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SETTING: An urban demographic surveillance site in Bissau, the capital of Guinea-Bissau, West Africa.BACKGROUND We hypothesised that if previous malnutrition plays a part in acquiring active tuberculosis (TB) disease, households of TB cases would have a higher prevalence of malnutrition than those of healthy controls. DESIGN: A cross-sectional study comparing nutritional and socio-economic status of all newly diagnosed patients with TB in 2014 with household contacts (persons residing in the household of TB cases) and random controls. Exclusion criteria were extra-pulmonary TB, age <15 years and pregnancy. RESULTS: Prevalence of malnutrition was 5% in household contacts and healthy controls, and 51% in patients with TB. Patients with TB had 22% (95%CI 19-25) lower body weight, 22% (95%CI 20-25) lower body mass index and 22% (95%CI 19-24) lower mid-upper arm circumference than healthy controls (P < 0.001); household contacts and healthy controls were comparable for all measures. The socio-economic status of households with TB cases was lower. CONCLUSIONS: We did not find a higher prevalence of malnourishment in households with TB cases. This finding did not support the hypothesis that malnourishment was an important causative factor for the development of active TB among patients in this study.
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Trazado de Contacto , Desnutrición/epidemiología , Tuberculosis Pulmonar/epidemiología , Población Urbana , Adolescente , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Guinea Bissau/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores Socioeconómicos , Adulto JovenRESUMEN
INTRODUCTION: Metal-on-metal hip articulations have been intensely debated after reports of adverse reactions and high failure rates. The aim of this study was to retrospectively evaluate the implant of a metal-on.metal total hip articulation (MOM THA) from a single manufacture in a two-center study. MATERIALS AND METHODS: 108 CONSERVE(®) MOM THA were implanted in 92 patients between November 2005 and December 2010. Patients had at time of retrospective evaluation their journals reviewed for re-operations and adverse reactions. RESULTS: 20 hips were re-operated (18.4%) at a mean follow up of 53 months. 4 pseudotumors were diagnosed at time of follow up but no substantiated link was made between adverse reactions and re-operations. CONCLUSION: The high re-operation rates found in this study raised concern about the usage of the MOM THA and subsequently lead to the termination of implantation of this MOM THA at the two orthopaedic departments.
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OBJECTIVE: Patients with burning mouth syndrome (BMS) often represent a clinical challenge as available agents for symptomatic treatment are few and often ineffective. The aim was to evaluate the effect of a bupivacaine lozenge on oral mucosal pain, xerostomia, and taste alterations in patients with BMS. METHODS: Eighteen patients (4 men and 14 women) aged 39-71 years with BMS were included in this randomized, double-blinded, placebo-controlled, crossover trial. Lozenges (containing bupivacaine or placebo) were administrated three times a day for 2 weeks for two separate treatment periods. Assessment of oral mucosal pain, xerostomia, and taste alterations was performed in a patient diary on a visual analog scale (ranging from 0 to 100 mm) before and after the lozenge was dissolved. RESULTS: The bupivacaine lozenge significantly reduced the burning oral pain (P < 0.001), increased the sense of taste disturbances (P < 0.001), and had no impact on xerostomia, when adjusted for the treatment period. CONCLUSIONS: Our results indicate that the bupivacaine lozenge offers a novel therapeutic modality to patients with BMS, although without alleviating effect on the associated symptoms, taste alterations, and xerostomia.
