DOM Recent Discoveries

Subscribe to DOM Recent Discoveries feed NCBI pubmed

URL: https://eutils.ncbi.nlm.nih.gov/entrez/eutils/erss.cgi?rss_guid=1ZSp7ZOQTWbaf7UNhc_yGLkNMqadiJYLoEpLqIZGIwVtkz5EuX

Updated: 18 hours 17 min ago

Items Per Page:             

Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma.

Related Articles

Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma.

J Allergy Clin Immunol. 2017 Jan;139(1):66-71.e3

Authors: Carroll KN, Gebretsadik T, Escobar GJ, Wu P, Li SX, Walsh EM, Mitchel E, Sloan CD, Dupont WD, Hartert TV

Abstract
BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory tract infection is implicated in asthma development. RSV immunoprophylaxis during infancy is efficacious in preventing RSV-related hospitalizations and has been associated with decreased wheezing in the first years of life.
OBJECTIVE: We investigated whether greater adherence to immunoprophylaxis in infants at high risk for severe RSV would be associated with decreased childhood asthma.
METHODS: We conducted a retrospective cohort investigation including children born from 1996-2003 who were enrolled in Kaiser Permanente Northern California or Tennessee Medicaid and eligible to receive RSV immunoprophylaxis. Asthma was defined at 4.5 to 6 years of age by using asthma-specific health care visits and medication fills. We classified children into immunoprophylaxis eligibility groups and calculated adherence (percentage receipt of recommended doses). We used a set of statistical strategies (multivariable logistic regression and propensity score [PS]-adjusted and PS-matched analyses) to overcome confounding by medical complexity because infants with higher adherence (≥70%) have higher prevalence of chronic lung disease, lower birth weight, and longer nursery stays.
RESULTS: By using multivariable logistic regression and PS-adjusted models in the combined group, higher adherence to RSV immunoprophylaxis was not associated with decreased asthma. However, in PS-matched analysis, treated children with 70% or greater adherence had decreased odds of asthma compared with those with 20% or less adherence (odds ratio, 0.62; 95% CI, 0.50-0.78).
CONCLUSIONS: This investigation of RSV immunoprophylaxis in high-risk children primarily found nonsignificant associations on prevention of asthma in specific preterm groups. Our findings highlight the need for larger studies and prospective cohorts and provide estimates of potential preventive effect sizes in high-risk children.

PMID: 27212083 [PubMed - indexed for MEDLINE]

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.

Related Articles

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.

J Am Coll Cardiol. 2017 Feb 21;69(7):823-836

Authors: Webb TR, Erdmann J, Stirrups KE, Stitziel NO, Masca NG, Jansen H, Kanoni S, Nelson CP, Ferrario PG, König IR, Eicher JD, Johnson AD, Hamby SE, Betsholtz C, Ruusalepp A, Franzén O, Schadt EE, Björkegren JL, Weeke PE, Auer PL, Schick UM, Lu Y, Zhang H, Dube MP, Goel A, Farrall M, Peloso GM, Won HH, Do R, van Iperen E, Kruppa J, Mahajan A, Scott RA, Willenborg C, Braund PS, van Capelleveen JC, Doney AS, Donnelly LA, Asselta R, Merlini PA, Duga S, Marziliano N, Denny JC, Shaffer C, El-Mokhtari NE, Franke A, Heilmann S, Hengstenberg C, Hoffmann P, Holmen OL, Hveem K, Jansson JH, Jöckel KH, Kessler T, Kriebel J, Laugwitz KL, Marouli E, Martinelli N, McCarthy MI, Van Zuydam NR, Meisinger C, Esko T, Mihailov E, Escher SA, Alver M, Moebus S, Morris AD, Virtamo J, Nikpay M, Olivieri O, Provost S, AlQarawi A, Robertson NR, Akinsansya KO, Reilly DF, Vogt TF, Yin W, Asselbergs FW, Kooperberg C, Jackson RD, Stahl E, Müller-Nurasyid M, Strauch K, Varga TV, Waldenberger M, Wellcome Trust Case Control Consortium, Zeng L, Chowdhury R, Salomaa V, Ford I, Jukema JW, Amouyel P, Kontto J, MORGAM Investigators, Nordestgaard BG, Ferrières J, Saleheen D, Sattar N, Surendran P, Wagner A, Young R, Howson JM, Butterworth AS, Danesh J, Ardissino D, Bottinger EP, Erbel R, Franks PW, Girelli D, Hall AS, Hovingh GK, Kastrati A, Lieb W, Meitinger T, Kraus WE, Shah SH, McPherson R, Orho-Melander M, Melander O, Metspalu A, Palmer CN, Peters A, Rader DJ, Reilly MP, Loos RJ, Reiner AP, Roden DM, Tardif JC, Thompson JR, Wareham NJ, Watkins H, Willer CJ, Samani NJ, Schunkert H, Deloukas P, Kathiresan S, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

