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INTRODUCTION: Exposure to environmental pollutants such as diesel exhaust particles (DEP) increases the risk of asthma and asthma exacerbation. However, the exact mechanisms inducing asthma to low doses of allergens remain poorly understood. The present study aimed to analyse the immunomodulatory effect of the inhalation of DEP in a mouse model exposed to non-asthmagenic doses of soybean hull extract (SHE). MATERIAL AND METHODS: BALB/c ByJ mice were randomly divided into four experimental groups. Two groups received nasal instillations of saline and the other two groups received 3 mg ml-1 SHE during 5 days per week for 3 weeks. One group in each pair also received 150 µg of DEP in the same instillations 3 days per week. SHE-specific IgE levels, oxidative stress, leukocyte pattern and optical projection tomography (OPT) imaging studies were assessed. RESULTS: Inhalation of SHE and/or DEP increased levels of H2O2 in BAL, while coexposure to SHE and DEP increased SHE-specific IgE levels in serum. Inhalation of SHE alone increased eosinophils, B cells, total and resident monocytes and decreased levels of NK cells, while inhalation of DEP increased neutrophils and decreased total monocytes. Regarding dendritic cells (DC), the inhalation of SHE and/or DEP increased the total population, while the inhalation of SHE alone increased Th2-related DCs (CD11b + Ly6C-) and decreased tolerogenic DCs (CD11b-Ly6C-). However, coexposure to SHE and DEP increased oxidative stress-sensitive DCs (CD11b-Ly6C+) and decreased Th1-related DCs (CD11b + Ly6C+). As regards macrophages, inhalation of SHE and DEP decreased total and alveolar populations. DEP deposition in lung tissue did not differ between groups. CONCLUSION: Coexposure to DEP activates the asthmatic response to low doses of soy by triggering the immune response and oxidative stress.
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Contaminantes Atmosféricos , Asma , Contaminantes Atmosféricos/toxicidad , Alérgenos , Animales , Asma/inducido químicamente , Peróxido de Hidrógeno , Ratones , Ratones Endogámicos BALB C , Glycine max , Emisiones de Vehículos/toxicidadRESUMEN
INTRODUCTION: Since the immunopathological mechanisms of bird fancier's lung (BFL) are not well known, we created two models of the disease (acute and chronic BFL) to study and compare the pathways involved in its immunopathogenesis. MATERIALS AND METHODS: C57BL/6 mice were used. Two intraperitoneal injections of 100 µL of commercial pigeon serum (PS) or saline (SAL) were administered with an interval of 48 h in between. Subsequently, intranasal instillations of 40 µL of PS or SAL were performed three days a week, for three weeks in the acute model (AC/PS) and for twelve weeks in the chronic model (CR/PS). Total lung capacity (TLC) was assessed. Pulmonary inflammation was evaluated in bronchoalveolar lavage (BAL), and total serum immunoglobulin (Ig) G was measured in serum samples 24 h, 7 days and 14 days after the last exposure. Histological studies of lungs were assessed. RESULTS: A drop in TLC was observed in treated mice. This decrease was more marked in the CR/PS group (p < 0.001). Neutrophil and lymphocyte counts increased in both AC/PS and CR/PS groups (p < 0.01). The extent of airway inflammation was also examined in the histological analysis of the lungs, which showed predominant perivascular and peribronchiolar inflammation, with centrilobular oedema and subpleural inflammation in the AC/PS group. In the CR/PS group, the changes were greater, with increased levels of IL-5, IL-17F, IL-13 and IL-10 and decreased levels of IL-2. CONCLUSIONS: Bronchial inflammation is present in acute and chronic models of HP following exposure to PS. Our results support the role of neutrophils and IL-17 in the development of the disease and an evolution towards a Th-2 immune response in chronic HP. These models may serve as a tool for future studies of the pathogenesis of HP.
