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1. Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

Author

Mohan K. Raizada, Juan Duarte, Manuel Sánchez, Manuel Gómez-Guzmán, Marta Toral, Cristina González-Correa, Tao Yang, Javier Moleón, Iñaki Robles-Vera, Rosario Jiménez, Néstor de la Visitación, Miguel Romero, Ministerio de Economía y Competitividad (España), Junta de Andalucía, European Union, Instituto de Salud Carlos III - ISCIII, National Heart, Lung, and Blood Institute (United States), European Regional Development Fund (ERDF/FEDER), [Robles-Vera,I, de la Visitación,N, Sánchez,M, Gómez-Guzmán,M, Jiménez,R, Moleón,J, González-Correa,C, Romero,M, Duarte,J] Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain. [Sánchez,M, Gómez-Guzmán,M, Jiménez,R, Duarte,J] Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA,Granada, Spain. [Jiménez,R, Toral,M, Duarte,J] Ciber de Enfermedades Cardiovasculares (CIBERCV), Granada, Spain. [Yang,T] Microbiome Consortium and Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA. [Raizada,MK] Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA. [Toral,M] Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., This work was supported by Grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R), Junta de Andalucía (CTS-164), with funds from the European Union, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain, and National Heart, Lung and Blood Institute (NHLBI) grant HL102033. M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program). I.R.V. is a predoctoral fellow of MINECO. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, 'FEDER una manera de hacer Europa')., Regional Government of Andalusia (España), Unión Europea, Instituto de Salud Carlos III, NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), and Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)

Subjects
0301 basic medicine, Physiology, Clinical Biochemistry, mycophenolate, gut dysbiosis, hypertension, oxidative stress, inflammation, (deoxycorticosterone acetate) DOCA-salt model, (Deoxycorticosterone acetate) DOCA-salt model, 030204 cardiovascular system & hematology, Gut flora, medicine.disease_cause, Biochemistry, Anatomy::Cardiovascular System::Blood Vessels::Arteries::Aorta [Medical Subject Headings], Gut dysbiosis, 0302 clinical medicine, Organisms::Eukaryota::Animals [Medical Subject Headings], oxidative stress, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, Wistar [Medical Subject Headings], Endothelial dysfunction, mycophenolate, biology, Microbiota, Estrés oxidativo, Organisms::Bacteria::Bacteria, Anaerobic [Medical Subject Headings], Phenomena and Processes::Microbiological Phenomena::Microbiota [Medical Subject Headings], Hypertension, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Dysbiosis [Medical Subject Headings], Anaerobic bacteria, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, hypertension, Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Acetates [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Inflammation, Acetato de desoxicorticosterona, Article, Diseases::Cardiovascular Diseases::Vascular Diseases::Hypertension [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Physiological Processes::Stress, Physiological::Oxidative Stress [Medical Subject Headings], 03 medical and health sciences, gut dysbiosis, Internal medicine, Hipertensión, Phenomena and Processes::Circulatory and Respiratory Physiological Phenomena::Cardiovascular Physiological Phenomena::Hemodynamics::Blood Pressure [Medical Subject Headings], medicine, Mycophenolate, Molecular Biology, Neuroinflammation, Inflamación, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Mineralocorticoids [Medical Subject Headings], business.industry, lcsh:RM1-950, (deoxycorticosterone acetate) DOCA-salt model, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Hydroxy Acids::Lactates::Lactic Acid [Medical Subject Headings], Cell Biology, Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hypothalamus [Medical Subject Headings], medicine.disease, biology.organism_classification, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Endocrinology, Blood pressure, inflammation, Oxidative stress, business, Dysbiosis
Abstract

Microbiota is involved in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzed whether MMF improves dysbiosis in mineralocorticoid-induced hypertension. MaleWistar rats were assigned to three groups: untreated (CTR), deoxycorticosterone acetate (DOCA)-salt, and DOCA treated with MMF for 4 weeks. MMF treatment reduced systolic BP, improved endothelial dysfunction, and reduced oxidative stress and inflammation in aorta. A clear separation in the gut bacterial community between CTR andDOCAgroups was found, whereas the cluster belonging toDOCA-MMF group was found to be intermixed. No changes were found at the phylum level among all experimental groups. MMF restored the elevation in lactate-producing bacteria found in DOCA-salt joined to an increase in the acetate-producing bacteria. MMF restored the percentage of anaerobic bacteria in the DOCA-salt group to values similar to control rats. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. This study demonstrates for the first time that MMF reduces gut dysbiosis in DOCA-salt hypertension models. This e ect seems to be related to its capacity to improve gut integrity due to reduced sympathetic drive in the gut associated with reduced brain neuroinflammation., Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad SAF2017-84894-R, Junta de Andalucía CTS-164, European Union (EU), Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) HL102033, European Union (Fondo Europeo de Desarrollo Regional, FEDER, "FEDER una manera de hacer Europa")

Published
2020
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2. Mycophenolate mediated remodeling of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rats

Author

Néstor de la Visitación, Manuel Sánchez, Manuel Gómez-Guzmán, Rosario Jiménez, Iñaki Robles-Vera, Miguel Romero, Juan Duarte, Marta Toral, [Robles-Vera,I, de la Visitación,N, Sánchez,M, Gómez-Guzmán,M, Jiménez,R, Romero,M, Duarte,J] Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain. [Toral,M, Duarte,J] Ciber de Enfermedades Cardiovasculares (CIBERCV), Spain. [Toral,M] Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. [Sánchez.M, Duarte,J] Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, Granada, Spain, and This work was supported by Grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R), Junta de Andalucía (CTS-164) with funds from the European Union, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program). I.R.-V. is a predoctoral fellow of MINECO. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, 'FEDER una manera de hacer Europa').

