SCOPE

Our mission is to give the opportunity to develop critical thinking skills needed to carry out a well- sustained investigation, in order to spread knowledge with great responsibility in the constant search for academic, scientific and research excellence that science demands world-

wide.

Journal of Medical Students Reviews is a student-founded, student-administered and student managed digital and free Access journal, under guidance of faculty and staff. Created to give opportunity to develop the critical thinking skills needed to carry out a well- sustained investigation.

THE JOURNAL OF MEDICAL'S STUDENTS REVIEWS is a quarterly publication of the Faculty of Medicine, Universidad Autónoma de San Luis Potosí, Av. Venustiano Carranza #2405 Col los Filtros CP. 78210, San Luis Potosí, S.L.P. 8 26 23 00 ext. 6688. Web page: www.medicina.uaslp.mx/Publicaciones/JMSR Chief Editor: Mauricio Pierdant Pérez. Reserva de derechos al autor exclusivo and Inter-national Estándar Serial Number: in process, both awarded by the Instituto Nacional del Derecho del Autor. Responsible for the latest

update of this issue. Date of last update.The opinions expressed in the content of the articles are the responsibility of the authors and do not necessarily reflect the point of view of the reviewers or the publisher. It is totally forbidden the total or partial reproduction of the content of this magazine by any means

even electronic, nor translated into other languages without written authorization of its publishers. Journal of Medical Students Reviews by Facultad de Medicina UASLP is licensed under a Creative Commons Reconocimiento-NoCo-

mercial-SinObraDerivada 4.0 Internacional License.

MISSION

VALUES

By 2023 we will be an international magazine included in the most important indexes of quality and quotation in the area of health, in constant growth and with publications of the

highest quality.

VISION

HonestyMedical student empowerment

Compromise Responsibility

DIRECTIVE COMMITTEE

RECTOR OF THE UNIVERSITYDIRECTORCHIEF EDITORASSOCIATE EDITOR

MANUEL FERMÍN VILLAR RUBIO M ARCH

ALEJANDRO JAVIER ZERMEÑO GUERRA MDMAURICIO PIERDANT PÉREZ MD, MSC

MARÍA ISABEL PATIÑO LÓPEZ MLIS

LILIANA ITAMAR CARRILLO BARBA MSANDRÉS CASTILLO DIMAS MSALEJANDRA DE LA TORRE SOTO MSROCÍO DANIELA OCHOA VALTIERRA MSLIZETH GUADALUPE ORTIZ VÁZQUEZ MS

AREA EDITORS

BLANCA ARIADNA CARRILLO ÁVALOS MD MARIANA SALGADO BUSTAMANTE MD, PhDCHRISTIAN A. GARCÍA SEPÚLVEDA MD, PhDSERGIO SÁNCHEZ-ARMÁSS ACUÑA MD, PhDESTHER LAYSECA ESPINOSA MD, PhDUCIEL RENÉ OCHOA PÉREZ MD MSC

ANTONIO A. GORDILLO MOSCOSO MD, PhD EMMANUEL RIVERA LÓPEZ MDDAVID DE DANIEL ESMER SÁNCHEZ MDRAÚL ROQUE SÁNCHEZ MDJUAN CARLOS TORO ORTIZ MDAMADO NIETO CARAVEO MD, MSC

MARISOL OROCIO CONTRERAS MD, PhD

EDITORIAL COMMITTEE

MORPHOLOGYBIOCHEMISTRYMOLECULAR BIOLOGYPHYSIOLOGYIMMUNOLOGYMICROBIOLOGYPHARMACOLOGYINTERNAL MEDICINESURGERYPEDIATRICSGYNECOLOGYPUBLIC HEALTHMENTAL HEALTH

ÍNDEX

EditorialMAURICIO PIERDANT PEREZ.CHIEF EDITOR

Vital Disorder:Is the lipid membrane asymmetry associated with autoimmune diseases?

ALEJANDRA DE LA TORRE SOTO MS

ANDRÉS CASTILLO DIMAS MS

How should drug-drug interactions be taught at medschool? LILIANA ITAMAR CARRILLO BARBA MS

Antibiotics use in early life, its relation on the development of obesity and the impact in the microbiota.

ROCÍO DANIELA OCHOA VALTIERRA MS

LIZETH GUADALUPE ORTIZ VÁZQUEZ MS

1-2 p.

3-9 p.

10-16 p.

17-22 p.

Guide for authors JMSR

ARTICLES

23 p.

EDITORIAL

WELcOmE TO ThE JOuRnAL Of mEDIcAL STuDEnTS REvIEWS

Pierdant-Pérez Mauricio1

1Chief Editor.

Facultad de Medicina. Universidad Autónoma de San Luis PotosíAv. Venustiano Carranza #2405. San Luis Potosí, SLP, Z.P. 78210. Mexico

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This project began in the year 2010 when we decided to formally create the subject of medical informatics at our school of medicine, coupled with this we were concerned that medical students had no interest nor instruction in relation to clinical and basic research and that it was difficult for them to learn the dynamics of critical reading, document search and understanding of technical texts in the health area.

Initially the course aproached certain elements of critical thinking that were evolving as the subject advanced, from the year 2012 it contained four modules that guide students toward the acquisition of skills in four categories that proved to be critical: development of critical thinking, analysis of literature from clinical

research, advanced computer search and analysis of the evidence, culminating with a documentary research in the form of a systematic review of the medical literature; this allowed medical students within the basic areas of their training, to understand the different dimensions of the evidence shown to them. As all active process, starting from the year 2014, the students presented best documentary research which allowed a glimpse of the state of the art of various topics, which were worked on by students from the cognitive elements displayed by their teachers of the first two years of the career of a physician.

Documentary research turned into locally produced systematic reviews that allowed us to define elements for future research

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and students showed more interest in the publication of results and the dissemination of their ideas as well as the interaction with teachers and students from different places, all this gave rise to the creation of a digital magazine that would show the results of these reviews and that lead students to the information management and the intricate world of publications scientific.

The spirit of the project is also to empower the medical student so he can become the creative motor of published research in the journal, so it is required to be a medical student to be able to collaborate and publish in the journal, once the student gets the degree of medical doctor it is no longer possible to use the network magazine for publication.

This premise gives meaning to the editorial committee which is constituted by medical students of different academic years, who have taken the subject of “Medical Informatics” and who have been involved in the Journal. Once they get their grade they become part of the editorial board. For the operational part of the different areas of medicine we have an extensive group of professors of different subjects that constitute the area editors and give strength and academic recognition and they help the editor in Chief and the editorial Committee to give a critical review of the material emanating from the Journal.

This initial number presents three papers of the students of the editorial comitte, the first one establishes a search for the relationship between the lipid cell membrane asymmetry and its association with autoimmune diseases as an etiological pursue; the second is a systematic review linking the use of antibiotics in the first months of life, the impact on the intestinal microbiota and its role in the emergence of obesity and ultimately a review article with a small survey , about how to teach pharmacological interactiones in Medical School. All the collaborators that work on this project of the Journal of Medical Students Reviews invite you to subscribe and follow us on our social networks.

How to cite this article: Pierdant-Pérez M. Welcome to the Journal of Medical Students Reviews. JMSR. 2017 Jul-Sep;1(1):1-2.

VITAL DISORDER:Is the lipid membrane asymmetry associated with autoimmune diseases?

De la Torre-Soto Alejandra1 ; Castillo-Dimas Andrés1

1Facultad de Medicina. Universidad Autónoma de San Luis PotosíAv. Venustiano Carranza #2405. San Luis Potosí, SLP, Z.P. 78210. Mexico

Abstract

Key Words: MEMBRANE ASYMMETRY, LIPID BILAYER, AUTOIMMUNITY, APOPTOSIS, AUTOIMMUNE

DISEASES.