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Pulmón de Criadores de Aves , Sistema Inmunológico , Pulmón , Animales , Pulmón de Criadores de Aves/inmunología , Líquido del Lavado Bronquioalveolar , Columbidae , Modelos Animales de Enfermedad , Inflamación , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Modelos AnimalesAsunto(s)
Sustancias para la Guerra Química/efectos adversos , Cloro/administración & dosificación , Cloro/efectos adversos , Administración por Inhalación , Biomarcadores , Voluntarios Sanos , Humanos , Exposición por Inhalación , Recuento de Leucocitos , Proyectos Piloto , Pruebas de Función Respiratoria , Factores de TiempoRESUMEN
BACKGROUND: The role of immunoglobulin (Ig)-E in occupational asthma (OA) due to low molecular weight (LMW) agents is not well established compared to classical atopic asthma. In this study, we evaluate whether anti-IgE monoclonal antibody (mAb) has an effect in a mouse model of OA, using persulfate salts. METHODS: On days 1 and 8, BALB/C mice were dermally sensitized with 5% ammonium persulfate (AP) or dimethyl sulfoxide (DMSO). On days 15, 18, and 21, animals were injected intraperitoneally with anti-IgE mAb or PBS 6 hours before challenge with AP or saline. Airway hyper-responsiveness (AHR) using a methacholine test, airway inflammation in bronchoalveolar lavage (BAL) and lung tissue, and total free IgE in serum samples were analyzed 24, 48, and 96 hours after the last challenge. RESULTS: Anti-IgE mAb treatment almost completely neutralized free serum IgE. In AP-sensitized and challenged mice, anti-IgE mAb treatment abolished AHR 24 hour and 48 hour after the last challenge and significantly reduced the total number of eosinophils and neutrophils 48 hour and 96 hour after the last AP challenge compared with nontreated mice. Levels of interleukin (IL)-13 in BAL were also significantly decreased after anti-IgE administration 24 hour and 48 hour after the last AP challenge. Histological analysis of the lung sections from anti-IgE-treated mice revealed normal inflammatory patterns similar to control groups 48 hour after the last challenge. CONCLUSIONS: Anti-IgE-treated mice showed a significant improvement in asthma features related to the AHR and airway inflammation. Anti-IgE mAb has positive effects in OA induced by persulfate salts.
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Anticuerpos Antiidiotipos/farmacología , Asma Ocupacional/tratamiento farmacológico , Sulfato de Amonio/farmacología , Animales , Anticuerpos Antiidiotipos/uso terapéutico , Asma Ocupacional/etiología , Inflamación/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Hipersensibilidad Respiratoria/tratamiento farmacológicoRESUMEN
BACKGROUND: There is very little evidence of the utility of the exhaled fraction of NO (FeNO) for the diagnosis of interstitial lung disease and nearly all of it is related with connective tissue disease. Some authors have suggested that in patients with hypersensitivity pneumonitis (HP), evolution to pulmonary fibrosis may be mediated by a Th2 mechanism, which could redound in a potential utility of FeNO. The aim of this study was to investigate the values of FeNO before and after antigenic exposure with the specific inhalation challenge (SIC) and to analyze its potential utility for the diagnosis of HP. METHODS: It was a prospective, cross-sectional study of all patients older than 18 years referred to our center for suspected chronic HP between May 2012 and May 2014 and who underwent a SIC. FeNO was collected before and after SIC. RESULTS: The study sample comprised 25 patients. Eleven were diagnosed with chronic HP; six had been exposed to avian proteins and five to fungal agents. Of these 11 patients, seven had positive SICs. In the 14 patients with diagnoses other than HP, all the SICs were negative. No significant differences in baseline characteristics were observed according to HP diagnosis, except in the BAL lymphocyte count. No differences were found after the test in patients diagnosed with HP; nor were there differences in baseline FeNO in patients diagnosed with HP and those who received alternative diagnoses. CONCLUSIONS: The results suggest that FeNO measurement is not useful for the diagnosis of chronic HP.
