Mitochondrial Ultrastructure and Activity Are Differentially Regulated by Glycolysis-, Krebs Cycle-, and Microbiota-Derived Metabolites in Monocytes.

Several intermediate metabolites harbour cell-signalling properties, thus, it is likely that specific metabolites enable the communication between neighbouring cells, as well as between host cells with the microbiota, pathogens, and tumour cells. Mitochondria, a source of intermediate metabolites, participate in a wide array of biological processes beyond that of ATP production, such as intracellular calcium homeostasis, cell signalling, apoptosis, regulation of immune responses, and host cell-microbiota crosstalk. In this regard, mitochondria's plasticity allows them to adapt their bioenergetics status to intra- and extra-cellular cues, and the mechanisms driving such plasticity are currently a matter of intensive research. Here, we addressed whether mitochondrial ultrastructure and activity are differentially shaped when human monocytes are exposed to an exogenous source of lactate (derived from glycolysis), succinate, and fumarate (Krebs cycle metabolic intermediates), or butyrate and acetate (short-chain fatty acids produced by intestinal microbiota). It has previously been shown that fumarate induces mitochondrial fusion, increases the mitochondrial membrane potential (Δψm), and reshapes the mitochondrial cristae ultrastructure. Here, we provide evidence that, in contrast to fumarate, lactate, succinate, and butyrate induce mitochondrial fission, while acetate induces mitochondrial swelling. These traits, along with mitochondrial calcium influx kinetics and glycolytic vs. mitochondrial ATP-production rates, suggest that these metabolites differentially shape mitochondrial function, paving the way for the understanding of metabolite-induced metabolic reprogramming of monocytes and its possible use for immune-response intervention.

The mitochondrial activity of leukocytes from Artibeus jamaicensis bats remains unaltered after several weeks of flying restriction.

Bats are the only flying mammals known. They have longer lifespan than other mammals of similar size and weight and can resist high loads of many pathogens, mostly viruses, with no signs of disease. These distinctive characteristics have been attributed to their metabolic rate that is thought to be the result of their flying lifestyle. Compared with non-flying mammals, bats have lower production of reactive oxygen species (ROS), and high levels of antioxidant enzymes such as superoxide dismutase. This anti-oxidative vs. oxidative profile may help to explain bat's longer than expected lifespans. The aim of this study was to assess the effect that a significant reduction in flying has on bats leukocytes mitochondrial activity. This was assessed using samples of lymphoid and myeloid cells from peripheral blood from Artibeus jamaicensis bats shortly after capture and up to six weeks after flying deprivation. Mitochondrial membrane potential (Δψm), mitochondrial calcium (mCa2+), and mitochondrial ROS (mROS) were used as key indicators of mitochondrial activity, while total ROS and glucose uptake were used as additional indicators of cell metabolism. Results showed that total ROS and glucose uptake were statistically significantly lower at six weeks of flying deprivation (p < 0.05), in both lymphoid and myeloid cells, however no significant changes in mitochondrial activity associated with flying deprivation was observed (p > 0.05). These results suggest that bat mitochondria are stable to sudden changes in physical activity, at least up to six weeks of flying deprivation. However, decrease in total ROS and glucose uptake in myeloid cells after six weeks of captivity suggest a compensatory mechanism due to the lack of the highly metabolic demands associated with flying.

Immunogenic analysis of epitope-based vaccine candidate induced by photodynamic therapy in MDA-MB-231 triple-negative breast cancer cells.