Corresponding autors

Castillo-Dimas Andrésandrescasdim@gmail.com

De La Torre-Soto Alejandraale_ts96@hotmail.com

How to cite this article: De la Torre-Soto A, Castillo-Dimas A. Vital disorder: is the lipid membrane asymmetry associated with autoinmmune diseases. JMSR. 2017 Jul-Sep;1(1):3-9.

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Autoimmune diseases are complex, they arise when the immune system attacks one or more of the body's normal components as if they were foreign or invaders. When the immune system fails to recognize "self" it may produce autoantibodies that target its own cells. Those attacks cause inflammation and tissue damage that lead to autoimmune disorders. It has been proposed that a related factor that triggers these types of diseases can be imputed to the loss of normal composition of cell membranes. Cell membranes are composed by several types of structures, a main component is the lipid bilayer (two leaflets), which has been firmly established as the universal basis for cell-membrane structure. Lipid bilayer is a membrane made of two layers of lipid molecules; it is a barrier for the cell which is in charge of preventing molecules or proteins to get into the cell when they are no required, and ….The two leaflets of the cell membrane differ in lipid composition: the outer leaflet comprises mainly neutral choline containing phospholipids (amphipathic molecules) whereas the aminophospholipids reside almost exclusively in the cytoplasmic leaflet. The different components and concentrations maintained in the Lipid membrane within its leaflets is called membrane asymmetry.

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Studying the physiology of eukaryotic cell membranes, it was stated on the article “la membrana plasmática: modelos, balsas y señalización by Ulises Meza, Ana Catalina Romero-Méndez, Yamhilette Licón y Sergio Sánchez-Armáss” , that the proper maintenance of membrane asymmetry is related to prevention of autoimmune diseases, with no further information given we decided to carry out a deeper investigation about this topic.

METHODS

PubMed and Big metasearch engines were used to retrieve the articles quoted and the following criteria were followed; articles based only on eukaryotic cells and with no publication date restrictions.The first inquiry was made using the key words “lipid membrane” AND “asymmetry” giving 1170 matches, the keyword “immunity” was added to the search narrowing it down to 27 matches.Still in the need of more information a second search was conducted implying the key words “membrane asymmetry” AND “immunity”, 42 matches were given by PubMed, which were analyzed with the previously mentioned criteria.

Only 14 articles were taken in to account due to that eleven of them were not related with the type of information we were seeking for.Later on using ProQuest MEDLINE, we made a final search using keywords “autoimmune diseases” AND “lipid bilayer” MeSH terms, obtaining 21 results and using just two of them, because they embraced important information for this inquiry.

Cell membrane asymmetry can be observed in several ways, for simplicity purposes in this review; we will describe horizontal and vertical asymmetry. Viewing the lipid bilayers we can observe that one side of the membrane interacts with the inner part of the cell (cytosolic layer) and the other side interacts with the surroundings (external layer). The cell membrane is not a rigid structure and some of its components are capable of moving to different sides of the cell making it possible for these components to interact with others near them, this is called lateral asymmetry. The functionality of the cell depends on both of these factors since they determine its ability to interact with its surroundings.As it will be mentioned, the outer monolayer of the plasma membrane is composed mainly of phosphatidylcholine and sphingomyelin, whereas the internal monolayer preferably includes phosphatidylserine and phosphatidylethanolamine. Lipid asymmetry between monolayers of bio membranes is generated through different processes, for example, spontaneous transfer of lipid components between these monolayers by an event called “flip-flop”, ATPases activity of lipid species and specific retention of certain lipids in one or other monolayers.

HORIZONTAL/LATERAL ASYMMETRY:

In order to start describing the importance of horizontal asymmetry we must first describe some components that are of relevance. There are lateral domains within the bilayer plane, known as lipid rafts.(1)

Lipid rafts are domains of the plasma

QUESTION AND CONTEXT INTRODUCTION

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membrane that contain high concentrations of cholesterol and glycosphingolipids. Glycosylphosphatidylinositol (GPI) is a glycolipid that is covalently linked by a glucosamine to the C terminus of proteins as a post-translational modification. GPI-anchored proteins have a significant role in the control of autoimmunity. GPI-anchored proteins are enriched in lipid rafts, they regulate the apoptotic function of the cell and T lymphocytes expressing CD4 (Th1/Th2) which are regarded as being the most prolific cytokine producers and this could be related to the control of autoimmunity because they can recognize normal tissue during episodes of autoimmune diseases.(2)

Several studies reported that cross-linking glycosyl-phosphatidylinositol–anchored proteins (GPI-Aps) by antibodies could induce intracellular signals. Lipid rafts have an important role in controlling appropriate protein interactions in resting and activated T cells, and that aggregation of rafts following receptor ligation is a structural associated mechanism for promoting immune cell signaling. T cell activation is necessary for normal physiological function, otherwise autoimmune or other diseases may occur.(2)

VERTICAL ASYMMETRY:

As described before, vertical asymmetry will be influenced by internal and external factors that will give the cell different biophysical properties to each side of the membrane(3) influencing numerous cellular functions. This asymmetry will be given by the concentrations of different components in each side of the membrane and for purposes of this review we shall board only phospholipids, for example phosphatidylcoline, sphingomyelin and

glycosphingolipids that are primarily found on the outer leaflet while phosphatidylserine (PS) and phosphatidylethanolamine (PE) are enriched in the cytosolic leaflet.(4) Changes in these concentrations will have effects on the cell, for example; when phosphatidylserine (PS) is exposed to the outer side of the cellular membrane it could act as a recognition or “eat me” signal for phagocytes(5) and also promote the blood coagulation cascade.(3)

This non-random distribution of different lipid species in the lipid bilayer is controlled by different proteins (called flippases) that are transporters capable of assisting in the active phospholipid translocation across the bilayer.(6) There are at least three models that have been proposed for these enzymes that are ATP dependent; a “flippase” that catalyzes an inward transport of lipids, a “floppase” that causes an outward movement of lipids and a “scramblase” which stimulates a bidirectional movement of lipids.(3) The first two enzymes mentioned above have the function to create and maintain the lipid asymmetry while on the other hand bi-

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directional movement of lipids causes the collapse of asymmetry.(3)

Talking more specifically there is a type of component that interact in such matter with the cellular membrane called P4-ATPases which can flip lipids from the outer part of the bilayer to the inner part of the bilayer.(3,7)

Opposite to the P4-ATPases there are molecules called ABC (ATP-binding cassette) transporters which have different substrates but also work in the opposite direction (in to out) in the movement of lipids. It has been described that ions play an important role in the maintenance of membrane asymmetry, such as calcium, since there are some scramblases that are Ca2+ dependent and others with the opposite effect, like the aminophospholipid translocase (a plasma membrane Mg2(+)-ATPase which selectively moves the aminophospholipids PS and phosphatidylethanolamine from the outer to the inner layer) that are inhibited by such ions. (3) Studies have shown that exposure of PS by an apoptotic cell (programed cell death) in its outer membrane can serve as an “eat me” signal for macrophages in order for its correct removal,(5) Ca2+ seems to be an active part in the regulation of both cell survival and cell death since it appears that PS exposure to the outer leaflet of the membrane in cells undergoing death receptor-mediated apoptosis is Ca2+ dependent yet not Ca2+ regulated in some cells. ASYMMETRY AND AUTOIMMUNITY:

Autoimmunity can be defined as a process characterized by the loss of tolerance to body cells, from immune system. This leads to the production of large quantities of autoreactive antibodies and the formation

of immune complexes, which causes tissue damage. Genetic defects, drug exposure, infectious agents, and environmental factors can also contribute to the pathogenesis of this disease.(8)

A group of Mexican investigators(8) developed a mouse model of autoimmune disease resembling human lupus that can be induced in normal mice. In this model, the disease is unfettered by liposomes with non-bilayer phospholipid arrangements. Liposomes are model membranes made of cylindrical phospholipids, such as phosphatidylcholine, and conical phospholipids, such as phosphatidic acid, phosphatidylserine, or cardiolipin.

