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Background Provisional gout remission criteria including five domains (serum urate, tophus, flares, pain due to gout, and patient global assessment) have been proposed. The aim of this study was to test the concurrent validity of the provisional gout remission criteria by comparing the criteria with dual-energy CT (DECT) findings. Methods Patients with gout on allopurinol ≥ 300 mg daily were prospectively recruited into a multicenter DECT study. Participants attended a standardized study visit which recorded gout flare frequency in the preceding 12 months, physical examination for tophus, serum urate, and patient questionnaires. DECT scans of both hands/wrists, feet/ankles/Achilles, and knees were analyzed by two DECT radiologists. The relationship between the DECT urate crystal volume and deposition with individual domains as well as the provisional remission criteria set was analyzed. Results The provisional remission criteria were fulfilled in 23 (15.1%) participants. DECT urate crystal deposition was observed less frequently in those fulfilling the provisional remission criteria (44%), compared with those not fulfilling the criteria (73.6%, odds ratio 0.28, P  = 0.004). The median (range) DECT urate crystal volume was 0.00 (0.00–0.46) cm 3 for those fulfilling the remission criteria, compared with 0.08 (0.00–19.53) cm 3 for those not fulfilling the criteria ( P  = 0.002). In multivariate regression analysis, the serum urate and tophus domains were most strongly associated with DECT urate crystal deposition. Conclusions In people with gout established on allopurinol, a state of remission as defined by the provisional remission criteria is associated with less DECT urate crystal deposition. While this study provides support for the validity of the provisional gout remission criteria, it also demonstrates that some crystal deposition may be present in people achieving these criteria.

Background In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy. Methods Patients receiving combined lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study (“200CONT”, “400CONT”), whereas those receiving only febuxostat 80 mg were randomized to lesinurad 200 or 400 mg with febuxostat (“200CROSS”, “400CROSS”). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of lesinurad exposure, 800 days). Results Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT ( n  = 64), 200CROSS ( n  = 33), 400CONT ( n  = 65), and 400CROSS ( n  = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged lesinurad exposure in the extension study. Conclusions Patients receiving lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study. Trial registration ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.

Elevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits. We evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance-components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation on renal disease was tested in the NIDDK-AASK cohort. Norepinephrine secretion rose across eGFR tertiles while eGFR fell (p<0.0001). eGFR was heritable, at h(2) = 67.3±4.7% (p = 3.0E-18), as were secretion of norepinephrine (h(2) = 66.5±5.0%, p = 3.2E-16) and dopamine (h(2) = 56.5±5.6%, p = 1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (ρG = -0.557±0.088, p = 1.11E-08) as well as dopamine (ρG = -0.223±0.101, p = 2.3E-02). Since dopamine β-hydroxylase (DBH) catalyzes conversion of dopamine to norepinephrine, we studied functional variation at DBH; DBH promoter haplotypes predicted transcriptional activity (p<0.001), plasma DBH (p<0.0001) and norepinephrine (p = 0.0297) secretion; transcriptional activity was inversely (p<0.0001) associated with basal eGFR. Meta-analysis validated DBH haplotype effects on eGFR across 3 samples. In NIDDK-AASK, we established a role for DBH promoter variation in long-term renal decline rate (GFR slope, p = 0.003). The heritable GFR trait shares genetic determination with catecholamines, suggesting new pathophysiologic, diagnostic and therapeutic approaches towards disorders of GFR as well as CKD. Adrenergic activity may play a role in progressive renal decline, and genetic variation at DBH may assist in profiling subjects for rational preventive treatment.

Study Objective: To evaluate whether actigraphy-measured total sleep time and other sleep characteristics predict incident hypertension in older men. Methods: Study subjects were community-dwelling participants in the ancillary sleep study of the Osteoporotic Fractures in Men Study (MrOS) who were normotensive at the time of actigraphy (based on self-report, lack of antihypertensive medication use, and with systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg). In 853 community-dwelling men 67 years and older (mean 75.1 years), sleep measures (total sleep time [TST]), percent sleep [%-sleep], latency, and wake after sleep onset [WASO]) were obtained using validated wrist actigraphy with data collected over a mean duration of 5.2 consecutive 24-h periods. We evaluated incident hypertension (based on self-report, use of antihypertensive medication, or measured systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg) at a follow-up visit an average of 3.4 years later. Baseline prehypertension was defined as a systolic blood pressure 120 to < 140 mm Hg or diastolic blood pressure 80 to < 90 mm Hg. Results: At follow-up, 31% of initially normotensive men were hypertensive (264 of 853). Those with incident hypertension had higher baseline body mass index (BMI; kg/m 2 ) and were more likely to have had prehypertension at the sleep visit than those men who remained normotensive. However, neither TST (reference 6 to < 8 h; < 6 h OR 0.96 [95% CI 0.7, 1.3] and ≥ 8 h OR 0.93 [0.5, 1.7]) nor the other actigraphic-measured sleep variables, including % -sleep (reference > 85%; < 70% OR 1.17 [0.66, 2.08]) and 70% to ≤ 85% OR 1.23 (0.9, 1.68), sleep latency (reference < 30 min; ≥ 30 min OR 1.29 [0.94, 1.76]), or WASO (reference < 30 min; 30 to < 60 min OR 0.7 [0.43, 1.14] and ≥ 60 min OR 0.92 [0.58, 1.47]) differed in those community-dwelling men who developed incident hypertension compared to those who remained normotensive. Conclusion: TST and other sleep parameters determined by wrist actigraphy were not associated with incident hypertension in community-dwelling older men. Citation: Fung MM; Peters K; Ancoli-Israel S; Redline S; Stone KL; Barrett-Connor E. Total sleep time and other sleep characteristics measured by actigraphy do not predict incident hypertension in a cohort of community-dwelling older men. J Clin Sleep Med 2013;9(6):585-591.