Subjects
0301 basic medicine, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Cardiovascular Agents::Antihypertensive Agents [Medical Subject Headings], Sympathetic Nervous System, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes::T-Lymphocyte Subsets::T-Lymphocytes, Regulatory [Medical Subject Headings], Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Inbred Strains::Rats, Inbred Strains::Rats, Inbred SHR [Medical Subject Headings], Disbiosis, T-Lymphocytes, Anatomy::Nervous System::Peripheral Nervous System::Autonomic Nervous System::Sympathetic Nervous System [Medical Subject Headings], Anatomy::Digestive System::Gastrointestinal Tract::Intestines::Intestine, Large::Colon [Medical Subject Headings], Aorta, Thoracic, Blood Pressure, Gut flora, Rats, Inbred WKY, Anatomy::Cardiovascular System::Blood Vessels::Arteries::Aorta [Medical Subject Headings], SHR, Gut dysbiosis, 0302 clinical medicine, Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Caproates::Mycophenolic Acid [Medical Subject Headings], Rats, Inbred SHR, Organisms::Eukaryota::Animals [Medical Subject Headings], Mesenteric lymph nodes, Lymph nodes, Cells, Cultured, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Hydroxy Acids::Lactates [Medical Subject Headings], biology, Ganglios linfáticos, Estrés oxidativo, Citocinas, General Medicine, Organisms::Bacteria::Bacteroidetes [Medical Subject Headings], Organisms::Bacteria::Bacteria, Anaerobic [Medical Subject Headings], Phenomena and Processes::Microbiological Phenomena::Microbiota [Medical Subject Headings], medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hypertension, Ácido micofenólico, Cytokines, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Dysbiosis [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Electrophysiological Phenomena::Electrophysiological Processes::Neuroimmunomodulation [Medical Subject Headings], Anaerobic bacteria, medicine.symptom, Inflammation Mediators, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Biological::Models, Genetic [Medical Subject Headings], medicine.medical_specialty, Colon, Neuroimmunomodulation, Gut–brain axis, Ratas endogámicas SHR, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Inbred Strains::Rats, Inbred Strains::Rats, Inbred WKY [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Inflammation, RM1-950, Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Diencephalon::Hypothalamus::Hypothalamus, Anterior::Paraventricular Hypothalamic Nucleus [Medical Subject Headings], Diseases::Cardiovascular Diseases::Vascular Diseases::Hypertension [Medical Subject Headings], 03 medical and health sciences, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Volatile::Acetates [Medical Subject Headings], Internal medicine, Hipertensión, Phenomena and Processes::Circulatory and Respiratory Physiological Phenomena::Cardiovascular Physiological Phenomena::Hemodynamics::Blood Pressure [Medical Subject Headings], Genetic model, medicine, Animals, Mycophenolate, Organisms::Bacteria [Medical Subject Headings], Neuroinflammation, Antihypertensive Agents, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines [Medical Subject Headings], Pharmacology, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Volatile::Butyrates [Medical Subject Headings], Inflamación, Bacteria, business.industry, Anatomy::Cardiovascular System::Blood Vessels::Arteries::Aorta::Aorta, Thoracic [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hypothalamus [Medical Subject Headings], Mycophenolic Acid, biology.organism_classification, medicine.disease, Diseases::Animal Diseases::Disease Models, Animal [Medical Subject Headings], Gastrointestinal Microbiome, Disease Models, Animal, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats [Medical Subject Headings], 030104 developmental biology, Endocrinology, Oxidative stress, Anatomy::Cells::Cells, Cultured [Medical Subject Headings], Dysbiosis, Therapeutics. Pharmacology, business, Anatomy::Tissues::Lymphoid Tissue::Lymph Nodes [Medical Subject Headings], Chemicals and Drugs::Biological Factors::Inflammation Mediators [Medical Subject Headings], Paraventricular Hypothalamic Nucleus
Abstract

This work was supported by Grants from Comisi´on Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R), Junta de Andalucía (CTS-164) with funds from the European Union, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program). I.R.-V. is a predoctoral fellow of MINECO. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”)., Microbiota has a role in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzes whether MMF improves dysbiosis in a genetic model of hypertension. Twenty weeks old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into three groups: untreated WKY, untreated SHR, and SHR treated with MMF for 5 weeks. MMF treatment restored gut bacteria from the phyla Firmicutes and Bacteroidetes, and acetate- and lactate-producing bacteria to levels similar to those found in WKY, increasing butyrate-producing bacteria. MMF increased the percentage of anaerobic bacteria in the gut. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. MMF increased the lower regulatory T cells proportion in mesenteric lymph nodes and Th17 and Th1 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that MMF reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity due to reduced sympathetic drive in the gut associated to the reduced brain neuroinflammation., Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad SAF201784894R, Junta de Andalucia CTS-164, European Commission, Spanish Government, Instituto de Salud Carlos III (CIBERCV) , Spain, European Union (Fondo Europeo de Desarrollo Regional, FEDER, "FEDER una manera de hacer Europa")

Published
2020
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3. Levothyroxine enhances glucose clearance and blunts the onset of experimental type 1 diabetes mellitus in mice

Author

Lopez-Noriega, Livia, Cobo-Vuilleumier, Nadia, Jesus Narbona-Perez, Alvaro, Luis Araujo-Garrido, Juan, Isabel Lorenzo, Petra, Manuel Mellado-Gil, Jose, Carlos Moreno, Jose, Gauthier, Benoit R., Martin-Montalvo, Alejandro, [Lopez-Noriega, Livia] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Cobo-Vuilleumier, Nadia] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Jesus Narbona-Perez, Alvaro] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Luis Araujo-Garrido, Juan] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Isabel Lorenzo, Petra] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Manuel Mellado-Gil, Jose] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Gauthier, Benoit R.] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Martin-Montalvo, Alejandro] Univ Seville, Univ Pablo de Olavide, Pancreat Islet Dev & Regenerat Unit, Lab Aging Biol,CSIC,Ctr Andaluz Biol Mol & Med Re, Seville, Spain, [Carlos Moreno, Jose] Autonomous Univ Madrid, La Paz Univ Hosp, Inst Med & Mol Genet INGEMM, Thyroid Mol Lab, Madrid, Spain, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III - Fondos FEdeR, FEdeR, and Instituto de Salud Carlos III - Instituto de Salud Carlos III

