[Clinicopathological Features of Primary Small Cell Neuroendocrine Carcinoma of the Bladder].

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34ßE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

BACKGROUND: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. METHODS: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. RESULTS: Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056). CONCLUSIONS: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

Incidence of nephrolithiasis in relation to environmental exposure to lead and cadmium in a population study.

Whether environmental exposure to nephrotoxic agents that potentially interfere with calcium homeostasis, such as lead and cadmium, contribute to the incidence of nephrolithiasis needs further clarification. We investigated the relation between nephrolithiasis incidence and environmental lead and cadmium exposure in a general population. In 1302 participants randomly recruited from a Flemish population (50.9% women; mean age, 47.9 years), we obtained baseline measurements (1985-2005) of blood lead (BPb), blood cadmium (BCd), 24-h urinary cadmium (UCd) and covariables. We monitored the incidence of kidney stones until October 6, 2014. We used Cox regression to calculate multivariable-adjusted hazard ratios for nephrolithiasis. At baseline, geometric mean BPb, BCd and UCd was 0.29µmol/L, 9.0nmol/L, and 8.5nmol per 24h, respectively. Over 11.5 years (median), nephrolithiasis occurred in 40 people. Contrasting the low and top tertiles of the distributions, the sex- and age-standardized rates of nephrolithiasis expressed as events per 1000 person-years were 0.68 vs. 3.36 (p=0.0016) for BPb, 1.80 vs. 3.28 (p=0.11) for BCd, and 1.65 vs. 2.95 (p=0.28) for UCd. In continuous analysis, with adjustments applied for sex, age, serum magnesium, and 24-h urinary volume and calcium, the hazard ratios expressing the risk associated with a doubling of the exposure biomarkers were 1.35 (p=0.015) for BPb, 1.13 (p=0.22) for BCd, and 1.23 (p=0.070) for UCd. In conclusion, our results suggest that environmental lead exposure is a risk factor for nephrolithiasis in the general population.

Ambulatory hypertension subtypes and 24-hour systolic and diastolic blood pressure as distinct outcome predictors in 8341 untreated people recruited from 12 populations.

BACKGROUND: Data on risk associated with 24-hour ambulatory diastolic (DBP24) versus systolic (SBP24) blood pressure are scarce. METHODS AND RESULTS: We recorded 24-hour blood pressure and health outcomes in 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations. We computed hazard ratios (HRs) using multivariable-adjusted Cox regression. Over 11.2 years (median), 927 (11.1%) participants died, 356 (4.3%) from cardiovascular causes, and 744 (8.9%) experienced a fatal or nonfatal cardiovascular event. Isolated diastolic hypertension (DBP24≥80 mm Hg) did not increase the risk of total mortality, cardiovascular mortality, or stroke (HRs≤1.54; P≥0.18), but was associated with a higher risk of fatal combined with nonfatal cardiovascular, cardiac, or coronary events (HRs≥1.75; P≤0.0054). Isolated systolic hypertension (SBP24≥130 mm Hg) and mixed diastolic plus systolic hypertension were associated with increased risks of all aforementioned end points (P≤0.0012). Below age 50, DBP24 was the main driver of risk, reaching significance for total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and for all cardiovascular end points combined (HR, 1.74; P=0.039) with a nonsignificant contribution of SBP24 (HR≤0.92; P≥0.068); above age 50, SBP24 predicted all end points (HR≥1.19; P≤0.0002) with a nonsignificant contribution of DBP24 (0.96≤HR≤1.14; P≥0.10). The interactions of age with SBP24 and DBP24 were significant for all cardiovascular and coronary events (P≤0.043). CONCLUSIONS: The risks conferred by DBP24 and SBP24 are age dependent. DBP24 and isolated diastolic hypertension drive coronary complications below age 50, whereas above age 50 SBP24 and isolated systolic and mixed hypertension are the predominant risk factors.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). CONCLUSIONS: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

Study for Promotion of Health in Recycling Lead - Rationale and design.

