Quantitative Analysis of Vasodilatory Action of Quercetin on Intramural Coronary Resistance Arteries of the Rat In Vitro

Background

Dietary quercetin improves cardiovascular health, relaxes some vascular smooth muscle and has been demonstrated to serve as a substrate for the cyclooxygenase enzyme.

Aims

1. To test quantitatively a potential direct vasodilatory effect on intramural coronary resistance artery segments, in different concentrations. 2. To scale vasorelaxation at different intraluminal pressure loads on such vessels of different size. 3. To test the potential role of prostanoids in vasodilatation induced by quercetin.

Methods

Coronary arterioles (70–240 µm) were prepared from 24 rats and pressurized in PSS, using a pressure microangiometer.

Results

The spontaneous tone that developed at 50 mmHg was relaxed by quercetin in the 10⁻⁹ moles/lit concentration (p<0.05), while 10⁻⁵ moles/lit caused full relaxation. Significant relaxation was observed at all pressure levels (10–100 mmHg) at 10⁻⁷ moles/lit concentration of quercetin. The cyclooxygenase blocker indomethacin (10⁻⁵moles/lit) induced no relaxation but contraction when physiological concentrations of quercetin were present in the tissue bath (p<0.02 with Anova), this contraction being more prominent in smaller vessels and in the higher pressure range (p<0.05, Pearson correlation). A further 2–8% contraction could be elicited by the NO blocker L-NAME (10⁻⁴ moles/lit).

Conclusion

These results demonstrate that circulating levels of quercetin (10⁻⁷ moles/lit) exhibit a substantial coronary vasodilatory effect. The extent of it is commeasurable with that of several other physiological mechanisms of coronary blood flow control. At least part of this relaxation is the result of an altered balance toward the production of endogenous vasodilatory prostanoids in the coronary arteriole wall.     

Activation of GPER Induces Differentiation and Inhibition of Coronary Artery Smooth Muscle Cell Proliferation

Background

Vascular pathology and dysfunction are direct life-threatening outcomes resulting from atherosclerosis or vascular injury, which are primarily attributed to contractile smooth muscle cells (SMCs) dedifferentiation and proliferation by re-entering cell cycle. Increasing evidence suggests potent protective effects of G-protein coupled estrogen receptor 1 (GPER) activation against cardiovascular diseases. However, the mechanism underlying GPER function remains poorly understood, especially if it plays a potential role in modulating coronary artery smooth muscle cells (CASMCs).

Methodology/Principal Findings

The objective of our study was to understand the functional role of GPER in CASMC proliferation and differentiation in coronary arteries using from humans and swine models. We found that the GPER agonist, G-1, inhibited both human and porcine CASMC proliferation in a concentration- (10⁻⁸ to 10⁻⁵ M) and time-dependent manner. Flow cytometry revealed that treatment with G-1 significantly decreased the proportion of S-phase and G2/M cells in the growing cell population, suggesting that G-1 inhibits cell proliferation by slowing progression of the cell cycle. Further, G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21, and partially mediated by suppressed ERK1/2 and Akt pathways. In addition, G-1 induces SMC differentiation evidenced by increased α-smooth muscle actin (α-actin) and smooth muscle protein 22α (SM22α) protein expressions and inhibits CASMC migration induced by growth medium.

Conclusion

GPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. GPER may constitute a novel mechanism to suppress intimal migration and/or synthetic phenotype of VSMC.     

Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs

Background

The role of vascular endothelial growth factor (VEGF)-induced 3 different nitric oxide synthase (NOS) isoforms in lung development and injury in the newborn (NB) lung are not known. We hypothesized that VEGF-induced specific NOS pathways are critical regulators of lung development and injury.

Methodology

We studied NB wild type (WT), lung epithelial cell-targeted VEGF165 doxycycline-inducible overexpressing transgenic (VEGFTG), VEGFTG treated with a NOS1 inhibitor (L-NIO), VEGFTG x NOS2^-/- and VEGFTG x NOS3^+/- mice in room air (RA) for 7 postnatal (PN) days. Lung morphometry (chord length), vascular markers (Ang1, Ang2, Notch2, vWF, CD31 and VE-cadherin), cell proliferation (Ki67), vascular permeability, injury and oxidative stress markers (hemosiderin, nitrotyrosine and 8-OHdG) were evaluated.

