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1.
BMJ Open ; 9(7): e026848, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31278097

RESUMO

INTRODUCTION: Postoperative acute kidney injury (AKI) is a common complication in cardiac surgery. Levels of intravascular haemolysis are strongly associated with postoperative AKI and with prolonged (>90 min) use of cardiopulmonary bypass (CPB). Ferrous plasma haemoglobin released into the circulation acts as a scavenger of nitric oxide (NO) produced by endothelial cells. Consequently, the vascular bioavailability of NO is reduced, leading to vasoconstriction and impaired renal function. In patients with cardiovascular risk factors, the endothelium is dysfunctional and cannot replenish the NO deficit. A previous clinical study in young cardiac surgical patients with rheumatic fever, without evidence of endothelial dysfunction, showed that supplementation of NO gas decreases AKI by converting ferrous plasma haemoglobin to ferric methaemoglobin, thus preserving vascular NO. In this current trial, we hypothesised that 24 hours administration of NO gas will reduce AKI following CPB in patients with endothelial dysfunction. METHODS: This is a single-centre, randomised (1:1) controlled, parallel-arm superiority trial that includes patients with endothelial dysfunction, stable kidney function and who are undergoing cardiac surgery procedures with an expected CPB duration >90 min. After randomisation, 80 parts per million (ppm) NO (intervention group) or 80 ppm nitrogen (N2, control group) are added to the gas mixture. Test gases (N2 or NO) are delivered during CPB and for 24 hours after surgery. The primary study outcome is the occurrence of AKI among study groups. Key secondary outcomes include AKI severity, occurrence of renal replacement therapy, major adverse kidney events at 6 weeks after surgery and mortality. We are recruiting 250 patients, allowing detection of a 35% AKI relative risk reduction, assuming a two-sided error of 0.05. ETHICS AND DISSEMINATION: The Partners Human Research Committee approved this trial. Recruitment began in February 2017. Dissemination plans include presentations at scientific conferences, scientific publications and advertising flyers and posters at Massachusetts General Hospital. TRIAL REGISTRATION NUMBER: NCT02836899.

3.
Circulation ; 140(5): 353-365, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31132875

RESUMO

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is currently no consensus on how to define HFpEF according to various society and clinical trial criteria. How clinical and hemodynamic profiles of patients vary across definitions is unclear. We sought to determine clinical characteristics, as well as physiologic and prognostic implications of applying various criteria to define HFpEF. METHODS: We examined consecutive patients with chronic exertional dyspnea (New York Heart Association class II to IV) and ejection fraction ≥50% referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. We applied societal and clinical trial HFpEF definitions and compared clinical profiles, exercise responses, and cardiovascular outcomes. RESULTS: Of 461 patients (age 58±15 years, 62% women), 416 met American College of Cardiology/American Heart Association (ACC/AHA), 205 met European Society of Cardiology (ESC), and 55 met Heart Failure Society of America (HFSA) criteria for HFpEF. Clinical profiles and exercise capacity varied across definitions, with peak oxygen uptake of 16.2±5.2 (ACC/AHA), 14.1±4.2 (ESC), and 12.7±3.1 mL·kg-1·min-1 (HFSA). A total of 243 patients had hemodynamic evidence of HFpEF (abnormal rest or exercise filling pressures), of whom 222 met ACC/AHA, 161 met ESC, and 41 met HFSA criteria. Over a mean follow-up of 3.8 years, the incidence of cardiovascular outcomes ranged from 75 (ACC/AHA) to 298 events per 1000 person-years (HFSA). Application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. CONCLUSIONS: Use of different HFpEF classifications variably enriches for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure highlights the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF subgrouping to test therapeutic interventions.

