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INTRODUCTION/AIMS: Cough impairment is common in individuals with neuromuscular disorders and is associated with respiratory infections and shorter survival. Cough strength is assessed by measuring cough peak flow (CPF) using a flow meter, but this method requires a complex device setup and trained staff. The aim of the study is to evaluate the reliability of a smartphone app to estimate CPF based on cough sounds in a cohort of individuals with neuromuscular disorders. METHODS: Individuals with neuromuscular disorders underwent CPF measurement with a flow meter and a smartphone app. A CPF <270 L/min was considered abnormal. RESULTS: Of the 50 patients studied, 26 had amyotrophic lateral sclerosis (52%), 15 had hereditary myopathies (30%), and 9 had myasthenia gravis (18%). The intraclass correlation coefficient (ICC) between the CPF measured with a flow meter and CPF estimated with cough sounds was 0.774 (p < .001) even if the patients had orofacial weakness (ICC = 0.806, p < .001). The smartphone app had 94.4% sensitivity and 100% specificity to detect patients with CPF of less than 270 L/min. DISCUSSION: Our findings suggest that sounds measured with a smartphone app provide a reliable estimate of CPF in patients with neuromuscular disorders, even in the presence of with orofacial weakness. This may be a convenient way to monitor respiratory involvement in patients with neuromuscular disorders, but larger studies of more diverse patient cohorts are needed.
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Enfermedades del Sistema Nervioso , Enfermedades Neuromusculares , Humanos , Reproducibilidad de los Resultados , Enfermedades Neuromusculares/complicaciones , Ápice del Flujo Espiratorio , TosRESUMEN
BACKGROUND: The possibility of having methods to assess dysphagia in amyotrophic lateral sclerosis (ALS) patients in a minimally invasive manner could facilitate follow-up and allow performing of therapeutic interventions at earlier stages of the disease. The aim of the study was to analyze the role of tongue strength and thickness in ALS patients and their correlation with dysphagia and bulbar function. METHODS: A sample of outpatients with ALS was evaluated for demographic and clinical features. Tongue thickness and strength have been measured for each patient, and quantitative and qualitative data of the videofluoroscopy swallow study have been analyzed. RESULTS: Of the 38 ALS patients studied, 47.4% were women, and 26.3% had bulbar onset. The median time between symptom onset and the study was 24 months (IQR 11.5-48), and 55.3% of the patients were carriers of non-invasive mechanical ventilation. Tongue strength identified patients with impaired oral and pharyngeal transit and those with bolus residue scale (BRS) > 1 or penetration-aspiration scale (PAS) ≥ 3. In contrast, tongue thickness is only associated with impaired oral transit. Finally, anterior tongue strength ≤ 34 kPa and posterior tongue strength ≤ 34.5 kPa detected ALS penetrators/aspirators (PAS ≥ 3) and patients with ALS with post-swallow residue (BRS > 1). CONCLUSIONS: Our results suggest that measures that assess the functionality (strength) of the tongue are more valuable than morphological measurements (thickness) for the follow-up of patients with ALS. Alterations of the anterior and posterior lingual strength correlate with the presence of bronchoaspiration and post-swallowing residue (BRS > 1).
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Esclerosis Amiotrófica Lateral , Trastornos de Deglución , Humanos , Femenino , Masculino , Trastornos de Deglución/diagnóstico por imagen , Trastornos de Deglución/etiología , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Deglución/fisiología , Lengua/diagnóstico por imagen , BiomarcadoresRESUMEN
BACKGROUND & AIMS: We recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism. METHODS: We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells. RESULTS: Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes. CONCLUSIONS: Altered metabolite levels and messenger RNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH.
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Desdiferenciación Celular , Metabolismo Energético , Perfilación de la Expresión Génica , Glucosa/metabolismo , Hepatitis Alcohólica/enzimología , Hepatocitos/enzimología , Hexoquinasa/metabolismo , Hígado/enzimología , Metabolómica , Lesión Renal Aguda/enzimología , Lesión Renal Aguda/genética , Adaptación Fisiológica , Animales , Europa (Continente) , Femenino , Regulación Enzimológica de la Expresión Génica , Glucosa-6-Fosfato/metabolismo , Glucógeno/metabolismo , Células Hep G2 , Hepatitis Alcohólica/genética , Hepatitis Alcohólica/patología , Hepatocitos/patología , Hexoquinasa/genética , Humanos , Hígado/patología , Masculino , Metaboloma , Persona de Mediana Edad , Ratas Wistar , Transcriptoma , Estados UnidosRESUMEN
OBJECTIVE: Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. DESIGN: Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. RESULTS: Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. CONCLUSIONS: p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis.