BACKGROUND: Photodynamic therapy (PDT) is used to treat tumors through selective cytotoxic effects. PDT induces damage-associated molecular patterns (DAMPs) expression, which can cause an immunogenic death cell (IDC). In this study we identified potential immunogenic epitopes generated by PDT on triple-negative breast cancer cell line (MDA-MB-231). METHODS: MDA-MB-231 cells were exposed to PDT using ALA (160 µg/mL)/630 nm at 8 J/cm2. Membrane proteins were extracted and separated by 2D PAGE. Proteins overexpressed were identified by LC-MS/MS and analyzed in silico through a peptide-HLA docking in order to identify the epitopes with more immunogenicity and antigenicity properties, as well as lower allergenicity and toxicity activity. The selected peptides were evaluated in response to macrophage activation and cytokine release by flow cytometry. RESULTS: Differential proteins were overexpressed in the cells treated with PDT. A group of 16 peptides were identified from them, established in a rigorous selection by measuring antigenicity, immunogenicity, allergenicity, and toxicity in silico. The final selection was based on molecular dynamics, where 2 peptides showed the highest stability regarding to the RMSD value. These peptides were obtained from the proteins calreticulin and HSP90. The cytokine analysis evidenced macrophage activation by the releasing of TNF. CONCLUSION: Two peptides were identified from calreticulin and HSP90; proteins induced by PDT in MDA-MB-231 cells. Both epitopes showed immunogenic potential as a peptide-based vaccine for triple-negative breast cancer.

Hábitos de prescripción para el abordaje del dolor neuropático en España: resultados de la encuesta del grupo de trabajo de dolor neuropático de la Sociedad Española del Dolor / Prescribing habits for neuropathic pain management in Spain: results of the survey of the neuropathic pain working group of the Spanish Pain Society

Objetivos: Hace más de diez años que salieron al mercado los últimos fármacos con indicación en las guías internacionales de dolor neuropático (DN). Estas recomiendan iniciar con monoterapia y sitúan el tratamiento combinado en el segundo escalón. Un considerable número de pacientes no alcanza un suficiente alivio del dolor o mejora de su calidad de vida con los fármacos disponibles. Bajo esta perspectiva, el Grupo de Trabajo (GT) de DN de la Sociedad Española del Dolor (SED) diseñó una encuesta para el abordaje del DN mediante fármacos, técnicas intervencionistas y tratamientos fuera de indicación en nuestro medio. En este artículo se analiza solo la parte de tratamientos farmacológicos. Material y métodos: Estudio descriptivo mediante un cuestionario autoadministrado difundido por correo electrónico a los socios de la SED en dos oleadas durante 2019. Al inicio del cuestionario se realizaba una pregunta de selección sobre si utilizaban o no tratamientos fuera de ficha técnica o fuera de indicación. Solo los que respondieron afirmativamente procedieron a todo el conjunto de preguntas. Este se dividió en los siguientes bloques: antiepilépticos, antidepresivos, antipsicóticos, anestésicos, anti-nmda, cannabinoides, naltrexona, tratamientos tópicos, toxina botulínica, polifarmacia y tratamientos fuera de ficha. Dentro de la sección de tratamientos tópicos se incluyó la toxina botulínica. Resultados: La tasa de respuesta fue del 13,82 %, siendo del 10,05 % una vez descartadas las no válidas. El 21 % comienzan el tratamiento del DN con polifarmacia y un 43 % lo hace cuando no responden a una primera línea. El 40 % de los encuestados opinan que no hay evidencia suficiente para el uso de polifarmacia. El 70 % de los participantes trataban hasta un 30 % de sus pacientes con DN con fármacos fuera de indicación. El 23,3 % utilizaban medicamentos fuera de ficha técnica entre el 40 % y el 60 % de los pacientes con DN y un 6,6 % lo hacía en un 70-90 %...(AU)

