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1.
Arch Pathol Lab Med ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150458

RESUMO

CONTEXT.­: Mitotic count is an important histologic criterion for grading and prognostication in phyllodes tumors (PTs). Counting mitoses is a routine practice for pathologists evaluating neoplasms, but different microscopes, variable field selection, and areas have led to possible misclassification. OBJECTIVE.­: To determine whether 10 high-power fields (HPFs) or whole slide mitotic counts correlated better with PT clinicopathologic parameters using digital pathology (DP). We also aimed to find out whether this study might serve as a basis for an artificial intelligence (AI) protocol to count mitosis. DESIGN.­: Representative slides were chosen from 93 cases of PTs diagnosed between 2014 and 2015. The slides were scanned and viewed with DP. Mitotic counting was conducted on the whole slide image, before choosing 10 HPFs and demarcating the tumor area in DP. Values of mitoses per millimeter squared were used to compare results between 10 HPFs and the whole slide. Correlations with clinicopathologic parameters were conducted. RESULTS.­: Both whole slide counting of mitoses and 10 HPFs had similar statistically significant correlation coefficients with grade, stromal atypia, and stromal hypercellularity. Neither whole slide mitotic counts nor mitoses per 10 HPFs showed statistically significant correlations with patient age and tumor size. CONCLUSIONS.­: Accurate mitosis counting in breast PTs is important for grading. Exploring machine learning on digital whole slides may influence approaches to training, testing, and validation of a future AI algorithm.

2.
Clin Exp Hypertens ; : 1-7, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31955636

RESUMO

Background: A blood pressure (BP) of 130-139/80-89 mmHg has been defined as stage 1 hypertension by the 2017 American College of Cardiology/American Heart Association High Blood Pressure Clinical Practice Guidelines. This study was conducted to assess the association of cardiovascular risk factors (CRFs) and newly defined stage 1 hypertension in China.Methods: We analyzed the data of 84,489 adults with a BP of <140/90 mmHg. The 10-year cardiovascular disease (CVD) risk score was calculated using the China-PAR equation. Logistic analysis was used to assess the association between CRFs and stage 1 hypertension.Results: The mean values of CRFs, the proportion of metabolic abnormalities, the prevalence of ≥2 CRFs, and the 10-year CVD risk of individuals with a BP of 130-139/80-89 mmHg were significantly higher than those of the population with a BP of <130/80 mmHg. The adjusted odds ratios (ORs) of waist circumference, fasting plasma glucose (FPG), and triglycerides were 1.362 (CI 95% = 1.081-1.715, p = .009), 1.264 (CI 95% = 1.093-1.462, p = .002), and 1.331 (CI 95% = 1.009-1.755, p = .043), respectively. Other CRFs were not significantly associated with stage 1 hypertension.Conclusions: Multidisciplinary and targeted interventions are required to manage the CRFs (especially abdominal obesity, elevated FPG, and hypertriglyceridemia) of the population with a BP of 130-139/80-89 mmHg in China.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31999502

RESUMO

Background: Nonobese individuals with disproportionate body fat distribution are also vulnerable to dysglycemia. This study aimed to evaluate the association between three visceral adiposity surrogates and impaired fasting glucose (IFG) in nonobese Chinese individuals. Methods: A total of 70,200 nonobese adults without diabetes were included in this analysis. Two diagnostic criteria (IFG-ADA and IFG-WHO) were used to define IFG. The values of the visceral adiposity index, lipid accumulation product index (LAP), and cardiometabolic index (CMI) were calculated. Multivariable logistic analysis was used to evaluate the association between these surrogates and IFG. Results: Among the three indicators, only LAP and CMI were positively correlated with fasting plasma glucose (all P < 0.001). After fully adjusting for confounders, only LAP and CMI exhibited significant associations with IFG. For women, the odds ratios (ORs) for IFG-ADA in the highest quartile of the LAP and CMI were 1.967 (95% confidence interval [CI]: 1.645-2.353) and 1.594 (95% CI: 1.383-1.836), respectively; and were 2.025 (95% CI: 1.597-2.567) and 2.017 (95% CI: 1.647-2.470), respectively, for IFG-WHO (all P < 0.001). For men, the ORs for IFG-ADA of the LAP and CMI were 1.503 (95% CI: 1.233-1.833) and 2.045 (95% CI: 1.752-2.388), respectively; and were 1.534 (95% CI: 1.174-2.005) and 2.541 (95% CI: 2.025-3.188), respectively, for IFG-WHO (all P < 0.001). Conclusions: The LAP and CMI, cost-effective and simple visceral adiposity surrogates, are strongly associated with IFG in nonobese Chinese individuals. These surrogates might be potential targets to monitor for the recognition and management of excess visceral adiposity in nonobese individuals with prediabetes.