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Alveolitis Alérgica Extrínseca/diagnóstico , Óxido Nítrico/análisis , Adulto , Anciano , Alveolitis Alérgica Extrínseca/fisiopatología , Pulmón de Criadores de Aves/diagnóstico , Pulmón de Criadores de Aves/fisiopatología , Pruebas Respiratorias , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/citología , Monóxido de Carbono , Estudios Transversales , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Capacidad de Difusión Pulmonar , Capacidad VitalRESUMEN
BACKGROUND: The aim of this study was to investigate the influence of the specific inhalation challenge (SIC) on changes of pH values in exhaled breath condensate (EBC) in patients with hypersensitivity pneumonitis (HP). METHODS: A prospective study of 85 patients with suspected HP, of whom 63 were diagnosed with HP due to exposure to avian or fungal antigens. In all cases, EBC samples were collected before and after completion of the SIC and pH values were determined. RESULTS: Taken as a whole, patients with HP did not present changes in EBC pH after SIC. However, considering only patients with exposure to molds, those diagnosed with HP had a significantly more acid pH post-SIC than those with another diagnosis (p = 0.011). This fact is not observed in patients exposed to bird's antigens. A ROC curve showed that a reduction in EBC pH of 0.3 units or more after SIC in patients diagnosed with HP due to exposure to molds had a sensitivity of 30 % (CI: 12.8 to 54.3 %) and a specificity of 100 % (CI: 65.5 to 100 %). CONCLUSION: EBC pH may be useful in interpreting SIC results in patients with HP, especially in those patients exposed to molds. Further studies are now required to test the validity of these proposals.
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Alveolitis Alérgica Extrínseca/inmunología , Antígenos Fúngicos/inmunología , Aves/inmunología , Inmunoglobulina G/inmunología , Adulto , Anciano , Alveolitis Alérgica Extrínseca/diagnóstico , Animales , Aspergillus fumigatus/inmunología , Pulmón de Criadores de Aves , Pruebas Respiratorias , Pruebas de Provocación Bronquial , Estudios de Cohortes , Columbidae/inmunología , Estudios Transversales , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Mucor/inmunología , Periquitos/inmunología , Loros/inmunología , Penicillium/inmunología , Estudios ProspectivosRESUMEN
OBJECTIVES: The aim of the study was to assess the progression of liver fibrosis in HIV/hepatitis C virus (HCV)-coinfected patients with no or mild-to-moderate fibrosis (stages F0-F2). METHODS: Liver fibrosis was reassessed by transient elastometry (TE) between January 2009 and November 2011 in HIV/HCV-coinfected patients with stage F0-F2 fibrosis in a liver biopsy performed between January 1997 and December 2007. Patients with liver stiffness at the end of follow-up < 7.1 kPa were defined as nonprogressors, and those with values ≥ 9.5 kPa or who died from liver disease were defined as progressors. Cirrhosis was defined as a cut-off of 14.6 kPa. The follow-up period was the time between liver biopsy and TE. Cox regression models adjusted for age, gender and liver fibrosis stage at baseline were applied. RESULTS: The median follow-up time was 7.8 years [interquartile range (IQR) 5.5-10 years]. The study population comprised 162 patients [115 (71%) nonprogressors and 47 (29%) progressors; 19 patients (11.7%) had cirrhosis]. The median time from the diagnosis of HCV infection to the end of follow-up was 20 years (IQR 16.3-23.1 years). Three progressors died from liver disease (1.8%). The variables associated with a lower risk of progression were age ≤ 38 years (hazard ratio (HR) 0.32; 95% confidence interval (CI) 0.16-0.62; P = 0.001], having received interferon (HR 2.18; 95% CI 1.14-4.15; P = 0.017), being hepatitis B virus surface antigen (HBsAg) negative (HR 0.20; 95% CI 0.04-0.92; P = 0.039), and baseline F0-F1 (HR 0.43; 95% CI 0.28-0.86; P = 0.017). CONCLUSIONS: A high proportion of patients with stage F0-F2 fibrosis progress to advanced liver fibrosis. Advanced liver fibrosis must be included in the list of diseases associated with aging. Our results support the recommendation to offer HCV antiviral therapy to HIV/HCV-coinfected patients at early stages of liver fibrosis.
