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Spironolactone-induced Degradation of the TFIIH Core Complex XPB Subunit Suppresses NF-κB and AP-1 Signaling.

Tue, 10/17/2017 - 12:45

Spironolactone-induced Degradation of the TFIIH Core Complex XPB Subunit Suppresses NF-κB and AP-1 Signaling.

Cardiovasc Res. 2017 Sep 27;:

Authors: Elinoff JM, Chen LY, Dougherty EJ, Awad KS, Wang S, Biancotto A, Siddiqui AH, Weir NA, Cai R, Sun J, Preston IR, Solomon MA, Danner RL

PMID: 29036418 [PubMed - as supplied by publisher]

Radiation Reduction in the Pediatric Catheterization Laboratory Using a Novel Imaging System.

Tue, 10/17/2017 - 12:45

Radiation Reduction in the Pediatric Catheterization Laboratory Using a Novel Imaging System.

J Invasive Cardiol. 2017 Oct 15;:

Authors: Manu S, Suntharos P, Boyle GJ, Wang L, Prieto LR

Abstract
OBJECTIVES: Radiation dose was compared between two modern imaging systems with different x-ray tube technology (Megalix vs Gigalix) and detector type (amorphous vs crystalline silicon) at the same institution.
BACKGROUND: Further reduction in radiation dose than currently reported may be achievable with advances in x-ray tube and detector technology.
METHODS: Radiation dose (air kerma, dose-area product [DAP]) was retrospectively compared for post-transplant pediatric patients undergoing right heart catheterization/biopsy (fluoroscopy only) or "annual" catheterization with coronary angiography in one of two imaging systems between January 2014 and December 2016. Comparisons were also made with published radiation doses.
RESULTS: A total of 122 right heart catheterizations with biopsy were performed in the Megalix/amorphous silicon (Si) lab and 168 in the Gigalix/crystalline Si lab. Age and weight were not statistically different for the two groups. There was a 50% decrease in median air kerma (2.2 mGy vs 1.1 mGy; P<.001) and 66% decrease in median DAP (52.2 μGy•m² vs 18.0 μGy•m²; P<.001) for the Gigalix/crystalline Si lab. A total of 24 "annual" catheterizations were performed in the Megalix/amorphous Si lab and 22 were performed in the Gigalix/crystalline Si lab. There was a 57% reduction in median air kerma (458.6 mGy vs 198.6 mGy; P<.001) and a 46% reduction in median DAP (2548.0 μGy•m² vs 1367.1 μGy•m²; P<.01) for the Gigalix/crystalline Si lab. Similar reductions were found on comparison with published doses.
CONCLUSION: The Gigalix tube and crystalline Si detector decrease radiation dose by 50%-60% for fluoroscopy and cine acquisition in pediatric patients.

PMID: 29035845 [PubMed - as supplied by publisher]

Initial Report of the Korean Organ Transplant Registry (KOTRY): Heart Transplantation.

Tue, 10/17/2017 - 12:45

Initial Report of the Korean Organ Transplant Registry (KOTRY): Heart Transplantation.

Korean Circ J. 2017 Aug 16;:

Authors: Lee HY, Jeon ES, Kang SM, Kim JJ

Abstract
BACKGROUND AND OBJECTIVES: The Korean Organ Transplant Registry (KOTRY), which was the first national transplant registry in Korea, was founded by the Korean Society for Transplantation and the Korean Center for Disease Control in 2014. Here, we present the initial report of the Korean Heart Transplant Registry.
METHODS: A total of 183 heart transplantation (HTPL) patients performed at 4 nationally representative hospitals were collected from April 2014 to December 2015. We analyzed donor and recipient characteristics, treatment patterns, and immediate post-transplantation outcomes.
RESULTS: One hundred and eighty-three patients were enrolled. The mean age of the patients was 50.5±13.5 years. The mean age of the male recipients was 4 years greater than that of the female recipients (51.7±13.3 years vs. 47.9±13.7 years, p<0.050). The mean age of donors was more than 12 years younger than that of heart recipients (37.6±10.1 years). Dilated cardiomyopathy was the predominant cause (69%) of heart failure in recipients, followed by ischemic heart diseases (14%) and valvular heart disease (4%). Rejection episodes were most frequent in the 1-6-month period after transplantation (48%), and rarely required intensive treatment. Infection episodes were most frequent <1 month after transplantation (66%) and bacterial and viral infections were equally reported. The 1-year survival rate was 91.6% and most mortality cases occurred during the perioperative period within 1 month after transplantation.
CONCLUSION: With the establishment of the KOTRY in 2014, it is now possible to present nationwide epidemiological data for HTPL in Korea for the first time. The KOTRY is the first national HTPL registry in Korea, and will continue until 2023.