Conical phospholipids can form molecular associations distinct to lipid bilayers, known as non-bilayer phospholipid arrangements, in the presence of inducers such as Mn 2+. Non-bilayer phospholipid arrangements are made of an inverted micelle that distorts the phospholipid bilayer´s shape. They demonstrated that liposomes with non-bilayer phospholipid arrangements, induced by Mn 2+, cause an autoimmune disease resembling human lupus in mice.In the study, they investigated whether liposomes with non-bilayer phospholipid arrangements are Toll-like receptor (TLR-4) and myeloid differentiation factor 2 (MD-2) agonists, because the activation of this innate immune receptor leads to the production of pro-inflammatory cytokines. TLR-4 and MD-2 form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules.(9)

The findings reported in the study are were based on a mouse model in which non-bilayer phospholipid arrangements directly activate TLR-4 and TLR-2/TLR-6 and lead

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to the production of pro-inflammatory cytokines. This environment leads to the activation of the adaptive immune response to the production of IgG antibodies specific for non-bilayer phospholipid arrangements. These antibodies bind to the non-bilayer phospholipid arrangements that are transitorily formed on the surface of many cells and cause cell lysis. The further exposure of intracellular antigens could lead to the formation of anti-cardiolipin, anti-histone, and anti-coagulant antibodies. Furthermore, the inflammatory environment can cause complement-mediated tissue damage and IFN- ß production. Thus, this mouse model of autoimmune disease recapitulates many features of human lupus.(10) All these is related somehow with membrane asymmetry. The clearance of apoptotic cells is granted by high levels of redundancy including receptors and “opsonins” among others. This said evidence shows that these mechanisms also do not have the same relevance(5) so we can assume that failure in one of these systems can have a greater effect than others. When the mechanism of apoptotic cell clearance is impaired or overloaded with an excessive rate of apoptosis or affected by abnormal production of cytokines this can lead to an increase in availability of potentially immunogenic material to the immune response (apoptotic cell residues). A relevant event is that the binding of PS-exposing apoptotic cells to the PS-receptor will trigger the release of anti-inflammatory cytokines such as TGF-ß and IL-10, which inhibits the production of pro-inflammatory cytokines.(5)

Macrophages are not the only cells able to phagocyte apoptotic cells, also dendritic cells (often referred as the professional antigen presenters of the immune system)

possess the capacity of phagocyte apoptotic cells and help with cell clearance yet not with the same efficiency as macrophages. Afterwards dendritic cells process protein antigens from apoptotic cells and present them using their MHC class I molecules yet according to studies, they will not be able to induce T stimulation because of the lack of co-stimulation.In the case of a “danger signal” such as with necrotic cells or a viral infection, they can lead to not only the presentation of peptides but also in the expression of enough co-stimulatory molecules such as cytokines and pro-inflammatory molecules to activate the dendritic cell and cause auto-presentation of peptides from apoptotic cells(5) to the immune system.Apoptosis and cell clearance signaling is not the only biological implication of membrane asymmetry but also the appearance of PS and PE on the cell surface have been implicated in processes such as blood coagulation, myotube formation, vesicle fusion, cell division, sperm capacitation,(13) as mentioned before phagocytic recognition and clearance of apoptotic cell corpses, we shall board this subjects next.(3) Moving on to the previously explained lateral asymmetry specifically talking about lipid rafts, one of the functions attributed to them is signal transduction due to the presence of key signaling proteins such as Src-family kinases, GTP binding proteins and GPI-linked receptors.(11) Lipid rafts appear to play a key role in the protein-protein interactions within T-cells where the adequate spatio-temporal localization of proteins is essential for determining signaling activity, in the case of the TCR a key requirement for its signal transduction is dual acetylation of Lck and since acetylation of proteins determines

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their localization to cholesterol-sensitive lipid raft domains shows evidence that supports that lipid rafts play a role in TCR signaling.(12) Higher levels of CD45 observed in lipid rafts in lymphocytes of patients with autoimmune diseases and stimulation of cells with anti-CD3/CD28 revealed faster kinetics of CD45 reorientation in relation to the cell: bead contact area(12) being strong evidence that compositional these changes among others within the lipid rafts and alteration in its function play a role in autoimmune diseases but these mechanisms are not yet clearly understood.

DISEASES ASSOCIATED TO LOSS OF LIPID MEMBRANE ASYMMETRY.

Kidney stone disease.Abnormal exposure of (PS) on renal epithelial cells has to be with the formation of kidney stones. When PS is exposed, it promotes the binding of calcium oxaloacetate crystals and the growth of renal stones.(13) Scott syndrome.It is a rare and severe bleeding disorder. It consists on impaired blood coagulation of platelets. It is due to an ineffective scramblase resulting in an impaired scrambling of the PL after activation, leading to an alteration on the clotting cascade.(13)

CONCLUSIONS

Maintaining this membrane asymmetry is of vital importance for the cell since it plays a role with the interaction of its components among themselves and with the cell’s surroundings. Talking about vertical asymmetry it will mediate the exposure of different components to the outer and inner leaflet, while it is not independent of horizontal asymmetry (lipid rafts)

since it will mediate the capacity of those components to interact with each other, cells and biomolecules in order to maintain cellular stability. It is important to find more information about this topic to improve treatments even prevention of these type of diseases.

•Cellular membrane asymmetry is a non-random event with systemic implications.•Membrane asymmetry grants or prevents components from interaction with themselves as well as with surrounding cells and biomolecules.•It is vital to understand the way autoimmunity occurs in order to, in a future, understand and prevent these kinds of diseases.•Autoimmune diseases can develop as the consequence of the increase in availability of potentially immunogenic material to the immune response.•Even though dendritic cells phagocyte apoptotic cells they will not be able to induce T stimulation unless they have proper co-stimulation. Author’s contributionsDe la Torre-Soto and Castillo Dimas made the same contribution to the review.

AcknowledgmentsThe completion of this undertaking could not have been possible without the participation and assistance of Dr. Sergio Sanchez-Armass.

1. Nickels JD, Smith JC, Cheng X. Lateral organization, bilayer

asymmetry, and inter-leaflet coupling of biological membranes.

Chem Phys Lipids. 2015 Nov;192:87-99.

2. Luo C, Wang K, Liu DQ, Li Y, Zhao QS. The functional roles

of lipid rafts in T cell activation, immune diseases and HIV

infection and prevention. Cell Mol Immunol. 2008;5(1):1-7.

POINTS TO REMEMBER

BIBLIOGRAPHY

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3. Fadeel B, Xue D. The ins and outs of phospholipid asymmetry

in the plasma membrane: roles in health and disease. Crit Rev

Biochem Mol Biol. 2009 Sep-Oct;44(5):264-277.

4. Van Meer G, Voelker DR, Feigenson GW. Membrane lipids:

where they are and how they behave. Nat Rev Mol Cell Biol.

2008 Feb;9(2):112-124.

5. Pittoni V, Valesini G. The clearance of apoptotic cells:

implications for autoimmunity. Autoimmun Rev. 2002

May;1(3):154-161.

6. Balasubramanian K, Schroit AJ. Aminophospholipid

asymmetry: A matter of life and death. Annu Rev Physiol.

2003;65:701-734.

7. Waddington KE, Jury EC. Manipulating membrane lipid

profiles to restore T-cell function in autoimmunity. Biochem

Soc Trans. 2015 Aug ;43(4):745-751.

8. Wong-Baeza C, Hernández-Pando R, Reséndiz A, Tescucano

A, Bustos I, Ibáñez M, et al. Molecular organization of the non-

bilayer phospholipid arrangements that induce an autoimmune

disease resembling human lupus in mice. Mol Membr Biol.

