Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease

[EN]MicroRNAs (miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAs in alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease

Sphingobacterium multivorum: An Atypical Bacterium in an Atypical Place

We present the case of a 75-year-old woman admitted to hospital because of an infected pressure ulcer. Cultures revealed that the responsible bacterium was Sphingobacterium multivorum, which was successfully eradicated with ciprofloxacin. Over the last few years, there have been reports of new cases of infection caused by bacteria previously not thought to be harmful to humans, like S. multivorum. Previous cases were reported mostly in immunosuppressed patients and the present report is, to our knowledge, the first describing a pressure ulcer infected by this bacterium

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

De-novo non-convulsive status epilepticus in adult medical inpatients without known epilepsy: Analysis of mortality related factors and literature review

BACKGROUND: Non-convulsive status epilepticus (NCSE) often goes unnoticed and is not easily detected in patients with a decreased level of consciousness, especially in older patients. In this sense, lack of data in this population is available. AIMS: The aim of the present study was to examine daily clinical practice and evaluate factors that may influence the prognosis of NCSE in non-epileptic medical inpatients. METHODS: We conducted a retrospective analysis including patients admitted by any cause in an Internal Medicine ward. All patients with compatible symptoms, exclusion of other causes, clinical suspicion or diagnosis of NCSE, and compatible EEG were included. Patients with a previous diagnosis of epilepsy were excluded. We also conducted a literature review by searching the PubMed/Medline database with the terms: Nonconvulsive Status OR Non-Convulsive Status. RESULTS: We included 54 patients, mortality rate reached 37% and the main factors linked to it were hypernatremia (OR = 16.2; 95% CI, 1.6-165.6; P = 0.019) and atrial fibrillation (OR = 6.7; 95% CI, 1.7-26; P = 0.006). There were no differences regarding mortality when comparing different diagnosis approach or treatment regimens. Our literature review showed that the main etiology of NCSE were neurovascular causes (17.8%), followed by antibiotic treatment (17.2%) and metabolic causes (17%). Global mortality in the literature review, excluding our series, reached 20%. DISCUSSION: We present the largest series of NCSE cases in medical patients, which showed that this entity is probably misdiagnosed in older patients and is linked to a high mortality. CONCLUSION: The presence of atrial fibrillation and hypernatremia in patients diagnosed with NCSE should advise physicians of a high mortality risk

Atrial fibrillation as a new prognosis factor in chronic patients after hospitalization: the CHRONIBERIA index

A collaborative project in different areas of Spain and Portugal was designed to find out the variables that influence the mortality after discharge and develop a prognostic model adapted to the current healthcare needs of chronic patients in an internal medicine ward. Inclusion criteria were being admitted to an Internal Medicine department and at least one chronic disease. Patients’ physical dependence was measured through Barthel index (BI). Pfeiffer test (PT) was used to establish cognitive status. We conducted logistic regression and Cox proportional hazard models to analyze the influence of those variables on one-year mortality. We also developed an external validation once decided the variables included in the index. We enrolled 1406 patients. Mean age was 79.5 (SD = 11.5) and females were 56.5%. After the follow-up period, 514 patients (36.6%) died. Five variables were identified as significantly associated with 1 year mortality: age, being male, lower BI punctuation, neoplasia and atrial fibrillation. A model with such variables was created to estimate one-year mortality risk, leading to the CHRONIBERIA. A ROC curve was made to determine the reliability of this index when applied to the global sample. An AUC of 0.72 (0.7–0.75) was obtained. The external validation of the index was successful and showed an AUC of 0.73 (0.67–0.79). Atrial fibrillation along with an advanced age, being male, low BI score, or an active neoplasia in chronic patients could be critical to identify high risk multiple chronic conditions patients. Together, these variables constitute the new CHRONIBERIA index

Treatment variability and its relationships to outcomes among patients with Wernicke's encephalopathy: A multicenter retrospective study

Background: Despite guidelines and recommendations, Wernicke's encephalopathy (WE) treatment lacks evidence, leading to clinical practice variability.Aims: Given the overall lack of information on thiamine use for WE treatment, we analyzed data from a large, well-characterized multicenter sample of patients with WE, examining thiamine dosages; factors associated with the use of different doses, frequencies, and routes; and the influence of differences in thiamine treatment on the outcome.Methods: This retrospective study was conducted with data from 443 patients from 21 centers obtained from a nationwide registry of the Spanish Society of Internal Medicine (from 2000 to 2012). Discharge codes and Caine criteria were applied for WE diagnosis, and treatment-related (thiamine dosage, frequency, and route of administration) demographic, clinical, and outcome variables were analyzed.Results: We found marked variability in WE treatment and a low rate of high-dose intravenous thiamine administration. Seventy-eight patients out of 373 (20.9%) received > 300 mg/day of thiamine as initial dose. Patients fulfilling the Caine criteria or presenting with the classic WE triad more frequently received parenteral treatment. Delayed diagnosis (after 24 h hospitalization), the fulfillment of more than two Caine criteria at diagnosis, mental status alterations, and folic acid deficiency were associated significantly with the lack of complete recovery. Malnutrition, reduced consciousness, folic acid deficiency, and the lack of timely thiamine treatment were risk factors for mortality.Conclusions: Our results clearly show extreme variability in thiamine dosages and routes used in the management of WE. Measures should be implemented to ensure adherence to current guidelines and to correct potential nutritional deficits in patients with alcohol use disorders or other risk factors for WE

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Polimorfismos genéticos en la vía de los Micro-ARN y su relación con el alcoholismo

