Review article: Oesophageal disorders in chronic liver disease.

BACKGROUND: Oesophageal disorders and chronic liver disease are common worldwide and significantly impact quality of life. The intricate link between these conditions, including how oesophageal disorders like GERD, Barrett's oesophagus and oesophageal cancer affect and are affected by chronic liver disease, remains poorly understood. AIMS: To review the relationship between oesophageal disorders and chronic liver disease, evaluating epidemiology, pathophysiology and therapeutic factors. METHODS: We reviewed the literature on the relationship between oesophageal disorders and chronic liver disease, including cirrhosis, using the PubMed database RESULTS: Oesophageal disorders such as gastroesophageal reflux disease, Barrett's oesophagus, oesophageal cancer, oesophageal motor disorders and oesophageal candidiasis are prevalent among individuals with cirrhosis, exacerbating the burden of liver disease. These diseases have a multifaceted symptomatology and pathogenic basis, posing a significant challenge in cirrhotic patients that necessitates careful diagnosis and management. Additionally, therapies frequently used for these diseases, such as proton pump inhibitors, require careful consideration in cirrhotic patients due to potential adverse effects and altered pharmacokinetics. Managing oesophageal disorders in cirrhotic patients requires a cautious approach due to possible interactions with medications and the risk of adverse effects. Furthermore, symptoms associated with these conditions are often exacerbated by common interventions in patients with cirrhosis, such as band ligation for oesophageal varices. CONCLUSIONS: Oesophageal disorders are common in cirrhosis and increase the disease burden. These conditions require careful management due to complex symptoms and treatment risks. Proton pump inhibitors and other therapies must be used cautiously, as cirrhosis interventions can worsen symptoms.

The Janus of a disease: Diabetes and metabolic dysfunction-associated fatty liver disease.

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.

Second Hematologic Malignancies Associated With Primary Mediastinal Germ Cell Tumors: A Population-based Study.

BACKGROUND: Studies addressing second hematologic malignancies (SHMs) in patients with primary mediastinal germ cell tumors (PMGCTs) are scarce. To better describe this phenomenon, we analyzed a large case series from a population-based registry. METHODS: The Surveillance, Epidemiology, and End Results database was used to report the clinical characteristics and incidence of SHMs in patients with PMGCT. RESULTS: Among 1297 PMGCTs, 27 cases (2.08%) of SHM were found, with a median latency period of 12 months (95% CI: 5-41). All SHM occurred in males, 20 of whom (74.1%) had a previous nonseminomatous tumor. Acute myeloid leukemia was the most frequent SHM, accounting for 13 cases, 4 of which were acute megakaryoblastic leukemia that occurred within 5 months of diagnosis. The median survival after the diagnosis of SHM was 6 months (95% CI: 2-41). The risk of SHM was significantly higher than expected for the reference population, with a standardized incidence ratio of 6.21 (95% CI: 3.31-10.62) and an absolute excess risk of 19.19 per 10,000 person-years. CONCLUSIONS: Patients with PMGCT are at a higher risk of developing SHMs than the general population, particularly acute myeloid leukemia. This risk ranges from synchronous diagnosis of acute megakaryoblastic leukemia to the later onset of other hematological disorders that might be related to PMGCT therapies. Our findings may help create follow-up schedules for patients with PMGCT and raise the level of suspicion surrounding this association.

Teaching Palliative Care to Emergency Medicine Residents Using Gamified Deliberate Practice-Based Simulation: Palliative Gaming Simulation Study.