Objectives: Latest drugs with an indication for neuropathic pain (NP) in the international guidelines came onto the market more than ten years ago. They recommend starting with monotherapy and place the combined treatment in the second step. A considerable number of patients do not achieve sufficient pain relief or improvement in their quality of life with the available drugs. From this perspective, the NP Working Group (WG) of the Spanish Pain Society (SED) designed a survey to address how NP drugs, off-label treatments and interventional techniques are being used in our setting. In this article we will only discuss the pharmacological treatment options.Material and methods: Descriptive study using a self-administered questionnaire distributed by email to SED members in two waves during 2019. At the beginning of the questionnaire, a selection question was asked whether or not they used non-technical or off-label treatments. Only those who answered affirmatively proceeded to the entire set of questions. It was divided into the following blocks: antiepileptics, antidepressants, antipsychotics, anesthetics, anti-nmda, cannabinoids, naltrexone, topical treatments, botulinum toxin, polypharmacy and off-label treatments. Botulinum toxin was included in the topical treatments section. Results: The response rate was 13.82 %, being 10.05 % once the invalid ones had been ruled out. 21 % begin the treatment of NP directly on polypharmacy and 43 % do so when they do not respond to a first line. 40 % of those surveyed think that there is insufficient evidence for the use of polypharmacy. 70 % of the participants treated up to 30 % of their NP patients with off-label drugs. 23.3 % used off-label me­dications in between 40 % and 60 % of patients with NP and 6.6 % did so in 70-90 % of patients...(AU)

Mitochondrial Signature in Human Monocytes and Resistance to Infection in C. elegans During Fumarate-Induced Innate Immune Training.

Monocytes can develop immunological memory, a functional characteristic widely recognized as innate immune training, to distinguish it from memory in adaptive immune cells. Upon a secondary immune challenge, either homologous or heterologous, trained monocytes/macrophages exhibit a more robust production of pro-inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, than untrained monocytes. Candida albicans, ß-glucan, and BCG are all inducers of monocyte training and recent metabolic profiling analyses have revealed that training induction is dependent on glycolysis, glutaminolysis, and the cholesterol synthesis pathway, along with fumarate accumulation; interestingly, fumarate itself can induce training. Since fumarate is produced by the tricarboxylic acid (TCA) cycle within mitochondria, we asked whether extra-mitochondrial fumarate has an effect on mitochondrial function. Results showed that the addition of fumarate to monocytes induces mitochondrial Ca2+ uptake, fusion, and increased membrane potential (Δψm), while mitochondrial cristae became closer to each other, suggesting that immediate (from minutes to hours) mitochondrial activation plays a role in the induction phase of innate immune training of monocytes. To establish whether fumarate induces similar mitochondrial changes in vivo in a multicellular organism, effects of fumarate supplementation were tested in the nematode worm Caenorhabditis elegans. This induced mitochondrial fusion in both muscle and intestinal cells and also increased resistance to infection of the pharynx with E. coli. Together, these findings contribute to defining a mitochondrial signature associated with the induction of innate immune training by fumarate treatment, and to the understanding of whole organism infection resistance.

Metamizol como inmunomodulador en el dolor neuropático / Metamizole as an immunomodulator in neuropathic pain

No disponible

Plan Universitario de Formación en Dolor de la Sociedad Española del Dolor / No disponible

No disponible

[Assessment of the impact of pain on work productivity: validation of the Spanish WPAI:Pain questionnaire]. / Valoración de la repercusión del dolor sobre la productividad laboral: validación del cuestionario WPAI:Pain.

BACKGROUND: Health measuring instruments are essential in daily clinical practice. However, a validation process is needed in order to certify the validity and reliability of it. The aim of our study is to validate a questionnaire to assess the consequences of pain in work productivity. METHODS: Based on the Work Productivity and Activity Impairment Questionnaire ­ General Health we have created a modified version called WPAI:Pain in order to be able to measure the consequences of pain in work productivity. The study was conducted following the usual guidelines of test validation, omitting face validity as WPAI:Pain is a modification of an existing questionnaire. Validity and reliability were calculated. RESULTS: A total of 577 questionnaires were obtained in 2 spanish university hospitals. The questionnaire's discriminating power was verified by Mann-Whitney test. Reliability tests were realized, Cronbach's alpha was 0.896 and Guttman split-half was 0.921. Stability was evaluated with a test-retest which was significant. Construct validity was established by Pearson correlation comparing the results of the questionnaire with the pain visual analog scale, which was statistically significant for all values. CONCLUSIONS: The WPAI:Pain questionnaire is a valid instrument for measuring the consequences of pain in work productivity.It is currently the only one validated in Spanish.Major studies are needed in order to establish its universal validity.