Abstract
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.
OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.
METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.
RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits.
CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

PMID: 28209224 [PubMed - indexed for MEDLINE]

Blocking TGF-β and β-Catenin Epithelial Crosstalk Exacerbates CKD.

Related Articles

Blocking TGF-β and β-Catenin Epithelial Crosstalk Exacerbates CKD.

J Am Soc Nephrol. 2017 Jul 12;:

Authors: Nlandu-Khodo S, Neelisetty S, Phillips M, Manolopoulou M, Bhave G, May L, Clark PE, Yang H, Fogo AB, Harris RC, Taketo MM, Lee E, Gewin LS

Abstract
The TGF-β and Wnt/β-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF-β has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF-β signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF-β type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF-β receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF-β receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/β-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF-β receptor impaired β-catenin activity in vitro and in vivo Genetically restoring β-catenin activity in proximal tubules lacking the TGF-β receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF-β receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of β-catenin activity or an indirect effect of β-catenin interacting with other growth factors. In conclusion, blocking TGF-β and β-catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.

PMID: 28701516 [PubMed - as supplied by publisher]

Rare and low-frequency coding variants alter human adult height.

Related Articles

Rare and low-frequency coding variants alter human adult height.

Nature. 2017 02 09;542(7640):186-190

Authors: Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C, Highland HM, Rüeger S, Thorleifsson G, Justice AE, Lamparter D, Stirrups KE, Turcot V, Young KL, Winkler TW, Esko T, Karaderi T, Locke AE, Masca NG, Ng MC, Mudgal P, Rivas MA, Vedantam S, Mahajan A, Guo X, Abecasis G, Aben KK, Adair LS, Alam DS, Albrecht E, Allin KH, Allison M, Amouyel P, Appel EV, Arveiler D, Asselbergs FW, Auer PL, Balkau B, Banas B, Bang LE, Benn M, Bergmann S, Bielak LF, Blüher M, Boeing H, Boerwinkle E, Böger CA, Bonnycastle LL, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Burt AA, Butterworth AS, Carey DJ, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Galbany JC, Cox AJ, Cuellar-Partida G, Danesh J, Davies G, de Bakker PI, de Borst GJ, de Denus S, de Groot MC, de Mutsert R, Deary IJ, Dedoussis G, Demerath EW, den Hollander AI, Dennis JG, Di Angelantonio E, Drenos F, Du M, Dunning AM, Easton DF, Ebeling T, Edwards TL, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Faul JD, Feitosa MF, Feng S, Ferrannini E, Ferrario MM, Ferrieres J, Florez JC, Ford I, Fornage M, Franks PW, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Giedraitis V, Giri A, Girotto G, Gordon SD, Gordon-Larsen P, Gorski M, Grarup N, Grove ML, Gudnason V, Gustafsson S, Hansen T, Harris KM, Harris TB, Hattersley AT, Hayward C, He L, Heid IM, Heikkilä K, Helgeland Ø, Hernesniemi J, Hewitt AW, Hocking LJ, Hollensted M, Holmen OL, Hovingh GK, Howson JM, Hoyng CB, Huang PL, Hveem K, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jhun MA, Jia Y, Jiang X, Johansson S, Jørgensen ME, Jørgensen T, Jousilahti P, Jukema JW, Kahali B, Kahn RS, Kähönen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SL, Karpe F, Kee F, Keeman R, Kiemeney LA, Kitajima H, Kluivers KB, Kocher T, Komulainen P, Kontto J, Kooner JS, Kooperberg C, Kovacs P, Kriebel J, Kuivaniemi H, Küry S, Kuusisto J, La Bianca M, Laakso M, Lakka TA, Lange EM, Lange LA, Langefeld CD, Langenberg C, Larson EB, Lee IT, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu Y, Liu Y, Lophatananon A, Luan J, Lubitz SA, Lyytikäinen LP, Mackey DA, Madden PA, Manning AK, Männistö S, Marenne G, Marten J, Martin NG, Mazul AL, Meidtner K, Metspalu A, Mitchell