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Hepatitis Alcohólica/complicaciones , Hepatitis Alcohólica/enzimología , Cirrosis Hepática/etiología , Proteínas Quinasas S6 Ribosómicas 90-kDa/fisiología , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana EdadRESUMEN
OBJECTIVE: Alcoholic hepatitis (AH) is a severe clinical condition that needs novel therapies. The identification of targets for therapy is hampered by the lack of animal models of advanced AH. The authors performed a translational study through a transcriptome analysis in patients with AH to identify new molecular targets. DESIGN: Hepatic gene expression profiling was assessed by DNA microarray in patients with AH (n=15) and normal livers (n=7). Functional analysis was assessed by gene set enrichment analysis. Quantitative PCR was performed in patients with AH (n=40), hepatitis C (n=18), non-alcoholic steatohepatitis (n=20) and in mouse models of acute and chronic liver injury. Protein expression was assessed by immunohistochemistry and western blotting. RESULTS: Gene expression analysis showed 207 genes >5-fold differentially expressed in patients with AH and revealed seven pathways differentially regulated including 'cytokine-cytokine receptor interaction'. Several tumour necrosis factor (TNF) superfamily receptors, but not ligands, were overexpressed in AH. Importantly, Fn14 was the only TNF superfamily receptor exclusively upregulated in AH compared with other liver diseases and correlated with both 90-day mortality and severity of portal hypertension. Fn14 protein expression was detected in areas of fibrogenesis and in a population of hepatocytes. Fn14 expression was increased in experimental models of liver injury and was detected in progenitor cells. CONCLUSION: Translational research revealed that TNF superfamily receptors are overexpressed in AH. Fn14, the receptor for TNF-like weak inducer of apoptosis, is selectively upregulated in patients with AH. TNF superfamily receptors could represent a potential target for therapy.
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Regulación de la Expresión Génica/fisiología , Hepatitis Alcohólica/genética , Receptores del Factor de Necrosis Tumoral/genética , Animales , Western Blotting , Análisis por Conglomerados , Citocinas/genética , Citocinas/metabolismo , Femenino , Perfilación de la Expresión Génica , Hepatitis Alcohólica/tratamiento farmacológico , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis por Micromatrices , Persona de Mediana Edad , Terapia Molecular Dirigida , Pronóstico , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal , Receptor de TWEAK , Regulación hacia ArribaRESUMEN
UNLABELLED: The prevalence of cigarette smoking (CS) is increased among obese subjects, who are susceptible to develop nonalcoholic fatty liver disease (NAFLD). We investigated the hepatic effects of CS in control and obese rats. Control and obese Zucker rats were divided into smokers and nonsmokers (n = 12 per group). Smoker rats were exposed to 2 cigarettes/day, 5 days/week for 4 weeks. The effects of CS were assessed by biochemical analysis, hepatic histological examination, immunohistochemistry, and gene expression analysis. Phosphorylation of AKT and extracellular signal-regulated kinase (ERK) and quantification of carbonylated proteins were assessed by western blotting. As expected, obese rats showed hypercholesterolemia, insulin resistance, and histological features of NAFLD. Smoking did not modify the lipidic or glucidic serum profiles. Smoking increased alanine aminotransferase serum levels and the degree of liver injury in obese rats, whereas it only induced minor changes in control rats. Importantly, CS increased the histological severity of NAFLD in obese rats. We also explored the potential mechanisms involved in the deleterious effects of CS. Smoking increased the degree of oxidative stress and hepatocellular apoptosis in obese rats, but not in controls. Similarly, smoking increased the hepatic expression of tissue inhibitor of metalloproteinase-1 and procollagen-alpha2(I) in obese rats, but not in controls. Finally, smoking regulated ERK and AKT phosphorylation. The deleterious effects of CS were not observed after a short exposure (5 days). CONCLUSION: CS causes oxidative stress and worsens the severity of NAFLD in obese rats. Further studies should assess whether this finding also occurs in patients with obesity and NAFLD.