PMID: 29035428 [PubMed - as supplied by publisher]

Risks factors and timing of genital human papillomavirus (HPV) infection in female stem cell transplant survivors: a longitudinal study.

Tue, 10/17/2017 - 12:45

Risks factors and timing of genital human papillomavirus (HPV) infection in female stem cell transplant survivors: a longitudinal study.

Bone Marrow Transplant. 2017 Oct 16;:

Authors: Shanis D, Anandi P, Grant C, Bachi A, Vyas N, Merideth MA, Pophali PA, Koklanaris E, Ito S, Savani BN, Barrett AJ, Battiwalla M, Stratton P

Abstract
This longitudinal single-center study describes the timing and risk factors for genital human papillomavirus (HPV) disease in women after allogeneic hematopoietic cell transplantation (HCT). Between 1994 and 2014, 109 females underwent HCT of whom 82 surviving transplant for >1 year had regular, comprehensive genital tract assessment and treatment of HPV disease. The cumulative proportions of any genital HPV infection at 1, 3, 5, 10 and 20 years were 4.8%, 14.9%, 28.1%, 36.7% and 40.9%, respectively. Demographic, disease-related factors, chronic GvHD (cGvHD) and its treatment were analyzed for their association with persistent, multifocal or severe genital HPV disease. Pre-transplant HPV disease was strongly associated with any posttransplant HPV (odds ratio (OR)=6.5, 95% confidence interval (CI)=1.65-25.85, P=0.008). Having either extensive or genital cGvHD was associated with increased risk of any HPV disease (OR=5.7, 95% CI=1.90-17.16, P=0.002) and a higher risk for severe genital dysplasia (CIN II-III/VIN II-III; OR=13.1, 95% CI=1.59-108.26, P=0.017), but no one developed HPV-related genital cancer. Persistent, multifocal or severe HPV disease occurred more frequently than in healthy populations. Women with extensive cGvHD, genital cGvHD or pre-transplant HPV are at greatest risk for post-transplant HPV disease. Early initiation of annual screening, comprehensive genital tract assessment and active management are cornerstones of their gynecology care.Bone Marrow Transplantation advance online publication, 16 October 2017; doi:10.1038/bmt.2017.210.

PMID: 29035398 [PubMed - as supplied by publisher]

Use of sacubitril/valsartan in acute decompensated heart failure: a case report.

Tue, 10/17/2017 - 12:45

Use of sacubitril/valsartan in acute decompensated heart failure: a case report.

ESC Heart Fail. 2017 Oct 16;:

Authors: Bell TD, Mazer AJ, Miller PE, Strich JR, Sachdev V, Wright ME, Solomon MA

Abstract
Refractory heart failure typically requires costly long-term, continuous intravenous inodilator infusions while patients await mechanical circulatory support or cardiac transplantation. The combined angiotensin receptor blocker-neprilysin inhibitor, sacubitril/valsartan, is a novel therapy that can increase levels of endogenous vasoactive peptides. This therapy has been recommended as an alternative agent in patients with chronic heart failure with reduced ejection fraction and New York Heart Association class II-III symptoms. Here, we report a case of a patient with refractory stage D heart failure with reduced ejection fraction who was successfully weaned off continuous intravenous inodilator support using sacubitril/valsartan after prior failed attempts using standard therapies.

PMID: 29035000 [PubMed - as supplied by publisher]

An atypical pseudoaneurysm as complication of prosthetic aortic-valve endocarditis.

Tue, 10/17/2017 - 12:45

An atypical pseudoaneurysm as complication of prosthetic aortic-valve endocarditis.

