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1.
Value Health Reg Issues ; 43: 101007, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38865765

ABSTRACT

OBJECTIVES: This study investigated the epidemiology, treatment patterns, and resource utilization in patients with alopecia areata (AA) in Taiwan using the National Health Insurance Research Database. AA severity was determined by treatment use and diagnostic codes in the year after enrollment (including corticosteroids, systemic immunosuppressants, topical immunotherapy, and phototherapy). METHODS: The cross-sectional analysis was conducted to estimate the incidence and prevalence of AA from 2016 to 2020. For the longitudinal analysis, 2 cohorts were identified: mild/moderate and severe. The cohorts were matched based on age, gender, and comorbidities. Patients were enrolled upon their first claim with an AA diagnosis during the index period of 2017-2018. RESULTS: The number of patients with AA increased from 3221 in 2016 to 3855 in 2020. The longitudinal analysis identified 1808 mild/moderate patients and 452 severe patients. Mild/moderate patients used higher levels of topical corticosteroids (82.41%) than severe patients (73.45%). Conversely, severe patients used more topical nonsteroids (41.81%) and systemic therapies (51.77%) than mild/moderate patients (0.44% and 16.15%, respectively). Oral glucocorticoids use was higher in severe patients (47.57%) relative to mild/moderate patients (14.88%), whereas the use of injectable forms was similar. The most used systemic immunosuppressants were methotrexate, cyclosporin, and azathioprine. Topical immunotherapy utilization decreased with subsequent treatment lines for severe patients. Treatment persistence at 6 months was low for all treatments. Severe patients had higher annual AA-related outpatient visits than the mild/moderate cohort. CONCLUSIONS: These findings highlight the need for additional innovations and therapies to address the clinical and economic burden of AA.

2.
Am J Phys Med Rehabil ; 101(10): e156-e157, 2022 10 01.
Article in English | MEDLINE | ID: mdl-35583437
4.
bioRxiv ; 2021 Jan 18.
Article in English | MEDLINE | ID: mdl-33469586

ABSTRACT

Acute respiratory distress syndrome (ARDS) occurred in ~12% of hospitalized COVID-19 patients in a recent New York City cohort. Pulmonary endothelial dysfunction, characterized by increased expression of inflammatory genes and increased monolayer permeability, is a major component of ARDS. Vascular leak results in parenchymal accumulation of leukocytes, protein, and extravascular water, leading to pulmonary edema, ischemia, and activation of coagulation associated with COVID-19. Endothelial inflammation further contributes to uncontrolled cytokine storm in ARDS. We have recently demonstrated that Kruppel-like factor 2 (KLF2), a transcription factor which promotes endothelial quiescence and monolayer integrity, is significantly reduced in experimental models of ARDS. Lung inflammation and high-tidal volume ventilation result in reduced KLF2, leading to pulmonary endothelial dysfunction and acute lung injury. Mechanistically, we found that KLF2 is a potent transcriptional activator of Rap guanine nucleotide exchange factor 3 (RAPGEF3) which orchestrates and maintains vascular integrity. Moreover, KLF2 regulates multiple genome-wide association study (GWAS)-implicated ARDS genes. Whether lung KLF2 is regulated by SARS-CoV-2 infection is unknown. Here we report that endothelial KLF2 is significantly reduced in human lung autopsies from COVID-19 patients, which supports that ARDS due to SARS-CoV-2 is a vascular phenotype possibly attributed to KLF2 down-regulation. We provide additional data demonstrating that KLF2 is down-regulated in SARS-CoV infection in mice.

5.
Nat Commun ; 11(1): 4254, 2020 08 26.
Article in English | MEDLINE | ID: mdl-32848143

ABSTRACT

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFß1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFß1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.


Subject(s)
Idiopathic Pulmonary Fibrosis/etiology , Idiopathic Pulmonary Fibrosis/metabolism , Protein Disulfide-Isomerases/metabolism , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Receptor, Transforming Growth Factor-beta Type I/metabolism , Thioredoxins/metabolism , Transforming Growth Factor beta1/metabolism , Animals , Bleomycin/toxicity , Disease Models, Animal , Endoplasmic Reticulum Stress , Gene Deletion , Humans , Idiopathic Pulmonary Fibrosis/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Disulfide-Isomerases/genetics , Protein Folding , Protein Stability , Pulmonary Fibrosis/pathology , Receptor, Transforming Growth Factor-beta Type I/chemistry , Signal Transduction , Thioredoxins/antagonists & inhibitors , Thioredoxins/genetics , Up-Regulation
6.
Circ Res ; 122(8): 1052-1068, 2018 04 13.
Article in English | MEDLINE | ID: mdl-29535165