4.
Mol Ther ; 28(1): 279-292, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31636038

RESUMO

Inflammation is associated with retinal diseases. Our recent data demonstrate that immunoproteasome catalytic subunit ß2i contributes to angiotensin II (Ang II)-induced retinopathy in mice. Here, we investigated the role of another catalytic subunit ß5i in regulating retinopathy and its underlying mechanisms. We induced a murine model of retinopathy by infusing Ang II (3,000 ng/kg/min) for 3 weeks into wild-type (WT) mice, ß5i-knockout (KO) mice, or WT mice injected with either adenovirus-expressing ß5i (Ad-ß5i) or angiotensin II type 1 receptor (AT1R)-associated protein (Ad-ATRAP), which inhibits AT1R. The ß5i expression and chymotrypsin-like activity were most significantly elevated in Ang II-infused retinas and serum from patients with hypertensive retinopathy. Moreover, Ang II infusion-induced retinopathy was markedly attenuated in ß5i-KO mice but aggravated in Ad-ß5i-injected mice. Accordingly, ß5i KO markedly restored Ang II-induced downregulation of ATRAP and activation of AT1R downstream mediators, which was further enhanced in Ad-ß5i-injected mice. Interestingly, overexpression of ATRAP significantly abrogated Ang II-induced retinopathy in Ad-ß5i-injected mice. This study found that ß5i promoted Ang II-induced retinopathy by promoting ATRAP degradation and activation of AT1R-mediated signals.

5.
Hypertens Res ; 43(3): 168-177, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31700166

RESUMO

Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 µg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-ß/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.

6.
Lab Invest ; 100(3): 378-386, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31527830

RESUMO

Monocyte and adhesion infiltration into the arterial subendothelium are initial steps in hypertension development. The endothelial intercellular adhesion molecule-1 (ICAM-1) has been implicated in the recruitment and adhesion of leukocytes in several cardiac diseases. However, the role of ICAM-1 in angiotensin II (Ang II)-induced hypertension development remains unknown. Hypertension was induced by administering an infusion of Ang II (1000 ng/kg/min) to wild-type (WT) mice treated with an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse/day, respectively). Blood pressure was determined using the tail-cuff system. Vascular remodeling was assessed by performing a histological examination. Inflammation and reactive oxygen species (ROS) levels were determined by using immunostaining. Vascular dysfunction was assessed by aortic ring assay. The expression of fibrotic markers, cytokines and NOX was evaluated by quantitative real-time PCR analysis. Our results demonstrate that Ang II infusion markedly increased the ICAM-1 level in the aorta. Blocking ICAM-1 with a neutralizing antibody significantly attenuated Ang II-induced arterial hypertension, vascular hypertrophy, fibrosis, macrophage infiltration, and ROS production and improved vascular relaxation. In conclusion, ICAM-1-mediated monocyte adhesion and migration play a critical role in Ang II-induced arterial hypertension and vascular dysfunction. ICAM-1 inhibitors may represent a new therapeutic strategy for the treatment of this disease.

