Bartira Ercília Pinheiro da Costa

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Background: Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of renal diseases, and imbalanced MMP-2 and its endogenous inhibitor (the tissue inhibitor of metalloproteinases-2; TIMP-2) are implicated in the vascular alterations of end-stage kidney disease (ESKD) patients. We have examined whether MMP-2 gene polymorphisms and haplotypes modify MMP-2 and TIMP-2 levels in ESKD patients as well as the effects of hemodialysis on the concentrations of these biomarkers. Methods: We determined MMP-2 and TIMP-2 plasma levels by gelatin zymography and ELISA, respectively, in 98 ESKD patients and in 38 healthy controls. Genotypes for two relevant MMP-2 polymorphisms (C–1306T and C–735T in the promoter region) were determined by TaqMan® allele discrimination assay and real-time polymerase chain reaction. The software program PHASE 2.1 was used to estimate the haplotype frequencies. Results: We found increased plasma MMP-2 and TIMP-2 levels in ESKD patients compared to controls (p < 0.05), and hemodialysis decreased MMP-2 (but not TIMP-2) levels (p < 0.05). The T allele for the C–735T polymorphism and the C-T haplotype were associated with higher MMP-2 (but not TIMP-2) levels (p < 0.05), whereas the C–1306T had no effects. Hemodialysis decreased MMP-2 (but not TIMP-2) levels independently of MMP-2 genotypes or haplotypes (p < 0.05). Conclusions: MMP-2 genotypes or haplotypes modify MMP-2 levels in ESKD patients, and may help to identify patients with increased MMP-2 activity in plasma. Hemodialysis reduces MMP-2 levels independently of MMP-2 genetic variants.

Does uric acid provide information about maternal condition and fetal outcome in pregnant women with hypertension

Objective: To evaluate associations between maternal serum uric acid (UA) levels, maternal status, and fetal outcome. Methods: Maternal UA, urinary protein-creatinine ratio (P/C), blood pressure (BP), gestational age at delivery, and birth weight were evaluated in hypertensive pregnant women (n = 58). These were divided into two groups: high UA (≥357 μmol/L) or normal UA (<357 μmol/L). Results: Maternal diastolic BP and P/C ratio were higher in pregnant women with elevated UA levels. Systolic BP, gestational age and birth weight were not significantly different. Conclusion. UA equal or above 357 μmol/L in pregnant hypertensive women was associated with proteinuria and diastolic BP, but not with fetal outcome.OBJECTIVE To evaluate associations between maternal serum uric acid (UA) levels, maternal status, and fetal outcome. METHODS Maternal UA, urinary protein-creatinine ratio (P/C), blood pressure (BP), gestational age at delivery, and birth weight were evaluated in hypertensive pregnant women (n = 58). These were divided into two groups: high UA (> or =357 micromol/L) or normal UA (<357 micromol/L). RESULTS Maternal diastolic BP and P/C ratio were higher in pregnant women with elevated UA levels. Systolic BP, gestational age and birth weight were not significantly different. CONCLUSION UA equal or above 357 micromol/L in pregnant hypertensive women was associated with proteinuria and diastolic BP, but not with fetal outcome.

Is the atherosclerotic phenotype of preeclamptic placentas due to altered lipoprotein concentrations and placental lipoprotein receptors? Role of a small-for-gestational-age phenotype.