P, Mohlke KL, Mook-Kanamori DO, Morgan A, Morris AD, Morris AP, Müller-Nurasyid M, Munroe PB, Nalls MA, Nauck M, Nelson CP, Neville M, Nielsen SF, Nikus K, Njølstad PR, Nordestgaard BG, Ntalla I, O'Connel JR, Oksa H, Loohuis LM, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CN, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JR, Person TN, Pirie A, Polasek O, Posthuma D, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Reiner AP, Renström F, Ridker PM, Rioux JD, Robertson N, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sandow K, Sapkota Y, Sattar N, Schmidt MK, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah S, Sim X, Sivapalaratnam S, Small KS, Smith AV, Smith JA, Southam L, Spector TD, Speliotes EK, Starr JM, Steinthorsdottir V, Stringham HM, Stumvoll M, Surendran P, 't Hart LM, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorsteinsdottir U, Thuesen BH, Tönjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Ulivi S, van der Laan SW, Van Der Leij AR, van Duijn CM, van Schoor NM, van Setten J, Varbo A, Varga TV, Varma R, Edwards DR, Vermeulen SH, Vestergaard H, Vitart V, Vogt TF, Vozzi D, Walker M, Wang F, Wang CA, Wang S, Wang Y, Wareham NJ, Warren HR, Wessel J, Willems SM, Wilson JG, Witte DR, Woods MO, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhao W, Zheng H, Zhou W, EPIC-InterAct Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators, Rotter JI, Boehnke M, Kathiresan S, McCarthy MI, Willer CJ, Stefansson K, Borecki IB, Liu DJ, North KE, Heard-Costa NL, Pers TH, Lindgren CM, Oxvig C, Kutalik Z, Rivadeneira F, Loos RJ, Frayling TM, Hirschhorn JN, Deloukas P, Lettre G

Abstract
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

PMID: 28146470 [PubMed - indexed for MEDLINE]

Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension.

Related Articles

Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension.

Circ Res. 2017 Jul 06;:

Authors: Dikalova AE, Itani HA, Nazarewicz RR, McMaster WG, Flynn CR, Uzhachenko RV, Fessel JP, Gamboa JL, Harrison DG, Dikalov SI

Abstract
Rationale: Clinical studies have shown that Sirt3 expression declines by 40% by age 65 paralleling the increased incidence of hypertension and metabolic conditions further inactivate Sirt3 due to increased NADH and acetyl-CoA levels. Sirt3 impairment reduces the activity of a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2), due to hyperacetylation. Objective: In this study we examined if loss of Sirt3 activity increases vascular oxidative stress due to SOD2 hyperacetylation and promotes endothelial dysfunction and hypertension. Methods and Results: Hypertension was markedly increased in Sirt3 knockout (Sirt3(-/-)) and SOD2 depleted (SOD2(+/-)) mice in response to low dose of angiotensin II (0.3 mg/kg/day) compared with wild-type C57Bl/6J mice. Sirt3 depletion increased SOD2 acetylation, elevated mitochondrial O2•, and diminished endothelial nitric oxide. Angiotensin II induced hypertension was associated with Sirt3 S-glutathionylation, acetylation of vascular SOD2 and reduced SOD2 activity. Scavenging of mitochondrial H2O2 in mCAT mice prevented Sirt3 and SOD2 impairment and attenuated hypertension. Treatment of mice after onset of hypertension with a mitochondria-targeted H2O2 scavenger, mitoEbselen, reduced Sirt3 S-glutathionylation, diminished SOD2 acetylation and reduced blood pressure in wild-type but not in Sirt3(-/-)) mice while an SOD2 mimetic, mitoTEMPO, reduced blood pressure and improved vasorelaxation both in Sirt3(-/-)) and wild type mice. SOD2 acetylation had an inverse correlation with SOD2 activity and a direct correlation with the severity of hypertension. Analysis of human subjects with essential hypertension showed 2.6-fold increase in SOD2 acetylation and 1.4-fold decrease in Sirt3 levels while SOD2 expression was not affected. Conclusions: Our data suggest that diminished Sirt3 expression and redox inactivation of Sirt3 lead to SOD2 inactivation and contributes to the pathogenesis of hypertension.