2012 Mar;29(2):52-67.

9. Park BS, Song DH, Kim HM, Choi B, Lee H, Lee J. The

structural basis of lipopolysaccharide recognition by the TLR4-

MD-2 complex. Nature. 2009 Apr 30;458(7242):1191-1195.

10. Wong-Baeza C, Tescucano A, Astudillo H, Resendiz A, Landa

C, España L, et al. Nonbilayer Phospholipid Arrangements

Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger

Inflammation in a Mouse Model Resembling Human Lupus. J

Immunol Res. 2015;2015:369462.

11. Witasp E, Kagan V, Fadeel B. Programmed cell clearance:

molecular mechanisms and role in autoimmue disease, chronic

inflammation, and anti-cancer immune responses. Curr

Immunol Rev. 2008;4:53–69.

12. Kabouridis PS, Jury EC. Lipid rafts and T-lymphocyte

function: implications for autoimmunity. FEBS Lett. 2008 Nov

12;582(27):3711-3718.

13. Frey B, Gaipl US. The immune functions of phosphatidylserine

in membranes of dying cells and microvesicles. Semin

Immunopathol. 2011 Sep;33(5):497-516.

14. Van der Mark V,A., Ghiboub M, Marsman C, Zhao J, van

Dijk R, Hiralall JK, et al. Phospholipid flippases attenuate LPS-

induced TLR4 signaling by mediating endocytic retrieval of

Toll-like receptor 4. Cell Mol Life Sci. 2017 Feb;74(4):715-730.

15. Fischer K, Voelkl S, Berger J, Andreesen R, Pomorski T,

Mackensen A. Antigen recognition induces phosphatidylserine

exposure on the cell surface of human CD8+ T cells. Blood.

2006 Dec;108(13):4094-4101.

16. Lopez-Marques R, Theorin L, PalmgrenMG, Pomorski TG.

P4-ATPases: lipid flippases in cell membranes. Pflugers Arch.

2014 Jul;466(7):1227-1240.

17. Frey B, Gaipl US. The immune functions of phosphatidylserine

in membranes of dying cells and microvesicles. Semin

Immunopathol. 2011 Sep;33(5):497-516.

18. Kabouridis PS, Jury EC. Lipid rafts and T-lymphocyte

function: implications for autoimmunity. FEBS Lett. 2008

Nov;582(27):3711-3718.

19. Bevers EM, Comfurius P, Zwaal RF. Regulatory mechanisms

in maintenance and modulation of transmembrane lipid

asymmetry: pathophysiological implications. Lupus. 1996

Oct;5(5):480-487.

20. Zhang X, Zhang D, Liu W, Li H, Fu R, Liu X, et al. Abnormal

lipid rafts related ganglioside expression and signaling in

T lymphocytes in immune thrombocytopenia patients.

Autoimmunity. 2016;49(1):58-68.

21. Fadok VA, de Cathelineau A, Daleke DL, Henson PM, Bratton

DL. Loss of phospholipid asymmetry and surface exposure of

phosphatidylserine is required for phagocytosis of apoptotic

cells by macrophages and fibroblasts. J Biol Chem. 2001 Jan

12;276(2):1071-1077.

Antibiotics use in early life, its relation on the development of obesity and the impact in the microbiota.

Ochoa-Valtierra Rocío Daniela1 , Ortiz-Vázquez Lizeth Guadalupe1

1 Facultad de Medicina. Universidad Autónoma de San Luis PotosíAv. Venustiano Carranza #2405. San Luis Potosí, SLP, Z.P. 78210. Mexico

Corresponding autors.

Ochoa-Valtierra Rocío Danielardovalti@gmail.com

Ortiz-Vázquez Lizeth Guadalupelgortizvazquez@gmail.com

How to cite this article: Ochoa-Valtierra RD, Ortiz-Vázquez LG. Antibiotics use in early life, its relation on the development of obesity and the impact in the microbiota. JMSR. 2017 Jul-Sep;1(1):10-18.

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Abstract

Key Words: ANTIBIOTICS, OBESITY, MICROBIOTA.

Obesity is a serious public health problem and estimated prevalence 3.4 million of adults worldwide who die every year as a result of being overweight or obese according to the WHO. Pediatric obesity has significant public health importance due to increasing risk of adult premature mortality, type 2 diabetes, and cardiovascular disease. Obesity results from the accumulation of excess adipose tissue, unfortunately, there is no single cause but it is multifactorial. Microbiota arises as a potential partaker in the development of obesity and other metabolic pathologies. Gut microbiota, its evolutive dynamics and influence on host through its protective, trophic and metabolic actions, has a key role in health; the number of bacteria within the gastrointestinal tract is approximately ten times higher than that of all of the cells of the human body. Alterations on gut microbiota composition have been associated with plenty disorders. For a long time antibiotics were widely used as growth promoters in agriculture. Altered intestinal microbiota during early life, potentially resulting from mode of delivery, maternal diet, antibiotic use, hormones, and/or breastfeeding may seed an obesogenic microbiome that contributes to the development of obesity in early life. The origin of obesity is multifactorial and this review exposes one of the possible causes that are the alterations of the microbiota by the use of antibiotics in the first years of life and their impact on children’s weight.

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In recent years, advances in gastrointestinal physiology have shown that the microbiota plays an important metabolic role both in health and in disease of populations and aware of the obesity pandemic and the important problem that represents for the health system. We found that many of the adults who are obese were since children, with the knowledge of the indiscriminate use of antibiotics in pediatric ages, we decided to look for the association that had the early use of antibiotics and their repercussion on the intestinal flora and subsequent development of obesity in the individual.

INTRODUCTION

Colonization of the gut begins at birth and is influenced by a variety of factors. Recent evidence suggests bacteria differ in their ability to extract energy, and colonization patterns can influence growth in both animal models and humans. The intestinal microbiome plays an important role in host energy metabolism, nutritional and immunologic processes. Previous studies have suggested that antibiotic exposure can alter the microbial diversity and composition. Compared to adults, the infant microbiome is quite unstable, especially during early postnatal life when the microbiota is vulnerable to disruption by environmental influences. According to a report in the United States, one in six children are obese and one in three are overweight.(1)

The microbiota can promote weight gain in animals being raised for market consumption and increase adiposity in young mice; levels of gastrointestinal inhibitory peptide was also

increased in mice treaties with antibiotics.(2)

The association between antibiotic use and an increase in fat mass has been confirmed in experimental animals. Emerging epidemiological studies have shown that this phenomenon can also occur in humans. (3,4)

Farmers, who routinely give low-dose antibiotics to animals, to fatten them, have exploited knowledge that alterations in the microbiota change ‘feed efficiency’ since years. The earlier in life exposed, the greater the weight gain.Since the advent of antibiotics, the morbidity and mortality associated with a large number of infectious diseases have been improved, with enormous advantages from a medical, social and economic point of view.(3) Antibacterial agents are frequently prescribed worldwide for infants and children, both appropriately and inappropriately, despite a substantial number of expert guidelines advocating more limited use. In particular, orally administered broad spectrum antibiotics have a potential to influence the microbiota.(5) Infections of the respiratory tract, ears, skin and urinary tract are the most common pathologies for which antibiotics are prescribed at early age.(1,6)

PubMed and Trip Database metasearch and Medic Latina, SpringerLink, Wiley Online Library, Web of Science, Scopus / Science Direct, Academic Search Complete, Biblioteca Virtual en Salud and Nature data bases were used to retrieve the articles quoted and the criteria used for the selection were, important text reflect relevant information in the summary, comply with established limits. The exclusion criteria were, do not comply with the general theme,

QUESTION AND CONTEXT

METHODS

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and contain at least one keyword, documents with different typology than the indicated limits.Obtaining the following results with the different combinations of keywords, where the first number are the articles obtained and the second are those that were used, discarded articles were those that did not meet the inclusion and exclusion criteria or that were repeated in the searches made: Anti-Bacterial Agents AND Obesity AND Microbiota 162/19; Anti-Bacterial Agents (MeSh) AND Obesity (MeSh) AND Microbiota (MeSh) 19/0 weren´t useful because they did not meet the criteria or were duplicated to the previously obtained results. ((("Anti-Bacterial Agents"[Mesh] OR Antibiotics)) AND ("Obesity"[Mesh] OR Obesity)) AND ("Microbiota"[Mesh] OR gut microbiota))) 150/15; ((Anti-Bacterial Agents OR Antibiotics)) AND (Obesity)) AND ((Microbiota OR gut microbiota)) 6938/10; Antibacterianos AND Obesidad AND Microbiota 61/0; Antibiotics AND Obesity 1536/16; Antibiotics AND Obesity AND microbiota 533/6 (Table 1).