Atherosis of spiral arteries in uteroplacental beds from preeclamptic women resemble those of atherosclerosis, characterized by increased plasma lipids and lipoproteins. We hypothesized that: 1) lipoprotein receptors/transporters in the placenta would be upregulated in preeclampsia, associated with increased maternal and fetal lipoprotein concentrations; and 2) expression of these would be reduced in preeclamptic placentae from women delivering small-for-gestational-age (SGA) infants. Placental biopsies and maternal and umbilical serum samples were taken from 27 normotensive and 24 preeclamptic women. Maternal/umbilical cord serum LDL, HDL, total cholesterol, and triglycerides were measured. Placental mRNA expression of lipoprotein receptors/transporters were quantified using quantitative RT-PCR. Protein localization/expression of LDL receptor-related protein 1 (LRP-1) in the preeclamptic placentae with/without SGA was measured by immunohistochemistry. Placental mRNA expression of all genes except paraoxonase-1 (PON-1), microsomal triglyceride transfer protein (MTTP), and protein disulfide isomerase family A member 2 (PDIA2) were observed. No differences for any lipoprotein receptors/transporters were found between groups; however, in the preeclamptic group placental LRP-1 expression was lower in SGA delivering mothers (n = 7; P = 0.036). LRP-1 protein was localized around fetal vessels and Hofbauer cells. This is the first detailed study of maternal/fetal lipoprotein concentrations and placental lipoprotein receptor mRNA expression in normotensive and preeclamptic pregnancies. These findings do not support a role of altered lipid metabolism in preeclampsia, but may be involved in fetal growth.

Blood–Brain Barrier Breakdown in Reduced Uterine Perfusion Pressure: A Possible Model of Posterior Reversible Encephalopathy Syndrome

BACKGROUND Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by headaches, altered mental status, seizures, and visual disturbances and is associated with white matter vasogenic edema. There are no experimental models to study PRES brain changes. METHODS Twenty-eight pregnant Wistar rats were divided into 4 groups of 7: (1) pregnant-control; (2) reduced uterine perfusion pressure (RUPP); (3) invasive blood pressure (IBP); and (4) reduced uterine perfusion pressure plus invasive blood pressure (RUPP-IBP). The RUPP and RUPP-IBP groups were submitted to a reduction of uterine perfusion pressure at pregnancy days 13 to 15. The invasive mean arterial pressure of the IBP and RUPP-IBP groups was measured on day 20. The blood-brain barriers (BBBs) of all groups were analyzed using 2% Evans Blue dye on day 21. RESULTS RUPP rats had higher blood pressures and increased BBB permeability to Evans Blue dye compared with the control animals. Brain staining occurred in 11 of 14 RUPP rats and in none of the control groups (P < .0001). CONCLUSIONS The physiopathology of PRES remains unclear. Here, we described the use of RUPP rats as a potential model to better comprehend this syndrome.

Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels

BACKGROUND Altered levels of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in cardiovascular alterations associated with end stage kidney disease (ESKD). Genetic polymorphisms in MMP-9 gene affect MMP-9 levels. We examined how MMP-9 polymorphisms and haplotypes affect the changes in plasma MMP-9 and TIMP-1 levels found in patients with ESKD undergoing hemodialysis. METHODS We studied 94 ESKD patients undergoing hemodialysis for at least 3 months. MMP-9 and TIMP-1 were measured by ELISA in plasma from blood samples collected before and after a session of hemodialysis. Genotypes for three MMP-9 polymorphisms (C(-1562)T, rs3918242; -90 (CA)(14-24), rs2234681; and Q279R, rs17576) were determined by Taqman® Allele Discrimination Assay and real-time polymerase chain reaction. Haplotype frequencies were determined with the software program PHASE 2.1. RESULTS Hemodialysis increased MMP-9 and TIMP-1 levels (P<0.05). Genotypes had no effects on baseline MMP-9 and TIMP-1 levels (P>0.05). Hemodialysis increased MMP-9 and TIMP-1 levels in subjects with the CC (but not CT or TT) genotype for the C(-1562)T polymorphism (P<0.05), and increased MMP-9 levels in subjects with the QQ (but not QR or RR) genotype for the Q279R polymorphism (P<0.05), whereas the CA(n)(14-24) polymorphism had no major effects. While MMP-9 haplotypes had no effects on baseline MMP-9 levels (P>0.05), hemodialysis increased MMP-9 levels and MMP-9/TIMP-1 ratios in subjects carrying the CLQ haplotype (P=0.0012 and P=0.0045, respectively). CONCLUSION ESKD patients with the QQ genotype for the Q279R polymorphism or with the CLQ haplotype are exposed to more severe increases in MMP-9 levels after hemodialysis. Such patients may benefit from the use of MMP inhibitors.

