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1.
Appetite ; : 107546, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38871299

RESUMEN

Eating together is a primordial social activity with robust normative expectations. This study examines a series of instances where appreciative elements about the food during a shared meal are treated as noticeably absent and where some of the participants are attributed to exhibit a negative stance towards the food, which furthermore is used as a resource for engaging in membership categorization. Situated within the cognate approaches of ethnomethodology and conversation analysis, this study draws on video recordings of an integrated language and cooking workshop organized for immigrants in the French speaking part of Switzerland. The participants include a French teacher, two chefs and five immigrant women with various native languages. The detailed sequential, multimodal analysis details and explains how the participants treat gustatory features of eating as publicly available and accountable, and how the absence of evaluative elements contribute to the situated achievement of a plural "you" as a group that does not like "this" food. Ascribing (dis)taste for food on behalf of others, occasions accounts for just how to eat, showing the strong normative features that make up to the recognizability of sharing a meal as a competent member - including how sensorial experiences are evaluated and expressed. In this way, this study contributes to our understanding of the (non)ordinary features of eating together as a situated, embodied achievement and social institution that is built in and through interaction.

2.
J Antimicrob Chemother ; 70(9): 2474-82, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26031466

RESUMEN

OBJECTIVES: In Denmark, the incidence of vancomycin-resistant Enterococcus faecium (VREfm) has increased since 2012. The aim of this study was to investigate the epidemiology and clonal relatedness of VREfm isolates in Danish hospitals in 2012-13 using WGS. The second aim was to evaluate if WGS-based typing could replace PFGE for typing of VREfm. METHODS: A population-based study was conducted including all VREfm isolates submitted for national surveillance from January 2012 to April 2013. All isolates were investigated by WGS, MLST and PFGE. RESULTS: One-hundred and thirty-two isolates were included. The majority of the isolates were from clinical samples (77%). Gastroenterology/abdominal surgery (29%) and ICUs (29%) were the predominant departments with VREfm. Genomics revealed a polyclonal structure of the VREfm outbreak. Seven subgroups of 3-44 genetically closely related isolates (separated by <17 SNPs) were identified using WGS. Direct or indirect transmission of VREfm between patients and intra- and inter-regional spreading clones was observed. We identified 10 STs. PFGE identified four major clusters (13-43 isolates) and seven minor clusters (two to three isolates). The results from the typing methods were highly concordant. However, WGS-based typing had the highest discriminatory power. CONCLUSIONS: This study emphasizes the importance of infection control measures to limit transmission of VREfm between patients. However, the diversity of the VREfm isolates points to the fact that other important factors may also affect the VREfm increase in Denmark. Finally, WGS is suitable for typing of VREfm and has replaced PFGE for typing of VREfm in Denmark.


Asunto(s)
Proteínas Bacterianas/genética , Ligasas de Carbono-Oxígeno/genética , Infección Hospitalaria/epidemiología , Brotes de Enfermedades , Enterococcus faecium/aislamiento & purificación , Infecciones por Bacterias Grampositivas/epidemiología , Tipificación Molecular/métodos , Enterococos Resistentes a la Vancomicina/aislamiento & purificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Infección Hospitalaria/microbiología , ADN Bacteriano/química , ADN Bacteriano/genética , Dinamarca/epidemiología , Enterococcus faecium/clasificación , Enterococcus faecium/genética , Femenino , Genotipo , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Masculino , Persona de Mediana Edad , Epidemiología Molecular/métodos , Enterococos Resistentes a la Vancomicina/clasificación , Enterococos Resistentes a la Vancomicina/genética , Adulto Joven
3.
Proc Natl Acad Sci U S A ; 109(12): 4550-5, 2012 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-22393007

