Blood Reflux-Induced Epigenetic Factors HDACs and DNMTs Are Associated with the Development of Human Chronic Venous Disease.

Blood reflux and metabolic regulation play important roles in chronic venous disease (CVD) development. Histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) serve as repressors that inhibit metabolic signaling, which is induced by proatherogenic flow to promote aortic endothelial cell (EC) dysfunction and atherosclerosis. The aim of this study was to elucidate the relationship between blood reflux and epigenetic factors HDACs and DNMTs in CVD. Human varicose veins with different levels of blood reflux versus normal veins with normal venous flow were examined. The results show that HDAC-1, -2, -3, -5, and -7 are overexpressed in the endothelium of varicose veins with blood reflux. Blood reflux-induced HDACs are enhanced in the varicose veins with a longer duration time of blood reflux. In contrast, these HDACs are rarely expressed in the endothelium of the normal vein with normal venous flow. Similar results are obtained for DNMT1 and DNMT3a. Our findings suggest that the epigenetic factors, HDACs and DNMTs, are induced in venous ECs in response to blood reflux but are inhibited in response to normal venous flow. Blood reflux-induced HDACs and DNMTs could inhibit metabolic regulation and promote venous EC dysfunction, which is highly correlated with CVD pathogenesis.

The Development and Evaluation of a Smartphone-Aided Diagnosis Application to Measure Tympanic Membrane Perforations.

OBJECTIVES: Chronic otitis media is a long-term infection of the middle ear. It is characterized by persistent discharge from the middle ear through a perforated tympanic membrane. It is one of the most common causes of preventable hearing loss, especially in developing countries. Precise estimation of the size of tympanic membrane perforation is essential for successful clinical management. In this study, we developed a smartphone-based application to calculate the ratio of the area of tympanic membrane perforation to the area of the tympanic membrane. Twelve standardized patients and 60 medical students were involved to assess the area of tympanic membrane perforation, in particular, the percentage of perforation size. METHODS: In total, 60 student doctors (including year 5 and year 6 medical students, intern and post-graduate year training of doctors) were recruited during their rotation at the Otolaryngology department of Taipei Medical University Shuang-Ho Hospital. Twelve standardized patients with chronic otitis media were recruited through a single otology practice. Oto-endoscopic examination was performed for all patients by using a commercially-available digital oto-endoscope, and clinical images of the tympanic membrane perforation were obtained. To demonstrate the variability of perforation size estimation by different student doctors, we calculated the percentage of perforation using the smartphone-based application for 12 tympanic membranes objectively and compared the results with those visually estimated by the 60 student doctors subjectively. RESULTS: The variance in the visual estimation by the 60 student doctors was large. By contrast, variances in smartphone-based application calculations were smaller, indicating consistency in the results obtained from different users. The smartphone-based application accurately estimated the presence of perforation for tympanic membranes with high consistency. The differences in visual estimations can be considerably great and the variances can be large among different individuals. CONCLUSIONS: The smartphone-based application is a dependable tool for precisely evaluating the size of tympanic membrane perforation.

Can Face- and Smartphone-Touching Behaviors Be Altered with Personal Hygiene Reminders during the COVID-19 Pandemic Period? An Observational Study.

As part of the new measures to prevent the spread of the 2019 coronavirus disease (COVID-19), medical students were advised to wear a mask in class and avoid touching their faces. Few studies have analyzed the influence of health education on the frequency of face- and smartphone-touching behaviors during the COVID-19 pandemic. This research compared the frequency of in-class face- and smartphone-touching behaviors of medical students before and after the delivery of personal hygiene education during the COVID-19 pandemic. A behavioral observational study was conducted involving medical students at Taipei Medical University. Eighty medical students were recruited during a lecture on otorhinolaryngology. All medical students were required to wear a mask. Their face- and smartphone-touching behavior was observed by viewing the 4 k resolution video tape recorded in class. The recording lasted for 2 h, comprising 1 h prior to the health educational reminder and 1 h afterwards. The frequencies of hand-to-face contact and hand-to-smartphone contact were analyzed before and after the delivery of health education emphasizing personal hygiene. Comprehensive health education and reminders effectively reduce the rate of face- and smartphone-touching behaviors.

