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Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation

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World Journal of Gastroenterology 2020年第34期26卷 5101-5117页

作者： David Fernández-Ramos Fernando Lopitz-Otsoa Laura Delacruz-Villar Jon Bilbao Martina Pagano Laura Mosca Maider Bizkarguenaga Marina Serrano-Macia Mikel Azkargorta Marta Iruarrizaga-Lejarreta Jesús Sot Darya Tsvirkun Sebastiaan martijn van Liempd Felix M Goni cristina Alonso María Luz Martínez-chantar Felix Elortza Liat Hayardeny Shelly c Lu JoséM Mato Precision Medicine and Metabolism Laboratory Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160BizkaiaSpain cIBERehd-centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas Madrid 28029Spain Department of Precision Medicine University of Campania"Luigi Vanvitelli"Naples 80138Italy Liver Disease Laboratory Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160Spain Proteomics Platform Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160Spain OWL Metabolomics Derio 48160Spain Instituto Biofisika(UPV/EHU CSIC)Leioa 48940SpainDepartamento de Bioquímica y Biología MolecularUniversidad del País VascoLeioa 48940Spain Pre-clinical and chemistry Manufacturing and ControlsGalmed PharmaceuticalsTel Aviv 6578317Israel Metabolomics Platform Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160Spain Division of Digestive and Liver Diseases Cedars-Sinai Medical CenterLos AngelesCA 90048United States

BAcKGROUND Arachidyl amido cholanoic acid(Aramchol)is a potent downregulator of hepatic stearoyl-coA desaturase 1(ScD1)protein expression that reduces liver triglycerides and fibrosis in animal models of *** a phase IIb clinical trial in patients with nonalcoholic steatohepatitis(NASH),52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c,an indicator of glycemic *** To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model[induced with a 0.1%methionine and choline deficient diet(0.1McD)]after treatment with *** Isolated primary mouse hepatocytes were incubated with 20μmol/L Aramchol or vehicle for 48 ***,analyses were performed including Western blot,proteomics by mass spectrometry,and fluxomic analysis with 13c-uniformly labeled *** the in vivo part of the study,male c57BL/6J mice were randomly fed a control or 0.1McD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 *** metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related *** combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORc1 was decreased by Aramchol in *** translated into changes in the content of their downstream targets including proteins involved in fatty acid(FA)synthesis and oxidation[PAccα/β(S79),ScD1,cPT1A/B,HADHA,and HADHB],oxidative phosphorylation(NDUFA9,NDUFB11,NDUFS1,NDUFV1,ETFDH,and UQcRc2),tricarboxylic acid(TcA)cycle(MDH2,SUcLA2,and SUcLG2),and ribosome(P-p70S6K[T389]and P-S6[S235/S236]).Flux experiments with 13cuniformely labeled glucose showed that TcA cycle cataplerosis was reduced by Aramchol in hepatocytes,as indicated by the increase in the number of rounds that malate remained in the TcA ***,liver metabolomic analysis showed

关键词： Nonalcoholic fatty liver disease Steatohepatitis Methionine and choline deficient diet Tricarboxylic acid cycle Hemoglobin A1c Stearoyl-coA desaturase 1

Value of a comprehensive geriatric assessment for predicting one-year outcomes in patients undergoing transcatheter aortic valve implantation: results from the cGA-TAVI multicentre registry

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Journal of Geriatric cardiology 2019年第6期16卷 468-477页

作者： martijn S.van Mourik Nathalie van der Velde Giulio Mannarino Marie-Pierre Thibodeau Jean-Bernard Masson Gennaro Santoro Jan Baan Sofie Jansen Jana Kurucova Martin Thoenes cornelia Deutsch ANDreas W.Schoenenberger ANDrea Ungar Peter Bramlage M Marije Vis Department of cardiology Amsterdam UMC University of Amsterdam Department of Internal Medicine Section of Geriatric Medicine Amsterdam UMC University of Amsterdam Geriatric Intensive care Unit Department of Geriatrics and Medicine Careggi Hospital and University of Florence centre Hospitalier de l’Université de Montréal Edwards Lifesciences Edwards Lifesciences Nyon Switzerland Institute for Pharmacology und Preventive Medicine Department of Geriatrics Inselspital Bern University Hospital University of Bern Switzerland

