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Factors associated with dAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients

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World Journal of Hepatology 2018年第11期10卷 856-866页

作者： dominique Salmon Pascale Trimoulet Camille Gilbert Caroline Solas eva Lafourcade Julie Chas Lionel Piroth Karine Lacombe Christine Katlama Gilles Peytavin Hugues Aumaitre Laurent Alric Franoois Boué Philippe Morlat Isabelle Poizot-Martin Eric Billaud Eric Rosenthal Alissa Naqvi Patrick Miailhes Firouzé Bani-Sadr Laure Esterle Patrizia Carrieri Franoois dabis Philippe Sogni Linda Wittkop 无 Assistance Publique des Hopitaux de Paris Hopitaux Universitaires Paris CentreHopital Hotel DieuUnitédes Maladies infectieuses et tropicalesParis 75004France Université Paris descartes Sorbonne Paris CitéParis 75006France Trimoulet CHU de BordeauxHopital PellegrinLaboratoire de VirologieBordeaux 33000France Trimoulet CNRS-UMR 5234Microbiologie fondamentale et PathogénicitéUniversitéde BordeauxBordeaux 3000France Philippe Morlat Laure EsterleFrancois DabisLinda WittkopUniv.BordeauxISPEDInsermBordeaux Population Health Research Centerteam MORPH3EUSUMR 1219CIC-EC 1401Bordeaux F-33000France APHM Hopital La TimoneLaboratoire de Pharmacocinétique et ToxicologieMarseille 13005France Centre Hospitalier Universitaire de dijon Département d'InfectiologieDijon cedex 21079France INSERM-CIC 1342 Universitéde Bourgogne Dijon 21000France Assistance Publique des Hopitaux de Paris GHUEP site Saint-AntoineServices Maladies infectieuses et tropicalesParis 75011France UniversitéPierre et Marie Curie UMR S1136Institut Pierre Louis d' Epidémiologie et de SantéPubliqueParis 75646France UniversitéParis-Sorbonne Paris 75005France Assistance Publique des Hopitaux de Paris Hopital PitiéSalpêtrière Services Maladies infectieuses et tropicalesParis 75013France Assistance Publique des Hopitaux de Paris Hopital Bichat-Claude BernardLaboratoire de PharmacologieParis 75877France IAME UMR 1137Sorbonne Paris CitéINSERMUniversitéParis DiderotParis 75890France Centre Hospitalier de Perpignan Service Maladies infectieuses et tropicalesPerpignan 66000Franc Centre Hospitalier Universitaire de Toulouse Hopital PurpanService Médecine interne-Pole DigestifToulouse 31300France UMR 152 IRd UniversitéToulouseⅢ Paul SabatierToulouse 31330France Hopital Antoine-Béclère Assistance Publique des Hopitaux de ParisUniversitéParis SudService Médecine interne et immunologieClamart 92140France Centre Hospitalier Universitaire de Bordeaux Service de médecine interneHopital Saint-AndréBordeaux 33000France Uni

AIM To describe factors associated with treatment failure and frequency of resistance-associated substitutions(RAS).METHOdS Human immunodeficiency virus(HIV)/hepatitis C virus(HCV) coinfected patients starting a first direct-acting antiviral(dAA) regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defined as:(1) non-response [HCV-RNA remained detectable during treatment, at end of treatment(EOT)]; and(2) relapse(HCVRNA suppressed at EOT but detectable thereafter). Sequencing analysis was performed to describe prevalence of drug class-specific RAS. Factors associated with failure were determined using logistic regression *** Among 559 patients, 77% had suppressed plasma HIV-RNA dAA treatment initiation, 41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in 22 patients and were mainly relapses(17, 77%) then undefined failures(3, 14%) and non-responses(2, 9%). Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5 A or NS5 B RAS were detected in 10/14 patients with samples available for sequencing analysis. After adjustment for age, sex, ribavirin use, HCV genotype and treatment duration, low platelet count was the only factor significantly associated with a higher risk of failure(OR: 6.5; 95%CI: 1.8-22.6). CONCLUSION Only 3.9% HIV-HCV coinfected patients failed dAA regimens and RAS were found in 70% of those failing. Low platelet count was independently associated with virological failure.

