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1.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32518627

RESUMO

The hormone leptin plays a critical role in energy homeostasis, although our overall understanding of acutely changing leptin levels still needs improvement. Several developments allow a fresh look at recent and early data on leptin action. This review highlights select recent publications that are relevant for understanding the role played by dynamic changes in circulating leptin levels. We further discuss the relevance for our current understanding of leptin signaling in central neuronal feeding and energy expenditure circuits and highlight cohesive and discrepant findings that need to be addressed in future studies to understand how leptin couples with physiological adaptations of food intake and energy expenditure.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32399622

RESUMO

PURPOSE: This study assessed whether the newly developed PET radioligand [11C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain. METHODS: Brain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy individuals. The one- and unconstrained two-tissue compartment models, as well as the Logan graphical analysis were compared, and test-retest reliability and time-stability of total distribution volume (VT) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas. RESULTS: In the brain, [11C]PS13 showed highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared with adjacent neocortices. The two-tissue compartment model showed the best fit in all the brain regions, and the results from the Logan graphical analysis were consistent with those from the two-tissue compartment model. VT values showed excellent test-retest variability (range 6.0-8.5%) and good reliability (intraclass correlation coefficient range 0.74-0.87). VT values also showed excellent time-stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT. Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that [11C]PS13 binding reflects actual COX-1 density in the human brain. CONCLUSIONS: These results from the first-in-human evaluation of the ability of [11C]PS13 to image COX-1 in the brain justifies extending the study to disease populations with neuroinflammation. CLINICAL TRIAL REGISTRATION: NCT03324646 at https://clinicaltrials.gov/. Registered October 30, 2017. Retrospectively registered.

3.
Microbiol Res ; 237: 126482, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32353683

RESUMO

Seed biopriming is an emerging technique to enhance seed germination under stress conditions. An integrated approach of tomato seed biopriming with ascorbic acid, Trichoderma asperellum BHU P-1 and Ochrobactrum sp. BHU PB-1 was applied to observe the response against wilt pathogen of tomato Fusarium oxysporum f. sp. lycopersici (FOL). Tomato seeds bioprimed with the aforementioned application expressed augmented seed germination and activated of defense response. Seed germination was recorded higher (80 %) at low concentration (1 pM) of ascorbic acid as compared to high concentration of 1 mM (41 %). Combination of both ascorbic acid and antagonistic microbe treatments (T5 & T6) significantly reduced disease incidence (up to 28 %) in tomato plants at 10 days. T5 and T6 treated plants exhibited higher accumulation of total phenol content and increased activity of Phenylammonia lyase (PAL), Peroxidase (PO), Chitinase (Chi) and Polyphenol oxidase (PPO) as compared to control (T1) plants. ROS formation in the form of H2O2 was also found to be reduced in combined treatment. Histochemical analysis revealed that phenylpropanoid pathway (lignin deposition) was more activated in combined priming treatment plants as compared to individual treatment upon challenge inoculation with FOL. Transcript expression analysis of defense genes confirmed the up-regulation of PAL (2.1 fold), Chi (0.92 fold), Pathogenesis related proteins (PR) (1.58 fold) and Lipoxygenase (Lox) (0.72 fold) in T6 treatment as compared to T1 treatment plants at 96 h. This study reveals that ascorbic acid treatment with antagonistic microbes through seed priming effectively induced seed germination and elicited defense mechanism to control wilt disease in tomato plants.