4.
Indian J Public Health ; 63(1): 33-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880735

RESUMO

Introduction: Tobacco products are the major contributors for various cancers and other diseases. In India, tobacco-related cancers (TRCs) contribute nearly half of the total cancers in males and one-fifth in females. Objective: The objective of the study is to investigate 25-year trends and projection of TRCs for 2018-2022. Methods: Joinpoint analysis was performed to assess the trends of TRCs on world age-adjusted rates. Age-period-cohort model with power link function was performed to project the future incidence burden of TRCs in urban Delhi. Results: During the 25 years, a total of 67,129 TRCs (53,125 males and 14,004 females) were registered which was 25.4% of total cancer cases registered. Males contributed 39.1% and females 10.8% of total cases. In males, TRCs declined significantly from 1988 to 2003 with estimated annual percentage change (EAPC) = -0.91% and thereafter increasing trend was observed with EAPC = 3.42%, while in females, the EAPC values were 2.2% and 3.54% respectively for the same period. The total burden of TRCs will be doubled in 2018-2022 with around 46% change due to cancer risk and around 54% due to population age and size in both the genders. The average annual count in males will be 7310 in 2018-2022 as compared to 3571 in 2008-2012 while in females this count will be increased to 2066 from 955 based on recent slope. Conclusion: The incidence of TRCs is increasing due to increase in population age, size, and factors other than population. TRCs are the preventable cancers, and load of these cancers can be controlled with strictly adhering the policy and acts.


Assuntos
Neoplasias/epidemiologia , Neoplasias/etiologia , Tabaco/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Índia/epidemiologia , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Sistema de Registros , Fatores de Risco , Distribuição por Sexo , Adulto Jovem
6.
Invest Ophthalmol Vis Sci ; 60(1): 134-146, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30629727

RESUMO

Purpose: Glaucoma, a leading cause of blindness worldwide, often remains undetected until irreversible vision loss has occurred. Treatments focus on lowering intraocular pressure (IOP), the only modifiable and readily measurable risk factor. However, IOP can vary and does not always predict disease progression. MicroRNAs (miRNAs) are promising biomarkers. They are abundant and stable in biological fluids, including plasma and aqueous humor (AqH). We aimed to identify differentially expressed miRNAs in AqH and plasma from glaucoma, exfoliation syndrome (XFS), and control subjects. Methods: Plasma and AqH from two ethnic cohorts were harvested from glaucoma or XFS (often associated with glaucoma, n = 33) and control (n = 31) patients undergoing elective surgery. A custom miRNA array measured 372 miRNAs. Molecular target prediction and pathway analysis were performed with Ingenuity Pathway Analysis (IPA) and DIANA bioinformatical tools. Results: Levels of miRNAs in plasma, a readily accessible biomarker source, correlated with miRNA levels in AqH. Twenty circulating miRNAs were at least 1.5-fold higher in glaucoma or XFS patients than in controls across two ethnic cohorts: miR-4667-5p (P = 4.1 × 10-5), miR-99b-3p (P = 4.8 × 10-5), miR-637 (P = 5.1 × 10-5), miR-4490 (P = 5.7 × 10-5), miR-1253 (P = 6.0 × 10-5), miR-3190-3p (P = 3.1 × 10-4), miR-3173-3p (P = 0.001), miR-608 (P = 0.001), miR-4725-3p (P = 0.002), miR-4448 (P = 0.002), and miR-323b-5p (P = 0.002), miR-4538 (P = 0.003), miR-3913-3p (P = 0.003), miR-3159 (P = 0.003), miR-4663 (P = 0.003), miR-4767 (P = 0.003), miR-4724-5p (P = 0.003), miR-1306-5p (P = 0.003), miR-181b-3p (P = 0.004), and miR-433-3p (P = 0.004). miR-637, miR-1306-5p, and miR-3159, in combination, allowed discrimination between glaucoma patients and control subjects (AUC = 0.91 ± 0.008, sensitivity 85.0%, specificity 87.5%). Conclusions: These results identify specific miRNAs as potential biomarkers and provide insight into the molecular processes underlying glaucoma.