RESUMEN

Whole-genome sequencing offers new insights into the evolution of bacterial pathogens and the etiology of bacterial disease. Staphylococcus aureus is a major cause of bacteria-associated mortality and invasive disease and is carried asymptomatically by 27% of adults. Eighty percent of bacteremias match the carried strain. However, the role of evolutionary change in the pathogen during the progression from carriage to disease is incompletely understood. Here we use high-throughput genome sequencing to discover the genetic changes that accompany the transition from nasal carriage to fatal bloodstream infection in an individual colonized with methicillin-sensitive S. aureus. We found a single, cohesive population exhibiting a repertoire of 30 single-nucleotide polymorphisms and four insertion/deletion variants. Mutations accumulated at a steady rate over a 13-mo period, except for a cluster of mutations preceding the transition to disease. Although bloodstream bacteria differed by just eight mutations from the original nasally carried bacteria, half of those mutations caused truncation of proteins, including a premature stop codon in an AraC-family transcriptional regulator that has been implicated in pathogenicity. Comparison with evolution in two asymptomatic carriers supported the conclusion that clusters of protein-truncating mutations are highly unusual. Our results demonstrate that bacterial diversity in vivo is limited but nonetheless detectable by whole-genome sequencing, enabling the study of evolutionary dynamics within the host. Regulatory or structural changes that occur during carriage may be functionally important for pathogenesis; therefore identifying those changes is a crucial step in understanding the biological causes of invasive bacterial disease.


Asunto(s)
Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Teorema de Bayes , Análisis por Conglomerados , Progresión de la Enfermedad , Evolución Molecular , Eliminación de Gen , Variación Genética , Genoma Bacteriano , Humanos , Meticilina/farmacología , Mutación , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Factores de Tiempo
4.
J Clin Microbiol ; 52(12): 4305-8, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25297335

RESUMEN

spa typing of methicillin-resistant Staphylococcus aureus (MRSA) has traditionally been done by PCR amplification and Sanger sequencing of the spa repeat region. At Hvidovre Hospital, Denmark, whole-genome sequencing (WGS) of all MRSA isolates has been performed routinely since January 2013, and an in-house analysis pipeline determines the spa types. Due to national surveillance, all MRSA isolates are sent to Statens Serum Institut, where the spa type is determined by PCR and Sanger sequencing. The purpose of this study was to evaluate the reliability of the spa types obtained by 150-bp paired-end Illumina WGS. MRSA isolates from new MRSA patients in 2013 (n = 699) in the capital region of Denmark were included. We found a 97% agreement between spa types obtained by the two methods. All isolates achieved a spa type by both methods. Nineteen isolates differed in spa types by the two methods, in most cases due to the lack of 24-bp repeats in the whole-genome-sequenced isolates. These related but incorrect spa types should have no consequence in outbreak investigations, since all epidemiologically linked isolates, regardless of spa type, will be included in the single nucleotide polymorphism (SNP) analysis. This will reveal the close relatedness of the spa types. In conclusion, our data show that WGS is a reliable method to determine the spa type of MRSA.


Asunto(s)
Staphylococcus aureus Resistente a Meticilina/clasificación , Staphylococcus aureus Resistente a Meticilina/genética , Tipificación Molecular/métodos , Análisis de Secuencia de ADN/métodos , Proteína Estafilocócica A/genética , Dinamarca/epidemiología , Humanos , Epidemiología Molecular/métodos , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/microbiología
5.
Int J Geriatr Psychiatry ; 27(3): 296-304, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21538537

RESUMEN

OBJECTIVE: The objective of this study was to assess the safety and tolerability of extended-release quetiapine fumarate (quetiapine XR) compared with quetiapine immediate-release (quetiapine IR) in older patients with Alzheimer's disease with symptoms of psychosis and/or agitation. METHODS: This was a 6-week, double-blind, double-dummy, randomised study. Of the 109 patients screened, 100 were randomised to receive quetiapine XR (n = 68) or quetiapine IR (n = 32), at doses of 50 and 25 mg/day, respectively. Treatment was escalated to 100 mg/day by Day 4. At Day 8, a flexible-dose (50-300 mg/day) period began when dose adjustment was made at the investigator's discretion. The primary variable was incidence and type of adverse events (AEs). Secondary variables included efficacy and other safety assessments. RESULTS: Mean daily doses were 143.6 and 142.0 mg in the quetiapine XR and quetiapine IR groups, respectively. Ninety patients completed the study; only one withdrew (in the quetiapine XR group) because of an AE. Laboratory evaluations identified severe neutropaenia (one patient), mild neutropaenia (three patients) and eosinophilia (five patients); however, these were not reported, as AEs and confounding factors, such as patient age, concomitant illness and medication, made it difficult to determine any relationship to quetiapine treatment. Numerical improvements from baseline were seen across both treatment groups in Neuropsychiatric Inventory frequency × severity total, Neuropsychiatric Inventory-Nursing Home version, Cohen-Mansfield Agitation Inventory, Clinical Global Impression-Severity of Illness and Clinical Global Impression-Improvement scores. CONCLUSION: Quetiapine XR dosed up to 300 mg/day was generally well tolerated, with a similar profile to that of quetiapine IR.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antipsicóticos/administración & dosificación , Dibenzotiazepinas/administración & dosificación , Agitación Psicomotora/tratamiento farmacológico , Trastornos Psicóticos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Antipsicóticos/efectos adversos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Dibenzotiazepinas/efectos adversos , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Agitación Psicomotora/etiología , Trastornos Psicóticos/etiología , Fumarato de Quetiapina
6.
Respir Res ; 11: 68, 2010 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-20525168