4.
Mayo Clin Proc ; 95(6): 1138-1147, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376101

RESUMO

OBJECTIVE: To identify markers associated with in-hospital death in patients with coronavirus disease 2019 (COVID-19)-associated pneumonia. PATIENTS AND METHODS: A retrospective cohort study was conducted of 140 patients with moderate to critical COVID-19-associated pneumonia requiring oxygen supplementation admitted to the hospital from January 28, 2020, through February 28, 2020, and followed up through March 13, 2020, in Union Hospital, Wuhan, China. Oxygen saturation (SpO2) and other measures were tested as predictors of in-hospital mortality in survival analysis. RESULTS: Of 140 patients with COVID-19-associated pneumonia, 72 (51.4%) were men, with a median age of 60 years. Patients with SpO2 values of 90% or less were older and were more likely to be men, to have hypertension, and to present with dyspnea than those with SpO2 values greater than 90%. Overall, 36 patients (25.7%) died during hospitalization after median 14-day follow-up. Higher SpO2 levels after oxygen supplementation were associated with reduced mortality independently of age and sex (hazard ratio per 1-U SpO2, 0.93; 95% CI, 0.91 to 0.95; P<.001). The SpO2 cutoff value of 90.5% yielded 84.6% sensitivity and 97.2% specificity for prediction of survival. Dyspnea was also independently associated with death in multivariable analysis (hazard ratio, 2.60; 95% CI, 1.24 to 5.43; P=.01). CONCLUSION: In this cohort of patients with COVID-19, hypoxemia was independently associated with in-hospital mortality. These results may help guide the clinical management of patients with severe COVID-19, particularly in settings requiring strategic allocation of limited critical care resources. TRIAL REGISTRATION: Chictr.org.cn Identifier: ChiCTR2000030852.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus , Hipóxia , Oxigenoterapia , Pandemias , Pneumonia Viral , China , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Feminino , Mortalidade Hospitalar , Humanos , Hipóxia/diagnóstico , Hipóxia/etiologia , Hipóxia/terapia , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Consumo de Oxigênio , Oxigenoterapia/métodos , Oxigenoterapia/estatística & dados numéricos , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Índice de Gravidade de Doença
5.
Sci Rep ; 10(1): 6846, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321999

RESUMO

Obstructive sleep apnea (OSA) is a common sleep disorder associated with obesity. Emerging evidence suggest that OSA increases the risk of cardiovascular morbidity and mortality partly via accelerating the process of cellular aging. Thus, we sought to examine the effects of intermittent hypoxia (IH), a hallmark of OSA, on senescence in human white preadipocytes. We demonstrate that chronic IH is associated with an increased generation of mitochondrial reactive oxygen species along with increased prevalence of cells with nuclear localization of γH2AX & p16. A higher prevalence of cells positive for senescence-associated ß-galactosidase activity was also evident with chronic IH exposure. Intervention with aspirin, atorvastatin or renin-angiotensin system (RAS) inhibitors effectively attenuated IH-mediated senescence-like phenotype. Importantly, the validity of in vitro findings was confirmed by examination of the subcutaneous abdominal adipose tissue which showed that OSA patients had a significantly higher percentage of cells with nuclear localization of γH2AX & p16 than non-OSA individuals (20.1 ± 10.8% vs. 10.3 ± 2.7%, Padjusted < 0.001). Furthermore, the frequency of dual positive γH2AX & p16 nuclei in adipose tissue of OSA patients receiving statin, aspirin, and/or RAS inhibitors was comparable to non-OSA individuals. This study identifies chronic IH as a trigger of senescence-like phenotype in preadipocytes. Together, our data suggest that OSA may be considered as a senescence-related disorder.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31879765

RESUMO

BACKGROUND: Despite increasing neonatal antibiotic stewardship efforts, understanding of interhospital variation in neonatal antibiotic use is limited. METHODS: A retrospective cohort study was conducted among primarily academically affiliated hospitals participating in the Vizient Clinical Database/Resource Manager. Neonatal discharges were identified by admission age <1 month, excluding nonviable neonates and normal newborns. Hospitals with ≥100 neonatal discharges and complete data for January-December 2016 were included. Antibiotic use was measured in days of therapy per 1000 patient-days (DOT/1000 pd). A composite measure of neonatal care complexity (NCC; low, medium, high) was based on the volume of very low-birth-weight neonates and neonates undergoing surgical procedures, cardiac surgery, or extracorporeal membranous oxygenation. RESULTS: The 118 included hospitals represented 184 716 neonatal discharges; 22 hospitals with low NCC, 56 with medium NCC, and 40 with high NCC. Mean antibiotic DOT/1000 pd was 363 (standard deviation [SD], 94) in high NCC hospitals, 243 (SD, 88) in medium NCC hospitals, and 184 (SD, 122) in low NCC hospitals. Increasing NCC was associated with higher antibiotic use, with an incidence rate ratio (IRR) of 1.95 (95% confidence interval [CI], 1.55 to 2.47) for high vs low NCC and IRR 1.31 (95% CI, 1.05 to 1.64) for medium vs low NCC. Increasing case mix index was associated with higher antibiotic use (IRR 1.86 per unit increase; 95% CI, 1.50 to 2.31). CONCLUSIONS: Aggregate antibiotic use among hospitalized neonates varies based on care complexity. Substantial variation despite stratification by complexity suggests incomplete risk adjustment and/or avoidable variation in care.