Background In a three-month report from the cGA-TAVI registry, we found the Multidimensional Prognostic Index (MPI) and Short Physical Performance Battery (SPPB) to be of value for predicting short-term outcomes in elderly patients undergoing transcatheter aortic valve implantation (TAVI). In the present analysis, we examined the association of these tools with outcomes up to one year post-TAVI. Methods cGA-TAVI is an international, observational registry of geriatric patients undergoing TAVI. Patients were assessed using the MPI and SPPB. Efficacy of baseline values and any postoperative change for predicting outcome were established using logistic regression. Kaplan- Meier analysis was carried out for each comprehensive geriatric assessment tool, with survival stratified by risk category. Results One year after TAVI, 14.1% of patients deceased, while 17.4% met the combined endpoint of death and/or non-fatal stroke, and 37.7% the combined endpoint of death and/or hospitalisation and/or non-fatal stroke. A high-risk MPI score was associated with an increased risk of all-cause mortality (aOR = 36.13, 95% cI: 2.77–470.78, P = 0.006) and death and/or non-fatal stroke (aOR = 10.10, 95% cI: 1.48–68.75, P = 0.018). No significant associations were found between a high-risk SPPB score and mortality or two main combined endpoints. In contrast to a worsening SPPB, an aggravating MPI score at three months post-TAVI was associated with an increased risk of death and/or non-fatal stoke at one year (aOR = 95.16, 95% cI: 3.41–2657.01). conclusions The MPI showed value for predicting the likelihood of death and a combination of death and/or non-fatal stroke by one year after TAVI in elderly patients.

关键词： comprehensive geriatric assessment Multidimensional prognostic index Short physical performance battery Silver code Transcatheter aortic valve implantation

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肺动静脉畸形栓塞和偏头痛患病率下降

世界核心医学期刊文摘(神经病学分册) 2006年第11期 47-48页

作者： post M.c ThijsV Schonewille W.J 郭俊 Department of cardiology St. Antonius Hospital Koekoekslaan 1 3435 CM Nieuwegein Netherlands Dr.

OBJEcTIVE: To determine if embolization of pulmonary arteriovenous malformations (PAVMs) decreases the occurrence of migraine. METHODS: All 105 patients with hereditary hemorrhagic telangiectasia (HHT), minimum age 16 years, who underwent an embolization of PAVM in our hospital between June 1995 and April 2004, were included in this study. A structured headache questionnaire was sent to all patients and focused on two periods: 1 year before and at least 6 months after embolization. Two independent neurologists diagnosed migraine according to the International Headache Society criteria. RESULTS: Eighty-four patients (80%) sent back the questionnaire (mean age 47.8 ±15.1 years, 51 female). Median follow-up time was 48 months (first quartile: 23 months; third quartile: 66 months). The overall prevalence of migraine decreased from 45.2%before to 34.5%after embolization (p = 0.01). The prevalence of migraine with aura decreased from 33.3%before to 19.0%after embolization (p = 0.002). The severity of headache attacks decreased in patients who still had migraine (p = 0.15) or migraine with aura after embolization (p = 0.11). cONcLUSION: Embolization of pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia seems to be related to a decrease in prevalence of migraine, suggesting that the presence of a right-to-left shunt rather than the localization of this shunt plays a causative role in the pathogenesis of migraine.

