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Early tacrolimus exposure does not impact long-term outcomes after liver transplantation

World Journal of Hepatology 2021年第3期13卷 362-374页

作者： Mikel Gastaca Patricia Ruiz Javier Bustamante Lorea Martinez-Indart Alberto Ventoso JoséRamón Fernandez Ibone Palomares Mikel Prieto milagros testillano Patricia Salvador Maria Senosiain Maria Jesus Suárez Andres Valdivieso Department of HPB Surgery and Liver Transplantation Unit Hospital Universitario CrucesBilbao 48903Spain Department of Hepatology Unit Hospital Universitario CrucesBilbao 48903Spain Department of Bioinformatics and Statistics Platform Biocruces Bizkaia Health Research InstituteHospital Universitario CrucesBilbao 48903Spain

BACKGROUND Tacrolimus trough levels(TTL)during the first weeks after liver transplantation(LT)have been related with long-term renal function and hepatocellular carcinoma ***,the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate AIM To evaluate the effect of TTL during the first month on the long-term outcomes after *** One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively *** with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction *** were classified into 2 groups according to their mean TTL within the first month after transplantation:≤10(n=98)and>10 ng/mL(n=57).Multivariate analyses were performed to assess risk factors for patient *** Mean levels within the first month post-transplant were 7.4±1.7 and 12.6±2.2 ng/mL in the≤10 and>10 groups,*** age was higher in the high TTL group 62.9±16.8 years vs 45.7±17.5 years(P=0.002)whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7%vs 15.8%(P=0.02).Recipient features were generally similar across *** a median follow-up of 52.8 mo(range 2.8-81.1),no significant differences were observed in:Mean estimated glomerular filtration rate(P=0.69),hepatocellular carcinoma recurrence(P=0.44),de novo tumors(P=0.77),new-onset diabetes(P=0.13),or biopsy-proven acute rejection rate(12.2%and 8.8%,respectively;P=0.50).Eighteen patients died during the follow-up and were evenly distributed across groups(P=0.83).Five-year patient survival was 90.5%and 84.9%,respectively(P=0.44),while 5-year graft survival was 88.2%and 80.8%,respectively(P=0.42).Early TTL was not an independent factor for patient mortality in multivariate *** Differences in tacrolimus levels restricted to the fi

关键词： Liver transplantation Tacrolimus levels Prolonged released tacrolimus Oncedaily tacrolimus Renal function Survival Outcomes

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Effectiveness and safety of first-generation protease inhibitors in clinical practice:Hepatitis C virus patients with advanced fibrosis

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World Journal of Gastroenterology 2015年第30期21卷 9163-9174页

作者： Javier Salmeron Carmen Vinaixa Ruben Berenguer Juan Manuel Pascasio Juan Jose Sanchez Ruano Miguel angel Serra Ana Gila Moises Diago Manuel Romero-Gomez Jose Maria Navarro milagros testillano Conrado Fernandez Dolores Espinosa Isabel Carmona Jose Antonio Pons Francisco Jorquera Francisco Javier Rodriguez Ramon Perez Jose Luis Montero Rafael Granados Miguel Fernandez Ana Belen Martin Paloma Munoz de Rueda Rosa Quiles CIBERehd Instituto de Salud Carlos Ⅲ28029 MadridSpain Unit for Clinical Management of Digestive Diseases Complejo Hospitalario Universitario de Granada Instituto de Investigacion Biosanitaria de Granada University Hospital Politecnico La Fe Unit for Clinical Management of Digestive Diseases University Hospital Virgen Del Rocio Hospital Toledo University Clinic Hospital of Valencia University General Hospital of Valencia Unit for Clinical Management of Digestive Diseases University Hospital Nuestra Senora de Valme Department of Gastroenterology and Hepatology Agencia Sanitaria Costa del Sol University Hospital Cruces Gastroenterology Unit University Hospital Fundacion Alcorcon University Hospital Virgen Macarena University Hospital Virgen de la Arrixaca Hospital of Leon University General Hospital Reina Sofia Department Gastroenterology and Hepatology University Hospital Central de Asturias University Hospital Reina Sofia University Hospital De Gran Canaria Dr. Negrin Hospital San Pedro de Alcantara