7.
Sci Total Environ ; 694: 133427, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756815

RESUMO

Providing drinking water with safe arsenic levels in Latin American (LA) countries (a total of 22 countries) is a major current challenge. Arsenic's presence in water has been neglected for many decades since it was first reported ~100 years ago in Argentina. The major arsenic source in this region is geogenic. So far, arsenic has been reported in 15 LA countries. Arsenic concentrations in drinking water have been reported up to >200 fold (2000 µg/L) the WHO limit of 10 µg/L. About 14 million people in the arsenic affected LA countries depend on contaminated water characterized by >10 µg/L of arsenic. Low-cost, easy to use, efficient, and sustainable solutions are needed to supply arsenic safe water to the rural and peri-urban population in the affected areas. In the present study, >250 research articles published on various emerging technologies used for arsenic remediation in rural and peri-urban areas of LA countries are critically reviewed. Special attention has been given to arsenic adsorption methods. The manuscript focuses on providing insights into low cost emergent adsorbents with an implementation potential in Latin America. Natural, modified and synthetic adsorbents used for arsenic decontamination were reviewed and compared. Advantages and disadvantages of treatment methods are summarized. Adsorbent selection criteria are developed. Recommendations concerning emerging adsorbents for aqueous arsenic removal in LA countries have also been made.


Assuntos
Arsênico/análise , Água Potável/química , Poluentes Químicos da Água/análise , Purificação da Água/métodos , América Latina , Poluição da Água
8.
Anesth Essays Res ; 13(2): 370-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198262

RESUMO

Introduction: Midazolam is a water-soluble benzodiazepine which is frequently administered by intravenous and oral routes. Its nasal spray has become recently available. Materials and Methods: In this study, after obtaining clearance from the ethical committe, 66 patients between the age group of 4 and 10 years comparable in demographic variables were randomly allocated into two groups of 33 each. Group "O" received oral midazolam (0.5 mg/kg) 20 min before induction. Group "N" received intranasal midazolam (0.2 mg/kg) 20 min before induction. The heart rate and blood pressure (systolic, diastolic, and mean) and oxygen saturation (SPO2) were recorded. Statistical Analysis Used: The statistical analysis was done using SPSS (Statistical Package for the Social Sciences) version 15.0 software. The values were represented in number (%) and mean±sd. Results: Satisfactory sedation scores were better in nasal spray group than oral group. Satisfactory ease of induction scores, recovery times, and postanesthesia recovery scores were better in the nasal spray group than in the oral group. Conclusion: Nasal midazolam spray is acceptable and is a good alternative to oral midazolam as premedication in the pediatric population.

9.
Cells ; 8(5)2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027347

RESUMO

Telomere length (TL) is associated with cardiovascular disease (CVD) and cancer. Obstructive sleep apnea (OSA) is also linked to higher risk of CVD and cancer, and to TL. We investigated the association between TL and risk of major adverse cardiac events (MACE) and cancer in OSA patients. We studied 210 individuals undergoing sleep-related studies between 2000 and 2007. Baseline characteristics and follow-up data (available in 164 subjects) were obtained from clinic records. Incidence rates were calculated for the entire group and by OSA status. Hazard ratios were calculated to estimate effects of OSA and TL on risk of MACE and cancer. In total, 32 individuals (20%) developed MACE and/or cancer during 12.7-year follow-up. The OSA group had a higher likelihood of cancer (16.0 vs. 4.9 events per 1000 person-years, P = 0.044) but no clear evidence of an elevated incidence of MACE (10.8 vs. 4.8 events per 1000 person-years, P = 0.293) compared to the non-OSA group. There was no association between TL and MACE- (HR = 1.01, 95% CI 0.78-1.28), or cancer-risk (HR = 1.18, 95% CI 0.96-1.43). Our study warrants further investigation of any modulating effect of OSA on TL and the risk of MACE and cancer.