PMID: 28684630 [PubMed - as supplied by publisher]

Increasing use of allogeneic hematopoietic cell transplantation in patients age 70 years and older in the United States.

Increasing use of allogeneic hematopoietic cell transplantation in patients age 70 years and older in the United States.

Blood. 2017 Jul 03;:

Authors: Muffly L, Pasquini MC, Martens M, Brazauskas R, Zhu X, Adekola K, Aljurf M, Ballen KK, Bajel A, Baron F, Battiwalla M, Beitinjaneh A, Cahn JY, Carabasi M, Chen YB, Chhabra S, Ciurea S, Copelan E, D'Souza A, Edwards J, Foran J, Freytes CO, Fung HC, Gale RP, Giralt S, Hashmi SK, Hildebrandt GC, Ho V, Jakubowski A, Lazarus H, Luskin MR, Martino R, Maziarz R, McCarthy P, Nishihori T, Olin R, Olsson RF, Pawarode A, Peres E, Rezvani AR, Rizzieri D, Savani BN, Schouten HC, Sabloff M, Seftel M, Seo S, Sorror ML, Szer J, Wirk BM, Wood WA, Artz A

Abstract
PURPOSE: To evaluate trends and outcomes of allogeneic HCT in adults ≥70 years with hematologic malignancies across the United States (US).
PATIENTS AND METHODS: Adults 70 years and older with a hematologic malignancy undergoing first allogeneic HCT in the US between 2000 and 2013 and reported to the CIBMTR were eligible. Transplant utilization and transplant outcomes including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied.
RESULTS: Across 103 transplant centers between 2000 and 2013, 1,106 patients ≥70 years underwent HCT. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS, 26% [95% CI, 21%-33%] in 2000-2007 to 39% [95% CI, 35%-42%] in 2008-2013, P< 0.001); PFS, 22% [16%-28%] in 2000-2007 to 32% [95% CI, 29%-36%] in 2008-2013, P= 0.003). Two-year transplant-related mortality ranged from 33-35% and was unchanged over time (P=0.54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by hematopoietic cell transplant-comorbidity index ≥3 (HR= 1.27, P= 0.006), umbilical cord blood graft (HR=1.97, P= 0.0002), and myeloablative conditioning (HR=1.61, P=0.0002) as adverse factors.
CONCLUSION: Over the past decade, utilization and survival after allogeneic transplant have increased in patients 70 years and older. Select adults 70 years and older with hematologic malignancies should be considered for transplant.

PMID: 28674027 [PubMed - as supplied by publisher]

Penicillin Allergy Is Not Necessarily Forever.

Penicillin Allergy Is Not Necessarily Forever.

JAMA. 2017 Jul 04;318(1):82-83

Authors: Trubiano JA, Adkinson NF, Phillips EJ

PMID: 28672303 [PubMed - in process]

Clinical and Biological Insights Into Combined Post- and Pre-Capillary Pulmonary Hypertension.

Related Articles

Clinical and Biological Insights Into Combined Post- and Pre-Capillary Pulmonary Hypertension.