BACKGROUND: The level at which low-level lead exposure produces subclinical adverse health effects in adults remains to be established. METHODS: The Study for Promotion of Health in Recycling Lead (SPHERL) will enroll 500 newly hired workers, whose blood lead during 2 years of follow-up is expected to increase from levels less than 2 µg/dl, as currently observed in the US population, to 20-30 µg/dl. The main outcome variables to be studied are (i) blood pressure (BP) analyzed as a continuous or categorical variable, both cross-sectionally and longitudinally, and using conventional and ambulatory BP measurement; (ii) indexes of glomerular and tubular renal function, (iii) heart rate variability analyzed in the frequency domain as measure of autonomous sympathetic modulation, (iv) peripheral nerve conductivity velocity, (v) neurocognitive performance, and (vi) quality of life. Expected outcomes. Assuming a 10-fold increase in blood lead, SPHERL will have sufficient statistical power to detect over 2 years a steepening of the age-related rise in systolic BP from 1 to 5 mmHg and a doubling of the age-related decline in the estimated glomerular filtration rate from 3.5 to 7.0 ml/min/1.73 m(2). The longitudinal design of our study complies with the temporality principle of the Bradford-Hill criteria for assessing possible causality between outcomes and exposure. SPHERL will attempt to resolve the apparent contradiction between general population studies showing associations between adverse health effects and low lead exposure with blood lead levels below 5 µg/dl and studies conducted in occupational cohorts indicating that adverse effects of lead exposure occur at much higher blood lead levels.

PEAR1 is not a human hypertension-susceptibility gene.

OBJECTIVE: Platelet endothelial aggregation receptor 1 (PEAR1) is a membrane protein involved in platelet contact-induced activation and sustained platelet aggregation. Experimental studies identified PEAR1, as a candidate gene that may be linked to the blood-pressure driven kidney injury in salt-sensitive Dahl rats. AIM: In a family-based European population study (mean age 39.7 years; 52.2% women), we searched for association of changes in blood pressure or incidence of hypertension with genetic variation in PEAR1. METHODS: Among 1973 randomly recruited people, genotyped for PEAR1, we measured blood pressure at baseline and follow-up. RESULTS: Median follow-up was 10.0 years. While accounting for family clusters and blood pressure at baseline and with adjustments applied for sex, age, body mass index, smoking and drinking, total cholesterol, and antihypertensive drug treatment, all associations of systolic and diastolic blood pressure changes with nine single nucleotide polymorphisms (SNPs) in PEAR1 were all non-significant (p ≥ 0.059). With similar adjustments, the incidence of hypertension (397 cases among 1532 participants were normotensive at baseline [25.9%]) was not related to the SNPs in PEAR1 (hazard ratios ≤ 1.09; p ≥ 0.09). CONCLUSION: Our study suggests that PEAR1 is not a hypertension susceptibility gene in humans.

The urinary proteome as correlate and predictor of renal function in a population study.

BACKGROUND: We investigate whether the urinary proteome refines the diagnosis of renal dysfunction, which affects over 10% of the adult population. METHODS: We measured serum creatinine, estimated glomerular filtration rate (eGFR) and 24-h albuminuria in 797 people randomly recruited from a population. We applied capillary electrophoresis coupled with mass spectrometry to measure multi-dimensional urinary proteomic classifiers developed for renal dysfunction (CKD273) or left ventricular dysfunction (HF1 and HF2). Renal function was followed up in 621 participants and the incidence of cardiovascular events in the whole study population. RESULTS: In multivariable-adjusted cross-sectional analyses, higher biomarker levels analysed separately or combined by principal component analysis into a single factor (SF), correlated (P ≤ 0.010) with worse renal function. Over 4.8 years, higher HF1 and SF predicted (P ≤ 0.014) lowering of eGFR; higher HF2 predicted (P ≤ 0.049) increase in serum creatinine and decrease eGFR. HF1, HF2 and SF predicted progression from CKD Stages 2 or ≤2 to Stage ≥3, with risk estimates for a 1-SD increment in the urinary biomarkers ranging from 38 to 71% (P ≤ 0.039). HF1, HF2 and SF yielded a net reclassification improvement of 31-51% (P ≤ 0.029). Over 6.1 years, 47 cardiovascular events occurred. HF2 and SF, independent of baseline eGFR, 24-h albuminuria and other covariables were significant predictors of cardiovascular complications with risk estimates for 1-SD increases ranging from 32 to 41% (P ≤ 0.047). CONCLUSIONS: The urinary proteome refines the diagnosis of existing or progressing renal dysfunction and predicts cardiovascular complications.

Construction of chimeric E3s expression plasmids targeting oncoprotein ras.