关键词：耐药性治疗方法患者肝病

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evaluation of paracetamol toxicity in the cynomolgus monkey

Evaluation of paracetamol toxicity in the cynomolgus monkey

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作者： YU Hong Nigel BARRASS Sonya GALES eva LENZ dan WESTON lan WILSONB Tony PARRY Helen POWELL dale THURMAN QIAO Jun-wen QIN Qiu-ping REN Jin Centre for drug Safety evaluation and Research Shanghai Institute of Materia Medica Global Safety Assessment

Paracetamol(acetaminophen,APAP) was administered orally in a rising dose protocol to 2 male and 2 female Cynomolgus monkeys to determine the Maximum Tolerated dose(MTd) for subsequent toxicology *** the subsequent repeat dose study involving 6 monkeys,no dose-limiting toxicity was seen at up to 900 mg·kg~(-1)·d~(-1) APAP for 14 *** analysis showed that plasma exposure rose,albeit less than proportionally,with increasing *** were some fluctuations in clinical chemistry and haematology parameters,but these were not dose-related, and there were no compound-related findings observed *** monkeys at 900 mg·kg~(-1)·d~(-1) had a 5 cm, gas filled segment in their large intestine that was considered *** profiling of the urine showed parent and glucuronidated APAP,but the cysteinyl conjugate which would be anticipated if the monkey has similar metabolism to rats and man was notably *** opens the possibility that metabolism in the cynomolgus monkey differs from that in the other species,and shows that the cynomolgus monkey is a poor model for investigating paracetamol-mediated toxicity in humans.

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evaluation of paracetamol toxicity in the cynomolgus monkey

Evaluation of paracetamol toxicity in the cynomolgus monkey

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2013年（第三届）中国药物毒理学年会暨药物非临床安全性评价研究论坛

Paracetamol(acetominophen,APAP) was administered orally in a rising dose protocol to 2 male and 2 female Cynomolgus monkeys to determine the Maximum Tolerated dose(MTd) for subsequent toxicology *** the subsequent repeat dose study involving 6 monkeys,no dose-limiting toxicity was seen at up to 900 mg·kg·d APAP for 14 *** analysis showed that plasma exposure rose,albeit less than proportionally,with increasing *** were some fluctuations in clinical chemistry and haematology parameters,but these were not dose-related, and there were no compound-related findings observed *** monkeys at 900 mg·kg·d had a 5 cm, gas filled segment in their large intestine that was considered *** profiling of the urine showed parent and glucuronidated APAP,but the cysteinyl conjugate which would be anticipated if the monkey has similar metabolism to rats and man was notably *** opens the possibility that metabolism in the cynomolgus monkey differs from that in the other species,and shows that the cynomolgus monkey is a poor model for investigating paracetamol-mediated toxicity in humans.

关键词： acetominophen toxicity

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Custom-Made Mouthguards: Electromyographic Analysis of Masticatory Muscles and Cardiopulmonary Tests in Athletes of different Sports

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Health 2019年第4期11卷 428-438页

作者： d. Tripodi d. Fulco A. Beraldi P. Ripari G. Izzi S. d’Ercole department of Medical Oral and Biotechnological Sciences University “G. d’Annunzio” of Chieti-Pescara Chieti Italy

