(-)-Epicatechin metabolites as a GPER ligands: a theoretical perspective.

Diet habits and nutrition quality significantly impact health and disease. Here is delve into the intricate relationship between diet habits, nutrition quality, and their direct impact on health and homeostasis. Focusing on (-)-Epicatechin, a natural flavanol found in various foods like green tea and cocoa, known for its positive effects on cardiovascular health and diabetes prevention. The investigation encompasses the absorption, metabolism, and distribution of (-)-Epicatechin in the human body, revealing a diverse array of metabolites in the circulatory system. Notably, (-)-Epicatechin demonstrates an ability to activate nitric oxide synthase (eNOS) through the G protein-coupled estrogen receptor (GPER). While the precise role of GPER and its interaction with classical estrogen receptors (ERs) remains under scrutiny, the study employs computational methods, including density functional theory, molecular docking, and molecular dynamics simulations, to assess the physicochemical properties and binding affinities of key (-)-Epicatechin metabolites with GPER. DFT analysis revealed distinct physicochemical properties among metabolites, influencing their reactivity and stability. Rigid and flexible molecular docking demonstrated varying binding affinities, with some metabolites surpassing (-)-Epicatechin. Molecular dynamics simulations highlighted potential binding pose variations, while MMGBSA analysis provided insights into the energetics of GPER-metabolite interactions. The outcomes elucidate distinct interactions, providing insights into potential molecular mechanisms underlying the effects of (-)-Epicatechin across varied biological contexts.

Incidental detection of raised serum levels of vitamin B12 and its association with neoplasms.

BACKGROUND AND OBJECTIVES: Elevated serum levels of vitamin B12 have been associated with oncohematological diseases. However, the relevance of its incidental detection in subjects without a previous diagnosis of cancer is unknown. The aim of this study was to evaluate the relationship between incidental hypercobalaminemia (vitamin B12 > 1000 pg/mL) and the diagnosis of a tumor process in patients without a diagnosis and to establish the risk factors. MATERIAL AND METHODS: Retrospective observational study of a cohort of patients with hypercobalaminemia. The incidence of neoplasms was compared with a cohort of patients with vitamin B12 levels <1000 pg/mL. RESULTS: Vitamin B12 determinations of 4800 subjects were selected. Of them, 345 (7.1%) had levels >1000 pg/mL. 68 (28.4%) were excluded due to exogenous administration, 12 (5%) due to insufficient data and 15 (3%) due to having an active neoplasia, selecting 250 patients, with a median follow-up of 22 (IQR 12-39) months. Structural liver disease was detected in 59 (23.6%). 18.2% (44 patients) had solid organ cancer and 17 (7.1%) had malignant hemopathy. The average time from the detection of hypercobalaminemia to the diagnosis of cancer was about 10 months. The median until the diagnosis of neoplasia was higher in the high vitamin B12 group (13 vs. 51 months p < 0.001). Hypercobalaminemia (HR 11.8; 95% CI 2.8-49.6; p = 0.001) and smoking (HR 4.0; 95% CI, 2.15-7.59; p < 0.001) were independent predictors of neoplasia in the multivariate analysis. CONCLUSIONS: Incidental detection of serum vitamin B12 levels >1000 pg/mL is high in the population. The diagnosis of solid organ and hematological neoplasia is frequent during the following year of follow-up, with hypercobalaminemia and smoking being predictors of a higher risk of cancer.

Differential histological features and myogenic protein levels in distinct muscles of d-sarcoglycan null muscular dystrophy mouse model.