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Hígado Graso/etiología , Fumar/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Obesidad/complicaciones , Obesidad/metabolismo , Estrés Oxidativo , Ratas , Ratas Zucker , Inhibidor Tisular de Metaloproteinasa-1/biosíntesisRESUMEN
UNLABELLED: There are no effective antifibrotic therapies for patients with liver diseases. We performed an experimental and translational study to investigate whether ghrelin, an orexigenic hormone with pleiotropic properties, modulates liver fibrogenesis. Recombinant ghrelin was administered to rats with chronic (bile duct ligation) and acute (carbon tetrachloride) liver injury. Hepatic gene expression was analyzed by way of microarray analysis and quantitative polymerase chain reaction. The hepatic response to chronic injury was also evaluated in wild-type and ghrelin-deficient mice. Primary human hepatic stellate cells were used to study the effects of ghrelin in vitro. Ghrelin hepatic gene expression and serum levels were assessed in patients with chronic liver diseases. Ghrelin gene polymorphisms were analyzed in patients with chronic hepatitis C. Recombinant ghrelin treatment reduced the fibrogenic response, decreased liver injury and myofibroblast accumulation, and attenuated the altered gene expression profile in bile duct-ligated rats. Moreover, ghrelin reduced the fibrogenic properties of hepatic stellate cells. Ghrelin also protected rats from acute liver injury and reduced the extent of oxidative stress and inflammation. Ghrelin-deficient mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis, and ghrelin gene hepatic expression correlated with expression of fibrogenic genes. In patients with chronic hepatitis C, polymorphisms of the ghrelin gene (-994CT and -604GA) influenced the progression of liver fibrosis. CONCLUSION: Ghrelin exerts antifibrotic effects in the liver and may represent a novel antifibrotic therapy.
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Ghrelina/fisiología , Ghrelina/uso terapéutico , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/prevención & control , Animales , Células Cultivadas , Progresión de la Enfermedad , Humanos , Masculino , Ratones , Ratas , Ratas Wistar , Proteínas Recombinantes/uso terapéuticoRESUMEN
UNLABELLED: There is no effective therapy for advanced liver fibrosis. Angiotensin type 1 (AT1) receptor blockers attenuate liver fibrogenesis, yet their efficacy in reversing advanced fibrosis is unknown. We investigated whether the specific delivery of an AT1 receptor blocker to activated hepatic stellate cells (HSCs) reduces established liver fibrosis. We used a platinum-based linker to develop a conjugate of the AT1 receptor blocker losartan and the HSC-selective drug carrier mannose-6-phosphate modified human serum albumin (losartan-M6PHSA). An average of seven losartan molecules were successfully coupled to M6PHSA. Rats with advanced liver fibrosis due to prolonged bile duct ligation or carbon tetrachloride administration were treated with daily doses of saline, losartan-M6PHSA, M6PHSA or oral losartan during 3 days. Computer-based morphometric quantification of inflammatory cells (CD43), myofibroblasts (smooth muscle alpha-actin [alpha-SMA]) and collagen deposition (Sirius red and hydroxyproline content) were measured. Hepatic expression of procollagen alpha2(I) and genes involved in fibrogenesis was assessed by quantitative polymerase chain reaction. Losartan-M6PHSA accumulated in the fibrotic livers and colocalized with HSCs, as assessed by immunostaining of anti-HSA and anti-alpha-SMA. Losartan-M6PHSA, but not oral losartan, reduced collagen deposition, accumulation of myofibroblasts, inflammation and procollagen alpha2(I) gene expression. Losartan-M6PHSA did not affect metalloproteinase type 2 and 9 activity and did not cause apoptosis of activated HSCs. CONCLUSION: Short-term treatment with HSC-targeted losartan markedly reduces advanced liver fibrosis. This approach may provide a novel means to treat chronic liver diseases.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Losartán/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Animales , Células Cultivadas , Progresión de la Enfermedad , Sistemas de Liberación de Medicamentos , Losartán/administración & dosificación , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
