A novel mutation in human EMD gene and mitochondrial dysfunction in emerin knockdown cardiomyocytes.

Emerin is an inner nuclear envelope protein encoded by the EMD gene, mutations in which cause Emery-Dreifuss muscular dystrophy type 1 (EDMD1). Cardiac involvement has become a major threat to patients with EDMD1; however, the cardiovascular phenotype spectrums of emerinopathy and the mechanisms by which emerin regulates cardiac pathophysiology remain unclear. Here, we identified a novel nonsense mutation (c.C57G, p.Y19X) in the EMD gene in a Han Chinese family through high-throughput sequencing. Two family members were found to have EDMD1 with muscle weakness and cardiac arrhythmia. Mechanistically, we first discovered that knockdown of emerin in HL-1 or H9C2 cardiomyocytes lead to impaired mitochondrial oxidative phosphorylation capacity with downregulation of electron transport chain complex I and IV and upregulation of complex III and V. Moreover, loss of emerin in HL-1 cells resulted in collapsed mitochondrial membrane potential, altered mitochondrial networks and downregulated multiple factors in RNA and protein level, such as PGC1α, DRP1, MFF, MFN2, which are involved in regulation of mitochondrial biogenesis, fission and fusion. Our findings suggest that targeting mitochondrial bioenergetics might be an effective strategy against cardiac disorders caused by EMD mutations.

Identification and Verification of Feature Biomarkers Associated With Immune Cells in Dilated Cardiomyopathy by Bioinformatics Analysis.

Objective: To explore immune-related feature genes in patients with dilated cardiomyopathy (DCM). Methods: Expression profiles from three datasets (GSE1145, GSE21610 and GSE21819) of human cardiac tissues of DCM and healthy controls were downloaded from the GEO database. After data preprocessing, differentially expressed genes (DEGs) were identified by the 'limma' package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were then performed to identify biological functions of the DEGs. The compositional patterns of stromal and immune cells were estimated using xCell. Hub genes and functional modules were identified based on protein-protein interaction (PPI) network analysis by STRING webtool and Cytoscape application. Correlation analysis was performed between immune cell subtypes and hub genes. Hub genes with |correlation coefficient| > 0.5 and p value <0.05 were selected as feature biomarkers. A logistic regression model was constructed based on the selected biomarkers and validated in datasets GSE5406 and GSE57338. Results: A total of 1,005 DEGs were identified. Functional enrichment analyses indicated that extracellular matrix remodeling and immune and inflammation disorder played important roles in the pathogenesis of DCM. Immune cells, including CD8+ T-cells, macrophages M1 and Th1 cells, were proved to be significantly changed in DCM patients by immune cell infiltration analysis. In the PPI network analysis, STAT3, IL6, CCL2, PIK3R1, ESR1, CCL5, IL17A, TLR2, BUB1B and MYC were identified as hub genes, among which CCL2, CCL5 and TLR2 were further screened as feature biomarkers by using hub genes and immune cells correlation analysis. A diagnosis model was successfully constructed by using the three biomarkers with area under the curve (AUC) scores 0.981, 0.867 and 0.946 in merged dataset, GSE5406 and GSE57338, respectively. Conclusion: The present study identified three immune-related genes as diagnostic biomarkers for DCM, providing a novel perspective of immune and inflammatory response for the exploration of DCM molecular mechanisms.

Dry eye disease and psychiatric disorders: A systematic review and meta-analysis.

The association between dry eye disease (DED) and psychiatric conditions is a highly researched topic. This work reviews the literature on this relationship, examining the prevalence and correlations of depression and anxiety with dry eye signs and symptoms. A comprehensive literature search of MEDLINE, EMBASE, PsycINFO, and gray literature was conducted, with keywords for dry eye and mood disorders, depression, anxiety, and suicide. Eligible studies underwent quality assessment using the Newcastle-Ottawa Scale. Meta-analysis was performed using STATA 15.0. Fixed- and random-effects models were computed based on the presence of heterogeneity. Thirty-two studies were included, with 31 reporting on depression and 19 on anxiety. Meta-analysis results found a depression prevalence of 40% (CI: [0.29, 0.52]) in DED patients, with 1.81 times higher odds of prevalence compared to controls (CI: [1.61, 2.02]). Prevalence of anxiety was 39% (CI: [0.15, 0.64]), with 2.32 times higher odds of prevalence compared to controls (CI: [1.67, 3.23]). Depression scores were significantly higher in patients with DED in all studies. Anxiety scores were significantly higher in DED patients in studies using all scales except the Hospital Anxiety and Depression Scale-Anxiety Subscale. DED symptom scores were significantly associated with depression (ES = 0.43; CI: [0.31, 0.55]) and anxiety (ES = 0.41; CI: [0.32, 0.50]) scores. In conclusion, depression and anxiety are more prevalent and severe in DED patients and are correlated with dry eye symptoms but not signs. These findings highlight the interrelationship between these disorders and have important implications for providing appropriate care to these patients.