BACKGROUND: Emergency departments (EDs) care for many patients nearing the end of life with advanced serious illnesses. Simulation training offers an opportunity to teach physicians the interpersonal skills required to manage end-of-life care. OBJECTIVE: We hypothesized a gaming simulation of an imminently dying patient using the LIVE. DIE. REPEAT (LDR) format, would be perceived as an effective method to teach end-of-life communication and palliative care management skills. METHODS: This was a gaming simulation replicating the experience of caring for a dying patient with advanced serious illness in the ED. The scenario involved a patient with pancreatic cancer presenting with sepsis and respiratory distress, with a previously established goal of comfort care. The gaming simulation game was divided into 4 stages, and at each level, learners were tasked with completing 1 critical action. The gaming simulation was designed using the LDR serious game scheme in which learners are allowed infinite opportunities to progress through defined stages depicting a single patient scenario. If learners successfully complete the predetermined critical actions of each stage, the game is paused, and there is a debriefing to reinforce knowledge or skills before progressing to the next stage of the gaming simulation. Conversely, if learners do not achieve the critical actions, the game is over, and learners undergo debriefing before repeating the failed stage with an immediate transition into the next. We used the Simulation Effectiveness Tool-Modified survey to evaluate perceived effectiveness in teaching end-of-life management. RESULTS: Eighty percent (16/20) of residents completed the Simulation Effectiveness Tool-Modified survey, and nearly 100% (20/20) either strongly or somewhat agreed that the gaming simulation improved their skills and confidence at the end of life in the following dimensions: (1) better prepared to respond to changes in condition, (2) more confident in assessment skills, (3) teaching patients, (4) reporting to the health care team, (5) empowered to make clinical decisions, and (6) able to prioritize care and interventions. All residents felt the debriefing contributed to learning and provided opportunities to self-reflect. All strongly or somewhat agree that they felt better prepared to respond to changes in the patient's condition, had a better understanding of pathophysiology, were more confident on their assessment skills, and had a better understanding of the medications and therapies after the gaming simulation. A total of 88% (14/16) of them feel more empowered to make clinical decisions. After completing the gaming simulation, 88% (14/16) of residents strongly agreed that they would feel more confident communicating with a patient and prioritizing care interventions in this context. CONCLUSIONS: This palliative gaming simulation using the LDR format was perceived by resident physicians to improve confidence in end-of-life communication and palliative care management.

Neurolupus como manifestación de primer brote psicótico Reporte de caso / Neurolupus as a manifestation of the first psychotic episode: case report

Resumen Antecedentes: El lupus eritematoso sistémico (LES) es una enfermedad auto inmunitaria crónica multisistémica con diversas manifestaciones clínicas. Siendo las mujeres la pobla ción vulnerable y con mayor afectación a nivel neurológico, al presentar mayor riesgo de convulsiones. Las manifestaciones neuropsiquiátricas ocurren en etapas tempranas de la enfermedad y del diagnóstico, ya que pueden presentarse junto con manifestaciones sistémicas o no. La frecuencia de manifestaciones neuropsiquiátricas en el lupus eritematoso sistémico se ha descrito del 14 al 75%, siendo las alteraciones cognitivas uno de los grandes síntomas a destacar1. La cual puede ir acompañada de trastornos afectivos de tipo depresión y ansiedad. Ya que la psicosis secundaria a LES se remarca por su baja prevalencia (10%)2, los estudios de laboratorio nos suelen orientar hacia el diagnóstico definitivo, siendo los anticuerpos ribosomales P los que se han relacionado más específicamente con la psicosis lúpica. La resonancia magnética es la prueba de elección y las lesiones cerebrales están dominadas por hiperintensidades de materia blanca en forma de punción3. En el siguiente reporte de caso, presentamos a una paciente de 20 años, la cual contaba con antecedentes de esteatosis hepática diagnosticado, diabetes tipo MODY y resección de ovario derecho por teratoma maduro de 9 años de evolución, pero sin antecedentes psiquiátricos de importancia para el momento de su valoración. Sin embargo, de forma aguda presentó un brote psicótico caracterizado por ideas delirantes de grandiosidad y referencia, así como alteraciones conductuales, cognitivas y afectivas. Por las que tuvieron que acudir a hospital de 3er nivel durante el periodo de contingencia sanitaria en el 2020. Tras el antecedente de presentar infección por SARS-CoV-2 tres meses antes de su patología neuropsiquiátricas. Se sospechó en síntomas neurológicos secundarios a infección por COVID-19, así como patología psiquiátrica aislada. Por lo que se realizó abordaje de estudio de primer brote psicótico, diagnosticándose lupus eritematoso sistémico con manifestaciones neuropsiquiátricas. El tratamiento se basó en un bolo de metilprednisolona y antipsicóticos, luego modificada por terapia con corticoesteroides orales y antipsicótico de depósito. Conclusión: El lupus eritematoso sistémico con manifestaciones neuropsiquiátricas es una presentación poco frecuente del padecimiento, por la amplia variación en la aparición de este, los pacientes con síntomas psiquiátricos en contexto de hospital general deben de ser tomados en cuenta para abordajes extensos4. De la misma forma, el tener este conocimiento del caso podrá ampliar nuestro conocimiento sobre las complicaciones de esta patología reumatológica. Y una de sus complicaciones más graves como la psicosis lúpica para poder realizar un mejor abordaje del primer brote psicótico en hospitales generales, donde la valoración de un especialista puede ser más complicada para mejorar las condiciones médicas de estos pacientes.