Results

VEGF overexpression in RA led to increased chord length and vascular markers at PN7, which were significantly decreased to control values in VEGFTG x NOS2^−/− and VEGFTG x NOS3^+/- lungs. However, we found no noticeable effect on chord length and vascular markers in the VEGFTG / NOS1 inhibited group. In the NB VEGFTG mouse model, we found VEGF-induced vascular permeability in the NB murine lung was partially dependent on NOS2 and NOS3-signaling pathways. In addition, the inhibition of NOS2 and NOS3 resulted in a significant decrease in VEGF-induced hemosiderin, nitrotyrosine- and 8-OHdG positive cells at PN7. NOS1 inhibition had no significant effect.

Conclusion

Our data showed that the complete absence of NOS2 and partial deficiency of NOS3 confers protection against VEGF-induced pathologic lung vascular and alveolar developmental changes, as well as injury markers. Inhibition of NOS1 does not have any modulating role on VEGF-induced changes in the NB lung. Overall, our data suggests that there is a significant differential regulation in the NOS-mediated effects of VEGF overexpression in the developing mouse lung.     

Prognostic Value of Umbilical and Cerebral Doppler in Fetal Growth Restriction: Comparison of Dichorionic Twins and Singletons

Objective

To compare the prognostic value of fetal Doppler in dichorionic twins and singletons by measuring the interval between diagnosis of an abnormal Doppler flow and birth in fetuses who are small for gestational age (SGA).

Design

Comparative retrospective study using a prospectively collected database.

Setting

A level 3 maternity unit in France.

Population

Fetuses from singleton and dichorionic pregnancies who are SGA (vascular or unexplained), defined by an abdominal circumference (AC) measurement below the 10^th percentile and confirmed by a birth weight below the 10^th percentile.

Methods

Fisher''s exact and Chi-2 tests were used to compare frequencies, and the Mann-Whitney-Wilcoxon test was used to compare medians in non-Gaussian distributions.

Main outcome measures

Both neonatal outcomes and intervals between the first Doppler abnormality and birth were compared in the groups of dichorionic twins and singletons.

Results

Obstetric and neonatal outcome were similar in the 104 SGA dichorionic twins and 170 SGA singletons. Abnormalities of umbilical artery Doppler, regardless of type, appeared at the same frequency in both groups (52.9%) but were identified earlier in twins (25 versus 28 weeks, p = 0.02). Among fetuses with abnormal Doppler flow, the interval between the finding and birth was significantly longer in the twins than the singletons (44 vs 15 days, p<0.01).

Conclusions

The prognostic value of an abnormal Doppler finding for the course of a pregnancy may be different in dichorionic twins and singletons. The management of women carrying SGA twins and the information provided to them should take these results into account.     

Reliability and Responsiveness of Cardiopulmonary Exercise Testing in Fatigued Persons with Multiple Sclerosis and Low to Mild Disability

Background

Peak oxygen uptake (VO₂peak) via cardiopulmonary exercise testing is considered the gold standard for testing aerobic capacity in healthy participants and people with various medical conditions. The reliability and responsiveness of cardiopulmonary exercise testing outcomes in persons with MS (PwMS) have not been extensively studied.

Objective

(1) to investigate the reliability of cardiopulmonary exercise parameters in PwMS; (2) to determine the responsiveness, in terms of the smallest detectable change (SDC), for each parameter.

Design

Two repeated measurements of cardiopulmonary exercise outcomes were obtained, with a median time interval of 16 days.

Methods

Thirty-two PwMS suffering from subjective fatigue performed cardiopulmonary exercise tests on a cycle ergometer, to voluntary exhaustion. We calculated the reliability, in terms of the intra-class correlation coefficient (ICC [2,k]; absolute agreement), and the measurement error, in terms of standard error of measurement (SEM) and SDC at individual (SDC_individual) and group level (SDC_group).

Results

The ICC for VO₂peak was 0.951, with an SEM of 0.131 L∙min⁻¹ and an SDC_individual of 0.364 L∙min⁻¹. When corrected for bodyweight, the ICC of VO₂peak was 0.933, with an SEM of 1.7 mL∙kg⁻¹∙min⁻¹ and in an SDC_individual of 4.6 mL∙kg⁻¹∙min⁻¹.

Limitations

Generalization of our study results is restricted to fatigued PwMS with a low to mild level of disability.