Validation of a Personalized Hearing Screening Mobile Health Application for Persons with Moderate Hearing Impairment.

Hearing impairment is a frequent human sensory impairment. It was estimated that over 50% of those aged >75 years experience hearing impairment in the United States. Several hearing impairment-related factors are detectable through screening; thus, further deterioration can be avoided. Early identification of hearing impairment is the key to effective management. However, hearing screening resources are scarce or inaccessible, underlining the importance of developing user-friendly mobile health care systems for universal hearing screening. Mobile health (mHealth) applications (apps) act as platforms for personalized hearing screening to evaluate an individual's risk of developing hearing impairment. We aimed to evaluate and compare the accuracy of smartphone-based air conduction and bone conduction audiometry self-tests with that of standard air conduction and bone conduction pure-tone audiometry tests. Moreover, we evaluated the use of smartphone-based air conduction and bone conduction audiometry self-tests in conductive hearing loss diagnosis. We recruited 103 patients (206 ears) from an otology clinic. All patients were aged ≥20 years. Patients who were diagnosed with active otorrhea was excluded. Moderate hearing impairment was defined as hearing loss with mean hearing thresholds >40 dB. All patients underwent four hearing tests performed by a board-certified audiologist: a smartphone-based air conduction audiometry self-test, smartphone-based bone conduction audiometry self-test, standard air-conduction pure-tone audiometry, and standard bone conduction pure-tone audiometry. We compared and analyzed the results of the smartphone-based air conduction and bone conduction audiometry self-tests with those of the standard air conduction and bone conduction pure-tone audiometry tests. The sensitivity of the smartphone-based air conduction audiometry self-test was 0.80 (95% confidence interval CI = 0.71-0.88) and its specificity was 0.84 (95% CI = 0.76-0.90), respectively. The sensitivity of the smartphone-based bone conduction audiometry self-test was 0.64 (95% CI = 0.53-0.75) and its specificity was 0.71 (95% CI = 0.62-0.78). Among all the ears, 24 were diagnosed with conductive hearing loss. The smartphone-based audiometry self-tests correctly diagnosed conductive hearing loss in 17 of those ears. The personalized smartphone-based audiometry self-tests correctly diagnosed hearing loss with high sensitivity and high specificity, and they can be a reliable screening test to rule out moderate hearing impairment among the population. It provided patients with moderate hearing impairment with personalized strategies for symptomatic control and facilitated individual case management for medical practitioners.

Screening for Hearing Impairment in Older Adults by Smartphone-Based Audiometry, Self-Perception, HHIE Screening Questionnaire, and Free-Field Voice Test: Comparative Evaluation of the Screening Accuracy With Standard Pure-Tone Audiometry.