RESULTS

MICROBIOTA

Currently the knowledge of the intestinal flora and its role in the metabolism and immunological functions of the individual have raised the possibility of the manipulation of this as a strategy for the balance of these functions.

In recent comparative studies a correlation has been found between bacteria in the gut such as Formicutes and Bacteroides and body mass. Where overweight

individuals have a higher proportion: Lactobacillus, Staphylococcus, Firmicutes and Faecalibacterium; While the thin ones present: Bacteroidetes, Methanobrevibacter, and Bifidobacterium. (6, 7, 8, 9, 10, 11)

The functions of microbiota are metabolic, trophic, and the regulation of mucosal and systemic immunity. Bacteria are responsible for carbohydrate fermentation through the production of short-chain fatty acids, and are important for vitamin and ion absorption.(12, 13) It is important to mention the mechanisms in which the microbiota participates to understand and know their role in the development of the person, besides understanding how their manipulation and not only their presence, but their proportion among species is related to metabolic problems such as the obesity: 1) increasing dietary energy harvest, 2) promoting fat deposition, 3) triggering systemic inflammation, 4) perhaps modifying locomotor activity, 5) and having central effects on satiety.(14)

In humans at the beginning of life the intestinal microbiota develops over four time periods: (1) during the first 2 weeks of life there is rapid colonization with “pioneer bacteria” or aero tolerant microbes; (2) after 2 weeks of life and throughout breast-feeding there is continued development of these aero tolerant microbes; (3) during weaning, the stepwise appearance of strict anaerobes occurs; and (4) by ages 2 to 3 years, the intestinal microbiota resembles that of an adult. (15, 16)

Retrospective studies have shown a window of vulnerability in the microbiota from the first 6 months to 2 years because it is the time where the microbiota profile of the individual is developed.(17)

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ANTIBIOTICS AND MICROBIOTA

Experiments in rats have shown that administration of antibiotics was associated with an increase in fat mass compared to controls that did not receive antibiotics, whereas lean weight was not significantly different, it is also mentioned that mostly after administration of antibiotics body composition was changed but not weight. It has been postulated in multiple studies that exposure to antibiotics makes a selection in which the microbiota remaining in the organism has an increased metabolic activity and therefore draws more energy from the diet that was indigestible in the control mice (18), together with a selection of bacteria of a certain species, which may or may not be related to the development of obesity, showing how characteristic that Actinobacteria, Ruminococcaceae and Clostridiales are found in a population with a higher proportion of fat mass, whereas Bacilli (Streptococcus), Lactobacillus and Lachnospiraseae are found in a non-obese population, showing a greater abundance of Firmicutes in non-obese population (19). Enhanced caloric absorption has been implicated as a mechanism for increased weight gain in other murine obesity models.

Cox et al. In an experiment in which multiple groups of rats exposed to different environments were evaluated, from low fat diet such as light diet, administration of antibiotics and non-administration, administration of few antibiotic intakes and administration of up to 28 exposures. It is found that the number of exposures ranging from 4 to 28 is directly related to a subsequent development of obesity. (19)

ANTIBIOTICS AND ITS USE AS A PROMOTER OF WEIGHT GAIN

For over 50 years, treatment with certain antibiotics at low doses have been used on farms to promote weight gain in chickens and pigs.(20)

Actually, laboratory studies have been done to find out how low doses of antibiotics can promote weight gain on animal farms, it is important to note that the obese phenotype seems to be a transmissible trait: transplantation of an obese microbiota to germ-free mice results in increased adi- posity compared with transplantation of a lean microbiota. Colonization of germ-free mice increases serum levels of glucose and short-chain fatty acids, which induce hepatic lip genesis.(4) The elevated triglyceride production is associated with increased adiposity and decreased glucose tolerance.(21)

Over the years antibiotics have been used as therapies to help gain weight for underweight children, it has been demonstrated that the role of microbiota in metabolism and alteration can lead to different results such as obesity, which has been reviewed in the literature(22) that the microbiota in malnourished patients have high relevance in their prevalence, combined in Malawi children with kwashiorkor, marasmus or marasmic kwashiorkor, the effects of 1 week of oral amoxicillin, cefdinir or Placebo plus RUTF are investigated, in which case the use of antibiotics as a protective factor and promoter of weight gain in malnourished patients. It has been concluded that the use of antibiotics helps reduce mortality in severe uncomplicated malnutrition.(23)

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USE OF ANTIBIOTICS AT EARLY LIFE AND DEVELOPMENT OF OBESITY

When analyzing the relationship between the early use of antibiotics and the development of obesity in children in different studies, it has been found that there is a linear relationship between the number of exposures and the increase in BMI (Body Mass Index), determining that if the first exposure to antibiotics is before 6 months of age or 12 to 24 months repeated exposures have a more pronounced effect on weight gain in children. (16,24, 25, 26)

Takes particular importance the type of antibiotic used, because broad spectrum antibiotics such as macrolides and beta lactams have a greater effect on the decrease of bacterial diversity and a greater increase in the production of endotoxins, effects that have not been observed with simple penicillins.(16, 25, 26)

Narrow spectrum antibiotics are not significantly associated with overweight or childhood obesity, even when there are repeated exposures. (17)

High Bacteroides fragilis and low Staphylococcus concentrations in infants between the age of 3 weeks and 1 year were associated with higher BMI SDS in preschool children.(11)

Intestinal flora disturbed by the use of antibiotics is not fully recovered after discontinuation.(25)

In the multiple studies analyzed it was found that there was a weight gain in 10 of the 12 analyzed, only Gerber et al. and Edmonson did not obtain a significant result in weight gain with the use of antibiotics. Showing a higher prevalence in males in 3 of them, so it is proposed that weight gain due to the

use of antibiotics is associated mostly in boys than in girls.(27)

Multiple exposures to antibiotics (> 3 exposures), age at which it was administered (greater risk <6 months), as well as the spectrum of each of the drugs used were related to weight gain. (Table 2).

Other variables such as the mode of birth, breastfeeding, smoking and alcoholism in pregnancy were adjusted so as not to interfere with the objective of the articles, which was to study the impact of the administration of antibiotics.

DISCUSSION

In the multiple studies analyzed, a direct relationship was found mostly with the number of exposures, the type of antibiotic and the subsequent development of obesity. Although in multiple studies, the age range in terms of exposure studied varies from 12 months to 24 months, it was found that the administration of antibiotics in the first 6 months of age presents vulnerability for the modification of microbiota, while exposures after childhood were not related to an increase in weight. The result of weight gain can be seen especially at the age of 7 years, however, this does not rule out that the weight cannot increase in previous years, or even in later years, coupled with the scarce study of the result in adulthood, also showing a increased predisposition in boys compared to girls. Broad spectrum antibiotics, such as beta-lactams, were also related to the effect on weight, because of this, the spectrum of antibiotics used as treatment is a modifiable risk factor. The indiscriminate use of antibiotics may not be the only reason for the current epidemic of childhood obesity, but these effects play an important role, thus

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underlining the relevance of the judicious use of antibiotics during childhood and preference to narrow-spectrum antibiotics.