Assuntos
Doenças Cardiovasculares/epidemiologia , Neoplasias/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/genética , Homeostase do Telômero , Encurtamento do Telômero , Adulto , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Risco , Adulto Jovem
10.
J Pediatr Surg ; 54(11): 2416-2420, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30879754

RESUMO

PURPOSE: Cloacal exstrophy (CE) is the most severe presentation of the Exstrophy-Epispadias Complex (EEC) and is associated with an omphalocele, making the bladder and abdominal wall closure difficult. If the bladder closure fails, a secondary closure is necessary. The objective of this study is to identify patient or surgical factors associated with a successful secondary closure. METHODS: The institution's EEC database was reviewed for CE patients between 1975 and 2015. Inclusion criteria included a failed primary bladder closure with a secondary closure. Patient demographics, surgical factors and outcomes of the secondary bladder closure were reviewed. RESULTS: Twenty-four patients met inclusion criteria. 8/8 patients had a successful two-staged closure at the author's institution (100%); 2/16 patients had a successful closure at an outside institution (12.5%). Older median age at secondary closure was associated with outcome, p = 0.045. Pelvic osteotomy was associated with successful secondary closure, p = 0.013. Using Buck's immobilization with external fixation was associated with a higher proportion of successful secondary closures compared to Spica cast, p = 0.012. CONCLUSION: Successful reclosure in CE patients is associated with the use of osteotomy as well as Buck's immobilization with external fixation. While successful reclosure can be achieved, it is often at the cost of multiple procedures and, therefore, all efforts should be expended to achieve a successful primary closure. TYPE OF STUDY: Prognostic. LEVEL OF EVIDENCE: III.


Assuntos
Anus Imperfurado/cirurgia , Extrofia Vesical/cirurgia , Hérnia Umbilical/cirurgia , Escoliose/cirurgia , Anormalidades Urogenitais/cirurgia , Procedimentos Cirúrgicos Urológicos , Epispadia/cirurgia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Osteotomia , Prognóstico , Estudos Retrospectivos , Falha de Tratamento
12.
Stroke ; 50(2): 373-380, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30636572

RESUMO

Background and Purpose- Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls. Methods- To image CBF, we acquired [15O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7-3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location. Results- Logistic regression showed that anterior ( P<0.0001) and middle cerebral artery territory regions ( P=0.003) in Moyamoya patients were susceptible to hypoperfusion, whereas posterior regions were not. Cortical regions supplied by arteries with stenosis on MR angiography showed more hypoperfusion than normal arteries ( P=0.001), but the extent of hypoperfusion was not different between mild-moderate versus severe stenosis. Multidelay ASL did not perform differently from [15O]-water PET in detecting perfusion abnormalities, but standard ASL overestimated the extent of hypoperfusion in patients ( P=0.003). Conclusions- This simultaneous PET/MRI study supports the use of multidelay ASL MRI in clinical evaluation of Moyamoya disease in settings where nuclear medicine imaging is not available and application of a normative perfusion database to automatically identify abnormal CBF in patients.


Assuntos
Bases de Dados Factuais , Imagem por Ressonância Magnética , Artéria Cerebral Média , Doença de Moyamoya , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/fisiopatologia , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/fisiopatologia , Marcadores de Spin
13.
Am J Cardiol ; 123(4): 632-637, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30554649