Future Cardiol. 2017 Oct 16;:

Authors: Guaricci AI, Musci RL, Santis D, Argentiero D, Sgarra L, Losito C, Marangelli V, Nacci F, Zanna D, Favale S

Abstract
Endocarditis of a prosthetic heart valve is a life-threatening condition that is associated with high morbidity and mortality. Perivalvular extension in infective endocarditis includes complications such as periannular or intramyocardial abscesses, pseudoaneurysms and fistulae. The incidence of perivalvular extension ranges from 10 to 30% in native valve endocarditis and 30 to 55% in prosthetic aortic-valve endocarditis. Herein, we describe a case of a 66-year-old man who presented endocarditis of a prosthetic aortic valve complicated by infective pseudoaneurysm with localization next to the right coronary sinus of Valsalva. Moreover, we underscore the importance of the diagnostic imaging tools options and surgical timing.

PMID: 29034726 [PubMed - as supplied by publisher]

Optimizing outcomes after heart transplantation.

Tue, 10/17/2017 - 12:45
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Optimizing outcomes after heart transplantation.

Eur J Heart Fail. 2017 Oct 16;:

Authors: Lund LH

PMID: 29034592 [PubMed - as supplied by publisher]

Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice.

Tue, 10/17/2017 - 12:45
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Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice.

Mol Ther Methods Clin Dev. 2017 Dec 15;7:60-73

Authors: Lee S, Kivimäe S, Szoka FC

Abstract
New methods to produce large numbers of myeloid progenitor cells, precursors to macrophages (MΦs), by maintaining Hoxb8 transcription factor activity(1) has reinvigorated interest in MΦ cell therapies. We generated Hoxb8-dependent myeloid progenitors (HDPs) by transducing lineage-negative bone marrow cells with a constitutively expressed Hoxb8 flanked by loxP. HDPs proliferate indefinitely and differentiate into MΦ when Hoxb8 is removed by a tamoxifen-inducible Cre. We genetically modified HDPs with a constitutively active GMCSF receptor and the tamoxifen-induced transcription factor IRF8, which we have termed "HDP-on." The HDP-on proliferates without GMCSF and differentiates into the MΦ upon exposure to tamoxifen and ruxolitinib (GMCSF inhibitor via JAK1/2 blockade). We quantified the biodistribution of HDPs transplanted via intraperitoneal injection into immunodeficient NCG mice with a luciferase reporter; HDPs are detected for 14 days in the peritoneal cavity, liver, spleen, kidney, bone marrow, brain, lung, heart, and blood. In immunocompetent BALB/c mice, HDP-on cells, but not HDPs, are detected 1 day post-transplantation in the peritoneal cavity. Pretreatment of BALB/c mice with liposomal clodronate significantly enhances survival at day 7 for HDPs and HDP-on cells in the peritoneal cavity, spleen, and liver, but cells are undetectable at day 14. Short-term post-transplantation survival of HDPs is significantly improved using HDP-on and liposomal clodronate, opening a path for MΦ-based therapeutics.

PMID: 29034260 [PubMed]

Epigenetic Activation of Pro-angiogenic Signaling Pathways in Human Endothelial Progenitors Increases Vasculogenesis.

Tue, 10/17/2017 - 12:45
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Epigenetic Activation of Pro-angiogenic Signaling Pathways in Human Endothelial Progenitors Increases Vasculogenesis.

Stem Cell Reports. 2017 Oct 11;:

Authors: Fraineau S, Palii CG, McNeill B, Ritso M, Shelley WC, Prasain N, Chu A, Vion E, Rieck K, Nilufar S, Perkins TJ, Rudnicki MA, Allan DS, Yoder MC, Suuronen EJ, Brand M

Abstract
Human endothelial colony-forming cells (ECFCs) represent a promising source of adult stem cells for vascular repair, yet their regenerative capacity is limited. Here, we set out to understand the molecular mechanism restricting the repair function of ECFCs. We found that key pro-angiogenic pathways are repressed in ECFCs due to the presence of bivalent (H3K27me3/H3K4me3) epigenetic marks, which decreases the cells' regenerative potential. Importantly, ex vivo treatment with a combination of epigenetic drugs that resolves bivalent marks toward the transcriptionally active H3K4me3 state leads to the simultaneous activation of multiple pro-angiogenic signaling pathways (VEGFR, CXCR4, WNT, NOTCH, SHH). This in turn results in improved capacity of ECFCs to form capillary-like networks in vitro and in vivo. Furthermore, restoration of perfusion is accelerated upon transplantation of drug-treated ECFCs in a model of hindlimb ischemia. Thus, ex vivo treatment with epigenetic drugs increases the vascular repair properties of ECFCs through transient activation of pro-angiogenic signaling pathways.