RESUMEN

BACKGROUND: Despite the widespread induction of miR-146a during the innate immune response little is known regarding its biogenesis, function and mechanism. We have therefore examined the role of miR-146a during the interleukin (IL)-1beta-stimulated IL-6 and IL-8 release and proliferation in primary human airway smooth muscle (HASM) cells. METHODS: HASM cells were isolated from human lung re-section, cultured to a maximum of 3 - 6 passages and then exposed to IL-1beta. miR-146a expression were determined by qRT-PCR, IL-6 and IL-8 release by ELISA and proliferation using bromodeoxyuridine incorporation. The role of NF-kappaB and the MAP kinase pathways was assessed using pharmacological inhibitors of IKK2 (TPCA-1), JNK (SP600125), p38 MAP kinase (SB203580) and MEK-1/2 (PD98059). miR-146a function was determined following transfection of HASM with inhibitors and mimics using Amaxa electroporation. RESULTS: IL-1beta induced a time-dependent and prolonged 100-fold induction in miR-146a expression, which correlated with release of IL-6 and IL-8. Exposure to IL-1beta had no effect upon HASM proliferation. Pharmacological studies showed that expression of primary miR-146a was regulated at the transcriptional levels by NF-kappaB whilst post-transcriptional processing to mature miR-146a was regulated by MEK-1/2 and JNK-1/2. Functional studies indicated that IL-1beta-induced miR-146a expression does not negatively regulate IL-6 and IL-8 release or basal proliferation. However, inhibition of IL-1beta-induced IL-6 and IL-8 release was observed at the super-maximal intracellular miR-146a levels obtained by transfection with miR-146a mimics and indicates that studies using miRNA mimics can produce false positive results. Mechanistic studies showed that in the presence of super-maximal levels, the action of miR-146a mimics was mediated at a step following IL-6 and IL-8 mRNA transcription and not through down-regulation of IL-1 receptor associated kinase 1 (IRAK-1) and TNF receptor-associated factor 6 (TRAF6) protein expression, two predicted miR-146a targets involved in IL-1beta signalling. CONCLUSIONS: We have shown that IL-1beta-induced miR-146a expression in HASM and that this was regulated at the transcriptional level by NF-kappaB and at the post-transcriptional level by the MEK-1/2 and JNK-1/2. Unlike previous reports, studies using miRNA inhibitors showed that miR-146a expression did not regulate IL-6 and IL-8 release or proliferation and suggest miR-146a function and mechanism is cell-type dependent.


