Dahl (S x R) Congenic Strain Analysis Confirms and Defines a Chromosome 5 Female-Specific Blood Pressure Quantitative Trait Locus to <7 Mbp

The detection of multiple sex-specific blood pressure (BP) quantitative trait loci (QTLs) in independent total genome analyses of F2 (Dahl S x R)-intercross male and female rat cohorts confirms clinical observations of sex-specific disease cause and response to treatment among hypertensive patients, and mandate the identification of sex-specific hypertension genes/mechanisms. We developed and studied two congenic strains, S.R5A and S.R5B introgressing Dahl R-chromosome 5 segments into Dahl S chromosome 5 region spanning putative BP-f1 and BP-f2 QTLs. Radiotelemetric non-stressed 24-hour BP analysis at four weeks post-high salt diet (8% NaCl) challenge, identified only S.R5B congenic rats with lower SBP (−26.5 mmHg, P = 0.002), DBP (−23.7 mmHg, P = 0.004) and MAP (−25.1 mmHg, P = 0.002) compared with Dahl S female controls at four months of age confirming BP-f1 but not BP-f2 QTL on rat chromosome 5. The S.R5B congenic segment did not affect pulse pressure and relative heart weight indicating that the gene underlying BP-f1 does not influence arterial stiffness and cardiac hypertrophy. The results of our congenic analysis narrowed BP-f1 to chromosome 5 coordinates 134.9–141.5 Mbp setting up the basis for further fine mapping of BP-f1 and eventual identification of the specific gene variant accounting for BP-f1 effect on blood pressure.     

Dahl (S × R) Rat Congenic Strain Analysis Confirms and Defines a Chromosome 17 Spatial Navigation Quantitative Trait Locus to <10 Mbp

A quantitative trait locus (QTL) linked with ability to find a platform in the Morris Water Maze (MWM) was located on chromosome 17 (Nav-5 QTL) using intercross between Dahl S and Dahl R rats. We developed two congenic strains, S.R17A and S.R17B introgressing Dahl R-chromosome 17 segments into Dahl S chromosome 17 region spanning putative Nav-5 QTL. Performance analysis of S.R17A, S.R17B and Dahl S rats in the Morris water maze (MWM) task showed a significantly decreased spatial navigation performance in S.R17B congenic rats when compared with Dahl S controls (P = 0.02). The S.R17A congenic segment did not affect MWM performance delimiting Nav-5 to the chromosome 17 65.02–74.66 Mbp region. Additional fine mapping is necessary to identify the specific gene variant accounting for Nav-5 effect on spatial learning and memory in Dahl rats.     

Diabetic Retinopathy and Estimated Cerebrospinal Fluid Pressure. The Beijing Eye Study 2011

Purpose

The cerebrospinal fluid pressure (CSFP) is a major determinant of central retinal vein pressure and thus of retinal capillary pressure. We tested the hypothesis whether prevalence and severity of diabetic retinopathy are associated with CSFP.

Methods

The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years. A detailed ophthalmic examination was performed including fundus photography for the assessment of diabetic retinopathy according. Based on a previous study with lumbar cerebrospinal fluid pressure (CSFP) measurements, CSFP was calculated as CSFP[mmHg] = 0.44xBody Mass Index[kg/m²]+0.16 Diastolic Blood Pressure[mmHg]–0.18xAge[Years]−1.91.

Results

In binary regression analysis, presence of diabetic retinopathy was significantly associated with higher levels of HbA1c (P<0.001; regression coefficient B:0.25; odds ratio (OR):1.28; 95% confidence interval (CI):1.15,1.43), higher blood concentration of glucose (P<0.001; B:0.40;OR:1.49;95%CI:1.36,1.63), longer known duration of diabetes mellitus (P<0.001; B:0.14;OR:1.15; 95%CI:1.11,1.19), higher systolic blood pressure (P<0.001; B:0.03;OR:1.03;95%CI:1.02,1.04), lower diastolic blood pressure (P<0.001; B:−0.06;OR:0.94;95%CI:0.91,0.97), and higher CSFP (P = 0.002; B:0.13;OR:1.14;95%CI:1.05,1.24). Severity of diabetic retinopathy was significantly associated with higher HbA1c value (P<0.001; standardized coefficient beta: 0.19; correlation coefficient B: 0.07;95%CI:0.05,0.08), higher blood concentration of glucose (P<0.001; beta:0.18;B:0.04;95%CI:0.04,0.05), longer known duration of diabetes mellitus (P<0.001; beta:0.20;B:0.03;95%CI:0.02,0.03), lower level of education (P = 0.001; beta:−0.05;B:−0.02;95%CI:−0.03,−0.01), lower diastolic blood pressure (P = 0.002; beta:−0.08;B:−0.001;95%CI:−0.004,−0.001), higher systolic blood pressure (P = 0.006; beta:0.06;B:0.001;95%CI:0.000,0.001), and higher CSFP (P = 0.006; beta:0.06;B:0.006;95%CI:0.002,0.010).