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Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Interferones/uso terapéutico , Cirrosis Hepática/patología , Ribavirina/uso terapéutico , Adulto , Factores de Edad , Terapia Antirretroviral Altamente Activa , Antivirales/administración & dosificación , Progresión de la Enfermedad , Femenino , Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Humanos , Interferones/administración & dosificación , Cirrosis Hepática/mortalidad , Masculino , Estudios Prospectivos , Estudios Retrospectivos , Ribavirina/administración & dosificación , Factores de RiesgoRESUMEN
Chronic hepatitis C virus (HCV) infection follows an accelerated course in patients co-infected with human immunodeficiency virus (HIV); establishing the extent of liver fibrosis is crucial for disease staging and determining treatment strategy in these patients. The utility of noninvasive markers of fibrosis as alternatives to liver biopsy has not been well-studied in these patients. We evaluated the predictive value of serum transforming growth factor-beta1 (TGF-beta1) and hyaluronic acid (HA) levels for determining the extent of liver fibrosis. Liver biopsies and blood samples were collected from 69 consecutive patients (74% male; median age, 41 years) between May 2005 and November 2006. Serum TGF-beta1 and HA were analysed using commercial kits. Aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase levels were elevated in 81%, 70% and 60% of patients, respectively. Fifty-three patients (90%) were on highly active antiretroviral therapy and the median CD4-positive cell count was 422 cells/microL. The extent of fibrosis according to Scheuer's scoring was 32% F0 (no fibrosis), 16.5% F1, 16.5% F2, 26% F3 and 7% F4 (cirrhosis). Mean serum TGF-beta1 was 36.1 +/- 14.4 ng/mL; mean serum HA was 75.2 +/- 85.0 microg/L. Serum HA was positively associated and significantly correlated with the stage of fibrosis (r = 0.56; P < 0.05). The area under the curve for discriminating mild (F0-F2) from significant (F3-F4) fibrosis in receiver operating analysis using HA was 0.83 (sensitivity, 87%; specificity, 70%). These data suggest that HA is clinically useful for predicting liver fibrosis and cirrhosis in patients co-infected with HCV/HIV. However, serum TGF-beta1 was not predictive of histological damage in co-infected individuals treated with HAART.
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Infecciones por VIH/complicaciones , Hepatitis C Crónica/complicaciones , Ácido Hialurónico/sangre , Cirrosis Hepática/diagnóstico , Hígado/patología , Factor de Crecimiento Transformador beta1/sangre , Adulto , Biopsia , Recuento de Linfocito CD4 , Femenino , Humanos , Cirrosis Hepática/patología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Interleukin-6 has been involved in restoration of liver function after partial hepatectomy and toxic liver injury. However, normal liver regeneration in interleukin-6 knockout mice has also been reported. The aim of this work was to investigate the effect of interleukin-6 deficiency on liver injury and its regeneration in a model of long term carbon tetrachloride (CCl4) administration. DESIGN: Serum and whole livers from wild type and interleukin-6 knockout mice treated with carbon tetrachloride (0.25 mL kg(-1)) twice a week were obtained after 4, 6 and 8 weeks (n = 4-6). Sections were assessed for liver regeneration, liver injury and hepatocyte apoptosis whereas sera were assayed for aminotransferase levels. Nuclear extracts and total liver lysates were assayed for transcription factor activation and apoptosis related proteins, respectively. RESULTS: When compared to wild type, interleukin-6 knockout mice showed reduced liver damage scores, lower aminotransferase levels and diminished apoptosis, as well as reduced nuclear factor kappa B activation. Although the level of active protein was lower, activation of signal transducer and activator of transcription 3 still takes place in knockout mice. Furthermore, liver regeneration measured by bromodeoxyuridine incorporation showed no differences between wild type and knockout animals after 6 and 8 weeks of treatment. CONCLUSIONS: Compared to the wild type mice liver regeneration after chronic treatment with carbon tetrachloride proceeds at a slower rate in interleukin-6 deficient mice. However, this low recovery rate is accompanied by a reduction not only in hepatocyte apoptosis, but also in activation of nuclear factor kappa B and liver injury.
