Targeted uptake of folic acid-functionalized polymeric nanoparticles loading glycoalkaloidic extract in vitro and in vivo assays.

Solanum lycocarpum fruits contain two major glycoalkaloids (GAs), solamargine (SM) and solasonine (SS). These compounds are reported as cytotoxic. However, they have poor water solubility and low bioavailability. To overcome these disadvantages and getting an efficient formulation the current study aimed to develop, characterize, and test the effectiveness of a nanotechnology-based strategy using poly(D,L-lactide) (PLA) nanoparticles functionalized with folate as delivery system of glycoalkaloidic extract (AE) for bladder cancer therapy. The strategic of adding folic acid into nanoformulations can increase the selectivity of the compounds to the cancer cells reducing the side effects. Our results revealed the successful preparation of AE-loaded folate-targeted nanoparticles (NP-F-AE) with particle size around 177 nm, negative zeta potential, polydispersity index <0.20, and higher efficiency of encapsulation for both GAs present in the extract (>85 %). To investigate the cellular uptake, the fluorescent dye coumarin-6 was encapsulated into the nanoparticle (NP-F-C6). The cell studies showed high uptake of nanoparticles by breast (MDA-MB-231) and bladder (RT4) cancer cells, but not for normal keratinocytes cells (HaCaT) indicating the target uptake to cancer cells. The cytotoxicity of nanoparticles was evaluated on RT4 2D culture model showing 2.16-fold lower IC50 than the free AE. Furthermore, the IC50 increased on the RT4 spheroids compared to 2D model. The nanoparticles penetrated homogeneously into the urotheliumof porcine bladder. These results showed that folate-conjugated polymeric nanoparticles are potential carriers for targeted glycoalkaloidic extract delivery to bladder cancer cells.

QSPR modelling of the soil sorption coefficient from training sets of different sizes.

Quantitative structure-property relationship (QSPR) modelling has been used in many scientific fields. This approach has been extensively applied in environmental research to predict physicochemical properties of compounds with potential environmental impact. The soil sorption coefficient is an important parameter for the evaluation of environmental risks, and it helps to determine the final fate of substances in the environment. In the last few years, different QSPR models have been developed for the determination of the sorption coefficient. In this study, several QSPR models were generated and evaluated for the prediction of log Koc from the relationship with log P. These models were obtained from an extensive and diverse training set (n = 639) and from subsets of this initial set (i.e. halves, fourths and eighths). The aim of this study was to investigate whether the size of the training set affects the statistical quality of the obtained models. Furthermore, statistical equivalence was verified between the models obtained from smaller sets and the model obtained from the total training set. The results confirmed the equivalence between the models, thus indicating the possibility of using smaller training sets without compromising the statistical quality and predictive capability, as long as most chemical classes in the test set are represented in the training set.

High-pressure studies on heavy-fermion antiferromagnet CeCuBi2.

We report in-plane electrical resistivity studies of CeCuBi2 and LaCuBi2 single crystals under applied pressure. At ambient pressure, CeCuBi2 is a c-axis Ising antiferromagnet with a transition temperature [Formula: see text] K. In a magnetic field applied along the c-axis at [Formula: see text] K a spin-flop transition takes place [Formula: see text] T. Applying pressure on CeCuBi2 suppresses T N at a slow rate. [Formula: see text] extrapolates to zero temperature at [Formula: see text] GPa. The critical field of the spin-flop transition [Formula: see text] displays a maximum of 6.8 T at [Formula: see text] GPa. At low temperatures, a zero-resistance superconducting state emerges upon the application of external pressure having a maximum T c of 7 K at 2.6 GPa in CeCuBi2. High-pressure electrical-resistivity experiments on the non-magnetic reference compound LaCuBi2 reveal also a zero resistance state with similar critical temperatures in the same pressure range as CeCuBi2. The great similarity between the superconducting properties of both materials and elemental Bi suggests a common origin of the superconductivity. We discuss that the appearance of this zero resistance state superconductivity may be related to the Bi layers present in the crystalline structure of both compounds and, therefore, could be intrinsic to CeCuBi2 and LaCuBi2, however further experiments under pressure are necessary to clarify this issue.