Conclusions

Higher prevalence and severity of diabetic retinopathy were associated with higher estimated CSFP after adjusting for systemic parameters. Higher CSFP through a higher retinal vein pressure may lead to more marked retinal venous congestion and vascular leakage in diabetic retinae.     

Trans-Lamina Cribrosa Pressure Difference and Open-Angle Glaucoma. The Central India Eye and Medical Study

Purpose

To assess associations of the trans-lamina cribrosa pressure difference (TLCPD) with glaucomatous optic neuropathy.

Methods

The population-based Central India Eye and Medical Study included 4711 subjects. Based on a previous study with lumbar cerebrospinal fluid pressure (CSFP) measurements, CSFP was calculated as CSFP[mmHg] = 0.44 Body Mass Index[kg/m2]+0.16 Diastolic Blood Pressure[mmHg]−0.18×Age[Years] −1.91. TLCPD was IOP–CSFP.

Results

Mean TLCPD was 3.64±4.25 mm Hg in the non-glaucomatous population and 9.65±8.17 mmHg in the glaucomatous group. In multivariate analysis, TLCPD was associated with older age (P<0.001; standardized coefficient beta:0.53; regression coefficient B:0.18; 95% confidence interval (CI):0.17, 0.18), lower body mass index (P<0.001; beta: −0.28; B: −0.36; 95%CI: −0.38, −0.31), lower diastolic blood pressure (P<0.001; beta: −0.31; B: −0.12; 95%CI: −0.13, −0.11), higher pulse (P<0.001; beta:0.05; B:0.02; 95%CI:0.01,0.2), lower body height (P = 0.02; beta: −0.02; B: −0.01; 95%CI: −0.02,0.00), higher educational level (P<0.001; beta:0.04; B:0.15; 95%CI:0.09,0.22), higher cholesterol blood concentrations (P<0.001; beta:0.04; B:0.01; 95%CI:0.01,0.01), longer axial length (P = 0.006; beta:0.03; B:0.14; 95%CI:0.04,0.24), thicker central cornea (P<0.001; beta:0.15; B:0.02; 95%CI:0.02,0.02), higher corneal refractive power (P<0.001; beta:0.07; B:0.18; 95%CI:0.13,0.23) and presence of glaucomatous optic neuropathy (P<0.001; beta:0.11; B:3.43; 95%CI:2.96,3.99). Differences between glaucomatous subjects and non-glaucomatous subjects in CSFP were more pronounced for open-angle glaucoma (OAG) than for angle-closure glaucoma (ACG) (3.0 mmHg versus 1.8 mmHg), while differences between glaucomatous subjects and non-glaucomatous subjects in IOP were higher for ACG than for OAG (8.5 mmHg versus 3.0 mmHg). Presence of OAG was significantly associated with TLCPD (P<0.001; OR:1.24; 95%CI:1.19,1.29) but not with IOP (P = 0.08; OR:0.96; 95%CI:0.91,1.00). Prevalence of ACG was significantly associated with IOP (P = 0.04; OR:1.19; 95%CI:1.01,1.40) but not with TLCPD (P = 0.92).

Conclusions

In OAG, but not in ACG, calculated TLCPD versus IOP showed a better association with glaucoma presence and amount of glaucomatous optic neuropathy. It supports the notion of a potential role of low CSFP in the pathogenesis of open-angle glaucoma.     

Gastric Bypass Surgery Is Followed by Lowered Blood Pressure and Increased Diuresis - Long Term Results from the Swedish Obese Subjects (SOS) Study

Objective

To compare two bariatric surgical principles with regard to effects on blood pressure and salt intake.

Background

In most patients bariatric surgery induces a sustained weight loss and a reduced cardiovascular risk profile but the long-term effect on blood pressure is uncertain.

Methods

Cohort study with data from the prospective, controlled Swedish Obese Subjects (SOS) study involving 480 primary health care centres and 25 surgical departments in Sweden. Obese patients treated with non-surgical methods (Controls, n = 1636 and n = 1132 at 2 y and 10 y follow up, respectively) were compared to patients treated with gastric bypass (GBP, n = 245 and n = 277, respectively) or purely restrictive procedures (vertical banded gastroplasty or gastric banding; VBG/B, n = 1534 and n = 1064, respectively).

Results

At long-term follow-up (median 10 y) GBP was associated with lowered systolic (mean: −5.1 mm Hg) and diastolic pressure (−5.6 mmHg) differing significantly from both VBG/B (−1.5 and −2.1 mmHg, respectively; p<0.001) and Controls (+1.2 and −3.8 mmHg, respectively; p<0.01). Diurnal urinary output was +100 ml (P<0.05) and +170 ml (P<0.001) higher in GBP subjects than in weight-loss matched VBG/B subjects at the 2 y and 10 y follow-ups, respectively. Urinary output was linearly associated with blood pressure only after GBP and these patients consumed approximately 1 g salt per day more at the follow-ups than did VBG/B (P<0.01).