Abstract Background: Systemic lupus erythematosus is a chronic multisystemic autoimmune disease with diverse clinical manifestations. Women are the most vulnerable population and have the greatest neurological involvement with a higher risk of seizures. Neuropsychiatric manifestations occur in early stages of the disease and diagnosis since they can occur together with systemic manifestations or not. The frequency of neuropsychiatric manifestations in systemic lupus erythematosus has been described from 14 to 75%; being cognitive alterations one of the major symptoms to highlight. Which, in the same way can be accompanied by affective disorders such as depression and anxiety. Since psychosis, secondary to SLE, stands out for its low prevalence (10%), laboratory studies usually guide us towards a definitive diagnosis, being ribosomal P antibodies the ones that have been more specifically related to lupus psychosis. MRI is the test of choice and brain lesions are dominated by punctate white matter hyperintensities. In the following case report, we present a 20-year-old patient who had a history of diagnosed hepatic steatosis, MODY type diabetes and resection of the right ovary for mature teratoma of 9 years of evolution; but with no psychiatric history of importance at the time of her evaluation. However, she acutely presented a psychotic outbreak characterized by delusions of grandiosity and reference; as well as behavioral, cognitive, and affective alterations. For which she had to go to a 3rd level hospital during the period of health contingency in 2020. After a history of SARS-CoV-2 infection three months before her neuropsychiatric pathology, neurological symptoms secondary to COVID-19 infection were suspected, as well as isolated psychiatric pathology. Therefore, a study approach of the first psychotic outbreak was performed, diagnosing systemic lupus erythematosus with neuropsychiatric manifestations. Treatment was based on a bolus of methylprednisolone and antipsychotics; later modified by therapy with oral corticosteroids and depot antipsychotic. Conclusion: Systemic lupus erythematosus with neuropsychiatric manifestations is an infrequent presentation of the disease, because of the wide variation in its appearance, patients with psychiatric symptoms in a general hospital setting should be considered for extensive approaches. In the same way, having this knowledge of this case may broaden our knowledge about the complications of this rheumatologic pathology. And one of its most serious complications such as lupus psychosis to be able to make a better approach to the first psychotic outbreak in general hospitals, where the assessment of a specialist can be more complicated.

Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells.

Genetic and epidemiologic studies have significantly advanced our understanding of the genetic factors contributing to age-related macular degeneration (AMD). In particular, recent expression quantitative trait loci (eQTL) studies have highlighted POLDIP2 as a significant gene that confers risk of developing AMD. However, the role of POLDIP2 in retinal cells such as retinal pigment epithelium (RPE) and how it contributes to AMD pathology are unknown. Here we report the generation of a stable human RPE cell line ARPE-19 with POLDIP2 knockout using CRISPR/Cas, providing an in vitro model to investigate the functions of POLDIP2. We conducted functional studies on the POLDIP2 knockout cell line and showed that it retained normal levels of cell proliferation, cell viability, phagocytosis and autophagy. Also, we performed RNA sequencing to profile the transcriptome of POLDIP2 knockout cells. Our results highlighted significant changes in genes involved in immune response, complement activation, oxidative damage and vascular development. We showed that loss of POLDIP2 caused a reduction in mitochondrial superoxide levels, which is consistent with the upregulation of the mitochondrial superoxide dismutase SOD2. In conclusion, this study demonstrates a novel link between POLDIP2 and SOD2 in ARPE-19, which supports a potential role of POLDIP2 in regulating oxidative stress in AMD pathology.

Immunotherapy for Cancer: Common Gastrointestinal, Liver, and Pancreatic Side Effects and Their Management.

Cancer cells can block the activation of T lymphocytes by deploying inhibitory signals to cell surface receptors that downregulate the immune response. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that regulate the immune response by acting on these receptors. The use of ICI has been successful for cancer types that do not respond well to conventional chemotherapy, showing clinical benefit in various advanced and metastatic cancers and supporting the promise of cancer immunotherapy. However, in some cases, these treatments are associated with immune-related adverse events, many of which affect the digestive system. The treatment of immune-related adverse events depends on the affected organ and the severity of symptoms. Here, we review the commonly used US FDA-approved ICI and briefly outline their mechanism of action. We also describe the resulting collateral effects on the gastrointestinal tract, liver, and pancreas and discuss their management and prognosis.