Determinants of left ventricular diastolic dysfunction in hypertensive patients.

INTRODUCTION: The progression of hypertensive heart disease leads to the left ventricular diastolic dysfunction (LVDD), which is associated with increased cardiovascular morbidity and mortality. The purpose of this analysis is to explore the determinants for LVDD in patients with hypertension. METHODS: This is a secondary analysis of data of Impedance Cardiography in the Evaluation of Left Ventricular Diastolic Dysfunction in Patients with Arterial Hypertension (IMPEDDANS) Study. Mann-Whitney and Chi-square tests were used for univariable analysis. Multiple logistic regression was used to model for LVDD occurrence and discriminative capacity of the model assessed by the value of the area under the curve given by the receiver-operating characteristic curve. RESULTS: Older age (65 vs. 58 years, p<0.001), longer duration of hypertension (160 vs. 48 months, p<0.001), uncontrolled hypertension (59.8 vs. 15.9%, p<0.001), tobacco smoking (17.8 vs. 3.8%, p=0.016), higher systolic blood pressure (133 vs. 124mmHg, p=0.001) and slower heart rate (62 vs. 66bpm, p=0.023) were associated with LVDD. Multivariate model identified uncontrolled hypertension (AdjOR 36.90; 95% CI 7.94-171.58; p<0.001), smoking (AdjOR 6.66; 95% CI 1.63-27.26; p=0.008), eccentric hypertrophy (AdjOR 3.59; 95% CI 0.89-14.39; p=0.072), duration of hypertension (AdjOR 1.03; 95% CI 1.02-1.05; p<0.001) and concentric remodeling (AdjOR 0.19; 95% CI 0.04-0.93; p=0.041) as the more determinant for occurrence of LVDD. The discriminative capacity of the model was AUC=0.95 (95% CI 0.91-0.98). CONCLUSION: The occurrence of LVDD in hypertensive patients was strongly associated to long-lasting, uncontrolled hypertension, tobacco smoking, concentric remodeling and eccentric hypertrophy.

Unraveling 5f-6d hybridization in uranium compounds via spin-resolved L-edge spectroscopy.

The multifaceted character of 5f electrons in actinide materials, from localized to itinerant and in between, together with their complex interactions with 6d and other conduction electron states, has thwarted efforts for fully understanding this class of compounds. While theoretical efforts abound, direct experimental probes of relevant electronic states and their hybridization are limited. Here we exploit the presence of sizable quadrupolar and dipolar contributions in the uranium L3-edge X-ray absorption cross section to provide unique information on the extent of spin-polarized hybridization between 5f and 6d electronic states by means of X-ray magnetic circular dichroism. As a result, we show how this 5f-6d hybridization regulates the magnetism of each sublattice in UCu2Si2 and UMn2Si2 compounds, demonstrating the potentiality of this methodology to investigate a plethora of magnetic actinide compounds.

Ising-type Magnetic Anisotropy in CePd2As2.

We investigated the anisotropic magnetic properties of CePd2As2 by magnetic, thermal and electrical transport studies. X-ray diffraction confirmed the tetragonal ThCr2Si2-type structure and the high-quality of the single crystals. Magnetisation and magnetic susceptibility data taken along the different crystallographic directions evidence a huge crystalline electric field (CEF) induced Ising-type magneto-crystalline anisotropy with a large c-axis moment and a small in-plane moment at low temperature. A detailed CEF analysis based on the magnetic susceptibility data indicates an almost pure |±5/2〉 CEF ground-state doublet with the dominantly |±3/2〉 and the |±1/2〉 doublets at 290 K and 330 K, respectively. At low temperature, we observe a uniaxial antiferromagnetic (AFM) transition at T N = 14.7 K with the crystallographic c-direction being the magnetic easy-axis. The magnetic entropy gain up to T N reaches almost R ln 2 indicating localised 4 f-electron magnetism without significant Kondo-type interactions. Below T N , the application of a magnetic field along the c-axis induces a metamagnetic transition from the AFM to a field-polarised phase at µ 0 H c0 = 0.95 T, exhibiting a text-book example of a spin-flip transition as anticipated for an Ising-type AFM.