Asunto(s)
Inmunidad Innata , Interleucina-1beta/metabolismo , Pulmón/metabolismo , MicroARNs/metabolismo , Miocitos del Músculo Liso/metabolismo , Proliferación Celular , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/antagonistas & inhibidores , MAP Quinasa Quinasa 2/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/inmunología , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Reacción en Cadena de la Polimerasa , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Postranscripcional del ARN , Factores de Tiempo , Transcripción Genética , Transfección , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
7.
J Socioling ; 24(4): 441-468, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38607822

RESUMEN

Using multimodal conversation analysis this article examines embodied and tactile greetings in social interaction, documenting their change during the Covid-19 pandemic. Recognizing social interaction as foundational for human sociality, we consider greetings as a crucial normative, organizational, and ritual practice for mutually engaging in intersubjective action. Analyses use video recordings made in Switzerland (featuring (Swiss-)German and English as a lingua-franca), focusing on embodied greetings of acquainted people in public spaces at the age of Covid19-a historical moment in which physical proximity and contact are targeted by official measures restricting social interactions. Studying a range of tactile embodied greetings, the paper shows how they change from routine greetings to hesitated, suspended yet still completed ones, and to projected but resisted and refused ones. Furthermore, it reveals some 'new' practices of greeting (elbow/feetbumps, hugs-in-the-air) and their non-straightforward and accountable character, as well as how they sediment and normalize during the pandemic.


Dans le cadre de l'analyse conversationnelle multimodale, cet article se penche sur les salutations incarnées et tactiles dans l'interaction sociale, pour en documenter les changements observables durant la pandémie de Covid­19. En reconnaissant que l'interaction sociale a un rôle fondateur pour la socialité humaine, nous considérons les salutations comme des pratiques normatives, organisationnelles, et rituelles cruciales pour s'engager mutuellement dans l'action intersubjective. Les analyses proposées reposent sur des enregistrements vidéo effectués en Suisse (langues impliquées: Allemand, Suisse­Allemand, Anglais lingua franca), documentant des salutations incarnées entre interconnaissances dans les espaces publics à l'ère de la Covid­19­un moment historique durant lequel la proximité physique et le contact corporel sont la cible de mesures officielles restreignant les interactions sociales. En étudiant une variété de salutations incarnées tactiles, cette étude montre comment elles changent, passant de salutations routinières à des salutations hésitantes, suspendues, tout en continuant à être complétées, aboutissant à des salutations projetées, mais faisant l'objet de résistance et de refus. Enfin, l'étude montre l'émergence de quelques "nouvelles" pratiques de salutations (avec les pieds, les coudes, et des embrassades en l'air), leur caractère initialement non­évident, puis progressivement sédimenté et normalisé au fil de la pandémie.

8.
Biochem Soc Trans ; 36(Pt 6): 1211-5, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19021527

RESUMEN

In mammalian cells, miRNAs (microRNAs) are the most abundant family of small non-coding RNAs that regulate mRNA translation through the RNA interference pathway. In general, it appears that the major function of miRNAs is in development, differentiation and homoeostasis, which is indicated by studies showing aberrant miRNA expression during the development of cancer. Interestingly, changes in the expression of miR-146a have been implicated in both the development of multiple cancers and in the negative regulation of inflammation induced via the innate immune response. Furthermore, miR-146a expression is driven by the transcription factor NF-kappaB (nuclear factor kappaB), which has been implicated as an important causal link between inflammation and carcinogenesis. In the present article, we review the evidence for a role of miR-146a in innate immunity and cancer and assess whether changes in miR-146a might link these two biological responses.


Asunto(s)
Inmunidad Innata/inmunología , MicroARNs/metabolismo , Neoplasias/metabolismo , Animales , Hematopoyesis/fisiología , Humanos , Inflamación/metabolismo , MicroARNs/genética , Neoplasias/genética
9.
Nat Commun ; 5: 3956, 2014 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-24853639

RESUMEN

Horizontal gene transfer is an important driver of bacterial evolution, but genetic exchange in the core genome of clonal species, including the major pathogen Staphylococcus aureus, is incompletely understood. Here we reveal widespread homologous recombination in S. aureus at the species level, in contrast to its near-complete absence between closely related strains. We discover a patchwork of hotspots and coldspots at fine scales falling against a backdrop of broad-scale trends in rate variation. Over megabases, homoplasy rates fluctuate 1.9-fold, peaking towards the origin-of-replication. Over kilobases, we find core recombination hotspots of up to 2.5-fold enrichment situated near fault lines in the genome associated with mobile elements. The strongest hotspots include regions flanking conjugative transposon ICE6013, the staphylococcal cassette chromosome (SCC) and genomic island νSaα. Mobile element-driven core genome transfer represents an opportunity for adaptation and challenges our understanding of the recombination landscape in predominantly clonal pathogens, with important implications for genotype-phenotype mapping.


