ABSTRACT
BACKGROUND AND PURPOSE: IL-11 is a member of the IL-6 family of cytokine initially considered as haematopoietic and cytoprotective factor. Recent evidence indicates that IL-11 promotes lung fibrosis and pulmonary hypertension in animal models and is elevated in lung tissue of patients with pulmonary fibrosis and pulmonary hypertension. Fibrocytes are bone marrow-derived circulating cells that participate in lung fibrosis and pulmonary hypertension, but the role of IL-11 on fibrocytes is unknown. We investigated the role of IL-11 system on fibrocyte activation in different in vitro and in vivo models of lung fibrosis associated with pulmonary hypertension. EXPERIMENTAL APPROACH: Human fibrocytes were isolated from peripheral blood of six healthy donors. Recombinant human (rh)-IL-11 and soluble rh-IL-11 receptor, α subunit (IL-11Rα) were used to stimulated fibrocytes in vitro to measure:- cell migration in a chemotactic migration chamber, fibrocyte to endothelial cell adhesion in a microscope-flow chamber and fibrocyte to myofibroblast transition. Mouse lung fibrosis and pulmonary hypertension was induced using either IL-11 (s.c.) or bleomycin (intra-tracheal), while in the rat monocrotaline (intra-tracheal) was used. In vivo siRNA-IL-11 was administered to suppress IL-11 in vivo. KEY RESULTS: RhIL-11 and soluble rhIL-11Rα promote fibrocyte migration, endothelial cell adhesion and myofibroblast transition. Subcutaneous (s.c.) IL-11 infusion elevates blood, bronchoalveolar and lung tissue fibrocytes. SiRNA-IL-11 transfection in bleomycin and monocrotaline animal models reduces blood and lung tissue fibrocytes and reduces serum CXCL12 and CXCL12/CXCR4 lung expression. CONCLUSION AND IMPLICATIONS: Targeting IL-11 reduces fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension-associated lung fibrosis.
ABSTRACT
OBJECTIVE: Neuropsychiatrists often resort to drugs with broad interindividual pharmacokinetic variability metabolized by highly polymorphic enzymes such as CYP2D6 and CYP2C19. Pharmacokinetics and pharmacogenetics offer considerable promise as techniques capable to allow individualized adjustments in treatments with psychoactive drugs. The purpose of this study was to review the existing evidence for the application of pharmacokinetics and pharmacodynamics to the dosing of drugs used in neuropsychiatry. METHOD: A literature search was conducted in PubMed and Embase to find prospective studies published between January 2000 and April 2021 that used determination of psychotropic drug plasma levels or genotyping to improve response to treatment or minimize adverse events in adult patients with psychiatric conditions. MeSH terms and free search terms were used. Each article was reviewed by two independent reviewers to ensure that they met the inclusion criteria. A quantitative method was established to assess the quality of the articles selected. Results: A total of 27 articles met the inclusion criteria of which 16 used pharmacokinetic and 11 pharmacogenetic techniques. Fifty percent of pharmacokinetic studies met the five predefined quality criteria. Eight of the 16 papers were on antidepressants; the remainder were on antipsychotics. Two of the latter did not find an association with efficacy or safety. None of the pharmacogenetic studies met the five quality criteria. Only one of the two studies on antipsychotics found fewer adverse events with genetics-guided dosing in patients on CYP2D6 substrate antipsychotics. Six of the nine studies on antidepressants found that pharmacogeneticsbased dosing improved efficacy. CONCLUSIONS: The evidence available on pharmacokinetics and harmacodynamics- based personalization of treatment with psychoactive drugs is scarce. Many existing studies analyze associations between genotypes and response or toxicity but provide few data on the efficacy of treatment individualization. The results obtained suggest the existence of significant differences in pharmacokinetic parameters between responding and nonresponding patients, particularly in the treatment of depression. Given that the availability of pharmacogenetic information may be useful at the beginning of treatment, combining both techniques could help optimize pharmacotherapy. However, clinical trials are needed to establish their benefits with greater accuracy.