OBJECTIVE: To construct certain chimeric E3s expression plasmids targetting oncoprotein Ras by harnessing the theory of protein knockdown. METHODS: We chose the binding domain of Raf-1, PI3K, RalGDS, and the function domain of F-Box as well as the U-Box to construct the plasmids. Then used the double enzyme, PCR, and sequence to test the validity and integrity of the cloned nucleotide fragments. The expression efficiency of the plasmids in eukaryotic cells was detected by Western blot analysis. RESULTS: Five of 6 plasmids in this study expressed the corresponding fusion proteins in HEK293T cells, and (RBD+CRD)(Raf-1)- U-Box-pcDNA3.1 can knocked down the protein level of Ras in PANC-1 cells. CONCLUSIONS: We successfully constructed the chimeric E3 expression plasmids, which provides a solid basis for further research on protein knockdown.

Distribution and characterization of higher chlorinated benzenes in outdoor dust collected from a fast developing city in North China.

Five higher chlorinated benzenes (CBs), include hexachlorobenzene (HCB), pentachlorobenzene (PeCB) and three isomers of tetrachlorobenzens, were analyzed in 20 outdoor dust samples collected from a fast developing city, Xinxiang. Only HCB was detected in all outdoor dust samples. The dominate part of the CBs residue in most samples was HCB and the mean HCB concentration (4.13 ng/g dry weight) in this study was in the range of global background soil HCB levels (ranging from 0.010 to 5.20 ng/g dry weight). The higher ratios of HCB/PeCB in the outdoor dust samples in the present study indicate that pesticide application may be an important source of HCB in China.

The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS.

Aberrantly expressed microRNA (miRNA) is frequently associated with a variety of cancers, including pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the expression and possible role of miR-217 in PDAC. Data obtained by locked nucleic acid in situ hybridization and real-time quantitative polymerase chain reaction showed that miR-217 was downregulated in 76.2% (16/21) of PDAC tissues and in all tested PDAC cell lines when compared with the corresponding normal pancreatic tissue. Overexpression of miR-217 in PDAC cells inhibited tumor cell growth and anchorage-independent colony formation and miR-217 decreased tumor cell growth in nude mouse xenografts in vivo. Using in silico predictions, KRAS was defined as a potential direct target of miR-217. Data from the dual-luciferase reporter gene assay showed that KRAS was a direct target of miR-217. Upregulation of miR-217 could decrease KRAS protein levels and reduce the constitutive phosphorylation of downstream AKT. Downregulation of miR-217 expression in PDAC cells could increase cell anchorage-independent colony formation and KRAS protein levels. Furthermore, miR-217 expression was observed to be negatively correlated with KRAS protein expression in PDAC cell lines. We conclude that the frequently downregulated miR-217 can regulate KRAS and function as a tumor suppressor in PDAC. Therefore, miR-217 may serve as a useful therapeutic agent for miRNA-based PDAC therapy.

Elevated thymosin beta15 expression is associated with progression and metastasis of non-small cell lung cancer.

Thymosin beta15 (Tbeta15) is a small protein that comprises 44 amino acid residues. Tbeta15 is upregulated in malignant human prostate and breast tumors. The expression of Tbeta15 correlates with the metastatic potential of mouse lung cancer and human breast carcinoma cells. However, the correlation of Tbeta15 expression with human lung cancer remains unclear. Using immunohistochemistry and in situ hybridization, we analyzed the expression of Tbeta15 in tumors and tumor-adjacent tissues obtained from 76 patients with non-small cell lung cancer (NSCLC). The relationship between Tbeta15 expression and clinicopathological factors was investigated. Our findings showed that in NSCLC, Tbeta15 protein and mRNA were mainly expressed in the cytoplasm, and their expression correlated with stage (p=0.018 for both), differentiation (p=0.013 and 0.006, respectively), and lymph node metastasis (p=0.001 and 0.009, respectively). Tbeta15 expression was examined in PG-BE1 and PG-LH7 lung cancer cells. We found that both Tbeta15 protein and mRNA were highly expressed in BE1 cells as compared to LH7 cells. After transfecting the PG-LH7 cells with the pEGFP-Tbeta15 plasmid in order to increase Tbeta15 expression, the migration ability of the cells was enhanced. These findings suggest that increased Tbeta15 expression correlates with the progression and metastasis of NSCLC.

BCSG1 methylation status and BCSG1 expression in breast tissues derived from Chinese women with breast cancer.