Asunto(s)
Elementos Transponibles de ADN/genética , Genoma Bacteriano/genética , Recombinación Genética , Staphylococcus aureus/genética , Cromosomas Bacterianos/genética , Transferencia de Gen Horizontal/genética , Variación Genética , Funciones de Verosimilitud , Desequilibrio de Ligamiento/genética , Filogenia , Especificidad de la Especie , Staphylococcus aureus/aislamiento & purificación
10.
Pain ; 154(11): 2494-2499, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23886521

RESUMEN

A randomized, double-blind, three-period cross-over study was performed to characterize the sensory phenotype and pain demographics in patients with Morton neuroma (n=27) and to explore the effects of local administration (2mL) of placebo and lidocaine (1 and 10mg/mL) around the neuroma. Using the pain quality assessment scale (PQAS), the highest rating was seen for unpleasant pain and intensity of deep pain and the lowest for sensitive skin. Ongoing pain was reported in 32% of patients. Patients reported mild to moderate average pain, and that pain had interfered with sleep only marginally. Quantitative sensory testing (QST) measurements in the innervation territory showed hypophenomena or hyperphenomena in all patients, indicating that all had neuropathy. There was no particular QST modality that appeared to be specifically affected. Even the high-dose lidocaine resulted in limited effects on nerve-impulse conduction as judged by the effect on QST variables. However, both doses of lidocaine significantly reduced pain after step-ups, compared to placebo, indicating that lidocaine in this setting affected predominantly impulse generation and not impulse conduction. Following placebo treatment, pain after step-ups was similar in patients with and without hyperalgesia, indicating that the presence of hyperalgesia does not affect the pain intensity evoked by step-ups or walking. This pain model in patients with Morton neuroma allows investigation of drugs in a cross-over design and provides an opportunity to explore drug effects on both pain and QST variables. Commonly, neuromas are surgically removed and can be characterized in depth in vitro, thereby allowing close links to be established between pathophysiology and drug effect.


Asunto(s)
Neuralgia/etiología , Neuroma/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anestésicos Locales/efectos adversos , Anestésicos Locales/uso terapéutico , Frío , Estudios Cruzados , Método Doble Ciego , Femenino , Pie/fisiología , Calor , Humanos , Hiperalgesia/etiología , Hiperalgesia/psicología , Canales Iónicos/efectos de los fármacos , Canales Iónicos/metabolismo , Lidocaína/efectos adversos , Lidocaína/uso terapéutico , Masculino , Persona de Mediana Edad , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Neuroma/tratamiento farmacológico , Neuroma/fisiopatología , Dimensión del Dolor , Umbral del Dolor/fisiología , Estimulación Física , Tamaño de la Muestra , Sensación Térmica/fisiología , Adulto Joven
11.
Genome Announc ; 1(3)2013 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-23792746

RESUMEN

We report the genome sequence, in five contigs, of a methicillin-resistant Staphylococcus aureus isolate designated M1. This clinical isolate was from the index patient of a methicillin-resistant Staphylococcus aureus (MRSA) outbreak in Copenhagen, Denmark, that started in 2003. This strain is sequence type 8 (ST8), spa type t024, and staphylococcal cassette chromosome mec element (SCCmec) type IVa.

