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Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Background: Low birth weight (LBW) might be a risk factor for acquiring lower respiratory tract infections (LRTIs) associated with disease related complications in early childhood. HFMD, a frequent viral infection in southern China, is a leading cause of lower respiratory tract infections in children. We analyzed whether LBW is a risk factor for children with HFMD to develop lower respiratory tract infections.
Methods: A total of 298 children with HFMD, admitted to a hospital in Qingyuan city, Guangdong province, were recruited. Demographic data and clinical parameters such as serum glucose level and inflammatory markers including peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate were routinely collected on admission. Birth weight data were derived from birth records.
Results: Mean birth weight (BW) was 167 g lower in patients with HFMD and LRTIs as compared to patients with solely HFMD (p = 0.022) and the frequency of birth weight below the tenth percentile was significantly higher in patients with HFMD and LRTIs (p = 0.002).
Conclusions: The results of the study show that low birth weight is associated with a higher incidence of lower respiratory tract infections in young children with HFMD.
Background/Aims: Cortisol plays an important role during pregnancy. It controls maternal glucose metabolism and fetal development. Cortisol metabolism is partially controlled by the 11b-HSD2. This enzyme is expressed in the kidney and human placenta. The activity of the enzyme is partially controlled by functional polymorphisms: the HSD11B2[CA]n microsatellite polymorphism. The impact of this functional gene polymorphism on cortisol metabolism and potential effects on the newborn's is unknown so far. Methods: In the current prospective birth cohort study in southern Asia, we analyzed the association of the HSD11B2[CA]n microsatellite polymorphisms in 187 mothers and their newborn's on maternal and newborn's serum cortisol concentrations. Results: Using multivariable regression analyses considering known confounding ( gestational age, newborn's gender, the labor uterine contraction states and the timing during the day of blood taking), we showed that the fetal HSD11B2[CA]n microsatellite polymorphisms in the first intron was related to maternal cortisol concentration ( R2=0.26, B=96.27, p=0.007), whereas as the newborn's cortisol concentrations were independent of fetal and maternal HSD11B2[CA] n microsatellite polymorphism. Conclusions: Our study showed for the first time that the fetal HSD11B2[CA]n microsatellite polymorphism of the HSD11B2 gene in healthy uncomplicated human pregnancy is associated with maternal cortisol concentration. This indicates that fetal genes controlling cortisol metabolism may affect maternal cortisol concentration and hence physiology in healthy pregnant women.
Background and objectives Trials with the antioxidant vitamin E have failed to show benefit in the general population. Considering the different causes of death in ESRD, this study investigated the association between plasma concentrations of alpha-tocopherol and specific clinical outcomes in diabetic hemodialysis patients.
Design, settings, participants, & measurements In 1046 diabetic hemodialysis patients (participants of the German Diabetes and Dialysis Study), alpha-tocopherol was measured in plasma by reversed-phase HPLC. By Cox regression analyses, hazard ratios were determined for prespecified end points according to baseline plasma alpha-tocopherol levels: sudden death (n=134), myocardial infarction (n=172), stroke (n=89), combined cardiovascular events (n=398), fatal infection (n=107), and all-cause mortality (n=508).
Results Patients had a mean age of 66 8 years, and mean plasma alpha-tocopherol level was 22.8+/-9.6 mu mol/L. Levels of alpha-tocopherol were highly correlated to triglycerides (r=0.63, P<0.001). Patients in the lowest alpha-tocopherol quartile had (in unadjusted analyses) a 79% higher risk of stroke and a 31% higher risk of all-cause mortality compared with patients in the highest quartile. The associations were attenuated after adjustment for confounders (hazard ratio(stroke)=1.56, 95% confidence interval=0.75-3.25; hazard ratio(mortality)=1.22, 95% confidence interval=0.89-1.69, respectively). There was no association between alpha-tocopherol and myocardial infarction, sudden death, or infectious death.
Conclusions Plasma alpha-tocopherol concentrations were not independently associated with cardiovascular outcomes, infectious deaths, or all-cause mortality in diabetic hemodialysis patients. The lack of association can partly be explained by a confounding influence of malnutrition, which should be considered in the planning of trials to reduce cardiovascular risk in dialysis patients.
Preclinical work indicates that calcitriol restores vascular function by normalizing the endothelial expression of cyclooxygenase-2 and thromboxane-prostanoid receptors in conditions of estrogen deficiency and thus prevents the thromboxane-prostanoid receptor activation-induced inhibition of nitric oxide synthase. Since endothelial dysfunction is a key factor in the pathogenesis of cardiovascular diseases, this finding may have an important translational impact. It provides a clear rationale to use endothelial function in clinical trials aiming to find the optimal dose of vitamin D for the prevention of cardiovascular events in postmenopausal women.
Background: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia.
Methods: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min.