ABSTRACT

RATIONALE: Cardiac fibrosis plays a critical role in the pathogenesis of heart failure. Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited, and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting coexpression gene network analysis on RNA sequencing data from failing human heart, we identified TXNDC5 (thioredoxin domain containing 5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum protein, as a potential novel mediator of cardiac fibrosis, and we completed experiments to test this hypothesis directly. OBJECTIVE: The objective of this study was to determine the functional role of TXNDC5 in the pathogenesis of cardiac fibrosis. METHODS AND RESULTS: RNA sequencing and Western blot analyses revealed that TXNDC5 mRNA and protein were highly upregulated in failing human left ventricles and in hypertrophied/failing mouse left ventricle. In addition, cardiac TXNDC5 mRNA expression levels were positively correlated with those of transcripts encoding transforming growth factor ß1 and ECM proteins in vivo. TXNDC5 mRNA and protein were increased in human CF (hCF) under transforming growth factor ß1 stimulation in vitro. Knockdown of TXNDC5 attenuated transforming growth factor ß1-induced hCF activation and ECM protein upregulation independent of SMAD3 (SMAD family member 3), whereas increasing expression of TXNDC5 triggered hCF activation and proliferation and increased ECM protein production. Further experiments showed that TXNDC5, a protein disulfide isomerase, facilitated ECM protein folding and that depletion of TXNDC5 led to ECM protein misfolding and degradation in CF. In addition, TXNDC5 promotes hCF activation and proliferation by enhancing c-Jun N-terminal kinase activity via increased reactive oxygen species, derived from NAD(P)H oxidase 4. Transforming growth factor ß1-induced TXNDC5 upregulation in hCF was dependent on endoplasmic reticulum stress and activating transcription factor 6-mediated transcriptional control. Targeted disruption of Txndc5 in mice (Txndc5-/-) revealed protective effects against isoproterenol-induced cardiac hypertrophy, reduced fibrosis (by ≈70%), and markedly improved left ventricle function; post-isoproterenol left ventricular ejection fraction was 59.1±1.5 versus 40.1±2.5 (P<0.001) in Txndc5-/- versus wild-type mice, respectively. CONCLUSIONS: The endoplasmic reticulum protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive c-Jun N-terminal kinase signaling. Loss of TXNDC5 protects against ß agonist-induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in patients with heart failure.


Subject(s)
Cardiomyopathy, Hypertrophic/metabolism , Extracellular Matrix Proteins/metabolism , Fibroblasts/metabolism , Heart Failure/metabolism , Myocardium/pathology , Protein Disulfide-Isomerases/physiology , Protein Folding , Thioredoxins/physiology , Activating Transcription Factor 6/biosynthesis , Activating Transcription Factor 6/genetics , Animals , Cardiomyopathy, Hypertrophic/pathology , Cells, Cultured , Fibroblasts/pathology , Fibrosis/metabolism , Gene Expression Regulation , Heart Failure/chemically induced , Heart Failure/pathology , Humans , Isoproterenol/toxicity , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardium/metabolism , NADPH Oxidase 4/biosynthesis , NADPH Oxidase 4/genetics , NIH 3T3 Cells , Oxidation-Reduction , Protein Disulfide-Isomerases/antagonists & inhibitors , Protein Disulfide-Isomerases/genetics , RNA Interference , RNA, Small Interfering/pharmacology , Thioredoxins/antagonists & inhibitors , Thioredoxins/genetics
7.
Am J Phys Med Rehabil ; 90(10): 856-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21862908

ABSTRACT

We present the case of a 47-yr-old gentleman with cervical cord injury after he received massage in the neck area. Magnetic resonance imaging of the cervical spine showed a herniation of the nucleus pulposus and compressive myelopathy. The patient required surgical intervention and rehabilitation. Despite 6 mos of rehabilitation, residual hand dysfunction and minor ambulation problems persisted. Although massage has many benefits, this case reminds us that there is potential danger in performing neck massage.


Subject(s)
Cervical Vertebrae , Intervertebral Disc Displacement/etiology , Massage/adverse effects , Spinal Cord Compression/etiology , Humans , Intervertebral Disc Displacement/diagnosis , Intervertebral Disc Displacement/therapy , Male , Middle Aged , Spinal Cord Compression/diagnosis , Spinal Cord Compression/therapy
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