Skeletal muscle (SkM) comprises slow and fast-twitch fibers, which differ in molecular composition, function, and systemic energy consumption. In addition, muscular dystrophies (DM), a group of diverse hereditary diseases, present different patterns of muscle involvement, progression, and severity, suggesting that the regeneration-degeneration process may differ depending on the muscle type. Therefore, the study aimed to explore the expression of proteins involved in the repair process in different muscles at an early stage of muscular dystrophy in the δ-sarcoglycan null mice (Sgcd-null), a limb-girdle muscular dystrophy 2 F model. Hematoxylin & Eosin (H&E) Staining showed a high number of central nuclei in soleus (Sol), tibialis (Ta), gastrocnemius (Gas), and extensor digitorum longus (Edl) from four months Sgcd-null mice. However, fibrosis, determined by trichrome of Gomori modified staining, was only observed in Sgcd-null Sol. In addition, the number of Type I and II fibers variated differentially in the Sgcd-null muscles vs. wild-type muscles. Besides, the protein expression level of ß-catenin, myomaker, MyoD, and myogenin also presented different expression levels in all the Sgcd-null muscles studied. In summary, our study reveals that muscles with different metabolic characteristics showed distinct expression patterns of proteins involved in the muscle regeneration process. These results could be relevant in designing therapies for genetic and acquired myopathy.

Detection of Exudates and Microaneurysms in the Retina by Segmentation in Fundus Images / Detección de Exudados y Microaneurismas en la Retina por Segmentación en Imágenes de Fondo

ABSTRACT This article proposes two methodologies for the detection of lesions in the retina, which may indicate the presence of diabetic retinopathy (DR). Through the use of digital image processing techniques, it is possible to isolate the pixels that correspond to a lesion of RD, to achieve segmenting microaneurysms, the edges of the objects contained in the image are highlighted in order to detect the contours of the objects to select by size those that meet an area of 15 to 25 pixels in the case of 512x512 images and identify the objects as possible microaneurysms, while for the detection of exudates the green channel is selected to contrast the luminous objects in the retinography and from the conversion to gray scale, a histogram is graphed to identify the ideal threshold for the segmentation of the pixels that belong to the exudates at the end of the optical disk previously identified by a specialist. A confusion matrix supervised by an ophthalmologist was created to quantify the results obtained by the two methodologies, obtaining a specificity of 0.94 and a sensitivity of 0.97, values that are outstanding to proceed with the classification stage.

RESUMEN Este artículo propone dos metodologías para la detección de lesiones en la retina, que pueden significar la presencia de retinopatía diabética (RD). Mediante el uso de técnicas de procesamiento de imágenes digitales se logra aislar los pixeles que corresponden a una lesión propia de RD, para lograr segmentar microaneurismas se resaltan los bordes de los objetos contenido en la imagen con la finalidad de detectar los contornos de los objetos para seleccionar por tamaño los que cumplan con un área de 15 a 25 pixeles en el caso de imágenes de 512x512 y se identifiquen los objetos como posibles microaneurismas, mientras que para la detección de exudados se selecciona el canal verde para contrastar los objetos luminosos en la retinografía y a partir de la conversión a escala de grises se grafica un histograma para identificar el umbral idóneo para la segmentación de los pixeles que pertenecen a los exudados al final eliminar el disco óptico previamente identificado por un especialista. Se creó una matriz de confusión supervisada por un oftalmólogo para cuantificar los resultados obtenidos por las dos metodologías obteniendo una especificidad del 0.94 y una sensibilidad del 0.97, unos valores que son sobresalientes para proceder con la etapa de clasificación.

Small-cell lung cancer in never-smokers.

BACKGROUND: Lung cancer is a public health problem worldwide. Small-cell lung cancer (SCLC) is the most aggressive histologic type, with a 5-year survival <10%. SCLC is closely associated with tobacco consumption and infrequent in never-smokers. We aim to describe SCLC characteristics in never-smokers recruited in a radon-prone area. PATIENTS AND METHODS: We designed a multicentric case series where SCLC cases were recruited consecutively following histologic confirmation. Detailed information was obtained for indoor radon exposure, occupation and environmental tobacco smoke. We also collected different clinical characteristics such as extended or limited disease at diagnosis. RESULTS: We recruited 32 never-smoking SCLC cases. Median age was 75 years and 87.5% were women; 47% had extended disease. Median radon concentration was 182 Bq/m3. There were no statistically significant differences in residential radon concentration neither regarding age at diagnosis nor regarding sex. The most frequent symptoms were constitutional syndrome (23.1%) and coughing (23.1%). As much as 63% of cases had an Eastern Cooperative Oncology Group Study (ECOG) status of 0-2. The 1- and 2-year survival rates were 34.4% and 21.9%, respectively. The 2-year survival rate with a localized tumor was 26.7%, compared with 18.8% for extended disease. CONCLUSIONS: These results show, for the first time, that indoor radon might not be associated with SCLC characteristics at diagnosis in never-smokers, and also confirms the low survival of this aggressive type of lung cancer also for never-smokers.

