The metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, is associated with subsequent ...development of type 2 diabetes mellitus and cardiovascular disease (CVD). Despite its high prevalence, little is known of the prospective association of the metabolic syndrome with cardiovascular and overall mortality.
To assess the association of the metabolic syndrome with cardiovascular and overall mortality using recently proposed definitions and factor analysis.
The Kuopio Ischaemic Heart Disease Risk Factor Study, a population-based, prospective cohort study of 1209 Finnish men aged 42 to 60 years at baseline (1984-1989) who were initially without CVD, cancer, or diabetes. Follow-up continued through December 1998.
Death due to coronary heart disease (CHD), CVD, and any cause among men with vs without the metabolic syndrome, using 4 definitions based on the National Cholesterol Education Program (NCEP) and the World Health Organization (WHO).
The prevalence of the metabolic syndrome ranged from 8.8% to 14.3%, depending on the definition. There were 109 deaths during the approximately 11.4-year follow-up, of which 46 and 27 were due to CVD and CHD, respectively. Men with the metabolic syndrome as defined by the NCEP were 2.9 (95% confidence interval CI, 1.2-7.2) to 4.2 (95% CI, 1.6-10.8) times more likely and, as defined by the WHO, 2.9 (95% CI, 1.2-6.8) to 3.3 (95% CI, 1.4-7.7) times more likely to die of CHD after adjustment for conventional cardiovascular risk factors. The metabolic syndrome as defined by the WHO was associated with 2.6 (95% CI, 1.4-5.1) to 3.0 (95% CI, 1.5-5.7) times higher CVD mortality and 1.9 (95% CI, 1.2-3.0) to 2.1 (95% CI, 1.3-3.3) times higher all-cause mortality. The NCEP definition less consistently predicted CVD and all-cause mortality. Factor analysis using 13 variables associated with metabolic or cardiovascular risk yielded a metabolic syndrome factor that explained 18% of total variance. Men with loadings on the metabolic factor in the highest quarter were 3.6 (95% CI, 1.7-7.9), 3.2 (95% CI, 1.7-5.8), and 2.3 (95% CI, 1.5-3.4) times more likely to die of CHD, CVD, and any cause, respectively.
Cardiovascular disease and all-cause mortality are increased in men with the metabolic syndrome, even in the absence of baseline CVD and diabetes. Early identification, treatment, and prevention of the metabolic syndrome present a major challenge for health care professionals facing an epidemic of overweight and sedentary lifestyle.
Little is known about the association of leisure-time physical activity (LTPA) and cardiorespiratory fitness with development of the metabolic syndrome, which predisposes diseases such as diabetes ...and atherosclerosis. We studied the associations of LTPA and cardiorespiratory fitness with development of the metabolic syndrome (World Health Organization WHO and the National Cholesterol Education Program NCEP definitions).
LTPA over the previous 12 months, VO(2max) (ml. kg(-1). min(-1)), and cardiovascular and metabolic risk factors were assessed in a population-based cohort of 612 middle-aged men without the metabolic syndrome.
At the 4-year follow-up, 107 men had metabolic syndrome (WHO definition). Men engaging in >3 h/week of moderate or vigorous LTPA were half as likely as sedentary men to have the metabolic syndrome after adjustment for major confounders (age, BMI, smoking, alcohol, and socioeconomic status) or potentially mediating factors (insulin, glucose, lipids, and blood pressure), especially in high-risk men. Vigorous LTPA had an even stronger inverse association, particularly in unfit men. Men in the upper third of VO(2max) were 75% less likely than unfit men to develop the metabolic syndrome, even after adjustment for major confounders. Adjustment for possible mediating factors attenuated the association. Associations of LTPA and VO(2max) with development of the metabolic syndrome, as defined by the NCEP, were qualitatively similar.
In particular, high-risk men engaging in currently recommended levels of physical activity were less likely to develop the metabolic syndrome than sedentary men. Cardiorespiratory fitness was also strongly protective, although possibly not independent of mediating factors.
Cancer has long been associated with thrombosis and many of the standard chemotherapeutics used to treat cancer are pro-thrombotic. Thus, the identification of novel selective anticancer drugs that ...also have antithrombotic properties is of enormous significance. Amblyomin-X is an anticancer protein derived from the salivary glands of the Amblyomma cajennense tick.
In this work, we determined the inhibition profile of Amblyomin-X and its effect on activated partial thromboplastin time (aPTT) and prothrombin time (PT), using various approaches such as, kinetic analyses, amidolytic assays, SDS-PAGE, and mass spectrometry.