OBJETIVO: Dentro de la neuropsiquiatría es habitual el empleo de fármacos con amplia variabilidad farmacocinética interindividual y etabolizados por enzimas altamente polimórficas como CYP2D6 y CYP2C19. La farmacocinética y la farmacogenética se vislumbran como herramientas de ayuda para conseguir un ajuste personalizado en el tratamiento con psicofármacos. El objetivo de este trabajo es revisar la evidencia existente sobre la aplicación de farmacocinética y farmacogenética en la selección de dosis de los medicamentos empleados en neuropsicofarmacología.Método: Se realizó una búsqueda en PubMed y Embase para localizar estudios prospectivos, publicados entre enero de 2000 y abril de 021, que utilizasen la determinación de niveles plasmáticos de psicofármacos o genotipado para mejorar la respuesta o minimizar efectos adversos en pacientes adultos con trastornos psiquiátricos. Se emplearon términos MeSH y texto libre. Cada artículo fue revisado por dos revisores independientes para asegurar que cumplían los criterios de inclusión. Se estableció un método cuantitativo para valorar la calidad de los artículos incluidos. Resultados: Se incluyeron 27 artículos, 16 utilizaban farmacocinética y 11 farmacogenética. El 50% de los estudios de farmacocinética cumplieron los cinco criterios de calidad predefinidos. Ocho de los 16 trabajos analizaron antidepresivos y los estudios restantes antipsicóticos. Dos de estos 8, no encontraron asociación con eficacia o seguridad. Ninguno de los estudios de farmacogenética cumplía los cinco criterios de calidad. Sólo 1 de los 2 estudios de antipsicóticos encuentra reducción de efectos adversos con dosis guiadas por genética en pacientes con antipsicóticos sustratos del CYP2D6. Seis de los 9 estudios con antidepresivos encuentran mayor eficacia al dosificar utilizando farmacogenética. CONCLUSIONES: La evidencia disponible sobre farmacocinética y farmacogénetica en individualización del tratamiento con psicofármacos es escasa. Gran parte de los estudios analizan asociaciones entre genotipos y respuesta o toxicidad, proporcionando pocos datos sobre la eficacia en la individualización del tratamiento. Los resultados obtenidos apuntan a la existencia de diferencias significativas en parámetros farmacocinéticos entre pacientes respondedores y no respondedores, especialmente en el tratamiento de la depresión. Disponer de información farmacogenética puede ser de utilidad al inicio del tratamiento, por lo que combinar ambas técnicas podría ayudar a optimizar la farmacoterapia, pero hacen falta ensayos clínicos para establecer claramente su beneficio.
Subject(s)
Antidepressive Agents , Pharmacogenetics , Adult , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/therapeutic use , Cytochrome P-450 CYP2D6/genetics , Genotype , Humans , Pharmacogenetics/methods , Prospective StudiesABSTRACT
Objetivo: Dentro de la neuropsiquiatría es habitual el empleo de fármacos con amplia variabilidad farmacocinética interindividual y metabolizados por enzimas altamente polimórficas como CYP2D6 y CYP2C19. Lafarmacocinética y la farmacogenética se vislumbran como herramientasde ayuda para conseguir un ajuste personalizado en el tratamiento conpsicofármacos. El objetivo de este trabajo es revisar la evidencia existentesobre la aplicación de farmacocinética y farmacogenética en la selecciónde dosis de los medicamentos empleados en neuropsicofarmacología.Método: Se realizó una búsqueda en PubMed y Embase para localizarestudios prospectivos, publicados entre enero de 2000 y abril de 2021, queutilizasen la determinación de niveles plasmáticos de psicofármacos o genotipado para mejorar la respuesta o minimizar efectos adversos en pacientesadultos con trastornos psiquiátricos. Se emplearon términos MeSH y textolibre. Cada artículo fue revisado por dos revisores independientes para asegurar que cumplían los criterios de inclusión. Se estableció un método cuantitativo para valorar la calidad de los artículos incluidos.Resultados: Se incluyeron 27 artículos, 16 utilizaban farmacocinéticay 11 farmacogenética. El 50% de los estudios de farmacocinética cumplieron los cinco criterios de calidad predefinidos. Ocho de los 16 trabajos analizaron antidepresivos y los estudios restantes antipsicóticos. Dosde estos 8, no encontraron asociación con eficacia o seguridad. guno de los estudios de farmacogenética cumplía los cinco criterios decalidad. Sólo 1 de los 2 estudios de antipsicóticos encuentra reducciónde efectos adversos con dosis guiadas por genética en pacientes conantipsicóticos sustratos del CYP2D6. Seis de los 9 estudios con antidepresivos encuentran mayor eficacia al dosificar utilizando farmacogenética. (AU)