Conclusions

The purely restrictive techniques VBG/B exerted a transient blood pressure lowering effect, whereas gastric bypass was associated with a sustained blood pressure reduction and an increased diuresis. The daily salt consumption was higher after gastric bypass than after restrictive bariatric surgery.     

Multi Frequency Phase Fluorimetry (MFPF) for Oxygen Partial Pressure Measurement: Ex Vivo Validation by Polarographic Clark-Type Electrode

Background

Measurement of partial pressure of oxygen (P_O2) at high temporal resolution remains a technological challenge. This study introduces a novel P_O2 sensing technology based on Multi-Frequency Phase Fluorimetry (MFPF). The aim was to validate MFPF against polarographic Clark-type electrode (CTE) P_O2 measurements.

Methodology/Principal Findings

MFPF technology was first investigated in N = 8 anaesthetised pigs at F_IO2 of 0.21, 0.4, 0.6, 0.8 and 1.0. At each F_IO2 level, blood samples were withdrawn and P_O2 was measured in vitro with MFPF using two FOXY-AL300 probes immediately followed by CTE measurement. Secondly, MFPF-P_O2 readings were compared to CTE in an artificial circulatory setup (human packed red blood cells, haematocrit of 30%). The impacts of temperature (20, 30, 40°C) and blood flow (0.8, 1.6, 2.4, 3.2, 4.0 L min⁻¹) on MFPF-P_O2 measurements were assessed. MFPF response time in the gas- and blood-phase was determined. Porcine MFPF-P_O2 ranged from 63 to 749 mmHg; the corresponding CTE samples from 43 to 712 mmHg. Linear regression: CTE = 15.59+1.18*MFPF (R² = 0.93; P<0.0001). Bland Altman analysis: mean_diff 69.2 mmHg, range_diff -50.1/215.6 mmHg, 1.96-SD limits -56.3/194.8 mmHg. In artificial circulatory setup, MFPF-P_O2 ranged from 20 to 567 mmHg and CTE samples from 11 to 575 mmHg. Linear regression: CTE = −8.73+1.05*MFPF (R² = 0.99; P<0.0001). Bland-Altman analysis: mean_diff 6.6 mmHg, range_diff -9.7/20.5 mmHg, 1.96-SD limits -12.7/25.8 mmHg. Differences between MFPF and CTE-P_O2 due to variations of temperature were less than 6 mmHg (range 0–140 mmHg) and less than 35 mmHg (range 140–750 mmHg); differences due to variations in blood flow were less than 15 mmHg (all P-values>0.05). MFPF response-time (monoexponential) was 1.48±0.26 s for the gas-phase and 1.51±0.20 s for the blood-phase.

Conclusions/Significance

MFPF-derived P_O2 readings were reproducible and showed excellent correlation and good agreement with Clark-type electrode-based P_O2 measurements. There was no relevant impact of temperature and blood flow upon MFPF-P_O2 measurements. The response time of the MFPF FOXY-AL300 probe was adequate for real-time sensing in the blood phase.     

Five-Year Change in Intraocular Pressure Associated with Changes in Arterial Blood Pressure and Body Mass Index. The Beijing Eye Study

Purpose

To examine a potential association between longitudinal changes in intraocular pressure (IOP), arterial blood pressure and body mass index (BMI) in a population-based setting.

Methods

The longitudinal population-based Beijing Eye Study included 2355 subjects with an age of 45+ years who were examined in 2006 and in 2011. The participants underwent a detailed ophthalmic examination including tonometry and measurement of arterial blood pressure and BMI.

Results

Data on IOP, arterial blood pressure and BMI measured in 2006 and in 2011 were available for 2257 (95.8%) subjects with a mean age of 59.5±9.7 years. The mean change in IOP was −1.25±2.26 mm Hg, mean change in mean blood pressure −7.4±12.1 mmHg, and mean change in BMI was 0.01±2.04 kg/m². In multivariate analysis, the 5-year change in IOP was significantly associated with a higher change in mean blood pressure (P<0.001; standardized regression coefficient Beta:0.11; regression coefficient B:0.02; 95% confidence interval (CI):0.01,0.03) after adjusting for younger age (P<0.001;Beta:−0.18;B:−0.04;95% CI:−0.05,−0.03), shorter body stature (P = 0.002;Beta:−0.06;B:−0.06;95% CI:−0.03,−0.01), thicker central corneal thickness (P<0.001;Beta:0.19;B:0.02;95% CI:0.01,0.02), deeper anterior chamber depth (P = 0.01;Beta:0.05;B:0.33;95% CI:0.07,0.60), and lower intraocular pressure at baseline (P<0.001;Beta:−0.56;B:−0.42;95% CI:−0.45,−0.39). If the analysis included only longitudinal parameters, the change in IOP was significantly associated with a higher change in mean arterial blood pressure (P<0.001;Beta:0.10;B:0.02;95% CI:0.01,0.03) and a higher change in body mass index (P<0.04;Beta:0.04;B:0.04;95% CI:0.01,0.09).