Extragonadal Germ Cell Tumors of the Mediastinum and Retroperitoneum: A Surveillance, Epidemiology, and End Results-based Study.

OBJECTIVES: Extragonadal germ cell tumors (EGCT) are a rare entity, most of them being located in the mediastinum and retroperitoneum. Information on these tumors is scarce, requiring carrying out large population-based studies to better understand these diseases. We aimed to determine the clinical features and prognosis of patients with EGCT of the mediastinum and retroperitoneum. MATERIALS AND METHODS: Demographic and clinicopathological features of patients diagnosed with EGCT of the mediastinum and retroperitoneum from 1975 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: A total of 1674 patients were included, 1297 (77.5%) of mediastinal origin and 377 (22.5%) of retroperitoneum. Nonseminomatous tumors (56.3%) were slightly more frequent than seminomas (43.7%) with similar distribution between mediastinum and retroperitoneum. After a median follow-up of 137 months, the median overall survival was 263 months (95% CI, 220-296) whereas the median cause-specific survival (CSS) has still not been reached. The 10-year overall survival and CSS were 57.4% (95% CI, 55-59.7) and 63% (95% CI, 60.6-65.2) respectively. Multivariate analysis showed that older age, mediastinal location, nonseminomatous histology, and distant disease at diagnosis were independent prognostic factors correlated with a worse prognosis. Patients with mediastinal choriocarcinoma and embryonal carcinoma have the worst prognosis, both with a median CSS of only 12 months. CONCLUSIONS: Despite a decreasing incidence observed in recent decades, EGCT continues to represent a challenge for oncologists. The prognosis of choriocarcinoma and embryonal carcinoma of the mediastinum remains poor and treatment strategies need to be improved urgently.

Pharmacological Activities of Aminophenoxazinones.

Aminophenoxazinones are degradation products resulting from the metabolism of different plant species, which comprise a family of natural products well known for their pharmacological activities. This review provides an overview of the pharmacological properties and applications proved by these compounds and their structural derivatives during 2000-2021. The bibliography was selected according to our purpose from the references obtained in a SciFinder database search for the Phx-3 structure (the base molecule of the aminophenoxazinones). Compounds Phx-1 and Phx-3 are among the most studied, especially as anticancer drugs for the treatment of gastric and colon cancer, glioblastoma and melanoma, among others types of relevant cancers. The main information available in the literature about their mechanisms is also described. Similarly, antibacterial, antifungal, antiviral and antiparasitic activities are presented, including species related directly or indirectly to significant diseases. Therefore, we present diverse compounds based on aminophenoxazinones with high potential as drugs, considering their levels of activity and few adverse effects.

Assessment of hepatic fatty acids during non-alcoholic steatohepatitis progression using magnetic resonance spectroscopy.

INTRODUCTION AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver abnormalities including steatosis, steatohepatitis, fibrosis, and cirrhosis. Liver biopsy remains the gold standard method to determine the disease stage in NAFLD but is an invasive and risky procedure. Studies have previously reported that changes in intrahepatic fatty acids (FA) composition are related to the progression of NAFLD, mainly in its early stages. The aim of this study was to characterize the liver FA composition in mice fed a Choline-deficient L-amino-defined (CDAA) diet at different stages of NAFLD using magnetic resonance spectroscopy (MRS). METHODS: We used in-vivo MRS to perform a longitudinal characterization of hepatic FA changes in NAFLD mice for 10 weeks. We validated our findings with ex-vivo MRS, gas chromatography-mass spectrometry and histology. RESULTS: In-vivo and ex-vivo results showed that livers from CDAA-fed mice exhibit a significant increase in liver FA content as well as a change in FA composition compared with control mice. After 4 weeks of CDAA diet, a decrease in polyunsaturated and an increase in monounsaturated FA were observed. These changes were associated with the appearance of early stages of steatohepatitis, confirmed by histology (NAFLD Activity Score (NAS) = 4.5). After 10 weeks of CDAA-diet, the liver FA composition remained stable while the NAS increased further to 6 showing a combination of early and late stages of steatohepatitis. CONCLUSION: Our results suggest that monitoring lipid composition in addition to total water/fat with MRS may yield additional insights that can be translated for non-invasive stratification of high-risk NAFLD patients.