[ES] INTRODUCCIÓN: El consumo de alcohol es una práctica extendida y aceptada en España, si bien un consumo excesivo conlleva el riesgo de desarrollo de trastornos asociados al mismo, como la enfermedad hepática alcohólica o a dependencia del alcohol, entre otros. Estudios previos han mostrado que la inflamación inducida por el consumo de alcohol supone (fundamentalmente a través de la vía TLR4/NF¿B), tanto a nivel hepático como cerebral, uno de los pilares fundamentales en la fisiopatología de estos procesos. Además, existe una gran variabilidad en cuanto al grado de inflamación inducido por el alcohol en pacientes con consumos similares. Esta diferencia podría deberse a una predisposición genética al desarrollo de neuroinflamación o inflamación hepática inducidas por el alcohol. Hasta la actualidad, numerosos estudios han tratado de dilucidar si determinadas variantes genéticas, fundamentalmente polimorfismos genéticos en enzimas, neurotransmisores y mediadores proinflamatorios, podrían estar implicados en dicha predisposición, pero ninguno de ellos ha mostrado resultados concluyentes. Desde su descripción, los micro-ARN han surgido como un nuevo campo de estudio y, debido a su acción reguladora sobre la expresión de otros genes, se ha postulado que variaciones en su función, como las provocadas por polimorfismos genéticos en la vía de los micro-ARN, podrían estar involucradas en el desarrollo de enfermedades. OBJETIVOS: estudiar la posible relación de polimorfismos en la vía de los micro-ARN relacionados con la transmisión de la respuesta inflamatoria a través de la vía TLR4/NF¿B con el desarrollo de alcoholismo o hepatopatía alcohólica. PACIENTES Y MÉTODOS: se incluyeron 301 pacientes alcohólicos (62,8% dependientes y 34,2% con cirrosis hepática) y 156 controles sanos. Se realizó una selección de polimorfismos potencialmente implicados a través de revisión bibliográfica y análisis mediante bases de datos de micro-ARN y modelos matemáticos predictivos (miRanda, miRbase, TragetScan). Se seleccionaron los siguientes polimorfismos: polimorfismo 60 C>G del gen MIR146A (rs2910164), polimorfismo 78 C>T del gen MIR196A2 (rs11614913), polimorfismo 3377 T>G del gen KRAS (rs61764370), polimorfismo 2124 G>T del gen IL12B (rs1368439), polimorfismo 5000 C>T del gen IL16 (rs1131445), polimorfismo 3114 C>T del gen IL1R1 (rs3917328), polimorfismo 3400 A>G del gen NFKB1 (rs4648143). Corresponden a genes que codifican micro-ARN o puntos de unión de micro-ARN a través de los cuales estos ejercen su acción reguladora sobre la expresión de otros genes. Se realizó un análisis de discriminación alélica mediante extracción y purificación de ADN y PCR a tiempo real. RESULTADOS Y DISCUSIÓN: Se encontró una diferencia significativa en la distribución alélica del polimorfismo 60 C>G del gen MIR146A (rs2910164) al comparar pacientes alcohólicos y controles sanos, siendo el alelo C más frecuente entre los primeros. Tras el análisis multivariante se concluye que la posesión del alelo C (genotipos CG y CC) se asoció con un mayor riesgo de alcoholismo: OR = 1,615 (IC 95% = 1,067 ¿ 2,442; P = 0,023). La hipótesis que se postula para el papel del polimorfismo 60 C>G en el alcoholismo es la siguiente: la presencia del alelo C conlleva una reducción de los niveles de miR-146a, cuya función de retroalimentación negativa y control de la respuesta inflamatoria se ve reducida. Por tanto, esto conduce a un aumento de respuesta inflamatoria cerebral, que induciría una predisposición al desarrollo de alcoholismo. No se encontró asociación con el desarrollo de hepatopatía al estudiar este polimorfismo. Se encontró una diferencia significativa en la distribución alélica del polimorfismo 3114 C>T del gen IL1R1 (rs3917328) al comparar pacientes alcohólicos y controles sanos, siendo más frecuente el alelo T en controles sanos. El análisis multivariante no confirmo este hallazgos. Este resultado parece apuntar hacia una relación de este polimorfismo con el desarrollo de alcoholismo e inflamación, se localiza en un punto de unión de micro-ARN. La presencia del alelo T podría ser un posible factor protector. No se encontró asociación con el desarrollo de hepatopatía al estudiar este polimorfismo. Tras analizar los polimorfismos 78 C>T del gen MIR196A2 (rs11614913), 3377 T>G del gen KRAS (rs61764370), 2124 G>T del gen IL12B (rs1368439), 5000 C>T del gen IL16 (rs1131445), y 3400 A>G del gen NFKB1 (rs4648143), no se encontró asociación con el desarrollo de alcoholismo o enfermedad hepática alcohólica. CONCLUSIONES: La posesión del alelo C del polimorfismo 60 C>G del gen MIR146A se asocia con alcoholismo, entendido como abuso o dependencia del alcohol. Los datos previos sugieren que este alelo puede alterar la función reguladora de miR-146a sobre la vía TLR4/NF¿B, implicada en la inflamación hepática y cerebral provocada por el alcohol, induciendo una mayor respuesta inflamatoria. Por ello, los resultados del presente trabajo sugieren que la posesión del alelo C conlleva un mayor riesgo de desarrollar alcoholismo, y constituyen la primera evidencia de la implicación de polimorfismos de micro-ARN en esta patología