Conclusions

In the 5-year follow-up of our population-based sample, a change in IOP was associated with a corresponding change in arterial blood pressure and with a corresponding change in body mass index. These longitudinal data support the notion of a physiological relationship between arterial blood pressure, intraocular pressure and body mass index. These findings may be of interest for the discussion of the pathogenesis of glaucomatous optic neuropathy.     

The Relationship of Retinal Vessel Diameters and Fractal Dimensions with Blood Pressure and Cardiovascular Risk Factors

Background

This study aimed to investigate the correlation between quantitative retinal vascular parameters such as central retinal arteriolar equivalent (CRAE) and retinal vascular fractal dimension (D(f)), and cardiovascular risk factors in the Chinese Han population residing in the in islands of southeast China.

Methodology/Principle Findings

In this cross-sectional study, fundus photographs were collected and semi-automated analysis software was used to analyze retinal vessel diameters and fractal dimensions. Cardiovascular risk factors such as relevant medical history, blood pressure (BP), lipids, and blood glucose data were collected. Subjects had a mean age of 51.9±12.0 years and included 812 (37.4%) males and 1,357 (62.6%) females. Of the subjects, 726 (33.5%) were overweight, 226 (10.4%) were obese, 272 (12.5%) had diabetes, 738 (34.0%) had hypertension, and 1,156 (53.3%) had metabolic syndrome. After controlling for the effects of potential confounders, multivariate analyses found that age (β = 0.06, P = 0.008), sex (β = 1.33, P = 0.015), mean arterial blood pressure (β = −0.12, P<0.001), high-sensitivity C-reactive protein (β = −0.22, P = 0.008), and CRVE (β = 0.23, P<0.001) were significantly associated with CRAE. Age (β = −0.0012, P<0.001), BP classification (prehypertension: β = −0.0075, P = 0.014; hypertension: β = −0.0131, P = 0.002), and hypertension history (β = −0.0007, P = 0.009) were significantly associated with D(f).

Conclusions/Significance

D(f) exhibits a stronger association with BP than CRAE. Thus, D(f) may become a useful indicator of cardiovascular risk.     

Ocular Hypertension: General Characteristics and Estimated Cerebrospinal Fluid Pressure. The Beijing Eye Study 2011

Purpose

To examine characteristics of ocular hypertensive subjects and potential associations with estimated cerebrospinal fluid pressure (estCSFP).

Methods

The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years. Ocular hypertension was defined as intraocular pressure (IOP) >21 mmHg, normal optic nerve head appearance and normal retinal nerve fiber layer thickness. IOP was corrected for its dependence on central corneal thickness (CCT) and corneal curvature radius. Estimated CSFP was calculated as CSFP [mmHg] = 0.44×Body Mass Index [kg/m²]+0.16×Diastolic Blood Pressure [mmHg]−0.18×Age [Years]−1.91. Estimated trans-lamina cribrosa pressure difference (estTLCPD) was IOP–estCSFP.

Results

EstCSFP (10.5±3.6 mmHg versus 9.0±3.7 mmHg; P = 0.003) and estTLCPD (12.0±4.4 mmHg versus 5.4±3.8 mmHg; P<0.001) were higher in the ocular hypertensive group than in the normotensive group. In binary regression analysis, ocular hypertension was associated with increased estCSFP (P = 0.03; odds ratio (OR): 1.08; 95% confidence interval (CI): 1.01, 1.17) after adjusting for prevalence of arterial hypertension (P = 0.07; OR: 1.79; 95%CI: 0.96, 3.34), retinal nerve fiber layer thickness (P = 0.03; OR: 0.97; 95%CI: 0.95, 0.997) and blood glucose concentration (P = 0.006; OR: 1.17; 95%CI: 1.04, 1.30).

Conclusions

Ocular hypertensive subjects (with IOP correction for CCT and corneal curvature) as compared to ocular normotensive subjects had a significantly higher estCSFP in univariate analysis and in multivariate analysis. Despite of a higher estCSFP, estTLCPD was still markedly higher in ocular hypertensive eyes than in ocular normotensive eyes.     

Effects of T-Type Calcium Channel Blockers on Renal Function and Aldosterone in Patients with Hypertension: A Systematic Review and Meta-Analysis

Background

High blood pressure can cause kidney damage, which can increase blood pressure, leading to a vicious cycle. It is not clear whether the protective effects of T-type calcium channel blockers (T-type CCBs) on renal function are better than those of L-type CCBs or renin-angiotensin system (RAS) antagonists in patients with hypertension.