Temperature, urbanization and body color polymorphism in South Brazilian populations of Drosophila kikkawai (Diptera, Drosophilidae)

Body color polymorphism of urban populations of cosmopolite fly Drosophila kikkawai Burla, 1954 was investigated in relation to its possible association with environmental temperature. Samples of D. kikkawai were collected in spring, summer, autumn and winter between 1987 to 1988, in zones with different levels of urbanization in the southern Brazilian city of Porto Alegre, Rio Grande do Sul. A clear association was observed between darker flies and both seasons with low temperatures and areas of low urbanization (where temperature is generally lower than in urbanized areas). Results of preliminary laboratory experiments involving six generations of flies grown in chambers at temperatures of 17o and 25oC confirmed this tendency to a relationship between body color and temperature, with allele frequency of the main gene involved in body pigmentation changing over time.

Endocan-1 concentrations in maternal and fetal plasma and placentae in pre-eclampsia in the third trimester of pregnancy.

INTRODUCTION Endocan-1 has been proposed as a possible biomarker and predictor of vascular endothelial related pathologies. Thus, we hypothesised that Endocan-1 levels would be up-regulated in maternal plasma and placentae from women with pre-eclampsia. The aim of our study was to compare Endocan-1 concentrations in maternal/fetal plasma and placentae from normotensive and pre-eclamptic pregnancies. METHODS Observational and case-controlled study, at the São Lucas Hospital, Brazil. Placental biopsies, maternal/umbilical venous (fetal) plasma were taken from 67 normotensive and 50 pre-eclamptic women. Endocan-1 levels were quantified using MagPlex(TH)-C and analysed by Analysis of Covariance and Pearson correlation. The null hypothesis was rejected at p<0.05. RESULTS Higher levels of Endocan-1 were found in maternal plasma in the pre-eclamptic group (mean ratio=1.49; 95% confidence interval: 1.19-1.85, p=0.001), with a moderate effect size (Cohens D=0.84). Placental Endocan-1 levels (μg/g) were lower in pre-eclampsia (1.52 [1.10, 2.40] vs. 2.24 [1.32, 3.75], p=0.033) and fetal Endocan-1 concentration (ng/ml) did not show any difference between groups (3.10 [2.60, 4.54] vs. 2.91 [2.20, 3.66] p=0.085). In addition, an up-regulation of maternal plasma Endocan-1 in the pre-eclamptic group was observed when stratified in relation to gestational age, systolic blood pressure and proteinuria (p<0.05, for all). Furthermore, a positive correlation between Endocan-1 concentration in maternal vs. fetal plasma was also found (r=0.258, p=0.015). For the matched samples, a negative correlation between Endocan-1 in maternal/fetal plasma with birthweights, placental weights and gestational age at delivery was observed (p<0.05 for all). DISCUSSION Endocan-1 is increased in women with pre-eclampsia for all strata, which highlight the importance of this molecule as a possible biomarker. The negative correlations between Endocan-1 and clinical data suggest that this molecule may also be involved with prematurity and low birth weight, which warrants further investigations.

Increased levels of the soluble receptor of Interleukin-6 in patients with preeclampsia compared to normotensive pregnant women

