysical sources of ionizing radiation on biospheres - stellar flares, giant flares from soft gamma repeaters (SGR), supernovae and GRB. The main damaging features of them are briefly discussed and illustrated. We point out some open problems and ongoing work. Received 28 February 2012, accepted 6 July 2012, first published online 10 August 2012

On the diurnal cycle of urban aerosols, black carbon and the occurrence of new particle formation events in springtime Sao Paulo, Brazil

Large conurbations are a significant source of the anthropogenic pollution and demographic differences between cities that result in a different pollution burden. The metropolitan area of Sao Paulo (MASP, population 20 million) accounts for one fifth of the Brazilian vehicular fleet. A feature of MASP is the amount of ethanol used by the vehicular fleet, known to exacerbate air quality. The study describes the diurnal behaviour of the submicron aerosol and relies on total particle number concentration, particle number size distribution, light scattering and light absorption measurements. Modelled planetary boundary layer (PBL) depth and air mass movement data were used to aid the interpretation. During morning rush-hour, stagnant air and a shallow PBL height favour the accumulation of aerosol pollution. During clear-sky conditions, there was a wind shift towards the edge of the city indicating a heat island effect with implications on particulate pollution levels at the site. The median total particle number concentration for the submicron aerosol typically varied in the range 1.6 x 10(4)-3.2 x 10(4) cm(-3) frequently exceeding 4 x 10(4) cm-3 during the day. During weekdays, nucleation-mode particles are responsible for most of the particles by numbers. The highest concentrations of total particle number concentrations and black carbon (BC) were observed on Fridays. Median diurnal values for light absorption and light scattering (at 637 nm wavelength) varied in the range 12-33 Mm(-1) and 21-64 Mm(-1), respectively. The former one is equal to 1.8-5.0 mu g m(-3) of BC. The growth of the PBL, from the morning rush-hour until noon, is consistent with the diurnal cycle of BC mass concentrations. Weekday hourly median single-scattering albedo (omega(0)) varied in the range 0.59-0.76. Overall, this suggests a top of atmosphere (TOA) warming effect. However, considering the low surface reflectance of urban areas, for the given range of omega(0), the TOA radiative forcing can be either positive or negative for the sources within the MASP. On the average, weekend omega(0) values were 0.074 higher than during weekdays. During 11% of the days, new particle formation (NPF) events occurred. The analysed events growth rates ranged between 9 and 25 nm h(-1). Sulphuric acid proxy concentrations calculated for the site were less than 5% of the concentration needed to explain the observed growth. Thus, other vapours are likely contributors to the observed growth.

Evaluation of Viral Load Thresholds for Predicting New World Health Organization Stage 3 and 4 Events in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy

Background: This study evaluated a wide range of viral load (VL) thresholds to identify a cut-point that best predicts new clinical events in children on stable highly active antiretroviral therapy (HAART). Methods: Cox proportional hazards modeling was used to assess the adjusted risk for World Health Organization stage 3 or 4 clinical events (WHO events) as a function of time-varying CD4, VL, and hemoglobin values in a cohort study of Latin American children on HAART >= 6 months. Models were fit using different VL cut-points between 400 and 50,000 copies per milliliter, with model fit evaluated on the basis of the minimum Akaike information criterion value, a standard model fit statistic. Results: Models were based on 67 subjects with WHO events out of 550 subjects on study. The VL cut-points of >2600 and >32,000 copies per milliliter corresponded to the lowest Akaike information criterion values and were associated with the highest hazard ratios (2.0, P = 0.015; and 2.1, P = 0.0058, respectively) for WHO events. Conclusions: In HIV-infected Latin American children on stable HAART, 2 distinct VL thresholds (>2600 and >32,000 copies/mL) were identified for predicting children at significantly increased risk for HIV-related clinical illness, after accounting for CD4 level, hemoglobin level, and other significant factors.

Vorapaxar in the Secondary Prevention of Atherothrombotic Events

BACKGROUND Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)