Thermopower and thermal conductivity in the Weyl semimetal NbP.

The Weyl semimetal NbP exhibits an extremely large magnetoresistance and an ultra-high mobility. The large magnetoresistance originates from a combination of the nearly perfect compensation between electron- and hole-type charge carriers and the high mobility, which is relevant to the topological band structure. In this work we report on temperature- and field-dependent thermopower and thermal conductivity experiments on NbP. Additionally, we carried out complementary heat capacity, magnetization, and electrical resistivity measurements. We found a giant adiabatic magnetothermopower with a maximum of [Formula: see text] at 50 K in a field of 9 T. Such large effects have been observed rarely in bulk materials. We further observe pronounced quantum oscillations in both thermal conductivity and thermopower. The obtained frequencies compare well with our heat capacity and magnetization data.

Geriatric nutritional risk index as a nutritional and survival risk assessment tool in stable outpatients with systolic heart failure.

BACKGROUND AND AIMS: Malnutrition is frequent in heart failure (HF). However, the best tool for evaluating malnutrition in geriatric patients with HF with reduced ejection fraction (HFrEF) is unknown. This study aimed to evaluate the incremental prognostic value of the geriatric nutritional risk index (GNRI) in stable geriatric outpatients with HFrEF compared with a clinical/laboratory prognostic model. METHODS AND RESULTS: A total of 143 outpatients with HFrEF, aged >65 years, a LVEF <40%, and who were stable and on optimal therapy were studied. Follow-up lasted 3 years. The outcome was all-cause death. The GNRI was calculated as follows: [(1.489 × serum albumin (g/L)) + (41.7 × (current body weight/ideal weight)]. The 3-year death rate was 36.4% and 16 (11.2%) patients were at risk of malnutrition (GNRI ≤98). Deceased patients had a lower GNRI (113.6 ± 9.1 vs. 105.6 ± 9.2; p < 0.001) than did survivors. Greater values of the GNRI (hazard ratio = 0.93, 95% confidence interval [CI] = 0.90-0.95; p < 0.001) and GNRI >98 (hazard ratio = 0.29, 95% CI 0.15-0.57; p < 0.001) were associated with better survival. These factors remained significant after adjustment of significant confounders. The GNRI was a better discriminator of death than weight and albumin. Adding the GNRI to the clinical/laboratory predictor survival model significantly increased the c-statistics from 0.93 to 0.95 (p < 0.001) and the chi-square likelihood ratio test from 106.15 to 119.9. CONCLUSION: The risk of malnutrition, as assessed by the GNRI, in stable geriatric outpatients with HFrEF is a strong independent predictor of survival. The GNRI adds significant prognostic information to the clinical/laboratory model.

Descending facilitatory pain pathways mediate ongoing pain and tactile hypersensitivity in a rat model of trigeminal neuropathic pain.

The Chronic Constriction Injury of the Infraorbital Nerve (CCI-ION) is a well-established model to study facial sensory changes related to trigeminal neuropathic pain. CCI-ION induces heat hypersensitivity that resolves within 2-3 weeks and a delayed mechanical hypersensitivity that emerges during the second week post-injury. The role of descending facilitatory pain pathways from the rostro ventromedial medulla (RVM) in mediating the heat and tactile hypersensitivity was examined. CCI-ION induced heat hypersensitivity observed 5days post-surgery was reversed by systemic, but not RVM lidocaine. CCI-ION-induced tactile hypersensitivity observed 15days post-surgery was reversed by systemic lidocaine and attenuated by RVM lidocaine. CCI-ION-induced spontaneous pain was determined using conditioned place preference (CPP) to pain relief at each time-point. At day 5 post-CCI-ION, neither systemic nor RVM lidocaine induced CPP. However, at 15days post-CCI-ION, CPP was observed to the chamber paired with RVM lidocaine, but not systemic lidocaine. These data indicate that CCI-ION induced heat hypersensitivity is not dependent on descending facilitatory pain pathways 5-days post-injury whereas descending facilitatory pain pathways mediate tactile allodynia and spontaneous pain 15days post-CCI-ION. This suggests that CCI-ION induces early peripheral sensitization followed by development of central sensitization that mediates spontaneous pain and contributes to mechanical hypersensitivity.