CONCLUSIONS

The use of antibiotics has spread in infants, without taking into account the impact on microbiota, thus affecting the metabolic processes in which it is involved. In this work we have found a relationship between the use of antibiotics and the subsequent development of overweight, also evidencing that the administration at an earlier age has a greater impact. It was also found that there is a more significant increase in boys than in girls; showing likewise <6 months there is a window of vulnerability in the intestinal flora in both sexes.

The studies demonstrate the great importance of the conscious use of antibiotics in infants, and avoid their repeated and repeated use.Future studies are necessary, where prospective analyzes are made to eliminate possible biases that can be generated in obtaining the information.

POINTS TO REMEMBER

• Conscious use of antibiotics at an early age is paramount.• If necessary, to prefer the use of narrow spectrum antibiotics over broad spectrum antibiotics. • Limit repeated exposures to antibiotics.• There is a window of vulnerability regarding the microbiota <6 months.• Good nutrition and exercise should always be an important part of people´s lifestyle, regardless of age.

Clarifications:To evaluate the original article´s quality, we used OPMER scale.Ochoa Valtierra and Ortiz Vázquez made the same degree of contribution to the review.Conflict of interest:The authors declare no conflicts of interest.

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Apr 19;14:57.

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role in obesity--exposure to antibiotics early in life can lead to

increased adiposity. Nat Rev Endocrinol. 2012 Nov;8(11):623.

3. Principi N, Esposito S. Antibiotic administration and the

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2016 Mar;47(3):171–177.

4. Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat

Rev Endocrinol. 2015 Mar;11(3):182–190.

5. Liou AP, Turnbaugh PJ. Antibiotic exposure promotes fat gain.

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6. Ajslev TA, Andersen CS, Gamborg M, Sørensen TIA, Jess

T. Childhood overweight after establishment of the gut

microbiota: the role of delivery mode, pre-pregnancy weight

and early administration of antibiotics. Int J Obes. 2011

Apr;35(4):522–529.

7. Million M, Raoult D. The role of the manipulation of the gut

microbiota in obesity. Curr Infect Dis Rep. 2013;15(1):25-30.

8. Bifulco M. Antibiotics exposure in obesity: an update of a

complex relationship. Endocrine. 2015 Feb;48(1):12–13.

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mice undergoing accelerated postnatal growth. Sci Rep. 2016

Jun 9;6(27780):1-13.

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throughout the lifespan from infancy to elderly. Int Dairy J.

2010 Apr 1;20(4):281–291.

11. Vael C, Verhulst SL, Nelen V, Goossens H, Desager KN.

Intestinal microflora and body mass index during the first

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12. Scarpellini E, Campanale M, Leone D, Purchiaroni F, Vitale G,

Lauritano EC, et al. Gut microbiota and obesity. Intern Emerg

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13. Gérard P. Gut microbiota and obesity. Cell Mol Life Sci.

2016 Jan;73(1):147–162.

14. Tsai F, Coyle WJ. The microbiome and obesity: is obesity

linked to our gut flora?. Curr Gastroenterol Rep. 2009

Aug;11(4):307–313

15. Yallapragada SG, Nash CB, Robinson DT. Early-Life Exposure

to Antibiotics, Alterations in the Intestinal Microbiome, and

Risk of Metabolic Disease in Children and Adults. Pediatr Ann.

2015 Nov;44(11):e265-269.

16. Mbakwa CA, Scheres L, Penders J, Mommers M, Thijs C, Arts

ICW. Early Life Antibiotic Exposure and Weight Development

in Children. J Pediatr. 2016 Sep;176:105–113.e2.

17. Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A,

DeRusso PA. Association of antibiotics in infancy with early

childhood obesity. JAMA Pediatr. 2014 Nov;168(11):1063–

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Antibiotics in early life alter the murine colonic microbiome

and adiposity. Nature. 2012 Aug 8;488(7413):621–626.

19. Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM,

Cho I, et al. Altering the intestinal microbiota during a critical

developmental window has lasting metabolic consequences.

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20. Flint HJ. Microbiology: Antibiotics and adiposity. Nature.

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21. Reinhardt C, Reigstad CS, Bäckhed F. Intestinal microbiota

during infancy and its implications for obesity. J Pediatr

Gastroenterol Nutr. 2009;48(3):249–256.

22. Tilg H, Moschen AR. Malnutrition and microbiota: a new

relationship?. Nat Rev Gastroenterol Hepatol. 2013;10(5):261–

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Maleta KM, et al. Antibiotics as part of the management of

severe acute malnutrition. N Engl J Med. 2013;368(5):425–435.

24. Scott FI, Horton DB, Mamtani R, Haynes K, Goldberg

DS, Lee DY, et al. Administration of Antibiotics to Children

Before Age 2 Years Increases Risk for Childhood Obesity.

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Schwartz BS. Associations of prenatal and childhood antibiotic

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RJ, Mitchell EA, et al. Antibiotic treatment during infancy and

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SE, Nau C, et al. Antibiotic use and childhood body mass index

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How should drug-drug interactions be taught at medschool?

Carrillo-Barba Itamar1

1 Facultad de Medicina. Universidad Autónoma de San Luis PotosíAv. Venustiano Carranza #2405. San Luis Potosí, SLP, Z.P. 78210. Mexico

Abstract

Key Words:

DRUG INTERACTIONS, EDUCATION, TEACHING, HEALTH OCCUPATIONS.

Corresponding autors.

Itamar Carrillo-Barba itamarcarrillo@gmail.com

How to cite this article: Carrillo-Barba I. How should drug-drug interactions be taught at medschool?. JMSR. 2017 Jul-Sep;1(1):19-24.

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Objective: to identify the most effective method of teaching drug-drug interactions (DDIs) in a clinical scenario. Methods: a systematic research on Spanish and English was conducted, using the terms: drug interactions, education, teaching and health occupations. Results and discussion: there are few articles that show how DDIs should be instructed to health profession students. They analyze pharmacy students and different methods of teaching and evaluating DDI. Most of these studies take place in the United States, in a very different context than Mexico. In Mexico, the profession such as pharmacology has still been left out; therefore, most of the primary responsibility of detecting and avoiding DDIs lies with doctors prescribing patients’ drugs. An online survey conducted to UASLP medical students shows that more than one third (37%) of the students believe that the best way to learn DDIs is self-taught, and only 22% suggest that the most appropriate would be having a course or workshop. Conclusions: it is possible to avoid DDI if clinicians are aware of them. The DDI teaching methods vary widely and should be taught at various levels. The UASLP’s Faculty of Medicine, should consider a course and/or workshop that enables students to critically analyze DDI and formulate appropriate management; based on real study cases that they had contact with.

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Pharmacology is a compulsory subject in the core curriculum for medical students at the Autonomous University of San Luis Potosi (UASLP). One class teaches the concept of drug-drug interactions (DDIs) and instructs in the use of online software to evaluate the potential existence of interactions among the drugs for any prescription given by a doctor.During my clinical practice at the university affiliated hospital, I extensively applied the software to identify DDIs for hospitalized patients. I was taken aback by the number of interactions I discovered in patients that I had contact with. This caused me to question which was the most effective way to teach mechanisms, identification and management of DDIs in order to avoid harming the patient. The objective of this review is to identify the most effective method for teaching and identifying drug-drug interactions in a clinical scenario.

INTRODUCTION

DDIs are defined as the effects of one drug that is altered by the action of another drug, food, drink or any environmental chemical agents. Such changes can vary, showing additive, antagonist or idiosyncratic effects.(1)

Literature reports a broad range of prevalence values as a result of different research methods.(2) DDIs represent 6 to 30% of all adverse drug reactions (ADR). In one study, a hospital detected 7% of ADR for patients taking 6-10 medications, and raised to 40% for those with 16-20 drugs prescribed.(1) In another study DDIs accounted for 3-5% of medication errors in hospitalized patients

and were claimed major source of patients visiting the emergency department. (3)

Despite the fact that DDIs prevalence is uncertain; they are often predictable as a result of a considerable amount of published research, lately reinforced by the development of computerized software. Hence DDI may be considered preventable to certain extent.