Conclusions

At individual level, cardiopulmonary exercise testing can be used reliably to assess physical fitness in terms of VO₂peak, but less so to determine significant changes. At group level, VO₂peak can be reliably used to determine physical fitness status and establish change over time.     

Pregnancy and Delivery in Patients with Mastocytosis Treated at the Polish Center of the European Competence Network on Mastocytosis (ECNM)

Objective

To present current guidelines regarding treatment of mastocytosis in pregnancy on the example of observed patients.

Design

Case control national study.

Setting

Polish Center of the European Competence Network on Mastocytosis (ECNM).

Population or Sample

23 singleton spontaneous pregnancies in 17 women diagnosed with mastocytosis in years 1999–2014, before becoming pregnant.

Methods

Prospective analysis outcomes of pregnancies and deliveries.

Main Outcome Measures

Survey developed in cooperation with the Spanish Instituto de Estudios de Mastocitosis de Castilla-La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Red Espańola de Mastocitosis (REMA), Spain.

Results

All 23 pregnancies resulted from natural conception. Obstetrical complications recorded in the first trimester included spontaneous miscarriage (5 pregnancies). Four patients delivered preterm, including one delivery due to preeclampsia at 26 weeks which resulted with neonate death due to extreme prematurity. Five women delivered via cesarean: four due to obstetrical indications and one due to mastocytosis, during which no anesthesia related complications were recorded. Of patients delivering vaginally, two received extradural anesthesia, three required oxytocin infusion due to uterine hypotonia. No labor complications were recorded. In one woman with pregnancy-induced hypertension, early puerperium was complicated by the presence of persistent arterial hypertension. One neonate was born with the signs of cutaneous mastocytosis. Another neonate was diagnosed with Patau syndrome. Four women were treated for mastocytosis prior to conception and continued therapy after becoming pregnant. One patient was put on medications in the first trimester due to worsening of her symptoms. Pregnancy exerted only a slight effect on the intensity and frequency of mastocytosis-related symptoms observed. Worsening of the disease-related symptoms was documented in only four patients (23%). None of the patients showed the signs of anaphylaxis, either before becoming pregnant, or during pregnancy and puerperium.

Conclusions

There is no contraindication to pregnancy when mastocystosis-related pathologies are under appropriate medical control.     

Turbulent Kinetic Energy Measurement Using Phase Contrast MRI for Estimating the Post-Stenotic Pressure Drop: In Vitro Validation and Clinical Application

Background

Although the measurement of turbulence kinetic energy (TKE) by using magnetic resonance imaging (MRI) has been introduced as an alternative index for quantifying energy loss through the cardiac valve, experimental verification and clinical application of this parameter are still required.

Objectives

The goal of this study is to verify MRI measurements of TKE by using a phantom stenosis with particle image velocimetry (PIV) as the reference standard. In addition, the feasibility of measuring TKE with MRI is explored.

Methods

MRI measurements of TKE through a phantom stenosis was performed by using clinical 3T MRI scanner. The MRI measurements were verified experimentally by using PIV as the reference standard. In vivo application of MRI-driven TKE was explored in seven patients with aortic valve disease and one healthy volunteer. Transvalvular gradients measured by MRI and echocardiography were compared.

Results

MRI and PIV measurements of TKE are consistent for turbulent flow (0.666 < R² < 0.738) with a mean difference of −11.13 J/m³ (SD = 4.34 J/m³). Results of MRI and PIV measurements differ by 2.76 ± 0.82 cm/s (velocity) and −11.13 ± 4.34 J/m³ (TKE) for turbulent flow (Re > 400). The turbulence pressure drop correlates strongly with total TKE (R² = 0.986). However, in vivo measurements of TKE are not consistent with the transvalvular pressure gradient estimated by echocardiography.

Conclusions

These results suggest that TKE measurement via MRI may provide a potential benefit as an energy-loss index to characterize blood flow through the aortic valve. However, further clinical studies are necessary to reach definitive conclusions regarding this technique.     

Postnatal Depression among Rural Women in South India: Do Socio-Demographic,Obstetric and Pregnancy Outcome Have a Role to Play?

Introduction

Postnatal depression (PND) is one of the most common psychopathology and is considered as a serious public health issue because of its devastating effects on mother, family, and infant or the child.

Objective

To elicit socio-demographic, obstetric and pregnancy outcome predictors of Postnatal Depression (PND) among rural postnatal women in Karnataka state, India.