Assuntos
Humor Aquoso/metabolismo , Biomarcadores/sangue , Síndrome de Exfoliação/sangue , Glaucoma de Ângulo Aberto/sangue , MicroRNAs/sangue , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Europeu/etnologia , Síndrome de Exfoliação/etnologia , Síndrome de Exfoliação/cirurgia , Feminino , Perfilação da Expressão Gênica , Glaucoma de Ângulo Aberto/etnologia , Glaucoma de Ângulo Aberto/cirurgia , Humanos , Pressão Intraocular , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Estados Unidos/epidemiologia
7.
JCI Insight ; 4(2)2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30674723

RESUMO

Patients with heterozygous missense mutations in the ACTA2 or MYH11 gene are known to exhibit thoracic aortic aneurysm and a risk of early-onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Herein we implicate the HDAC9 complex in transcriptional silencing of contractile protein-associated genes, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in HDAC9- or MALAT1-deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the HDAC9 complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 (catalytic mediator recruited by the HDAC9 complex) reduced neointimal formation. In conclusion, we report the implication of the HDAC9 complex in stenotic disease and demonstrate that pharmacologic therapy targeting epigenetic complexes can ameliorate arterial obstruction in an experimental system.

8.
Expert Opin Drug Saf ; 18(1): 29-35, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30574812

RESUMO

INTRODUCTION: Calciphylaxis is a rare but devastating disease with a mortality rate up to 50% in 1 year. It is characterized by profoundly painful ischemic skin lesions and vascular calcification that affects predominantly patients with end stage renal disease. The use of certain medications is an important modifiable risk factor in calciphylaxis and discontinuation of these is a mainstay of treatment. AREAS COVERED: This review will provide an overview of calciphylaxis and will focus on how certain therapeutic agents can affect the risk of calcification and associated thrombosis, key processes involved in the development of calciphylaxis. EXPERT OPINION: Calciphylaxis treatment requires a multi-modal approach including prevention, risk factor management, wound care, reperfusion, and use of fibrinolytics and antioxidants. Patients with end stage renal disease represent the most affected population. This population often has multiple medications prescribed, some worth reconsidering before starting or continuing them. When possible, we recommend stopping all potentially contributing medications in patients with calciphylaxis, including warfarin, active vitamin D, calcium supplements, and iron.


Assuntos
Calciofilaxia/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Falência Renal Crônica/complicações , Animais , Calciofilaxia/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Fatores de Risco , Trombose/induzido quimicamente , Trombose/epidemiologia
9.
Circulation ; 139(6): 815-827, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30586713

RESUMO

BACKGROUND: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). METHODS: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR-/-) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. RESULTS: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045). CONCLUSIONS: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

10.
J Cardiovasc Med (Hagerstown) ; 20(4): 223-225, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30540649

RESUMO

BACKGROUND: The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency. METHODS: The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level >300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation >20% at the end of the study. RESULTS: The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16. CONCLUSION: This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Suplementos Nutricionais , Insuficiência Cardíaca/tratamento farmacológico , Hematínicos/administração & dosagem , Compostos de Ferro/administração & dosagem , Função Ventricular Esquerda , Administração Oral , Idoso , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Biomarcadores/sangue , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Tolerância ao Exercício , Feminino , Ferritinas/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Hematínicos/efeitos adversos , Humanos , Compostos de Ferro/efeitos adversos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Recuperação de Função Fisiológica , Volume Sistólico , Fatores de Tempo , Transferrina/metabolismo , Resultado do Tratamento
11.
Arterioscler Thromb Vasc Biol ; 39(2): 178-187, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30587002

RESUMO

Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp-/-/ Ldlr-/-) mice and Hamp+/+/ Ldlr-/- control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp-/-/ Ldlr-/- mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp-/-/ Ldlr-/- mice was considered. Hamp+/+/ Ldlr-/- mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp+/+/ Ldlr-/- mice. Aortic macrophages from Hamp-/-/ Ldlr-/- mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp+/+/ Ldlr-/- mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30520688

RESUMO

Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 (Ndufs4-/-) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4-/- mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen (PaO2) during LMBO was lower in Ndufs4-/- and in piericidin A-treated mice than in matched controls. Impairment of HPV in air-breathing Ndufs4-/- mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4 deficient mice, three weeks of breathing 11% O2 restored HPV in response to LMBO. Compared to Ndufs4-/- mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically-inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30334902

