Familial hypercholesterolemia: Is there a role for PCSK9 and thrombin generation?

INTRODUCTION: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease. The prevalence of FH has previously been reported as 1 in 500 in the general population. This study aimed to evaluate the proprotein convertase subtilisin/kexin 9 (PCSK9) levels, lipid profile and thrombin generation in FH patients undergoing treatment or not. METHODS: Eighty individuals with FH were selected and distributed in 2 groups: individuals treated with statins alone or conjugate therapy (statin + ezetimibe) (T = 53) and those non treated (NT = 27). PCSK9 levels were determined by ELISA, the lipid profile by colorimetric enzyme method and thrombin generation assay (TGA) by CAT method. RESULTS: Individuals treated with conjugate therapy (statin + ezetimibe) showed a significant reduction in the levels of total cholesterol (TC) low density lipoprotein cholesterol (LDLc) and in the potential for thrombin generation (ETP with low and high concentration of tissue factor), compared to the treated individuals with monotherapy (statins). PCSK9 was positively correlated with increased levels of TC, LDLc and triglycerides, while TGA parameters were positively correlated with PCSK9 and lipid profile. CONCLUSION: PCSK9 levels appear to be associated with components of the lipid and hemostatic profiles, in addition to being influenced by age. In general, our findings suggest that combined therapy for the treatment of FH is associated with a significant improvement in both lipid and hemostatic profiles assessed by TGA, suggesting a reduction in atherogenic and thrombogenic risks and, therefore, more promising compared to the use of statin monotherapy.

Phytotoxic potential of Senna occidentalis (L.) Link extracts on seed germination and oxidative stress of Ipê seedlings.

Senna occidentalis is an invasive plant producing a series of allelochemicals that might inhibit the development of other plants. The objective of this study was to assess the phytotoxic effect of S. occidentalis extracts on the germination, development and antioxidant defence of the native species Tabebuia chrysotricha, T. pentaphylla, T. roseoalba and Handroanthus impetiginosus (Ipê species). We evaluated the effects of chemicals extracted from S. occidentalis on the germination rate, germination speed index (GSI) and biometric parameters of the test species under controlled conditions. The effect of the extracts on the pigment content, amount of H2 O2 and malondialdehyde (MDA), and the activity of the antioxidant enzymes in roots and leaves were also tested. Alkaloids, coumarins, phenols, saponins, free steroids and condensed tannins were present in all extracts of S. occidentalis, while catechins were present only in leaf and stem extracts. Stem and root extracts caused a growth reduction in all Ipê species and total inhibition of seed germination in T. chrysotricha and T. roseoalba. All target species showed an increase in H2 O2 and MDA in radicles and leaves. Oxidative stress contributed strongly to the morphological changes, such as seed blackening, thinning and darkening of radicle tips and reduction of biomass allocation in all Ipê species. Although there was activation of antioxidant defence mechanisms, such as an increase in activity of ascorbate peroxidase (APX) and peroxidase (POD) enzymes, the joint action of the allelochemicals caused phytotoxicity, leading to cell dysfunction in all Ipê species.

Resistance of Collard Green Genotypes to Bemisia tabaci Biotype B: Characterization of Antixenosis.

Bemisia tabaci (Genn.) biotype B (Hemiptera: Aleyrodidae) is an important pest of vegetable crops, including collard greens Brassica oleracea var. acephala (Brassicaceae). The use of resistant genotypes is an interesting option to reduce insect populations and can be used as an important tool for integrated pest management (IPM). This study evaluated 32 genotypes of collard greens against the attack of silver leaf whitefly, with the aim to characterize antixenosis. Initially, a multiple-choice trial was conducted using all genotypes, in which the adult attractiveness was assessed on two leaves per genotype at 24 and 48 h after infestation. After 48 h, one leaf of each genotype was randomly selected for the determination of the number of eggs per square centimeter. From the results of the multiple-choice trial, 13 genotypes were selected for a no-choice oviposition test, following the same method of the previous test. Colorimetric analyses were also performed to establish possible correlations between leaf color and insect colonization. Genotypes HS-20, OE, and VA were less attractive, demonstrating antixenosis. Genotypes LG, VE, J, MG, MOP, HS-20, VA, and MT had less oviposition in the multiple-choice test, which indicated expression of antixenosis. In the no-choice test, genotypes VE, P1C, CCB, RI-919, H, and J had less oviposition, which also characterized antixenosis. Therefore, genotypes VE and J showed the highest resistance stability because both had less oviposition in both test modalities. Thus, the resistance to B. tabaci biotype B indicates the genotypes HS-20, OE, VA, VE, and J are promising for use in breeding programs to develop resistance to whitefly.