Lipoprotein receptor SR-B1 deficiency enhances adipose tissue inflammation and reduces susceptibility to hepatic steatosis during diet-induced obesity in mice.

Scavenger receptor class B type 1 (SR-B1) is a membrane lipoprotein receptor/lipid transporter involved in the pathogenesis of atherosclerosis, but its role in obesity and fatty liver development is unclear. Here, we determined the effects of SR-B1 deficiency on plasma metabolic and inflammatory parameters as well as fat deposition in adipose tissue and liver during obesity. To induce obesity, we performed high-fat diet (HFD) exposure for 12 weeks in male SR-B1 knock-out (SR-B1-/-, n = 14) and wild-type (WT, n = 12) mice. Compared to HFD-fed WT mice, plasma from HFD-fed SR-B1-/- animals exhibited increased total cholesterol, triglycerides (TG) and tumor necrosis factor-α (TNF-α) levels. In addition, hypertrophied adipocytes and macrophage-containing crown-like structures (CLS) were observed in adipose tissue from HFD-fed SR-B1 deficient mice. Remarkably, liver from obese SR-B1-/- mice showed attenuated TG content, dysregulation in hepatic peroxisome proliferator-activated receptors (PPARs) expression, increased hepatic TG secretion, and altered hepatic fatty acid (FA) composition. In conclusion, we show that SR-B1 deficiency alters the metabolic environment of obese mice through modulation of liver and adipose tissue lipid accumulation. Our findings provide the basis for further elucidation of SR-B1's role in obesity and fatty liver, two major public health issues that increase the risk of advanced chronic diseases and overall mortality.

Extracellular vesicles derived from fat-laden hepatocytes undergoing chemical hypoxia promote a pro-fibrotic phenotype in hepatic stellate cells.

BACKGROUND: The transition from steatosis to non-alcoholic steatohepatitis (NASH) is a key issue in non-alcoholic fatty liver disease (NAFLD). Observations in patients with obstructive sleep apnea syndrome (OSAS) suggest that hypoxia contributes to progression to NASH and liver fibrosis, and the release of extracellular vesicles (EVs) by injured hepatocytes has been implicated in NAFLD progression. AIM: To evaluate the effects of hypoxia on hepatic pro-fibrotic response and EV release in experimental NAFLD and to assess cellular crosstalk between hepatocytes and human hepatic stellate cells (LX-2). METHODS: HepG2 cells were treated with fatty acids and subjected to chemically induced hypoxia using the hypoxia-inducible factor 1 alpha (HIF-1α) stabilizer cobalt chloride (CoCl2). Lipid droplets, oxidative stress, apoptosis and pro-inflammatory and pro-fibrotic-associated genes were assessed. EVs were isolated by ultracentrifugation. LX-2 cells were treated with EVs from hepatocytes. The CDAA-fed mouse model was used to assess the effects of intermittent hypoxia (IH) in experimental NASH. RESULTS: Chemical hypoxia increased steatosis, oxidative stress, apoptosis and pro-inflammatory and pro-fibrotic gene expressions in fat-laden HepG2 cells. Chemical hypoxia also increased the release of EVs from HepG2 cells. Treatment of LX2 cells with EVs from fat-laden HepG2 cells undergoing chemical hypoxia increased expression pro-fibrotic markers. CDAA-fed animals exposed to IH exhibited increased portal inflammation and fibrosis that correlated with an increase in circulating EVs. CONCLUSION: Chemical hypoxia promotes hepatocellular damage and pro-inflammatory and pro-fibrotic signaling in steatotic hepatocytes both in vitro and in vivo. EVs from fat-laden hepatocytes undergoing chemical hypoxia evoke pro-fibrotic responses in LX-2 cells.

High prevalence of hepatic steatosis and vascular thrombosis in COVID-19: A systematic review and meta-analysis of autopsy data.