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Anestésicos Locales/administración & dosificación , Bupivacaína/administración & dosificación , Síndrome de Boca Ardiente/tratamiento farmacológico , Mucosa Bucal/efectos de los fármacos , Administración a través de la Mucosa , Adulto , Anciano , Síndrome de Boca Ardiente/complicaciones , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Gusto/tratamiento farmacológico , Trastornos del Gusto/etiología , Xerostomía/tratamiento farmacológico , Xerostomía/etiologíaRESUMEN
BACKGROUND: Insertion of an epidural catheter for pain relief is frequently used in anaesthetic practice. Little is known regarding patients' expected vs. experienced pain and discomfort due to the epidural block procedure. The purpose of this study was to investigate the expected and experienced pain, respectively, associated with the epidural procedure in patients undergoing major abdominal surgery. METHODS: Thirty adult, unselected patients scheduled for elective major abdominal surgery were included in this study, which was approved by the ethics committee. Pre-operative insertion of an epidural catheter had to be a part of the anaesthetic routine procedure. Immediately before the epidural procedure, the patients were asked to grade the pain they expected from the procedure on an 11-point numeric rating system scale, ranging from 0 to 10, where '0' is no pain and '10' is worst imaginable pain. When the procedure had been carried out, the patients were once again asked to grade how much pain they had experienced. RESULTS: The median expected pain as a result of the epidural procedure was 5.0. Median experienced pain was 2.0. The median difference between the expected and experienced pain was -3.0 (P < 0.0001). The only patient who expected less pain than she subsequently experienced had a paraesthetic sensation. Gender, age, or previous experience from central neuraxial block did not significantly affect neither expected nor experienced pain. CONCLUSIONS: Patients expect significantly more pain than they experience from receiving an epidural block.
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Anestesia Epidural/efectos adversos , Cateterismo/efectos adversos , Dolor/etiología , Dolor/psicología , Abdomen/cirugía , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Parestesia/etiologíaRESUMEN
BACKGROUND AND PURPOSE: Hypoxia causes vasodilatation of coronary arteries, but the underlying mechanisms are poorly understood. We hypothesized that hypoxia reduces intracellular Ca(2+) concentration ([Ca(2+)](i)) by opening of K channels and release of H2S. EXPERIMENTAL APPROACH: Porcine coronary arteries without endothelium were mounted for measurement of isometric tension and [Ca(2+)](i), and the expression of voltage-gated K channels K(V)7 channels (encoded by KCNQ genes) and large-conductance calcium-activated K channels (K(Ca)1.1) was examined. Voltage clamp assessed the role of K(V)7 channels in hypoxia. KEY RESULTS: Gradual reduction of oxygen concentration from 95 to 1% dilated the precontracted coronary arteries and this was associated with reduced [Ca(2+)](i) in PGF(2α) (10 µM)-contracted arteries whereas no fall in [Ca(2+)](i) was observed in 30 mM K-contracted arteries. Blockers of ATP-sensitive voltage-gated potassium channels and K(Ca)1.1 inhibited hypoxia-induced dilatation in PGF2α -contracted arteries; this inhibition was more marked in the presence of the K(v)7 channel blockers, XE991 and linopirdine, while a K(V)7.1 blocker, failed to change hypoxic vasodilatation. XE991 also inhibited H2S- and adenosine-induced vasodilatation. PCR revealed the expression of K(V)7.1, K(V)7.4, K(V)7.5 and K(Ca)1.1 channels, and K(Ca)1.1, K(V)7.4 and K(V)7.5 were also identified by immunoblotting. Voltage clamp studies showed the XE991-sensitive current was more marked in hypoxic conditions. CONCLUSION: The K(V)7.4 and K(V)7.5 channels, which we identified in the coronary arteries, appear to have a major role in hypoxia-induced vasodilatation. The voltage clamp results further support the involvement of K(V)7 channels in this vasodilatation. Activation of these K(V)7 channels may be induced by H2S and adenosine.
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Hipoxia/metabolismo , Canales de Potasio KCNQ/metabolismo , Músculo Liso Vascular/metabolismo , Oxígeno/metabolismo , Vasodilatación , Adenosina/farmacología , Animales , Señalización del Calcio , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Relación Dosis-Respuesta a Droga , Sulfuro de Hidrógeno/farmacología , Hipoxia/genética , Hipoxia/fisiopatología , Canales de Potasio KCNQ/efectos de los fármacos , Canales de Potasio KCNQ/genética , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Potenciales de la Membrana , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Bloqueadores de los Canales de Potasio/farmacología , Transducción de Señal , Porcinos , Factores de Tiempo , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
A recent decline in onset of puberty - especially among girls - has been observed, first in the US in the mid-1990s and now also in Europe. The development of breast tissue in girls occurs at a much younger age and the incidence of precocious puberty (PP) is increasing. Genetic factors and increasing prevalence of adiposity may contribute, but environmental factors are also likely to be involved. In particular, the widespread presence of endocrine-disrupting chemicals (EDCs) is suspected to contribute to the trend of earlier pubertal onset. The factors regulating the physiological onset of normal puberty are poorly understood. This hampers investigation of the possible role of environmental influences. There are many types of EDCs. One chemical may have more than one mode of action and the effects may depend on dose and duration of the exposure, as well as the developmental stage of the exposed individual. There may also be a wide range of genetic susceptibility to EDCs. Human exposure scenarios are complex and our knowledge about effects of mixtures of EDCs is limited. Importantly, the consequences of an exposure may not be apparent at the actual time of exposure, but may manifest later in life. Most known EDCs have oestrogenic and/or anti-androgenic actions and only few have androgenic or anti-oestrogenic effects. Thus, it appears plausible that they interfere with normal onset of puberty. The age at menarche has only declined by a few months whereas the age at breast development has declined by 1 year; thus, the time span from initiation of breast development to menarche has increased. This may indicate an oestrogen-like effect without concomitant central activation of the hypothalamic-pituitary axis. The effects may differ between boys and girls, as there are sex differences in age at onset of puberty, hormonal profiles and prevalence of precocius puberty.