Design

Hospital based analytical cross sectional study

Setting

A rural tertiary care hospital of Mandya District, Karnataka state, India.

Sample

PND prevalence based estimated sample of 102 women who came for postnatal follow up from 4th to 10th week of lactation.

Method

Study participants were interviewed using validated kannada version of Edinburgh Postnatal Depression Scale (EPDS). Cut-off score of ≥13 was used as high risk of PND. The percentage of women at risk of PND was estimated, and differences according to socio-demographic, obstetric and pregnancy outcome were described. Logistic regression was applied to identify the independent predictors of PND risk.

Main Outcome Measures

Prevalence, Odds ratio (OR) and adjusted (adj) OR of PND

Results

Prevalence of PND was 31.4% (95% CI 22.7–41.4%). PND showed significant (P<0.05) association with joint family, working women, non-farmer husbands, poverty, female baby and pregnancy complications or known medical illness. In binomial logistic regression poverty (adjOR: 11.95, 95% CI:1.36–105), birth of female baby (adjOR: 3.6, 95% CI:1.26–10.23) and pregnancy complications or known medical illness (adjOR: 17.4, 95% CI:2.5–121.2) remained as independent predictors of PND.

Conclusion

Risk of PND among rural postnatal women was high (31.4%). Birth of female baby, poverty and complications in pregnancy or known medical illness could predict the high risk of PND. PND screening should be an integral part of postnatal care. Capacity building of grass root level workers and feasibility trials for screening PND by them are needed.     

Individualized Exercise Training at Maximal Fat Oxidation Combined with Fruit and Vegetable-Rich Diet in Overweight or Obese Women: The LIPOXmax-Réunion Randomized Controlled Trial

Objectives

Lifestyle combined interventions are a key strategy for preventing type-2 diabetes (T2DM) in overweight or obese subjects. In this framework, LIPOXmax individualized training, based on maximal fat oxidation [MFO], may be a promising intervention to promote fat mass (FM) reduction and prevent T2DM. Our primary objective was to compare three training programs of physical activity combined with a fruit- and vegetable-rich diet in reducing FM in overweight or obese women.

Design and setting

A five months non-blinded randomized controlled trial (RCT) with three parallel groups in La Réunion Island, a region where metabolic diseases are highly prevalent.

Subjects

One hundred and thirty-six non-diabetic obese (body mass index [BMI]: 27–40 kg/m²) young women (aged 20–40) were randomized (G1: MFO intensity; G2: 60% of VO₂-peak intensity; G3: free moderate-intensity at-home exercise following good physical practices).

Outcomes

Anthropometry (BMI, bodyweight, FM, fat-free mass), glucose (fasting plasma glucose, insulin, HOMA-IR) and lipid (cholesterol and triglycerides) profiles, and MFO values were measured at month-0, month-3 and month-5.

Results

At month-5, among 109 women assessed on body composition, the three groups exhibited a significant FM reduction over time (G1: -4.1±0.54 kg; G2: -4.7±0.53 kg; G3: -3.5±0.78 kg, p<0.001, respectively) without inter-group differences (p = 0.135). All groups exhibited significant reductions in insulin levels or HOMA-IR index, and higher MFO values over time (p<0.001, respectively) but glucose control improvement was higher in G1 than in G3 while MFO values were higher in G1 than in G2 and G3. Changes in other outcome measures and inter-group differences were not significant.

Conclusion

In our RCT the LIPOXmax intervention did not show a superiority in reducing FM in overweight or obese women but is associated with higher MFO and better glucose control improvements. Other studies are required before proposing LIPOXmax training for the prevention of T2DM in overweight or obese women.

Trial Registration

ClincialTrials.gov NCT01464073     

Maternal Snoring May Predict Adverse Pregnancy Outcomes: A Cohort Study in China

Objective

To examine the prevalence of snoring during pregnancy and its effects on key pregnancy outcomes.

Methods

Pregnant women were consecutively recruited in their first trimester. Habitual snoring was screened by using a questionnaire in the 1^st and 3^rd trimester, respectively. According to the time of snoring, participants were divided into pregnancy onset snorers, chronic snorers and non-snorers. Logistic regressions were performed to examine the associations between snoring and pregnancy outcomes.