Results: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals.
Conclusions: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells.
Objective:To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension.Methods:Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (n=14-18 per group) receiving: telmisartan (10mg/kg per day in drinking water), linagliptin (89ppm in chow), combination (linagliptin 89ppm+telmisartan 10mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed.Results:Renal stenosis caused an increase in meanSD systolic BP as compared with the sham group (157.7 +/- 29.3 vs. 106.2 +/- 20.5mmHg, respectively; P<0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1 +/- 24.3mmHg and 100.4 +/- 13.9mmHg, respectively; P<0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (P=0.03 vs. placebo) and in combination with telmisartan (P=0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (P=0.04 vs. placebo).Conclusion:Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent.
Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients
(2013)
Background: It was shown that nonoxidized PTH (n-oxPTH) is bioactive, whereas the oxidation of PTH results in a loss of biological activity.
Methods: In this study we analyzed the association of n-oxPTH on mortality in hemodialysis patients using a recently developed assay system.
Results: Hemodialysis patients (224 men, 116 women) had a median age of 66 years. One hundred seventy patients (50%) died during the follow-up period of 5 years. Median n-oxPTH levels were higher in survivors (7.2 ng/L) compared with deceased patients (5.0 ng/L; P = .002). Survival analysis showed an increased survival in the highest n-oxPTH tertile compared with the lowest n-oxPTH tertile (chi(2), 14.3; P = 0008). Median survival was 1702 days in the highest n-oxPTH tertile, whereas it was only 453 days in the lowest n-oxPTH tertile. Multivariable-adjusted Cox regression showed that higher age increased odds for death, whereas higher n-oxPTH reduced the odds for death. Another model analyzing a subgroup of patients with intact PTH (iPTH) concentrations at baseline above the upper normal range of the iPTH assay (70 ng/L) revealed that mortality in this subgroup was associated with oxidized PTH but not with n-oxPTH levels.
Conclusions: The predictive power of n-oxPTH and iPTH on the mortality of hemodialysis patients differs substantially. Measurements of n-oxPTH may reflect the hormone status more precisely. The iPTH-associated mortality is most likely describing oxidative stress-related mortality.
Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase III trial in acute heart failure patients. However, lessons can be learned from these and other studies, and there might still be a potential role for the clinical use of adenosine A1 antagonists. We review the role of adenosine A1 receptors in the regulation of renal function, and emerging data regarding the safety and efficacy of A1 adenosine receptor antagonists based on all available completed and reported clinical trials using A1 adenosine receptor antagonists. The majority of trials were done in heart failure patients. However, there is clear clinical evidence for a role of this new class in hepatorenal syndrome, hypotension on dialysis, and radiocontrast media-induced nephropathy.
Endothelins (ETs), potent endothelium-derived mediators, stimulate formation of nitric oxide, which, in turn, protects against suicidal erythrocyte death or eryptosis, characterized by phosphatidylserine exposure at the erythrocyte surface and triggered by increase in cytosolic Ca2+ ([Ca2+](i)). The present study explored whether the ET1- receptor ETB influences suicidal erythrocyte death. To this end, [Ca2+](i) (Fluo3-fluorescence) and phosphatidylserine exposure (annexin V-binding) were determined utilizing FACS analysis. Energy depletion increased [Ca2+]i and phosphatidylserine-exposure, effects significantly blunted by ET1 (IC50 approximate to 100 nM) and the ETB receptor- agonist sarafotoxin 6c (IC50 approximate to 10 nM) but not by ET2 and ET3. ET1 and sarafotoxin significantly delayed the kinetics of suicidal erythrocyte death following energy depletion. ETB stimulation did not blunt the effect of Ca2+- ionophore ionomycin (1 mu M) on phosphatidylserine exposure. The in vivo significance was tested using rescued ETB- knockout (etb(-/-)) and wild-type (etb(+/+)) mice. The number of phosphatidylserine-exposing erythrocytes, of reticulocytes and spleen size were significantly larger in etb(-/-) mice than in etb(+/+)-mice. The etb(-/-) erythrocytes were more susceptible to the eryptotic effect of oxidative stress and more rapidly cleared from circulating blood than etb(+/+) erythrocytes. Finally, the spleens from etb(-/-) mice were enlarged and contained markedly more phosphatidylserine- exposing erythrocytes than spleens from etb(+/+) mice. The observations disclose a novel function of ET1, i. e., protection from suicidal erythrocyte death.
Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25- dihydroxyvitamin-D-3 [1,25(OH)(2)D-3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klothohm mice and wild-type mice (klotho(+/+)) were subjected to a normal (D+) or vitamin D-deficient (D-) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D-/+). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/ +)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D-3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. Plasma volume was significantly smaller in klotho(hm)D(-/+) mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca2+-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho(hm)D(+) mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)(2)D-3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.
Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.