PMID: 29033304 [PubMed - as supplied by publisher]

The first Italian heart transplantation: The history of the pioneers' experience.

Tue, 10/17/2017 - 12:45
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The first Italian heart transplantation: The history of the pioneers' experience.

J Heart Lung Transplant. 2017 Sep 25;:

Authors: Zanatta A, Zampieri F

PMID: 29033163 [PubMed - as supplied by publisher]

Regular tachycardia despite Wenckebach atrioventricular conduction.

Tue, 10/17/2017 - 12:45
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Regular tachycardia despite Wenckebach atrioventricular conduction.

J Electrocardiol. 2017 Sep 01;:

Authors: Fuest S, Gleva MJ, Noheria A

Abstract
We present a 21-year-old woman status post orthotopic heart transplantation initially presenting with a regular narrow complex tachycardia at 159beats/min. With intravenous diltiazem the rhythm transitioned to a regular tachycardia at 106beats/min, 2/3rd of the initial heart rate. We demonstrate this to be a novel description of 3:2second-degree Mobitz type I atrioventricular block (Wenckebach) with the absence of the hallmark regularly irregular (grouped beating) pattern.

PMID: 29033052 [PubMed - as supplied by publisher]

Third Generation Ventricular Assist Device: Mid-Term Outcomes of the HeartWare HVAD in Pediatric Patients.

Tue, 10/17/2017 - 12:45
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Third Generation Ventricular Assist Device: Mid-Term Outcomes of the HeartWare HVAD in Pediatric Patients.

Artif Organs. 2017 Oct 15;:

Authors: Pac M, Kocabeyoglu SS, Kervan U, Sert DE, Koca S, Ece I, Pac FA

Abstract
The HeartWare HVAD is a small, third generation continuous flow pump that is intracorporeally placed for support of a failing ventricle in adult patients. This device is small in size when compared to other left ventricular assist devices and can therefore be used in smaller sized pediatric patients. We present our initial experience using the HVAD as a bridge to heart transplantation in the pediatric population. We performed a retrospective, single center, nonrandomized review of 17 pediatric patients who underwent HVAD implantation between June 2013 and March 2016. The primary endpoints evaluated in this study were overall survival to heart transplantation, ongoing device support, or death. In this patient cohort, nine (53%) of 17 patients were male. The median age of the patients was 13.4 ± 3.8 (range 5-17) years. The median body surface area was 1.4 ± 0.4(0.7-2) m(2) . Etiologies of heart failure requiring HVAD support were dilated cardiomyopathy (n = 8), myocarditis (n = 5) and noncompaction cardiomyopathy (n = 4). The overall mean length of HVAD support was 254 ± 298 (range 2-804) days. A successful outcome (bridge to transplant and ongoing mechanical support) was achieved in 13 patients (76.5%). Of the 13 patients, nine (69.2%) were bridged to heart transplantation and four continue to receive support (30.7%) and are eligible for transplantation. Post-transplant survival has been 100%, with a mean follow-up of 296 ± 264.5 (range 18-785) days. The most common complication was pump thrombosis (23.5%) in follow-up. Four patients (23.5%) experienced no complications. The HVAD continuous flow ventricular assist device can be safely used to bridge pediatric patients to cardiac transplantation. Favorable outcomes of this device are comparable to the adult population. This analysis demonstrated safe and effective implantation of the HVAD System in a child with a BSA of 0.7 m(2) .

PMID: 29032583 [PubMed - as supplied by publisher]

Screening of Pulmonary Arterial Hypertension.

Tue, 10/17/2017 - 12:45
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Screening of Pulmonary Arterial Hypertension.

Semin Respir Crit Care Med. 2017 Oct;38(5):596-605

Authors: Lau EMT, Celermajer DS, Keogh A, Thakkar V

PMID: 29032563 [PubMed - in process]

Myocardial biopsy: techniques and indications.

Tue, 10/17/2017 - 12:45
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Myocardial biopsy: techniques and indications.