Biotic Potential and Life Table of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) from Three Brazilian Regions.

This study aimed to evaluate the biotic potential and life table of individuals of Helicoverpa armigera (Hübner) from different host plants (citrus, corn, and cotton) and Brazilian states (São Paulo, Distrito Federal, and Bahia) in artificial diet, under laboratory conditions (25 ± 1°C, 70 ± 10% RH, 14 h photophase). The longevity, pre-, post- and oviposition periods, fecundity, and fertility of 15 mating pairs per origin were evaluated. We also compared the reproductive parameters of each group of insects (São Paulo (SP), Distrito Federal (DF), and Bahia (BA)), including the net reproductive rate (Ro), mean generation time (T), intrinsic rate of increase (r m), and finite rate of increase (λ). Microsatellite analysis from individuals collected in different locations and host plants did not show differences among the parental insects. It was verified that parental progeny collected in cotton fields from Bahia had a higher biotic potential, a higher reproductive rate (Ro), and a better fecundity compared to the insects from remaining regions. The life table charts indicate that the highest values for the reproductive parameters of the Bahia progeny are associated with higher specific fertility, particularly in early adulthood. The greatest biotic potential of the Bahia progeny may be due to increased selection pressure from the insecticide used (organophosphate and pyrethroid) on cotton crops compared to that of other crops, as well due to the massive adoption of Bt cotton-producing areas of that state from 2013 outbreaks.

Total cross sections for electron scattering by 1-propanol at impact energies in the range 40-500 eV.

Absolute total cross section (TCS) measurements for electron scattering from 1-propanol molecules are reported for impact energies from 40 to 500 eV. These measurements were obtained using a new apparatus developed at Juiz de Fora Federal University-Brazil, which is based on the measurement of the attenuation of a collimated electron beam through a gas cell containing the molecules to be studied at a given pressure. Besides these experimental measurements, we have also calculated TCS using the Independent-Atom Model with Screening Corrected Additivity Rule and Interference (IAM-SCAR+I) approach with the level of agreement between them being typically found to be very good.

Characterization of Antixenosis in Soybean Genotypes to Bemisia tabaci (Hemiptera: Aleyrodidae) Biotype B.

Bemisia tabaci biotype B (Gennadius) is one of the most important soybean pest worldwide. Herein, 15 soybean genotypes were evaluated, to characterize the occurrence of antixenosis to B. tabaci biotype B. Initially, a multiple-choice test with all genotypes was carried out, evaluating the settling and oviposition preference at 3 d after infestation, and the colonization by nymphs after 48 d of infestation. Subsequently, a no-choice test, using 14 genotypes, was conducted with infested plants individually, and the number of eggs was counted after 72 h. Then, 10 genotypes were selected (indicative of resistance and susceptibility), which were evaluated for whitefly settling 24, 48, and 72 h after infestation and for oviposition 72 h after infestation. The trichomes of the leaflets were characterized for density, size, and inclination to establish possible correlations with the settling and oviposition in the genotypes. In the first multiple-choice test, involving 15 genotypes, 'IAC-17,' 'IAC-19,' and UX-2569-159 expressed antixenosis against B. tabaci. 'Jackson,' 'P98Y11,' and PI-229358 exhibited the same behavior in the no-choice test. In the multiple-choice test, 'Jackson,' 'P98Y11,' and 'TMG1176 RR' were the least attractive and least used for oviposition. The antixenosis shown by 'Jackson,' 'P98Y11,' and PI-229358 may be related to the characteristics of the trichomes (lower density and inclined). Based on the experiments carried out, 'IAC-17,' 'IAC-19,' 'Jackson,' 'P98Y11,' PI-229358, TMG1176 RR, and UX-2569-159 are considered promising for resistance to B. tabaci biotype B and may be exploited in soybean breeding programs for resistance to insects.

Microparticles: Inflammatory and haemostatic biomarkers in Polycystic Ovary Syndrome.

Polycystic Ovary Syndrome (PCOS) is associated with a chronic low-grade inflammation and predisposition to hemostatic and atherosclerotic complications. This case-control study evaluated the microparticles (MPs) profile in patients with the PCOS and related these MPs to clinical and biochemical parameters. MPs derived from platelets (PMPs), leuckocytes (LMPs) and endothelial cells (EMPs) were evaluated, as well as MPs expressing tissue factor (TFMPs), by flow cytometry, comparing women with PCOS (n = 50) and a healthy control group (n = 50). PCOS women presented increased total MPs, PMPs, LMPs and EMPs levels when compared to control group (all p < 0.05). TFMPs was similar between the groups (p = 0.379). In conclusion, these MPs populations could be useful biomarkers for association with thrombosis and cardiovascular disease in PCOS women.