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Disruptores Endocrinos/toxicidad , Pubertad/efectos de los fármacos , Pubertad/fisiología , Antagonistas de Andrógenos/farmacología , Población Negra , Niño , Contaminantes Ambientales , Estrógenos/farmacología , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Menarquia/efectos de los fármacos , Menarquia/fisiología , Encuestas Nutricionales , Pubertad Tardía/etiología , Pubertad Precoz/inducido químicamente , Pubertad Precoz/epidemiología , Maduración Sexual/efectos de los fármacos , Maduración Sexual/fisiología , Estados Unidos/epidemiología , Población BlancaRESUMEN
UNLABELLED: Robust assessment of Advanced Life Support (ALS) competence is paramount to the credibility of ALS-provider certification and for estimating the learning outcome and retention of ALS competence following the courses. The European Resuscitation Council (ERC) provides two sets of MCQs and four Cardiac Arrest Simulation Test (CASTest) scenarios for the assessments according to guidelines 2005. AIMS: To analyse the reliability and validity of the individual sub-tests provided by ERC and to find a combination of MCQ and CASTest that provides a reliable and valid single effect measure of ALS competence. METHODS: Two groups of participants were included in this randomised, controlled experimental study: a group of newly graduated doctors, who had not taken the ALS course (N=17) and a group of students, who had passed the ALS course 9 months before the study (N=16). Reliability in terms of inter-rater agreement and generalisability across skills scenarios were estimated. Validity was studied in terms of equality of test difficulty and ability to discriminate performance between the groups. RESULTS: Inter-rater agreement on checklist scores were generally high, Intraclass Correlation Coefficients between 0.766 and 0.977. Inter-rater agreements on pass/fail decisions were not perfect. The one MCQ test was significantly more difficult than the other. There were no significant differences between CASTests. Generalisability theory was use to identify a composite of MCQ and CASTest scenarios that possessed high reliability, equality of test sets, and ability to discriminate between the two groups of supposedly different ALS competence. CONCLUSIONS: ERC sub-tests of ALS competence possess sufficient reliability and validity. A combined ALS score with equal weighting of one MCQ and one CASTest can be used as a single measurement of ALS competence.
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Apoyo Vital Cardíaco Avanzado/educación , Competencia Clínica , Evaluación Educacional/métodos , Certificación , Europa (Continente) , Humanos , Variaciones Dependientes del Observador , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: In accordance with the literature on ventriculoatrial (VA) shunts, a percutaneous approach to the internal jugular vein is preferable to surgical preparation of the vein before catheter placement. Inspired by the above and the problems still remaining in the percutaneous method and successful results from anaesthesiology with the use of ultrasound-guided placement of central venous catheters, we have implemented an ultrasound-guided percutaneous technique for placement of VA shunts including pre- and intraoperative ultrasound guidance. METHODS: Data on 26 VA shunt operations were collected and analysed with special reference to the applicability of the method to pediatric patients, surgical complications and differences between revisions and first-time VA shunts. CONCLUSIONS: All patients with VA shunt indications were operated successfully with this technique including children down to the age of 5 years. The ultrasound-guided percutaneous technique results in a safe, quick and easy procedure with preoperative knowledge of the diameter of the vein, no accidental carotid artery puncture or pneumothorax, a minimal blood loss, a short operative time, few infectious complications and a good cosmetic result. Results for all parameters were identical in first-time VA shunt operations and revisions.