BACKGROUND: Coronavirus disease 2019 (COVID-19) disease can frequently affect the liver. Data on hepatic histopathological findings in COVID-19 is scarce. AIM: To characterize hepatic pathological findings in patients with COVID-19. METHODS: We conducted a systematic review with meta-analysis registered on PROSPERO (CRD42020192813), following PRISMA guidelines. Eligible trials were those including patients of any age and COVID-19 diagnosis based on a molecular test. Histopathological reports from deceased COVID-19 patients undergoing autopsy or liver biopsy were reviewed. Articles including less than ten patients were excluded. Proportions were pooled using random-effects models. Q statistic and I 2 were used to assess heterogeneity and levels of evidence, respectively. RESULTS: We identified 18 studies from 7 countries; all were case reports and case series from autopsies. All the patients were over 15 years old, and 67.2% were male. We performed a meta-analysis of 5 studies, including 116 patients. Pooled prevalence estimates of liver histopathological findings were hepatic steatosis 55.1% [95% confidence interval (CI): 46.2-63.8], congestion of hepatic sinuses 34.7% (95%CI: 7.9-68.4), vascular thrombosis 29.4% (95%CI: 0.4-87.2), fibrosis 20.5% (95%CI: 0.6-57.9), Kupffer cell hyperplasia 13.5% (95%CI: 0.6-54.3), portal inflammation 13.2% (95%CI: 0.1-48.8), and lobular inflammation 11.6% (95%CI: 0.3-35.7). We also identified the presence of venous outflow obstruction, phlebosclerosis of the portal vein, herniated portal vein, periportal abnormal vessels, hemophagocytosis, and necrosis. CONCLUSION: We found a high prevalence of hepatic steatosis and vascular thrombosis as major histological liver features. Other frequent findings included portal and lobular inflammation and Kupffer cell hyperplasia or proliferation. Further studies are needed to establish the mechanisms and implications of these findings.

N-Acetyl Cysteine Attenuates the Sarcopenia and Muscle Apoptosis Induced by Chronic Liver Disease.

BACKGROUND: Sarcopenia is characterized by the loss of muscle mass and strength (muscle atrophy) because of aging or chronic diseases, such as chronic liver disease (CLD). Different mechanisms are involved in skeletal muscle atrophy, including decreased muscle fibre diameter and myosin heavy chain levels and increased ubiquitin-proteasome pathway activity, oxidative stress and myonuclear apoptosis. We recently found that all these mechanisms, except myonuclear apoptosis, which was not evaluated in the previous study, were involved in muscle atrophy associated with hepatotoxin 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced CLD. OBJECTIVE: In the present study, we evaluated the involvement of myonuclear apoptosis in CLD-associated sarcopenia and the effect of N-acetyl cysteine (NAC) treatment on muscle strength and apoptosis, using a DDC-supplemented diet-fed mouse model. METHODS: Four-month-old male C57BL6 mice were fed with a standard or DDCsupplemented diet for six weeks in the absence or presence of NAC treatment. RESULTS: Our results showed that NAC attenuated the decrease in muscle fibre diameter and muscle strength associated with CLD-induced muscle wasting in gastrocnemius (GA) muscle of DDC-supplemented diet-fed mice. In addition, in GA muscle of the mice fed with DDC-supplemented diet-induced CLD showed increased myonuclear apoptosis compared with the GA muscle of the control diet-fed mice, as evidenced by increased apoptotic nuclei number, caspase-8 and caspase-9 expression, enzymatic activity of caspase-3 and BAX/BCL-2 ratio. NAC treatment inhibited all the mechanisms associated with myonuclear apoptosis in the GA muscle. CONCLUSION: To our knowledge, this is the first study which reports the redox regulation of muscle strength and myonuclear apoptosis in CLD-induced sarcopenia.

Using transcription factors for direct reprogramming of neurons in vitro.

Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries. However, a key challenge is the cellular source for transplantation which is often limited by donor availability. Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes in vitro, which have the potential to be used for autologous transplantation, as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy. Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic, GABAergic, dopaminergic, sensory and retinal neurons. We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes, and summarize their use in promoting direct reprogramming into different neuronal subtypes. Furthermore, we will discuss up-and-coming technologies that advance the cell reprogramming field, including the use of computational prediction of reprogramming factors, opportunity of cellular reprogramming using small chemicals and microRNA, as well as the exciting potential for applying direct reprogramming in vivo as a novel approach to promote neuro-regeneration within the body. Finally, we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.

Mitochondrial Dysfunction in Skeletal Muscle Pathologies.

Several molecular mechanisms are involved in the regulation of skeletal muscle function. Among them, mitochondrial activity can be identified. The mitochondria is an important and essential organelle in the skeletal muscle that is involved in metabolic regulation and ATP production, which are two key elements of muscle contractibility and plasticity. Thus, in this review, we present the critical and recent antecedents regarding the mechanisms through which mitochondrial dysfunction can be involved in the generation and development of skeletal muscle pathologies, its contribution to detrimental functioning in skeletal muscle and its crosstalk with other typical signaling pathways related to muscle diseases. In addition, an update on the development of new strategies with therapeutic potential to inhibit the deleterious impact of mitochondrial dysfunction in skeletal muscle is discussed.