The purpose of this study is to analyse the neuromuscular balance of the masticatory muscles and the influence on the athlete respiratory parameters induced by custom-made mouthguard. Twenty-six athletes (24 males and 2 females), of different disciplines, average age of 32.12 ± 12.05, were recruited. Each athlete received a custom-made mouthguard in the Ethylene-Vinyl-Acetate (eva) thermoplastic material and using surface electromyography, the masseter muscles and the frontal beams of the temporal muscles were analysed, with and without mouthguard. The athletes were then subjected to a medical examination and cardiopulmonary test, in the condition with and without mouthguard. The use of mouthguard caused an improvement of all the electromyographic indexes analysed. In particular, GLOBAL INdEX (p = 0.0021), BAR (p = 0.0005), IMPACT (p = 0.0076) and ASIM (p = 0.0290) showed an enhancement statistically significant. For the cardiopulmonary test indexes as maximum oxygen uptake (VO2max), minute ventilation (VE), breathing reserve (BR), not statistically differences (p > 0.05) were reported. The custom-made mouthguard improved the neuromuscular balance of the masticatory muscles, symmetrizing the masseters and temporalis muscles work. It produced a better balancing distribution of occlusal loads both in the anterior-posterior direction and in the lateral direction and offered the possibility to produce more muscular work. Moreover, it did not constitute an impediment that can significantly disturb the athlete’s breathing during physical activity.

关键词： Mouthguard Sport Masticatory Muscles Neuromuscular Balance Electromyography

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Interstitial lung disease in rheumatoid arthritis:Current concepts in pathogenesis,diagnosis and therapeutics

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World Journal of Rheumatology 2015年第1期5卷 1-22页

作者： eva M Olivas-Flores david Bonilla-Lara Jorge I Gamez-Nava Alberto d Rocha-Muoz Laura Gonzalez-Lopez Hospital General Regional 180 Instituto Mexicano del Seguro Social (IMSS) Centro Universitario de Ciencias de la Salud (CUCS) Universidad de Guadalajara Hospital de Especialidades Centro Medico Nacional de Occidente Instituto Mexicano del Seguro Social (IMSS) Hospital General Regional 110 departamento de Medicina Interna-Reumatologia Instituto Mexicano del Seguro Social (IMSS)

Rheumatoid arthritis(RA) is the most common chronic autoimmune inflammatory joint disease. RA-associated interstitial lung disease(RA-ILd) is a major extraarticular complication and causes symptoms that lead to a deterioration in the quality of life, high utilization of health resources, and an increased risk of earlier mortality. Early in the course of RA-ILd, symptoms are highly variable, making the diagnosis difficult. Therefore, a rational diagnostic strategy that combines an adequate clinical assessment with the appropriate use of clinical tests, including pulmonary function tests and high-resolution computed tomography, should be used. In special cases, lung biopsy or bronchioalveolar lavage should be performed to achieve an early diagnosis. Several distinct histopathological subtypes of RA-ILd are currently recognized. These subtypes also have different clinical presentations, which vary in therapeutic response and prognosis. This article reviews current evidence about the epidemiology of RA-ILd and discusses the varying prevalence rates observed in different studies. Additionally, aspects of RA-ILd pathogenesis, including the role of cytokines and other molecules such as autoantibodies, as well as the evidence linking several drugs used to treat RA with lung damage will be discussed. Some aspects of the clinical characteristics of RA-ILd are noted, and diagnostic strategies are reviewed. Finally, this article analyzes current treatments for RA-ILd, including immunosuppressive therapies and biologic agents, as well as other therapeutic modalities. The prognosis of this severe complication of RA is discussed. Additionally, this paper examines updated evidence from studies identifying an association between drugs used for the treatment of RA and the development of ILd.

关键词： Rheumatoid arthritis Interstitial lung disease Pathogenesis diagnosis Therapeutic

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evaluation of paracetamol toxicity in the cynomolgus monkey

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中国药理学与毒理学杂志 2013年第3期 544-544页

作者： YU Hong Nigel BARRASS Sonya GALES eva LENZ dan WESTON Ian WILSONB Tony PARRY Helen POWELL dale THURMAN QIAO Jun-wen QIN Qiu-ping REN Jin Centre for drug Safety evaluation and Research Shanghai Institute of Materia Medica Global Safety Assessment AstraZeneca R&D BostonMAUSA and UK