BACKGROUND & AIMS: Alcoholic hepatitis (AH) is characterized by hepatocellular damage, inflammation, and fibrosis. We performed a prospective study to associate hepatic expression of the CXC subfamily of chemokines with histology findings and prognosis of patients with AH. METHODS: Liver biopsy samples from 105 patients with AH and 5 normal liver samples (controls) were evaluated for steatosis, inflammation, fibrosis, and cholestasis. Computer-based morphometric analysis assessed the numbers of infiltrating CD3+ T cells and CD15+ cells (neutrophils); terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining was used to quantify apoptosis. Expression of CXC and CC chemokines and selected signaling components were assessed by quantitative reverse-transcription polymerase chain reaction; protein levels of interleukin (IL)-8 and Gro-alpha also were determined by immunohistochemistry. Serum levels of IL-8 and Gro-alpha were measured by enzyme-linked immunosorbent assay. The Cox regression model identified variables associated with mortality. RESULTS: Most patients (75%) had severe AH; their 90-day mortality rate was 21.9%. In AH liver samples, expression of the CXC subfamily members IL-8, Gro-alpha, CXCL5, CXCL6, CXCL10, and platelet factor 4 was up-regulated and compared with controls. The CC chemokine CCL2, but not CCL5, also was up-regulated. Higher expression levels of IL-8, CXCL5, Gro-gamma, and CXCL6 were associated with worse prognosis. Expression of CXC components correlated with neutrophil infiltration and the severity of portal hypertension. In the multivariate analysis, IL-8 protein levels were an independent predictor of 90-day mortality. IL-8 and Gro-alpha serum levels did not correlate with prognosis. CONCLUSIONS: Hepatic expression of CXC components correlates with prognosis of patients with AH. Reagents that target CXC chemokines might be developed as therapeutics.
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Quimiocinas CXC/metabolismo , Hepatitis Alcohólica/metabolismo , Hipertensión Portal/metabolismo , Hígado/metabolismo , Apoptosis , Biopsia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocinas CXC/genética , Femenino , Expresión Génica , Hepatitis Alcohólica/genética , Hepatitis Alcohólica/mortalidad , Hepatitis Alcohólica/patología , Humanos , Hipertensión Portal/genética , Hipertensión Portal/mortalidad , Hipertensión Portal/patología , Etiquetado Corte-Fin in Situ , Interleucina-8/genética , Interleucina-8/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Activated hepatic stellate cells (HSC) and other fibrogenic cell types are frequently found around hepatocellular carcinoma. It is unknown whether hepatocarcinoma cells regulate the biological functions of HSC. AIMS: This study aimed to investigate the paracrine effects of hepatocarcinoma cells on human HSC using a co-culture system. METHODS: Huh7 or HepG2 cells, human hepatocarcinoma cell lines, were co-cultured with primary human HSC. Intracellular calcium mobilization, proliferation, migration, expression of pro-angiogenic and fibrogenic genes, smooth muscle alpha-actin (alpha-SMA) protein expression, inflammatory properties (nuclear factor kappa B activation and interleukin 8 secretion) and intracellular signalling pathways (AKT and ERK) were analysed in HSC. RESULTS: Culture of HSC with Huh7 cells for 24 h stimulated HSC proliferation, migration and expression of pro-angiogenic genes. The migration effect was corroborated with HepG2 cells. The effects of Huh7 cells on cell proliferation and migration were mediated mainly by PI3K/AKT activation. Moreover, Huh7 cells reduced the expression of genes involved in fibrogenesis, while they did not modify the inflammatory properties of HSC. The expression of alpha-SMA was induced by Huh7 cells. Because hepatitis C virus (HCV) infection is a major cause of hepatocarcinoma, we next investigated whether these effects are regulated by the expression of HCV in hepatocarcinoma cells. Expression of a subgenomic replicon expressing HCV nonstructural proteins (NS3-NS5) in Huh7 cells did not affect paracrine actions in HSC (cell proliferation and migration). CONCLUSIONS: These results suggested that there is a cross-talk between hepatocarcinoma cells and HSC. Activated HSC may be stimulated by cancer cells to accumulate and express angiogenic genes.