7.
J Pathol ; 250(3): 275-287, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31758542

RESUMO

The immunoproteasome contains three catalytic subunits (ß1i, ß2i and ß5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between ß5i and human atherosclerotic plaque instability; however, the causative role of ß5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice with genetic deletion or pharmacological inhibition of ß5i. We found that ß5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). ß5i/Apoe double KO (dKO) mice fed on the ATD had a significant decrease in both lesion area and necrotic core area, compared with eKO controls. Moreover, dKO mice had less caspase-3+ apoptotic cell accumulation but enhanced efferocytosis of apoptotic cells and increased expression of Mer receptor tyrosine kinase (MERTK). Consistently, similar phenotypes were observed in eKO mice transplanted with dKO bone marrow or treated with ß5i-specific inhibitor PR-957. Mechanistic studies in vitro revealed that ß5i deletion reduced IκBα degradation and inhibited NF-κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that ß5i plays an important role in diet-induced atherosclerosis by altering MERTK-mediated efferocytosis. ß5i might be a potential pharmaceutical target against atherosclerosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

8.
J Diabetes Investig ; 11(1): 184-191, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31145541

RESUMO

AIMS/INTRODUCTION: To investigate the association between serum 25-hydroxyvitamin D (25-[OH]D) concentrations and metabolic syndrome (MetS) in the middle-aged and elderly Chinese population. METHODS: The present study included 2,764 participants (aged >50 years). The joint interim statement was used for the standard definition of MetS. Serum 25-(OH)D concentrations were measured by electrochemiluminescence immunoassay. The study participants were categorized into quartiles based on serum 25-(OH)D concentrations, and the quartiles were calculated for the differences using anova and the χ2 -test for continuous and categorical data, respectively. A logistic regression analysis model was applied to estimate the odds ratios and 95% confidence intervals (95% CI) for each quartile of serum 25-(OH)D concentrations compared with the highest quartile. RESULTS: Serum 25-(OH)D levels were markedly lower in men in the MetS group than in those without MetS. We observed a negative correlation between the higher quartiles of serum 25-(OH)D levels and the presence of MetS among men. The correlation between serum 25-(OH)D levels and the prevalence of MetS persisted even after adjusting for potential confounders, including age, cigarette smoking status, alcohol consumption, physical activity, low-density lipoprotein, creatinine and total serum cholesterol. Adjusted odds ratios of MetS in the second through fourth compared with the lowest quartile for serum 25-(OH)D levels were 0.93 (95% CI 0.54-1.59), 0.89 (95% CI 0.50-1.56) and 0.48 (95% CI 0.28-0.84), respectively. CONCLUSIONS: Decreased serum 25-(OH)D level is significantly correlated with MetS in middle-aged men.

9.
Small ; 16(4): e1905925, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31880079

RESUMO

Protein-based therapies are potential treatments for cancer, immunological, and cardiovascular diseases. However, effective delivery systems are needed because of their instability, immunogenicity, and so on. Crosslinked negatively charged heparin polysaccharide nanoparticle (HepNP) is proposed for protein delivery. HepNP can efficiently condense vascular endothelial growth factor (VEGF) because of the unique electronegative sulfonic acid and carboxyl domain of heparin. HepNP is then assembled with VEGF-C (Hep@VEGF-C) or VEGF-A (Hep@VEGF-A) protein for the therapy of myocardial infarction (MI) via intravenous (iv) injection. Hep@VEGF-A-mediated improvement of cardiac function by promoting angiogenesis is limited because of elevated vascular permeability, while Hep@VEGF-C effectively promotes lymphangiogenesis and reduces edema. On this basis, a graded delivery of VEGF-C (0.5-1 h post-MI) and VEGF-A (5 d post-MI) using HepNP is developed. At the dose ratio of 3:1 (Hep@VEGF-C vs Hep@VEGF-A), Hep@VEGF functional complexes substantially reduce the scar formation (≈-39%; p < 0.05) and improve cardiac function (≈+74%; p < 0.05). Such a HepNP delivery system provides a simple and effective therapeutic strategy for cardiovascular diseases by delivering functional proteins. Because of the unique binding ability of heparin with cytokines and growth factors, HepNP also has considerable application prospects in protein therapy for other serious diseases.