Association of ADAMTS7 gene polymorphism with cardiovascular survival in coronary artery disease.

Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and vascular smooth muscular cell (VSMC) migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1,128 patients with angiographic proven CAD, who were followed up prospectively for a mean follow-up period of 63 (range 6-182) mo, were genotyped for rs3825807 A/G. Survival statistics (Cox regression) compared heterozygous (AG) and wild-type (AA) with the reference homozygous GG. Kaplan-Meier (K-M) survival curves were performed according to ADAMTS7 genotypes for CV mortality. Results showed that 47.3% of patients were heterozygous (AG), 36.5% were homozygous for the wild-type allele (AA) and only 16.2% were homozygous for the GG genotype. During the follow-up period, 109 (9.7%) patients died, 77 (6.8%) of CV causes. Survival analysis showed that AA genotype was an independent risk factor for CV mortality compared with reference genotype GG (HR = 2.7, P = 0.025). At the end of follow-up, the estimated survival probability (K-M) was 89.8% for GG genotype, 82.2% for AG and 72.3% for AA genotype (P = 0.039). Carriage of the mutant G allele of the ADAMTS7 gene was associated with improved CV survival in patients with documented CAD. The native overfunctional ADAMTS7 allele (A) may accelerate VSMC migration and lead to neointimal thickening, atherosclerosis progression and acute plaque events. ADAMTS7 gene should be further explored in CAD for risk prediction, mechanistic and therapeutic goals.

Cyclin D1 expression in prostate carcinoma

The purpose of this study was to investigate the relationship between cyclin D1 expression and clinicopathological parameters in patients with prostate carcinoma. We assessed cyclin D1 expression by conventional immunohistochemistry in 85 patients who underwent radical prostatectomy for prostate carcinoma and 10 normal prostate tissue samples retrieved from autopsies. We measured nuclear immunostaining in the entire tumor area and based the results on the percentage of positive tumor cells. The preoperative prostate-specific antigen (PSA) level was 8.68±5.16 ng/mL (mean±SD). Cyclin D1 staining was positive (cyclin D1 expression in REPLACE_GT5% of tumor cells) in 64 cases (75.4%) and negative (cyclin D1 expression in ≤5% of tumor cells) in 21 cases (including 15 cases with no immunostaining). Normal prostate tissues were negative for cyclin D1. Among patients with a high-grade Gleason score (≧7), 86% of patients demonstrated cyclin D1 immunostaining of REPLACE_GT5% (PREPLACE_LT0.05). In the crude analysis of cyclin D1 expression, the high-grade Gleason score group showed a mean expression of 39.6%, compared to 26.9% in the low-grade Gleason score group (PREPLACE_LT0.05). Perineural invasion tended to be associated with cyclin D1 expression (P=0.07), whereas cyclin D1 expression was not associated with PSA levels or other parameters. Our results suggest that high cyclin D1 expression could be a potential marker for tumor aggressiveness.

Nutritional status of geriatric outpatients with systolic heart failure and its prognostic value regarding death or hospitalization, biomarkers and quality of life.