RESUMO

Bone marrow iron estimation remains the gold standard for diagnosing iron-deficiency anemia (IDA); serum ferritin, total iron-binding capacity, and transferrin saturation are routinely used as surrogate markers of IDA. However, these tests are marred by problems like poor specificity and sensitivity. Recently, hepcidin, a protein hormone synthesized in the liver and excreted in urine, has been shown to be related to iron status. We estimated the serum and urinary hepcidin levels in healthy children aged 6 to 60 months with (n=30) and without IDA (n=30). The mean (SD) serum hepcidin levels in children with IDA were significantly lower than those in children without IDA (3.03 [1.06] vs. 4.78 [3.94] ng/mL; P=0.02). The mean (SD) urinary hepcidin levels were also significantly lower in children with IDA than those in children without IDA (2.29 [0.53] vs. 2.79 [0.75] ng/mL; P=0.004). Performance of urinary and serum hepcidin compared with serum ferritin (<12 µg/L) for diagnosing IDA in terms of area under the receiver operating characteristic curve was 0.704 (P=0.007) and 0.59 (P=0.22), respectively. Serum hepcidin is not useful for diagnosing IDA in under-5 children. In contrast, urinary hepcidin holds promise as a noninvasive diagnostic tool for IDA in under-5 children.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30312106

RESUMO

RATIONALE: Bone Morphogenetic Protein 9 (BMP9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors and downstream effectors have been reported in heritable PAH. OBJECTIVES: We sought to determine how an acquired deficiency of BMP9 signaling might contribute to PAH. METHODS AND RESULTS: Plasma levels of BMP9 and antagonist soluble Endoglin (sEng) were measured in Group 1 PAH, Group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) vs. healthy controls, or other etiologies of PAH or PH, distinguished PoPH from patients with liver disease without PAH, and was an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of BMP9 ligand trap ALK1-Fc exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia vs. hypoxia alone. CONCLUSIONS: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

15.
Nitric Oxide ; 80: 52-60, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30114529

RESUMO

BACKGROUND: Endogenous nitric oxide (NO) may contribute to ischemic and anesthetic preconditioning while exogenous NO protects against ischemia-reperfusion (I/R) injury in the heart and other organs. Why those beneficial effects observed in animal models do not always translate into clinical effectiveness remains unclear. To mitigate reperfusion damage a source of NO is required. NO inhalation is known to increase tissue NO metabolites, but little information exists about the lifetime of these species. We therefore sought to investigate the fate of major NO metabolite classes following NO inhalation in mice in vivo. METHODS: C57BL/6J mice were exposed to 80 ppm NO for 1 h. NO metabolites were measured in blood (plasma and erythrocytes) and tissues (heart, liver, lung, kidney and brain) immediately after NO exposure and up to 48 h thereafter. Concentrations of S-nitrosothiols, N-nitrosamines and NO-heme products as well as nitrite and nitrate were quantified by gas-phase chemiluminescence and ion chromatography. In separate experiments, mice breathed 80 ppm NO for 1 h prior to cardiac I/R injury (induced by coronary arterial ligation for 1 h, followed by recovery). After sacrifice, the size of the myocardial infarction (MI) and the area at risk (AAR) were measured. RESULTS: After NO inhalation, elevated nitroso/nitrosyl levels returned to baseline over the next 24 h, with distinct multi-phasic decay profiles in each compartment. S/N-nitroso compounds and NO-hemoglobin in blood decreased exponentially, but remained above baseline for up to 30min, whereas nitrate was elevated for up to 3hrs after discontinuing NO breathing. Hepatic S/N-nitroso species concentrations remained steady for 30min before dropping exponentially. Nitrate only rose in blood, liver and kidney; nitrite tended to be lower in all organs immediately after NO inhalation but fluctuated considerably in concentration thereafter. NO inhalation before myocardial ischemia decreased the ratio of MI/AAR by 30% vs controls (p = 0.002); only cardiac S-nitrosothiols and NO-hemes were elevated at time of reperfusion onset. CONCLUSIONS: Metabolites in blood do not reflect NO metabolite status of any organ. Although NO is rapidly inactivated by hemoglobin-mediated oxidation in the circulation, long-lived tissue metabolites may account for the myocardial preconditioning effects of inhaled NO. NO inhalation may afford similar protection in other organs.