Amblyomin-X inhibited factor Xa, prothrombinase and tenase activities. It was hydrolyzed by trypsin and plasmin. MS/MS data of tryptic hydrolysate of Amblyomin-X suggested the presence of Cys8-Cys59 and Cys19-Cys42 but not Cys34-Cys55 disulfide bond. Instead of Cys34-Cys55, two noncanonical Cys34-Cys74 and Cys55-Cys74 disulfide bonds were identified. Furthermore, when Amblyomin-X (1mg/kg) injected in rabbits, it prolonged aPTT and PT.
Amblyomin-X is a noncompetitive inhibitor (Ki=3.9μM) of factor Xa. It is a substrate for plasmin and trypsin, but not for factor Xa and thrombin. The disulfide Cys34-Cys55 bond probably scrambles with interchain seventh free cysteine residues (Cys74) of Amblyomin-X. The prolongation of PT and aPTT is reversible.
General Significance.
In term of anticoagulant property, this is structural and functional characterization of Amblyomin-X. All together, these results and previous findings suggest that Amblyomin-X has a potential to become an anticancer drug with antithrombotic property.
•Amblyomin-X is a noncompetitive inhibitor of factor Xa and substrate for plasmin.•The binding cleft of Amblyomin-X is distinct from classical Kunitz-type inhibitors.•The seventh free cysteine residue of Amblyomin-X scrambles with Cys34-Cys55 bond.•Amblyomin-X cause reversible prolongation PT and aPTT.•The anticancer molecule Amblyomin-X also has antithrombotic property.
A novel concept for white organic light emitting diodes (OLEDs) enabling the utilization of all electrically generated excitons for light generation is introduced. The key feature is a fluorescent ...blue emitter with high triplet energy, rendering it possible to harvest its triplet excitons by letting them diffuse to an orange phosphorescent iridium complex.
The fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii are the causative agents of paracoccidioidomycosis (PCM), a systemic mycosis endemic to Latin America. This fungus is considered a ...facultative intracellular pathogen that is able to survive and replicate inside macrophages. The survival of the fungus during infection depends on its adaptability to various conditions, such as nitrosative/oxidative stress produced by the host immune cells, particularly alveolar macrophages. Currently, there is little knowledge about the Paracoccidioides spp. signaling pathways involved in the fungus evasion mechanism of the host defense response. However, it is known that some of these pathways are triggered by reactive oxygen species and reactive nitrogen species (ROS/RNS) produced by host cells. Considering that the effects of NO (nitric oxide) on pathogens are concentration dependent, such effects could alter the redox state of cysteine residues by influencing (activating or inhibiting) a variety of protein functions, notably S-nitrosylation, a highly important NO-dependent posttranslational modification that regulates cellular functions and signaling pathways. It has been demonstrated by our group that P. brasiliensis yeast cells proliferate when exposed to low NO concentrations. Thus, this work investigated the modulation profile of S-nitrosylated proteins of P. brasiliensis, as well as identifying S-nitrosylation sites after treatment with RNS. Through mass spectrometry analysis (LC-MS/MS) and label-free quantification, it was possible to identify 474 proteins in the S-nitrosylated proteome study. With this approach, we observed that proteins treated with NO at low concentrations presented a proliferative response pattern, with several proteins involved in cellular cycle regulation and growth being activated. These proteins appear to play important roles in fungal virulence. On the other hand, fungus stimulated by high NO concentrations exhibited a survival response pattern. Among these S-nitrosylated proteins we identified several potential molecular targets for fungal disease therapy, including cell wall integrity (CWI) pathway, amino acid and folic acid metabolisms. In addition, we detected that the transnitrosylation/denitrosylation redox signaling are preserved in this fungus. Finally, this work may help to uncover the beneficial and antifungal properties of NO in the P. brasiliensis and point to useful targets for the development of antifungal drugs.The fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii are the causative agents of paracoccidioidomycosis (PCM), a systemic mycosis endemic to Latin America. This fungus is considered a facultative intracellular pathogen that is able to survive and replicate inside macrophages. The survival of the fungus during infection depends on its adaptability to various conditions, such as nitrosative/oxidative stress produced by the host immune cells, particularly alveolar macrophages. Currently, there is little knowledge about the Paracoccidioides spp. signaling pathways involved in the fungus evasion mechanism of the host defense response. However, it is known that some of these pathways are triggered by reactive oxygen species and reactive nitrogen species (ROS/RNS) produced by host cells. Considering that the effects of NO (nitric oxide) on pathogens are concentration dependent, such effects could alter the redox state of cysteine residues by influencing (activating or inhibiting) a