INTRODUCTION: The prevalence of malnutrition in ambulatory patients with heart failure is difficult to determine, depending on the timing and methodology. OBJECTIVE: To determine the nutritional status of outpatients with systolic heart failure with the Mini Nutritional Assessment (MNA) full and short-form versions, and evaluate its relationship with the short-term prognosis, biomarkers and quality of life. METHODS: Fifty consecutive (70% male), geriatric (74.3+ 6.2years old) stable outpatient with heart failure (NYHA class II 68%, III 32%) and left ventricular ejection fraction of 26.7 +11.5% were included and followed during 12 months. At a routine visit to the heart failure clinic, the MNA, the Minnesota Living with Heart Failure questionnaire (MLHFQ) were applied. According to the MNA screening score the nutritional status was classified using the MNA full (MNA-F) and the short-form (MNA-F) versions of the questionnaire. The recorded events were death and hospitalization. STATISTICS: The survival and hospitalizations curves were evaluated with the Log-Rank test and Cox Regression analysis. The association between parameters was analyzed with the Pearson and Spearmann correlation coefficient. RESULTS: (1) The mortality and hospitalization rates were 12% and 42%, respectively. (2) With the MNA-SF 7.6% of the patients had malnutrition and 20% were at risk of malnutrition. There was a good agreement (90%) between the MNA-SF and the MNA-F classifications. (3) There was a significant relationship between the MNA screening score and the MLHFQ (rs= -0.592 p<0.001), Nt-ProBNP (rs= -0.49 p<0.001) and total plasma protein (r= 0.672 p=0.006); (3) The MNA-SF nutritional classification was associated with the 12 months survival (Log-Rank p=0.044) and hospitalization (Log-Rank p=0.005) curves. (4) Those patients with malnutrition by the MNA-SF were at greater risk of death (HR= 8.0 p=0.059) and hospitalization (HR 8.1 p=0.008). CONCLUSION: The MNA is useful for the evaluation of the nutritional status of elderly outpatients with systolic heart failure. It is a good predictor of the short-term outcome and is also associated with the quality of life and Nt-ProBNP.

Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis.

The objective of this study was to clarify the role of bisphosphonates in the treatment of osteoporosis in patients with prostate adenocarcinoma under androgen deprivation therapy (ADT). The Medline, EMBASE, Cancerlit and the American Society of Clinical Oncology abstract databases were searched for published randomized, placebo-controlled trials evaluating the usage of bisphosphonates in patients with prostate cancer (PC) under ADT. The outcomes assessed were fracture, osteoporosis, incidence of adverse events and changes in bone mineral density (BMD) during treatment. A total of 15 articles (2634 participants) were included in the meta-analysis. Treatment with bisphosphonates showed a substantial effect in preventing fractures (risk ratio (RR), 0.80; P = 0.005) and osteoporosis (RR, 0.39; P <0.00001). Zoledronic acid showed the best number needed to treat (NTT), compared with placebo, in relation to fractures and osteoporosis (NNT = 14.9 and NNT = 2.68, respectively). The between-group difference (bisphosphonates vs placebo) in the lumbar spine and femoral neck BMD were 5.18 ± 3.38% and 2.35 ± 1.16%, respectively. This benefit of bone loss prevention could be reached without major side effects (cardiovascular or gastrointestinal events). Bisphosphonates are effective in preventing bone loss in patients with PC who are under ADT.

Anti-müllerian hormone is the best predictor of poor response in ICSI cycles of patients with endometriosis.

PURPOSE: To correlate ovarian reserve (OR) markers with response in assisted reproduction techniques (ART) and determine their ability to predict poor response among patients with endometriosis (EDT). METHODS: We evaluated ART cycles of 27 women with EDT and 50 with exclusive male factor. Basal follicle stimulating hormone (FSH) and anti-müllerian hormone (AMH) levels were determined. Ovarian response to gonadotropin stimulation was assessed and correlation coefficients calculated between the variables and reserve markers. Areas under the curve (AUC) determined ability of tests to predict poor response. RESULTS: AMH was significantly correlated with response in both groups and it was the only marker with significant discriminative capacity to predict poor response among EDT (AUC = 0.842; 95% CI: 0.651-0.952) and control group (AUC = 0.869; 95% CI: 0.743-0.947). CONCLUSION: Infertile patients with endometriosis can benefit from the pre-therapeutic assessment of OR markers. However, regardless of disease presence, only AMH predicts poor response to stimulus.

Study of the magnetocaloric properties of the antiferromagnetic compounds RGa2 (R = Ce, Pr, Nd, Dy, Ho and Er).