RESUMO

Periodic limb movements in sleep (PLMS) are associated with adverse outcomes in patients with heart failure (HF). The aim of this study was to investigate whether PLMS change in response to adaptive servo-ventilation (ASV) for central sleep apnea (CSA) in patients with HF. We examined polysomnographic studies conducted between 2010 and 2014 at Mayo Clinic, Rochester, Minnesota (n = 14,444). In those, 314 of 579 patients with CSA completed the sleep study with a protocol that began with diagnostic polysomnography, followed by continuous positive airway pressure, and, for persistent CSA, by ASV titration. Patients with HF (n = 118) had a significantly higher median PLM index compared with those without HF (n = 196): 33.7 versus 6.1 events/h (p <0.001). HF was associated with a significant PLM arousal index (PLMAI) increase from diagnostic trial to ASV (odds ratio [OR]  = 1.79, p = 0.032) after adjusting for demographics, co-morbidities and medications. In patients aged >68 years, HF was associated with PLMI and PLMAI increases during ASV (OR  = 2.16, p = 0.016 and OR  = 2.05, p = 0.024), which persisted in multivariable models (OR  = 2.36, p = 0.025 and OR  = 2.33, p = 0.026). In multivariable analysis, patients with ejection fraction ≤45% had higher odds of increased PLMAI during ASV than those with ejection fraction >45% (OR  = 1.98, p = 0.022). In conclusion, PLMS may increase in HF patients after suppression of CSA by ASV. Whereas the clinical significance of increased post-ASV PLMS in HF prognosis needs to be determined, these increases may contribute to worsening outcomes in HF patients with CSA treated with ASV.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Insuficiência Cardíaca/complicações , Síndrome da Mioclonia Noturna/epidemiologia , Apneia do Sono Tipo Central/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome da Mioclonia Noturna/diagnóstico , Polissonografia , Prevalência , Estudos Retrospectivos , Apneia do Sono Tipo Central/complicações , Apneia do Sono Tipo Central/diagnóstico
14.
Molecules ; 23(11)2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30400142

RESUMO

Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positronemitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Tomografia por Emissão de Pósitrons , Pirimidinas/química , Compostos Radiofarmacêuticos , Animais , Radioisótopos de Carbono , Técnicas de Química Sintética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Descoberta de Drogas , Radioisótopos de Flúor , Humanos , Ligantes , Tomografia por Emissão de Pósitrons/métodos
15.
Front Physiol ; 9: 1370, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364113

RESUMO

Body fat distribution contributes to obesity-related metabolic and cardiovascular disorders. Visceral fat is more detrimental than subcutaneous fat. However, the mechanisms underlying visceral fat-mediated cardiometabolic dysregulation are not completely understood. Localized increases in expression of the renin angiotensin system (RAS) in adipose tissue (AT) may be implicated. We therefore investigated mRNA and protein expression of RAS components in visceral versus subcutaneous AT using paired samples from individuals undergoing surgery (N = 20, body mass index: 45.6 ± 6.2 kg/m2, and age: 44.6 ± 9.1 years). We also examined RAS-related proteins in AT obtained from individuals on renin angiotensin aldosterone system (RAAS) targeted drugs (N = 10, body mass index: 47.2 ± 9.3 kg/m2, and age: 53.3 ± 10.1 years). Comparison of protein expression between subcutaneous and visceral AT samples showed an increase in renin (p = 0.004) and no change in angiotensinogen (p = 0.987) expression in visceral AT. Among proteins involved in angiotensin peptide generation, angiotensin converting enzyme (p = 0.02) was increased in subcutaneous AT while chymase (p = 0.001) and angiotensin converting enzyme-2 (p = 0.001) were elevated in visceral fat. Furthermore, visceral fat expression of angiotensin II type-2 receptor (p = 0.007) and angiotensin II type-1 receptor (p = 0.031) was higher, and MAS receptor (p < 0.001) was lower. Phosphorylated-p53 (p = 0.147), AT fibrosis (p = 0.138) and average adipocyte size (p = 0.846) were similar in the two depots. Nonetheless, visceral AT showed increased mRNA expression of inflammatory (TNFα, p < 0.001; IL-6, p = 0.001) and oxidative stress markers (NOX2, p = 0.038; NOX4, p < 0.001). Of note, mRNA and protein expression of RAS components did not differ between subjects taking or not taking RAAS related drugs. In summary, several RAS related proteins are differentially expressed in subcutaneous versus visceral AT. This differential expression may not alter AngII but likely increases Ang1-7 generation in visceral fat. These potential differences in active angiotensin peptides and receptor expression in the two depots suggest that localized RAS may not be involved in differences in visceral vs subcutaneous AT function in obese individuals. Our findings do not support a role for localized RAS differences in visceral fat-mediated development of cardiovascular and metabolic pathology.