12.
PLoS One ; 8(5): e61319, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23658690

RESUMEN

BACKGROUND: Staphylococcus aureus is a major cause of healthcare associated mortality, but like many important bacterial pathogens, it is a common constituent of the normal human body flora. Around a third of healthy adults are carriers. Recent evidence suggests that evolution of S. aureus during nasal carriage may be associated with progression to invasive disease. However, a more detailed understanding of within-host evolution under natural conditions is required to appreciate the evolutionary and mechanistic reasons why commensal bacteria such as S. aureus cause disease. Therefore we examined in detail the evolutionary dynamics of normal, asymptomatic carriage. Sequencing a total of 131 genomes across 13 singly colonized hosts using the Illumina platform, we investigated diversity, selection, population dynamics and transmission during the short-term evolution of S. aureus. PRINCIPAL FINDINGS: We characterized the processes by which the raw material for evolution is generated: micro-mutation (point mutation and small insertions/deletions), macro-mutation (large insertions/deletions) and the loss or acquisition of mobile elements (plasmids and bacteriophages). Through an analysis of synonymous, non-synonymous and intergenic mutations we discovered a fitness landscape dominated by purifying selection, with rare examples of adaptive change in genes encoding surface-anchored proteins and an enterotoxin. We found evidence for dramatic, hundred-fold fluctuations in the size of the within-host population over time, which we related to the cycle of colonization and clearance. Using a newly-developed population genetics approach to detect recent transmission among hosts, we revealed evidence for recent transmission between some of our subjects, including a husband and wife both carrying populations of methicillin-resistant S. aureus (MRSA). SIGNIFICANCE: This investigation begins to paint a picture of the within-host evolution of an important bacterial pathogen during its prevailing natural state, asymptomatic carriage. These results also have wider significance as a benchmark for future systematic studies of evolution during invasive S. aureus disease.


Asunto(s)
Evolución Molecular , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Adulto , Infecciones Asintomáticas , Portador Sano , Genoma Bacteriano , Humanos , Mutación INDEL , Nariz/microbiología , Polimorfismo de Nucleótido Simple , Selección Genética , Análisis de Secuencia de ADN , Infecciones Estafilocócicas/transmisión
13.
FEBS Lett ; 583(20): 3349-55, 2009 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-19786024

RESUMEN

We have previously reported that IL-beta-induced miR-146a and miR-146b expression negatively regulates IL-8 and RANTES release in human alveolar A549 epithelial cells. To determine the intracellular pathways that regulate this response, we demonstrate IL-1beta-induced activation of the nuclear factor (NF)-kappaB, extracellular regulated kinase (ERK)-1/2, c-jun N-terminal kinase (JNK)-1/2 and p38 mitogen activated kinase (MAP) kinase pathways. Subsequent pharmacological studies show that IL-1beta-induced miR-146a, IL-8 and RANTES production was regulated via NF-kappaB and JNK-1/2 whilst miR-146b expression was mediated via MEK-1/2 and JNK-1/2. These divergent intracellular pathways likely explain the differential expression and biological action of the miR-146 isoforms.


Asunto(s)
Quimiocina CCL5/metabolismo , Células Epiteliales/metabolismo , Interleucina-8/metabolismo , MicroARNs/metabolismo , Mucosa Respiratoria/citología , Transducción de Señal/fisiología , Activación Enzimática , Inhibidores Enzimáticos/metabolismo , Células Epiteliales/citología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/genética , MAP Quinasa Quinasa 2/metabolismo , MicroARNs/genética , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/genética , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Alveolos Pulmonares/citología , Mucosa Respiratoria/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
14.
PLoS One ; 4(6): e5889, 2009 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-19521514

RESUMEN

BACKGROUND: Asthma is a common disease characterised by reversible airflow obstruction, bronchial hyperresponsiveness and chronic inflammation, which is commonly treated using corticosteroids such as budesonide. MicroRNAs (miRNAs) are a recently identified family of non-protein encoding genes that regulate protein translation by a mechanism entitled RNA interference. Previous studies have shown lung-specific miRNA expression profiles, although their importance in regulating gene expression is unresolved. We determined whether miRNA expression was differentially expressed in mild asthma and the effect of corticosteroid treatment. METHODOLOGY/PRINCIPAL FINDINGS: We have examined changes in miRNA using a highly sensitive RT-PCR based approach to measure the expression of 227 miRNAs in airway biopsies obtained from normal and mild asthmatic patients. We have also determined whether the anti-inflammatory action of corticosteroids are mediated through miRNAs by determining the profile of miRNA expression in mild asthmatics, before and following 1 month twice daily treatment with inhaled budesonide. Furthermore, we have analysed the expression of miRNAs from individual cell populations from the airway and lung. We found no significant difference in the expression of 227 miRNAs in the airway biopsies obtained from normal and mild asthmatic patients. In addition, despite improved lung function, we found no significant difference in the miRNA expression following one month treatment with the corticosteroid, budesonide. However, analysis of bronchial and alveolar epithelial cells, airway smooth muscle cells, alveolar macrophages and lung fibroblasts demonstrate a miRNA expression profile that is specific to individual cell types and demonstrates the complex cellular heterogeneity within whole tissue samples. CONCLUSIONS: Changes in miRNA expression do not appear to be involved in the development of a mild asthmatic phenotype or in the anti-inflammatory action of the corticosteroid budesonide.