16.
J Clin Transl Endocrinol ; 13: 20-25, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30013937

RESUMO

Aims: Presence of bimodality in plasma glucose distribution (BPG) and its relevance for gestational diabetes mellitus (GDM) diagnosis were studied in Asian Indian pregnant women. Methods: Fasting (FPG) and two hour plasma glucose (2-h PG) values of oral glucose tolerance tests performed in 36,530 pregnant women for GDM screening (2006-16 period), were analyzed for BPG. A unimodal normal and a mixture of two normal distributions were fitted to log-transformed FPG and 2-h PG data. The mixture model was compared to unimodal model for BPG using likelihood ratio test (LRT) and the comparison was further verified by bootstrapping. The cut points of the two normal distribution curves in the mixture models of FPG and 2-h PG were noted. Results: Fasting and 2-h PG distribution was bimodal in all pregnant women. The comparison of mixture and unimodal models using LRT revealed p value <0.001 in all age groups. The cut points for FPG and 2-h PG were 5.81 mmol/L (95% CI: 5.69-5.92) and 8.41 mmol/l (95% CI: 8.09-8.75) respectively. Conclusion: BPG is noted for both FPG and 2-hPG in Asian Indian pregnant women. The cutpoints of normal distribution curves are close to threshold values for FPG and 2-h PG proposed in NICE (National Institute for health and Care Excellence) and IADPSG (International Association of Diabetes and Pregnancy Study Group) GDM diagnostic criteria respectively. Further research on BPG in pregnant women of racial groups with high GDM prevalence, is likely to be of value in GDM diagnosis.

17.
Anesthesiology ; 129(4): 821-828, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30020101

RESUMO

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The incidence of substance use disorders in the United States among residents in anesthesiology is between 1% and 2%. A recent study reported that the incidence of substance use disorders in U.S. anesthesiology residents has been increasing. There are no reports of effective methods to prevent substance use disorder in residents. A comprehensive drug testing program including a random component may reduce the incidence of substance use disorders. METHODS: The authors initiated a comprehensive urine drug screening program of residents, fellows, faculty physicians, and certified nurse anesthetists. The authors performed 3,190 tests over 13 yr. The authors determined the incidence of substance use disorders among residents in our large anesthesiology residency program during the decade before (January 1, 1994, to December 31, 2003) and for the 13 yr after (January 1, 2004 to December 31, 2016) instituting a random urine drug testing program. A total of 628 residents trained in the program over these 23 yr; they contributed a total of 1,721 resident years for analysis. Fewer faculty and certified nurse anesthetists were studied, so we do not include them in our analysis. RESULTS: The incidence of substance use disorders among trainees in our department during the 10 yr before initiation of urine drug screening was four incidents in 719 resident years or 0.0056 incidents per resident-year. In the 13 yr after the introduction of urine drug screening, there have been zero incidents in 1,002 resident years in our residency program (P = 0.0305). CONCLUSIONS: This single-center, comprehensive program including preplacement and random drug testing was associated with a reduction of the incidence of substance use disorders among our residents in anesthesiology. There were no instances of substance use disorders in our residents over the recent 13 yr. A large, multicenter trial of a more diverse sample of academic, government, and community institutions is needed to determine if such a program can predictably reduce the incidence of substance use disorders in a larger group of anesthesiology residents.

18.
Cell Stem Cell ; 23(3): 329-341, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-29910150

RESUMO

In injured tissues, regeneration is often associated with cell fate plasticity, in that cells deviate from their normal lineage paths. It is becoming increasingly clear that this plasticity often creates alternative strategies to restore damaged or lost cells. Alternatively, cell fate plasticity is also part and parcel of pathologic tissue transformations that accompany disease. In this Perspective, we summarize a few illustrative examples of physiologic and aberrant cellular plasticity. Then, we speculate on how one could enhance endogenous plasticity to promote regeneration and reverse pathologic plasticity, perhaps inspiring interest in a new class of therapies targeting cell fate modulation.