AIMS: To compare Interleukin-6 soluble receptor (IL-6sR) plasmatic levels between normotensive pregnant controls and preeclamptic women. METHODS: Maternal blood samples were collected before delivery from 21 patients with preeclampsia and 39 normotensive pregnant controls. Samples were stored at -80°C until laboratory assay. IL-6sR was measured by ELISA enzyme immunoassay. To compare groups Students t test was used. Results with P less than 0.05 were considered significant. RESULTS: Data from preeclampsia and normotensive pregnant controls were respectively: maternal age 22.3±4.8 vs 26.0±3.7 years (P=0.06); gestational age 32.7±5.8 vs 40.1±0.8 weeks (P=0.01); systolic blood pressure 143.0±2.2 vs 118.8±3.1 mmHg (P=0.01); diastolic blood pressure 112.5±4.0 vs 77.2±10.2 mmHg (P=0.01); uric acid 5.87±1.10 vs 4.57±0.12 mg/dL (P=0.02); creatinine 0.82±0.12 vs 0.73±0.09 mg/dL (P=0.01); birth weight 2130.7±839.3 vs 3555.0±261.0 g (P=0.01); placental weight 621.3±167.0 vs 796.3±154.2 g (P=0,05). Proteinuria over creatininuria ratio in the preeclampsia group was 2.40±1.31. The concentration of IL-6sR (ng/dL) was 28.7±10.8 in preeclampsia vs 16.5±6.4 in normotensive pregnant controls (P=0.01). CONCLUSIONS: These results show an increased plasma levels of IL-6sRin patients with preeclampsia compared to normotensive pregnant women. More studies are necessary to clarify the pathophysiology of this entity, including the analysis of other cytokines linked to this receptor, due to the fact that they can be the key for the systemic inflammatory response that occurs in these patients and therefore for their treatment.

Endothelial Nitric Oxide Genotypes and Haplotypes Are Not Associated with End-Stage Renal Disease

The identification of genetic markers associated with chronic kidney disease (CKD) may help to predict its development. Because reduced nitric oxide (NO) bioavailability and endothelial dysfunction are involved in CKD, genetic polymorphisms in the gene encoding the enzyme involved in NO synthesis (endothelial NO synthase [eNos]) may affect the susceptibility to CKD and the development of end-stage renal disease (ESRD). We compared genotype and haplotype distributions of three relevant eNOS polymorphisms (T(-786)C in the promoter region, Glu298Asp in exon 7, and 4b/4a in intron 4) in 110 healthy control subjects and 127 ESRD patients. Genotypes for the T(-786)C and Glu298Asp polymorphisms were determined by TaqMan(®) Allele Discrimination assay and real-time polymerase chain reaction. Genotypes for the intron 4 polymorphism were determined by polymerase chain reaction and fragment separation by electrophoresis. The software program PHASE 2.1 was used to estimate the haplotypes frequencies. We considered significant a probability value of p < 0.05/number of haplotypes (p < 0.05/8 = 0.0063). We found no significant differences between groups with respect to age, ethnicity, and gender. CKD patients had higher blood pressure, total cholesterol, and creatinine levels than healthy control subjects (all p < 0.05). Genotype and allele distributions for the three eNOS polymorphisms were similar in both groups (p > 0.05). We found no significant differences in haplotype distribution between groups (p > 0.05). The lack of significant associations between eNOS polymorphisms and ESRD suggests that eNOS polymorphisms may not be relevant to the genetic component of CKD that leads to ESRD.

Arterial hypertension in nursing personnel of an emergency hospital

Risk factors related to the workplace environment are being studied to identify positive associations with hypertension disorders. Hypertension is considered as one of the main modifiable risk factors and most important public health issues. The study aims to describe the prevalence of hypertension and associate it with sociodemographic, labour and health aspects, in the health-care nursing staff of an emergency hospital.Cross-sectional study enrolled 606 nursing workers. The data were collected from February to June, and the analysis was conducted in November 2010. Arterial blood pressure, body mass index (BMI), waist-to-hip ratio (WHR) were assessed, and sociodemographic and labour variables were investigated by means of a questionnaire. The data were analysed by descriptive statistics, univariate and multivariate analysis. The prevalence of hypertension was 32% (n = 388), with positive associations with age > 49 years (OR = 2.55 (CI: 1.19 to 5.43)), ethnicity (non-white) (odds ratio (OR) = 2.22, confidence interval (CI) 1.16 to 1.24), BMI (OR = 2.24 (CI: 1.25 to 4.01)) and WHR (OR = 2.65 (CI: 1.95 to 7.763)). Arterial hypertension was frequent in the nursing staff of this emergency hospital. Further studies are needed to better understand the relationship between occupational aspects and arterial hypertension.