Asunto(s)
Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Bronquios/metabolismo , Perfilación de la Expresión Génica , Pulmón/metabolismo , MicroARNs/metabolismo , Alveolos Pulmonares/metabolismo , Adolescente , Adulto , Biopsia , Bronquios/efectos de los fármacos , Budesonida/uso terapéutico , Femenino , Humanos , Inflamación/tratamiento farmacológico , Pulmón/efectos de los fármacos , Masculino , Alveolos Pulmonares/efectos de los fármacos
15.
J Immunol ; 180(8): 5689-98, 2008 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-18390754

RESUMEN

Posttranscriptional regulation of gene expression by microRNAs (miRNAs) has been implicated in the regulation of chronic physiological and pathological responses. In this report, we demonstrate that changes in the expression of miRNAs can also regulate acute inflammatory responses in human lung alveolar epithelial cells. Thus, stimulation with IL-1beta results in a rapid time- and concentration-dependent increase in miRNA-146a and, to a lesser extent, miRNA-146b expression, although these increases were only observed at high IL-1beta concentration. Examination of miRNA function by overexpression and inhibition showed that increased miRNA-146a expression negatively regulated the release of the proinflammatory chemokines IL-8 and RANTES. Subsequent examination of the mechanism demonstrated that the action of miRNA-146a was mediated at the translational level and not through the down-regulation of proteins involved in the IL-1beta signaling pathway or chemokine transcription or secretion. Overall, these studies indicate that rapid increase in miRNA-146a expression provides a novel mechanism for the negative regulation of severe inflammation during the innate immune response.


Asunto(s)
Células Epiteliales/inmunología , Inflamación/metabolismo , Interleucina-1beta/inmunología , MicroARNs/metabolismo , Alveolos Pulmonares/inmunología , Línea Celular Tumoral , Quimiocina CCL5/inmunología , Quimiocina CCL5/metabolismo , Regulación hacia Abajo , Células Epiteliales/metabolismo , Perfilación de la Expresión Génica , Humanos , Inflamación/inmunología , Interleucina-1beta/metabolismo , Interleucina-8/inmunología , Interleucina-8/metabolismo , Alveolos Pulmonares/metabolismo , Transducción de Señal
16.
Curr Med Res Opin ; 23(7): 1531-9, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17559748

RESUMEN

OBJECTIVE: NXY-059 is a novel free-radical trapping neuroprotectant. Digoxin treatment is common in acute ischaemic stroke, the intended patient population for NXY-059. Since both digoxin and NXY-059 are eliminated primarily renally, with a substantial contribution by active renal secretion, and because digoxin has a narrow therapeutic window, this open, randomised, crossover, two-period study investigated whether NXY-059 affects the pharmacokinetics (PK) of digoxin. RESEARCH DESIGN AND METHODS: Twenty-two healthy subjects received 0.5 mg oral digoxin 2 h after the start of 60-h intravenous infusions of NXY-059 and placebo separated by a 14-day washout. Blood and urine were collected for 60 h. Digoxin concentrations were measured by a novel liquid chromatography-mass spectrometry assay. MAIN OUTCOME MEASURES: The ratio of the geometric mean (90% confidence interval) between NXY-059 and placebo for the digoxin area under the concentration-versus-time curve was 0.91 (0.83-0.99) and was within the predefined range for no interaction (0.80-1.25). No safety concerns were raised in the study. No serious adverse events were recorded. The most common adverse event was headache with similar frequencies in the two treatments. CONCLUSIONS: NXY-059 had no clinically significant effect on the PK of digoxin.