J Am Coll Cardiol. 2016 Dec 13;68(23):2525-2536

Authors: Assad TR, Hemnes AR, Larkin EK, Glazer AM, Xu M, Wells QS, Farber-Eger EH, Sheng Q, Shyr Y, Harrell FE, Newman JH, Brittain EL

Abstract
BACKGROUND: Pulmonary hypertension (PH) is a common and morbid complication of left heart disease with 2 subtypes: isolated post-capillary pulmonary hypertension (Ipc-PH) and combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH). Little is known about the clinical or physiological characteristics that distinguish these 2 subphenotypes or if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH).
OBJECTIVES: The goal of this study was to test the hypothesis that the hemodynamic and genetic profile of Cpc-PH would more closely resemble PAH than Ipc-PH.
METHODS: Vanderbilt University's electronic medical record linked to a DNA biorepository was used to extract demographic characteristics, clinical data, invasive hemodynamic data, echocardiography, and vital status for all patients referred for right heart catheterization between 1998 and 2014. Shared genetic variants between PAH and Cpc-PH compared with Ipc-PH were identified by using pre-existing single-nucleotide polymorphism data.
RESULTS: A total of 2,817 patients with PH (13% Cpc-PH, 52% Ipc-PH, and 20% PAH) were identified. Patients with Cpc-PH were on average 6 years younger, with more severe pulmonary vascular disease than patients with Ipc-PH, despite similar comorbidities and prevalence, severity, and chronicity of left heart disease. After adjusting for relevant covariates, the risk of death was similar between the Cpc-PH and Ipc-PH groups (hazard ratio: 1.14; 95% confidence interval: 0.96 to 1.35; p = 0.15) when defined according to diastolic pressure gradient. We identified 75 shared exonic single-nucleotide polymorphisms between Cpc-PH and PAH enriched in pathways involving cell structure, extracellular matrix, and immune function. These genes are expressed, on average, 32% higher in lungs relative to other tissues.
CONCLUSIONS: Patients with Cpc-PH develop pulmonary vascular disease similar to patients with PAH, despite younger age and similar prevalence of obesity, diabetes mellitus, and left heart disease compared with patients with Ipc-PH. An exploratory genetic analysis in Cpc-PH identified genes and biological pathways in the lung known to contribute to PAH pathophysiology, suggesting that Cpc-PH may be a distinct and highly morbid PH subphenotype.

PMID: 27931609 [PubMed - indexed for MEDLINE]

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).

Related Articles

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).

J Am Coll Cardiol. 2016 Jul 12;68(2):161-72

Authors: Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, Judge DP, Lenihan DJ, Gottlieb SS, Shah SJ, Steidley DE, Ventura H, Murali S, Silver MA, Jacoby D, Fedson S, Hummel SL, Kristen AV, Damy T, Planté-Bordeneuve V, Coelho T, Mundayat R, Suhr OB, Waddington Cruz M, Rapezzi C, THAOS Investigators

Abstract
BACKGROUND: Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.
OBJECTIVES: The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.
METHODS: Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).
RESULTS: U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.
CONCLUSIONS: In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

PMID: 27386769 [PubMed - indexed for MEDLINE]

Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD.

Related Articles

Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD.

J Am Soc Nephrol. 2017 Jun;28(6):1867-1876

Authors: Schneider MP, Raff U, Kopp C, Scheppach JB, Toncar S, Wanner C, Schlieper G, Saritas T, Floege J, Schmid M, Birukov A, Dahlmann A, Linz P, Janka R, Uder M, Schmieder RE, Titze JM, Eckardt KU

Abstract
The pathogenesis of left ventricular hypertrophy in patients with CKD is incompletely understood. Sodium intake, which is usually assessed by measuring urinary sodium excretion, has been inconsistently linked with left ventricular hypertrophy. However, tissues such as skin and muscle may store sodium. Using (23)sodium-magnetic resonance imaging, a technique recently developed for the assessment of tissue sodium content in humans, we determined skin sodium content at the level of the calf in 99 patients with mild to moderate CKD (42 women; median [range] age, 65 [23-78] years). We also assessed total body overhydration (bioimpedance spectroscopy), 24-hour BP, and left ventricular mass (cardiac magnetic resonance imaging). Skin sodium content, but not total body overhydration, correlated with systolic BP (r=0.33, P=0.002). Moreover, skin sodium content correlated more strongly than total body overhydration did with left ventricular mass (r=0.56, P<0.001 versus r=0.35, P<0.001; P<0.01 between the two correlations). Linear regression analysis demonstrated that skin sodium content is a strong explanatory variable for left ventricular mass, unaffected by BP and total body overhydration. In conclusion, we found skin sodium content to be closely linked to left ventricular mass in patients with CKD. Interventions that reduce skin sodium content might improve cardiovascular outcomes in these patients.