19.
Asian Pac J Cancer Prev ; 19(6): 1647-1654, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29937537

RESUMO

Introduction: Lung cancer (LC) has been one of the most commonly diagnosed cancers worldwide, both in terms of new cases and mortality. Exponential growth of economic and industrial activities in recent decades in the Delhi urban area may have increased the incidence of LC. The primary objective of this study was to evaluate the time trend according to gender. Method: LC incidence data over 25 years were obtained from the population based urban Delhi cancer registry. Joinpoint regression analysis was applied for evaluating the time trend of age-standardized incidence rates. The age-period-cohort (APC) model was employed using Poisson distribution with a log link function and the intrinsic estimator method. Results: During the 25 years, 13,489 male and 3,259 female LC cases were registered, accounting for 9.78% of male and 2.53% of female total cancer cases. Joinpoint regression analysis revealed that LC incidence in males continued to increase during the entire period, a sharp acceleration being observed starting from 2009. In females the LC incidence rate remained a plateau during 1988-2002 and thereafter increased. The cumulative risks for 1988-2012 were 1.79% and 0.45%. The full APC (IE) model showed best fit for an age-period-cohort effect on LC incidence, with significant increase with age peaking at 70-74 years in males and 65-69 years in females. A rising period effect was observed after adjusting for age and cohort effects in both genders and a declining cohort effect was identified after controlling for age and period effects. Conclusion: The incidence of LC in urban Delhi showed increasing trend from 1988-2012. Known factors such as environmental conservation, tobacco control, physical activity awareness and medical security should be implemented more vigorously over the long term in our population.


Assuntos
Neoplasias Pulmonares/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Feminino , Seguimentos , Humanos , Incidência , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Fatores de Tempo , Adulto Jovem
20.
Circ Heart Fail ; 11(5): e004750, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29695381

RESUMO

BACKGROUND: Single measurements of left ventricular filling pressure at rest lack sensitivity for identifying heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea on exertion. We hypothesized that exercise hemodynamic measurements (ie, changes in pulmonary capillary wedge pressure [PCWP] indexed to cardiac output [CO]) may more sensitively differentiate HFpEF and non-HFpEF disease states, reflect aerobic capacity, and forecast heart failure outcomes in individuals with normal PCWP at rest. METHODS AND RESULTS: We studied 175 patients referred for cardiopulmonary exercise testing with hemodynamic monitoring: controls (n=33), HFpEF with resting PCWP≥15 mm Hg (n=32), and patients with dyspnea on exertion with normal resting PCWP and left ventricular ejection fraction (DOE-nlrW; n=110). Across 1835 paired PCWP-CO measurements throughout exercise, we used regression techniques to define normative bounds of "PCWP/CO slope" in controls and tested the association of PCWP/CO slope with exercise capacity and composite cardiac outcomes (defined as cardiac death, incident resting PCWP elevation, or heart failure hospitalization) in the DOE-nlrW group. Relative to controls (PCWP/CO slope, 1.2±0.4 mm Hg/L/min), patients with HFpEF had a PCWP/CO slope of 3.4±1.9 mm Hg/L/min. We used a threshold (2 SD above the mean in controls) of 2 mm Hg/L/min to define abnormal. PCWP/CO slope >2 in DOE-nlrW patients was common (n=45/110) and was associated with reduced peak Vo2 (P<0.001) and adverse cardiac outcomes after adjustment for age, sex, and body mass index (hazard ratio, 3.47; P=0.03) at a median 5.3-year follow-up. CONCLUSIONS: Elevated PCWP/CO slope during exercise (>2 mm Hg/L/min) is common in DOE-nlrW and predicts exercise capacity and heart failure outcomes. These findings suggest that current definitions of HFpEF based on single measures during rest are insufficient and that assessment of exercise PCWP/CO slope may refine early HFpEF diagnosis.

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