Subjects
Pharmacology, Beta-cell proliferation, Skeletal-muscle, In-vivo, 3,5-diiodo-l-thyronine, Expression, Thyroid-hormone analogs, Concise guide, Induced insulin-resistance, Mouse model
Abstract

BACKGROUND AND PURPOSEThyroid hormones induce several changes in whole body metabolism that are known to improve metabolic homeostasis. However, adverse side effects have prevented its use in the clinic. In view of the promising effects of thyroid hormones, we investigated the effects of levothyroxine supplementation on glucose homeostasis.EXPERIMENTAL APPROACHC57BL/6 mice were treated with levothyroxine from birth to 24 weeks of age, when mice were killed. The effects of levothyroxine supplementation on metabolic health were determined. C57BL/6 mice treated with levothyroxine for 2 weeks and then challenged with streptozotocin to monitor survival. Mechanistic experiments were conducted in the pancreas, liver and skeletal muscle. RIP-B7.1 mice were treated with levothyroxine for 2 weeks and were subsequently immunized to trigger experimental autoimmune diabetes (EAD). Metabolic tests were performed. Mice were killed and metabolic tissues were extracted for immunohistological analyses.KEY RESULTSLong-term levothyroxine supplementation enhanced glucose clearance and reduced circulating glucose in C57BL/6 mice. Levothyroxine increased simultaneously the proliferation and apoptosis of pancreatic beta cells, promoting the maintenance of a highly insulin-expressing beta cell population. Levothyroxine increased circulating insulin levels, inducing sustained activation of IRS1-AKT signalling in insulin-target tissues. Levothyroxine-treated C57BL/6 mice challenged with streptozotocin exhibited extended survival. Levothyroxine blunted the onset of EAD in RIP-B7.1 mice by inducing beta cell proliferation and preservation of insulin-expressing cells.CONCLUSIONS AND IMPLICATIONSInterventions based on the use of thyroid hormones or thyromimetics could be explored to provide therapeutic benefit in patients with type 1 diabetes mellitus.

Published
2017

4. Efficacy of β-Lactam/β-Lactamase Inhibitor Combinations for the Treatment of Bloodstream Infection Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae in Hematological Patients with Neutropenia

Author

F. Herrera, Jordi Carratalà, Guillermo Maestro de la Calle, Cristina Royo-Cebrecos, Carlos Cervera, Murat Akova, Maddalena Peghin, Georg Maschmeyer, Pilar Martín-Dávila, Mercè Gurguí, Jesús Rodríguez-Baño, Isabel Ruiz-Camps, Angela Cano, Yolanda Meije, Adriana Manzur, Teresa C. Sukiennik, Edson Abdala, Wanessa Trindade Clemente, Alison G. Freifeld, Cristian Tebe, Miguel Montejo, Thomas Gottlieb, Lucía Gómez, Carlota Gudiol, R. Alvarez, European Society of Clinical Microbiology and Infectious Diseases, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Red Española de Investigación en Patología Infecciosa, [Gudiol, Carlota] Univ Barcelona, Bellvitge Univ Hosp, IDIBELL, Infect Dis Dept, Barcelona, Spain, [Royo-Cebrecos, Cristina] Univ Barcelona, Bellvitge Univ Hosp, IDIBELL, Infect Dis Dept, Barcelona, Spain, [Carratala, Jordi] Univ Barcelona, Bellvitge Univ Hosp, IDIBELL, Infect Dis Dept, Barcelona, Spain, [Gudiol, Carlota] Duran & Reynals Hosp, ICO, Barcelona, Spain, [Abdala, Edson] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Sao Paulo, Brazil, [Akova, Murat] Hacettepe Univ, Sch Med, Ankara, Turkey, [Alvarez, Rocio] Univ Seville, CSIC, Univ Hosp Virgen Rocio & Virgen Macarena, Inst Biomed Seville IBiS,Infect Dis Res Grp,Clin, Seville, Spain, [Maestro-de la Calle, Guillermo] Univ Complutense, Sch Med, Octubre Univ Hosp 12, Inst Invest Hosp Octubre 12 i 12,Infect Dis Unit, Madrid, Spain, [Cano, Angela] UCO, Reina Sofia Univ Hosp, IMIBIC, Cordoba, Spain, [Cervera, Carlos] Univ Alberta Hosp, Edmonton, AB, Canada, [Clemente, Wanessa T.] Univ Fed Minas Gerais, Hosp Clin, Digest Transplant Serv, Belo Horizonte, MG, Brazil, [Martin-Davila, Pilar] Hosp Ramon & Cajal, Infect Dis Dept, Madrid, Spain, [Freifeld, Alison] Univ Nebraska, Med Ctr, Internal Med Infect Dis Sect, Omaha, NE 68182 USA, [Gomez, Lucia] Univ Hosp Mutua Terrassa, Internal Med, Barcelona, Spain, [Gottlieb, Thomas] Concord Hosp, Dept Microbiol & Infect Dis, Concord, NSW, Australia, [Gurgui, Merce] Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Infect Dis Unit, Barcelona, Spain, [Gurgui, Merce] Univ Autonoma Barcelona, Inst Invest Biomed Sant Pau, Barcelona, Spain, [Herrera, Fabian] CEMIC, Dept Med, Infect Dis Sect, Buenos Aires, DF, Argentina, [Manzur, Adriana] Hosp Rawson, Infect Dis, San Juan, Argentina, [Maschmeyer, Georg] Charite, Med Sch, Acad Teaching Hosp, Dept Hematol Oncol & Palliat Care,Klinikum Ernst, Berlin, Germany, [Meije, Yolanda] Barcelona Hosp, SCIAS, Internal Med Dept, Infect Dis Unit, Barcelona, Spain, [Montejo, Miguel] Cruces Univ Hosp, Infect Dis Unit, Bilbao, Spain, [Peghin, Maddalena] Santa Maria Misericordia Univ Hosp, Infect Dis Div, Udine, Italy, [Rodriguez-Bano, Jesus] Univ Seville, Univ Hosp Virgen Macarena & Virgen Rocio IBiS, Dept Med, Clin Unit Infect Dis Microbiol & Prevent Med, Seville, Spain, [Ruiz-Camps, Isabel] Vall Hebron Univ Hosp, Infect Dis Dept, Barcelona, Spain, [Sukiennik, Teresa C.] Hosp Santa Casa Misericordia Porto Alegre, Porto Alegre, RS, Brazil, [Tebe, Cristian] Rovira & Virgili Univ, Inst Biomed Res Bellvitge, Stat Advisory Serv, Tarragona, Spain, [Gudiol, Carlota] Inst Salud Carlos III, REIPI Spanish Network Res Infect Dis, Madrid, Spain, [Royo-Cebrecos, Cristina] Inst Salud Carlos III, REIPI Spanish Network Res Infect Dis, Madrid, Spain, [Meije, Yolanda] Inst Salud Carlos III, REIPI Spanish Network Res Infect Dis, Madrid, Spain, [Montejo, Miguel] Inst Salud Carlos III, REIPI Spanish Network Res Infect Dis, Madrid, Spain, [Rodriguez-Bano, Jesus] Inst Salud Carlos III, REIPI Spanish Network Res Infect Dis, Madrid, Spain, [Ruiz-Camps, Isabel] Inst Salud Carlos III, REIPI Spanish Network Res Infect Dis, Madrid, Spain, [Carratala, Jordi] Inst Salud Carlos III, REIPI Spanish Network Res Infect Dis, Madrid, Spain, ESGBIS, ESGICH, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III - European Development Regional Fund 'A way to achieve Europe' EDRF, Spanish Network for the Research in Infectious Diseases, COMBACTE-NET, COMBACTE-CARE, COMBACTE-MAGNET, Innovative Medicines Initiative (European Union), Innovative Medicines Initiative (EFPIA), Merck, Astellas, Novartis, Pfizer, MSD, Janssen, Astra-Zeneca, and İç Hastalıkları