Valoración de la repercusión del dolor sobre la productividad laboral: validación del cuestionario WPAI: pain / Assessment of the impact of pain on work productivity: validation of the Spanish WPAI: pain questionnaire

Fundamento: Los instrumentos de medida de salud son esenciales en la actividad clínica diaria. Sin embargo, es necesario un proceso de validación para poder certificar la validez y fiabilidad de los mismos. En la actualidad no existe ninguno que permita evaluar la repercusión del dolor en la productividad laboral de los pacientes. El objetivo de nuestro estudio es validar un cuestionario para evaluar las consecuencias del dolor en dicha productividad. Método: En base al Work Productivity and Activity Impairment Questionnaire - General Health hemos creado una versión modificada denominada WPAI:Pain con el fin obtener un cuestionario que pudiera medir las consecuencias del dolor en la productividad laboral. El estudio se realizó siguiendo las pautas habituales de validación de pruebas, omitiéndose las fases de redacción y validez de contenido ya que se modificaba un cuestionario existente. Resultados: Se obtuvieron 577 cuestionarios en dos hospitales universitarios españoles. Se comprobó la capacidad discriminante del cuestionario mediante prueba de U de Mann-Whitney. Se realizaron los test de fiabilidad obteniéndose un alfa de Cronbach de 0,896 con un test de dos mitades de Guttman de 0,921. Se comprobó la estabilidad con un test-retest estadísticamente significativo. La validez de constructo se estableció mediante correlación de Pearson comparando los resultados del cuestionario con el dolor en escala visual analógica, que resultó estadísticamente significativa para todos los valores. Conclusiones: El cuestionario WPAI:Pain es un instrumento de medida válido para determinar las consecuencias del dolor en la productividad laboral de los pacientes, siendo el único validado en español. Sin embargo, se requieren estudios de mayor envergadura para poder confirmar una validez universal (AU)

Background: Health measuring instruments are essential in daily clinical practice. However, a validation process is needed in order to certify the validity and reliability of it. The aim of our study is to validate a questionnaire to assess the consequences of pain in work productivity. Methods: Based on the Work Productivity and Activity Impairment Questionnaire - General Health we have created a modified version called WPAI:Pain in order to be able to measure the consequences of pain in work productivity. The study was conducted following the usual guidelines of test validation, omitting face validity as WPAI:Pain is a modification of an existing questionnaire. Validity and reliability were calculated. Results: A total of 577 questionnaires were obtained in 2 spanish university hospitals. The questionnaire's discriminating power was verified by Mann-Whitney test. Reliability tests were realized, Cronbach's alpha was 0.896 and Guttman split-half was 0.921. Stability was evaluated with a test-retest which was significant. Construct validity was established by Pearson correlation comparing the results of the questionnaire with the pain visual analog scale, which was statistically significant for all values. Conclusions: The WPAI:Pain questionnaire is a valid instrument for measuring the consequences of pain in work productivity. It is currently the only one validated in Spanish. Major studies are needed in order to establish its universal validity (AU)

Real Decreto de prescripción y dispensación de estupefacientes / No disponible

No disponible

Analgesia postoperatoria con lornoxicam frente a metamizol en cirugía mayor ambulatoria. Estudio prospectivo aleatorio / Postoperative analgesia with lornoxicam versus metamizol for outpatient major surgery. A randomized prospective study

