Background and objectives Elevated parathyroid hormone levels may be associated with adverse clinical outcomes in patients on dialysis. After the introduction of practice guidelines suggesting higher parathyroid hormone targets than those previously recommended, changes in parathyroid hormone levels and treatment regimens over time have not been well documented.Design, setting, participants, & measurements Using data from the international Dialysis Outcomes and Practice Patterns Study, trends in parathyroid hormone levels and secondary hyperparathyroidism therapies over the past 15 years and the associations between parathyroid hormone and clinical outcomes are reported; 35,655 participants from the Dialysis Outcomes and Practice Patterns Study phases 1-4 (1996-2011) were included.Results Median parathyroid hormone increased from phase 1 to phase 4 in all regions except for Japan, where it remained stable. Prescriptions of intravenous vitamin D analogs and cinacalcet increased and parathyroidectomy rates decreased in all regions over time. Compared with 150-300 pg/ml, in adjusted models, all-cause mortality risk was higher for parathyroid hormone=301-450 (hazard ratio, 1.09; 95% confidence interval, 1.01 to 1.18) and .600 pg/ml (hazard ratio, 1.23; 95% confidence interval, 1.12 to 1.34). Parathyroid hormone .600 pg/ml was also associated with higher risk of cardiovascular mortality as well as all-cause and cardiovascular hospitalizations. In a subgroup analysis of 5387 patients not receiving vitamin D analogs or cinacalcet and with no prior parathyroidectomy, very low parathyroid hormone (,50 pg/ml) was associated with mortality (hazard ratio, 1.25; 95% confidence interval, 1.04 to 1.51). ConclusionsIn a large international sample of patients on hemodialysis, parathyroid hormone levels increased in most countries, and secondary hyperparathyroidism treatments changed over time. Very low and very high parathyroid hormone levels were associated with adverse outcomes. In the absence of definitive evidence in support of a specific parathyroid hormone target, there is an urgent need for additional research to inform clinical practice.

Chronic kidney disease (CKD), the result of permanent loss of kidney function, is a major global problem. We identify common genetic variants at chr2p12-p13, chr6q26, chr17q23 and chr19q13 associated with serum creatinine, a marker of kidney function (P=10−10 to 10−15). SNPs rs10206899 (near NAT8, chr2p12-p13) and rs4805834 (near SLC7A9, chr19q13) were also associated with CKD. Our findings provide new insight into metabolic, solute and drug-transport pathways underlying susceptibility to CKD.

BACKGROUND: Adolescents and young adults (AYAs) with cancer demonstrate biomedical risks and psychosocial issues distinct from those of children or older adults. In this study, the authors examined and compared the extent to which AYAs treated in pediatric or adult oncology settings reported use of, and unmet need for, psychosocial support services. METHODS: Within 4 months of initial cancer diagnosis, 215 AYAs ages 14 to 39 years (99 from pediatric care settings and 116 from adult care settings; 75% response rate) were assessed for reporting use of information resources, emotional support services, and practical support services. Statistical analyses derived odds ratios and 95% confidence intervals for service use and unmet needs after controlling for race, employment/ school status, sex, relationship status, severity of cancer, treatment, and treatment-related side effects. RESULTS: AYAs ages 20 to 29 years were significantly less likely than teens and older patients ages 30 to 39 years to report using professional mental health services and were significantly more likely to report an unmet need with regard to cancer information, infertility information, and diet/ nutrition information. Compared with teens who were treated in pediatric facilities, AYAs who were treated in adult facilities were more likely to report an unmet need for age-appropriate Internet sites, professional mental health services, camp/retreats programs, transportation assistance, and complementary and alternative health services. CONCLUSIONS: Substantial proportions of AYAs are not getting their psychosocial care needs met. Bolstering psychosocial support staff and patient referral to community-based social service agencies and reputable Internet resources may enhance care and improve quality of life for AYAs.

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CD4؉ CD25 ؉ regulatory T cells (CD25 ؉ Tregs) play a key role in immune regulation. Since hepatitis C virus (HCV) persists with increased circulating CD4 ؉ CD25 ؉ T cells and virus-specific effector T-cell dysfunction, we asked if CD4 ؉ CD25 ؉ T cells in HCV-infected individuals are similar to natural Tregs in uninfected individuals and if they include HCV-specific Tregs using the specific Treg marker FoxP3 at the single-cell level. We report that HCV-infected patients display increased circulating FoxP3 ؉ Tregs that are phenotypically and functionally indistinguishable from FoxP3 ؉ Tregs in uninfected subjects. Furthermore, HCV-specific FoxP3 ؉ Tregs were detected in HCV-seropositive persons with antigen-specific expansion, major histocompatibility complex class II/peptide tetramer binding affinity, and preferential suppression of HCV-specific CD8 T cells. Transforming growth factor ␤ contributed to antigen-specific Treg expansion in vitro, suggesting that it may contribute to antigen-specific Treg expansion in vivo. Interestingly, FoxP3 expression was also detected in influenza virus-specific CD4 T cells. In conclusion, functionally active and virus-specific FoxP3 ؉ Tregs are induced in HCV infection, thus providing targeted immune regulation in vivo. Detection of FoxP3 expression in non-HCV-specific CD4 T cells suggests that immune regulation through antigen-specific Treg induction extends beyond HCV.Hepatitis C virus (HCV) is a highly persistent human pathogen that causes chronic necroinflammatory liver disease with progression to liver failure and cancer (25, 31). While T cells play a critical role in HCV clearance (24, 53), the virus generally persists, along with impaired antiviral effector T-cell responses (13,59,63,69). While the precise underlying mechanisms for HCV persistence and disease pathogenesis are not fully defined, a role for CD4 ϩ CD25 ϩ regulatory T cells (CD25 ϩ Tregs) has been proposed based on increased circulating CD4 ϩ CD25 ϩ T cells that can suppress HCV-specific T cells in HCV-infected patients (10,12,48,54). CD25ϩ Tregs are a subset of naturally occurring, thymus-derived CD4 ϩ regulatory T cells that highly express CD25 (the interleukin-2 [IL-2] receptor alpha chain) and play a critical role in immune tolerance to self and nonself antigens (27,44,49,51). The role of CD25 ϩ Tregs in immune regulation has been demonstrated in animal models of organ-specific autoimmune diseases, in which pathology is precipitated by their depletion and ameliorated by their reconstitution (52). The key marker of CD25 ϩ Tregs is the forkhead/winged helix family transcription factor FoxP3 (70). Impaired FoxP3 gene expression results in severe autoimmunity in human immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (8, 67) and in Scurfy mice (11); furthermore, forced FoxP3 expression in FoxP3 Ϫ T cells confers regulatory properties in vitro (21, 65). CD25 ϩ Tregs may also contribute to pathogen-specific immune regulation in viral infections, including those with hepatitis B and C, her...