Spatial cognitive deficits in an animal model of Wernicke-Korsakoff syndrome are related to changes in thalamic VDAC protein concentrations.

Proteomic profiles of the thalamus and the correlation between the rats' performance on a spatial learning task and differential protein expression were assessed in the thiamine deficiency (TD) rat model of Wernicke-Korsakoff syndrome. Two-dimensional gel-electrophoresis detected 320 spots and a significant increase or decrease in seven proteins. Four proteins were correlated to rat behavioral performance in the Morris Water Maze. One of the four proteins was identified by mass spectrometry as Voltage-Dependent Anion Channels (VDACs). The association of VDAC is evident in trials in which the rats' performance was worst, in which the VDAC protein was reduced, as confirmed by Western blot. No difference was observed on the mRNA of Vdac genes, indicating that the decreased VDAC expression may be related to a post-transcriptional process. The results show that TD neurodegeneration involves changes in thalamic proteins and suggest that VDAC protein activity might play an important role in an initial stage of the spatial learning process.

Estrogen receptor αlpha gene (ESR1) PvuII and XbaI polymorphisms are associated to metabolic and proinflammatory factors in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that involves multiple factors. Although the etiology of PCOS is unknown, there is an involvement of sex steroid hormones in the pathophysiology of this syndrome. Therefore, polymorphisms in genes involved in the action of estrogen may contribute to a woman's susceptibility to PCOS. AIM: This study aimed to evaluate the association between the polymorphisms PvuII and XbaI in the estrogen receptor alpha (ESR1) gene and the occurrence of PCOS. The study also aimed to assess the influence of these polymorphisms on the metabolic and inflammatory profiles of women with PCOS. MATERIAL AND METHODS: This case-control study included 99 women with PCOS, diagnosed according to the Rotterdam criteria, and 104 age-matched healthy women. The polymorphisms were evaluated using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: No association between the ESR1 gene polymorphisms and the presence of PCOS was observed. However, we found associations between the PvuII polymorphism and C-reactive protein levels, testosterone levels, family history of diabetes, and waist circumference. The XbaI polymorphism was associated with fasting glucose and a family history of hypertension. CONCLUSION: These polymorphisms are not associated with PCOS development, but they are involved in the phenotype of complications of the syndrome. Therefore, prior knowledge of these genomic variants might contribute to taking preventive measures that could delay the metabolic and reproductive complications commonly seen in women with PCOS.

[Policy-making tiers of the Unified Health System (SUS) in the State of Rio de Janeiro and the decision-making process]. / As instâncias colegiadas do SUS no Estado do Rio de Janeiro e o processo decisório.

The literature concerning governmental policy-making generally encompasses the entire policy-making field. This study focused on one particular aspect of this process in the State of Rio de Janeiro, from January 1998 to July 1999: the formal decision-making tiers represented by State Health Council (CES) and the Bipartite Inter-Managerial Commission (CIB), as well as the relationships between these councils and the State Health Secretariat (SES), which holds political responsibility for approving or rejecting decisions and is thus a key player in the implementation of the Unified Health System (SUS) at the State level. Despite the political confrontation among the SES, CIB, and CES, we have observed that the new design in health policy vis-à-vis the decision-making process has fostered increasing influence by social actors involved in decisions and that the negotiated arrangements, although the result of a given correlation of forces, have favored the democratization of policy-making in the health sector.

Chronic activation of central alpha2-adrenoceptors prevents hypertension in DOCA-salt rats.