Chromatin Landscape During Skeletal Muscle Differentiation.

Cellular commitment and differentiation involve highly coordinated mechanisms by which tissue-specific genes are activated while others are repressed. These mechanisms rely on the activity of specific transcription factors, chromatin remodeling enzymes, and higher-order chromatin organization in order to modulate transcriptional regulation on multiple cellular contexts. Tissue-specific transcription factors are key mediators of cell fate specification with the ability to reprogram cell types into different lineages. A classic example of a master transcription factor is the muscle specific factor MyoD, which belongs to the family of myogenic regulatory factors (MRFs). MRFs regulate cell fate determination and terminal differentiation of the myogenic precursors in a multistep process that eventually culminate with formation of muscle fibers. This developmental progression involves the activation and proliferation of muscle stem cells, commitment, and cell cycle exit and fusion of mononucleated myoblast to generate myotubes and myofibers. Although the epigenetics of muscle regeneration has been extensively addressed and discussed over the recent years, the influence of higher-order chromatin organization in skeletal muscle regeneration is still a field of development. In this review, we will focus on the epigenetic mechanisms modulating muscle gene expression and on the incipient work that addresses three-dimensional genome architecture and its influence in cell fate determination and differentiation to achieve skeletal myogenesis. We will visit known alterations of genome organization mediated by chromosomal fusions giving rise to novel regulatory landscapes, enhancing oncogenic activation in muscle, such as alveolar rhabdomyosarcomas (ARMS).

Marco Técnico de Referencia para la Interoperabilidad de Expedientes Clínicos Electrónicos: Modelo del Dominio / Technical Reference Framework for the Interoperability of Electronic Medical Record: Domain Model

Resumen El objetivo de esta investigación es la modelación del dominio de un marco técnico de compartición e interacción de un expediente clínico electrónico (ECE) entre diversas instituciones de salud, públicas o privadas, como primer paso para lograr un marco técnico de refererencia para la interoperabilidad de sistemas de ECE en México. Se ha utilizado el proceso sistemático KMOS-RE para obterner los diversos artefactos que conforman el modelo: el léxico extendido del conocimiento del domino, los modelos conceptuales del dominio de aplicación y del dominio de la solución y los modelos de estados. Debido a que el diseño e implementación de los sistemas de ECE de cada una de las instituciones de salud se generan de manera independiente, realizar un marco técnico de referencia representa un gran desafío y una gran oportunidad, ya que ofrecerá ventajas importantes, como el hecho de contar con la información clínica de manera oportuna en cualquier institución de salud, la posibilidad de que el propio paciente acceda a su información y la facilidad de realizar investigación clínica a partir de los datos compartidos. Aún cuando la modelación de un dominio es dinámica, el contar con un modelo del dominio lo más preciso posible en este punto, facilitará los siguientes pasos para lograr el marco técnico de referencia propuesto.