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Tetracloruro de Carbono/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Interleucina-6/fisiología , Regeneración Hepática/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/genética , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-6/genética , Hígado/efectos de los fármacos , Hepatopatías/metabolismo , Hepatopatías/prevención & control , Regeneración Hepática/genética , Masculino , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Transducción de Señal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND AND AIMS: In liver cirrhosis, disruption of the intestinal barrier facilitates bacterial translocation and spontaneous bacterial peritonitis. Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesised by hepatocytes that displays hepatoprotective activities and trophic effects on the intestine. The aim of this study was to investigate the effect of IGF-I on intestinal barrier function in cirrhotic rats. METHODS: In rats with carbon tetrachloride induced cirrhosis, we investigated the effect of IGF-I therapy on: (a) portal pressure; (b) intestinal histology and permeability to endotoxin and bacteria; (c) intestinal expression of cyclooxygenase 2 (COX-2) and tumour necrosis factor alpha (TNF-alpha), two factors that influence in a positive and negative manner, respectively, the integrity of the intestinal barrier; (d) intestinal permeability to 3H-mannitol in rats with bile duct ligation (BDL); and (e) transepithelial electrical resistance (TER) of polarised monolayers of rat small intestine epithelial cells. RESULTS: IGF-I therapy reduced liver collagen expression and portal pressure in cirrhotic rats, induced improvement in intestinal histology, and caused a reduction in bacterial translocation and endotoxaemia. These changes were associated with diminished TNF-alpha expression and elevated COX-2 levels in the intestine. IGF-I reduced intestinal permeability in BDL rats and enhanced barrier function of the monolayers of epithelial intestinal cells where lipopolysaccharide (LPS) caused a decrease in TER that was reversed by IGF-I. This effect of IGF-I was associated with upregulation of COX-2 in LPS treated enterocytes. CONCLUSIONS: IGF-I enhances intestinal barrier function and reduces endotoxaemia and bacterial translocation in cirrhotic rats. IGF-I therapy might be useful in the prevention of spontaneous bacterial peritonitis in liver cirrhosis.
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Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Absorción Intestinal/efectos de los fármacos , Cirrosis Hepática Experimental/tratamiento farmacológico , Animales , Traslocación Bacteriana/efectos de los fármacos , Tetracloruro de Carbono , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Impedancia Eléctrica , Endotoxinas/sangre , Enterocitos/enzimología , Íleon/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lipopolisacáridos/farmacología , Cirrosis Hepática Experimental/microbiología , Cirrosis Hepática Experimental/patología , Cirrosis Hepática Experimental/fisiopatología , Masculino , Permeabilidad , Presión Portal , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVES: To evaluate the prevalence and incidence of antimalarial myopathy in patients with rheumatic diseases treated with antimalarial drugs. METHODS: Over a three year period, all patients with rheumatic diseases who were taking antimalarial drugs were studied. Serum muscle enzymes were assessed at the time of inclusion and every six months thereafter. Muscle strength, electromyography (EMG), and muscle biopsy were assessed in patients with a persistent muscle enzyme disturbances. RESULTS: 119 patients were included (111 chloroquine, eight hydroxychloroquine). Of these, 22 (18.5%) had a persistent muscle enzyme disturbance: lactate dehydrogenase 19/22 (86%); creatine kinase 7/22 (32%), and aldolase 3/22 (14%). Findings of antimalarial myopathy were detected in 3/15 biopsied patients (20%) by light microscopy and in all 15 by electron microscopy. Eleven patients had myopathy at the time of inclusion (prevalence 9.2%) and four patients developed muscle injury during follow up (annual incidence 1.2%). Muscle weakness was observed in 8 of 15 patients with biopsy proven myopathy, giving a prevalence of clinical antimalarial myopathy of 6.7%. All these patients also had a myopathic pattern on electromyography. CONCLUSIONS: The prevalence of antimalarial myopathy is higher than previously recognised when muscle enzyme determination is used as a screening method. When a persistent muscle enzyme disturbance is observed, clinical and electromyographic studies should be undertaken periodically to detect the development of clinical myopathy. In cases of clinical myopathy, an anatomical-pathological tissue study, including an ultrastructural study, is mandatory to confirm the diagnosis.