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Carcinoma Hepatocelular/patología , Regulación de la Expresión Génica , Células Estrelladas Hepáticas/patología , Neoplasias Hepáticas/patología , Neovascularización Patológica/genética , Biomarcadores/metabolismo , Calcio/metabolismo , Señalización del Calcio/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Técnicas de Cocultivo , Células Estrelladas Hepáticas/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinasas/biosíntesis , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Receptor Cross-Talk/fisiologíaRESUMEN
Molecular epidemiology and genomic characterisation studies require the screening of large numbers of individuals to achieve statistical significance. Although many of the novel DNA extraction methods offer convenient, high-throughput capabilities, their use for the processing of larger sample volumes becomes very expensive. We are currently compiling the Mexican Genomic DNA Collection in order to address specific health priorities through molecular techniques. Our approach employs a low-cost laundry detergent based DNA extraction technique that maximizes DNA yield and quality. We have optimised four different modalities (maxiprep, midiprep, miniprep and microprep) for two different sources (leukocyte concentrates and whole blood). Our optimised protocol produces 4.5 mg of DNA from 15 ml of blood-bank discarded leukocyte concentrates with spectrophotometric quality, genomic integrity and PCR suitability that rivals that of phenol-chloroform extracted samples. We present evidence of many PCR applications that we have carried out on samples extracted with this technique including Killer-cell Immunoglobulin-like Receptor genotyping, Short Tandem Repeat profiling as well as nucleic acid screening for hepatitis B and human immunodeficiency type-1 viruses. This paper highlights many of the advantages that this DNA extraction technique provides over existing methodologies, whether it is used to establish large genomic DNA collections (as was our main intention) or as a routine DNA extraction method for PCR applications.
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Bancos de Sangre , ADN/aislamiento & purificación , Genoma Humano/genética , Epidemiología Molecular/métodos , ADN/genética , Electroforesis en Gel de Agar , Estudios de Evaluación como Asunto , VIH/genética , VIH/aislamiento & purificación , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Leucocitos/metabolismo , Repeticiones de Microsatélite/genética , Reacción en Cadena de la Polimerasa , EspectrofotometríaRESUMEN
Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen alpha1(I) and alpha1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Hígado/efectos de los fármacos , Losartán/uso terapéutico , NADPH Oxidasas/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular/genética , Administración Oral , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Biopsia con Aguja , Colágeno/genética , Regulación hacia Abajo , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/enzimología , Hepatitis C Crónica/genética , Humanos , Mediadores de Inflamación/metabolismo , Hígado/enzimología , Hígado/virología , Cirrosis Hepática/enzimología , Cirrosis Hepática/genética , Cirrosis Hepática/virología , Losartán/administración & dosificación , Losartán/efectos adversos , Masculino , Metaloproteinasa 2 de la Matriz/genética , Persona de Mediana Edad , NADPH Oxidasas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , España , Factores de Tiempo , Resultado del Tratamiento , Activador de Plasminógeno de Tipo Uroquinasa/genética , Proteína de Unión al GTP rac1/genéticaRESUMEN
Breast cancer is the most common malignancy in women worldwide, and dietary lipids are important environmental factors influencing its etiology. We have investigated the effects, and the mechanisms associated, of high-fat diets on 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Animals were fed a low-fat, a high-corn-oil (HCO) or a high-extra-virgin-olive-oil (HOO) diet from weaning or after induction. The HCO diet had a clear stimulating effect on mammary carcinogenesis, especially when dietary intervention started after induction, whereas the tumors from HOO diet groups exhibited clinical and morphological characteristics similar to those from low-fat controls. Transcriptomic and further protein and immunohistochemical analyses of tumors also indicated different modulatory effects of high-fat diets affecting relevant biological functions: metabolism, immunosurveillance and proliferation/apoptosis pathways. Thus, the results suggested different metabolic adaptations with increased glycolysis by effect of HOO diet. Moreover, leukocyte tumor infiltration and inflammation mediators showed increased cytotoxic T cells and decreased TGFß1 expression by the HOO diet, while the HCO one increased arginase expression and IL-1α plasma levels. Furthermore, the study of proteins controlling proliferation/apoptosis pathways (Sema3A, Stat5, Smad1, Casp3) suggested an increase in proliferation by the HCO diet and an increase of apoptosis by the diet rich in olive oil. In conclusion, the HCO diet clearly stimulated mammary carcinogenesis, especially in the promotion phase, and induced molecular changes suggesting increased tumor proliferation/apoptosis balance and a proinflammatory microenvironment. The HOO diet, despite being high fat, had a weaker effect on tumorigenesis probably related to metabolic adaptations, enhanced immunosurveillance and increased apoptosis.