Heart. 2017 Oct 14;:

Authors: Francis R, Lewis C

PMID: 29032361 [PubMed - as supplied by publisher]

Preoperative Toxoplasma gondii serostatus does not affect long-term survival of cardiac transplant recipients. Analysis of the Spanish Heart Transplantation Registry.

Tue, 10/17/2017 - 12:45
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Preoperative Toxoplasma gondii serostatus does not affect long-term survival of cardiac transplant recipients. Analysis of the Spanish Heart Transplantation Registry.

Int J Cardiol. 2017 Oct 07;:

Authors: Barge-Caballero E, Almenar-Bonet L, Crespo-Leiro MG, Brossa-Loidi V, Rangel-Sousa D, Gómez-Bueno M, Farrero-Torres M, Díaz-Molina B, Delgado-Jiménez J, Martínez-Sellés M, López-Granados A, De-la-Fuente-Galán L, González-Costello J, Garrido-Bravo IP, Blasco-Peiró T, Rábago-Juan-Aracil G, González-Vílchez F

Abstract
BACKGROUND: It's unclear whether pre-transplant T. gondii seropositivity is associated with impaired survival in heart transplant recipients.
OBJECTIVES: To test the above-mentioned hypothesis in the Spanish Heart Transplantation Registry.
METHODS: Post-transplant outcomes of 4048 patients aged >16years who underwent first, single-organ heart transplantation in 17 Spanish institutions from 1984 to 2014 were studied. Long-term post-transplant survival and survival free of cardiac death or retransplantation of 2434 (60%) T. gondii seropositive recipients and 1614 (40%) T. gondii seronegative recipients were compared.
RESULTS: T. gondii seropositive recipients were older, had higher body mass index, and presented higher prevalence of hypertension, hypercholesterolemia, COPD and Cytomegalovirus seropositivity than T. gondii seronegative recipients. In univariable analysis, pre-transplant T. gondii seropositivity was associated with increased post-transplant all-cause mortality (non-adjusted HR 1.15; 95% CI 1.04-1.26). However, this effect was no longer statistically significant after multivariable adjustment by recipient's age and sex (adjusted HR 1.01, 95% CI 0.92-1.11). Extended multivariable adjustment by other potential confounders showed similar results (adjusted HR 0.99, 95% CI 0.89-1.11). T. gondii seropositivity had no significant effect on the composite outcome cardiac death or retransplantation (non-adjusted HR 1.08, 95% CI 0.95-1.24, p=0.235). The distribution of the causes of death was comparable in T. gondii seropositive and T. gondii seronegative recipients. No statistically significant impact of donor's T. gondii serostatus or donor-recipient T. gondii serostatus matching on post-transplant survival was observed.
CONCLUSIONS: Our analysis did not show a significant independent effect of preoperative T. gondii serostatus on long-term outcomes after heart transplantation.

PMID: 29031991 [PubMed - as supplied by publisher]

Surgical Thoracic Transplant Training: Super Fellowship-Is It Super?

Tue, 10/17/2017 - 12:45
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Surgical Thoracic Transplant Training: Super Fellowship-Is It Super?

J Surg Educ. 2017 Oct 11;:

Authors: Makdisi G, Makdisi T, Caldeira CC, Wang IW

Abstract
OBJECTIVE: The quality of training provided to thoracic transplant fellows is a critical step in the care of complex patients undergoing transplant. The training varies since it is not an accreditation council for graduate medical education accredited fellowship.
METHOD: A total of 104 heart or lung transplant program directors throughout the United States were sent a survey of 24 questions focusing on key aspects of training, fellowship training content and thoracic transplant job satisfaction. Out of the 104 programs surveyed 45 surveys (43%) were returned.
RESULTS: In total, 26 programs offering a transplant fellowship were included in the survey. Among these programs 69% currently have fellows of which 56% are American Board of Thoracic Surgery board eligible. According to the United Network for Organ Sharing (UNOS) requirements, 46% of the programs do not meet the requirements to be qualified as a primary heart transplant surgeon. A total of 23% of lung transplant programs also perform less than the UNOS minimum requirements. Only 24% have extra-surgical curriculum. Out of the participating programs, only 38% of fellows secured a job in a hospital setting for performing transplants. An astounding 77% of replies site an unpredictable work schedule as the main reason that makes thoracic transplant a less than favorable profession among new graduates. Long hours were also a complaint of 69% of graduates who agreed that their personal life is affected by excessive work hours.
CONCLUSION: Annually, almost half of all thoracic transplant programs perform fewer than the UNOS requirements to be a primary thoracic surgeon. This results in a majority of transplant fellows not finding a suitable transplant career. The current and future needs for highly qualified thoracic transplant surgeons will not be met through our existing training mechanisms.