Abstract This paper presents the domain modeling of a technical framework of sharing and interaction of an electronic medical record among different healthcare institutions, both public or private, as a first step to establish a technical reference framework for the interoperability of electronic medical record systems in Mexico. The artefact that make up the domain model were carried out using the KMOS-RE systematic process. Through this process, the following components have been obtained: the knowledge domain extended lexicon, the conceptual models, one for the application domain and another for the solution domain, as well as the state models. Since the design and implementation of the electronic medical record systems of different healthcare institutions are generated independently, having a technical reference framework represents a great challenge but also a great opportunity, since it will offer important advantages, such as having the clinical information in a timely manner in any healthcare institution, the possibility of the patient accessing their own information and the ease of conducting clinical research from the shared data. Even when a domain modeling is a dynamic task, having a precise domain model at this point will facilitate the next steps to achieve the proposed technical reference framework.

Multidisciplinary consensus statement on the clinical management of patients with stage III non-small cell lung cancer.

Stage III non-small cell lung cancer (NSCLC) is a very heterogeneous disease that encompasses patients with resected, potentially resectable and unresectable tumours. To improve the prognostic capacity of the TNM classification, it has been agreed to divide stage III into sub-stages IIIA, IIIB and IIIC that have very different 5-year survival rates (36, 26 and 13%, respectively). Currently, it is considered that both staging and optimal treatment of stage III NSCLC requires the joint work of a multidisciplinary team of expert physicians within the tumour committee. To improve the care of patients with stage III NSCLC, different scientific societies involved in the diagnosis and treatment of this disease have agreed to issue a series of recommendations that can contribute to homogenise the management of this disease, and ultimately to improve patient care.

New TNM staging in lung cancer (8th edition) and future perspectives.

BACKGROUND: Carrying out a correct anatomical classification of lung cancer is crucial to take clinical and therapeutic decisions in each patient. AIM: TNM staging classification provides an accurate anatomical description about the extension of the disease; however, the anatomical burden of the disease is just one aspect that changes the prognosis. RELEVANCE FOR PATIENTS: TNM staging classification is a tool that predicts survival, but we must consider that TNM is just one of the factors that concern the prognosis. The impact of a factor over the prognosis is complex due to: It depends on the specific environment, the treatment strategy, among others, and our level of certainty makes difficult to include all the factors just in a group of stages. In some groups, there are difficulties to get large series due to the low frequency of cases and the small number of events (metastasis, locoregional recurrence). It does not allow to obtain evidence in a short period of time. On the other hand, in the next years, new markers will be incorporated in the coming years, which are going to be included in the new TNM classification. It could help to improve the classification giving more information about prognosis and risk of recurrence. All these aspects are being used by the International Association for the Study of Lung Cancer (IASLC) to develop a new prognosis model. This continues the evolution of TNM system, allows us to overcome the difficulties, and build a flexible framework enough to continue improving the individual prognosis of the patients.

Monophasic synovial sarcoma of the greater omentum: case report and review of literature.

Synovial sarcoma is a malignant spindle cell neoplasm normally arising from tissues around joints, bursa and tendon sheaths. Several reports involving the gastrointestinal tract, mainly the oesophagus and stomach, have been documented; however, the omentum remains an extremely unusual location. Monophasic type is composed exclusively of spindle cells arranged in fascicles. Establishing the correct diagnosis of these tumours could be challenging because of the similarities with gastrointestinal stromal tumours and other mesenchymal tumours with similar histology.

Reliability of radiologic evaluation of abdominal aortic calcification using the 24-point scale.

OBJECTIVE: Calcification of the abdominal aorta is associated with increased cardiovascular morbidity, so a reliable method to quantify it is clinically transcendent. The 24-point scale (AAC-24) is the standard method for assessing abdominal aortic calcification on lateral plain films of the lumbar spine. The aim of this study was to determine the intraobserver and interobserver agreements for the AAC-24, taking into account the heterogeneity of the distribution of the calcifications in the design of the statistical analysis. MATERIAL AND METHODS: We analyzed the intraobserver agreement (in plain films from 81 patients, with a four-year separation between observations) and the interobserver agreement (in plain films from 100 patients, with three observers), using both intraclass correlation and Bland-Altman plots. RESULTS: The intraobserver intraclass correlation coefficient was 0.93 (95% confidence interval [CI95%]: 0.6-0.9), and the interobserver intraclass correlation coefficient was 0.91 (CI95%: 0.8-0.9) with an increase in the coefficient in the tercile with the greatest discrepancy. The difference in means ranged from 0.3 to 1.2 points, and the distance between the limits of agreement ranged from 4.7 to 9.4 points. These differences increased significantly as the calcification progressed. CONCLUSIONS: Using the AAC-24 on lateral plain films of the lumbar spine is a reliable and reproducible method of assessing calcification of the abdominal aorta; both intraobserver and interobserver agreement are higher during the initial phases of calcification.