Paracetamol(acetominophen,APAP) was administered orally in a rising dose protocol to 2 male and 2 female Cynomolgus monkeys to determine the Maximum Tolerated dose(MTd) for subsequent toxicology *** the subsequent repeat dose study involving 6 monkeys,no dose-limiting toxicity was seen at up to 900 mg·kg-1.d-1 APAP for 14 *** analysis showed that plasma exposure rose,albeit less than proportionally,with increasing *** were some fluctuations in clinical chemistry and haematology parameters,but these were not dose-related,and there were no compound-related findings observed *** monkeys at 900 mg·kg-1.d-1 had a 5 cm,gas filled segment in their large intestine that was considered *** profiling of the urine showed parent and glucuronidated APAP,but the cysteinyl conjugate which would be anticipated if the monkey has similar metabolism to rats and man was notably *** opens the possibility that metabolism in the cynomolgus monkey differs from that in the other species,and shows that the cynomolgus monkey is a poor model for investigating paracetamol-mediated toxicity in humans.

关键词： acetominophen toxicity

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Bone changes in alcoholic liver disease

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World Journal of Hepatology 2015年第9期7卷 1258-1264页

作者： Emilio González-Reimers Geraldine Quintero-Platt eva Rodríguez-Rodríguez Antonio Martínez-Riera Julio Alvisa-Negrín Francisco Santolaria-Fernández Servicio de Medicina Interna Hospital Universitario de Canarias Universidad de La Laguna

Alcoholism has been associated with growth impairment, osteomalacia, delayed fracture healing, and aseptic necrosis(primarily necrosis of the femoral head), but the main alterations observed in the bones of alcoholic patients are osteoporosis and an increased risk of fractures. decreased bone mass is a hallmark of osteoporosis, and it may be due either to decreased bone synthesis and/or to increased bone breakdown. Ethanol may affect both mechanisms. It is generally accepted that ethanol decreases bone synthesis, and most authors have reported decreased osteocalcin levels(a "marker" of bone synthesis), but some controversy exists regarding the effect of alcohol on bone breakdown, and, indeed, disparate results have been reported for telopeptide and other biochemical markers of bone resorption. In addition to the direct effect of ethanol, systemic alterations such as malnutrition, malabsorption, liver disease, increased levels of proinflammatory cytokines, alcoholic myopathy and neuropathy, low testosterone levels, and an increased risk of trauma, play contributory roles. The treatment of alcoholic bone disease should be aimed towards increasing bone formation and decreasing bone degradation. In this sense, vitamin d and calcium supplementation, together with biphosphonates are essential, but alcohol abstinence and nutritional improvement are equally important. In this review we study the pathogenesis of bone changes in alcoholic liver disease and discuss potential therapies.

关键词： Alcoholism Liver disease Osteoporosis Vitamin d Bone fractures

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PKR and PP1C Polymorphisms in Alzheimer’s disease Risk

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Neuroscience & Medicine 2011年第3期2卷 226-231页

作者： Ernest Palomer Gerard ILL-Raga Marta Tajes eva Ramos-Fernández Mònica Bosch-Morató Biuse Guivernau Jose J.Galan Jordi Clarimon Carmen Antunez Merce Boada Luis M.Real César Fandos Francisco J.Munoz Laboratory of Molecular Physiology and Channelopathies Department of Experimental and Health SciencesPompeu Fabra University(UPF)BarcelonaSpain NeoCodex SevillaSpain Alzheimer Laboratory Neurology DepartmentSanta Creu and Sant Pau HospitalBiomedical Research Center on Neurodegenerative Diseases(CIBERNED)BarcelonaSpain Fundacion Alzheimur Dementia UnitVirgen de la Arrixaca HospitalMurciaSpain Memory Clinic of ACE Foundation Catalan Institute of Applied NeurosciencesBarcelonaSpain Neurology department Vall d’Hebron Universitary HospitalBarcelonaSpain

Alzheimer’s disease (Ad) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ?-site APP cleaving enzyme 1 (BACE1), a key enzyme in Ad that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. due to the functional relationship between BACE1, PKR, PP1 and Ad we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with Ad risk was found, our results show that neither rs7480390 nor rs2254958 are associated with Ad susceptibility.