Objective: Neuropsychiatrists often resort to drugs with broad interindividual pharmacokinetic variability metabolized by highly polymorphicenzymes such as CYP2D6 and CYP2C19. Pharmacokinetics and pharmacogenetics offer considerable promise as techniques capable to allowindividualized adjustments in treatments with psychoactive drugs. The purpose of this study was to review the existing evidence for the applicationof pharmacokinetics and pharmacodynamics to the dosing of drugs usedin neuropsychiatry.Method: A literature search was conducted in PubMed and Embase tofind prospective studies published between January 2000 and April 2021that used determination of psychotropic drug plasma levels or genotyping to improve response to treatment or minimize adverse events in adultpatients with psychiatric conditions. MeSH terms and free search termswere used. Each article was reviewed by two independent reviewersto ensure that they met the inclusion criteria. A quantitative method wasestablished to assess the quality of the articles selected.Results: A total of 27 articles met the inclusion criteria of which 16 usedpharmacokinetic and 11 pharmacogenetic techniques. Fifty percent of pharmacokinetic studies met the five predefined quality criteria. Eight of the16 papers were on antidepressants; the remainder were on antipsychotics. Two of the latter did not find an association with efficacy or safety. None of the pharmacogenetic studies met the five quality criteria. Onlyone of the two studies on antipsychotics found fewer adverse events withgenetics-guided dosing in patients on CYP2D6 substrate antipsychotics.Six of the nine studies on antidepressants found that pharmacogeneticsbased dosing improved efficacy. (AU)
Subject(s)
Humans , Pharmacokinetics , Pharmacogenetics , Antidepressive Agents , Antipsychotic Agents , MedicineABSTRACT
La meningitis por enterococo es una entidad clínica muy poco frecuente, representando el 0,3-4% de las meningitis bacterianas y siendo Enterococcus faecalis (E. faecalis) la especie aislada más común. Existen factores de riesgo para su desarrollo en recién nacidos, como fiebre materna intraparto, corioamnionitis, prematuridad o resección intestinal previa. Nuestro objetivo es describir un caso de meningitis asociada a sepsis precoz causada por E. faecalis en un recién nacido que presentó fiebre, irritabilidad y mal estado general a las 24 h de nacer, coincidiendo con un examen de líquido cefalorraquídeo que mostró parámetros citoquímicos normales. Como antecedente de interés destaca fiebre materna intraparto. Los hallazgos clínicos y analíticos sugirieron un proceso infeccioso, que se confirmó con el aislamiento de E. faecalis en líquido cefalorraquídeo. La evolución de la paciente fue favorable tras tratamiento con ampicilina y gentamicina. El antecedente epidemiológico hizo suponer una transmisión vertical
Enterococcal meningitis is a very rare clinical entity, accounting for 0.3-4% of bacterial meningitis, with Enterococcus faecalis (E. faecalis) being the most common isolated species. There are risk factors for its development in newborns, such as maternal intrapartum fever, chorioamnionitis, prematurity, or previous intestinal resection. The aim of this article is to describe a case of meningitis associated with early sepsis caused by E. faecalis in a newborn with fever, irritability, and in a poor general condition at 24hours of birth, coinciding with normal cytochemical parameters in cerebrospinal fluid. The clinical and analytical findings suggested an infectious process, which was confirmed by the isolation of E. faecalis in cerebrospinal fluid. The patient outcome was favourable after treatment with ampicillin and gentamicin. The epidemiological history suggested a vertical transmission
Subject(s)
Humans , Female , Infant, Newborn , Enterococcus faecalis/isolation & purification , Neonatal Sepsis/diagnosis , Ampicillin/therapeutic use , Gentamicins/therapeutic use , Meningitis, Bacterial/diagnosis , Meningitis, Bacterial/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Neonatal Sepsis/complications , Meningitis/complications , Administration, Intravenous/methodsABSTRACT