16.
Sci Rep ; 8(1): 14110, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237409

RESUMO

Vascular dysfunction and insulin resistance (IR) are associated with obstructive sleep apnea (OSA), which is characterized by frequent episodes of nocturnal intermittent hypoxia (IH). While it is recognized that the balance between vasoconstrictive (endothelin-1) and vasodilatory molecules (nitric oxide, NO) determine vascular profile, molecular mechanisms contributing to vascular dysfunction and IR in OSA are not completely understood. Caveolin-1 is a membrane protein which regulates endothelial nitric oxide synthase (eNOS) activity which is responsible for NO generation and cellular insulin-signaling. Hence, we examined the effects of IH on caveolin-1, eNOS, and endothelin-1 in human coronary artery endothelial cells in the context of IR. Chronic 3-day IH exposure up-regulated caveolin-1 and endothelin-1 expression while reducing NO. Also, IH altered insulin-mediated activation of AKT but not ERK resulting in increased endothelin-1 transcription. Similarly, caveolin-1 overexpression attenuated basal and insulin-stimulated NO synthesis along with impaired insulin-dependent activation of AKT and eNOS, with no effect on insulin-stimulated ERK1/2 phosphorylation and endothelin-1 transcription. Our data suggest that IH contributes to a vasoconstrictive profile and to pathway-selective vascular IR, whereby insulin potentiates ET-1 expression. Moreover, IH may partly mediate its effects on NO and insulin-signaling via upregulating caveolin-1 expression.


Assuntos
Hipóxia Celular/fisiologia , Células Endoteliais/metabolismo , Insulina/farmacologia , Transdução de Sinais/fisiologia , Caveolina 1/metabolismo , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Endotelina-1/metabolismo , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
J Nucl Med ; 59(12): 1907-1912, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29959215

RESUMO

This study assessed whether the newly developed PET radioligands 11C-PS13 and 11C-MC1 could image constitutive levels of cyclooxygenase (COX)-1 and COX-2, respectively, in rhesus monkeys. Methods: After intravenous injection of either radioligand, 24 whole-body PET scans were performed. To measure enzyme-specific uptake, scans of the 2 radioligands were also performed after administration of a nonradioactive drug preferential for either COX-1 or COX-2. Concurrent venous samples were obtained to measure parent radioligand concentrations. SUVs were calculated from 10 to 90 min. Results: 11C-PS13 showed specific uptake in most organs, including spleen, gastrointestinal tract, kidneys, and brain, which was blocked by COX-1, but not COX-2, preferential inhibitors. Specific uptake of 11C-MC1 was not observed in any organ except the ovaries and possibly kidneys. Conclusion: The findings suggest that 11C-PS13 has adequate signal in monkeys to justify its extension to human subjects. In contrast, 11C-MC1 is unlikely to show significant signal in healthy humans, though it may be able to do so in inflammatory conditions.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Macaca mulatta/metabolismo , Tomografia por Emissão de Pósitrons/veterinária , Compostos Radiofarmacêuticos , Animais , Radioisótopos de Carbono , Feminino , Masculino , Tomografia por Emissão de Pósitrons/métodos , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Triazóis/química , Triazóis/farmacocinética , Imagem Corporal Total/métodos , Imagem Corporal Total/veterinária
18.
Curr Hypertens Rep ; 20(7): 57, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884924

RESUMO

PURPOSE OF REVIEW: Sleep deficiency has been proposed as a potential contributor to racial disparities in cardiovascular health. We present contemporary evidence on the unequal burden of insufficient sleep in Blacks/African-Americans and the repercussions for disparate risk of hypertension. RECENT FINDINGS: The prevalence of insufficient sleep is high and rising and has been recognized as an important cardiovascular risk factor. Presumably due to a constellation of environmental, psychosocial, and individual determinants, these risks appear exacerbated in Blacks/African-Americans, who are more likely to experience short sleep than other ethnic/racial groups. Population-based data suggest that the risk of hypertension associated with sleep deficiency is greater in those of African ancestry. However, there is a paucity of experimental evidence linking short sleep duration to blood pressure levels in African-Americans. Blacks/African-Americans may be more vulnerable to sleep deficiency and to its hypertensive effects. Future research is needed to unequivocally establish causality and determine the mechanism underlying the postulated racial inequalities in sleep adequacy and consequent cardiovascular risk.