10.
J Clin Ultrasound ; 48(1): 14-18, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654421

RESUMO

PURPOSE: To identify joints commonly exhibiting bone erosions using an extended 36-joint sonographic (US) examination in patients with rheumatoid arthritis (RA) and to study bone erosion in relation to US-detected joint inflammation. METHODS: In this cross-sectional study, power Doppler (PD) and gray-scale (GS) joint inflammation scores (semi-quantitative [0-3] grading) at each joint recess were summed to obtain a combined US score (CUS). Bone erosion was scored as present/absent. Generalized Estimating Equations were used to compare mean US scores between joint recesses with and without bone erosion. RESULTS: Bone erosion was found in 144/1080 (13.3%) joints and 189/1800 (10.5%) joint recesses in 30 RA patients. The five joints most frequently associated with bone erosion were: wrist, n = 49/144 (34.0%); first MTPJ, n = 19/144 (13.2%); thumb IPJ, n = 13/144 (9.0%); second MCPJ, n = 11/144 (7.6%); and third MCPJ, n = 11/144 (7.6%). Mean (95% CI) US scores for joint recesses with and without bone erosion were PD: 0.36 (0.21, 0.50) vs 0.01 (0.00, 0.02); GS: 1.77 (1.54, 2.00) vs 0.47 (0.40, 0.55); and CUS: 2.13 (1.78, 2.47) vs 0.49 (0.41, 0.57) (all differences significant at P < .001). CONCLUSION: The five joints most frequently showing bone erosion were identified. Joint recesses with bone erosion are more likely to exhibit greater PD and GS joint inflammation severity.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Articulações/diagnóstico por imagem , Ultrassonografia Doppler , Adulto , Idoso , Artrite Reumatoide/patologia , Estudos Transversais , Feminino , Humanos , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
11.
Am J Physiol Heart Circ Physiol ; 317(6): H1301-H1311, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729904

RESUMO

Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like superfamily of adhesion molecules that mediate leukocyte adhesion to vascular endothelium and are involved in several cardiovascular diseases, including ischemia-reperfusion injury, myocardial infarction, and atherosclerosis. However, the role of ICAM-1 in angiotensin II (ANG II)-induced cardiac remodeling in mice remains unclear. Wild-type mice were administered an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and ANG II (1,000 ng·kg-1·min-1) for up to 14 days. Cardiac contractile function and structure were detected by echocardiography. Hypertrophy, fibrosis, and inflammation were assessed by histological examination. The infiltration of lymphocyte function-associated antigen-1 (LFA-1+) monocytes/macrophages was assessed by immunostaining. The mRNA expression of genes was evaluated by quantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We found that ICAM-1 expression in ANG II-infused hearts and ICAM-1 levels in serum from human patients with heart failure were significantly increased. Moreover, ANG II infusion markedly enhanced ANG II-induced hypertension, caused cardiac contractile dysfunction, and promoted cardiac hypertrophy, fibrosis, and LFA-1+ macrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing antibody dose-dependently attenuated these effects. Moreover, our in vitro data further demonstrated that blocking ICAM-1 inhibited ANG II-induced LFA-1+ macrophage adhesion to endothelial cells and migration. In conclusion, these results provide novel evidence that blocking ICAM-1 exerts a protective effect in ANG II-induced cardiac remodeling at least in part through the modulation of adhesion and infiltration of LFA-1+ macrophages in the heart. Inhibition of ICAM-1 may represent a new therapeutic approach for hypertrophic heart diseases.NEW & NOTEWORTHY Leukocyte adhesion to vascular endothelium is a critical step in cardiovascular diseases. ICAM-1 is a member of immunoglobulin-like superfamily of adhesion molecules that binds LFA-1 to mediate leukocytes adhesion and migration. However, the significance of ICAM-1 in ANG II-induced cardiac remodeling remains unclear. This study reveals that blocking of ICAM-1 prevents ANG II-induced cardiac remodeling via modulating adhesion and migration of LFA-1+ monocytes, may serve as a novel therapeutic target for hypertensive cardiac diseases.