Contrasting roles for MyoD in organizing myogenic promoter structures during embryonic skeletal muscle development.

BACKGROUND: Among the complexities of skeletal muscle differentiation is a temporal distinction in the onset of expression of different lineage-specific genes. The lineage-determining factor MyoD is bound to myogenic genes at the onset of differentiation whether gene activation is immediate or delayed. How temporal regulation of differentiation-specific genes is established remains unclear. RESULTS: Using embryonic tissue, we addressed the molecular differences in the organization of the myogenin and muscle creatine kinase (MCK) gene promoters by examining regulatory factor binding as a function of both time and spatial organization during somitogenesis. At the myogenin promoter, binding of the homeodomain factor Pbx1 coincided with H3 hyperacetylation and was followed by binding of co-activators that modulate chromatin structure. MyoD and myogenin binding occurred subsequently, demonstrating that Pbx1 facilitates chromatin remodeling and modification before myogenic regulatory factor binding. At the same time, the MCK promoter was bound by HDAC2 and MyoD, and activating histone marks were largely absent. The association of HDAC2 and MyoD was confirmed by co-immunoprecipitation, proximity ligation assay (PLA), and sequential ChIP. CONCLUSIONS: MyoD differentially promotes activated and repressed chromatin structures at myogenic genes early after the onset of skeletal muscle differentiation in the developing mouse embryo.

[Lung cancer in Avila province, Spain. Incidence rates, epidemiolgy of the year 2012 and trends in the last 20 years]. / Cáncer de pulmón en la provincia de Ávila. Tasas de incidencia, epidemiología del año 2012 y tendencias en los últimos 20 años.

BACKGROUND AND OBJECTIVES: To determine the extent of lung cancer in Alvila. Its incidence rates and significant epidemiological aspects of the year 2012 were recorded, and the results of each 5-year period (up to 20 years) were compared with those of known studies conducted using the same methodology. PATIENTS AND METHODS: A prospective study was conducted on all patients diagnosed with lung cancer in the Province of Avila throughout the year 2012. RESULTS: A total of 81 patients were diagnosed, of whom 70 were males and 11 females, with a mean age of 72.1 years (range: 44-91), and was higher than that found in previous studies. This gave gross, and adjusted to the standard world population, incidence rates in 2012 of 80.99 and 31.23 per 100,000, respectively, in males, and 12.97 and 5.68 per 100,000, respectively in females. These rates are lower in both sexes than those found in Alvila in 2002. In 2012, 80.25% had been smokers (90% of males and 18.18% of the women), although, on diagnosis, 68.75% had quit smoking. A clinical-radiological diagnosis was made in 9 (11.1%), with a histocytological diagnosis in 72 (88.9%). The histological types were: adenocarcinomas in 37.5%; squamous in 33.3%; microcytic in 13.8%; undifferentiated non-small cell in 11.1%; large cell in 2.77%, and carcinoid in 1.38%. The most frequent treatments were chemotherapy (50.6%), symptomatic (23.4%), and surgery (12.3%). CONCLUSIONS: The incidence of lung cancer in Avila has decreased in both sexes in the last 10 years. In 2012, the patients have been older, the majority with adenocarcinoma histology, and receiving chemotherapy.

[Analysis of subdural intracraneal empyemas in a third level hospital]. / Análisis de los empiemas subdurales intracraneales en un hospital de tercer nivel.