关键词：偏头痛脑病栓塞病理患病率肺动静脉畸形

Systemic Inflammation in Patients with chronic Obstructive Pulmonary Disease: Results from the cosmic Study

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Open Journal of Respiratory Diseases 2012年第3期2卷 63-72页

作者： Marie-Kathrin Breyer Eric P. A. Rutten martijn A. Spruit Wim c. J. Hop Dirkje S. postma Emiel F. M. Wouters Department of Biostatistics Erasmus Medical Center Rotterdam The Netherlands Department of Pulmonology and Tuberculosis GRIAC Research Institute University Medical Center GroningenUniversity of Groningen Groningen The Netherlands Department of Respiratory Medicine Maastricht University Medical Center (MUMC) Maastricht The Netherlands Department of Respiratory Medicine Maastricht University Medical Center (MUMC) Maastricht The Netherlands Program Development center Center of Expertise for Chronic Organ Failure Horn The Netherlands Department of Respiratory Medicine Maastricht University Medical Center (MUMC) Maastricht The Netherlands Program Development center Center of Expertise for Chronic Organ Failure Horn The NetherlandsDepartment of Respiratory & Critical Care Medicine & Ludwig Boltzmann Institute for COPD and Pulmonary Epidemiology Otto Wagner Hospital Vienna Austria

Objective: The study aims to elucidate the association of host-related factors on systemic inflammation in cOPD patients. Methods: In 295 clinically stable and optimally treated cOPD patients from 39 outpatient centers, age, gender, and body composition (body mass index, BMI;fat-free mass index, FFMI;fat mass index, FMI) were related to inflammatory biomarkers: cRP, fibrinogen, TNFα, and its soluble receptors (s)TNFαR1 and sTNFαR2. Furthermore, forced expiratory volume in the first second (FEV1), BMI, FFMI, and FMI were stratified by quartiles to elucidate the influence on inflammatory biomarkers. Monovariate and multivariate regression analyses were performed for associations between inflammatory biomarkers. Results: Positive correlations were found for FFMI with sTNFαR1, FMI with cRP and age with TNFα, sTNFαR1 and sTNFαR2 (p correlated with body composition and inflammatory markers. Mono- and multivariate analysis showed weak correlations between the acute phase markers and the TNFα system after correcting for multiple co-variants. conclusions: This study highlights the modest role of age and body composition on levels of systemic inflammatory biomarkers in cOPD. Results show the degree of airflow limitation does not affect systemic inflammation. Last, a weak relationship between acute phase markers and markers of the TNFα system is present in cOPD.

关键词： Adipokines Body composition cRP Fibrinogen Obesity TNFα

PERFORMANcE MODELING AND ANALYSIS OF BLOOD FLOW IN ELASTIc ARTERIES

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Applied Mathematics and Mechanics(English Edition) 2005年第3期26卷 345-354页

作者： Anil Kumar c.L.Varshney G.c.Sharma Department of post-Graduate Studies and Research in Mathematics &computer Science S.Varshney College Aligarh-202001 IndiaDepartment of Post-Graduate Studies and Research in Mathematics &Computer Science S.Varshney College Aligarh-202001 IndiaInstitute of Basic Science Khandari Agra-282002 India

Two different non_Newtonian models for blood flow are considered,first a simple power law model displaying shear thinning viscosity,and second a generalized Maxwell model displaying both shear thinning viscosity and oscillating flow viscous_*** models are used along with a Newtonian model to study sinusoidal flow of blood in rigid and elastic straight arteries in the presence of magnetic *** elasticity of blood does not appear to influence its flow behavior under physiological conditions in the large arteries,purely viscous shear thinning model should be quite realistic for simulating blood flow under these *** using the power law model with high shear rate for sinusoidal flow simulation in elastic arteries,the mean and amplitude of the flow rate were found to be lower for a power law fluid compared to Newtonian fluid for the same pressure *** governing equations have been solved by crank_Niclson *** results are interpreted in the context of blood in the elastic arteries keeping the magnetic effects in *** physiological flow simulation in the aorta,an increase in mean wall shear stress,but a reduction in peak wall shear stress were observed for power law model compared to a Newtonian fluid model for matched flow rate wave *** flow in the presence of transverse magnetic field in an elastic artery is investigated and the influence of factors such as morphology and surface irregularity is evaluated.