12.
Mol Nutr Food Res ; 63(24): e1900418, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31655498

RESUMO

SCOPE: Cardiac fibrosis is a key feature of cardiac remodeling. Recently, a protective role for resveratrol (RES) in pressure-overload-induced cardiac hypertrophy and contractile dysfunction has been demonstrated. However, the effect of RES on cardiac fibrosis and diastolic function in this model remains unclear. METHODS AND RESULTS: Cardiac remodeling is induced in mice by transverse aortic constriction (TAC) for 2-4 weeks. RES is administered at dose of 5 or 50 mg kg-1  d-1 for 2 weeks. It is found that RES administration at 50 mg kg-1  d-1 significantly attenuates TAC-induced adverse cardiac systolic and diastolic function, fibrosis, inflammation, and oxidative stress via inhibiting PTEN degradation and the downstream mediators. However, RES at 5 mg kg-1  d-1 has no significant effects. RES at 50 mg kg-1  d-1 also ameliorates pre-established adverse cardiac function and remodeling induced by TAC. Treatment with PTEN inhibitor VO-OHpic (10 mg kg-1  d-1 ) for 2 weeks abolishes RES-mediated protective effects. Additionally, the effect of RES (100 µm) on inhibition of Ang II-induced fibroblast proliferation and activation in vitro is verified. CONCLUSIONS: The findings provide new evidence that RES plays a critical role in the progression of cardiac fibrosis and diastolic dysfunction, and suggest that RES may be a promising therapeutic agent for cardiac fibrosis.

13.
Respiration ; 98(5): 383-390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31578022

RESUMO

BACKGROUND: The ILD-GAP model was developed and validated in a Western cohort to predict 1-, 2- and 3-year mortality in chronic interstitial lung disease (ILD). OBJECTIVES: We aimed to validate the ILD-GAP model and identify predictors of mortality to derive a nomogram to predict mortality in our local Asian population. METHODS: Characteristics of patients on follow-up in a tertiary ILD referral center were retrospectively reviewed. RESULTS: There were 181 patients and 48 mortalities. 29.8% had idiopathic pulmonary fibrosis, 2.8% unclassifiable ILD, 33.1% connective tissue disease-associated interstitial lung disease (CTD-ILD), 28.7% idiopathic nonspecific interstitial pneumonia and 5.5% chronic hypersensitivity pneumonitis. Univariable analysis showed that a higher ILD-GAP index, unclassified ILD, males, older age, higher pulmonary artery systolic pressure, lower forced vital capacity percent predicted and carbon monoxide diffusion capacity (DLCO) correlated with increased mortality, and CTD had lower mortality. Multivariable analysis utilizing Akaike's information criterion stopping rule showed males and a lower DLCO predicted increased mortality, while CTD predicted lower mortality. These were used to generate a nomogram which predicted overall mortality better (C index 0.817, adequacy index 99.5%) than ILD-GAP (C index 0.777, adequacy index 60.7%) and provided superior estimates based on likelihood ratio testing. Calibration plots showed the nomogram predicted 1-year mortality better, whilst the ILD-GAP model predicted 2- and 3-year mortality closer to actual mortality rates but underpredicted 1-year mortality. CONCLUSION: The nomogram performed better than ILD-GAP in predicting overall mortality and 1-year mortality. Both demonstrated good performance in predicting mortality risk.