Methods and Findings

PUBMED, MEDLINE, EMBASE, OVID, Web of Science, Cochrane, CNKI, MEDCH, VIP, and WANFANG databases were searched for clinical trials published in English or Chinese from January 1, 1990, to December 31, 2013. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated and reported. A total of 1494 reports were collected, of which 24 studies with 1,696 participants (including 809 reports comparing T-type CCBs versus L-type CCBs and 887 reports comparing T-type CCB versus RAS antagonists) met the inclusion criteria. Compared with L-type CCBs, T-type CCBs resulted in a significant decline in aldosterone (mean difference = −15.19, 95% CI −19.65–−10.72, p<1×10⁻⁵), proteinuria (mean difference = −0.73, 95% CI −0.88–−0.57, p<1×10⁻⁵), protein to creatinine ratio (mean difference = −0.22, 95% CI −0.41–−0.03, p = 0.02), and urinary albumin to creatinine ratio (mean difference = −55.38, 95% CI −86.67–−24.09, p = 0.0005); no significant difference was noted for systolic blood pressure (SBP) (p = 0.76) and diastolic blood pressure (DBP) (p = 0.16). The effects of T-type CCBs did not significantly differ from those of RAS antagonists for SBP (p = 0.98), DBP (p = 0.86), glomerular filtration rate (p = 0.93), albuminuria (p = 0.97), creatinine clearance rate (p = 0.24), and serum creatinine (p = 0.27) in patients with hypertension.

Conclusion

In a pooled analysis of data from 24 studies measuring the effects of T-type CCBs on renal function and aldosterone, the protective effects of T-type CCBs on renal function were enhanced compared with L-type CCBs but did not differ from RAS antagonists. Their protective effects on renal function were independent of blood pressure.     

Intraocular Pressure and Associations in Children. The Gobi Desert Children Eye Study

Purpose

To assess the intraocular pressure (IOP) and its association in children in a population living in an oasis in the Gobi Desert.

Methods

The cross-sectional school-based study included all schools in the Ejina region. The children underwent an ophthalmic examination, non-contact tonometry and measurement of blood pressure and body height and weight.

Results

Out of eligible 1911 children, 1565 (81.9%) children with a mean age of 11.9±3.5 years (range: 6–21 years) participated. Mean spherical refractive error was −1.58±2.00 diopters. In multivariate analysis, higher IOP (right eye) was associated with younger age (P<0.001; standardized coefficient beta: −0.13; regression coefficient B: −0.13; 95% Confidence interval (CI):−0.18, −0.07), higher diastolic blood pressure (P<0.001;beta:0.13;B:0.05;95%CI:0.03,0.07), higher corneal refractive power (P<0.001;beta:0.11;B:0.23;95%CI:0.12,0.34), more myopic refractive error (P = 0.035;beta: −0.06;B: −0.10;95%CI: −0.19, −0.001), and Han Chinese ethnicity of the father (P = 0.03;beta:0.06;B:0.42;95%CI:0.04,0.89). If age and diastolic blood pressure were dropped, higher IOP was associated with higher estimated cerebrospinal fluid pressure (CSFP) (P<0.001;beta:0.09; B:0.13;95%CI:0.06,0.21) after adjusting for higher corneal refractive power (P<0.001) and Han Chinese ethnicity of the father (P = 0.04). Correspondingly, higher IOP of the left eye was associated with younger age (P<0.001;beta: −0.15;B: −0.16;95%CI: −0.21, −0.10), female gender (P<0.001;beta:0.09;B:0.65;95%CI:0.30,1.01), higher corneal refractive power (P<0.001;beta:0.08;B:0.19;95%CI:0.06,0.32), more myopic refractive error (P = 0.03;beta: −0.06;B: −0.12;95%CI: −0.22, −0.01), and higher estimated CSFP (P<0.001;beta:0.11;B:0.17;95%CI:0.09,0.24).

Conclusions

In school children, higher IOP was associated with steeper corneal curvature and with younger age and higher blood pressure, or alternatively, with higher estimated CSFP. Corneal curvature radius should be included in the correction of IOP measurements. The potential association between IOP and CSFP as also assumed in adults may warrant further research.     

Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array

The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region±10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P<10⁻³) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15×10⁻⁵), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5×10⁻⁵) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20×10⁻⁵). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10⁻³) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.     