variety of protein functions, notably S-nitrosylation, a highly important NO-dependent posttranslational modification that regulates cellular functions and signaling pathways. It has been demonstrated by our group that P. brasiliensis yeast cells proliferate when exposed to low NO concentrations. Thus, this work investigated the modulation profile of S-nitrosylated proteins of P. brasiliensis, as well as identifying S-nitrosylation sites after treatment with RNS. Through mass spectrometry analysis (LC-MS/MS) and label-free quantification, it was possible to identify 474 proteins in the S-nitrosylated proteome study. With this approach, we observed that proteins treated with NO at low concentrations presented a proliferative response pattern, with several proteins involved in cellular cycle regulation and growth being activated. These proteins appear to play important roles in fungal virulence. On the other hand, fungus stimulated by high NO concentrations exhibited a survival response pattern. Among these S-nitrosylated proteins we identified several potential molecular targets for fungal disease therapy, including cell wall integrity (CWI) pathway, amino acid and folic acid metabolisms. In addition, we detected that the transnitrosylation/denitrosylation redox signaling are preserved in this fungus. Finally, this work may help to uncover the beneficial and antifungal properties of NO in the P. brasiliensis and point to useful targets for the development of antifungal drugs.
The World Health Organization (WHO) and the National Cholesterol Education Program (NCEP) recently proposed definitions for the metabolic syndrome. Little is known of their validity, however. The ...authors assessed the sensitivity and specificity of the definitions of the metabolic syndrome for prevalent and incident diabetes mellitus in a Finnish population-based cohort of middle-aged men (n = 1,005) followed for 4 years since the late 1980s. Four definitions based on the WHO and NCEP recommendations were compared. All definitions identified persons at high risk for developing diabetes during the 4-year follow-up (odds ratios = 5.0–8.8). The WHO definition including waist-hip ratio > 0.90 or body mass index ≥ 30 kg/m2 was the most sensitive (0.83 and 0.67) and least specific (0.78 and 0.80) in detecting the 47 prevalent and 51 incident cases of diabetes. The NCEP definition in which adiposity was defined as waist girth > 102 cm detected only 61% of prevalent and 41% of incident diabetes, although it was the most specific (0.89 and 0.90). The WHO definition seems valid as judged by its relatively high sensitivity and specificity in predicting diabetes. The NCEP definition including waist > 102 cm also identifies persons at high risk for diabetes, but it is relatively insensitive in predicting diabetes.
OBJECTIVE An increased extent of resection (EOR) has been shown to improve overall survival of patients with glioblastoma (GBM) but has the potential for causing a new postoperative neurological ...deficit. To investigate the impact of surgical neurological morbidity on survival, the authors performed a retrospective analysis of the clinical data from patients with GBM to quantify the impact of a new neurological deficit on the survival benefit achieved with an increased EOR. METHODS The data from all GBM patients who underwent resection at the University of Florida from 2010 to 2015 with postoperative imaging within 72 hours of surgery were included in the study. Retrospective analysis was performed on clinical outcomes and tumor volumes determined on postoperative and follow-up imaging examinations. RESULTS Overall, 115 patients met the inclusion criteria for the study. Tumor volume at the time of presentation was a median of 59 cm
(enhanced on T1-weighted MRI scans). The mean EOR (± SD) was 94.2% ± 8.7% (range 59.9%-100%). Almost 30% of patients had a new postoperative neurological deficit, including motor weakness, sensory deficits, language difficulty, visual deficits, confusion, and ataxia. The neurological deficits had resolved in 41% of these patients on subsequent follow-up examinations. The median overall survival was 13.1 months (95% CI 10.9-15.2 months). Using a multipredictor Cox model, the authors observed that increased EOR was associated with improved survival except for patients with smaller tumor volumes (≤ 15 cm
). A residual volume of 2.5 cm
or less predicted a favorable overall survival. Developing a postoperative neurological deficit significantly affected survival (9.2 months compared with 14.7 months, p = 0.02), even if the neurological deficit had resolved by the first follow-up. However, there was a trend of improved survival among patients with resolution of a neurological deficit by the first follow-up compared with patients with a permanent neurological deficit. Any survival benefit from achieving a 95% EOR was abrogated by the development of a new neurological deficit postoperatively. CONCLUSIONS Developing a new neurological deficit after resection of GBM is associated with a decrease in overall survival. A careful balance between EOR and neurological compromise needs to be taken into account to reduce the likelihood of neurological morbidity from surgery.