Subjects
0301 basic medicine, Male, Definitive Therapy, Bacteremia, Escherichia-coli, Cohort Studies, chemistry.chemical_compound, Bloodstream infection, Case fatality rate, polycyclic compounds, beta-lactam/beta-lactamase inhibitors, Pharmacology (medical), Pharmacology & Pharmacy, Cancer, biology, Klebsiella-pneumoniae, Enterobacteriaceae Infections, Middle Aged, Enterobacteriaceae, Anti-Bacterial Agents, Risk-factors, Infectious Diseases, Beta-lactam/beta-lactamase inhibitors, Cohort, Lactam, Female, beta-Lactamase Inhibitors, Adult, medicine.medical_specialty, Neutropenia, 030106 microbiology, bloodstream infection, Outcomes, Clinical Therapeutics, beta-Lactams, Microbiology, beta-Lactamases, 03 medical and health sciences, β lactamase inhibitor, Piperacillin-tazobactam, Internal medicine, medicine, Humans, Mortality, Intensive care medicine, Pharmacology, business.industry, biochemical phenomena, metabolism, and nutrition, medicine.disease, biology.organism_classification, bacterial infections and mycoses, mortality, chemistry, ESBLs, Carbapenems, bacteria, Therapy, Bloodstream infections, business
Abstract

β-Lactam/β-lactamase inhibitors (BLBLIs) were compared to carbapenems in two cohorts of hematological neutropenic patients with extended-spectrum-β-lactamase (ESBL) bloodstream infection (BSI): the empirical therapy cohort (174 patients) and the definitive therapy cohort (251 patients). The 30-day case fatality rates and other secondary outcomes were similar in the two therapy groups of the two cohorts and also in the propensity-matched cohorts. BLBLIs might be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in these patients., We thank the ESGBIS and the ESGICH study groups for supporting the study. This study was supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—cofinanced by European Development Regional Fund “A way to achieve Europe” EDRF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).

Published
2017

5. The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

Author

Lorenzo, Petra I., Juarez-Vicente, Francisco, Cobo-Vuilleumier, Nadia, Garcia-Dominguez, Mario, Gauthier, Benoit R., [Lorenzo, Petra I.] Univ Pablo de Olavide, Dept Cell Regenerat & Adv Therapies, Pancreat Islet Dev & Regenerat Unit, CABIMER,Junta Andalucia,CSIC,Univ Sevilla, Calle Americo Vespucio 24, Seville 41092, Spain, [Cobo-Vuilleumier, Nadia] Univ Pablo de Olavide, Dept Cell Regenerat & Adv Therapies, Pancreat Islet Dev & Regenerat Unit, CABIMER,Junta Andalucia,CSIC,Univ Sevilla, Calle Americo Vespucio 24, Seville 41092, Spain, [Gauthier, Benoit R.] Univ Pablo de Olavide, Dept Cell Regenerat & Adv Therapies, Pancreat Islet Dev & Regenerat Unit, CABIMER,Junta Andalucia,CSIC,Univ Sevilla, Calle Americo Vespucio 24, Seville 41092, Spain, [Juarez-Vicente, Francisco] Univ Pablo de Olavide, Dept Cell Signaling & Dynam, Cell Differentiat Lab, CABIMER,Junta Andalucia,CSIC,Univ Sevilla, Calle Americo Vespucio 24, Seville 41092, Spain, [Garcia-Dominguez, Mario] Univ Pablo de Olavide, Dept Cell Signaling & Dynam, Cell Differentiat Lab, CABIMER,Junta Andalucia,CSIC,Univ Sevilla, Calle Americo Vespucio 24, Seville 41092, Spain, Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia, Consejeria de Economia, Innovacion y Ciencia, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III - Fondos FEDER, Ministerio de Economia y Competitividad, Plan Nacional, Fundacion Vencer el Cancer, and ALUSVI (Asociacion Lucha y Sonrie por la Vida, Pilas)

Subjects
PAX4, Beta-cells, Expression, SUMOylation, Stem-cells, Paired domain, regenerative therapy, Sequence recognition, Messenger-rna, beta-cell adaptation, Dna-binding, Differentiation, diabetes mellitus, Endocrine progenitors, Repressor, transcription regulation
Abstract

Paired box 4 (PAX4) is a key factor in the generation of insulin producing beta-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of beta-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates beta-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining beta-cells in parallel to the stimulation of their proliferation to replenish the beta-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action.