Background The Seventh Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure in 2003 created a prehypertension category for persons with blood pressures ranging from systolic blood pressure (SBP) of 120-139 mm Hg or diastolic blood pressure (DBP) from 80 to 89 mm Hg, due to increased risk of cardiovascular disease. Methods Our study utilized the University of California-San Diego (UCSD)Twin Hypertension Cohort. We measured comprehensive plasma cholesterol levels and metabolic (glucose, insulin, leptin) and inflammatory markers (interleukin-6 (IL-6), C-reactive protein (CRP),free fatty acids) to determine the differences between normotensive and prehypertensive subjects. Additionally, we determined whether angiotensin II receptor type-1 (AGTR1) polymorphisms, previously associated with hypertension, could predict prehypertension. Results A total of 455 white subjects were included in the study (mean age 37.1 years). Prehypertensive subjects were older with greater body mass index (BMI) than the normotensives, and after adjusting for sex and age, had greater plasma glucose, insulin, and IL-6. The common AGTR1 A1166C (rs5186) polymorphism in the 3′-UTR region, particularly the presence of the 1166C allele, which fails to downregulate gene expression, predicted greater likelihood of being in the prehypertension group and higher SBP. A lesser-studied polymorphism in intron-2 of AGTR1 (A/G; rs2276736) was associated with plasma high-density lipoprotein (HDL) and apolipoprotein A-1. In a subgroup analysis of nonobese subjects (N = 405), similar associations were noted. Conclusion Prehypertensive subjects already exhibit early pathophysiologic changes putting them at risk of future cardiovascular disease, and AGTR1 may also contribute to this increased risk. Further investigation is needed to confirm these findings and the precise molecular mechanisms of action. American Journal of Hypertension, advance online publication 23 September 2010;. doi:10.1038/ajh.2010.210

ObjectivesDetermine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.MethodsPatients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data.ResultsPatients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively.ConclusionLesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.Trial registration numberNCT01493531.

Because dopamine D1 receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5′-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5′-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease.

ObjectiveDual-energy CT (DECT) detects and quantifies monosodium urate (MSU) crystal deposition with high precision. This DECT study assessed crystal deposition in patients with gout treated with stable-dose allopurinol, and investigated potential clinical determinants for crystal deposition.MethodsPatients with gout treated with allopurinol ≥300 mg daily for at least 3 months were prospectively recruited from the USA and New Zealand, using monitored enrolment to include approximately 25% patients with palpable tophi and approximately 50% with serum urate (sUA) levels <6.0 mg/dL (<357µmol/L). MSU crystal deposition was measured in the hands/wrists, feet/ankles/Achilles and knees bilaterally. The presence and total volume of crystals were assessed by DECT and analysed according to sUA levels and gout characteristics.ResultsAmong 152 patients receiving allopurinol ≥300 mg/day for 5.1 years on average, 69.1% had crystal deposition on DECT, with a median total crystal volume of 0.16 cm3 (range: 0.01–19.53 cm3). The prevalence of crystal deposition ranged from 46.9% among patients with sUA <6.0 mg/dL and no palpable tophi to 90.0% among those with sUA ≥6.0 mg/dL and tophi. Total volume of crystal deposition was positively associated with sUA ≥6.0 mg/dL, gout flares within the past 3 months and tophi. Total volume of crystal deposition correlated positively with Patient Global Impression of Disease Activity scores.ConclusionA substantial proportion of patients without palpable tophi have MSU crystal deposition, despite receiving allopurinol doses ≥300 mg/day for a considerable duration. Patients with higher sUA and clinical features of severe disease have a higher frequency and greater volume of MSU crystal deposition.

