Establishing a Swine Model of Post-myocardial Infarction Heart Failure for Stem Cell Treatment

Although advances have been achieved in the treatment of heart failure (HF) following myocardial infarction (MI), HF following MI remains one of the major ...

University of Hong Kong

Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels.

Laminopathy is a disease closely related to deficiency of the nuclear matrix protein lamin A/C or failure in prelamin A processing, and leads to accumulation of the misfold protein causing progeria. The resultant disrupted lamin function is highly associated with abnormal nuclear architecture, cell senescence, apoptosis, and unstable genome integrity. To date, the effects of loss in nuclear integrity on the susceptible organ, striated muscle, have been commonly associated with muscular dystrophy, dilated cardiac myopathy (DCM), and conduction defeats, but have not been studied intensively. In this review, we aim to summarize recent breakthroughs in an in vivo laminopathy model and in vitro study using patient-specific human induced pluripotent stem cells (iPSCs) that reproduce the pathophysiological phenotype for further drug screening. We describe several in-vivo transgenic mouse models to elucidate the effects of Lmna H222P, N195K mutations, and LMNA knockout on cardiac function, in terms of hemodynamic and electrical signal propagation; certain strategies targeted on stress-related MAPK are mentioned. We will also discuss human iPSC cardiomyocytes serving as a platform to reveal the underlying mechanisms, such as the altered mechanical sensation in electrical coupling of the heart conduction system and ion channel alternation in relation to altered nuclear architecture, and furthermore to enable screening of drugs that can attenuate this cardiac premature aging phenotype by inhibition of prelamin misfolding and oxidative stress, and also enhancement of autophagy protein clearance and cardiac-protective microRNA.

Recent advances in animal and human pluripotent stem cell modeling of cardiac laminopathy.

Job strain is a major concern in view of its effects among civil servants associated with job burnout, mental fatigue and chronic diseases. The objective of this study was to assess the job strain level among civil servants and examine the effect of job strain on job burnout, mental fatigue and the resulting chronic diseases. A cross-sectional study with a representative sample consisting of 5000 civil servants was conducted from March to August 2014. Using a structured questionnaire, the job strain level, job burnout and mental fatigue were measured by using the Personal Strain Questionnaire (PSQ), Maslach Burnout Inventory (MBI) and Multidimensional Fatigue Inventory (MFI-20), respectively. Overall, 33.8% of the civil servants were found to be afflicted with high and moderate job strain. The characteristics of most of the civil servants with a higher-job strain level were as follows: female, Uygur, lower educational level and job title rank, shorter working experience, married marital status, and lower income level. Civil servants suffering from chronic disease mainly had hypertension and coronary heart disease, which accounted for 18.5% of the diseases. Civil servants with a high-job strain level exhibited higher rates of burnout, mental fatigue scores and incidence of chronic diseases. There was a multiple linear regression model composed of three predictor variables in job burnout, which accounted for 45.0% of its occurrence: female gender, lower-income level, higher-job strain in civil servants, the greater the rate of job burnout was. Four factors-male gender, lower-job title rank, higher-job strain, shorter-job tenure of civil servants-explained 25.0% of the mental fatigue model. Binary logistic regression showed that intermediate-rank employees (OR = 0.442, 95% CI: 0.028-0.634;  < 0.05), job tenure of 10-20 years (OR = 0.632, 95% CI: 0.359-0.989;  < 0.05), and low-job strain (OR = 0.657, 95% CI: 0.052-0.698;  < 0.05) were all associated with significantly lower odds of chronic disease. The risk of chronic disease was higher in civil servants with high-job burnout scores and mental fatigue scores compared with civil servants with lower scores (OR = 1.139, 95% CI: 1.012-3.198; OR = 1.697, 95% CI: 1.097-2.962). These data provide evidence for the effects of job strain on job burnout, mental fatigue and chronic diseases among civil servants.

Effect of Job Strain on Job Burnout, Mental Fatigue and Chronic Diseases among Civil Servants in the Xinjiang Uygur Autonomous Region of China.

Nonalcoholic steatohepatitis (NASH) is one of the top 3 indications for liver transplantation (LT) in Western countries. It is unknown whether renal dysfunction at the time of LT has any effect on post-LT outcomes in recipients with NASH. From the United Network for Organ Sharing-Standard Transplant Analysis and Research data set, we identified 4088 NASH recipients who received deceased donor LT. We divided our recipients a priori into 3 categories: group 1 with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m at the time of LT and/or received dialysis within 2 weeks preceding LT (n = 937); group 2 with recipients who had eGFR ≥30 mL/minute/1.73 m and who did not receive renal replacement therapy prior to LT (n = 2812); and group 3 with recipients who underwent simultaneous liver-kidney transplantation (n = 339). We examined the association of pretransplant renal dysfunction with death with a functioning graft, all-cause mortality, and graft loss using competing risk regression and Cox proportional hazards models. The mean ± standard deviation age of the cohort at baseline was 58 ± 8 years, 55% were male, 80% were Caucasian, and average exception Model for End-Stage Liver Disease score was 24 ± 9. The median follow-up period was 5 years (median, 1816 days; interquartile range, 1090-2723 days). Compared with group 1 recipients, group 2 recipients had 19% reduced trend for risk for death with a functioning graft (subhazard ratio [SHR], 0.81; 95% confidence interval [CI], 0.64-1.02) and similar risk for graft loss (SHR, 1.25; 95% CI, 0.59-2.62), whereas group 3 recipients had similar risk for death with a functioning graft (SHR, 1.23; 95% CI, 0.96-1.57) and graft loss (SHR, 0.18; 95% CI, 0.02-1.37) using an adjusted competing risk regression model. In conclusion, recipients with preserved renal function before LT showed a trend toward lower risk of death with a functioning graft compared with SLKT recipients and those with pretransplant severe renal dysfunction in patients with NASH.