OBJECTIVE: To investigate the role of DNA methylation in the regulation of BCSG1 gene expression in breast tissues derived from Chinese women with breast cancer. METHODS: The methylation status of exon 1 of the BCSG1 gene in breast cancer, and matched non-neoplastic adjacent and benign lesion tissues was extensively examined using methylation-specific PCR analysis. Corresponding mRNA expression levels were determined by real-time PCR. RESULTS: We found: (1) the BCSG1 gene was universally demethylated in all breast tissues regardless of the tissue state, although 50-60% of the samples displayed methylated products as well; (2) DNA methylation correlated to the expression of the BCSG1 gene in tumor tissues, but not in non-neoplastic adjacent and benign tissues; (3) breast tumor tissues expressed lower BCSG1 than non-neoplastic adjacent tissues. CONCLUSIONS: Our data revealed a unique expression pattern and methylation status of the BCSG1 gene in breast tissues derived from Chinese patients and suggested both methylation status and mechanisms underlying BCSG1 regulation might be closely related to the racial background.

[Extract of Ginkgo biloba and quercetin inhibit angiotensin-II induced hypertrophy in cultured neonatal rat cardiomyocytes].

OBJECTIVE: To investigate the effect and related mechanisms of extract of ginkgo biloba (EGb) and quercetin (Que) on angiotensin II (AngII) induced hypertrophy in the primary cultured neonatal rat cardiomyocytes. METHODS: Primary cultured neonatal rat cardiomyocytes were treated with placebo (control), AngII (10(-6) mol/L), AngII + EGb (40 microg/ml), AngII + Que (4 microg/ml), AngII + captopril (10(-5) mol/L) and AngII + DPI [diphenylene iodonium chloride, NADPH inhibitor (10 micromol/L)] respectively. Total protein content of cardiomyocytes, cardiomyocytes size, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured. The expression of phospho-Extracellular-signal regulated kinase 1/2, phospho-c-Jun N-terminal kinase and phospho-P38 were detected by Western blot. RESULTS: The total protein content and cell size of cardiomyocytes increased significantly in AngII treated cells and these effects could be blocked by EGb and Que. EGb and Que also enhanced the SOD activity and reduced the production of MDA. AngII significantly activated ERK1/2, JNK and P38 expressions and only JNK activation could be inhibited by Que and DPI. CONCLUSION: EGb and Que can inhibit AngII-induced cardiomyocyte hypertrophy through a ROS-dependent pathway. Que could also block the JNK activation induced by AngII.

Urinary Proteomics Pilot Study for Biomarker Discovery and Diagnosis in Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Biomarker discovery and new insights into the pathophysiology of heart failure with reduced ejection fraction (HFrEF) may emerge from recent advances in high-throughput urinary proteomics. This could lead to improved diagnosis, risk stratification and management of HFrEF. METHODS AND RESULTS: Urine samples were analyzed by on-line capillary electrophoresis coupled to electrospray ionization micro time-of-flight mass spectrometry (CE-MS) to generate individual urinary proteome profiles. In an initial biomarker discovery cohort, analysis of urinary proteome profiles from 33 HFrEF patients and 29 age- and sex-matched individuals without HFrEF resulted in identification of 103 peptides that were significantly differentially excreted in HFrEF. These 103 peptides were used to establish the support vector machine-based HFrEF classifier HFrEF103. In a subsequent validation cohort, HFrEF103 very accurately (area under the curve, AUC = 0.972) discriminated between HFrEF patients (N = 94, sensitivity = 93.6%) and control individuals with and without impaired renal function and hypertension (N = 552, specificity = 92.9%). Interestingly, HFrEF103 showed low sensitivity (12.6%) in individuals with diastolic left ventricular dysfunction (N = 176). The HFrEF-related peptide biomarkers mainly included fragments of fibrillar type I and III collagen but also, e.g., of fibrinogen beta and alpha-1-antitrypsin. CONCLUSION: CE-MS based urine proteome analysis served as a sensitive tool to determine a vast array of HFrEF-related urinary peptide biomarkers which might help improving our understanding and diagnosis of heart failure.

Conventional and Ambulatory Blood Pressure as Predictors of Retinal Arteriolar Narrowing.