PMID: 28154199 [PubMed - indexed for MEDLINE]

The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease.

Related Articles

The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease.

J Am Coll Cardiol. 2016 Oct 25;68(17):1898-1907

Authors: Jones WS, Roe MT, Antman EM, Pletcher MJ, Harrington RA, Rothman RL, Oetgen WJ, Rao SV, Krucoff MW, Curtis LH, Hernandez AF, Masoudi FA

Abstract
Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.

PMID: 27765193 [PubMed - indexed for MEDLINE]

Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin.

Related Articles

Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin.

J Allergy Clin Immunol. 2016 Sep;138(3):814-824.e11

Authors: Stier MT, Bloodworth MH, Toki S, Newcomb DC, Goleniewska K, Boyd KL, Quitalig M, Hotard AL, Moore ML, Hartert TV, Zhou B, McKenzie AN, Peebles RS

Abstract
BACKGROUND: Respiratory syncytial virus (RSV) is a major health care burden with a particularly high worldwide morbidity and mortality rate among infants. Data suggest that severe RSV-associated illness is in part caused by immunopathology associated with a robust type 2 response.
OBJECTIVE: We sought to determine the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model.
METHODS: Wild-type (WT) BALB/c, thymic stromal lymphopoietin receptor (TSLPR) knockout (KO), or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4 to 6 days of infection, lungs were collected for evaluation of viral load, protein concentration, airway mucus, airway reactivity, or ILC2 numbers. Results were confirmed with 2 additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential.
RESULTS: RSV induced a 3-fold increase in the number of IL-13-producing ILC2s at day 4 after infection, with a concurrent increase in total lung IL-13 levels. Both thymic stromal lymphopoietin (TSLP) and IL-33 levels were increased 12 hours after infection. TSLPR KO mice did not mount an IL-13-producing ILC2 response to RSV infection. Additionally, neutralization of TSLP significantly attenuated the RSV-induced IL-13-producing ILC2 response. TSLPR KO mice displayed reduced lung IL-13 protein levels, decreased airway mucus and reactivity, attenuated weight loss, and similar viral loads as WT mice. Both 12/11-19 and 12/12-6 similarly induced IL-13-producing ILC2s through a TSLP-dependent mechanism.
CONCLUSION: These data demonstrate that multiple pathogenic strains of RSV induce IL-13-producing ILC2 proliferation and activation through a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection.

PMID: 27156176 [PubMed - indexed for MEDLINE]

Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis.

Related Articles

Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis.

Blood. 2016 May 19;127(20):2427-38

Authors: Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, Green JS, Saad A, Antin JH, Savani BN, Lazarus HM, Seftel M, Saber W, Marks D, Aljurf M, Norkin M, Wingard JR, Lindemans CA, Boeckh M, Riches ML, Auletta JJ

Abstract
Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.

PMID: 26884374 [PubMed - indexed for MEDLINE]

Precaution and governance of emerging technologies.

Related Articles

Precaution and governance of emerging technologies.

Science. 2016 11 11;354(6313):710-711

Authors: Kaebnick GE, Heitman E, Collins JP, Delborne JA, Landis WG, Sawyer K, Taneyhill LA, Winickoff DE

PMID: 27846595 [PubMed - indexed for MEDLINE]

Single-Cell Mass Cytometry Analysis of the Human Endocrine Pancreas.

Related Articles

Single-Cell Mass Cytometry Analysis of the Human Endocrine Pancreas.