The Effects of Involuntary Respiratory Contractions on Cerebral Blood Flow during Maximal Apnoea in Trained Divers

The effects of involuntary respiratory contractions on the cerebral blood flow response to maximal apnoea is presently unclear. We hypothesised that while respiratory contractions may augment left ventricular stroke volume, cardiac output and ultimately cerebral blood flow during the struggle phase, these contractions would simultaneously cause marked ‘respiratory’ variability in blood flow to the brain. Respiratory, cardiovascular and cerebrovascular parameters were measured in ten trained, male apnoea divers during maximal ‘dry’ breath holding. Intrathoracic pressure was estimated via oesophageal pressure. Left ventricular stroke volume, cardiac output and mean arterial pressure were monitored using finger photoplethysmography, and cerebral blood flow velocity was obtained using transcranial ultrasound. The increasingly negative inspiratory intrathoracic pressure swings of the struggle phase significantly influenced the rise in left ventricular stroke volume (R ² = 0.63, P<0.05), thereby contributing to the increase in cerebral blood flow velocity throughout this phase of apnoea. However, these contractions also caused marked respiratory variability in left ventricular stroke volume, cardiac output, mean arterial pressure and cerebral blood flow velocity during the struggle phase (R ² = 0.99, P<0.05). Interestingly, the magnitude of respiratory variability in cerebral blood flow velocity was inversely correlated with struggle phase duration (R ² = 0.71, P<0.05). This study confirms the hypothesis that, on the one hand, involuntary respiratory contractions facilitate cerebral haemodynamics during the struggle phase while, on the other, these contractions produce marked respiratory variability in blood flow to the brain. In addition, our findings indicate that such variability in cerebral blood flow negatively impacts on struggle phase duration, and thus impairs breath holding performance.     

Prevalence and Risk Factors of Fluid Overload in Southern Chinese Continuous Ambulatory Peritoneal Dialysis Patients

Background

Fluid overload is frequently present in CAPD patients and one of important predictors of mortality. The aim of this study is to investigate the prevalence and associated risk factors in a cohort study of Southern Chinese CAPD patients.

Methods

The patients (receiving CAPD 3 months and more) in our center were investigated from January 1, 2008 to December 31, 2009. Multi-frequency bioelectrical impedance analysis was used to assess the patient’s body composition and fluid status.

Results

A total of 307 CAPD patients (43% male, mean age 47.8±15.3 years) were enrolled, with a median duration of PD 14.6 (5.9–30.9) months. Fluid overload (defined by Extracellular water/Total body water (ECW/TBW)≥0.40) was present in 205 (66.8%) patients. Univariate analysis indicated that ECW/TBW were inversely associated with body mass index (r = −0.11, P = 0.047), subjective global assessment score (r = −0.11, P = 0.004), body fat mass (r = −0.15, P = 0.05), serum albumin (r = −0.32, P<0.001), creatinine (r = −0.14, P = 0.02), potassium (r = −0.15, P = 0.02), and residual urine output (r = −0.14, P = 0.01), positively associated with age (r = 0.27, P<0.001), Chalrlson Comorbidity Index score (r = 0.29, P<0.001), and systolic blood pressure (r = 0.22, P<0.001). Multivariate linear regression showed that lower serum albumin (β = −0.223, P<0.001), lower body fat mass (β = −0.166, P = 0.033), old age (β = 0.268, P<0.001), higher systolic blood pressure (β = 0.16, P = 0.006), less residual urine output (β = −0.116, P = 0.042), and lower serum potassium (β = −0.126, P = 0.03) were independently associated with higher ECW/TBW. After 1 year of follow-up, the cardiac event rate was significantly higher in the patients with fluid overload (17.1% vs 6.9%, P = 0.023) than that of the normal hydrated patients.

Conclusions

The prevalence of fluid overload was high in CAPD patients. Fluid overload in CAPD patients were independently associated with protein-energy wasting, old age, and decreased residual urine output. Furthermore, CAPD patients with fluid overload had higher cardiac event rate than that of normal hydrated patents.     

A Vasoactive Role for Endogenous Relaxin in Mesenteric Arteries of Male Mice

The peptide hormone relaxin has striking effects on the vascular system. Specifically, endogenous relaxin treatment reduces myogenic reactivity through nitric oxide (NO)-mediated vasorelaxation and increases arterial compliance in small resistance arteries. However, less is known about the vascular roles of endogenous relaxin, particularly in males. Therefore, we used male wild-type (Rln ^+/+) and relaxin knockout (Rln ^−/−) mice to test the hypothesis that passive wall properties and vascular reactivity in mesenteric arteries would be compromised in Rln ^−/− mice. Passive compliance was determined in arteries (n = 8–9) mounted on a pressure myograph and in Ca²⁺-free Krebs containing 2 mM EGTA. Passive volume compliance was significantly (P = 0.01) decreased in the mesenteric arteries of Rln ^−/− mice. Vascular reactivity was assessed using wire myography. In mesenteric arteries (n = 5) of Rln ^−/− mice, there was a significant (P<0.03) increase in sensitivity to the vasoconstrictors phenylephrine and thromboxane-mimetic {"type":"entrez-nucleotide","attrs":{"text":"U41669","term_id":"1195477","term_text":"U41669"}}U41669. This enhanced responsiveness to vasoconstrictors was abolished by endothelial denudation, and attributed to impaired NO and prostanoid pathways in Rln ^−/− mice. Sensitivity to the endothelial agonist acetylcholine was significantly (n = 7–9, P≤0.03) decreased, and this was abolished in the presence of the cyclooxygenase inhibitor, indomethacin (2 µM). This indicates that prostanoid vasoconstrictor pathways were upregulated in the mesenteric arteries of Rln ^−/− mice. In summary, we demonstrate endothelial dysfunction and impaired arterial wall remodeling in male mice deficient in relaxin. Thus, our results highlight a role for endogenous relaxin in the maintenance of normal mesenteric artery structure and function in males.     