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Derivaciones del Líquido Cefalorraquídeo , Venas Yugulares/diagnóstico por imagen , Procedimientos Neuroquirúrgicos/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pérdida de Sangre Quirúrgica , Niño , Preescolar , Femenino , Atrios Cardíacos , Humanos , Hidrocefalia/cirugía , Venas Yugulares/cirugía , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Reoperación , UltrasonografíaRESUMEN
Macrophages respond to virus infections by rapidly secreting proinflammatory cytokines, which play an important role in the first line of defense. Tumor necrosis factor alpha (TNF-alpha) is one of the major macrophage-produced cytokines. In this study we have investigated the virus-cell interactions responsible for induction of TNF-alpha expression in herpes simplex virus (HSV)-infected macrophages. Both HSV type 1 (HSV-1) and HSV-2 induced TNF-alpha expression in macrophages activated with gamma interferon (IFN-gamma). This induction was to some extent sensitive to UV treatment of the virus. Virus particles unable to enter the cells displayed reduced capacity to stimulate TNF-alpha expression but retained a significant portion which was abolished by HSV-specific antibodies. Recombinant HSV-1 glycoprotein D was able to trigger TNF-alpha secretion in concert with IFN-gamma. Sugar moieties of HSV glycoproteins have been reported to be involved in induction of IFN-alpha but did not contribute to TNF-alpha expression in macrophages. Moreover, the entry-dependent portion of the TNF-alpha induction was investigated with HSV-1 mutants and found to be independent of the tegument proteins VP16 and UL13 and partly dependent on nuclear translocation of the viral DNA. Finally, we found that macrophages expressing an inactive mutant of the double-stranded RNA (dsRNA)-activated protein kinase (PKR) produced less TNF-alpha in response to infectious HSV infection than the empty-vector control cell line but displayed the same responsiveness to UV-inactivated virus. These results indicate that HSV induces TNF-alpha expression in macrophages through mechanisms involving (i) viral glycoproteins, (ii) early postentry events occurring prior to nuclear translocation of viral DNA, and (iii) viral dsRNA-PKR.
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Macrófagos/metabolismo , Simplexvirus/fisiología , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Línea Celular , Núcleo Celular/virología , Glicosilación , Proteína Vmw65 de Virus del Herpes Simple/fisiología , Interferón gamma/farmacología , Ratones , Proteínas Quinasas/fisiología , Activación Transcripcional , Proteínas del Envoltorio Viral/fisiología , eIF-2 Quinasa/fisiologíaRESUMEN
Here we have investigated the regulation of TNF-alpha expression in macrophages during HSV-2 infection. Despite a low basal level of TNF-alpha mRNA present in resting macrophages, no TNF-alpha protein is detectable. HSV-2 infection marginally increases the level of TNF-alpha mRNA and protein in resting macrophages, whereas a strong increase is observed in IFN-gamma-activated cells infected with the virus. By reporter gene assay it was found that HSV infection augments TNF-alpha promoter activity. Moreover, treatment of the cells with actinomycin D, which totally blocked mRNA synthesis, only partially prevented accumulation of TNF-alpha protein, indicating that the infection lifts a block on translation of TNF-alpha mRNA. EMSA analysis showed that specific binding to the kappaB#3 site of the murine TNF-alpha promoter was induced within 1 h after infection and persisted beyond 5 h where TNF-alpha expression is down-modulated. Binding to the cAMP responsive element site was also induced but more transiently with kinetics closely following activation of the TNF-alpha promoter. Inhibitors against either NF-kappaB activation or the activating transcription factor 2 kinase p38 abrogated TNF-alpha expression, showing a requirement for both signals for activation of the promoter. This observation was corroborated by reporter gene assays. As to the translational regulation of TNF-alpha, the AU-rich sequence in the 3' untranslated region of the mRNA was found to be responsible for this control because deletion of this region renders mRNA constitutively translationable. These results show that TNF-alpha production is induced by HSV-2 in macrophages through both transcriptional and translational regulation.