14.
J Mol Cell Cardiol ; 137: 34-45, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629736

RESUMO

Hypertensive cardiac remodeling is a major cause of heart failure. The immunoproteasome is an inducible form of the proteasome and its catalytic subunit ß5i (also named LMP7) is involved in angiotensin II-induced atrial fibrillation; however, its role in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. C57BL/6 J wild-type (WT) and ß5i knockout (ß5i KO) mice were subjected to uninephrectomy (sham) and DOCA-salt treatment for three weeks. Cardiac function, fibrosis, and inflammation were evaluated by echocardiography and histological analysis. Protein and gene expression levels were analyzed by quantitative real-time PCR and immunoblotting. Our results showed that after 21 days of DOCA-salt treatment, ß5i expression and chymotrypsin-like activity were the most significantly increased factors in the heart compared with the sham control. Moreover, DOCA-salt-induced elevation of blood pressure, adverse cardiac function, chamber and myocyte hypertrophy, interstitial fibrosis, oxidative stress, and inflammation were markedly attenuated in ß5i KO mice. These findings were verified in ß5i inhibitor PR-957-treated mice. Moreover, blocking of PTEN (the gene of phosphate and tensin homolog deleted on chromosome ten) markedly attenuated the inhibitory effect of ß5i knockout on DOCA-salt-induced cardiac remodeling. Mechanistically, DOCA-salt stress upregulated the expression of ß5i, which promoted the degradation of PTEN and the activation of downstream signals (AKT/mTOR, TGF-ß1/Smad2/3, NOX, and NF-κB), which ultimately led to cardiac hypertrophic remodeling. This study provides new evidence of the critical role of ß5i in DOCA-salt-induced cardiac remodeling through the regulation of PTEN stability, and indicates that the inhibition of ß5i may be a promising therapeutic target for the treatment of hypertensive heart diseases.

15.
Jpn J Radiol ; 37(11): 793-797, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31522386

RESUMO

PURPOSE: To determine if a novel individualized-ultrasound (IUS) method can detect more joints with erosion(s) in rheumatoid arthritis (RA) patients versus existing methods. MATERIALS AND METHODS: The IUS method selects up to 7 or 14 ultrasonographically most inflamed joints whereas existing methods pre-fix 7 or 14 joints for ultrasonography. Using ultrasonography, the mean total inflammatory score (TIS), mean number of affected joints and mean number of joints with erosion(s) were compared between novel and existing methods among 30 RA patients using the paired Student t test. RESULTS: Using 7-joint approach, comparing IUS versus existing methods, the mean (95% CI) for TIS, number of affected joints, and number of joints with erosion(s) were: 2.18 (1.88, 2.48) versus 0.95 (0.78, 1.11); 7 (7, 7) versus 4.43 (3.93, 4.94); 3.20 (2.44, 3.96) versus 1.33 (0.94, 1.72), respectively. Using 14-joint approach, comparing IUS versus existing methods, the mean (95% CI) for TIS, number of affected joints, and number of joints with erosion(s) were: 3.17 (2.75, 3.6) versus 1.71 (1.38, 2.04); 13.5 (13.05, 13.95) versus 8.13 (7.24, 9.02); 4.23 (3.13, 5.34) versus 2.77 (2.03, 3.50), respectively. p values all < 0.0001. CONCLUSIONS: A novel IUS method detects substantially more joints with erosion(s) in RA patients versus existing methods.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
16.
Biochim Biophys Acta Mol Basis Dis ; 1865(12): 165551, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494226