Ophthalmoscopic Assessment of the Retinal Nerve Fiber Layer. The Beijing Eye Study

Purpose

To examine the retinal nerve fiber layer (RNFL) ophthalmoscopically, to search for localized RNFL defects, and to assess factors associated with RNFL visibility in a population-based setting.

Methods

The population-based cross-sectional Beijing Eye Study 2006 included 3251 subjects. Using color fundus photographs, RNFL visibility was assessed in grades from 0 to 8 in 8 fundus sectors. Localized RNFL defects were defined as wedge-shaped defects running towards the optic disc.

Results

After exclusion of subjects with optic media opacities, 2602 subjects (mean age:58.1±9.0 years) were included. RNFL visibility score was highest (P<0.001) in the temporal inferior region, followed by the temporal superior region, nasal superior region, and nasal inferior region. In multivariate analysis, higher RNFL visibility score was associated with younger age (P<0.001;standardized coefficient beta:−0.44;regression coefficient B: −0.22; 95%CI: −0.24, −0.20), female gender (P<0.001;beta:0.11;B:1.00;95%CI:0.67,1.32), higher blood concentration of low-density lipoproteins (P = 0.002;beta:0.07;B:0.34;95%CI:0.13,0.56), absence of dyslipidemia (P = 0.001;beta: −0.07;B: −0.58;95%CI: −0.93, −0.24), lower blood glucose concentration (P = 0.006;beta: −0.05;B: −0.14;95%CI: −0.24, −0.04), hyperopic refractive error (P<0.001;beta:0.15;B:0.45;95%CI:0.34,0.56), smaller optic disc size (P<0.001;beta: −0.08; B:−0.72;95% CI:−1.04, −0.40), absence of glaucomatous optic neuropathy (P<0.001;beta: −0.06;B: −2.69;95%CI:–4.18, −1.21) and absence of non-glaucomatous optic nerve damage (P = 0.001;beta: −0.06;B: −4.80;95%CI:0. −7.64, −1.96). Localized RNFL defects were detected in 96 subjects (prevalence:3.7±0.45% (95% confidence interval(CI):3.0,4.4). In multivariate analysis, prevalence of localized RNFL defects was associated with higher blood pressure (P<0.001; odds ratio (OR):1.07;95%CI:1.03,1.10), higher concentration of low-density lipoproteins (P = 0.01;OR:1.42;95%CI:1.08,1.85), higher prevalence of glaucomatous optic neuropathy (P<0.001;OR:46.8;95%CI:19.4,113) and diabetic retinopathy (P = 0.002;OR:3.20;95%CI:1.53,6.67), and lower total RNFL visibility (P<0.001;OR:0.92;95%CI:0.88,0.96).

Conclusions

In Chinese aged 45+ years, a decreased RNFL visibility was associated with older age, male gender, dyslipidemia, hyperglycemia, myopia, larger optic disc, and glaucomatous or non-glaucomatous optic neuropathy. Localized RNFL defects (prevalence:3.7±0.45%) were correlated mainly with higher blood pressure, higher concentration of low-density lipoproteins, glaucomatous optic neuropathy and diabetic retinopathy. These data are helpful for the routine ophthalmoscopic examination of the RNFL.     

An In Vitro and In Vivo Analysis of the Correlation between Susceptibility-Weighted Imaging Phase Values and R2* in Cirrhotic Livers

Objective

To establish a baseline of susceptibility-weighted imaging (SWI) phase value as a means of detecting iron abnormalities in cirrhotic liver and to analyze its relationship with R2*.

Materials and Methods

Sixteen MnCl₂ phantoms, thirty-seven healthy individuals and 87 cirrhotic patients were performed SWI and multi-echo T2*-weighted imaging, and the signal processing in NMR (SPIN) software was used to measure the radian on SWI phase images and the R2* on T2* maps. The mean minus two times standard deviation (SD) of Siemens Phase Unit (SPU) in healthy individuals was designated as a threshold to separate the regions of interest (ROIs) into high- and low-iron areas in healthy participants and cirrhotic patients. The SWI phase values of high-iron areas were calculated. The R2* values was measured in the same ROI in both healthy participants and patients.