Magnetocaloric properties of antiferromagnetic RGa(2) (R = Ce, Pr, Nd, Dy, Ho and Er) compounds have been reported. These systems present an antiferromagnetic transition below 15 K and a field induced metamagnetic transition from the antiferromagnetic to ferromagnetic state. Our results show that the character of the magnetic field induced transition along the series affects the magnetocaloric properties. For the compounds with R = Ho, Dy and Er both negative and positive magnetocaloric effect (MCE) were observed above µ(0)ΔH = 2 T where the rate between negative and positive MCE contributions depends on how the magnetic transitions occur in these compounds. The evaluated values of maximum magnetocaloric properties of RGa(2) compounds are similar to other potential magnetic refrigerant materials reported in the literature.

Gene-gene interaction affects coronary artery disease risk.

INTRODUCTION: Various studies have compared coronary artery disease (CAD) patients with controls in order to determine which polymorphisms are associated with a higher risk of disease. The results have often been contradictory. Moreover, these studies evaluated polymorphisms in isolation and not in association, which is the way they occur in nature. OBJECTIVE: Our purpose was to evaluate the risk of CAD in patients with associated polymorphisms in the same gene or in differen genes. METHODS: We evaluated the risk associated with ACE DD, ACE 8 CC, ACT 174MM, AGT 235TT, MTHFR 677TT, MTHFR 1298AA, PON1 192RR and PON1 55MM in 298 CAD patients and 298 healthy individuals. We then evaluated the risk of associated polymorphisms in the same gene (ACE DD + ACE 8GG; AGT 174MM + AGT 235TT; MTHFR 677TT + MTHFR 1298AA). Finally, for the isolated polymorphisms which were significant, we evaluated the risk of polymorphism associations at different functional levels (ACE + AGT; ACE + MTHFR; ACE + PON1). Multiple logistic regression was used to identify independent risk factors for CAD. RESULTS: Isolated polymorphisms including ACE DD(p < 0.0001), ACE 8 gg (p=0.023), and MTHFR 1298AA (p = 0.049) presented with a significantly higher frequency in the CAD group. An association of polymorphisms in the same gene did not have an additive or synergistic effect, nor did it increase the risk of CAD. Polymorphic associations in different genes increased the risk of CAD, compared with the isolated polymorphisms. The association of ACE DD or ACE 8 GG with PON1 192RR increased the risk of CA fourfold (1.8 to 4.2). After logistic regression analysis, current smoking, family history, fibrinogen, diabetes, and the ACE DD or ACE 8 GG + MTHFR 1298AA and ACE DD or ACE 8 GG + PON1 192RR associations remained in the, model and proved to be independent predictors of CAD. CONCLUSIONS: The association of polymorphisms in the same gene did not increase the risk of the isolated polymorphism. The association of polymorphisms in genes belonging to different enzyme systems was always linked to increased risk compared to the isolated polymorphisms. This study may contribute to a better understanding of overall genetic risk for CAD rather than that associated with each polymorphism in isolation.

Serological testing for celiac disease in women with endometriosis. A pilot study.

PURPOSE OF INVESTIGATION: Celiac disease (CD) involves immunologically mediated intestinal damage with consequent micronutrient malabsorption and varied clinical manifestations, and there is a controversial association with infertility. The objective of the present study was to determine the presence of CD in a population of infertile women with endometriosis. METHODS: A total of 120 women with a diagnosis of endometriosis confirmed by laparoscopy (study group) and 1,500 healthy female donors aged 18 to 45 years were tested for CD by the determination of IgA-transglutaminase antibody against human tissue transglutaminase (t-TGA) and anti-endomysium (anti-EMA) antibodies. RESULTS: Nine of the 120 women in the study group were anti-tTGA positive and five of them were also anti-EMA positive. Four of these five patients were submitted to intestinal biopsy which revealed CD in three cases (2.5% prevalence). The overall CD prevalence among the population control group was 1:136 women (0.66%). CONCLUSION: This is the first study reporting the prevalence of CD among women with endometriosis, showing that CD is common in this population group (2.5%) and may be clinically relevant.

Metabolic and cardiovascular impact of oral contraceptives in polycystic ovary syndrome.