Plasma protein profiling analysis in patients with atrial fibrillation before and after three different ablation techniques.

Background: There are controversies on the pathophysiological alteration in patients with atrial fibrillation (AF) undergoing pulmonary vein isolation using different energy sources. Objectives: We evaluated the changes in plasma proteins in acute phase post-ablation in patients receiving cryoballoon ablation, radiofrequency balloon ablation, or radiofrequency ablation. Methods: Blood samples from eight healthy controls and 24 patients with AF were taken on the day of admission, day 1, and day 2 post-ablation and analyzed by the Olink proximity extension assay. Proteins were identified and performed with enrichment analysis. Protein-protein interaction network and module analysis were conducted using Cytoscape software. Results: Of 181 proteins, 42 proteins in the cryoballoon group, 46 proteins in the radiofrequency balloon group, and 43 proteins in the radiofrequency group significantly changed after ablation. Most of the proteins altered significantly on the first day after ablation. Altered proteins were mainly involved in cytokine-cytokine receptor interaction. Both balloon-based ablations showed a similar shift toward enhancing cell communication and regulation of signaling while inhibiting neutrophil chemotaxis. However, radiofrequency ablation presented a different trend. Seed proteins, including osteopontin, interleukin-6, interleukin-10, C-C motif ligand 8, and matrix metalloproteinase-1, were identified. More significant proteins associated with hemorrhage and coagulation were selected in balloon-based ablations by machine learning. Conclusion: Plasma protein response after three different ablations in patients with AF mainly occurred on the first day. Radiofrequency balloon ablation shared similar alteration in protein profile as cryoballoon ablation compared with radiofrequency ablation, suggesting that lesion size rather than energy source is the determinant in pathophysiological responses to the ablation.

Pro-inflammatory HDL in women with obesity and nonalcoholic steatohepatitis.

BACKGROUND: Individuals with non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), are at increased risk for cardiovascular events, independent of traditional risk factors. Limited data on pro-inflammatory high density lipoprotein (HDL) in NASH exists in the literature. We hypothesized that HDL from individuals with NASH would be more pro-inflammatory than HDL from individuals without NASH. METHODS: Study participants were individuals with obesity who had undergone bariatric surgery with wedge liver biopsy. Using HDL isolated from serum obtained from study participants at the time of surgery, HDL-elicited macrophage cytokine expression (TNF-α, IL-1ß, and IL-6) from THP-1 macrophages, HDL-associated receptor expression (ABCA1 and ABCG1) from apolipoprotein E deficient (apo E-/-) mouse peritoneal macrophages, and isolevuglandin (isoLG) modified HDL were measured. RESULTS: 11 women with NASH and 15 women without NASH were included in the study. Both TNF-α (P = 0.032) and IL-1ß (P = 0.029) were significantly more expressed by THP-1 macrophages exposed to HDL from women with NASH compared to women without NASH. ABCA1 and ABCG1 expression by apo E-/- mouse peritoneal macrophages was not significantly different when exposed to HDL from either women with NASH or women without NASH. IsoLG-modified HDL isolated from the serum of women with NASH trended higher than women without NASH. CONCLUSION: Our study suggests a more pro-inflammatory HDL in women with obesity and NASH compared to women with obesity and without NASH.

Incorporating teledermatology into emergency medicine.

OBJECTIVE: The aim of the present study was to investigate the feasibility of using a store-and-forward Skin Emergency Telemedicine Service (SETS) to provide rapid specialist diagnostic and management advice for dermatological cases in an ED. METHODS: This pilot study was conducted at the Princess Alexandra Hospital between August 2008 and August 2009. Study subjects were consenting patients over 18 years of age who presented with a dermatological condition to the ED. The ED doctor sent the patient's history, examination findings and the digital images of the skin conditions to a secure email address, which automatically forwarded this to the teledermatologist. The teledermatologist reviewed the cases and sent advice on diagnosis and management to the referring ED doctor via email and/or telephone. Face-to-face follow-up consultations with the patients were conducted within 2 weeks. The diagnostic and management concordance between ED doctors, teledermatologists and reviewing dermatologists were analysed. RESULTS: A total of 60 patients participated in the present study. SETS provided a rapid response with 56 (93%) of ED consultations receiving a dermatology opinion within 2 h. Face-to-face follow up occurred in 50 patients (83%). Statistical analysis showed significant levels of agreement between tele-diagnosis and ED diagnosis of 71.2% (Kappa 0.42) and tele-diagnosis and final clinical diagnosis of 98% (Kappa: 0.93). The clinical management concordance was 96% in complete agreement and 4% in relative agreement between the teledermatologists and reviewing dermatologists, based on chart review. CONCLUSION: The present study has shown that SETS can provide rapid and accurate diagnostic and treatment advice from a specialist for dermatological presentations to the ED.

A randomized controlled trial of an interactive voice response telephone system and specialist nurse support for childhood asthma management.