Assuntos
Afro-Americanos , Disparidades nos Níveis de Saúde , Hipertensão/etnologia , Privação do Sono/etnologia , Adulto , Afro-Americanos/estatística & dados numéricos , Pressão Sanguínea , Estudos Transversais , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Privação do Sono/complicações , Privação do Sono/epidemiologia , Estados Unidos
19.
Mayo Clin Proc ; 93(5): 618-626, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29728201

RESUMO

OBJECTIVE: To examine whether experimentally induced weight gain raises ambulatory blood pressure (BP) in healthy subjects and identify any relationship between changes in BP and changes in regional fat distribution. PATIENTS AND METHODS: Twenty-six normal weight subjects were randomized to 8 weeks of weight gain through overfeeding (n=16; age, 30.4±6.6 years) or to weight maintenance (controls; n=10; age, 27.1±7.7 years) between July 2004 and August 2010. Measures of body composition via dual energy X-ray absorptiometry and computed tomography, circulating biomarkers, and 24-hour ambulatory BP were obtained at baseline and after the 8-week experimental phase. RESULTS: Overfeeding resulted in 3.7 kg (95% CI, 2.9-4.5) increase in body weight in weight gainers, with increments in total (46.2 cm2; 95% CI, 27.6-64.9), visceral (13.8 cm2; 95% CI, 5.8-21.9), and subcutaneous fat (32.4 cm2; 95% CI, 13.5-51.3). No changes occurred in the maintenance group. Increases in 24-hour systolic BP (4 mm Hg; 95% CI, 1.6-6.3), mean BP (1.7 mm Hg; 95% CI, 0.3-3.3), and pulse pressure (2.8 mm Hg; 95% CI, 1.1-4.4) were evident after weight gain in the experimental group, whereas BP remained unchanged in controls. Changes in mean BP correlated only with changes in visceral fat (ρ=0.45; P=.02), but not with changes in other body composition measures. CONCLUSION: Modest weight gain causes elevation in 24-hour BP in healthy subjects. The association between increased BP and abdominal visceral fat accumulation suggests that visceral deposition of adipose tissue may contribute specifically to the enhanced risk of hypertension associated with weight gain.


Assuntos
Pressão Sanguínea/fisiologia , Gordura Intra-Abdominal , Ganho de Peso/fisiologia , Adulto , Monitorização Ambulatorial da Pressão Arterial , Composição Corporal/fisiologia , Fenômenos Fisiológicos Cardiovasculares , Feminino , Nível de Saúde , Humanos , Masculino , Adulto Jovem
20.
ACS Chem Neurosci ; 9(11): 2620-2627, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29792035

RESUMO

In our preceding paper (Part 1), we identified three 1,5-bis-diaryl-1,2,4-triazole-based compounds that merited evaluation as potential positron emission tomography (PET) radioligands for selectively imaging cyclooxygenase-1 (COX-1) in monkey and human brain, namely, 1,5-bis(4-methoxyphenyl)-3-(alkoxy)-1 H-1,2,4-triazoles bearing a 3-methoxy (PS1), a 3-(2,2,2-trifluoroethoxy) (PS13), or a 3-fluoromethoxy substituent (PS2). PS1 and PS13 were labeled from phenol precursors by O-11C-methylation with [11C]iodomethane and PS2 by O-18F-fluoroalkylation with [2H2,18F]fluorobromomethane. Here, we evaluated these PET radioligands in monkey. All three radioligands gave moderately high uptake in brain, although [2H2,18F]PS2 also showed undesirable radioactivity uptake in skull. [11C]PS13 was selected for further evaluation, mainly based on more favorable brain kinetics than [11C]PS1. Pharmacological preblock experiments showed that about 55% of the radioactivity uptake in brain was specifically bound to COX-1. An index of enzyme density, VT, was well identified from serial brain scans and from the concentrations of parent radioligand in arterial plasma. In addition, VT values were stable within 80 min, suggesting that brain uptake was not contaminated by radiometabolites. [11C]PS13 successfully images and quantifies COX-1 in monkey brain, and merits further investigation for imaging COX-1 in monkey models of neuroinflammation and in healthy human subjects.


Assuntos
Encéfalo/diagnóstico por imagem , Ciclo-Oxigenase 1/metabolismo , Compostos Radiofarmacêuticos/química , Triazóis/química , Animais , Encéfalo/metabolismo , Radioisótopos de Carbono , Macaca mulatta , Tomografia por Emissão de Pósitrons
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