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Antimaláricos/efectos adversos , Antirreumáticos/efectos adversos , Cloroquina/efectos adversos , Enfermedades Musculares/inducido químicamente , Enfermedades Reumáticas/tratamiento farmacológico , Adulto , Anciano , Biopsia , Pruebas Enzimáticas Clínicas/métodos , Electromiografía , Enzimas/sangre , Métodos Epidemiológicos , Femenino , Humanos , Hidroxicloroquina/efectos adversos , Masculino , Persona de Mediana Edad , Músculo Esquelético/enzimología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/patologíaRESUMEN
The myothonic dystrophy or Steinert's disease is a congenital, autosomal, dominant disorder which seriously affects the striated muscle and also to a certain extent, several organs and systems and on rare occasions, the intestinal smooth muscle. In the case, we treated a four years old girl in whom Steinert's disease was diagnosed when she was born and who developed the characteristics of severe constipation after a few months of life. The ano-rectal manometry showed a paradoxical reaction of external Sphincter with a normal inhibitory reflex. The rectal biopsy revelated a miophathy which affected the muscularis propia with the normal neuronal innervation. The X-ray studies showed that motility disorder was stopped in the distal area of the left colon. A colostomy in the healthy zone worked extremely well. Six months later, the normal colon was brought down retro-rectal. Only a partial incontinence remained in the external sphincter caused by Steinert's disease. The interest of this case lies in the pathological association, striade muscle and smooth muscle, in such an early age of life. It is a new contribution to the complex chapter of the intestinal pseudo-obstruction.
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Seudoobstrucción Intestinal/complicaciones , Seudoobstrucción Intestinal/cirugía , Distrofia Miotónica/complicaciones , Preescolar , Femenino , Humanos , Músculo Liso/patologíaRESUMEN
We present the case of a 16-year old woman with Alagille's syndrome, who had upper gastrointestinal bleeding due to rupture of esophageal varices secondary to presinusoidal portal hypertension without liver fibrosis. Portal thrombosis is a manifestation previously unreported in association to this syndrome.