Published
2017

6. Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms

Author

Juan Carlos Ramos Ramos, Michael Osthoff, Cameron J Jeremiah, N. Benito, Julián Torre-Cisneros, Bojana Beović, Marta Mora-Rillo, Isabel Machuca, Michel Wolff, Enrique Navas, Belén Loeches, José Antonio Martínez, Raúl Gilarranz, María José Jiménez-Martín, Marina Rodríguez, Miguel Sánchez-García, Maddalena Giannella, J.C. Pozo, Yehuda Carmeli, Elizabeth Temkin, Pierluigi Viale, [Temkin, Elizabeth] Tel Aviv Sourasky Med Ctr, Dept Epidemiol & Prevent Med, Tel Aviv, Israel, [Carmeli, Yehuda] Tel Aviv Sourasky Med Ctr, Dept Epidemiol & Prevent Med, Tel Aviv, Israel, [Beovic, Bojana] Univ Med Ctr Ljubljana, Dept Infect Dis, Ljubljana, Slovenia, [Benito, Natividad] Hosp Santa Creu & Sant Pau, Dept Med, Infect Dis Unit, Barcelona, Spain, [Benito, Natividad] Univ Autonoma Barcelona, Inst Invest Biomed St Pau, Barcelona, Spain, [Giannella, Maddalena] Univ Bologna, S Orsola Malpighi Hosp, Dept Med & Surg Sci, Infect Dis Unit, Bologna, Italy, [Gilarranz, Raul] Hosp Univ Gran Canaria Doctor Negrin, Dept Clin Microbiol, Las Palmas Gran Canaria, Spain, [Jeremiah, Cameron] St Vincents Hosp, Dept Infect Dis, Melbourne, Vic, Australia, [Loeches, Belen] Hosp Univ La Paz IdiPAZ, Infect Dis Unit, Madrid, Spain, [Mora-Rillo, Marta] Hosp Univ La Paz IdiPAZ, Infect Dis Unit, Madrid, Spain, [Ramos Ramos, Juan Carlos] Hosp Univ La Paz IdiPAZ, Infect Dis Unit, Madrid, Spain, [Torre-Cisneros, Julian] Hosp Univ Reina Sofia, Dept Infect Dis, Cordoba, Spain, [Machuca, Isabel] Hosp Univ Reina Sofia, Dept Infect Dis, Cordoba, Spain, [Torre-Cisneros, Julian] Univ Cordoba, Inst Maimonides Invest Biomed, Cordoba, Spain, [Machuca, Isabel] Univ Cordoba, Inst Maimonides Invest Biomed, Cordoba, Spain, [Jose Jimenez-Martin, Maria] Hosp Clin San Carlos, Crit Care Dept, Madrid, Spain, [Sanchez-Garcia, Miguel] Hosp Clin San Carlos, Crit Care Dept, Madrid, Spain, [Antonio Martinez, Jose] Univ Barcelona, IDIBAPS, Hosp Clin, Dept Infect Dis, Barcelona, Spain, [Navas, Enrique] Hosp Ramon & Cajal, Dept Infect Dis, Madrid, Spain, [Osthoff, Michael] Univ Basel Hosp, Div Infect Dis & Hosp Epidemiol, Basel, Switzerland, [Carlos Pozo, Juan] Hosp Univ Reina Sofia, Dept Crit Care Med, Cordoba, Spain, [Rodriguez, Marina] Hosp Univ Reina Sofia, Dept Crit Care Med, Cordoba, Spain, [Viale, Pierluigi] Alma Mater Studiorum Univ Bologna, Dept Med Surg Sci, Bologna, Italy, [Wolff, Michel] Ctr Hosp Univ Bichat Claude Bernard, AP HP, Paris, France, [Wolff, Michel] Univ Paris Diderot, Paris, France, [Carmeli, Yehuda] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel, AstraZeneca, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III, and European Development Regional Fund (ERDF)

Subjects
0301 basic medicine, Male, Antibiotics, Salvage therapy, Bacteremia, medicine.disease_cause, Ceftazidime, Medical microbiology, Plus metronidazole, Pharmacology (medical), Blood-stream infections, Case report form, ceftazidime-avibactam, case series, Klebsiella-pneumoniae, Double-blind, Klebsiella oxytoca, Middle Aged, Anti-Bacterial Agents, Exact test, Drug Combinations, Klebsiella pneumoniae, Infectious Diseases, Combination, Pseudomonas aeruginosa, Female, Safety, medicine.drug, medicine.medical_specialty, Efficacy, medicine.drug_class, 030106 microbiology, carbapenem resistance, Microbial Sensitivity Tests, Clinical Therapeutics, 03 medical and health sciences, Enterobacteriaceae, Internal medicine, medicine, Humans, Colistin-resistant, Aged, Pharmacology, Salvage Therapy, business.industry, Ceftazidime/avibactam, Clinical trial, Carbapenems, business, Azabicyclo Compounds
Abstract

Ceftazidime-avibactam (CAZ-AVI) is a recently approved β-lactam–β-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used the Wilcoxon rank sum test and Fisher's exact test to compare patients by treatment outcome. The sample included 36 patients infected with CRE and two with CRPa. The most common infections were intra-abdominal. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twenty-five patients (65.8%) concurrently received other antibiotics to which their pathogen was nonresistant in vitro . Twenty-eight patients (73.7%, 95% confidence interval [CI], 56.9 to 86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died ( P = 0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenem-resistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited.