RESUMO

System hypertension is a major risk factor for cardiac hypertrophy and heart failure. Our recent findings reveal that the ablation or inhibition of C-X-C chemokine receptor (CXCR) 2 blocks this process in mice; however, it is not clear whether the pharmacological inhibition of CXCR2 attenuates hypertension and subsequent cardiac remodeling in spontaneously hypertensive rats (SHRs). In the present study, we showed that chemokines (CXCL1 and CXCL2) and CXCR2 were significantly upregulated in SHR hearts compared with Wistar-Kyoto rat (WKY) hearts. Moreover, the administration of CXCR2-specific inhibitor N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)-urea (SB225002) in SHRs (at 2 months of age) for an additional 4 months significantly suppressed the elevation of blood pressure, cardiac myocyte hypertrophy, fibrosis, inflammation, and superoxide production and improved heart dysfunction in SHRs compared with vehicle-treated SHRs. SB225002 treatment also reduced established hypertension, cardiac remodeling and contractile dysfunction. Moreover, CXCR2-mediated increases in the recruitment of Mac-2-positive macrophages, proinflammatory cytokines, vascular permeability and ROS production in SHR hearts were markedly attenuated by SB225002. Accordingly, the inhibition of CXCR2 by SB225002 deactivates multiple signaling pathways (AKT/mTOR, ERK1/2, STAT3, calcineurin A, TGF-ß/Smad2/3, NF-κB-p65, and NOX). Our results provide new evidence that the chronic blocking of CXCR2 activation attenuates progression of cardiac hypertrophic remodeling and dysfunction in SHRs. These findings may be of value in understanding the benefits of CXCR2 inhibition for hypertensive cardiac hypertrophy and provide further support for the clinical application of CXCR2 inhibitors for the prevention and treatment of heart failure.

17.
Mol Genet Genomic Med ; 7(11): e604, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487119

RESUMO

BACKGROUND: The LRRK2 gene is associated with Parkinson's disease (PD) as a number of mutations within the gene have been shown to be susceptibility factors. Studies on various global populations have determined that mutations such as G2019S, G2385R, and R1628P in LRRK2 increase the risk of developing PD while the N551K-R1398H haplotype is associated with conferring protection against developing PD. Here we report a study looking at the N551K and R1398H variants for the first time in the Malaysian population. METHODS: Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age- and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay. RESULTS: A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta-analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H. CONCLUSION: This study reports that the N551K-R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.

18.
J Vasc Access ; : 1129729819865463, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31364454

RESUMO

INTRODUCTION: A successful arteriovenous fistula is essential for effective haemodialysis. We aim to validate the existing failure to maturation equation and to propose a new clinical scoring system by evaluating arteriovenous fistula success predictors. METHODS: Data of end-stage renal disease patients initiated on haemodialysis from January 2010 to December 2012 were retrospectively obtained from medical records with follow-up until 1 January 2014. Application of the failure to maturation equation was evaluated. A nomogram was developed using arteriovenous fistula success predictors and was calibrated with a bootstrapping technique. RESULTS: A total of 694 patients were included with mean duration of follow-up of 2.3 years. Arteriovenous fistula maturation was achieved by 542 patients (78%). Comparing our cohort with the failure to maturation cohort, there were statistically significant differences in mean age, ethnicity and presence of diabetes mellitus. The failure to maturation equation failed to predict arteriovenous fistula outcomes with area under the curve performance of 0.519 on a receiver operating characteristic curve. Multivariate logistic regression showed that Malay patients (odds ratio = 0.628; 95% confidence interval = 0.403-0.978; p < 0.05) and patients requiring preoperative vein mapping (odds ratio = 0.601; 95% confidence interval = 0.410-0.883; p < 0.01) had a lower chance of arteriovenous fistula success, whereas male gender (odds ratio = 1.526; 95% confidence interval = 1.040-2.241; p < 0.05) and presence of postoperative good thrill (odds ratio = 3.137; 95% confidence interval = 2.127-4.625; p < 0.0001) had a higher chance of arteriovenous fistula success. The derived nomogram predicted arteriovenous fistula success (odds ratio = 1.030; 95% confidence interval = 1.022-1.038; p < 0.0001) with the area under the curve of 0.695 on a receiver operating characteristic curve and an adequacy index of 99.86% (p < 0.0001). CONCLUSION: The failure to maturation equation was not validated in our cohort. The clinical utility of our proposed arteriovenous fistula scoring system requires external validation in larger studies.