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Regiones no Traducidas 3'/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/fisiología , Herpesvirus Humano 2/inmunología , Proteínas I-kappa B , Macrófagos Peritoneales/inmunología , FN-kappa B/fisiología , Proteínas Proto-Oncogénicas c-jun/fisiología , Factores de Transcripción/fisiología , Activación Transcripcional/fisiología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Transcripción Activador 2 , Animales , Sitios de Unión/genética , Sitios de Unión/inmunología , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Repeticiones de Dinucleótido/fisiología , Femenino , Interferón gamma/farmacología , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/virología , Ratones , Ratones Endogámicos C57BL , Mutación , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , Regiones Promotoras Genéticas/inmunología , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The radical nitric oxide (NO) constitutes an important part of the innate immune response to many viruses, and among these notably Herpes simplex virus (HSV). We have previously shown that HSV/tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma synergistically induce NO production in macrophages, and here we have investigated the molecular mechanism underlying this phenomenon. The enhancement of NO production was regulated at the level of NO synthase 2 (NOS2, iNOS) transcription. The ISRE element of the NOS2 promoter, which binds IFN regulatory factor (IRF)-1, was essential both for full responsiveness to IFN-gamma and the synergistic response. The GAS motif, binding signal transducer and activator of transcription 1 (STAT1), did not contribute to the cross-talk with virus/TNF-induced signals, but was necessary for full responsiveness to IFN-gamma. The distal binding site for nuclear factor (NF)-kappa B was important for the cooperative response, while the proximal kappa B site was not involved in the cooperative promoter activation but played a role in full promoter inducibility. By ectopic expression of IRF-1 and NF-kappa B (p65), we found that these factors synergistically induce NO accumulation. Together, our results show that binding of IRF-1 and NF-kappa B to their respective sites in the distal domain of the NOS2 promoter, creates a potent trans-activating complex with the ability to induce NOS2 transcription synergistically in response to simultaneous HSV-2/TNF-alpha and IFN-gamma treatment.
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Proteínas de Unión al ADN/fisiología , Herpesvirus Humano 2/fisiología , Interferón gamma/fisiología , Macrófagos/enzimología , FN-kappa B/fisiología , Óxido Nítrico Sintasa/biosíntesis , Fosfoproteínas/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Secuencia de Bases , Western Blotting , Línea Celular , Cartilla de ADN , Inducción Enzimática , Factor 1 Regulador del Interferón , Ratones , Óxido Nítrico Sintasa/genética , Regiones Promotoras Genéticas , Técnicas del Sistema de Dos HíbridosRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease expressed early in life. Disease development is primarily determined by as yet unknown genetic factors, leading to the accumulation of activated T lymphocytes in the skin. OBJECTIVES: To investigate the nature of these T cells. METHODS: T-cell lines could be established from AD skin biopsies, but not from normal skin or AD peripheral blood, when placed in RPMI 1640 medium with 10% human AB serum, antibiotics, and the T-lymphocyte growth factors interleukins 2 and 4. The cell lines were subjected to phenotypic analysis using a fluorescence-activated cell sorter and compared with lymphocytes from AD and normal control peripheral blood. RESULTS: T-cell lines from 22 of 24 consecutive skin biopsies taken from 24 adult patients with AD were established. All cells were T lymphocytes expressing several activation markers. A significant proportion of the lymphocytes had stable expression of a CD4+ CD8+ phenotype (26% +/- 6%; mean +/- SEM). Such double-positive T lymphocytes are normally only seen in the thymus and not in the peripheral immune system. CD4+ CD8+ cells in peripheral blood of the patients (12.5% +/- 3.3%) were also detected. CONCLUSIONS: We suggest that a basic pathophysiological change in AD may be a faulty maturation of the T-lymphocyte system, leading to skin inflammation with CD4+ CD8+ T lymphocytes resembling immature T cells. This is likely to lead to skewing of many immune reactions in the patients.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Dermatitis Atópica/inmunología , Piel/inmunología , Adolescente , Adulto , Anticuerpos Monoclonales/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , División Celular/inmunología , Línea Celular , Tamaño de la Célula , Dermatitis Atópica/enzimología , Femenino , Humanos , Inmunidad Celular , Inmunofenotipificación , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Piel/enzimología , Telomerasa/metabolismo , Telómero/ultraestructuraRESUMEN
Infection of human monocyte-derived macrophages with CMV decreased the respiratory burst when cells were stimulated with opsonized zymosan or Pneumocystis carinii (P. carinii). Such an effect, though smaller, was also seen with heat-inactivated CMV, but only when triggered by zymosan. The effect was most pronounced in cells obtained from CMV antibody-negative donors. Dexamethasone further reduced the respiratory burst, both in uninfected and CMV-infected cells. Interferon-gamma increased the response in uninfected cells and, to a lesser extend, in cells treated with heat-inactivated CMV, whereas no effect was seen with infective CMV. No overt productive infection or cytopathology could be detected, however, the monocytes incubated with infective but also heat-inactivated CMV formed clusters, a phenomenon that was equally pronounced in cultures from CMV antibody positive and negative-donors. These results might help explain the worse prognosis of P. carinii pneumonia in patients coinfected with CMV and receiving dexamethasone.