Published
2016

7. Oral decontamination with aminoglycosides is associated with lower risk of mortality and infections in high-risk patients colonized with colistin-resistant, KPC-producing Klebsiella pneumoniae

Author

Irene Gracia-Ahufinger, Belén Gutiérrez-Gutiérrez, Josefina Serrano, Julián Torre-Cisneros, José Barcala, Salvador Pérez Cortés, Jesús Rodríguez-Baño, Fernando Rodríguez-López, María Dolores Madrigal, Isabel Machuca, Ministerio de Economía y Competitividad (España), European Commission, Red Española de Investigación en Patología Infecciosa, [Machuca, Isabel] Univ Cordoba, IMIBIC, Hosp Univ Reina Sofia, Unit Infect Dis, Cordoba, Spain, [Torre-Cisneros, Julian] Univ Cordoba, IMIBIC, Hosp Univ Reina Sofia, Unit Infect Dis, Cordoba, Spain, [Gutierrez-Gutierrez, Belen] Univ Seville, Unit Infect Dis Clin Microbiol & Prevent Med, Hosp Univ Virgen Macarena & Virgen del Rocio, IBIS, Seville, Spain, [Rodriguez-Bano, Jesus] Univ Seville, Unit Infect Dis Clin Microbiol & Prevent Med, Hosp Univ Virgen Macarena & Virgen del Rocio, IBIS, Seville, Spain, [Gutierrez-Gutierrez, Belen] Univ Seville, Dept Med, Seville, Spain, [Rodriguez-Bano, Jesus] Univ Seville, Dept Med, Seville, Spain, [Perez Cortes, Salvador] Hosp Univ Jerez, Unit Infect Dis, Cadiz, Spain, [Barcala, Jose] Hosp Univ Jerez, Unit Infect Dis, Cadiz, Spain, [Gracia-Ahufinger, Irene] Univ Cordoba, Hosp Univ Reina Sofia, IMIBIC, Unit Microbiol, Cordoba, Spain, [Rodriguez-Lopez, Fernando] Univ Cordoba, Hosp Univ Reina Sofia, IMIBIC, Unit Microbiol, Cordoba, Spain, [Serrano, Josefina] Univ Cordoba, Hosp Univ Reina Sofia, IMIBIC, Unit Haematol, Cordoba, Spain, [Dolores Madrigal, Maria] Hosp Univ Jerez, Unit Haematol, Cadiz, Spain, [Machuca, Isabel] Spanish Network Res Infect Dis REIPI, Barcelona, Spain, [Gutierrez-Gutierrez, Belen] Spanish Network Res Infect Dis REIPI, Barcelona, Spain, [Gracia-Ahufinger, Irene] Spanish Network Res Infect Dis REIPI, Barcelona, Spain, [Rodriguez-Lopez, Fernando] Spanish Network Res Infect Dis REIPI, Barcelona, Spain, [Rodriguez-Bano, Jesus] Spanish Network Res Infect Dis REIPI, Barcelona, Spain, [Torre-Cisneros, Julian] Spanish Network Res Infect Dis REIPI, Barcelona, Spain, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III, European Development Regional Fund 'Away to achieve Europe' ERDF, Spanish Network for Research in Infectious Diseases, COMBACTE-CARE (Combatting bacterial resistance in Europe-Carbapenem resistance), Innovatives Medicine Initiative (IMI), European Union's Seventh Framework Programme (FP7), and EFPIA companies'

Subjects
0301 basic medicine, Male, Antibiotics, Administration, Oral, Drug resistance, 0302 clinical medicine, Pharmacology (medical), 030212 general & internal medicine, Gentamicin, Decontamination, Aged, 80 and over, Middle Aged, 3. Good health, Anti-Bacterial Agents, Klebsiella pneumoniae, Impact, Infectious Diseases, Treatment Outcome, Streptomycin, Carrier State, Female, Risk assessment, medicine.drug, Microbiology (medical), medicine.medical_specialty, medicine.drug_class, 030106 microbiology, Biology, Neutropenia, Lower risk, Risk Assessment, beta-Lactamases, Carbapenem-resistant, 03 medical and health sciences, Enterobacteriaceae, Sepsis, Internal medicine, Drug Resistance, Bacterial, medicine, Humans, Aged, Pharmacology, Predictors, Colistin, medicine.disease, Survival Analysis, Surgery, Klebsiella Infections, Aminoglycosides, Follow-Up Studies
Abstract

[Objectives] Invasive infections caused by KPC-producing Klebsiella pneumoniae (KPCKP) are associated with very high mortality. Because infection is usually preceded by rectal colonization, we investigated if decolonization therapy (DT) with aminoglycosides had a protective effect in selected patients., [Methods] Patients with rectal colonization by colistin-resistant KPCKP who were at high risk of developing infection (because of neutropenia, surgery, previous recurrent KPCKP infections or multiple comorbidities) were followed for 180 days. Cox regression analysis including a propensity score was used to investigate the impact of the use of two intestinal decolonization regimens with oral aminoglycosides (gentamicin and neomycin/streptomycin) on mortality, risk of KPCKP infections and microbiological success. The study was registered with ClinicalTrials.gov (NCT02604849)., [Results] The study sample comprised 77 colonized patients, of which 44 (57.1%) received DT. At 180 days of follow-up, decolonization was associated with a lower risk of mortality in multivariate analyses (HR 0.18; 95% CI 0.06–0.55) and a lower risk of KPCKP infections (HR 0.14; 95% CI 0.02–0.83) and increased microbiological success (HR 4.06; 95% CI 1.06–15.6). Specifically, gentamicin oral therapy was associated with a lower risk of crude mortality (HR 0.15; 95% CI 0.04–0.54), a lower risk of KPCKP infections (HR 0.86; 95% CI 0.008–0.94) and increased microbiological response at 180 days of follow-up (HR 5.67; 95% CI 1.33–24.1). Neomycin/streptomycin therapy was only associated with a lower risk of crude mortality (HR 0.22; 95% CI 0.06–0.9)., [Conclusions] Intestinal decolonization with aminoglycosides is associated with a reduction in crude mortality and KPCKP infections at 180 days after initiating treatment., Funded by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—co-financed by the European Development Regional Fund ‘A way to achieve Europe’ ERDF, the Spanish Network for Research in Infectious Diseases (REIPI RD12/0015). We also received funding from COMBACTE-CARE (Combatting bacterial resistance in Europe—Carbapenem resistance), the Innovatives Medicine Initiative (IMI), the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies′ in-kind contribution (call IMI 9th), Grant agreement 115620.