Cell Metab. 2016 Oct 11;24(4):616-626

Authors: Wang YJ, Golson ML, Schug J, Traum D, Liu C, Vivek K, Dorrell C, Naji A, Powers AC, Chang KM, Grompe M, Kaestner KH

Abstract
The human endocrine pancreas consists of multiple cell types and plays a critical role in glucose homeostasis. Here, we apply mass cytometry technology to measure all major islet hormones, proliferative markers, and readouts of signaling pathways involved in proliferation at single-cell resolution. Using this innovative technology, we simultaneously examined baseline proliferation levels of all endocrine cell types from birth through adulthood, as well as in response to the mitogen harmine. High-dimensional analysis of our marker protein expression revealed three major clusters of beta cells within individuals. Proliferating beta cells are confined to two of the clusters.

PMID: 27732837 [PubMed - indexed for MEDLINE]

Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans.

Related Articles

Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans.

Cell Metab. 2016 Jul 12;24(1):91-103

Authors: Gitschlag BL, Kirby CS, Samuels DC, Gangula RD, Mallal SA, Patel MR

Abstract
Mutant mitochondrial genomes (mtDNA) can be viewed as selfish genetic elements that persist in a state of heteroplasmy despite having potentially deleterious metabolic consequences. We sought to study regulation of selfish mtDNA dynamics. We establish that the large 3.1-kb deletion-bearing mtDNA variant uaDf5 is a selfish genome in Caenorhabditis elegans. Next, we show that uaDf5 mutant mtDNA replicates in addition to, not at the expense of, wild-type mtDNA. These data suggest the existence of a homeostatic copy-number control that is exploited by uaDf5 to "hitchhike" to high frequency. We also observe activation of the mitochondrial unfolded protein response (UPR(mt)) in uaDf5 animals. Loss of UPR(mt) causes a decrease in uaDf5 frequency, whereas its constitutive activation increases uaDf5 levels. UPR(mt) activation protects uaDf5 from mitophagy. Taken together, we propose that mtDNA copy-number control and UPR(mt) represent two homeostatic response mechanisms that play important roles in regulating selfish mitochondrial genome dynamics.

PMID: 27411011 [PubMed - indexed for MEDLINE]

Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.

Related Articles

Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.

Nat Genet. 2016 Oct;48(10):1162-70

Authors: Liu C, Kraja AT, Smith JA, Brody JA, Franceschini N, Bis JC, Rice K, Morrison AC, Lu Y, Weiss S, Guo X, Palmas W, Martin LW, Chen YD, Surendran P, Drenos F, Cook JP, Auer PL, Chu AY, Giri A, Zhao W, Jakobsdottir J, Lin LA, Stafford JM, Amin N, Mei H, Yao J, Voorman A, CHD Exome+ Consortium, ExomeBP Consortium, GoT2DGenes Consortium, T2D-GENES Consortium, Larson MG, Grove ML, Smith AV, Hwang SJ, Chen H, Huan T, Kosova G, Stitziel NO, Kathiresan S, Samani N, Schunkert H, Deloukas P, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, Li M, Fuchsberger C, Pattaro C, Gorski M, CKDGen Consortium, Kooperberg C, Papanicolaou GJ, Rossouw JE, Faul JD, Kardia SL, Bouchard C, Raffel LJ, Uitterlinden AG, Franco OH, Vasan RS, O'Donnell CJ, Taylor KD, Liu K, Bottinger EP, Gottesman O, Daw EW, Giulianini F, Ganesh S, Salfati E, Harris TB, Launer LJ, Dörr M, Felix SB, Rettig R, Völzke H, Kim E, Lee WJ, Lee IT, Sheu WH, Tsosie KS, Edwards DR, Liu Y, Correa A, Weir DR, Völker U, Ridker PM, Boerwinkle E, Gudnason V, Reiner AP, van Duijn CM, Borecki IB, Edwards TL, Chakravarti A, Rotter JI, Psaty BM, Loos RJ, Fornage M, Ehret GB, Newton-Cheh C, Levy D, Chasman DI

Abstract
Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

PMID: 27618448 [PubMed - indexed for MEDLINE]

First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

N Engl J Med. 2017 Jun 22;376(25):2415-2426

Authors: Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA, CheckMate 026 Investigators

Abstract
Background Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. Methods We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. Results Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. Conclusions Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

PMID: 28636851 [PubMed - in process]