Results

Of 3 079 pregnant women, 16.6% were habitual snorers, with 11.7% were pregnancy onset snorers and 4.9% were chronic snorers. After adjusting for potential confounders, chronic snorers were independently associated with gestational diabetes mellitus (GDM) (RR 1.66, 95%CI 1.09–2.53). Both pregnancy onset and chronic snorers were independently associated with placental adhesion (RR 1.96, 95%CI 1.17–3.27, and RR 2.33, 95%CI 1.22–4.46, respectively). Pregnancy onset snorers were at higher risk of caesarean delivery (RR 1.37, 95%CI 1.09–1.73) and having macrosomia (RR 1.54, 95%CI 1.05–2.27) and large for gestational age (LGA) (RR 1.71, 95%CI 1.31–2.24) infants. In addition, being overweight or obese before pregnancy plays an important role in mediating snoring and adverse pregnancy outcomes.

Conclusions

Maternal snoring may increase the risk of adverse pregnancy outcomes, and being overweight or obese before pregnancy with snoring is remarkable for researchers. Further studies are still needed to confirm our results.     

Optimal Timing of Delivery among Low-Risk Women with Prior Caesarean Section: A Secondary Analysis of the WHO Multicountry Survey on Maternal and Newborn Health

Objective

To investigate optimal timing of elective repeat caesarean section among low-risk pregnant women with prior caesarean section in a multicountry sample from largely low- and middle-income countries.

Design

Secondary analysis of a cross-sectional study.

Setting

Twenty-nine countries from the World Health Organization Multicountry Survey on Maternal and Newborn Health.

Population

29,647 women with prior caesarean section and no pregnancy complications in their current pregnancy who delivered a term singleton (live birth and stillbirth) at gestational age 37–41 weeks by pre-labour caesarean section, intra-partum caesarean section, or vaginal birth following spontaneous onset of labour.

Methods

We compared the rate of short-term adverse maternal and newborn outcomes following pre-labour caesarean section at a given gestational age, to those following ongoing pregnancies beyond that gestational age.

Main Outcome Measures

Severe maternal outcomes, neonatal morbidity, and intra-hospital early neonatal mortality.

Results

Odds of neonatal morbidity and intra-hospital early neonatal mortality were 0.48 (95% confidence interval [CI] 0.39–0.60) and 0.31 (95% CI 0.16–0.58) times lower for ongoing pregnancies compared to pre-labour caesarean section at 37 weeks. We did not find any significant change in the risk of severe maternal outcomes between pre-labour caesarean section at a given gestational age and ongoing pregnancies beyond that gestational age.

Conclusions

Elective repeat caesarean section at 37 weeks had higher risk of neonatal morbidity and mortality compared to ongoing pregnancy, however risks at later gestational ages did not differ between groups.     

Overweight Is an Independent Risk Factor for Reduced Lung Volumes in Myotonic Dystrophy Type 1

Background

In this large observational study population of 105 myotonic dystrophy type 1 (DM1) patients, we investigate whether bodyweight is a contributor of total lung capacity (TLC) independent of the impaired inspiratory muscle strength.

Methods

Body composition was assessed using the combination of body mass index (BMI) and fat-free mass index. Pulmonary function tests and respiratory muscle strength measurements were performed on the same day. Patients were stratified into normal (BMI < 25 kg/m²) and overweight (BMI ≥ 25 kg/m²) groups. Multiple linear regression was used to find significant contributors for TLC.

Results

Overweight was present in 59% of patients, and body composition was abnormal in almost all patients. In overweight patients, TLC was significantly (p = 2.40×10⁻³) decreased, compared with normal-weight patients, while inspiratory muscle strength was similar in both groups. The decrease in TLC in overweight patients was mainly due to a decrease in expiratory reserve volume (ERV) further illustrated by a highly significant (p = 1.33×10⁻¹⁰) correlation between BMI and ERV. Multiple linear regression showed that TLC can be predicted using only BMI and the forced inspiratory volume in 1 second, as these were the only significant contributors.

Conclusions

This study shows that, in DM1 patients, overweight further reduces lung volumes, as does impaired inspiratory muscle strength. Additionally, body composition is abnormal in almost all DM1 patients.     

The G Protein-Coupled Estrogen Receptor (GPER) Is Expressed in Two Different Subcellular Localizations Reflecting Distinct Tumor Properties in Breast Cancer

Introduction

The G protein-coupled estrogen receptor (GPER) is a novel estrogen receptor that mediates proliferative effects induced by estrogen but also by tamoxifen. The aim of our study was to analyze the frequency of GPER in a large collective of primary invasive breast carcinomas, with special emphasis on the subcellular expression and to evaluate the association with clinicopathological parameters and patient overall survival.