Published
2016

8. Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

Author

J. Pérez del Palacio, R. Parra Millán, L. F. López Cortés, Younes Smani, Caridad Díaz, V. Sánchez Encinales, R. Ayerbe Algaba, M. E. Pachón Ibáñez, M. E. Jiménez Mejías, A. Gutiérrez Valencia, Jerónimo Pachón, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Red Española de Investigación en Patología Infecciosa, Fundación MEDINA, [Parra Millan, R.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Jimenez Mejias, M. E.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Sanchez Encinales, V.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Ayerbe Algaba, R.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Gutierrez Valencia, A.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Pachon Ibanez, M. E.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Lopez Cortes, L. F.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Pachon, J.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Smani, Y.] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain, [Diaz, C.] Fdn MEDINA, Fdn Ctr Excelencia Invest Medicamentos Innovadore, Granada, Spain, [Perez del Palacio, J.] Fdn MEDINA, Fdn Ctr Excelencia Invest Medicamentos Innovadore, Granada, Spain, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases, Fundacion MEDINA, Merck Sharp & Dohme de Espana S.A./Universidad de Granada/Junta de Andalucia, and European Development Regional Fund

Subjects
0301 basic medicine, Acinetobacter baumannii, Imipenem, Cells, 030106 microbiology, Enzyme-Linked Immunosorbent Assay, Minocycline, Tigecycline, Microbial Sensitivity Tests, Microbiology, Sepsis, 03 medical and health sciences, Mice, medicine, polycyclic compounds, Animals, Experimental Therapeutics, Pharmacology (medical), Multidrug-resistant, Pharmacology, biology, business.industry, Colistin, Tumor Necrosis Factor-alpha, Lysophosphatidylcholines, Pneumonia, biochemical phenomena, metabolism, and nutrition, medicine.disease, Antimicrobial, biology.organism_classification, bacterial infections and mycoses, Anti-Bacterial Agents, Interleukin-10, Infectious Diseases, Bacteremia, Critically-ill patients, lipids (amino acids, peptides, and proteins), Rifampin, business, Infection, Immune-responses, medicine.drug
Abstract

Immune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We used Acinetobacter baumannii strain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD100) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD100 in murine peritoneal sepsis and pneumonia models. The levels of pro- and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P < 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-α and lower IL-10 levels than those with Ab186 (4 μg/ml versus 3 μg/ml [P < 0.05] and 2 μg/ml versus 3.4 μg/ml [P < 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection by A. baumannii strains with different resistance phenotypes compared to LPC monotherapy in both experimental models., This study was supported by the Instituto Carlos III, Proyectos de Investigación en Salud (grant PI13/01744). Y.S. was funded by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), by the Spanish Network for Research in Infectious Diseases (grant REIPI RD12/00015/0001), and by the Subprograma Miguel Servet Tipo I from the Ministerio de Economia y Competitividad of Spain (grant CP15/01358). The MEDINA authors disclose the receipt of financial support from Fundación MEDINA, a public-private partnership of Merck Sharp & Dohme de España S.A./Universidad de Granada/Junta de Andalucía.

Published
2016

9. PAX4 Defines an Expandable β-Cell Subpopulation in the Adult Pancreatic Islet

Author

Alejandro Martin-Montalvo, Petra I. Lorenzo, Nadia Cobo-Vuilleumier, Benoit R. Gauthier, Esther Fuente-Martín, Bernat Soria, José Manuel Mellado-Gil, Carmen Maria Jimenez-Moreno, Irene de Gracia Herrera Gómez, Livia López Noriega, Thierry Brun, [Lorenzo,PI, Fuente-Martín,E, Cobo-Vuilleumier,N, Jimenez-Moreno,CM, Herrera Gomez,IG, López Noriega,L, Mellado-Gil, JM, Martin-Montalvo,A, Gauthier,BR] Pancreatic Islet Development and Regeneration Unit, and [Soria,B] Cellular Therapy of Diabetes Mellitus and its Complications, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain. [Brun,T] Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. [Soria,B] CIBERDEM, Instituto Carlos III, Madrid, Spain, and This work was funded by grants from the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to B.R.G. and PI-0085-2013 to P.I.L.), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to B.R.G.), the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III co-funded by Fondos FEDER (PI10/00871 and PI13/00593 to B.R.G.) and the Fundacion Vencer el Cancer (to B.R.G.).

Subjects
Aumento de la célula, Apoptosis, Green fluorescent protein, Cell growth, Mice, Insulin-Secreting Cells, Insulin Secretion, Insulin, Paired Box Transcription Factors, Promoter Regions, Genetic, Regulation of gene expression, education.field_of_study, Multidisciplinary, geography.geographical_feature_category, ndocrine system and metabolic diseases, Islet, Enfermedades del sistema endocrino, Cell biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Peptide Hormones::Pancreatic Hormones::Insulins [Medical Subject Headings], Enfermedades metabólicas, medicine.medical_specialty, Green Fluorescent Proteins, Population, Cre recombinase, Mice, Transgenic, Biology, Article, Internal medicine, Diabetes Mellitus, medicine, Animals, Cell Lineage, Progenitor cell, education, Cell Proliferation, Homeodomain Proteins, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Dedifferentiation [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], geography, Anatomy::Digestive System::Pancreas::Islets of Langerhans [Medical Subject Headings], Anatomy::Cells::Endocrine Cells::Enteroendocrine Cells::Insulin-Secreting Cells [Medical Subject Headings], Cell Dedifferentiation, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis [Medical Subject Headings], Mice, Inbred C57BL, Endocrinology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Luminescent Proteins::Green Fluorescent Proteins [Medical Subject Headings], Gene Expression Regulation, Hyperglycemia, PAX4
Abstract

PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects β-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes β-cell dedifferentiation and hyperglycemia, mimicking β-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable β-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched β-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4+ progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP+ subpopulation expanded during pregnancy, a state of active β-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP+ cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP+ cells were more resistant to apoptosis than their GFP- counterparts. Our data suggest PAX4 defines an expandable β-cell sub population within adult islets.

