Improving Left Atrial Appendage Occlusion Device Size Determination by Three-Dimensional Printing-Based Preprocedural Simulation.

BACKGROUND: The two-dimensional (2D)-based left atrial appendage (LAA) occluder (LAAO) size determination by using transesophageal echocardiography (TEE) is limited by the structural complexity and wide anatomical variation of the LAA. OBJECTIVE: This study aimed to assess the accuracy of the LAAO size determination by implantation simulation by using a three-dimensional (3D)-printed model compared with the conventional method based on TEE. METHODS: We retrospectively reviewed patients with anatomically and physiologically properly implanted the Amplatzer Cardiac Plug and Amulet LAAO devices between January 2014 and December 2018 by using the final size of the implanted devices as a standard for size prediction accuracy. The use of 3D-printed model simulations in device sizing was compared with the conventional TEE-based method. RESULTS: A total of 28 cases with the percutaneous LAA occlusion were reviewed. There was a minimal difference [-0.11 mm; 95% CI (-0.93, 0.72 mm); P = 0.359] between CT-based reconstructed 3D images and 3D-printed left atrium (LA) models. Device size prediction based on TEE measurements showed poor agreement (32.1%), with a mean difference of 2.3 ± 3.2 mm [95% CI (-4.4, 9.0)]. The LAAO sizing by implantation simulation with 3D-printed models showed excellent correlation with the actually implanted LAAO size (r = 0.927; bias = 0.7 ± 2.5). The agreement between the 3D-printed and the implanted size was 67.9%, with a mean difference of 0.6 mm [95% CI (-1.9, 3.2)]. CONCLUSION: The use of 3D-printed LA models in the LAAO size determination showed improvement in comparison with conventional 2D TEE method.

Anmyungambi Decoction Ameliorates Obesity through Activation of Non-Shivering Thermogenesis in Brown and White Adipose Tissues.

Obesity is a burden to global health. Non-shivering thermogenesis of brown adipose tissue (BAT) and white adipose tissue (WAT) is a novel strategy for obesity treatment. Anmyungambi (AMGB) decoction is a multi-herb decoction with clinical anti-obesity effects. Here, we show the effects of AMGB decoction using high-fat diet (HFD)-fed C57BL6/J mice. All four versions of AMGB decoction (100 mg/kg/day, oral gavage for 28 days) suppressed body weight gain and obesity-related blood parameters in the HFD-fed obese mice. They also inhibited adipogenesis and induced lipolysis in inguinal WAT (iWAT). Especially, the AMGB-4 with 2:1:3:3 composition was the most effective; thus, further studies were performed with the AMGB-4 decoction. The AMGB-4 decoction displayed a dose-dependent body weight gain suppression. Serum triglyceride, total cholesterol, and blood glucose decreased as well. In epididymal WAT, iWAT, and BAT, the AMGB-4 decoction increased lipolysis markers. Additionally, the AMGB-4 decoction-fed mice showed an increased non-shivering thermogenic program in BAT and iWAT. Excessive reactive oxygen species (ROS) and suppressed antioxidative factors induced by the HFD feeding were also altered to normal levels by the AMGB-4 decoction treatment. Overall, our study supports the clinical use of AMGB decoction for obesity treatment by studying its mechanisms. AMGB decoction alleviates obesity through the activation of the lipolysis-thermogenesis program and the elimination of pathological ROS in thermogenic adipose tissues.

Characteristics of fractionated drop-in liquid fuel of plastic wastes from a commercial pyrolysis plant.

Pyrolysis is a waste conversion technology to solve an increasing plastic waste issue worldwide. Waste plastic pyrolysis fuel from a commercial-scale pyrolysis plant (10 ton/day) was comprehensively investigated using distillation methods by separating the crude pyrolysis fuel to isolate the diesel-like pyrolysis fuel fraction (C9-C25 for fraction 2 + fraction 3, middle distillate). Other fractions were C5-C10 for the light distillate (fraction 1), and >C25 for the heavy distillate (fraction 4). The relationship between the fuel boiling point and liquid vapor temperature were found for designing a scaled-up oil separation process. The diesel grade pyrolysis fuel fraction comprised approximately 70-80% of the crude pyrolysis fuel, wherein it had values of 43-45 MJ/kg, 1-6 cSt, and 12-42 mgKOH/goil. Meanwhile, the elemental ratios of the crude pyrolysis oil improved to 0.1 for O/C and 1.9 for H/C after separation, close to petroleum fuels (0.0 O/C and 1.95 H/C). The highest relative chemical composition was the olefins (46% in fraction 1 and 41% in fraction 2), whereas the paraffin was approximately 15-20% in the light fraction. Finally, the potential CO2 reduction for the plastic waste-to-energy process was evaluated, revealing that a total of 0.26 tCO2/tonwaste of emissions could be avoided during the waste plastic pyrolysis process.

Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation.

Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer's disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.

Ephedrae Herba in combination with herbal medicine (Zhizichi decoction and Phellodendri Cortex) for weight reduction: a case series.

BACKGROUNDS: Ephedrae Herba is widely used to treat obesity. There is a concern for adverse events (AEs) using it and we need to develop strategies to attenuate it without its effectiveness for weight-reducing potential. We investigated the effects of a combination of Ephedra Herba with Zhizichi decoction and Phellodendri Cortex (Anmyungambi (AMGB) decoction) in reducing the incidence of Ephedra Herba-related AEs. METHODS: We performed a retrospective chart review from a clinical case series of patients visiting the Jaonmi Korean Medicine Clinic (Seoul, Korea). The inclusion criteria was patients who were prescribed AMGB decoction, (containing Ephedrae Herba, Phellodendri Cortex, and Zhizichi decoction [Gardeniae Fructus, and Glycine Semen Preparata] in different proportions) for weight reduction. Exclusion of Phellodendri Cortex in the original AMGB preparation was allowed; conventional medications, acupuncture, and dietary supplements were not allowed. The primary outcome was absolute weight loss at the end of treatment. RESULTS: Twenty-seven patients (6 men and 21 women), aged 18-75 years (mean age, 42.6 ± 11.1 years) and the average treatment duration was 39.4 days. Absolute weight loss at the end of treatment was 4.49 ± 2.40 kg. Fifteen patients lost more than 5% weight (55.6%). Treatment >45 days resulted in significantly greater weight loss compared to treatment <30 days (p < 0.001). Not severe AEs were reported in 16 patients including constipation, fatigue, etc. CONCLUSION: A combination of Ephedra Herba with Zhizichi decoction and Phellodendri Cortex may be a safe and effective treatment for weight reduction in obese and overweight patients.

Pimozide reduces toxic forms of tau in TauC3 mice via 5' adenosine monophosphate-activated protein kinase-mediated autophagy.

In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non-mTOR pathways is a new option for autophagy-based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK-Unc-51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase-cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40-insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR-independent AMPK-ULK1 axis.

APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis.

Despite the fact that the epidermal growth factor (EGF) family member ERBB3 (HER3) is deregulated in many cancers, the list of ERBB3-interacting partners remains limited. Here, we report that the Apaf-1-interacting protein (APIP) stimulates heregulin-ß1 (HRG-ß1)/ERBB3-driven cell proliferation and tumorigenesis. APIP levels are frequently increased in human gastric cancers and gastric cancer-derived cells. Cell proliferation and tumor formation are repressed by APIP downregulation and stimulated by its overexpression. APIP's role in the ERBB3 pathway is not associated with its functions within the methionine salvage pathway. In response to HRG-ß1, APIP binds to the ERBB3 receptor, leading to an enhanced binding of ERBB3 and ERBB2 that results in sustained activations of ERK1/2 and AKT protein kinases. Furthermore, HRG-ß1/ERBB3-dependent signaling is gained in APIP transgenic mouse embryonic fibroblasts (MEFs), but not lost in Apip-/- MEFs. Our findings offer compelling evidence that APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis, warranting future development of therapeutic strategies for ERBB3-driven gastric cancer.

Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide analogue-naïve and nucleos(t)ide analogue-experienced chronic hepatitis B patients.

BACKGROUND/AIMS: This study investigated the antiviral effects of tenofovir disoproxil fumarate (TDF) monotherapy in nucleos(t)ide analogue (NA)-naive and NA-experienced chronic hepatitis B (CHB) patients. METHODS: CHB patients treated with TDF monotherapy (300 mg/day) for ≥12 weeks between December 2012 and July 2014 at a single center were retrospectively enrolled. Clinical, biochemical, and virological parameters were assessed every 12 weeks. RESULTS: In total, 136 patients (median age 49 years, 96 males, 94 HBeAg positive, and 51 with liver cirrhosis) were included. Sixty-two patients were nucleos(t)ide (NA)-naïve, and 74 patients had prior NA therapy (NA-exp group), and 31 patients in the NA-exp group had lamivudine (LAM)-resistance (LAM-R group). The baseline serum hepatitis B virus (HBV) DNA level was 4.9±2.3 log IU/mL (mean±SD), and was higher in the NA-naïve group than in the NA-exp and LAM-R groups (5.9±2.0 log IU/mL vs 3.9±2.0 log IU/mL vs 4.2±1.7 log IU/mL, P<0.01). The complete virological response (CVR) rate at week 48 in the NA-naïve group (71.4%) did not differ significantly from those in the NA-exp (71.3%) and LAM-R (66.1%) groups. In multivariate analysis, baseline serum HBV DNA was the only predictive factor for a CVR at week 48 (hazard ratio, 0.809; 95% confidence interval, 0.729-0.898), while the CVR rate did not differ with the NA experience. CONCLUSIONS: TDF monotherapy was effective for CHB treatment irrespective of prior NA treatment or LAM resistance. Baseline serum HBV DNA was the independent predictive factor for a CVR.

