Sound-based cough peak flow estimation in patients with neuromuscular disorders.

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.

Ultrasonographic and manometric study of the tongue as biomarkers of dysphagia in patients with amyotrophic lateral sclerosis.

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).

Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis.

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.

Characterization of the pattern of food consumption in severely obese patients prior to bariatric surgery.

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.

A high-corn-oil diet strongly stimulates mammary carcinogenesis, while a high-extra-virgin-olive-oil diet has a weak effect, through changes in metabolism, immune system function and proliferation/apoptosis pathways.

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.

Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis.

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.

Detección del virus de Epstein-Barr en un tumor miofibroblástico inflamatorio de bazo (seudotumor inflamatorio) / Detection of Epstein-Barr virus in an inflammatory myofibroblastic tumor of the spleen (inflammatory pseudotumor)

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[Rupture of splenic artery pseudoaneurysm: an unusual cause of upper gastrointetinal bleeding]. / Ruptura de pseudoaneurisma de la arteria esplénica: una causa poco frecuente de hemorragia digestiva alta.

BACKGROUND: Bleeding from a pancreatic pseudocyst is a severe complication after pancreatitis that can lead to a massive gastrointestinal blood loss. Pseudocyst rupture into the stomach is an unusual complication. CLINICAL CASE: We report the case of a 34-year-old woman with a history of alcoholism and a pancreatic pseudocyst. One year after follow-up of her pseudocyst, she arrived at the emergency room with an episode of upper gastrointestinal bleeding. An upper digestive endoscopy showed active bleeding in the subcardial fundus, which could not be endoscopically controlled. Abdominal angio-CT confirmed the diagnosis of a splenic artery pseudoaneurysm in close contact with the back wall of the stomach, as well as a likely fistulization of it. The patient was urgently operated and a distal splenopancreatectomy and fistulorrhaphy was performed. CONCLUSION: The rupture of a splenic artery pseudoaneurysm may rarely present as upper gastrointestinal bleeding. This may be lethal if not urgently treated.

Antecedentes: tras una pancreatitis, el sangrado de un pseudoquiste pancreático es una complicación grave que puede conducir a una hemorragia digestiva masiva. La ruptura de ese pseudoquiste en el estómago es rara. Caso clínico: se comunica el caso de una paciente femenina de 34 años de edad, con antecedentes de alcoholismo y un pseudoquiste pancreático. Después de abandonar el estudio y seguimiento del pseudoquiste pancreático un año más tarde reingresó de urgencia debido a un cuadro de hemorragia digestiva alta. En una endoscopia del tubo digestivo alto se encontró sangrado activo en la región del fundus gástrico, que no pudo controlarse. La angio-tomografía axial computada abdominal confirmó el diagnóstico de pseudoaneurisma de la arteria esplénica, en íntimo contacto con la pared posterior del estómago y quizá fistulizado al mismo. La paciente se intervino con carácter urgente realizándose esplenopancreatectomía distal y fistulorrafia. Conclusión: en raras ocasiones la ruptura de un pseudoaneurisma de la arteria esplénica puede iniciarse como una hemorragia digestiva alta, que puede ser letal si no es tratada con urgencia.

Linfangioma quístico mesentérico gigante como hallazgo incidental en adulto joven / Giant mesenteric cystic lymphangioma as an incidental finding in a young adult

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Activation-induced cell death in T lymphocytes from multiple sclerosis patients.

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.

Circulating levels of soluble apoptosis-related molecules in patients with multiple sclerosis.

Evidence exists that apoptotic elimination of autoreactive T lymphocytes is defective in multiple sclerosis (MS). Here, we measured serum levels of soluble forms of Fas (sFas), Fas ligand (sFasL) and TNF-related apoptosis-inducing ligand (sTRAIL) in 38 healthy controls (HC) and 92 untreated MS patients with different clinical forms and activity phases of the disease by immunoassay. Serum levels of sFas, sFasL and sTRAIL did not differ between MS patients and HC. sTRAIL levels were significantly decreased in RRMS during relapses. These findings support a role of TRAIL in the pathogenesis of MS, especially during the acute phases of the disease.

Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis.

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.

Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats.

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.