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Infecciones por Citomegalovirus/metabolismo , Citomegalovirus , Macrófagos/metabolismo , Infecciones por Pneumocystis/metabolismo , Pneumocystis , Estallido Respiratorio , Animales , Células Cultivadas , Humanos , Macrófagos/microbiología , Macrófagos/virología , Masculino , Ratas , Ratas WistarRESUMEN
Interleukin (IL)-13 is known to antagonize many interferon (IFN)-gamma-activated functions in macrophages and among these, nitric oxide (NO) production. We have previously shown that this function of IL-13 is reduced in Herpes simplex virus type 2 (HSV-2)-infected macrophages. In the present study we show that IL-13 and IFN-gamma are indeed produced during infection of BALB/c mice with HSV-2. The lack of inhibitory function of IL-13 in infected macrophages, which was not overcome even at very high concentrations of IL-13, was not due to impaired IL-13 signalling, since virus infection did not affect IL-13-mediated activation of STAT6 (signal transducer and activator of transcription 6). Neutralizing tumour necrosis factor (TNF)-alpha antibodies, however, largely restored the effect of IL-13 on NO production in virus-infected macrophages. The same was observed after treatment of the cells with inhibitors of nuclear factor (NF)-kappa B activation, known to be involved in enhancement of IFN-gamma-induced NO production. Even though IL-13 reduced TNF-alpha secretion by 50%, this did not impair NF-kappa B activation in IFN-gamma-treated cells infected with HSV-2. The results indicate that TNF-alpha, secreted by virus-infected macrophages, activates NF-kappa B which impairs the IL-13-mediated inhibition of inducible NO synthase (iNOS) expression. This could imply that a sustained NO production would be focused to sites of active virus replication.
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Herpes Genital/metabolismo , Herpesvirus Humano 2/patogenicidad , Interleucina-13/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/virología , FN-kappa B/metabolismo , Óxido Nítrico/biosíntesis , Factor de Necrosis Tumoral alfa/farmacología , Animales , Secuencia de Bases , Células Cultivadas , Cartilla de ADN/genética , Femenino , Herpes Genital/inmunología , Herpes Genital/virología , Herpesvirus Humano 2/fisiología , Interferón gamma/biosíntesis , Interleucina-13/biosíntesis , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Replicación ViralRESUMEN
Nitric oxide (NO) production in macrophages by the interferon (IFN)-gamma-inducible NO synthase has been shown to play a role in clearance of viral infections. We have previously shown that IFN-gamma-induced NO production is augmented by herpes simplex virus type 2 (HSV-2) infection through autocrine tumour necrosis factor (TNF)-alpha secretion and is inhibited by interleukin (IL)-4. Here we investigated the effect of HSV-2 infection on the inhibitory function of IL-4. Virus infection of mouse J774A.1 macrophages strongly reduced the ability of IL-4 to inhibit IFN-gamma-induced NO production, even at very high IL-4 concentrations. The effect of HSV-2 infection did not involve the IL-4 signal transduction pathway through STAT6. IL-4 reduced virus-induced TNF-alpha secretion and nuclear factor (NF)-kappaB activation significantly, but less in cells concomitantly treated with IFN-gamma. Furthermore, neutralisation of residual TNF-alpha activity or inhibition of NF-kappaB activation largely restored the inhibitory effect of IL-4. The data show that inhibition of IFN-gamma-induced NO production by IL-4 is impaired by HSV-2 infection due to autocrine TNF-alpha-mediated NF-kappaB activation. We suggest that the described phenomenon might be beneficial for the host by limiting high and sustained NO production to infectious foci.