At variance with the long established paradigm that retinal arteriolar narrowing trails hypertension, several longitudinal studies, all based on conventional blood pressure (CBP) measurement, proposed that retinal arteriolar narrowing indicates heightened microvascular resistance and precedes hypertension. In 783 randomly recruited Flemish (mean age, 38.2 years; 51.3% women), we investigated to what extent CBP and daytime (10 am to 8 pm) ambulatory blood pressure (ABP) measured at baseline (1989-2008) predicted the central retinal arteriolar equivalent (CRAE) in retinal photographs obtained at follow-up (2008-2015). Systolic/diastolic hypertension thresholds were 140/90 mm Hg for CBP and 135/85 mm Hg for ABP. In multivariable-adjusted models including both baseline CBP and ABP, CRAE after 10.3 years (median) of follow-up was unrelated to CBP (P≥0.14), whereas ABP predicted CRAE narrowing (P≤0.011). Per 1-SD increment in systolic/diastolic blood pressure, the association sizes were -0.95 µm (95% confidence interval, -2.20 to 0.30)/-0.75 µm (-1.93 to 0.42) for CBP and -1.76 µm (-2.95 to -0.58)/-1.48 µm (-2.61 to -0.34) for ABP. Patients with ambulatory hypertension at baseline (17.0%) had smaller CRAE (146.5 versus 152.6 µm; P<0.001) at follow-up. CRAE was not different (P≥0.31) between true normotension (normal CBP and ABP; prevalence, 77.6%) and white-coat hypertension (elevated CBP and normal ABP, 5.4%) and between masked hypertension (normal CBP and elevated ABP, 10.2%) and hypertension (elevated CBP and ABP, 6.8%). In conclusion, the paradigm that retinal arteriolar narrowing precedes hypertension can be explained by the limitations of CBP measurement, including nonidentification of masked and white-coat hypertension.

Renal glomerular dysfunction in relation to retinal arteriolar narrowing and high pulse pressure in seniors.

Retinal arteriolar narrowing and high pulse pressure (PP) are associated with macrovascular complications and microvascular renal disease. Few studies addressed whether in seniors (⩾60 years) estimated glomerular filtration rate (eGFR) is independently related to central retinal arteriolar equivalent (CRAE) and PP. In 292 randomly recruited seniors (49.3% women; mean, 68.2 years), we measured PP by standard sphygmomanometry, CRAE (IVAN software), eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) and stage of chronic kidney disease (CKD (Kidney Disease Outcomes Quality Initiative guideline)). Statistical methods included linear and logistic regression. PP, CRAE and eGFR averaged 59.2 mm Hg, 146.3 µm and 79.9 ml min(-1) per 1.73 m(2). Decline in eGFR (-2.27 ml min(-1) per 1.73 m(2) per 15 µm; P=0.011) occurred in parallel with CRAE narrowing. CRAE (effect size per 1-s.d. increment, -1.85 µm; P=0.032) and eGFR (-2.68 ml min(-1) per 1.73 m(2); P=0.003) both declined with higher PP. With PP increasing from 63 to 73 mm Hg (threshold for macrovascular complications), CRAE dropped by -4.70 µm (P⩽0.037). A 70-mm Hg PP threshold corresponded with a 150-µm CRAE cutoff. The risk of CKD (stage ⩾2 vs. 1; n=203 vs. 89) rose with CRAE <150 µm (odds ratio, 2.81; P<0.0001), but not with PP ⩾70 mm Hg (1.47; P=0.20). Additionally, CRAE added to PP increased the area under the curve from 0.58 to 0.64 (P=0.047) for identifying stage ⩾2 CKD. In seniors, CRAE and eGFR decline in parallel with higher PP. CRAE <150 µm identifies early decline in eGFR.

Retinal microvascular diameter, a hypertension-related trait, in ECG-gated vs. non-gated images analyzed by IVAN and SIVA.