Methods

The tissue microarrays from formalin-fixed, paraffin embedded samples of primary invasive breast carcinomas (n = 981) were analyzed for GPER expression using immunohistochemistry. Expression data were compared to the clinicopathological parameters and overall survival. GPER localization was also analyzed in two immortalized breast cancer cell lines T47D and MCF7 by confocal immunofluorescence microscopy.

Results

A predominantly cytoplasmic GPER expression was found in 189 carcinomas (19.3%), whereas a predominantly nuclear expression was observed in 529 cases (53.9%). A simultaneous comparable positive expression of both patterns was found in 32 of 981 cases (3.2%), and negative staining was detected in 295 cases (30%). Confocal microscopy confirmed the occurrence of cytoplasmic and nuclear GPER expression in T47D and MCF7. Cytoplasmic GPER expression was significantly associated with non-ductal histologic subtypes, low tumor stage, better histologic differentiation, as well as Luminal A and B subtypes. In contrast, nuclear GPER expression was significantly associated with poorly differentiated carcinomas and the triple-negative subtype. In univariate analysis, cytoplasmic GPER expression was associated with better overall survival (p = 0.012).

Conclusion

Our data suggest that predominantly cytoplasmic and/or nuclear GPER expression are two distinct immunohistochemical patterns in breast carcinomas and may reflect different biological features, reason why these patterns should be clearly distinguished in histological evaluations. Prospective studies will be needed to assess whether the expression status of GPER in breast carcinomas should be routinely observed by clinicians, for instance, before implementing endocrine breast cancer treatment.     

Lower Inter-Partum Interval and Unhealthy Life-Style Factors Are Inversely Associated with n-3 Essential Fatty Acids Changes during Pregnancy: A Prospective Cohort with Brazilian Women

Objective

To analyze serum fatty acids concentrations during healthy pregnancy and evaluate whether socioeconomic, demographic, obstetric, nutritional, anthropometric and lifestyle factors are associated with their longitudinal changes.

Study design

A prospective cohort of 225 pregnant women was followed in the 5^th–13^th, 20^th–26^th and 30^th–36^th weeks of gestation. Serum samples were collected in each trimester of pregnancy and analyzed to determine the fatty acids composition using a high-throughput robotic direct methylation method coupled with fast gas-liquid chromatography. The independent variables comprised the subjects’ socioeconomic and demographic status, obstetric history, early pregnancy body mass index (BMI), dietary and lifestyle parameters. Analyses were performed using linear mixed-effects models.

Results

The overall absolute concentrations of fatty acids increased from the 1^st to the 2^nd trimester and slightly increased from the 2^nd to the 3^rd trimester. Early pregnancy BMI, inter-partum interval and weekly fish intake were the factors associated with changes in eicosapentaenoic + docosahexaenoic acids (EPA+DHA) and total n-3 polyunsaturated fatty acids (PUFAs). Early pregnancy BMI, age and monthly per-capita income were inversely associated with the changes in the n-6/n-3 ratio. Alcohol consumption was positively associated with the n-6/n-3 ratio.

Conclusion

Early pregnancy BMI was positively associated with EPA+DHA and total n-3 PUFAs, while presenting a reduced weekly fish intake and a lower inter-partum interval were associated with lower levels of n-3 PUFAs. A lower per-capita family income and a drinking habit were factors that were positively associated with a higher n-6/n-3 ratio.     

Circulating NOS3 Modulates Left Ventricular Remodeling following Reperfused Myocardial Infarction

Purpose

Nitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.

Methods

To analyze the role of circulating NOS3 we transplanted bone marrow of NOS3^−/− and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC−/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24h, 4d, 1w, 2w and 3w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori’s One-step trichrome staining.

Results

Three weeks post MI, LV end-systolic (53.2±5.9μl;***p≤0.001;n = 5) and end-diastolic volumes (82.7±5.6μl;*p<0.05;n = 5) were significantly increased in BC−/EC+, along with decreased LV developed pressure (67.5±1.8mmHg;n = 18;***p≤0.001) and increased scar size/left ventricle (19.5±1.5%;n = 13;**p≤0.01) compared to BC+/EC+ (ESV:35.6±2.2μl; EDV:69.1±2.6μl n = 8; LVDP:83.2±3.2mmHg;n = 24;scar size/LV13.8±0.7%;n = 16). Myocardial scar of BC−/EC+ was characterized by increased total collagen content (20.2±0.8%;n = 13;***p≤0.001) compared to BC+/EC+ (15.9±0.5;n = 16), and increased collagen type I and III subtypes.