Background Poor nutritional status and both hyperphosphatemia and hypophosphatemia are associated with increased mortality in maintenance hemodialysis (MHD) patients. We assessed associations of PB prescription with survival and indicators of nutritional status among (MHD) patients. Study Design Prospective cohort study (DOPPS) 1996 to 2008. Setting and Participants 23,898 MHD patients at 923 facilities in 12 countries. Predictors Patient-level PB prescription; and case-mix-adjusted facility percentage PB prescription using an instrumental-variable analysis. Outcome All-cause mortality. Results Overall, 88% of patients were prescribed PBs. The distributions of age, comorbidities and other characteristics showed small differences between facilities with higher and lower percentage PB prescription. Patient-level PB prescription was strongly associated at baseline with indicators of better nutrition, i.e., higher serum creatinine, albumin, normalized protein-catabolic rate, BMI and absence of cachectic appearance. Overall, patients prescribed PBs displayed 25% lower mortality (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.68–0.83) when adjusted for serum phosphorus and other covariates; further adjustment for nutritional indicators attenuated this association (HR = 0.88, 95% CI = 0.80–0.97). This inverse association, however, was observed only for patients with serum phosphorus ≥3.5mg/dL. In the instrumental-variable analysis, case-mix-adjusted facility percentage PB prescription (range: 23–100%) was positively associated with better nutritional status and inversely associated with mortality (HR for 10% more PB = 0.93, 95% CI = 0.89–0.96). Further adjustment for nutritional indicators reduced this association to HR = 0.95 (95% CI = 0.92–0.99). Limitations Results were based on PB prescription; PB and nutritional data were cross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residual confounding. Conclusions Longer survival and better nutritional status were observed for MHD patients prescribed PBs and in facilities with greater percentage PB prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research.

Background: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. Methods: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. Results: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. Conclusion: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

Normal pregnancy and the follicular phase of the ovarian cycle are both estrogen-dominated physiological states that are characterized by elevations in uterine blood flow and endothelial nitric oxide synthase (eNOS) protein expression in the uterine artery (UA) endothelium. It is unknown if elevations in mRNA level account for the changes in protein or eNOS activity. We tested the hypothesis that pregnancy and the follicular phase are associated with increases in eNOS mRNA and the consequent elevated expression of eNOS protein results in increased circulating nitric oxide (NO) levels. UA were obtained from pregnant (PREG; n = 8; 110-130 days gestation; term = 145 +/- 3 days), nonpregnant luteal (LUT; n = 6), nonpregnant follicular (FOL; n = 6), and nonpregnant ovariectomized (OVEX; n = 6) sheep. Circulating NO levels were analyzed as total NO(2)-NO(3) (NO(x)). Western analysis performed on UA endothelial-isolated proteins demonstrated that eNOS protein levels were OVEX = LUT < or = FOL < PREG (P < 0.05), whereas eNOS mRNA expression (RT-PCR) in UA endothelial cells obtained by limited collagenase digestion was OVEX < LUT < FOL < PREG (P < 0.05). Pregnancy dramatically elevated eNOS protein (4.1- to 6.9-fold) and mRNA (2.4- to 6.9-fold) over LUT controls (P < 0.01). Circulating NO(x) levels were not altered by ovariectomy or the ovarian cycle but were elevated from 4.4 +/- 1.1 microM in LUT to 12 +/- 4, 22 +/- 3, and 41 +/- 3 microM at 110, 120, and 130 days gestation (P < 0.01). Systemic NO(x) levels in singleton (12.5 +/- 1.6 microM) were less (P < 0.01) than in multiple (twin 27.6 +/- 6.5 microM; triplet = 46 +/- 10 microM) pregnancies. Therefore, the follicular phase and, to a much greater extent, pregnancy are associated with elevations in UA endothelium-derived eNOS expression, although significant increases in systemic NO(x) levels were only observed in the PREG group (multiple > singleton). Thus, although UA endothelial increases in eNOS protein and mRNA levels are associated with high estrogen states, increases in local UA NO production may require additional eNOS protein activation to play its important role in the maintenance of uterine blood flow in pregnancy.