Asunto(s)
Antiarrítmicos/farmacocinética , Bencenosulfonatos/administración & dosificación , Digoxina/farmacocinética , Fármacos Neuroprotectores/administración & dosificación , Adolescente , Adulto , Antiarrítmicos/sangre , Antiarrítmicos/orina , Bencenosulfonatos/sangre , Bencenosulfonatos/orina , Cromatografía Liquida/métodos , Digoxina/sangre , Digoxina/orina , Femenino , Humanos , Masculino , Espectrometría de Masas/métodos , Persona de Mediana Edad , Fármacos Neuroprotectores/sangre , Fármacos Neuroprotectores/orina
17.
Am J Epidemiol ; 162(1): 73-9, 2005 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-15961589

RESUMEN

The authors investigated the association of smoking and smoking cessation with the incidence of cataract extraction in a population-based prospective cohort study. A total of 34,595 women aged 49-83 years in the Swedish Mammography Cohort were followed from September 1997 through June 2002. Information on smoking, diet, and other lifestyle factors was collected through a self-administered questionnaire. A total of 2,128 cases of age-related cataract extraction were identified. Relative risks were estimated as rate ratios using Cox proportional hazards models. The authors observed a significant dose-response association between intensity of smoking and risk of cataract extraction (among current smokers, p for trend = 0.02; among past smokers, p for trend = 0.0002). After cessation of smoking, the risk decreased with time. Among women with a moderate lifetime smoking intensity (6-10 cigarettes/day), the relative risk was not significantly different from the risk among never smokers 10 years after smoking cessation. Among women who had smoked more intensively (>10 cigarettes/day), after 20 years of nonsmoking the increased risk became small and no longer statistically significant in comparison with never smokers (for trend over time, p < 0.0001). This prospective study confirmed smoking as a risk factor for cataract, with a dose response for smoking intensity. Smoking cessation predicts reduced risk over time, but a longer period of time is needed with a higher smoking intensity.


Asunto(s)
Extracción de Catarata/estadística & datos numéricos , Medición de Riesgo , Cese del Hábito de Fumar/estadística & datos numéricos , Fumar/efectos adversos , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Fumar/epidemiología , Encuestas y Cuestionarios , Suecia/epidemiología
18.
BJOG ; 110(1): 12-7, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12504929

RESUMEN

OBJECTIVE: To evaluate whether the gold standard of 24-hour urine collection for measuring albumin excretion in pre-eclamptic women could be substituted by shorter collection periods. DESIGN: Prospective study. SETTING: Fetal maternity ward, university hospital. PARTICIPANTS: Thirty women with pre-eclampsia and a positive urinary test strip for protein of at least 2+. METHODS: From each woman, within a 25-hour period, three spot, two 12-hour (day and night) and one 24-hour urine sample were collected. Urine albumin concentrations in milligrammes per litre were analysed by rate nephelometry on a Beckman Array protein system. The urinary albumin concentrations in the spot and the 12-hour samples were compared with the concentration in the 24-hour urine collection. MAIN OUTCOME MEASURES: Urinary albumin concentrations in spot and 12-hour samples measured against the standard 24-hour albumin excretion. RESULTS: Albumin concentrations in the day and night collection fitted closely with the concentrations of the 24-hour collection. The median difference between the 24-hour and the day collection was -3 mg/L (interquartile range -264 to 116 mg/L). The median difference between the 24-hour and the night collection was 17 mg/L (interquartile range -186 to 210 mg/L). The association of urinary albumin concentration in the 24-hour collection and the spot samples was much weaker. Of the spot urine samples, the albumin concentration in the sample taken on the morning after admission to hospital was closest to the 24-hour urinary albumin excretion, with a median difference of -62 mg/L (interquartile range -1131 to 285 mg/L). CONCLUSION: The gold standard of 24-hour urinary excretion for assessment of albuminuria in pre-eclamptic women can be substituted with a 12-hour collection. Spot urine samples were inaccurate and are therefore not recommended for quantification of albumin excretion.


Asunto(s)
Albuminuria/diagnóstico , Preeclampsia/orina , Manejo de Especímenes/normas , Adulto , Biomarcadores/orina , Femenino , Humanos , Embarazo , Diagnóstico Prenatal/normas , Estudios Prospectivos , Sensibilidad y Especificidad
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