Conclusion

Circulating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.     

Trends in Cancer Incidence in Maputo,Mozambique, 1991–2008

Background

Very limited information is available regarding the incidence of cancer in sub-Saharan Africa. We analyzed changes in cancer patterns from 1991 to 2008 in Maputo (Mozambique).

Methods

We calculated the rates of incidence of different cancer sites by sex in the 5-year age-group of the population of Maputo city as well as age-standardized rates (ASRs) and average annual percentage changes (AAPC).

Results

Over the 18-year study period a total of 12,674 cases of cancer (56.9% females) were registered with an overall increase in the risk of cancer in both sexes. In males, the most common cancers were those of the prostate, Kaposi sarcoma (KS) and the liver. Prostate cancer showed the most dramatic increase over the whole study period (AAPC +11.3%; 95% CI: 9.7–13.0), with an ASR of 61.7 per 10⁵ in 2003–2008. In females, the most frequent cancers were of the uterine cervix, the breast and KS, with the former increasing along the whole study period (AAPC + 4.7%; 95% CI: 3.4–6) with an ASR of 62.0 per 10⁵ in 2003–2008 as well as breast cancer (AAPC +6.5%; 95%CI: 4.3–8.7).

Conclusions

Overall, the risk of cancer rose in both sexes during the study period, particularly among cancers associated with westernization of lifestyles (prostate, breast), combined with increasingly rising incidences or limited changes in cancers associated with infection and poverty (uterine cervix, liver). Moreover, the burden of AIDS-associated cancers has shown a marked increase.     

High Beta-Palmitate Fat Controls the Intestinal Inflammatory Response and Limits Intestinal Damage in Mucin Muc2 Deficient Mice

Background

Palmitic-acid esterified to the sn-1,3 positions of the glycerol backbone (alpha, alpha’-palmitate), the predominant palmitate conformation in regular infant formula fat, is poorly absorbed and might cause abdominal discomfort. In contrast, palmitic-acid esterified to the sn-2 position (beta-palmitate), the main palmitate conformation in human milk fat, is well absorbed. The aim of the present study was to examine the influence of high alpha, alpha’-palmitate fat (HAPF) diet and high beta-palmitate fat (HBPF) diet on colitis development in Muc2 deficient (Muc2^−/−) mice, a well-described animal model for spontaneous enterocolitis due to the lack of a protective mucus layer.

Methods

Muc2^−/− mice received AIN-93G reference diet, HAPF diet or HBPF diet for 5 weeks after weaning. Clinical symptoms, intestinal morphology and inflammation in the distal colon were analyzed.

Results

Both HBPF diet and AIN-93G diet limited the extent of intestinal erosions and morphological damage in Muc2^−/− mice compared with HAPF diet. In addition, the immunosuppressive regulatory T (Treg) cell response as demonstrated by the up-regulation of Foxp3, Tgfb1 and Ebi3 gene expression levels was enhanced by HBPF diet compared with AIN-93G and HAPF diets. HBPF diet also increased the gene expression of Pparg and enzymatic antioxidants (Sod1, Sod3 and Gpx1), genes all reported to be involved in promoting an immunosuppressive Treg cell response and to protect against colitis.

Conclusions

This study shows for the first time that HBPF diet limits the intestinal mucosal damage and controls the inflammatory response in Muc2^−/− mice by inducing an immunosuppressive Treg cell response.     

Divergent Cardiopulmonary Actions of Heme Oxygenase Enzymatic Products in Chronic Hypoxia

Background

Hypoxia and pressure-overload induce heme oxygenase-1 (HO-1) in cardiomyocytes and vascular smooth muscle cells (VSMCs). HO-1^−/− mice exposed to chronic hypoxia develop pulmonary arterial hypertension (PAH) with exaggerated right ventricular (RV) injury consisting of dilation, fibrosis, and mural thrombi. Our objective was to indentify the HO-1 product(s) mediating RV protection from hypoxic injury in HO-1^−/− mice.