Difference in adenoma detection rates according to colonoscopic withdrawal times and the level of expertise.

BACKGROUND/AIMS: Adequate screening colonoscopy in the general population decreases the mortality associated with colorectal cancer through detection and removal of adenomatous polyps. Prolonged colonoscopic withdrawal times (>6 min) are reportedly beneficial for adenoma detection rates (ADRs). However, the quality of the endoscopist compared with colonoscopic withdrawal times is not known. The aims of this study were to investigate the difference in ADRs between trainees and experienced examiners. METHODS: A total of 967 consecutive patients who underwent screening colonoscopy in a single University hospital from June 2010 to November 2011 were enrolled in this prospective observational study. Colonoscopy was performed by four experienced staff and seven gastroenterology fellows. RESULTS: Seven gastroenterology fellows performed 633 colonoscopies and four experienced staff performed 334 colonoscopies. The overall detection rates of colorectal adenoma were 31.5% with ADRs of fellows and staff of 29.4% and 35.6%, respectively (p=0.047). Fellows also showed lower advanced ADRs (5.7% vs. 9.9%, p=0.016), and fellows had longer mean withdrawal times than staff (12.4±B1;4.9 min vs. 8.2±B1;4.1 min, p<0.001). Multivariate analysis showed significantly increased ADRs and advanced ADRs for staff compared with fellows (adjusted OR 2.41, 95% CI 1.70-3.43; adjusted OR 2.55, 95% CI 1.47-4.45, respectively). CONCLUSIONS: ADRs were significantly lower when colonoscopy was performed by trainees, although withdrawal times were longer than those of staff. Our results demonstrated that the quality of colonoscopy, as measured by ADRs, may be improved by experienced examiners.

[A case of autoimmune hepatitis following acute hepatitis A].

The pathogenesis of autoimmune hepatitis (AIH) is unclear, but viral infections have been proposed as a potential trigger in patients with genetic predisposition. We report a case of AIH following acute hepatitis A (AHA). A 57-year-old woman presented with fatigue and pitting edema for last 3 months. She had been diagnosed as an AHA 15 months ago based on clinical features, biochemical tests and positive HAV IgM antibody at a local clinic. Her biochemical tests was normalized one month after AHA diagnosis, but the serum levels of aminotransferase started to rise four months after AHA diagnosis. Antinuclear antibody was positive at a titer of 1:40, and anti-smooth muscle antibody was also positive. Hypergammaglobulinemia and liver pathology were typical for AIH. The patients had a score of 17 according to the International Autoimmune Hepatitis Group's system. She was given prednisolone and azathioprine and showed complete response to immunosuppressive therapy. The present case is the first report on AIH triggered by AHA in Korea.

DNA array reveals altered gene expression in response to focal cerebral ischemia.

The gene expression profile in the cortex was analyzed in a rat model of focal cerebral ischemia by use of cDNA array. It was attempted to monitor changes of gene expression and to profile them into functional classification between ipsilateral and contralateral cortex at 6h after middle cerebral artery (MCA) occlusion. Seventy-one genes out of 1174 genes were significantly modulated by ischemia. Metabolism-, cell communication- and signal transduction-related genes were down-regulated, whereas genes involved in stress response were markedly increased. Besides numerous established ischemia-induced gene products such as macrophage inflammatory protein-1 alpha (MIP-1 alpha), orphan nuclear receptor Nurr 77, secretogranin II (SCG-II), and tumor necrosis factor-alpha (TNF-alpha), several genes were identified which have not previously been shown to be modulated following focal ischemia; these genes include interferon-induced protein (IFN-IP), neurodegeneration-associated protein-1 (NDGAP-1), and neuronal pentraxin receptor (NPR). The RT-PCR analyses of these genes at various time points revealed that mRNA level of IFN-IP was up-regulated, while NDGAP-1 and NPR were transcriptionally down-regulated. The results suggest of the involvement of these genes in neuronal cell damage caused by ischemia and the potential use as targets for the development of preventives/therapeutics of brain stroke.