No disponible
Subject(s)
Humans , Male , Child , Synostosis/diagnostic imaging , Synostosis/genetics , Muscle Hypotonia/diagnosis , Brain Diseases/diagnosis , Brain Diseases/genetics , Forearm/diagnostic imaging , Forearm/pathologySubject(s)
Klinefelter Syndrome/complications , Radius/abnormalities , Synostosis/etiology , Ulna/abnormalities , Child , Humans , Male , PhenotypeABSTRACT
La infección por Campylobacter spp. constituye una de las principales causas de enteritis bacteriana en los seres humanos. Mientras que Campylobacter fetus puede causar infecciones sistémicas tales como celulitis, osteomielitis, artritis, pericarditis y endocarditis, Campylobacter coli y Campylobacter jejuni producen por lo general infecciones gastrointestinales y raramente bacteriemia, excepto en individuos de edad avanzada o inmunodeprimidos. A continuación, exponemos el caso de un varón de 26 años afectado por la inmunodeficiencia XLA, que presentó un cuadro de fiebre de 2 semanas de evolución, con dolor e inflamación en el tobillo izquierdo postintervención quirúrgica y 5-6 deposiciones diarias de heces líquidas. La exploración y la analítica inicial evidenciaron un proceso infeccioso. Se procedió a la realización de coprocultivo y hemocultivo, constatándose bacteriemia por Campylobacter coli (AU)
Campylobacter spp. infection is considered as main bacterial enteritis causes in humans. Among Campylobacter spp., Campylobacter fetus can be a cause of systemic infections such as cellulitis, osteomyelitis, arthritis, pericarditis and endocarditis. However, Campylobacter coli and Campylobacter jejuni predominantly induce gastrointestinal infections and rarely cause bacteremia except in elderly and immunodeficient individuals. The case is presented of a 26 year-old male affected by XLA immunodeficiency, who had a clinical profile of 2 weeks evolution with fever, ankle left postintervention surgical and 5-6 daily liquid bowel movements without pathological products. Initial exploration and analytical showed an infectious process. We proceeded to carry out complementary, stool culture and blood culture tests where it was found Campylobacter coli bacteremia (AU)
Subject(s)
Humans , Male , Adult , Bacteremia/diagnosis , Bacteremia/immunology , Campylobacter coli/isolation & purification , Immunosuppression Therapy/methods , Immunosuppression Therapy , Immunoglobulins/therapeutic use , Polymerase Chain Reaction , Levofloxacin/therapeutic use , Campylobacter coli/pathogenicity , Microbial Sensitivity TestsABSTRACT
Copy number variants (CNV) are structural variants consisting of duplications or deletions of genomic fragments longer than 1 kb that present variability in the population and are heritable. The objective of this study was to identify CNV regions (CNVR) associated with 7 economically important traits (production, functional, and type traits) in Holstein cattle: fat yield, protein yield, somatic cell count, days open, stature, foot angle, and udder depth. Copy number variants were detected by using deep-sequencing data from 10 sequenced bulls and the Bovine SNP chip array hybridization signals. To reduce the number of false-positive calls, only CNV identified by both sequencing and Bovine SNP chip assays were kept in the final data set. This resulted in 823 CNVR. After filtering by minor allele frequency >0.01, a total of 90 CNVR appeared segregating in the bulls that had phenotypic data. Linear and quadratic CNVR effects were estimated using Bayesian approaches. A total of 15 CNVR were associated with the traits included in the analysis. One CNVR was associated with fat and protein yield, another 1 with fat yield, 3 with stature, 1 with foot angle, 7 with udder depth, and only 1 with days open. Among the genes located within these regions, highlighted were the MTHFSD gene that belongs to the folate metabolism genes, which play critical roles in regulating milk protein synthesis; the SNRPE gene that is related to several morphological pathologies; and the NF1 gene, which is associated with potential effects on fertility traits. The results obtained in the current study revealed that these CNVR segregate in the Holstein population, and therefore some potential exists to increase the frequencies of the favorable alleles in the population after independent validation of results in this study. However, genetic variance explained by the variants reported in this study was small.