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Herpesvirus Humano 2/fisiología , Interleucina-4/farmacología , Macrófagos/virología , FN-kappa B/metabolismo , Óxido Nítrico/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Línea Celular , Interferón gamma/farmacología , Interleucina-4/metabolismo , Ratones , Factor de Transcripción STAT6 , Transactivadores/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Upon interferon-gamma (IFN-gamma) stimulation, murine macrophages (Mphi) produce nitric oxide (NO) through expression of inducible nitric oxide synthase (iNOS). Interleukin (IL)-4 treatment, even delayed 12 h relative to IFN-gamma, antagonized this induction, whereas infection with herpes simplex virus type 2 (HSV-2) or treatment with tumour necrosis factor-alpha exerted a synergistic effect, which partly compensated for the antagonistic effect of IL-4. Neither IL-4 nor HSV-2 affected the IFN-gamma-activated Jak-STAT (Janus kinase-signal transducer and activator of transcription) pathway or altered the levels of IFN-gamma-induced interferon regulatory factor (IRF)-1 expression, which is STAT1-dependent and known to play a central role in IFN-gamma-mediated gene induction. The effect of IL-4 was completely dependent on de novo protein synthesis, indicating that a direct activation of latent inhibitors is not sufficient to explain the inhibitory effect of IL-4. Furthermore, IL-4 substantially augmented the IFN-gamma-induced expression of IRF-2, which is known to compete with IRF-1 for the DNA recognition site, ISRE (interferon-stimulated response element). Our findings could indicate that IL-4 suppresses IFN-gamma-stimulated iNOS transcription by elevating the level of IRF-2 which, through competition, prevents IRF-1 from binding to ISRE in the iNOS promoter. The virus-induced effects on iNOS and NO levels in IFN-gamma-stimulated Mphi do not seem to involve the Jak/STAT pathway or a differential expression of IRF-1 and IRF-2.
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Herpes Simple/inmunología , Interferón gamma/farmacología , Interleucina-4/farmacología , Macrófagos/metabolismo , Macrófagos/virología , Óxido Nítrico/antagonistas & inhibidores , Proteínas Represoras , Animales , Línea Celular , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Herpes Simple/enzimología , Herpes Simple/metabolismo , Herpesvirus Humano 2/inmunología , Factor 1 Regulador del Interferón , Factor 2 Regulador del Interferón , Janus Quinasa 1 , Macrófagos/inmunología , Ratones , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Fosfoproteínas/biosíntesis , Fosfoproteínas/genética , Fosforilación/efectos de los fármacos , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/biosíntesis , Factor de Transcripción STAT1 , Transducción de Señal/efectos de los fármacos , Transactivadores/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacosRESUMEN
The aim of this retrospective study was to investigate the accordance between the indications used for prescription of continuous domiciliary oxygen and the guidelines recommended by the Danish Society of Pulmonary Medicine. Sixty-two patients with chronic hypoxic respiratory insufficiency in chronic domiciliary oxygen therapy were investigated. Only one patient fulfilled all the prescribed recommendations and, in general, there were no registrations of compliance or of follow-ups in the patient records.