The number of ADR including DDI are associated with the number of drugs prescribed. Simultaneously, the increasing levels of comorbity (correlated with aging population) are associated with an enlarged prevalence of polypharmacy. Polypharmacy is defined as taking five or more drugs a day and is very common among older adults.(4) By 2016, adults aged 65 or older represents 6.6% of the Mexican population, while this figure in the United States is 15.2%.(5) Consequently the U.S. population is at higher risk of polypharmacy and therefore DDI than Mexico. A study in the U.S. reported that 4% of the elderly were at potential risk for major DDI.(2)

In nearly all cases it is possible to moderate the harm associated with DDIs (including patient safety and costs), by providing knowledge of the mechanisms, risk factors, clinical consequences etc.(6) However more important is to raise awareness among health workers.

METHODS To research this topic I established the Mesh and Decs (Spanish descriptors) terms. Those words were: drug interactions, education, teaching, health occupations. Metasearch engines were used like PubMed, BIG for all languages and BIREME for Spanish.

The Boolean operators were AND/OR.

QUESTION AND CONTEXT

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The strategy that produced better results was“(Teaching OR Education) AND Drug Interactions and Health Occupations”, with no limitations (time or availability).

RESULTS

Out of 88 results, there were found 11 articles applicable to the main question. There are few studies that show how DDIs should be instructed to health profession students (pharmacy, medicine and nursing).

In 2008 Trujillo(3) published the results of an elective DDI course for PharmD (Doctor of Pharmacy degree) students, where she emphasized that “the teaching and learning should not end at memorizing or recalling specific drug interactions”, thus during one semester students used case-based activities that required previous knowledge, evaluation of individual variables, and understanding of references; as a consequence, the students were able to give thoughtful recommendations for each patient.

The results revealed that students who attended the course displayed higher overall confidence in their ability to handle a study case and advise proper management for a particular patient (3.1 vs. 2.7 on a 4-point scale). They also performed better (42.2 vs 32.0 on a 51-point scale) when they were asked about mechanisms of interactions, consequences, and showed greater critical thinking, skills performance and assessment of clinical significance in a case scenario than the students who did not enroll the course.

Finally, students who took the class mentioned on the evaluations that the course should be a compulsory one, because they valued highly in their professional practice.

A group of Japanese researchers lead by Dr. Tsuruoka,(7) realized a laboratory exercise consisting of a furosemide-probenecid

interaction, at the end of a pharmacology course for medical students. Students were asked to take these drugs at safe doses and experience the diuretic effects caused by their interaction.(8)

The researches evaluated physicians with three to seven years of experience in clinical practice, including those who performed the laboratory practice.

They sent a questionnaire by mail to the graduates of Jichi Medical School and were asked to provide the questionnaire to colleagues graduated from another school. Dr. Tsuroka concludes that practitioners from schools with a pharmacology course in their core curriculum, including a DDI laboratory exercise, recognized clinically important drug interactions. Additionally his team thinks that it is important for the student to experience a DDI in order to raise awareness about such interactions.

In a study in a hospital in Nepal,(1) the DDIs were evaluated before and after a so called educational intervention on consultants, medical officers, interns and the head of the department. The educational intervention occurred during a clinical meeting and personal discussion. This intervention included theoretical aspects of DDI and pre-intervention findings. The results show that pre intervention 53% of the patients were at risk of developing at least one DDI, while in the post intervention phase it reduced to 41% of the patients. Simultaneously, there was a significant reduction in the number of drugs prescribed. They found that according to Micromedex, 58% of the potential DDI had a delayed start, making them predictable hence preventable.

The study concludes that educational interventions do have a favorable effect on the incidence of DDIs.

Nevertheless, most of the research evaluate

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short term retention after a brief session of case studies.A team from the University of Arizona has published various studies evaluating short term retention knowledge (on pharmacy and in some papers, medical and nursing students) after an educational intervention.(2, 6, 9, 10)

In one study, pharmacy and medical students attended an educational session, which was case-based on common DDI mechanisms. The researchers evaluated pharmacy and medical students after a year of the educational intervention, by using a knowledge and attitude evaluation instrument(11), after one year. In the results both groups registered poor scores on the evaluation. Pharmacy students, contrary to medical students, showed greater scores on the same evaluation (P <.001).(6)

In another similar study, this team showed that pharmacy students score higher than medical and nursing students (11 vs 5 and 4, respectively) in the pre-education test, but scored about the same in the post-test. At the University of Arizona, the pharmacy core curriculum contains more drug related content than the medical one.(2) In Mexico, there are few universities that offer pharmacology as a degree. Such profession has not been completely regulated plus health workers and society itself has not recognized it yet. Therefore, most of the primary responsibility of detecting and avoiding DDIs lies with doctors prescribing patients’ drugs.

Additionally, they conducted educational outreach visits to prescribers and evaluated the pre and post education prescriptions, finding no significant difference related to potential DDIs among both groups.(12)

Finally, the University of Arizona team concludes that DDI education should be part of the curricula for all students of

health professions. Such education should include: recognition, importance, mechanism of action, and clinical management strategies of DDI.

The studies exposed before were done in different scenarios than the ones we experience in Mexico, hence the conditions and needs may vary. In order to generate proposals for effective ways to learn DDIs, we must first assess the needs of the students in context.

An online survey was constructed with help of DDIs experts and distributed to UASLP medical students via social media. The survey evaluates DDI concepts and awareness, the use of online software or apps to look for potential DDIs, and it openly asks, “What do you think is the best way to learn DDI?” Out of 70 answers:• 75% were students in their third and fourth year, • 97% of the students know the concept of DDI,• 60% of the respondents are aware that DDIs are (33% and 27% for often and always) preventable,• 69% of the medical students think that the doctor prescribing is the main responsible for the DDIs,• Also 70% think the responsibility should be share with other health workers. Nurses was the most popular answer (28%), followed by QFB (Pharmacological chemist) (13%),• 54% of the students believe that there are too many DDIs to memorize them all,• 19% uses software program or apps on their daily basis (always 8%, often 11%), and 51% use this tools sometimes. The most popular instruments were Medscape (23%) and Micromedex (20%),• We asked students what they thought it is the best way to learn DDI; their open answers were then classified. The results and

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classification categories are shown in fugure 1. 37% of the students believe that the best way to learn DDIs is by studying them by themselves, followed by clinical practice or

experience (26%), and only 22% suggest that the most appropriate would be having a course or workshop.

It should be noted that almost two thirds of the students are mindful about DDIs being preventable, but only 19% use online tools to evaluate DDIs in their clinical practice.

Three quarters of students who answered this questionnaire are in their third and fourth year of medical school which are the first two years of clinical practice in Mexico; one quarter of the students responded that experience is the way to learn DDI.

CONCLUSIONS

The results of most of the articles show that if clinicians are aware and know about basic mechanisms, it is possible to avoid DDI. The DDI teaching methods should include: opportunities to actively think, including laboratory practice, case based, problem

based learning, identify and clinical managing.

Trujillo(3) reinforces that DDI should be taught at various levels. For example, at the pharmacology course the DDI mechanisms and drug interaction screening programs should be brought in; later while in the therapeutics course, individual DDIs and management may be introduced.

According to the articles revised and the survey, the UASLP’s Faculty of Medicine, should consider a course and/or workshop that enables students to critically analyze DDI and formulate appropriate management; based on real study cases that they have had contact with. Consequently, with a good background, and systematized brainwork, students will be able to have successful self-study sessions.