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Síndrome de Alagille/complicaciones , Hipertensión Portal/etiología , Vena Porta , Trombosis de la Vena/etiología , Adolescente , Síndrome de Alagille/genética , Proteínas de Unión al Calcio , Terapia Combinada , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/cirugía , Várices Esofágicas y Gástricas/terapia , Femenino , Hemorragia Gastrointestinal/etiología , Humanos , Péptidos y Proteínas de Señalización Intercelular , Proteínas de la Membrana , Derivación Portosistémica Quirúrgica , Mielofibrosis Primaria/etiología , Proteínas/genética , Escleroterapia , Proteínas Serrate-Jagged , EsplenectomíaRESUMEN
INTRODUCTION: Chloroquine is a drug that is widely used in rheumatology and occasionally prescribed in dermatology. From a neurotoxicological point of view, chloroquine can have effects on the peripheral nerves, muscles, neuromuscular junctions and the central nervous system. In this study we analyse the clinical, neurophysiological and anatomopathological findings in two patients with chloroquine induced neuromyopathy, which took the form of a polyradiculoneuropathy. CASE REPORTS: Case 1: a 75 year old female with rheumatoid arthritis treated with daily doses of 250 mg of chloroquine for four years. The patient visited because of several months history of predominantly proximal progressive tetraparesis with areflexia. Analytical tests and lumbar puncture were normal. Electromyogram (EMG): proximal myopathic and distal neuropathic patterns. Muscular biopsy: vacuolar myopathy with accumulations of phagolysosomes, lipids, lipofuscin, myelinic curvilinear bodies. Case 2: a 74 year old female with arthropathy treated with daily doses of 250 mg of chloroquine for nine months. The patient presented a progressive proximal paraparesis with generalised areflexia. Analytical tests and lumbar puncture were normal. EMG: mixed sensory motor polyneuropathy, myogenic pattern with high frequency discharges in the iliac psoas and a neurogenic pattern in the distal muscles. Muscular biopsy: vacuolar myopathy suggesting a myopathy due to chloroquine. After stopping treatment with this drug the patients progressed favourably. CONCLUSION: Chloroquine can induce a clinical pattern that suggests a polyradiculoneuropathy. It is important to establish a history of having taken this drug. If this is indeed the case, then an electromyographic study of the most proximal muscles should be performed in order to detect a myogenic pattern and the same exploration should be applied to the distal muscles to reveal a neurogenic pattern. The final diagnosis will be established by muscular biopsy.
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Antirreumáticos/efectos adversos , Cloroquina/efectos adversos , Enfermedades Musculares/inducido químicamente , Polirradiculoneuropatía/inducido químicamente , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Biopsia , Cloroquina/uso terapéutico , Electromiografía , Femenino , Humanos , Enfermedades Musculares/patología , Polirradiculoneuropatía/patologíaRESUMEN
To assess the factors associated with liver fibrosis in human immunodeficiency virus and hepatitis C virus (HIV/HCV) co-infected patients eligible for anti-HCV therapy, we performed an observational, single-centred, cross-sectional study of 180 HIV/HCV co-infected patients who underwent liver biopsy between May 1998 and November 2001. A total of 126 patients with a known date of HCV infection were evaluated. Liver fibrosis was defined as a Knodell stage of fibrosis 1-4. The mean age was 36.7 (3.8) years, 81% were male and had a mean age of 20.5 (3.8) years at HCV infection. Mean CD4 cell count and plasma HIV-1 RNA load at the time of biopsy were 552 cell/mm3 (239) and 2.5 log10 (0.9), respectively; 118 patients had been on antiretroviral therapy (ART) for a median of 45 months (Q1-Q3: 21-75) and 84 on protease inhibitor for a median of 12.0 months (Q1-Q3: 0-29.5); 55 had an AIDS event or a CD4 cell count nadir < 200 cells/mm3 prior to biopsy. Median histological activity index was 6 and 27% had a Knodell stage of fibrosis 0. On the multivariate analysis time on ART (OR for 6 months extra: 0.954, 95% CI: 0.859-0.994), CD4 cell count at the time of liver biopsy (OR for 100 cells/mL increase: 0.740, 95% CI: 0.670-0.905), age at HCV infection acquisition (OR for 5 years extra: 2.594, 95% CI: 1.326-5.133) and alcohol intake (> 50 g/day) (OR: 2.73, 95% CI: 1.108-6.731) were associated with liver fibrosis. Hence ART should be a priority in HIV/HCV co-infected patients eligible for anti-HCV treatment as it is a protective factor for liver fibrosis.