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Aceite de Maíz/efectos adversos , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/patología , Aceite de Oliva/farmacología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocinas/sangre , Femenino , Regulación Neoplásica de la Expresión Génica , Glándulas Mamarias Animales/inmunología , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/patología , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , TranscriptomaRESUMEN
INTRODUCTION: Introduction: severe obesity is increasing rapidly in several countries, as well as the number of bariatric surgeries performed. However, the pattern of food consumption of the population is not well defined. Objectives: the aim of the present study was to describe the food consumption pattern (comparing men and women) of severely obese patient candidates to bariatric surgery and to determine the promoting and protecting factors. Methods: food consumption and nutrient intake were measured by a validated food frequency questionnaire (FFQ), including food and beverages. Multivariate principal component analysis (PCA) was done to analyze the component that best relates to the food pattern consumption dividing the different food groups in promotors and protectors. Results: significant differences in the food consumption pattern of men and women with severe obesity addressed for bariatric surgery were found. A positive correlation was found between the food groups that are protective factors for obesity such as the fiber (r = 0.84), vegetables (r = 0.767) and fruits (r = 0.83), whereas a negative correlation was found with those factors that are promotors of obesity such as fats (r = -0.341), saturated fats (r = -0.411), soft drinks (r = -0.386), and fast food (r = -0.17).Multivariate analysis of principal components revealed that calorie consumption is the component that correlates better with the pattern. Conclusions: there are significant differences in the food consumption pattern of men and women with severe obesity addressed for bariatric surgery and these differences should be taken into account when planning nutritional intervention. Therefore, a healthy lifestyle behaviour should be highly encouraged among the severe obese population.
INTRODUCCIÓN: Introducción: la obesidad mórbida así como el número de cirugías bariátricas que se practican van en aumento en varios países. Sin embargo, el patrón de consumo alimentario de estos pacientes no está bien definido. Objetivos: describir el patrón de consumo de alimentos (comparando hombres y mujeres) de pacientes con obesidad severa candidatos a cirugía bariátrica y determinar los factores promotores y protectores de la obesidad. Métodos: el consumo de alimentos y la ingesta de nutrientes se midieron mediante un cuestionario de frecuencia de consumo de alimentos validado que incluye alimentos y bebidas. Se realizó un análisis multivariado de componentes principales para determinar qué componente se relaciona mejor con el consumo de patrones alimentarios promotores y protectores de obesidad. Resultados: el estudio mostró diferencias significativas en el patrón de consumo de alimentos entre hombres y mujeres. Se encontró una correlación positiva entre los grupos de alimentos considerados factores de protección para la obesidad, como la fibra (r = 0,84), las verduras (r = 0,767) y las frutas (r = 0,83), mientras que la correla-ción fue negativa con los factores promotores de la obesidad como las grasas (r = -0,341), las grasas saturadas (r = -0,411), los refrescos (r = -0,386) y la comida rápida (r = -0,17). El análisis multivariado de los componentes principales reveló que el consumo de calorías es el componente que se correlaciona mejor con el patrón. Conclusiones: existen diferencias significativas en el patrón de consumo de alimentos entre hombres y mujeres con obesidad severa y estas deben tenerse en cuenta al planificar la intervención nutricional. Asimismo, un consumo alimentario saludable debe promocionarse en la población obesa.