Methodology/Principal Findings

HO-1^−/− mice were exposed to seven weeks of hypoxia and treated with inhaled CO or biliverdin injections. CO reduced right ventricular systolic pressure (RVSP) and prevented hypoxic pulmonary arteriolar remodeling in both HO-1^−/− and control mice. Biliverdin had no significant effect on arteriolar remodeling or RVSP in either genotype. Despite this, biliverdin prevented RV failure in the hypoxic HO-1^−/− mice (0/14 manifested RV wall fibrosis or thrombus), while CO-treated HO-1^−/− mice developed RV insults similar to untreated controls. In vitro, CO inhibited hypoxic VSMC proliferation and migration but did not prevent cardiomyocyte death from anoxia-reoxygenation (A-R). In contrast, bilirubin limited A-R-induced cardiomyocyte death but did not inhibit VSMC proliferation and migration.

Conclusions/Significance

CO and bilirubin have distinct protective actions in the heart and pulmonary vasculature during chronic hypoxia. Moreover, reducing pulmonary vascular resistance may not prevent RV injury in hypoxia-induced PAH; supporting RV adaptation to hypoxia and preventing RV failure must be a therapeutic goal.     

Genome-Wide Association Study Identifies That the ABO Blood Group System Influences Interleukin-10 Levels and the Risk of Clinical Events in Patients with Acute Coronary Syndrome

Introduction

Acute coronary syndrome (ACS) is a major cause of mortality worldwide. We have previously shown that increased interleukin-10 (IL-10) levels are associated with poor outcome in ACS patients.

Method

We performed a genome-wide association study in 2864 ACS patients and 408 healthy controls, to identify genetic variants associated with IL-10 levels. Then haplotype analyses of the identified loci were done and comparisons to levels of IL-10 and other known ACS related biomarkers.

Results

Genetic variants at the ABO blood group locus associated with IL-10 levels (top SNP: rs676457, P = 4.4 × 10⁻¹⁰) were identified in the ACS patients. Haplotype analysis, using SNPs tagging the four main ABO antigens (A1, A2, B and O), showed that O and A2 homozygous individuals, or O/A2 heterozygotes have much higher levels of IL-10 compared to individuals with other antigen combinations. In the ACS patients, associations between ABO antigens and von Willebrand factor (VWF, P = 9.2 × 10⁻¹³), and soluble tissue factor (sTF, P = 8.6 × 10⁻⁴) were also found. In the healthy control cohort, the associations with VWF and sTF were similar to those in ACS patients (P = 1.2 × 10⁻¹⁵ and P = 1.0 × 10⁻⁵ respectively), but the healthy cohort showed no association with IL-10 levels (P>0.05). In the ACS patients, the O antigen was also associated with an increased risk of cardiovascular death, all causes of death, and recurrent myocardial infarction (odds ratio [OR] = 1.24–1.29, P = 0.029–0.00067).

Conclusion

Our results suggest that the ABO antigens play important roles, not only for the immunological response in ACS patients, but also for the outcome of the disease.     

Detection and Validation of Circulating Endothelial Cells,a Blood-based Diagnostic Marker of Acute Myocardial Infarction

Background

Circulating endothelial cells (CECs) are markers of vascular damage that have clinical relevance in many diseases, including acute myocardial infarction (AMI), and may be predictors of treatment responses. Herein, we investigated the diagnostic and prognostic value of CEC monitoring in AMI patients and a murine model.

Methodology/Principal Findings

CECs were defined as Hoechst 33342⁺/CD45^−/CD31⁺/CD146⁺/CD133⁻ in human blood samples and Hoechst 33342⁺/CD45^−/CD31⁺/KDR⁺/CD117⁻ in murine samples. To evaluate the validity and variability of our CEC detection system, peripheral blood samples of vascular endothelial growth factor-treated athymic nude mice and AMI patients were collected and subjected to intra-assay analysis. CEC detection by flow cytometry and real-time PCR were compared. Blood samples were obtained from 61 AMI patients, 45 healthy volunteers and 19 samples of the original AMI patients accepted one month treatment, via flow cytometry and expressed as a percentage of peripheral blood mononuclear cells.

Results

Our CEC detection method was validated and had limited variability. CEC concentrations were higher in AMI patients compared to healthy controls. One month post-treatment, CECs levels decreased significantly.

Conclusions/Significance

CEC levels may be useful as a diagnostic and prognostic biomarker in AMI patients.