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Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH-1/crecimiento & desarrollo , Hepacivirus/crecimiento & desarrollo , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Cirrosis Hepática/virología , Adulto , Factores de Edad , Antirretrovirales/uso terapéutico , Biopsia , Estudios Transversales , Femenino , Hepacivirus/metabolismo , Humanos , Modelos Logísticos , Masculino , Análisis Multivariante , ARN Viral/sangre , Factores Sexuales , Carga ViralRESUMEN
BACKGROUND AND AIMS: L-Arg is the substrate for nitric oxide, and also for L-ornithine which, in turn, is the precursor for the synthesis of collagen and polyamines. By these different metabolic pathways, L-Arg is involved in the mechanisms of inflammation, tissue repair and fibrosis. Thus, the aim of this study was to assess the effect of both different amounts of L-Arg supplementation and L-Arg-free diets upon colonic inflammatory damage and fibrosis in experimental colitis. METHODS: Sprague-Dawley rats with trinitrobenzene sulphonic acid (TNBS)-induced colitis received increasing doses of L-Arg (30, 100, 500 mg/day), or D-Arg (500 mg/day). In a second experiment, two L-Arg-free diets (one supplemented with L-Gly) were compared to a L-Arg diet. Nitrite/nitrate release in the lumen of the colon and colonic damage were evaluated. In the first experiment, tissue collagen levels and colonic mucosal proliferation were also assessed. RESULTS: In the acute phase of colitis, intracolonic nitrite/nitrate levels were significantly higher in the 100 and 500 mg supplemented L-Arg groups than in D-Arg group. However, only rats treated with 500 mg of L-Arg showed moderately higher inflammatory and fibrosis colonic scores than the D-Arg treated rats. There was no significant influence of L-Arg-free diets on the course of TNBS-induced colitis. However, L-Arg diet accelerated weight gain both pre- and post-TNBS. CONCLUSIONS: These results suggest that normal amounts of L-Arg in the diet are not harmful, whereas both absence of L-Arg or supplementation with high doses of this amino acid may be deleterious. In the former this might be due to a decrease of nitrogen retention in injured rats, whereas in the latter it may result from both nitric oxide-mediated tissue damage and collagen deposition.
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Arginina/administración & dosificación , Colitis/patología , Colon/patología , Óxido Nítrico/metabolismo , Enfermedad Aguda , Animales , Arginina/metabolismo , Peso Corporal/efectos de los fármacos , Enfermedad Crónica , Colitis/inducido químicamente , Colágeno/biosíntesis , Modelos Animales de Enfermedad , Femenino , Fibrosis , Inflamación , Mucosa Intestinal/patología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
PURPOSE: We designed this study to assess the frequency of K-ras mutations in patients with resected colorectal tumors and their association with survival. A second objective was to analyze the prognostic value of different K-ras genotypes. In a subgroup of patients we also investigated the presence of allelic imbalance on chromosome 18q and its relationship to clinical outcome. METHODS: One hundred fourteen colorectal tumors resected between 1983 and 1986 were analyzed to detect K-ras point mutations at codons 12, 13, and 61 by polymerase chain reaction followed by allele specific oligonucleotide hybridization. A subgroup of 77 tumors was further screened to detect loss of heterozygosity on chromosome 18q using three polymorphic microsatellite markers (D18S67, D18S474 and D18S58). RESULTS: K-ras mutations were detected in 29 percent (33/114) of patients. K-ras mutations correlated with age and preoperative carcinoembryonic antigen levels, and there was some indication that they may be linked to poor survival, especially in Stage II tumors, where a subgroup of patients with aspartic and serine mutations showed significantly reduced survival (P = 0.03) compared with K-ras-negative patients. 18q loss of heterozygosity was present in 39 percent (25/63) of tumors. A multivariate analysis of Stage II tumors showed that 18q loss of heterozygosity was significantly associated with a worse prognosis (P = 0.006). A significant decrease in survival was identified in ten patients harboring both genetic alterations (K-i mutations and 18q loss of heterozygosity; P = 0.02). CONCLUSIONS: In colorectal tumors, K-ras mutations and 18q loss of heterozygosity are two genetic markers which may identify patients with more aggressive behavior, mainly in Stage II tumors. These findings warrant further research, because they can be useful in customizing adjuvant chemotherapy.