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Cirugía Bariátrica , Ingestión de Alimentos , Conducta Alimentaria , Obesidad Mórbida/psicología , Adulto , Bebidas Gaseosas , Grasas de la Dieta , Fibras de la Dieta , Ingestión de Energía , Femenino , Frutas , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/cirugía , Factores Sexuales , Encuestas y CuestionariosRESUMEN
BACKGROUND & AIMS: Recent studies have suggested that the kallikrein-kinin system regulates tissue fibrogenesis. We hypothesize that bradykinin (BK), the main effector peptide of this system, regulates hepatic fibrogenesis. METHODS: Kallikrein-kinin system components were studied by quantitative reverse-transcription polymerase chain reaction analysis, immunohistochemistry, and Western blotting. The effect of bradykinin on liver injury was studied by infusing saline or bradykinin (1 and 100 ng/kg/min) through a subcutaneous pump into carbon tetrachloride-treated rats and mice treated with Fas-stimulating antibody. Bradykinin effects were studied in cultured hepatic stellate cells (HSCs) and hepatocytes. RESULTS: Bradykinin receptors and kallikrein-1 were detected in both normal and fibrotic human livers and HSCs. BK receptors were up-regulated in fibrotic livers and activated HSCs. Bradykinin infusion reduced liver damage, as indicated by decreased aminotransferase serum levels and reduced histologic necroinflammatory score without inducing changes in arterial pressure. Moreover, bradykinin attenuated hepatic fibrosis, as indicated by reduced collagen accumulation, smooth muscle alpha-actin content, as well as decreased pro-collagen-alpha1(I) and transforming growth factor-beta1 gene expression. Bradykinin infusion reduced hepatocellular apoptosis induced by anti-Fas-receptor antibody. HSCs responded to bradykinin with intracellular calcium mobilization. Bradykinin reduced procollagen-alpha1(I) and transforming growth factor-beta1 gene expression and induced matrix metalloproteinase-2 activation. Finally, BK induced prosurvival and proliferative intracellular signaling in primary hepatocytes. CONCLUSIONS: Bradykinin attenuates liver damage and fibrosis development in a rat model of chronic liver injury. Therefore, activation of the kallikrein-kinin system may be a new therapeutic approach to the management of chronic liver disease.
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Bradiquinina/inmunología , Sistema Calicreína-Quinina/inmunología , Hepatopatías/fisiopatología , Hígado/fisiopatología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fibrosis , Humanos , Hígado/inmunología , Hígado/patología , Masculino , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
OBJECTIVES: Prognostic stratification of patients with alcoholic hepatitis (AH) may improve the clinical management and facilitate clinical trials. We aimed at developing a scoring system capable of providing prognostic stratification of patients with AH. METHODS: Patients with biopsy-proven AH were prospectively included between 2000 and 2006. The biochemical, clinical, portal hemodynamic and histological parameters were evaluated. A Cox regression model was used for univariate and multivariate analyses. A predictive score was built using variables obtained at admission identified in the multivariate analysis. The resulting score was validated in an independent prospective cohort. RESULTS: In total, 103 patients with biopsy-proven AH were included in the study cohort. Age, serum bilirubin, serum creatinine, and international normalized ratio (INR) independently predicted 90-day mortality. We generated the Age, serum Bilirubin, INR, and serum Creatinine (ABIC) score: (age x 0.1) + (serum bilirubin x 0.08) + (serum creatinine x 0.3) + (INR x 0.8). The area under the curve (AUC) was 0.82. Using the Kaplan-Meier analysis with the cutoff values of 6.71 and 9.0, we identified patients with low, intermediate, and high risk of death at 90 days (100%, 70%, and 25% of survival rate, respectively). Using the same cutoff values, the ABIC score also stratified patients according to their risk of death at 1 yr. These results were validated by a confirmatory cohort (N = 80). CONCLUSIONS: The ABIC score is a new tool that allows the stratification of risk of death in patients with AH at 90 days and 1 yr. This score can help improve the management of these patients and also help to perform clinical trials.
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Hepatitis Alcohólica/mortalidad , Índice de Severidad de la Enfermedad , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Medición de RiesgoAsunto(s)
Enfermedades Duodenales/diagnóstico , Cálculos Biliares/diagnóstico , Obstrucción de la Salida Gástrica/etiología , Ileus/diagnóstico , Anciano , Enfermedades Duodenales/complicaciones , Obstrucción Duodenal/complicaciones , Obstrucción Duodenal/diagnóstico , Femenino , Cálculos Biliares/complicaciones , Obstrucción de la Salida Gástrica/diagnóstico , Humanos , Ileus/complicaciones , SíndromeRESUMEN
Apoptosis is a major mechanism regulating immune tolerance by the elimination of autoreactive T lymphocytes. A failure of activation induced cell-death (AICD) has been described in T lymphocytes from patients with multiple sclerosis (MS). The aims of this study were to evaluate AICD in T lymphocytes from patients with MS and healthy controls, and to explore the molecular mechanisms underlying the deregulation observed in apoptosis induction. PHA-induced AICD was reduced in T lymphocytes from patients with relapsing-remitting MS compared with controls. This finding was associated with a diminished expression of Fas and a failure in caspase 3 activation.