The effects of chronic intracerebroventricular (i.c.v.) injections of the alpha2-adrenoceptor agonist, xylazine, on blood pressure were examined in DOCA-salt rats. Acute studies also examined the renal sympathetic nerve activity (RSNA) and renal excretory responses produced by i.c.v. xylazine in rats with established DOCA-salt hypertension. Rats implanted with a chronic i.c.v. cannula for drug injection were used. In chronic studies, four groups were investigated: control rats treated with s.c. soybean oil and i.c.v. saline; DOCA-salt rats (s.c. deoxycorticosterone acetate) receiving i.c.v. saline, xylazine or the alpha2-adrenoceptor antagonist, yohimbine. During vehicle or DOCA-salt treatment, xylazine (0.2 ng/microg) or yohimbine (10O microg/kg) was injected i.c.v. daily (three times). In DOCA-salt rats receiving i.c.v. saline, resting mean arterial pressure (MAP) was elevated on days 15 and 30 (135 +/- 5 and 160 +/- 6 mmHg, respectively). Chronic i.c.v. xylazine significantly attenuated the rise in MAP produced by DOCA-salt (day 15, 118 +/- 5 mmHg; day 30, 121 +/- 4 mmHg). Alternatively, chronic i.c.v. yohimbine shortened the onset (day 15, 152 +/- 7 mmHg) and augmented the hypertension in DOCA-salt rats (0 survival by day 30). In acute studies, i.c.v. xylazine elicited a profound natriuresis and diuresis as well as a reduction in RSNA without altering MAP. This study demonstrates that the ongoing (tonic) activity of central alpha2-adrenoceptor mechanisms are critically involved in regulating blood pressure in the DOCA-salt treated rat. In this manner, an enhanced activity of central alpha2-adrenoceptor systems acts to protect against a rise in blood pressure. In contrast, the attenuation of central alpha2-adrenoceptor stimulation evokes hypertension. The central action of xylazine to prevent hypertension may be associated with the inhibition of sympathetic outflow to the kidneys and evokes an enhanced natriuresis. By inhibiting the avid sodium retention elicited by DOCA-salt treatment, the central activation of alpha2-adrenoceptors delays the onset and the severity of hypertension in this pathological model.

Diverse effects of renal denervation on ventricular hypertrophy and blood pressure in DOCA-salt hypertensive rats.

Cardiac hypertrophy that accompanies hypertension seems to be a phenomenon of multifactorial origin whose development does not seem to depend on an increased pressure load alone, but also on local growth factors and cardioadrenergic activity. The aim of the present study was to determine if sympathetic renal denervation and its effects on arterial pressure level can prevent cardiac hypertrophy and if it can also delay the onset and attenuate the severity of deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt treatment was initiated in rats seven days after uninephrectomy and contralateral renal denervation or sham renal denervation. DOCA (15 mg/kg, s.c.) or vehicle (soybean oil, 0.25 ml per animal) was administered twice a week for two weeks. Rats treated with DOCA or vehicle (control) were provided drinking water containing 1% NaCl and 0.03% KCl. At the end of the treatment period, mean arterial pressure (MAP) and heart rate measurements were made in conscious animals. Under ether anesthesia, the heart was removed and the right and left ventricles (including the septum) were separated and weighted. DOCA-salt treatment produced a significant increase in left ventricular weight/body weight (LVW/BW) ratio (2.44 +/- 0.09 mg/g) and right ventricular weight/body weight (RVW/BW) ratio (0.53 +/- 0.01 mg/g) compared to control (1.92 +/- 0.04 and 0.48 +/- 0.01 mg/g, respectively) rats. MAP was significantly higher (39%) in DOCA-salt rats. Renal denervation prevented (P > 0.05) the development of hypertension in DOCA-salt rats but did not prevent the increase in LVW/BW (2.27 +/- 0.03 mg/g) and RVW/BW (0.52 +/- 0.01 mg/g). We have shown that the increase in arterial pressure level is not responsible for cardiac hypertrophy, which may be more related to other events associated with DOCA-salt hypertension, such as an increase in cardiac sympathetic activity.

Diverse effects of renal denervation on ventricular hypertrophy and blood pressure in DOCA-salt hypertensive rats

Cardiac hypertrophy that accompanies hypertension seems to be a phenomenon of multifactorial origin whose development does not seem to depend on an increased pressure load alone, but also on local growth factores and cardioadrenergic activity. The aim of the present study was to determine if sympathetic renal denervation and its effects on arterial pressure level can prevent cardiac hypertrophy and if it can also delay the onset and attenuate the severity of deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt treatment was initiated in rats seven days after uninephrectomy and contralateral renal denervation or sham renal denervation. DOCA (15 mg/kg, sc) or vehicle (soybean oil, 0.25 ml per animal) was administered twice a week for two weeks. Rats treated with DOCA or vehicle (control) were provided drinking water containing 1 percent NaCl and 0.03 percent KCl. At the end of the treatment period, mean arterial pressure (MAP) and heart rate measurements were made in conscious animals. Under ether anesthesia, the heart was removed and the right and left ventricles (including the septum) were separated and weighed. DOCA-salt treatment produced a significant increase in left ventricular weight/body weight (LVW/BW) ratio (2.44 + 0.09 mg/g) and right ventricular weight/body weight (RVW/BW) ratio (0.53 + 0.01 mg/g) compared to control (1.92 + 0.04 and 0.48 + 0.01 mg/g, respectively) rats. MAP was significantly higher (39 percent) in DOCA-salt rats. Renal denervation prevented (P>0.05) the development of hypertension in DOCA-salt rats but did not prevent the increase in LVW/BW (2.27 + 0.03 mg/g) and RVW/BW (0.52 + 0.01 mg/g). We have shown that the increase in arterial pressure level is not responsible for cardiac hypertrophy, which may be more related to other events associated with DOCA-salt hypertension, such as an increase in cardiac sympathetic activity.