PMID: 29031521 [PubMed - as supplied by publisher]

Dynamic right ventricular outflow obstruction: A rare cause of hypotension during anestesia induction.

Tue, 10/17/2017 - 12:45
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Dynamic right ventricular outflow obstruction: A rare cause of hypotension during anestesia induction.

Int J Surg Case Rep. 2017 Oct 05;41:30-32

Authors: Antoniucci ME, Colizzi C, Arlotta G, Calabrese M, Corrado M, Guarneri S, Martinelli L, Scapigliati A, Zamparelli R, Cavaliere F

Abstract
INTRODUCTION: Dynamic obstruction of right ventricle outflow tract (RVOTO) is a rare condition that may acutely cause severe heart failure. It has been reported in some hypertrophic cardiomyopathies, after lung transplantation, and in some cases of hemodynamic instability after cardiopulmonary bypass.
PRESENTATION OF CASE: We report the case of a 71-year-old man who developed severe hypotension during the induction of general anesthesia for surgical coronary revascularization. Hypotension did not respond to the initial treatment with vasoconstrictors and fluids. RVOTO was suspected during pulmonary artery catheterization because of the difficulty of the catheter tip to move from the right ventricle to the pulmonary artery and, successively, because of the finding of a large gradient between the systolic pressure in the right ventricle and in the pulmonary artery. The diagnosis was confirmed by transesophageal echocardiogram (TEE). Hemodynamics recovered after the infusion of cristalloids, 1L, and the suspension of vasoconstrictors and inotropes.
DISCUSSION: This is the first case in which RVOTO was observed during the induction of general anesthesia. Although this is a rare condition, the diagnostic suspect is of outmost importance because treatment is mainly based on fluid administration, and drugs with positive inotropic properties (like most vasoconstrictors) are contraindicated.
CONCLUSIONS: RVOTO is an unusual, but possible cause of severe arterial hypotension during general anesthesia induction. TEE is useful for the evaluation of severely hypotensive patients who do not respond to routine treatment with fluids and vasoconstrictors.

PMID: 29031174 [PubMed - as supplied by publisher]

The competitive nature of STAT complex formation drives phenotype switching of T cells.

Tue, 10/17/2017 - 12:45
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The competitive nature of STAT complex formation drives phenotype switching of T cells.

Immunology. 2017 Oct 14;:

Authors: Sadreev II, Chen MZQ, Umezawa Y, Biktashev VN, Kemper C, Salakhieva DV, Welsh GI, Kotov NV

Abstract
Signal transducers and activators of transcription (STATs) are key molecular determinants of T cell fate and effector function. Several inflammatory diseases are characterized by an altered balance of T cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms by which the same STAT proteins regulate both the development of different T cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT-mediated regulation of T cell phenotype formation and plasticity using mathematical modeling and experimental data for intracellular STAT signaling proteins. The close fit of our model predictions to the experimental data allows us to propose a potential mechanism for T cell switching. According to this mechanism, T cell phenotype switching is due to the relative redistribution of STAT dimer complexes caused by the extracellular cytokine-dependent STAT competition effects. The developed model predicts that the balance between the intracellular STAT species defines the amount of the produced cytokines and thereby T cell phenotypes. The model predictions are consistent with the experimentally observed IFN-γ to IL-10 switching that regulates human Th1/Tr1 responses. The proposed model is applicable to a number of STAT signaling circuits. This article is protected by copyright. All rights reserved.

PMID: 29030870 [PubMed - as supplied by publisher]

Macrophage-Specific Expression of IL-37 in Hyperlipidemic Mice Attenuates Atherosclerosis.

Tue, 10/17/2017 - 12:45
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Macrophage-Specific Expression of IL-37 in Hyperlipidemic Mice Attenuates Atherosclerosis.