Association of Pretransplant Renal Function With Liver Graft and Patient Survival After Liver Transplantation in Patients With Nonalcoholic Steatohepatitis.

People living in rural China are more frequently exposed to some specific risk factors which made stillbirth rate higher than urban areas. National Free Preconception Health Examination Project was launched to investigate these risk factors and collected a representative sample of 248501 participants from 31 provinces in China from 2010 to 2013. Parental risk factors were ascertained twice before and during pregnancy respectively by questionnaires. Stillbirth or live birth were recorded by trained physicians. In the analysis, nested case-control study was conducted, and propensity score matching method was used to adjust the confounding. Multi-level logistic regression was used to fit for multi-level sampling. The overall stillbirth rate was 0.35% in rural China, it was higher in North (0.42%) and West (0.64%) areas. Maternal exposure to pesticide (OR (95%CI 1.06, 3.39)), hypertension (OR = 1.58 (95%CI 1.07, 2.34)), lack of appetite for vegetables (OR = 1.99 (95%CI 1.00, 3.93)), stress (compared with no pressure, OR of a little pressure was 1.34(95% CI 1.02, 1.76)); paternal exposure to smoking (OR = 1.22 (95% CI 1.02, 1.46)), organic solvents (OR = 1.64 (95% CI 1.01, 2.69)) were found independent risk factors of stillbirth. Folacin intake 3 months before pregnancy (OR = 0.72 (95%) CI 0.59, 0.89), folacin intake 1-2 months before pregnancy (OR = 0.71 (95% CI 0.55, 0.92)), folacin intake after pregnancy (OR = 0.81 (95% CI 0.65, 1.02) for) were protect factors of stillbirth. Maternal pesticide exposure, lack of vegetables, stress, paternal smoking and exposure to organic solvents were risk factors of stillbirth. Folic acid intake was protective factor of stillbirth, no matter when the intake began.

Risk factors of stillbirth in rural China: A national cohort study.

Optimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF.

Potent immunomodulation and angiogenic effects of mesenchymal stem cells versus cardiomyocytes derived from pluripotent stem cells for treatment of heart failure.

Morbid obesity is considered a relative contraindication for liver transplantation (LT). We investigated if body mass index (BMI; lean versus obese) is a risk factor for post-LT graft and overall survival in nonalcoholic steatohepatitis (NASH) and non-NASH patients. Using the United Network for Organ Sharing (UNOS) database, LT recipients from January 2002 to June 2013 (age ≥18 years) with follow-up until 2017 were included. The association of BMI categories calculated at LT with graft and overall survival after LT were examined. After adjusting for confounders, all obesity cohorts (overweight and class 1, class 2, and class 3 obesity) among LT recipients for NASH had significantly reduced risk of graft and patient loss at 10 years of follow-up compared with the lean BMI cohort. In contrast, the non-NASH group of LT recipients had no increased risk for graft and patient loss for overweight, class 1, and class 2 obesity groups but had significantly increased risk for graft (P < 0.001) and patient loss (P = 0.005) in the class 3 obesity group. In this retrospective analysis of the UNOS database, adult recipients selected for first LT and NASH patients with the lowest BMI have the worse longterm graft and patient survival as opposed to non-NASH patients where the survival was worse with higher BMI.

Posttransplant Outcome of Lean Compared With Obese Nonalcoholic Steatohepatitis in the United States: The Obesity Paradox.

Expert consensus on tubeless video-assisted thoracoscopic surgery (Guangzhou).

Expert consensus on spontaneous ventilation video-assisted thoracoscopic surgery in primary spontaneous pneumothorax (Guangzhou).

Parental exposure to tobacco smoke has been associated with an increased risk of stillbirth, while only a few studies took the overall parental tobacco exposure status into consideration. We aim to explore the relationship of parental smoking and passive smoking before and during pregnancy with stillbirth in a large Chinese rural cohort.

Yu Jiang

Cardiology Division,
Department of Medicine,
Queen Mary Hospital,
Cardiology Division, Department of Medicine, Queen Mary Hospital

University of Hong Kong

Establishing a Swine Model of Post-myocardial Infarction Heart Failure for Stem Cell Treatment

Yu Jiang

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Cardiology Division,Department of Medicine,Queen Mary Hospital,Cardiology Division, Department of Medicine, Queen Mary Hospital

University of Hong Kong

Establishing a Swine Model of Post-myocardial Infarction Heart Failure for Stem Cell Treatment

Cardiology Division,
Department of Medicine,
Queen Mary Hospital,
Cardiology Division, Department of Medicine, Queen Mary Hospital