Minimum fragments of the heparin molecule able to produce the accumulation and change of the sulfation pattern of an antithrombotic heparan sulfate from endothelial cells.

Heparin and low molecular weight heparins stimulate two to three fold the accumulation of an antithrombotic heparan sulfate secreted by endothelial cells in culture. This led us to search for the minimum structural requirements of the heparin molecule able to elicit the enhancement of the heparan sulfate. Fragments were prepared from heparin by degradation with bacterial heparinase and heparitinases. A heparin pentasulfated tetrasaccharide was shown to be the minimum structural sequence able to enhance two to three fold the secretion of heparan sulfate by endothelial cells. The stimulation is specific for the endothelial cell, is concentration dependent and the effect is already noticed after one hour of exposure of the cells to heparin and the tetrasaccharide. Degradation of the [35S]-heparan sulfate synthesized in the presence of heparin or the tetrasaccharide has shown a higher degree of sulfation of its iduronic acid residues.

Binding of heparin and compound Y to endothelial cells stimulates the synthesis of an antithrombotic heparan sulfate proteoglycan.

The mechanism by which heparin and antithrombotic agents, including a cyclic octaphenolsulfonic acid (compound Y), stimulate the synthesis of an antithrombotic heparan sulfate by endothelial cells in culture was investigated. Compound Y increases the amount of heparan sulfate from the cell surface and secreted to the medium by endothelial cells by three-fold. Binding experiments have shown saturation of the endothelial cell receptors at a concentration of 0.16 microM for heparin and 2.7 microM for compound Y. The kinetic binding constants (Ks) for compound Y and heparin were 1,333 nM and 42 nM, respectively. It was also shown that both compounds bind to the same receptors. The Scatchard plots indicated that 1,319 nmoles compound Y and 35 nmoles heparin bound per microgram cell protein, indicating that 40-fold more molecules of compound Y bound to the receptors when compared to heparin. No significant internalization of the compounds was observed.

Binding of heparin and compound Y to endothelial cells stimulates the synthesis of an antithrombotic heparan sulfate proteoglycan

The mechanism by which heparin and antithrombotic agents, including a cyclic octaphenolsufonic acid (compound Y), stimulate the synthesis of an antithrombotic heparan sulfate by endothelial cells in culture was investigated. Compound Y increases the amount of heparan sulfate from the cell surface and secreted to the endothelial cell receptors at a concentration of 0.16µM for heparin and 2.7µM for compound Y. The kinetic binding constants (Ks) for compound Y and heparin were 1,333 nM and 42 nM, respectively. It was also shown that both compounds bind to the same receptors. The Scatchard plots indicated that 1,319 nmoles compound Y and 35 nmoles heparin bound per microgram cell protein, indicating that 40-fold more molecules of compound Y bound to the receptors when compared to heparin. No significant internalization of the compounds was observed

A doença de Chagas em motoristas de táxi na cidade de Uberlândia / Chagas' disease in taxi drivers in the city of Uberlandia

A prevalencia de sorologia positiva para a doenca de Chagas foi pesquisada em 152 motoristas de taxi de Uberlandia (MG). Houve 21 individuos (13,8%) com diagnostico sorologico de infeccao pelo Trypanosoma cruzi. Destes, 16 casos foram avaliados clinicamente, pelo eletrocardiograma (ECG) convencional e pelo estudo radiologico do torax. Todos eram assintomaticos 9 tinham arritmias cardiacas "benignas" pelo ECG (2 dos quais, com area cardiaca aumentada), 7 mostraram ECG e radiografias do torax normais. Ressalta-se a alta prevalencia da tripanosomiase na amostra. Discute-se a conduta medico-trabalhista a assumir diante dos casos positivos e a necessidade da inclusao de exames laboratoriais para diagnostico da doenca de Chagas, na rotina para a obtencao de carteira de motorista (pelo menos para profissionais) nas areas endemicas