J Immunol. 2017 Oct 13;:

Authors: McCurdy S, Baumer Y, Toulmin E, Lee BH, Boisvert WA

Abstract
Atherosclerosis, the progressive buildup of plaque within arterial blood vessels, can lead to fatal downstream events, such as heart attack or stroke. A key event contributing to the development of atherosclerosis is the infiltration of monocytes and its associated inflammation, as well as the formation of lipid-laden macrophage foam cells within the vessel wall. IL-37 is recognized as an important anti-inflammatory cytokine expressed especially by immune cells. This study was undertaken to elucidate the role of macrophage-expressed IL-37 in reducing the production and effects of proinflammatory cytokines, preventing foam cell formation, and reducing the development of atherosclerosis. Expression of human IL-37 was achieved with a macrophage-specific overexpression system, using the CD68 promoter in mouse primary bone marrow-derived macrophages via retroviral transduction. Macrophage IL-37 expression in vitro resulted in decreased mRNA (e.g., IL-1B, IL-6, and IL-12) and secreted protein production (e.g., IL-6, M-CSF, and ICAM-1) of key inflammatory mediators. IL-37 expression also inhibited macrophage proliferation, apoptosis, and transmigration, as well as reduced lipid uptake, compared with controls in vitro. The in vivo effects of macrophage-expressed IL-37 were investigated through bone marrow transplantation of transduced hematopoietic stem cells into irradiated atherosclerosis-prone Ldlr(-/-) mice. After 10 wk on a high-fat/high-cholesterol diet, mice with IL-37-expressing macrophages showed reduced disease pathogenesis, which was demonstrated by significantly less arterial plaque development and systemic inflammation compared with control mice. The athero-protective effect of macrophage-expressed IL-37 has implications for development of future therapies to treat atherosclerosis, as well as other chronic inflammatory diseases.

PMID: 29030487 [PubMed - as supplied by publisher]

Survival of Idiopathic Pulmonary Arterial Hypertension Patients in the Modern Era in Australia and New Zealand.

Tue, 10/17/2017 - 12:45
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Survival of Idiopathic Pulmonary Arterial Hypertension Patients in the Modern Era in Australia and New Zealand.

Heart Lung Circ. 2017 Sep 20;:

Authors: Strange G, Lau EM, Giannoulatou E, Corrigan C, Kotlyar E, Kermeen F, Williams T, Celermajer DS, Dwyer N, Whitford H, Wrobel JP, Feenstra J, Lavender M, Whyte K, Collins N, Steele P, Proudman S, Thakkar V, Keating D, Keogh A, PHSANZ Registry

Abstract
BACKGROUND: Epidemiology and treatment strategies continue to evolve in pulmonary arterial hypertension (PAH). We sought to define the characteristics and survival of patients with idiopathic, heritable and drug-induced PAH in the current management era.
METHODS: Consecutive cases of idiopathic, heritable and drug-induced PAH were prospectively enrolled into an Australian and New Zealand Registry.
RESULTS: Between January 2012 and December 2016, a total of 220 incident cases were enrolled (mean age 57.2±18.7years, female 69.5%) and followed for a median duration of 26 months (IQR17-39). Co-morbidities were common such as obesity (34.1%), systemic hypertension (30.5%), coronary artery disease (16.4%) and diabetes mellitus (19.5%). Initial combination therapy was used in 54 patients (dual, n=50; triple, n=4). Estimated survival rates at 1-year, 2-years and 3-years were 95.6% (CI 92.8-98.5%), 87.3% (CI 82.5-92.4%) and 77.0% (CI 70.3-84.3%), respectively. Multivariate analysis showed that male sex and lower 6-minute distance at diagnosis independently predicted worse survival, whereas obesity was associated with improved survival. Co-morbidities other than obesity did not impact survival. Initial dual oral combination therapy was associated with a trend towards better survival compared with initial oral monotherapy (adjusted HR=0.27, CI 0.06-1.18, p=0.082) CONCLUSIONS: The epidemiology and survival of patients with idiopathic PAH in Australia and New Zealand are similar to contemporary registries reported in Europe and North America. Male sex and poorer exercise capacity are predictive of mortality whereas obesity appears to exert a protective effect. Despite current therapies, PAH remains a life-threatening disease associated with significant early mortality.

PMID: 29029950 [PubMed - as supplied by publisher]

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