OBJECTIVES: To evaluate the effects of an automated interactive voice response system (IVR) and Specialist Nurse Support to reduce health care utilization and improve health-related quality of life in children with asthma. STUDY DESIGN: A randomized controlled trial in 121 children with doctor-diagnosed asthma and an acute presentation with asthma in the previous 12 months aged between 3 and 16 years. Children were randomized to one of three groups for a 6-month intervention receiving asthma education and management support from a Specialist Nurse by telephone or e-mail (N = 41), from IVR (N = 39), or receiving usual care (control group; N = 41). Outcomes included health care utilization and use of oral steroid rescue. Health-related quality of life (HRQOL) data using the Pediatric Asthma Quality of Life Questionnaire and Pediatric Quality of Life Inventory were collected at baseline and at the end of the study. RESULTS: There was no statistically significant benefit identified for either the IVR or the Nurse Support interventions for health care utilization, use of oral steroid rescue, or HRQOL compared with controls. Relative to controls, the incremental costs were -A$225.73 (95% confidence interval [CI]: -A$840, A$391) per child for the Nurse Support intervention and -A$451.45 (-A$1075, A$173) per child for IVR. The results were most sensitive to the frequency of admissions to hospital. CONCLUSION: This study suggested that both IVR and Nurse Support interventions may be cost-saving from a health system perspective, with IVR providing the greatest benefit and this pilot study provides a strong basis for developing larger trials with longer follow-up.

A cost minimisation analysis of a telepaediatric otolaryngology service.

BACKGROUND: Paediatric ENT services in regional areas can be provided through telemedicine (tele-ENT) using videoconferencing or with a conventional outpatient department ENT service (OPD-ENT) in which patients travel to see the specialist. The objective of this study was to identify the least-cost approach to providing ENT services for paediatric outpatients. METHODS: A cost-minimisation analysis was conducted comparing the annual costs of the two modes of service provided by the Royal Children's Hospital (RCH) in Brisbane. Activity records were reviewed to analyse volume of activity during a 12 month period in 2005, i.e. number of clinics, duration of clinics, number of consultations via telemedicine and in outpatient clinics, diagnoses, and travel related information. A sensitivity analysis was conducted using factors where there was some uncertainty or potential future variation. RESULTS: During the study period, 88 ENT consultations were conducted via videoconference for 70 patients at Bundaberg Base Hospital. 177 ENT consultations were conducted at the RCH for 117 patients who had travelled from the Bundaberg region to Brisbane. The variable cost of providing the tele-ENT service was A$108 per consultation, compared with A$155 per consultation for the conventional outpatient service. Telemedicine was cheaper when the workload exceeded 100 consultations per year. If all 265 consultations were conducted as tele-ENT consultations, the cost-savings would be $7,621. CONCLUSION: The cost-minimisation analysis demonstrated that under the circumstances described in this paper, the tele-ENT service was a more economical method for the health department of providing specialist ENT services.

Accuracy of paediatric echocardiographic transmission via telemedicine.

We evaluated the accuracy of realtime echocardiography studies conducted via telemedicine (at 384 kbit/s) and prerecorded video studies, by comparing the results with subsequent in-person echocardiography examination performed at follow-up. Between January 2002 and December 2004, there were 769 paediatric echo studies of patients aged one day to 19 years by telemedicine. There were three cases (0.4%) in which the study could not be successfully transmitted in realtime due to ISDN line or equipment failure. These were recorded, then transmitted and reviewed within 24 h. A normal heart was demonstrated in 272 studies (35%). A non-urgent congenital heart defect (CHD) was detected in 311 studies (41%). A critical cardiac abnormality was identified in 25 studies (3% of the total). Sixty-seven studies were repeated in person at the tertiary centre. All but one of the follow-up echocardiograms confirmed our initial telemedicine diagnosis (99% sensitivity). There were 655 videorecorded studies delivered to the tertiary centre between February 2002 and November 2003. Thirty-two patients had a repeated echocardiogram performed there. There were either discrepancies or lack of diagnostic clarity in 12 studies (38%) compared with on-site echo evaluations. This suggests that echocardiography evaluation using videorecordings may be less accurate than via realtime telemedicine.

Evaluation of the Western Australian Department of Health telehealth project.

In 1999, the Department of Health in Western Australia began a telehealth project, which finished in 2004. The 75 videoconferencing sites funded by the project were part of a total state-wide videoconference network of 104 sites. During the period from January 2002 to December 2003, a total of 3,266 consultations, case reviews and patient education sessions took place. Clinical use grew to 30% of all telehealth activity. Educational use was approximately 40% (1,416 sessions) and management use was about 30% (1,031 sessions). The average overhead cost per telehealth session across all regions and usage types was 192 Australian dollars. Meaningful comparisons of the results of the present study with other public health providers were difficult, because many of the available Websites on telehealth were out of date. Despite the successful use of telehealth to deliver clinical services in Western Australia, sustaining the effort in the post-project phase will present significant challenges.