Subject(s)
Bayes Theorem , Polymorphism, Single Nucleotide , Animals , Cattle , DNA Copy Number Variations , Male , Milk/chemistry , PhenotypeABSTRACT
El virus de la infección por hepatitis E (HEV) es un importante problema de salud pública en muchos países en desarrollo, causando principalmente hepatitis aguda autolimitada por el consumo de agua contaminada. En países industrializados, la hepatitis E aguda presenta una incidencia puntual aunque de mayor gravedad, detectándose en viajeros procedentes de zonas endémicas, así como casos fortuitos debidos al consumo o contacto con carne de cerdo cruda o poco cocinada. En el Área de Salud de Mérida, se realizó un estudio de los casos de hepatitis E durante el periodo comprendido entre enero del 2013 y junio del 2015. Como resultado se detectaron 9 casos, localizados entre septiembre del 2014 y junio del 2015. Dichos casos se caracterizaban por hipertransaminasemia y, además, 5 de ellos presentaban factores de riesgo para la predisposición de la enfermedad. Los resultados en nuestro medio corresponden a casos esporádicos, en donde no se ha podido identificar la vía de trasmisión. Sin embargo, se sugiere la zoonosis como la causa más probable, al ser uno de los reservorios el cerdo doméstico y el jabalí salvaje, los cuales presentan una gran importancia en la agroalimentaria en el Área de Extremadura (AU)
Virus infection hepatitis E (HEV) is a serious public health problem in many developing countries, mainly self-limited acute hepatitis caused by drinking contaminated water. In industrialized countries, acute hepatitis E has a punctual incidence detected although more serious incident. It is detected in travelers from endemic areas and incidental circumstances due to raw or undercooked pork consumption or contact. A study of cases of hepatitis E was taken in Merida Health Area during the period of January 2013 to June 2015. As a result, nine cases were detected between September 2014 to June 2015. These cases were characterized by transaminases elevation. In addition, five of them presented HEV-disease predisposition risk factors. Sporadic cases were the result in our area. The route of HEV transmission has not been identified. However, zoonosis is suggested as the most probably transmission via. Domestic pigs and wild boar are the principal HEV reservoirs, which present an enormous importance over nutrition and agriculture in the Extremadura Area (AU)
Subject(s)
Humans , Male , Female , Hepatitis E/microbiology , Hepatitis E/pathology , Transaminases/analysis , Risk Factors , Hepatitis E virus/isolation & purification , Polymerase Chain Reaction/methods , Polymerase Chain Reaction/trends , Polymerase Chain Reaction , Zoonoses/diagnosis , Zoonoses/microbiology , Serology/methods , Serology/standards , Retrospective Studies , Immunoglobulin G/analysis , Immunoglobulin M/analysis , Genome/physiologyABSTRACT
No disponible