Autonomic Function in Hypertension Role of Genetic Variation at the Catecholamine Storage Vesicle Protein Chromogranin B Kuixing Zhang, MD, PhD ; Fangwen Rao, MD ; Brinda K. Rana, PhD ; Jiaur R. Gayen, PhD ; Federico Calegari, PhD ; Angus King, PhD ; Patrizia Rosa, PhD ; Wieland B. Huttner, MD ; Mats Stridsberg, PhD ; Manjula Mahata, PhD ; Sucheta Vaingankar, PhD ; Vafa Mahboubi, PhD ; Rany M. Salem, MPH ; Juan L. Rodriguez-Flores, MS ; Maple M. Fung, MD ; Douglas W. Smith, PhD ; Nicholas J. Schork, PhD ; Michael G. Ziegler, MD ; Laurent Taupenot, PhD ; Sushil K. Mahata, PhD and Daniel T. O'Connor, MD From the Departments of Medicine, Pharmacology, and the Center for Human Genetics and Genomics (K.Z., F.R., B.K.R., J.R.G., M.M., S.V., V.M., R.M.S., J.L.R.-F., M.M.F., D.W.S., N.J.S., M.G.Z., L.T., S.K.M., D.T.O.), University of California and the VA San Diego Healthcare System, San Diego, Calif; Max Planck Institute of Molecular Cell Biology and Genetics (F.C., A.K., W.B.H.), Dresden, Germany; Department of Medical Sciences (M.S.), Uppsala University, Uppsala, Sweden; and Department of Medical Pharmacology (P.R.), CNR Institute of Neuroscience, Cellular and Molecular Pharmacology, University of Milan, Italy. Correspondence to Sushil K. Mahata, PhD or Daniel T. O'Connor, MD, Department of Medicine and CHGG, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0838. E-mail: smahata{at}ucsd.edu or doconnor@ucsd.edu Received April 15, 2008; accepted November 20, 2008. Background— Hypertension is a complex trait, with deranged autonomic control of circulation. Chromogranin B ( CHGB ) is the most abundant core protein in human catecholamine secretory vesicles, playing an important role in their biogenesis. Does common interindividual variation at the CHGB locus contribute to phenotypic variation in CHGB and catecholamine secretion, autonomic stability of circulation, or blood pressure (BP) in the population? Methods and Results— To probe interindividual variability in CHGB , we systematically studied polymorphism across the locus by resequencing CHGB ( 6 kbp footprint spanning the promoter, 5 exons, exon/intron borders, untranslated regions) in 160 subjects (2n=320 chromosomes) of diverse biogeographic ancestries. We identified 53 single-nucleotide polymorphisms, of which 22 were common. We then studied 1182 subjects drawn from the most extreme BP values in the population (highest and lowest 5th percentiles), typing 4 common polymorphisms spanning the 14 kbp locus. Sliding-window haplotype analysis indicated BP associations peaking in the 5'/promoter region, most prominent in men, and a peak effect in the proximal promoter at variant A-261T (A>T), accounting for 8/ 6 mmHg BP in males. The promoter allele (A-261) that was a predictor of higher diastolic BP and systolic BP was also associated with lower circulating/plasma CHGB concentration (CHGB 439 to 451 epitope) in twin pairs. In twins, the same CHGB variants that were predictors of lower basal CHGB secretion were also associated with exaggerated catecholamine secretion and BP response to environmental (cold) stress; likewise, women displayed increased plasma CHGB 439 to 451 but decreased catecholamine secretion as well as BP response to environmental stress. The effect of A-261T on CHGB expression was confirmed in chromaffin cells by site-directed mutagenesis on transfected CHGB promoter/luciferase reporter activity, and the allelic effects of A-261T on gene expression were directionally coordinate in cella and in vivo. To confirm these clinical associations experimentally, we undertook targeted homozygous (–/–) ablation of the mouse CHGB gene; knockout mice displayed substantially increased BP, by 20/ 18 mmHg, confirming the mechanistic basis of our findings in humans. Conclusion— Common genetic variation at the CHGB locus, especially in the proximal promoter, influences CHGB expression and later catecholamine secretion and the early heritable responses to environmental stress, eventuating in changes in resting/basal BP in the population. Both the early (gene expression) and late (population BP) consequences of CHGB variation are sex dependent. These results point to new molecular strategies for probing autonomic control of circulation and, ultimately, the susceptibility to and pathogenesis of cardiovascular disease states such as hypertension. Key Words: genetics • hypertension • gene expression • catecholamine • epidemiology • nervous system • autonomic   CLINICAL PERSPECTIVE The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.785659/DC1. Related Article Autonomic Function in Hypertension: Role of Genetic Variation at the Catecholamine Storage Vesicle Protein Chromogranin B Kuixing Zhang, Fangwen Rao, Brinda K. Rana, Jiaur R. Gayen, Federico Calegari, Angus King, Patrizia Rosa, Wieland B. Huttner, Mats Stridsberg, Manjula Mahata, Sucheta Vaingankar, Vafa Mahboubi, Rany M. Salem, Juan L. Rodriguez-Flores, Maple M. Fung, Douglas W. Smith, Nicholas J. Schork, Michael G. Ziegler, Laurent Taupenot, Sushil K. Mahata, and Daniel T. O'Connor Circ Cardiovasc Genet 2009 2: 46-56. [Abstract] [Full Text] [PDF]