关键词： Alzheimer’s disease BACE1 PKR PP1 eIF2α

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雄激素受体的目标基因在骨骼肌的表达

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Asian Journal of Andrology 2014年第5期16卷 675-683,I0006页

作者： Kesha Rana Nicole KL Lee Jeffrey d Zajac Helen E MacLean department of Medicine Austin Health University of Melbourne Heidelberg Victoria Australia

We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor （AR）-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked dNA binding activity （AR△ZF2） versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR△ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7, p57Kip2, IEf2 and calcineurin Aa, was increased in AR△ZF2 muscle, and the expression of all but p57kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.

关键词： androgen receptor anabolic atrophy gene expression skeletal muscle

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Zinc phosphate-based nanoparticles as a novel antibacterial agent: in vivo study on rats after dietary exposure

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Journal of Animal Science and Biotechnology 2019年第2期10卷 463-474页

作者： Pavel Horky Sylvie Skalickova Lenka Urbankova daria Baholet Silvia Kociova Zuzana Bytesnikova Eliska Kabourkova Zuzana Lackova Natalia Cernei Milica Gagic Vedran Milosavljevic Vendula Smolikova eva Vaclavkova Pavel Nevrkla Pavel Knot Olga Krystofova david Hynek Pavel Kopel Jiri Skladanka Vojtech Adam Kristyna Smerkova department of Animal Nutrition and Forage Production Mendel University in BrnoZemedelska 1CZ-613 00 BrnoCzech Republic department of Chemistry and Biochemistry Mendel University in BrnoZemedelska 1CZ-613 00 BrnoCzech Republic Central European Institute of Technology Brno University of TechnologyPurkynova 123CZ-612 00 BrnoCzech Republic Institute of Animal Science Komenskeho 1239CZ-517 41 Kostelec nad OrliciCzech Republic department of Animal Breeding Mendel University in BrnoZemedelska 1CZ-613 00 BrnoCzech Republic.

Background: development of new nanomaterials that inhibit or kil bacteria is an important and timely research topic. For example, financial losses due to infectious diseases, such as diarrhea, are a major concern in livestock productions around the world. Antimicrobial nanoparticles(NPs) represent a promising alternative to antibiotics and may lower antibiotic use and consequently spread of antibiotic resistance traits among bacteria, including ***: Four formulations of zinc nanoparticles(Zn A, Zn B, Zn C, and Zn d) based on phosphates with spherical(Zn A, Zn B)or irregular(Zn C, Zn d) morphology were prepared. The highest in vitro inhibitory effect of our NPs was observed against Staphylococcus aureus(inhibitory concentration values, IC50, ranged from 0.5 to 1.6 mmol/L), fol owed by Escherichia coli(IC500.8–1.5 mmol/L). In contrast, methicil in resistant S. aureus(IC501.2–4.7 mmol/L) was least affected and this was similar to inhibitory patterns of commercial Zn O-based NPs and Zn O. After the successful in vitro testing, the in vivo study with rats based on dietary supplementation with zinc NPs was conducted. Four groups of rats were treated by 2,000 mg Zn/kg diet of Zn A, Zn B, Zn C, and Zn d, for comparison two groups were supplemented by 2,000 mg Zn/kg diet of Zn O-N and Zn O, and one group(control) was fed only by basal diet. The significantly higher(P d kidney of al treated groups was found, nevertheless Zn NPs did not greatly influence antioxidant status of rats. However,the total aerobic and coliform bacterial population in rat feces significantly decreased(P d of the treatment. Furthermore, when compared to the Zn O group, Zn A and Zn C nanoparticles reduced coliforms significantly more(P demonstrate that phosphate-based zinc nanoparticles have the potential to act as antibiotic agents.

关键词： Aerobic bacteria Antibiotics Coliforms Nanomaterials Oxidative stress

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