关键词： elastic artery model crank-Niclson scheme non-Newtonian fluid wall shear stress

cOMPUTATIONAL TEcHNIQUE FOR FLOW IN BLOODVESSELS WITH POROUS EFFEcTS

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Applied Mathematics and Mechanics(English Edition) 2005年第1期26卷 63-72页

A finite element solution for the Navier-Stokes equations for steady flow under the porosity effects through a double branched two-dimensional section of a three-dimensional model of a canine aorta was obtained. The numerical solution involves transforming a physical coordinates to a curvilinear boundary fitted coordinate *** steady flow,branch flow and shear stress under the porous effects were discussed in detail. The shear stress at the wall was calculated for Reynolds number of 1 000 with branch to main aortic flow rate ratio as a parameter. The results are compared with earlier works involving experimental data and it has been observed that our results are very close to the exact *** work is in fact an improvement of the work of Sharma et al. (2001) in the sense that computational technique is economic and (Reynolds) number is large.

关键词： wall shear stress porosity Galerkin's technique blood vessel

The development and role of microbialhost interactions in gut mucosal immune development

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Journal of Animal Science and Biotechnology 2017年第2期8卷 307-316页

作者： c.R.Stokes School of clinical Veterinary Science University of BristolLangford HouseLangfordNr Bristol BS40 5DUUK

At birth the piglet＇s immune system is immature and it is dependent upon passive maternal protection until *** piglet＇s mucosal immune system develops over the first few weeks but has not reached maturity at weaning ages which are common on commercial farms. At weaning piglets are presented with a vast and diverse range of microbial and dietary/environmental antigens. Their ability to distinguish between antigens and mount a protective response to potential pathogens and to develop tolerance to dietary antigens is critical to their survival and failure to do so is reflected in the high incidence of morbidity and mortality in the post-weaning period. A growing recognition that the widespread use of antibiotics to control infection during this critical period should be controlled has led to detailed studies of those factors which drive the development of the mucosal immune system, the role of gut microbiota in driving this process, the origin of the bacteria that colonise the young piglet＇s intestine and the impact of rearing environment. This review briefly describes how the mucosal immune system is equipped to respond ＂appropriately＂ to antigenic challenge and the programmed sequence by which it develops. The results of studies on the critical interplay between the host immune system and gut microbiota are discussed along with the effects of rearing environment. By comparing these with results from human studies on the development of allergies in children, an approach to promote an earlier maturation of the piglet immune system to resist the challenges of weaning are outlined.

关键词： Gut microbiota Intestine Mucosal immune development Pig Rearing environment

A Error Model of Vision-Based Measurement

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A Error Model of Vision-Based Measurement

What is left when anti-tumour necrosis factor therapy in inflammatory bowel diseases fails?

1996年第四届毫米波和远红外科学与技术国际会议

作者： Guoqi Ni Feilu Luo Antiaircraft Artillery Academy of the Air Addr.post Box 41 No.19 Gui Lin china P.c.541003

＜正＞The measurement technology of VcM（Vision-based 3-D coordinate Measurement） has the characteristics of intellectualized measurement and realization of noncontact *** can make the usage range of 3-D coordinate measurement technology more *** it is a kind of measurement technologies which has the good developing prospect.

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World Journal of Gastroenterology 2014年第5期20卷 1248-1258页

作者： Ian c Lawrance centre for Inflammatory Bowel Diseases Fremantle Hospital FremantleWA6059Australia Department of Medicine and Pharmacology University of Western Australia Fremantle Hospital FremantleWA6059Australia

The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient’s life for many years and these conditions require therapies that will be effective over the long-term. Surgery in crohn’s disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNFα) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNFα agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.

关键词： Inflammatory bowel disease Immunosuppression Anti-tumour necrosis factor agents Anti-integrin Long-term outcomes