AIM:To evaluates the effectiveness and safety of the first generation,NS3/4A protease inhibitors(PIs) in clinical practice against chronic C virus,especially in patients with advanced fibrosis. METHODS:Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1,treatment-na?ve(TN) or treatment-experienced(TE),who underwent triple therapy with the first generation NS3/4A protease inhibitors,boceprevir(BOC) and telaprevir(TVR),in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow ***:One thousand and fifty seven patients were included,405(38%) were treated with BOC and 652(62%) with TVR. Of this total,30%(n = 319) were TN and the remaining were TE:28%(n = 298) relapsers,12%(n = 123) partial responders(PR),25%(n = 260) null-responders(NR) and for 5%(n = 57) with prior response unknown. The rate of sustained virologic response(SVR) by intention-to-treatment(ITT) was greater in those treated with TVR(65%) than in those treated with BOC(52%)(P < 0.0001),whereas by modified intention-to-treatment(m ITT) no were found significant differences. By degree of fibrosis,56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients,both TN and TE. In the analysis by groups,the TN patients treated with TVR by ITT showed a higher SVR(P = 0.005). However,by m ITT there were no significant differences between BOC and TVR. In the multivariate analysis by m ITT,the significant SVR factors were relapsers,IL28 B CC and non-F4; the type of treatment(BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients,treated with BOC(46%) or with TVR(45%). 28% of the patients interrupted the treatment,mainly by non-viral response(51%):this outcome was

关键词： Hepatitis C Boceprevir Telaprevir First-generation protease inhibitors Advanced fibrosis

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Tracking of iron-labeled human neural stem cells by magnetic resonance imaging in cell replacement therapy for Parkinson＇s disease

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Neural Regeneration Research 2016年第1期11卷 49-52页

作者： milagros Ramos-Gómez Alberto Martínez-Serrano Centre for Biomedical Technology Polytechnic University of Madrid Madrid Spain Biomedical Research Networking'Center of Bioengineering Biomaterials and Nanomedicine (CIBER-BBN) Madrid Spain Department of Molecular Biology and Center of Molecular Biology"Severo Ochoa" Autonomous University of Madrid-C.S.I.C Madrid Spain

Human neural stem cells（h NSCs） derived from the ventral mesencephalon are powerful research tools and candidates for cell therapies in Parkinson＇s disease. However, their clinical translation has not been fully realized due, in part, to the limited ability to track stem cell regional localization and survival over long periods of time after in vivo transplantation. Magnetic resonance imaging provides an excellent non-invasive method to study the fate of transplanted cells in vivo. For magnetic resonance imaging cell tracking, cells need to be labeled with a contrast agent, such as magnetic nanoparticles, at a concentration high enough to be easily detected by magnetic resonance imaging. Grafting of human neural stem cells labeled with magnetic nanoparticles allows cell tracking by magnetic resonance imaging without impairment of cell survival, proliferation, self-renewal, and multipotency. However, the results reviewed here suggest that in long term grafting, activated microglia and macrophages could contribute to magnetic resonance imaging signal by engulfing dead labeled cells or iron nanoparticles dispersed freely in the brain parenchyma over time.

关键词： human neural stem cells Parkinson's disease magnetic resonance imaging magnetic nanoparticles stem cell transplantation

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Optimized high performance liquid chromatography–ultraviolet detection method using core-shell particles for the therapeutic monitoring of methotrexate

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Journal of Pharmaceutical Analysis 2016年第2期6卷 103-111页

作者： milagros montemurro maría m.de zan juan c.robles Laboratorio de Control de Calidad de Medicamentos Facultad de Bioqufmica y Ciendas Biologicas Universidad Nacional del Litoral Santa Fe Argentina

Methotrexate （MTX） is an antineoplastic drug, and due to its high toxicity, the therapeutic drug mon- itoring is strictly conducted in the clinical practice. The chemometric optimization and validation of a high performance liquid chromatography （HPLC） method using core-shell particles is presented for the determination of MTX in plasma during therapeutic monitoring. Experimental design and response surface methodology （RSM） were applied for the optimization of the chromatographic system and the analyte extraction step. A Poroshel1120 EC-C18 （3.0 mm × 75 mm, 2.7 μm） column was used to obtain a fast and efficient separation in a complete run time of 4 min. The optimum conditions for the chroma- tographic system resulted in a mobile phase consisting of acetic acid/sodium acetate buffer solution （85.0 mM, pH =4.00） and 11.2% of acetonitrile at a flow rate of 0.4 mL/min. Selectivity, linearity, accuracy and precision were demonstrated in a range of 0.10-6.0 μM of MTX. The application of the optimized method required only 150μL of patient plasma and a low consumption of solvent to provide rapid re- sults.