Objetivos:Comparar la eficacia analgésica postoperatoria en cirugíamayor ambulatoria de dos fármacos analgésicos noopioides: metamizol, habitualmente utilizado en nuestromedio, frente a lornoxicam, introducido recientemente parauso clínico. Métodos:Estudio prospectivo y aleatorio. Incluimos 73 pacientesprogramados para un procedimiento de cirugía mayor ambulatoria.Al final de la cirugía administramos una dosisúnica de metamizol i.v. a todos los pacientes. Cuando lospacientes comenzaron la tolerancia administramos medicaciónanalgésica oral aleatorizando los pacientes en dos grupos:en el grupo lornoxicam (n = 35) un comprimido delornoxicam 8 mg cada 12 horas y en el grupo metamizol (n= 38) un comprimido de metamizol 575 mg cada 8 horas.Evaluamos el dolor postoperatorio en cuatro momentosdistintos del proceso postoperatorio: en la Unidad de Reanimaciónal final de la cirugía, al inicio del tratamientoanalgésico con la tolerancia oral, al alta hospitalaria, y alas 48 horas tras la cirugía. Utilizamos la escala analógicavisual (EVA), una escala numérica sencilla para valorar eldolor por encuesta telefónica a las 48 horas, la satisfaccióndel paciente al final del procedimiento, la opinión del pacientesobre la medicación recibida, y la necesidad de medicaciónde rescate.Resultados:No encontramos diferencias estadísticamente significativasen el EVA en la Unidad de Reanimación, en el iniciodel tratamiento analgésico oral, ni en la valoración del dolora las 48 h de la cirugía. El EVA del alta domiciliaria fuemenor en el grupo metamizol que en el grupo lornoxicam(p < 0,05). La satisfacción del paciente también fue mejoren el grupo metamizol al igual que en la opinión del pacientesobre la medicación recibida (p < 0,05). En la necesidadde rescate no hubo diferencias significativas.Discusión:Ambos fármacos proporcionan una buena analgesiapostoperatoria, si bien con la pauta de administración deldiseño del estudio metamizol se muestra superior a lornoxicamtanto en la analgesia al alta hospitalaria como en lavaloración subjetiva de los pacientes sobre la medicaciónanalgésica administrada

Objectives:To compare the analgesic effectiveness for outpatientmajor surgery of two non-opiate analgesic drugs: metamizol,frequently used in our setting, versus lornoxicam, recentlyintroduced in the clinical practice.Methods:Prospective and randomized study in 73 patients scheduledfor outpatient major surgery. At the end of the procedure,all patients received a single dose of metamizol i.v.Oral analgesics were administered when patients started todevelop tolerance and were randomized to one of the followinggroups: Lornoxicam Group (n = 35), with onetablet of lornoxicam 8 mg each 12 hours; or MetamizolGroup, with one tablet of metamizol 575 mg each 8 hours.Post-operative pain was assessed at four different timepoints during the postoperative process: at the reanimationunit after surgery, at the beginning of the analgesic treatmentwith oral tolerance, upon hospital discharge and 48hours after surgery. We used the Visual Analogue Scale(VAS), a simple numerical scale to assess pain through aphone call performed at 48 hours, patient satisfaction atthe end of the procedure, patient opinion regarding themedication received and need for rescue medication.Results:We did not find any statically significant differences inVAS scores at the reanimation unit, the beginning of theoral analgesic treatment or the assessment of pain 48hours after surgery. VAS scores upon hospital dischargewere lower in the metamizol group compared to thelornoxicam group (p < 0.05). Patient satisfaction and patientopinion regarding the medication received were alsobetter in the metamizol group (p < 0.05). No significantdifferences were observed regarding the need for rescuemedication.Discussion:Both drugs provide appropriate postoperative analgesia,but perhaps the dosage regime used in the metamizolgroup provided better analgesia upon hospital dischargeand improved subjective assessment of patients regardingthe analgesic drug received

Citrato de fentanilo oral transmucosa en el tratamiento del dolor irruptivo en pacientes con cáncer en España: resultados del estudio EDIPAD / Transmucosal oral fentanyl citrate for the management of irruptive pain suffered by cancer patients in Spain: results of the EDIPAD study