POINTS TO REMEMBER

•DDI are the effects of one drug that is altered by the action of another drug, good, drink or environmental chemical agents. •Most of DDI are predictable and preventable. •In Mexico health workers such as clinical pharmacologists are not available at the hospitals, so the responsibility of identifying DDI rely on other health professionals. Some hospitals have already started pharmacovigilance practices in order to avoid these kinds of adverse reactions. •Doctors should be instructed about identifying and managing DDI in a clinical scenario. •More research should be done about the way to teach DDI, and ensure long term learning.

BIBLIOGRAPHY

1. Bista D, Saha A, Mishra P, Palaian S, Shankar PR. Impact of educational intervention on the pattern

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and incidence of potential drug-drug interactions in Nepal. Pharm Pract (Granada). 2009 Dec;7(4):242–247. 2. Harrington AR, Warholak TL, Hines LE, Taylor AM, Sherrill D, Malone DC. Healthcare professional students’ knowledge of drug-drug interactions. Am J Pharm Educ. 2011 Dec 15;75(10):199. 3. Trujillo J. A Drug interactions Elective Course. Am J Pharm Educ. 2009 Jul 10;73(4):72. 4. Wallace J, Paauw DS. Appropriate Prescribing and Important Drug Interactions in Older Adults. Med Clin North Am. 2015 Mar;99(2):295–310. 5. The World Bank. Data Bank. World development indicators [Internet]. DataBank. Available:http://databank.worldbank.org/data/reports.aspx?source=2&series=SP.POP.65UP.TO.ZS&country=MEX6. Hincapie AL, Warholak TL, Hines LE, Taylor AM, Malone DC. Impact of a drug-drug interaction intervention on pharmacy and medical students’ knowledge and attitudes: a 1-year follow-up. Res Social Adm Pharm. 2012 Sep-Oct;8(5):472–477. 7. Tsuruoka S, Kawaguchi A, Harada K, Fujimura A. Favorable effect on postgraduate clinical practice of a drug-interaction exercise for undergraduate students. Eur J Clin Pharmacol. 2006 Jul;62(7):571–576. 8. Kawaguchi A, Sugimoto K, Ohmori M, Tsuruoka S, Harada K, Kitoh Y, et al. Furosemide-probenecid interaction as a laboratory exercise for undergraduate education in clinical pharmacology. Clin Pharmacol Ther. 2001 Apr;69(4):232–237. 9. Wharholak TL, Hines LE, Song MC, Gessay A, Menke JM, Sherrill D, et al. Medical, nursing, and pharmacy students’ ability to recognize potential drug-drug interactions: a comparison of healthcare professional students. J Am Acad Nurse Pract. 2011 Apr;23(4):216–221. 10. Gilligan AM, Warholak TL, Murphy JE, Hines LE, Malone DC. Pharmacy Students’ Retention of Knowledge of Drug-Drug Interactions. Am J Pharm Educ. 2011 Aug 10;75(6):110. 11. Wharholak TL, Menke JM, Hines LE, Reel S, Malone DC. A drug-drug interaction knowledge assessment instrument for health professional students: A Rasch analysis of validity evidence. Res Social Adm Pharm. 2011 Mar; 7(1):16–26. 12. Malone DC, Liberman JN, Sun D. Effect of an Educational Outreach Program on Prescribing Potential Drug-Drug Interactions. J Manag Care Pharm. 2013 Sep;19(7):549–557.

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The research work to be submitted for review should contain the following items organized as shown below:

1.1 Title.

It is necessary that you generally reflect the content of your work in an attractive way.

1.2 Name of the authors.

It is recommended to analyze how they will be identified because it is necessary to standardize their name for future publications and have a first name, must include the full name, putting together the surnames with a hyphen.Example: Mauricio Pierdant-Pérez.

1.3 Adscription.

Record the degree of studies; career to which belong; Faculty and/or University of which you are student, fully registering the name of the institution. Separated with semicolons (;).Example: 2nd year student; Medical School; Faculty of Medicine, Autonomous University of San Luis Potosí.

1.4 ORCID

Relate your registration to obtain your Digital Identifier, in order to obtain a profile as a researcher and integrate links in each of your works.

1.5 Summary.

It should reflect a general description of the work with the most important points, with a maximum extension of 300 words.

1.6 Keyword.

Establish descriptors according to Medical Subject Headings (MeSH), available in the National Library of Medicine. (https://www.ncbi.nlm.nih.gov/mesh) DeCs for Spanish searches.

1.7 Corresponding author.

Name and e-Mail.

Research questions arise through reading, academic or social conversations, in classes or in a clinical context, so in this section a brief explanation of how your research question and / or problem arose, guiding to the reader the need that has arisen to carry out the development of his work.In case the origin arises within classes, the topic seen in class will be mentioned as well as the degree of information (sufficient or null) that allows to create the question mark.

It consists of the following elements:

3.1 Keywords.

It is necessary to identify the keywords of the subject that is being sought, as well as their synonyms. You need to use MeSH to perform searches.

3.2 Boolean operators.

Structure the MeSH term conjugations with the boolean operators, using AND to join two or three terms, OR so that the scope of the search is greater, and NOT to exclude unwanted terms.

3.3 Limits.

It is important to establish them to delimit our search, these tools will be found within each source of electronic information that identifies.

InfORmATIOn fOR AuThORS

Journal of Medical Students Reviews

1. MAIN PAGE, WHICH WILL CONTAIN 2. QUESTION AND CONTEXT

3. SEARCH STRATEGY

26

3.4 Information sources.

The electronic sources of information consulted divided into:Meta search engines: PuMed, BVS, Trip database, Ovid SPDatabases: Medic Latina, Science Direct, micromedex, Springer link, Wiley, etc.

3.5 Results.

The total result of each search will be displayed, specifying the total number of articles identified and the total number of articles retrieved (used).Example:

No Source of information

No. Identified articles

No. Recovered items

1 PubMed 200 342 Ovid Sp 140 10

For the analysis of the retrieved literature, OPMER will be used, a format that allows the methodological evaluation of the articles, as well as the selection of those that will be used in the work according to a scale.

It gave a general description of the subject, the results that you found.

In this section you will begin to describe what is found in the literature previously selected, the aspects to be considered are:

- Authors- Previous research- Results of other similar investigations- Identify Theories- Years in which the selected theme has had a greater impact

4. EVIDENCE EVALUATION

It will include the conclusion reached by the authors about the content of the subject to investigate, answering the question concretely, coherent and relevant.

In this section the students will expose the difficulties with which found developing the topic, leading to the development of new research related to the work developed.They can make recommendations within their area to prevent and / or treat certain diseases in case of being a clinical issue.

It will be in Vancouver-style bibliography based on Citing Medicine, the NLM Style Guide for Authors, Edithors and Publisers. Available in: https://www.ncbi.nlm.nih.gov/books/NBK7256/ As well as the Quick Reference Guide: Vancouver Style available at: https://es.slideshare.net/CICBI/guia-rapida- para-la- redacción-de-referenciasestilo-vancouver

The images, tables and graphics will be presented in JPG or PNG format presented at the end of the article.They should be mentioned within the article at the end of the paragraph in parentheses, named and listed consecutively with Arabic numerals.Example: (Image 1. Search methodology).For this journal considers as an image that photograph and / or figure that support the understanding of a paragraph; tables like those figures that are columns and rows that

5. INTRODUCTION

7.CONCLUSIONS

6. STATE OF THE ART/RESULTS

8. POINTS TO TAKE HOME

9. BIBLIOGRAPHY

10. TABLES AND GRAPHICS

27

are recommended for organize and present relevant information in the investigation.The Graphs will be used to represent the numerical data using circles, lines or bars the relationship between the data presented.

Authors must state that they do not have any type of conflict at the personal, institutional that compromise to a secondary benefit, nor to be obligatorily committed by third parties and be signed by each of them.

10. CONFLICT OF INTEREST