The diameters of the retinal microvasculature reflect intermediate target organ damage and predict adverse health outcomes. In view of the pulsatility of the cerebral blood flow and refinement of software used for off-line analysis, we assessed the repeatability of retinal microvascular diameters in ECG-gated vs. non-gated images using nonmydriatic retinal photographs (Canon Cr-DGi visualization system) postprocessed by IVAN (Vasculomatic ala Nicola, version 1.1) or SIVA (Singapore I Vessel Assessment, version 3.6). Using these algorithms, we determined the central retinal arteriolar (CRAE) and venular (CRVE) equivalents and their ratio (arteriole-to-venule ratio (AVR)). The estimates of CRAE (mean, 158.5 µm), CRVE (222.5 µm) and AVR (0.71) in 10 volunteers were unaffected (P⩾0.059) by ECG gating. We assessed intragrader repeatability by the Bland and Altman approach in 30 participants with non-gated images and 30 with ECG-gated photographs. Repeatability, which was expressed as the percentage of near maximal variability (4-s.d. range), did not improve with ECG gating. Using SIVA, CRAE and CRVE were systematically larger (P⩽0.031), and the AVR estimates were similar (P⩾0.15) compared with IVAN. The differences (IVAN-SIVA) averaged -5.4 µm for CRAE, -3.9 µm for CRVE and -0.012 for AVR in the non-gated images and -3.3 µm, -6.9 µm and 0.006, respectively, in the ECG-gated photographs. In conclusion, ECG gating does not affect estimates of the retinal microvascular diameters or improve intragrader repeatability. SIVA yields slightly but significantly larger estimates of the retinal arteriolar and venular diameters. Combining historical readings analyzed by IVAN with more recent readings by SIVA is possible only for AVR and is not recommended for either CRAE or CRVE.

Vitamin K Dependent Protection of Renal Function in Multi-ethnic Population Studies.

BACKGROUND: Following activation by vitamin K (VK), matrix Gla protein (MGP) inhibits arterial calcification, but its role in preserving renal function remains unknown. METHODS: In 1166 white Flemish (mean age, 38.2 years) and 714 South Africans (49.2% black; 40.6 years), we correlated estimated glomerular filtration (eGFR [CKD-EPI formula]) and stage of chronic kidney disease (CKD [KDOQI stages 2-3]) with inactive desphospho-uncarboxylated MGP (dp-ucMGP), using multivariable linear and logistic regression. RESULTS: Among Flemish and white and black Africans, between-group differences in eGFR (90, 100 and 122 mL/min/1.73 m(2)), dp-ucMGP (3.7, 6.5 and 3.2 µg/L), and CKD prevalence (53.5, 28.7 and 10.5%) were significant, but associations of eGFR with dp-ucMGP did not differ among ethnicities (P ≥ 0.075). For a doubling of dp-ucMGP, eGFR decreased by 1.5 (P = 0.023), 1.0 (P = 0.56), 2.8 (P = 0.0012) and 2.1 (P < 0.0001) mL/min/1.73 m(2) in Flemish, white Africans, black Africans and all participants combined; the odds ratios for moving up one CKD stage were 1.17 (P = 0.033), 1.03 (P = 0.87), 1.29 (P = 0.12) and 1.17 (P = 0.011), respectively. INTERPRETATION: In the general population, eGFR decreases and CKD risk increases with higher dp-ucMGP, a marker of VK deficiency. These findings highlight the possibility that VK supplementation might promote renal health.

Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study.

Detecting left ventricular (LV) dysfunction at an early stage is key in addressing the heart failure epidemic. In proteome profiling experiments in mice subjected either to aortic banding or sham, the circulating CXCR3 ligands monokine induced by interferon-γ (MIG) and interferon-γ inducible protein 10 (IP10) were 5 to 40 fold up-regulated at eight weeks. We assessed the diagnostic value of circulating NT-pro BNP and CXCR3 ligands (MIG, IP10, Interferon-inducible T-cell alpha chemo-attractant [I-TAC]) in patients with hypertension (≥140/90 mm Hg) associated with subclinical (n = 19) or symptomatic (n = 16) diastolic LV dysfunction on echocardiography and healthy controls. NT-pro BNP, MIG, IP10, I-TAC all increased (p ≤ 0.014) across the categories of worsening left ventricular dysfunction. In patients with symptomatic disease, MIG, IP10, and I-TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT-pro BNP. The optimal discrimination limits, obtained by maximizing Youden's index were 246 pmol/L, 65 pg/mL, 93 pg/mL, and 24 pg/mL, respectively. The odds ratios associated with the four biomarkers were significant (p ≤ 0.010), ranging from 4.00 for IP10 to 9.69 for MIG. With adjustment for NT-pro BNP, the CXCR3 ligands retained significance (p ≤ 0.028). Adding optimized thresholds for the CXCR3 ligands to NT-pro BNP enhanced (p ≤ 0.014) the integrated discrimination improvement and the net reclassification improvement. In conclusion, congruent with the concept that inflammation plays a key role in the pathogenesis of LV dysfunction, MIG, IP10 and I-TAC add diagnostic accuracy over and beyond NT-pro BNP.