DNA polymerase theta (Polθ), a member of the DNA polymerase family A, exhibits a polymerase C-terminal domain, a central domain, and an N-terminal helicase domain. Polθ plays important roles in DNA ...repair via its polymerase domain, regulating genome integrity. In addition, in mammals, Polθ modulates origin firing timing and MCM helicase recruitment to chromatin. In contrast, as a model eukaryote, Trypanosoma cruzi exhibits two individual putative orthologs of Polθ in different genomic loci; one ortholog is homologous to the Polθ C-terminal polymerase domain, and the other is homologous to the Polθ helicase domain, called Polθ-polymerase and Polθ-helicase, respectively. A pull-down assay using the T. cruzi component of the prereplication complex Orc1/Cdc6 as bait captured Polθ-helicase from the nuclear extract. Orc1/Cdc6 and Polθ-helicase directly interacted, and Polθ-helicase presented DNA unwinding and ATPase activities. A T. cruzi strain overexpressing the Polθ-helicase domain exhibited a significantly decreased amount of DNA-bound MCM7 and impaired replication origin firing. Taken together, these data suggest that Polθ-helicase modulates DNA replication by directly interacting with Orc1/Cdc6, which reduces the binding of MCM7 to DNA and thereby impairs the firing of replication origins.
The cross-sectional associations of leisure-time physical activity (LTPA) and cardiorespiratory fitness with the metabolic syndrome (MS) were investigated in a population-based sample of 1069 ...middle-aged men without diabetes, cardiovascular disease, or cancer.
LTPA was assessed using a detailed quantitative questionnaire. Maximal oxygen uptake VO(2max) and core and related features of the MS were determined. A modified World Health Organization definition of the MS and factor analysis were used.
Men who engaged in at least moderate-intensity (>or=4.5 metabolic equivalents) LTPA <1.0 h.wk-1 were 60% more likely to have the MS than those engaging in >or= 3.0 h.wk-1 even after adjustment for confounders. Low-intensity (<4.5 metabolic equivalents) LTPA was not associated with the metabolic syndrome. Men with a VO(2max) <29.1 mL x kg-1 x min-1 were almost seven times more likely to have the MS than those with a VO(2max) >or=35.5 mL.kg-1.min-1 even after adjusting for confounders. In first-order factor analysis using a promax rotation, the principal factor explained 20% of total variance and had heavy loadings for VO(2max) (-0.57) and at least moderate-intensity LTPA (-0.44), and moderate or heavy loadings for the main components of the MS. The second-order factor analysis generated a principal factor that was strongly loaded on by the main components of the MS and VO(2max) (-0.50) but not LTPA.
A sedentary lifestyle and especially poor cardiorespiratory fitness are not only associated with the MS but could also be considered features of the MS. Measurement of VO(2max) in sedentary men with risk factors may provide an efficient means for targeting individuals who would benefit from interventions to prevent the MS and its consequences.
•Constructing synthetics rocks obeying the dynamic similitude.•The dynamic similitude helps understand better wave propagation in real rocks.•Correct materials and control conditions can result in ...samples near to real rock.•The dynamic similitude is a desired similitude to be reached in petrophysics.
For decades, seismic and ultrasonic physical modeling has been used to help the geophysicists to understand the phenomena related to the elastic wave propagation on isotropic and anisotropic media. Most of the published works related to physical modeling use physical similitudes between model and field (geological environment) only in the geometric and, sometimes, in the kinematics sense. The dynamic similitude is approximately or, most of the time, not obeyed due to the difficulty to reproduce, in laboratory, the forces and tensions excited inside the earth when elastic waves propagate. In this work, we use expressions for dynamic similitude related to the ratio between stiffness coefficients or Lamé parameters. The resulting expression for dynamic similitude shows that this type of similitude has multiple solutions in the context of dynamic stress (non-uniqueness problem). However, the regularization of this problem can be reached by controlling porosity and clay content. Ultrasonic measurements (elastic) as well as petrophysical measurements (density, porosity and clay content) in synthetic sandstone rocks show how difficult it is to reproduce experimentally the three physical similarities studied in this work.
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