Intrahepatic fatty acids composition as a biomarker of NAFLD progression from steatosis to NASH by using 1H-MRS.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world and it is becoming one of the most frequent cause of liver transplantation. Unfortunately, the only available method that can reliably determine the stage of this disease is liver biopsy, however, it is invasive and risky for patients. The purpose of this study is to investigate changes in the intracellular composition of the liver fatty acids during the progression of the NAFLD in a mouse model fed with Western diet, with the aim of identify non-invasive biomarkers of NAFLD progression based in 1H-MRS. Our results showed that the intracellular liver fatty acid composition changes as NAFLD progresses from simple steatosis to steatohepatitis (NASH). Using principal component analysis with a clustering method, it was possible to identify the three most relevant clinical groups: normal, steatosis and NASH by using 1H-MRS. These results showed a good agreement with the results obtained by GC-MS and histology. Our results suggest that it would be possible to detect the progression of simple steatosis to NASH using 1H-MRS, that has the potential to be used routinely in clinical application for screening high-risk patients.

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia.

Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.

Access to primary care and computed tomography use in the emergency department.

BACKGROUND: The decision to obtain a computed tomography CT scan in the emergency department (ED) is complex, including a consideration of the risk posed by the test itself weighed against the importance of obtaining the result. In patients with limited access to primary care follow up the consequences of not making a diagnosis may be greater than for patients with ready access to primary care, impacting diagnostic reasoning. We set out to determine if there is an association between CT utilization in the ED and patient access to primary care. METHODS: We performed a cross-sectional study of all ED visits in which a CT scan was obtained between 2003 and 2012 at an academic, tertiary-care center. Data were abstracted from the electronic medical record and administrative databases and included type of CT obtained, demographics, comorbidities, and access to a local primary care provider (PCP). CT utilization rates were determined per 1000 patients. RESULTS: A total of 595,895 ED visits, including 98,001 visits in which a CT was obtained (16.4%) were included. Patients with an assigned PCP accounted for 55% of all visits. Overall, CT use per 1000 ED visits increased from 142.0 in 2003 to 169.2 in 2012 (p < 0.001), while the number of annual ED visits remained stable. CT use per 1000 ED visits increased from 169.4 to 205.8 over the 10-year period for patients without a PCP and from 118.9 to 142.0 for patients with a PCP. Patients without a PCP were more likely to have a CT performed compared to those with a PCP (OR 1.57, 95%CI 1.54 to 1.58; p < 0.001). After adjusting for age, gender, year of visit and number of comorbidities, patients without a PCP were more likely to have a CT performed (OR 1.20, 95% CI 1.18 to 1.21, p < 0.001). CONCLUSIONS: The overall rate of CT utilization in the ED increased over the past 10 years. CT utilization was significantly higher among patients without a PCP. Increased availability of primary care, particularly for follow-up from the ED, could reduce CT utilization and therefore decrease costs, ED lengths of stay, and radiation exposure.

TGF-ß and Hepatocellular Carcinoma: When A Friend Becomes An Enemy.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide accounting for more than 700 thousand deaths per year. Most of the HCC develops in a cirrhotic liver, a microenvironment where fibrotic tissue replaces parenchymal cells. Thus, there is a close connection between fibrosis and HCC development. Understanding the cellular and molecular mechanisms involved in this process is a crucial step to advance in novel therapeutic or pharmacological strategies to prevent or improve the course of this malignancy. A key molecular player capable of modulating cell growth and fibrosis is the Transforming Growth Factor-beta (TGF-ß). Interestingly, TGF-ß seems to act like a switch, since it has dual and opposite roles during early and late phases of cancer development. Therefore to develop therapies that target TGF-ß signaling pathway for HCC treatment is important to understand the underlying pathogenetic mechanisms at play with special emphasis in the crosstalk between TGF-ß and other signaling pathways. In recent years, a plethora of TGR-ß have been developed and some of them are under clinical investigations for testing in patients with advanced HCC. In this review, we summarize recent knowledge about the role of TGF-ß signaling pathway in HCC progression.