Chronic anovulation, polycystic ovarian morphology and hyperandrogenism are the diagnostic criteria for polycystic ovary syndrome (PCOS). Metabolic disturbances are more common in PCOS women who are prone to develop metabolic syndrome and to present higher levels of some cardiovascular disease risk marker. Oral contraceptives are widely used in PCOS, but conflicting data have been reported regarding their impact on carbohydrate and lipid metabolism on PCOS women. This paper presents a critical evaluation of combined oral contraceptives (COCs) metabolic effect - carbohydrate metabolism and insulin sensitivity, lipid metabolism, haemostasis, body weight, arterial pressure and cardiovascular impact - on PCOS women. Because of the paucity of data on the impact of COCs on cardiovascular and metabolic parameters in PCOS patients, most of there commendations are based on studies involving ovulatory women. The use of low-dose COCs is preferable in PCOS, especially among patients with glucose intolerance, insulin resistance and uncomplicated diabetes mellitus. Although reported as a side effect of COCs, marked weight gain has not been confirmed among users. However, when arterial hypertension or elevated risk for thromboembolism is present, progestogen-only hormonal contraceptives should be used instead of COCs. Regarding dyslipidaemia, COCs reduce low-density lipoprotein and total cholesterol and elevate high-density lipoprotein and triglycerides, and therefore are not recommended for women with high triglycerides levels. The choice of a COC, which alleviates the PCOS-induced hyperandrogenism without significant negative impact on cardiovascular risk, is one of the greatest challenges faced by gynaecologists nowadays.

Human paraoxonase gene polymorphisms and coronary artery disease risk.

BACKGROUND: Complex diseases such as coronary artery disease (CAD), hypertension and diabetes are usually caused by individual susceptibility to multiple genes, environmental factors, and the interaction between them. The paraoxonase 1 (PON1) enzyme has been implicated in the pathogenesis of atherosclerosis and CAD. Two common polymorphisms in the coding region of the PON1 gene, which lead to a glutamine (Q)/arginine (R) substitution at position 192 and a leucine (L)/methionine (M) substitution at position 55, influence PON1 activity. Studies have investigated the association between these polymorphisms and CAD, but with conflicting results. AIMS: 1) To evaluate the association between PON1 polymorphisms and CAD risk; and 2) to study the interaction between PON1 polymorphisms and others in different candidate genes. METHODS: We evaluated the risk of CAD associated with PON1 Q192R and L55M polymorphisms in 298 CAD patients and 298 healthy individuals. We then evaluated the risk associated with the interaction of the PON1 polymorphisms with ACE DD, ACE 8 GG and MTHFR 1298AA. Finally, using a logistic regression model, we evaluated which variables (genetic, biochemical and environmental) were linked significantly and independently with CAD. RESULTS: We found that the PON1 55MM genotype was more common in the CAD population, but this did not reach statistical significance as a risk factor for CAD, while PON1 192RR presented an 80% higher relative risk compared to the population without this polymorphism. The interaction between PON1 192RR and MTHFR 1298AA, sited in different genes, increased the risk for CAD, compared with the polymorphisms in isolation (OR=2.76; 95% CI=1.20-6.47; p=0.009), as did the association of PON1 192RR with ACE DD, which presented a 337% higher risk compared to the population without this polymorphic association (OR=4.37; 95% CI=1.47-13.87; p=0.002). Similarly, the association between PON1 192RR and ACE 8 GG was linked to an even higher risk (OR=6.23; 95% CI=1.67-27.37; p<0.001). After logistic regression, smoking, family history, fibrinogen, diabetes, Lp(a) and the association of PON1 192RR + ACE 8 GG remained in the regression model and proved to be significant and independent risk factors for CAD. In the regression model the latter association had OR=14.113; p=0.018. CONCLUSION: When analyzed separately, the PON1 192RR genotype presented a relative risk for CAD 80% higher than in the population without this genotype. Its association with other genetic polymorphisms sited in different genes, coding for different enzymes and belonging to different physiological systems, always increased the risk for CAD. After correction for other conventional and biochemical risk factors, the PON1 192RR + ACE 8 GG association remained a significant and independent risk factor for CAD.