Introducción: Se denomina dolor irruptivo o episódico a la crisis dolorosa de intensidad elevada y aparición brusca que se instaura sobre un dolor crónico de base controlado con opioides. El citrato de fentanilo oral transmucosa (CFOT) es un fármaco recientemente introducido en nuestro país, que ha sido específicamente desarrollado para el tratamiento de este tipo de dolor. Tras su comercialización en el año 2001, se planteó la realización de un estudio observacional post-autorización con el objetivo de evaluar la seguridad y tolerabilidad del mismo. Adicionalmente se planteó la obtención de datos de efectividad del CFOT y la comparación de los mismos con los obtenidos hasta la visita basal para otros tratamientos administrados, distintos a CFOT. Métodos: Para el estudio se reclutaron 312 pacientes oncológicos, con dolor de base controlado con opioides, que presentaban crisis de dolor irruptivo y fueron seguidos durante un mes, realizándose visitas de control semanales. Doscientos noventa y cinco pacientes fueron válidos para el estudio de la seguridad y tolerabilidad de CFOT (población de seguridad). Por otra parte, 138 pacientes fueron evaluados para efectividad, ya que cumplían los criterios de inclusión y exclusión del estudio y les habían sido administrados tratamientos distintos a CFOT antes de la visita basal. Se determinaron las siguientes variables: disminución de la intensidad del dolor tras la administración del tratamiento mediante una escala visual analógica (EVA) de 0 a 10 puntos, el tiempo transcurrido hasta que se producía el inicio del alivio del dolor y el alivio máximo tras el tratamiento administrado. Resultados: Seguridad: de los 295 pacientes evaluados, 59 (20 por ciento) presentaron alguna reacción adversa. Todas ellas fueron de intensidad leve o moderada. No se notificó ninguna reacción adversa grave durante el desarrollo del estudio. Las reacciones más frecuentemente descritas fueron las de origen gastrointestinal, seguidas de alteraciones del SNC (somnolencia, alucinaciones, desorientación y mareo), todas ellas propias del tratamiento con opioides. Efectividad: tras la administración de CFOT en la visita final (ñ 30 días), el tiempo transcurrido hasta el inicio del alivio del dolor fue significativamente menor que el transcurrido tras la administración de otros tratamientos distintos a CFOT antes de la visita basal (12,1 ñ12,9 minutos vs 29,4ñ18,1 minutos respectivamente; p< 0,001). Así mismo, la disminución de la intensidad del dolor irruptivo (DID) tras el tratamiento fue significativamente mayor tras el tratamiento con CFOT evaluado en la visita final, en comparación con la obtenida tras la administración de otros tratamientos distintos a CFOT hasta la visita basal (CFOT: DID= -4,9ñ1,7; vs tratamientos distintos a CFOT: DID= -4,4ñ1,6; -p=0,004-).Conclusiones: Este estudio observacional ha permitido corroborar que CFOT presenta un buen perfil de seguridad, comparable al de otros analgésicos opioides. Adicionalmente, los datos de efectividad obtenidos, pioneros en nuestro entorno, han permitido constatar que CFOT es un fármaco capaz de disminuir, de forma significativamente más rápida, eficaz y específica el dolor irruptivo que padecen los pacientes oncológicos, que otros tratamientos previamente usados por estos pacientes (AU)

Repercusion de la atencion del medico familiar en el medio rural. Comparacion de tres enfoques diferentes: individual, famiilar y comunitario. / Repercurssion of the care with family physicians in rural zone.Comparisson of 3 different approaches: individual, familiar and communitary

Mediante el empleo de tres controles diferentes, el periodico familiar, el comunitario y el individual, se estudio el efecto que las acciones preventivas, de educacion para la salud y asistenciales tenian sobre 72 familias del medio rural de Hoctun y Kimbila, Yucatan. Se encontro que, independientemente del control ejercido, el numero de consultas y la morbilidad fueron semejantes en los tres grupos y existieron unicamente diferencias significativas en cuanto al cumplimiento de programas preventivos en el grupo familiar y, principalmente, en el comunitario.Con base en los resultados obtenidos se concluye que, para elevar el nivel de salud de la poblacion rural, ademas de mejorar las condiciones sociales se requiere que el medico familiar se comprometa a enfocar integralmente a toda su comunidad y no solo a efectuar acciones individuales