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Servicios de Atención a Domicilio Provisto por Hospital , Terapia por Inhalación de Oxígeno , Insuficiencia Respiratoria/terapia , Dinamarca , Estudios de Seguimiento , Volumen Espiratorio Forzado , Guías como Asunto , Humanos , Presión Parcial , Estudios RetrospectivosRESUMEN
Nitric oxide (NO), produced in interferon (IFN)-gamma-activated murine macrophages by the enzyme inducible nitric oxide synthase (iNOS), has been found to have antiviral properties. We have previously shown that herpes simplex virus type 2 (HSV-2) infection of macrophages synergistically enhances IFN-gamma-induced NO production, and we now extend these findings by providing evidence that virus-induced tumour necrosis factor (TNF)-alpha mediates activation of the transcription factor nuclear factor (NF)-kappaB, which in turn is responsible for the synergistic effect. HSV-2 infection and IFN-gamma stimulation of macrophages synergistically induced TNF-alpha secretion and nuclear translocation of NF-kappaB, which bound to a sequence corresponding to a kappaB site in the iNOS promoter. The effect of HSV-2 on NF-kappaB and NO production was eliminated when cells were treated with antibodies to TNF-alpha, and direct inhibition of NF-kappaB activation with pyrrolidinedithiocarbamate (PDTC) also blocked the effect of HSV-2 infection on NO production. The effect of the NF-kappaB activation inhibitor was not mediated through inhibition of the production of interferon regulatory factor (IRF)-1 or of TNF-alpha itself, and a possible alternative mechanism of activation of NF-kappaB through virus-induced activation of the kinase PKR was also ruled out. Thus, our data indicate that NF-kappaB activation, through virus-induced autocrine TNF-alpha secretion, is responsible for the synergistic effect of HSV-2 infection on IFN-gamma-induced NO production, and that such activation might constitute a mechanism by which high-output NO production is targeted to infectious foci.
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Herpes Genital/metabolismo , Herpes Genital/virología , Herpesvirus Humano 2/fisiología , Interferón gamma/biosíntesis , Macrófagos/metabolismo , Macrófagos/virología , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Animales , Secuencia de Bases , Línea Celular , Sinergismo Farmacológico , Inducción Enzimática , Ratones , Datos de Secuencia Molecular , Óxido Nítrico Sintasa/biosíntesis , Replicación ViralRESUMEN
Interleukin (IL)-4 and IL-13 share a wide range of activities. Prominent among these is the ability to antagonize many interferon (IFN)-gamma-induced activities. Here we demonstrate that IL-4 and IL-13 totally abrogate IFN-gamma-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA and protein synthesis in a murine macrophage cell line. IFN-gamma-treated cells infected with herpes simplex virus type 2 (HSV-2) or costimulated with tumor necrosis factor (TNF)-alpha showed an enhanced reactivity, which was only partially reduced by IL-4/13. The results indicate that IL-4 and IL-13 function by intervening with a step prior to iNOS transcription by antagonizing IFN-gamma-induced signal(s) without counteracting synergistic virus- or TNF-alpha-induced signals. The beneficial effect of a sustained NO production in foci of virus infection is suggested.
Asunto(s)
Herpesvirus Humano 2/fisiología , Interferón gamma/farmacología , Interleucina-13/farmacología , Interleucina-4/farmacología , Macrófagos/metabolismo , Óxido Nítrico/biosíntesis , Animales , Northern Blotting , Western Blotting , Línea Celular , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Interferón gamma/antagonistas & inhibidores , Macrófagos/virología , Ratones , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estaurosporina/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
PURPOSE: A randomized, double-blind, placebo-controlled trial was performed to estimate the preventive effect of the antiherpetic drug acyclovir on fever, incidence of bacteremia, use of antibiotics, and presentation of infections in patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Ninety herpes simplex virus (HSV)-seropositive patients aged 18 to 84 years were included. Forty-five patients received acyclovir (800 mg by mouth daily) and 45 placebo. The patients were examined daily for 28 days from the initiation of remission-induction chemotherapy. RESULTS: Fever developed in all patients in both groups. Acyclovir prophylaxis postponed the development of an oral temperature > or = 38.0 degrees C by 3 days (95% confidence interval [CI], 1 to 4 days; P = .03) and the initiation of antibacterial treatment by 3 days (95% CI, 1 to 5 days; P = .008). The duration of fever, use of antibacterial treatment, incidence of bacteremia, and need for systemic antifungal therapy were not affected by acyclovir prophylaxis. At fever development, acyclovir prophylaxis affected the incidence and localization pattern of oral ulcers. Thus, in the acyclovir group, the number of nonfungal oral infections was reduced (relative risk, 0.45 [95% CI, 0.24 to 0.85]) and mainly located on the soft palate (relative risk, 2.49 [95% CI, 1.19 to 5.22]). CONCLUSION: Acyclovir prophylaxis has an impact on fever development, but not on the duration of fever or the need for antibiotics. It does not reduce the incidence of bacteremia, but the presentation of acute oral infections is changed.