Published
2015
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10. Detection of interleukin-2 is not useful for distinguishing between latent and active tuberculosis in clinical practice: a prospective cohort study

Author

Francesca Sánchez, Ángel Domínguez-Castellano, Jesús Agüero-Balbin, Diego J. Pargada-Ferrer, N. Jové, Elvira Pérez-Escolano, F. Morandeira-Rego, Edu A. Struzka, X. Casas-Garcia, R. Agüero-Balbín, Mónica Ríos, Juan F. Rodríguez-Gutiérrez, A. Gonzalez-Cuevas, A. Coira-Nieto, R. Rabuñal, Fernando Alcaide, Abel Pallarés-Sanmartín, Joan Climent, Miguel Santin, Luis Anibarro, M.D. López-Prieto, Antón Penas-Truque, M. Trigo-Daporta, A. Martinez-Meñaca, María Dolores González-Ripoll Navarro, [Santin, M.] Bellvitge Univ Hosp IDIBELL, Infect Dis Serv, Barcelona 08907, Spain, [Santin, M.] Univ Barcelona, Dept Clin Sci, Barcelona, Spain, [Morandeira-Rego, F.] Bellvitge Univ Hosp IDIBELL, Serv Immunol, Barcelona, Spain, [Alcaide, F.] Bellvitge Univ Hosp IDIBELL, Microbiol Serv, Barcelona, Spain, [Alcaide, F.] Univ Barcelona, Dept Pathol & Expt Therapy, Barcelona, Spain, [Rabunal, R.] Hosp Univ Lucus Augusti, Infect Dis Unit, Lugo, Spain, [Anibarro, L.] Complexo Hosp Univ Pontevedra, Serv Infect Dis Internal Med, Unit TB, Pontevedra, Spain, [Aguero-Balbin, R.] Hosp Univ Marques de Valdecilla, Serv Resp Dis, Santander, Spain, [Martinez-Menaca, A.] Hosp Univ Marques de Valdecilla, Serv Resp Dis, Santander, Spain, [Casas-Garcia, X.] Hosp Gen Parc Sanitari St Joan de Deu, Resp Dis, Barcelona, Spain, [Perez-Escolano, E.] Hosp Jerez, Unidad Gest Clin Enfermedades Infecciosas & Micro, Cadiz, Spain, [Lopez-Prieto, M. D.] Hosp Jerez, Unidad Gest Clin Enfermedades Infecciosas & Micro, Cadiz, Spain, [Navarro, M. D.] Hosp Virgen Macarena, Clin Unit Infect Dis & Prevent Med, Seville, Spain, [Dominguez-Castellano, A.] Hosp Virgen Macarena, Clin Unit Infect Dis & Prevent Med, Seville, Spain, [Sanchez, F.] Hosp del Mar, IMIM, Infect Dis Serv, Barcelona, Spain, [Jove, N.] Hosp del Mar, IMIM, Infect Dis Serv, Barcelona, Spain, [Coira-Nieto, A.] Hosp Univ Lucus Augusti, Microbiol Serv, Lugo, Spain, [Trigo-Daporta, M.] Complexo Hosp Univ Pontevedra, Microbiol Serv, Pontevedra, Spain, [Gonzalez-Cuevas, A.] Hosp Gen Parc Sanitari St Joan de Deu, Microbiol Serv, Barcelona, Spain, and Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (ISCIII) of the Spanish Government

Subjects
Adult, Male, 0301 basic medicine, Microbiology (medical), Interleukin 2, medicine.medical_specialty, Tuberculosis, Cells, 030106 microbiology, QuantiFERON, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Memory, Interquartile range, Internal medicine, medicine, Humans, Latent tuberculosis infection, Interferon gamma, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Tuberculosis, Pulmonary, Incubation, Aged, Latent tuberculosis, business.industry, General Medicine, Middle Aged, bacterial infections and mycoses, medicine.disease, Active tuberculosis, Infectious Diseases, Spain, Immunology, Interleukin-2, Female, business, Biomarkers, medicine.drug
Abstract

Previous reports have identified interleukin-2 (IL-2), quantified in the supernatants of QuantiFERONA multicentre study of 161 consecutive adult patients undergoing evaluation for active TB at eight TB Units in Spain. Interferon-γ (IFN-γ) and IL-2 were assessed in the supernatant of QFT after 16-24 h and 72 h of incubation. The accuracy of IL-2 for indicating latent TB infection (LTBI) was assessed by receiving operating characteristic curves. .Twenty-eight participants were not infected, 43 had LTBI, 69 had TB, and 21 were not classifiable. Median (interquartile range) IL-2 concentrations after 72 h of incubation were 0.0 pg/mL (0.0-0.0) in uninfected individuals, 261.0 pg/mL (81.0-853.0) in LTBI individuals, 166.5 pg/mL (33.5-551.5) in patients with extrapulmonary TB, 95.0 pg/mL (26.0-283.0) in patients with smear-negative pulmonary TB, and 38.5 pg/mL (7.5-178.0) in patients with smear-positive pulmonary TB (p0.0001). The area under the curve of the receiving operating characteristic curve (95% CI) of IL-2 after 72 h of incubation for the diagnosis of LTBI was 0.63 (0.53-0.74) when all TB cases were considered as a single group, ranging from 0.59 (0.47-0.71) to 0.72 (0.58-0.85) when only extrapulmonary and smear-positive pulmonary TB cases respectively were considered.Quantification of IL-2 in the supernatant of QFT after a prolonged incubation is not useful to distinguish between LTBI and active disease in clinical practice.

Published
2016
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