19.
Burns ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31447203

RESUMO

INTRODUCTION: Acute kidney injury (AKI) is a frequent complication of severe burn injury and is associated with a high mortality rate of up to 80%. We aimed to establish the incidence, mortality rate, and factors related to mortality in adult patients with severe burn injury and AKI with renal replacement therapy (RRT) in Singapore. METHODS: We performed a retrospective cohort study of severely burned patients who were admitted to the Burns Intensive Care Unit (BICU) at the Singapore General Hospital (SGH) from January 2008 to December 2016. We compared patients with AKI with RRT who survived with those who did not survive. As there were changes in the protocol for burns management after 2013, we also compared patients with AKI with RRT who survived with non-survivors in each of the 2008-2012 and 2013-2016 cohorts. RESULTS: Data of 201 patients were studied. The incidence of AKI with RRT use in severe burn injury was 21.9% and their mortality rate was 50.0%. The non-survivors had significantly higher median burned total body surface area (p = 0.043), earlier AKI (p = 0.046), earlier use of RRT (p = 0.035), lower rate of renal recovery (p = <0.0001), higher rates of adult respiratory distress syndrome (ARDS) (p = 0.005) and shock with vasopressors (p = 0.009) compared to the survivors. The survival rate was 36.8% in the 2008-2012 cohort, but improved to 60.0% in the 2013-2016 cohort. In the 2008-2012 cohort, the non-survivors developed AKI earlier (day 0 admission vs. day 3 admission, p = 0.039), and were initiated on RRT at lower serum creatinine level (173.5 µmol/L vs. 254.0 µmol/L, p = 0.042), when compared to the survivors in this same cohort. On the other hand, there were no significant differences in the renal status and fluid balance parameters between the non-survivors and survivors in the 2013-2016 cohort. CONCLUSIONS: The incidence of AKI with RRT in the Singapore study cohort was high, but their mortality rate was relatively lower compared to other study cohorts. Severity of AKI and use of RRT were associated with poor prognosis. Large scale study is required to further study the risk factors for mortality in this group of patients and establish cause-and-effect relationship.

20.
Radiol Med ; 124(10): 1037-1042, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31270722

RESUMO

OBJECTIVE: To investigate whether ultrasound greyscale (GS) and power Doppler (PD) joint inflammation may be useful in identifying rheumatoid arthritis (RA) patients in different states of structural damage and disease activity. METHODS: In this cross-sectional study utilizing 36-joint ultrasonography, bone erosion was scored dichotomously (1 = yes/0 = no) while GS and PD joint inflammations were graded semi-quantitatively (0-3) at each joint recess. Sensitivity, specificity and receiver operating characteristic (ROC) curve analysis was applied to study ultrasound joint inflammation as a clinical marker for identifying patients with erosion score > 4.5 (median) and DAS28 > 2.6, > 3.2 and > 5.1, respectively. RESULTS: 1080 joints and 1800 joint recesses were scanned in 30 RA patients (mean disease duration, 70.3 months). Patients with GS score > 35.5 (median) had significantly higher ultrasound erosion scores when compared to those with GS score ≤ 35.5 (mean (95% CI) ultrasound erosion scores, 9.27 (6.12-12.4) versus 3.33 (2.31-4.36), respectively. p = 0.0027). Patients with PD positivity had significantly higher DAS28 scores compared to those with PD negativity (mean (95% CI) DAS28, 3.84 (3.35, 4.34) versus 2.86 (2.18, 3.54), respectively. p = 0.0457). Area under the ROC curve (AUC) based on cut-off GS scores ≥ 38 to identify patients with ultrasound erosion score >4.5 was 0.82 (sensitivity = 73.3%, specificity = 86.7%, accuracy = 80%). AUC based on cut-off PD scores ≥ 2.5 for identifying patients with DAS28 > 5.1 was 0.88 (sensitivity = 100%, specificity = 69.2%, accuracy = 73.3%). CONCLUSIONS: Ultrasound GS and PD joint inflammation scores can be useful in identifying RA patients with high bone erosion burden (ultrasound erosion score > 4.5) and high disease activity (DAS28 > 5.1), respectively.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Curva ROC , Ultrassonografia/métodos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Ultrassonografia Doppler
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