BACKGROUND: Hearing impairment is the most frequent sensory deficit in humans, affecting more than 360 million people worldwide. In fact, hearing impairment is not merely a health problem, but it also has a great impact on the educational performance, economic income, and quality of life. Hearing impairment is therefore an important social concern. OBJECTIVE: We aimed to evaluate and compare the accuracy of self-perception, Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) questionnaire, free-field voice test, and smartphone-based audiometry as tests for screening moderate hearing impairment in older adults in China. METHODS: In this study, 41 patients were recruited through a single otology practice. All patients were older than 65 years. Patients with otorrhea and cognitive impairment were excluded. Moderate hearing impairment was defined as mean hearing thresholds at 500, 1000, 2000, and 4000 Hz >40 dB hearing loss (pure-tone average > 40 dB hearing loss). All patients completed 5 hearing tests, namely, the self-perception test, HHIE-S questionnaire test, free-field voice test, smartphone-based audiometry test, and standard pure-tone audiometry by the same audiologist. We compared the results of these tests to the standard audiogram in the better-hearing ear. RESULTS: The sensitivity and the specificity of the self-perception test were 0.58 (95% CI 0.29-0.84) and 0.34 (95% CI 0.19-0.54), respectively. The sensitivity and the specificity of the HHIE-S questionnaire test were 0.67 (95% CI 0.35-0.89) and 0.31 (95% CI 0.316-0.51), respectively. The sensitivity and the specificity of the free-field voice test were 0.83 (95% CI 0.51-0.97) and 0.41 (95% CI 0.24-0.61), respectively. The sensitivity and the specificity of the smartphone-based audiometry test were 0.92 (95% CI 0.60-0.99) and 0.76 (95% CI 0.56-0.89), respectively. Smartphone-based audiometry correctly diagnosed the presence of hearing loss with high sensitivity and high specificity. CONCLUSIONS: Smartphone-based audiometry may be a dependable screening test to rule out moderate hearing impairment in the older population.

Meta-analysis of social skills interventions of single-case research for individuals with autism spectrum disorders: results from three-level HLM.

This meta-analysis used hierarchical linear modeling to examine 115 single-case studies with 343 participants that examined the effectiveness of social skills interventions for individuals with autism spectrum disorder (ASD). The average effect size of the included studies was 1.40 (SD = 0.43, 95% CL = 1.32-1.48, N = 115). In the further, several common predictors including intervention length, age and gender of the participants, and study quality indicators (provision of sufficient, in-depth, and replicable information of participants, settings/materials, independent variables, and dependent variables) were not found to mediate the intervention effectiveness. Only research design that the study employed was found to impact the intervention effectiveness; the studies using multiple baseline or reversal design had larger effect sizes than studies using other designs. Implications of the results and limitations of this study are discussed.

Stem cell factor attenuates vascular smooth muscle apoptosis and increases intimal hyperplasia after vascular injury.

OBJECTIVE: Stem cell factor (SCF) through its cognate receptor, the tyrosine kinase c-kit, promotes survival and biological functions of hematopoietic stem cells and progenitors. However, whether SCF/c-kit interactions exacerbate intimal hyperplasia through attenuating VSMC apoptosis induced by vascular injury has not been thoroughly investigated. METHODS AND RESULTS: VSMCs were stimulated with serum deprivation and H2O2 to induce apoptosis. The transcription of c-kit mRNA and the expression of the c-kit protein by VSMCs were estimated by Q-polymerase chain reaction and Western blotting, respectively. The interactions of SCF and c-kit were investigated by in vitro and in vivo experiments. In vitro, H2O2 stimulation significantly induced apoptosis of VSMCs as evidenced by the 3- and 3.2-fold increases of cleaved caspase-3 compared with those in the control group by Western blot and flow cytometric analyses, respectively (P<0.01). Stimulation of apoptosis also caused 3.5- and 9-fold increases in c-kit mRNA transcription and protein expression, respectively, by VSMCs compared with those in the control group. Administration of SCF (10 to 1000 ng/mL) significantly lowered the amount of cleaved caspase-3 in H2O2-treated VSMCs (P<0.01). Specifically, SCF exerted this effect through activating Akt, followed by increasing Bcl-2 and then inhibiting the release of cytochrome-c from the mitochondria to the cytosol. In vivo, the mouse femoral artery was injured with a wire in SCF mutant (Sl/Sl(d)), c-kit mutant (W/W(v)), and colony control mice. In colony control mice, confocal microscopy demonstrated that the wire-injury generated a remarkable activation of caspase-3 on medial VSMCs, coinciding with upregulation of c-kit expression. The wire-injury also caused an increase in the expression of SCF on surviving medial VSMCs and cells in the adventitia. The upregulated c-kit expression in the vessel wall also facilitated homing by circulating SCF+ cells. Compared with colony control mice, vascular injury in SCF mutant and c-kit mutant mice caused a higher number of apoptotic VSMCs on day 14 and a lower number of proliferating cells, and resulted in significantly less neointimal formation (P<0.01) on day 28. CONCLUSIONS: The interactions between SCF and the c-kit receptor play an important role in protecting VSMCs against apoptosis and in maintaining intimal hyperplasia after vascular injury.

Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus.

BACKGROUND: Endothelial progenitor cells (EPCs) are present in peripheral blood and can promote postnatal angiogenesis. The number and function of circulating EPCs are altered in diabetics. This study sought to investigate whether the number and functional properties of EPCs from patients with type II diabetes could be improved by pioglitazone. METHODS: For this randomized controlled study, we recruited 36 type II diabetic patients on metformin monotherapy with a glycohemoglobin A1c of <7%. Patients were separated into pioglitazone (n = 24) and control (n = 12) groups. The number and functional activity of EPCs, and the brachial artery flow-mediated dilation were determined before and after pioglitazone treatment (8 weeks) as an add-on therapy to metformin. In addition, direct effects of pioglitazone on EPCs were also investigated. RESULTS: After pioglitazone treatment, the numbers of circulating EPCs significantly increased (from 0.44% +/- 0.14% to 0.89% +/- 0.29%, P = .01). The migratory response and the adhesive capacity to fibronectin and collagen were improved by 158%, 34%, and 83%, respectively (all P < .05). Treatment with pioglitazone significantly lowered triglyceride, very low density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hsCRP) levels, and increased high-density lipoprotein levels and insulin sensitivity (all P < .05). The increase in the number of circulating EPCs and the improvement in the migratory response after pioglitazone treatment were independently correlated to the decrease in hsCRP levels (P < or = .01). The increase in the adhesive capacity was independently correlated to the decreases in very low density lipoprotein cholesterol (P = .01) and hsCRP levels (P = .03). In addition, pioglitazone was also demonstrated to have direct effects on increasing EPC proliferation and colony formation, and attenuating EPC apoptosis (all P < .05, versus the controls). There were no significant changes in flow-mediated dilation in either group. CONCLUSIONS: Pioglitazone significantly increased the number and improved the functional properties of EPCs in type II diabetic patients through direct effects and/or anti-inflammation and lipid modification effects.

Enalapril increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system.

Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, reduces cardiovascular events in patients with acute myocardial infarction. However, whether the beneficial effect of enalapril is mediated in part through endothelial progenitor cells (EPCs) has yet to be elucidated. This study investigated the role of the CD26/dipeptidylpeptidase IV (DPP IV) system in enalapril-modulated EPC mobilization. C57 BL/6 mice were divided into control and enalapril-treated groups. Peripheral EPCs were enumerated before and after ischemic stress. CD26/DPP IV activity and stroma-derived factor-1alpha (SDF-1alpha) levels were measured in the blood and the bone marrow. In response to ischemic stress, the enalapril group displayed a significant increase in circulating EPCs (with a 3.6-fold increase of sca-1+KDR+ cells and a 2.2-fold increase of c-kit+CD31+ cells versus controls at 12 h). Enalapril also caused a sixfold increase in the contribution of bone marrow-derived EPCs to the ischemia-induced neovascularization. In the bone marrow, enalapril did not alter CD26+ cell numbers; however, it did amplify DPP IV activity. In the blood, through the anti-inflammatory effect, enalapril significantly decreased CD26+ cell numbers, leading to a decrease in total DPP IV activity. These phenomena were associated with a lower SDF-1alpha concentration in the bone marrow but higher in the blood in the enalapril group, compared to the controls. All these findings were not demonstrated without ischemic stress. The effect of enalapril on EPC mobilization could be substantially blocked by Diprotin-A, a DDP IV antagonist. This study demonstrates that one of the pleiotropic effects of enalapril on the cardiovascular system involves the modulation of circulating EPC numbers via the CD26/DPP IV system, which may serve as a potential target for mobilizing EPCs for therapeutic purposes.