Results

SWI phase values correlated linearly with R2* values in cases of MnCl₂ concentrations lower than 2.3 mM in vitro (r = −0.996, P<0.001). The mean value and SD of 37 healthy participants were 2003 and 15 (SPU), respectively. A threshold of 1973 SPU (−0.115 radians) was determined. The SWI phase value and R2* values had a negative correlation in the cirrhotic patients (r = −0.742, P<0.001). However, no similar relationship was found in the healthy individuals (r = 0.096, P = 0.576). Both SWI phase values and R2* values were found to have significant correlations with serum ferritin concentrations in 42 patients with blood samples (r = −0.512, P = 0.001 and r = 0.641, P<0.001, respectively).

Conclusion

SWI phase values had significant correlations with R2* after the establishment of a baseline on the phase image. SWI phase images may be used for non-invasive quantitative measurement of mild and moderate iron deposition in hepatic cirrhosis in vivo.     

Quantitative Assessment of the Association between rs2046210 at 6q25.1 and Breast Cancer Risk

Genome-wide association studies (GWAS) have identified several genetic susceptibility loci for breast cancer (BC). One of them, conducted among Chinese women, found an association of rs2046210 at 6q25.1 with the risk of BC recently. Since then, numerous association studies have been carried out to investigate the relationship between this polymorphism and BC risk in various populations. However, these have yielded contradictory results. We therefore performed a meta-analysis to clarify this inconsistency. Overall, a total of 235003 subjects based on 13 studies were included in our study. Significantly increased BC risk was detected in the pooled analysis [allele contrast: OR = 1.13, 95%CI = 1.10–1.17, P(Z) <10⁻⁵, P(Q) <10⁻⁴; dominant model: OR = 1.21, 95%CI = 1.14–1.27, P(Z) <10⁻⁵, P(Q) <10⁻⁴; recessive model: OR = 1.18, 95%CI = 1.12–1.24, P(Z) <10⁻⁵, P(Q) = 0.04]. In addition, our data revealed that rs2046210 conferred greater risk in estrogen receptor (ER)-negative tumors [OR = 1.27, 95%CI = 1.15–1.40, P(Z) <10⁻⁵, P(Q) <10⁻⁴] than in ER-positive ones [OR = 1.18, 95%CI = 1.09–1.28, P(Z) <10⁻⁴, P(Q) = 0.0003]. When stratified by ethnicity, significant associations were found in Caucasian and Asian populations, but not detected among Africans. There was evidence of heterogeneity (P<0.05), however, the heterogeneity largely disappeared after stratification by ethnicity. The present meta-analysis demonstrated that the rs2046210 polymorphism may be associated with increased BC susceptibility, but this association varies in different ethnicities.     

Daily Liquorice Consumption for Two Weeks Increases Augmentation Index and Central Systolic and Diastolic Blood Pressure

Background

Liquorice ingestion often elevates blood pressure, but the detailed haemodynamic alterations are unknown. We studied haemodynamic changes induced by liquorice consumption in 20 subjects versus 30 controls with average blood pressures of 120/68 and 116/64 mmHg, respectively.

Methods

Haemodynamic variables were measured in supine position before and after two weeks of liquorice consumption (daily glycyrrhizin dose 290–370 mg) with tonometric recording of radial blood pressure, pulse wave analysis, and whole-body impedance cardiography. Thirty age-matched healthy subjects maintaining their normal diet were studied as controls.

Results

Two weeks of liquorice ingestion elevated peripheral and central systolic and diastolic blood pressure (by 7/4 and 8/4 mmHg, 95% confidence intervals [CI] 2-11/1-8 and 3-13/1-8, respectively, P<0.05), and increased extracellular volume by 0.5 litres (P<0.05 versus controls). Also augmentation index adjusted to heart rate 75/min (from 7% to 11%, 95% CI for change 0.3-7.5, P<0.05) and aortic pulse pressure (by 4 mmHg, 95% CI 1-7, P<0.05) were elevated indicating increased wave reflection from the periphery. In contrast, peripheral (−3/−0.3 mmHg) and central blood pressure (−2/−0.5 mmHg), aortic pulse pressure (−1 mmHg), and augmentation index adjusted to heart rate 75/min (from 9% to 7%) decreased numerically but not statistically significantly without changes in extracellular volume in the control group. Heart rate, systemic vascular resistance, cardiac output, and pulse wave velocity did not differ between the groups.

Conclusions

Two weeks of daily liquorice consumption increased extracellular volume, amplified pressure wave reflection from the periphery, and elevated central systolic and diastolic blood pressure.

Trial Registration

EU Clinical Trials Register EudraCT 2006-002065-39</url>ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01742702","term_id":"NCT01742702"}}NCT01742702