关键词： HPLC Core-shell particles Methotrexate Drug monitoring

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Multiple responses optimization in the development of a headspace gas chromatography method for the determination of residual solvents in pharmaceuticals

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Journal of Pharmaceutical Analysis 2015年第5期5卷 296-306页

作者： Carla M.Teglia milagros Montemurro María M.De Zan María S.Cmara Laboratorio de Control de Calidad de Medicamentos Facultad de Bioquimica y Ciencias BiologicasUniversidad Nacional del Litoral

An efficient generic static headspace gas chromatography （HSGC） method was developed, optimized and validated for the routine determination of several residual solvents （RS） in drug substance, using a strategy with two sets of calibration. Dimethylsulfoxide （DMSO） was selected as the sample diluent and internal standards were used to minimize signal variations due to the preparative step. A gas chroma- tograph from Agilent Model 6890 equipped with flame ionization detector （FID） and a DB-624 （30 m × 0.53 mm i.d., 3.00 μm film thickness） column was used. The inlet split ratio was 5：1. The influ- encing factors in the chromatographic separation of the analytes were determined through a fractional factorial experimental design. Significant variables： the initial temperature （IT）, the final temperature （FT） of the oven and the carrier gas flow rate （F） were optimized using a central composite design. Response transformation and desirability function were applied to find out the optimal combination of the chromatographic variables to achieve an adequate resolution of the analytes and short analysis time. These conditions were 30 ℃ for IT, 158 ℃ for FT and 1.90 mL/min for F. The method was proven to be accurate, linear in a wide range and very sensitive for the analyzed solvents through a comprehensive validation according to the ICH guidelines.

关键词： Headspace gas chromatographyResidual solventsPharmaceuticalsSurface response methodologyDesirabiliW function

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Recent advances in bird sperm morphometric analysis and its role in male gamete characterization and reproduction technologies

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Asian Journal of Andrology 2016年第6期18卷 882-888页

作者： Julian Santiago-Moreno milagros Cristina Esteso Silvia Villaverde-Morcillo Adolfo Toledano-Diaz Cristina Castafio Rosario Velazquez Antonio Lopez-Sebastian Agustin Lopez Goya Javier Gimeno Martinez Department of Animal Reproduction INIA 28040 Madrid Spain Veterinary Clinical and Research Services Fieb Foundation 28760 Tres Cantos Madrid Spain FAUNIA 28032 Madrid Spain

Postcopulatory sexual selection through sperm competition may be an important evolutionary force affecting many reproductive traits, including sperm morphometrics. Environmental factors such as pollutants, pesticides, and climate change may affect different sperm traits, and thus reproduction, in sensitive bird species. Many sperm-handling processes used in assisted reproductive techniques may also affect the size of sperm cells. The accurately measured dimensions of sperm cell structures （especially the head） can thus be used as indicators of environmental influences, in improving our understanding of reproductive and evolutionary strategies, and for optimizing assisted reproductive techniques （e.g., sperm cryopreservation） for use with birds. Computer-assisted sperm morphometry analysis （CASA-Morph） provides an accurate and reliable method for assessing sperm morphometry, reducing the problem of subjectivity associated with human visual assessment. Computerized systems have been standardized for use with semen from different mammalian species. Avian spermatozoa, however, are filiform, limiting their analysis with such systems, which were developed to examine the approximately spherical heads of mammalian sperm cells. To help overcome this, the standardization of staining techniques to be used in compute^-assessed light microscopical methods is a priority. The present review discusses these points and describes the sperm morphometric characteristics of several wild and domestic bird species.

关键词： avian computer-assisted assay morphometry spermatozoa

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INTEGRAL REPRESENTATION OF NONLINEAR OPERATORS

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Journal of Mathematical Study 1994年第1期 142-147页

作者： milagros P Navarro Poily W Sy(Dept of Math, Univ of the PhiliPPines)

ＩＮＴＥＧＲＡＬＲＥＰＲＥＳＥＮＴＡＴＩＯＮＯＦＮＯＮＬＩＮＥＡＲＯＰＥＲＡＴＯＲＳ￥ＭｉｌａｇｒｏｓＰＮａｖａｒｒｏ；ＰｏｉｌｙＷＳｙ（ＤｅｐｔｏｆＭａｔｈ，ＵｎｉｖｏｆｔｈｅＰｈｉｌｉＰＰｉｎｅｓ）Ａｂｓｔｒａｃ...

ＩＮＴＥＧＲＡＬＲＥＰＲＥＳＥＮＴＡＴＩＯＮＯＦＮＯＮＬＩＮＥＡＲＯＰＥＲＡＴＯＲＳ￥ＭｉｌａｇｒｏｓＰＮａｖａｒｒｏ；ＰｏｉｌｙＷＳｙ（ＤｅｐｔｏｆＭａｔｈ，ＵｎｉｖｏｆｔｈｅＰｈｉｌｉＰＰｉｎｅｓ）Ａｂｓｔｒａｃｔ：Ａｃｏｎｔｉｎｕｏｕｓｌｉｎｅ...

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Modifications of sexual activity during uncomplicated pregnancy: A prospective investigation of Spanish women

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Health 2013年第8期5卷 1289-1294页

作者： Raquel Escudero-Rivas Pilar Carretero Africa Cano milagros Cruz Jesus Florido Department of Obstetrics and Gynecology San Cecilio University Hospital(HUSC)GranadaSpain Department of Obstetrics and Gynecology University of GranadaGranadaSpain

Introduction: Pregnancy is a time of profound changes in a woman’s life. These changes can influence her sexual behaviour and the relationship with her partner. The purpose of this article is to study sexual behaviour modification before and during pregnancy in a cohort of healthy Spanish pregnant women. Methods: This is a prospective cohort study in which 111 pregnant women took part. They completed a questionnaire about their sexual habits before pregnancy and at 20, 30 and 38 weeks (frequency of intercourse and orgasm, satisfaction with their relationships and pain or discomfort). Results: Intercourse frequency decreased progressively during pregnancy at all times studied relative to pre-regnancy periods, to a significant degree (p < 0.0001), accompanied by a reduction in sexual satisfaction. The incidence of orgasm was lightly modified, except in the weeks before parturition in which it underwent a notable decrease (p < 0.0001) with an increase in the rate of hypoorgasmia/ anorgasmia from 19% pre-pregnancy to 43% at 38th week. Conclusions: The longitudinal monitoring of this cohort permits the conclusion that during pregnancy, sexual behaviour undergoes a general decline with respect to prepregnancy levels. The differences vary depending on the sexual parameter considered, with intercourse frequency being the most affected variable in contrast to dyspareunia, which is the least affected.

关键词： Sexuality Frequency of Intercourse Satisfaction Orgasm

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H2 Production from Wind Power in a Wind Farm in Spain

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Journal of Energy and Power Engineering 2012年第1期6卷 49-59页

作者： milagros Rey Porto Monica Aguado Raquel Garde Gabriel Garcia Trinidad Carretero Gas Natural SDG S.A. Plaga del Gas 1 Barcelona 08003 Spain Renewable Energy Grid Integration Department National Renewable Energy Centre Sarriguren 31621 Spain Electrical and Electronic Engineering Department Public University of Navarra Pamplona 31006 Spain

A hydrogen production and conversion plant from wind power was installed in the Sotavento wind farm by Gas Natural and the Galician Government. This facility is the highest electrolysis power installed at the European level. It consists of an electrolyser of 300 kW, a piston compressor, a 1,725 Nm3 H2 storage system and an engine of 55 kW. This pilot plant is being operated by Natural Gas in order to extrapolate its behavior to that of an industrial facility capable of managing all the production of Sotavento wind farm following different strategies： balancing, peak-shaving and repowering. In this paper, preliminary results at the facility are presented. The aim of these first tests has been to describe the operation of equipment under operating conditions required in the management of wind power production, in order to understand the behavior of the different equipment and try to make them suitable for this type of applications. This paper shows the difficulty of operating these systems under the wind power requirements.

关键词： H2 wind power storage system electrolysis pilot plant.

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Alzheimer’s disease and type 2 diabetes mellitus:Pathophysiologic and pharmacotherapeutics links

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World Journal of Diabetes 2021年第6期12卷 745-766页

作者： milagros Rojas Mervin Chávez-Castillo Jordan Bautista Ángel Ortega Manuel Nava Juan Salazar Edgar Díaz-Camargo Oscar Medina Joselyn Rojas-Quintero Valmore Bermúdez Endocrine and Metabolic Diseases Research Center School of MedicineUniversity of ZuliaMaracaibo 4004Venezuela Universidad Simón Bolívar Facultad de Ciencias Jurídicas y SocialesCúcuta 540006Colombia Pulmonary and Critical Care Medicine Department Brigham and Women's HospitalHarvard Medical SchoolBostonMA 02155United States Universidad Simón Bolívar Facultad de Ciencias de la SaludBarranquilla 080001Colombia

At present,Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two highly prevalent disorders worldwide,especially among elderly individuals.T2DM appears to be associated with cognitive dysfunction,with a higher risk of developing neurocognitive disorders,including *** diseases have been observed to share various pathophysiological mechanisms,including alterations in insulin signaling,defects in glucose transporters(GLUTs),and mitochondrial dysfunctions in the ***,the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic *** this context,the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain,increase in reactive oxygen species,and production of mitochondrial alterations that occur in *** findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs,or,more recently,azeliragon,amylin,among others,which have shown possible beneficial effects in diabetic patients diagnosed with AD.

关键词： Alzheimer’s disease Type 2 diabetes mellitus Oxidative stress Islet amyloid polypeptide Glucagon-like peptide 1 Cognitive dysfunction Hypoglycemic agents

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