INTRODUCTION: Intracranial subdural empyema (ISE) is an infrequent infectious disorder of diverse etiology and difficult to diagnose because of its non-specific clinical features. PATIENTS AND METHODS: Retrospective study of patients diagnosed of ISE in a third-level university hospital in a 15-year period. RESULTS: Five men were included (mean age: 39.3 years). The most frequent primary source of infection was otic and sinusal (60%). The initial clinical manifestations were fever, headache, alteration of consciousness, and neurological focal symptoms. The mean time elapsed between onset of symptoms and diagnosis was 3.6 days. Diagnosis was performed by computed tomography in all patients. ISE was localized in the left hemisphere in 60% of cases mainly affecting the parietal lobe (80%). Anaerobic and streptococci germs were the most frequently isolated microorganisms. Therapy was based on antibiotics and surgical drainage in 100% of the cases. The surgical procedure used in the evacuation of empyema was craniotomy in all the patients. The mean time elapsed between diagnosis and surgery was 8.4 days. The mean Intensive Care Unit stay was 12.8 days, whereas the overall mean in-hospital stay was 45.2 days. Mortality was 40%. CONCLUSION: ISE, although infrequent, displays a high morbimortality that can be reduced with an early therapeutic approach which may include the surgical evacuation in all the cases.

Lung cancer incidence in the province of Avila, Spain in 2002 and decade-long trends.

OBJECTIVES: To determine lung cancer incidence in the province of Avila, Spain, in the year 2002 and compare it with incidences reported in 2 previous studies (for 1992-1993 and 1997). PATIENTS AND METHODS: Patients diagnosed in 2002 were evaluated prospectively by the method used in the previous studies. The reference population was obtained from the municipal records for 2001. RESULTS: In 2002, 87 patients (74 men and 13 women) were diagnosed with lung cancer. The crude incidence rate was 53.09 cases per 100 000 population (men: 89.92/100 000; women: 15.93/100 000). Of these, 87.3% had been smokers. Squamous cell carcinomas were the most frequent type overall (38.1%) and in men (42.4%). Adenocarcinomas were the most frequent type in women (60%). The most frequent treatment was chemotherapy (35.6%). Between the 1992-1993 study and our 2002 study, significant increases were found in crude incidence rates of lung cancer and the use of chemotherapy, as well as significant decreases both in squamous cell carcinomas and the use of radiotherapy alone. CONCLUSIONS: Between 1992 and 2002 the lung cancer incidence in men and women in the province of Avila increased significantly.

[Etiologic spectrum of solitary constitutional syndrome]. / Espectro etiológico del síndrome general solitario.

OBJECTIVE: To know the spectrum of diseases responsible for the solitary constitutional syndrome in our setting. This syndrome was defined as a clinical picture characterized by the presence of asthenia, anorexia, and weight loss of at least 5% of body weight in the last six months, not associated with any other symptom or sign suggesting the diagnosis of an organ or system disease. PATIENTS AND METHODS: All patients diagnosed of the solitary constitutional syndrome (328) in a tertiary-care level teaching hospital between January 1991 and December 1996. RESULTS: Fifty-two (170) percent of patients with solitary constitutional syndrome were males and 48% (158) females. The mean age was 65.4%, ranging from 15 to 97 years. The average of the monthly estimated weight loss was 3 to 4 kilograms. A total of 115 (35%) malignant neoplasms and 5 (1.5%) benign tumors were diagnosed. The most common malignant tumors corresponded to the digestive tract (51.3% of the total malignant tumors). The second cause in frequency of the solitary constitutional syndrome corresponded to psychiatric diseases, with a total of 80 patients (24.3%). A total of 116 non-neoplastic organic diseases were detected, with digestive tract diseases --mainly peptic disease-- being the most common cause in this group. After follow-up, only in twenty cases were we unable to detect the underlying disease responsible for the syndrome. In nine of these, the solitary constitutional syndrome was self-limited. Forty-four percent of patients had at least another concomitant disease and in 24% of patients more than one associated condition was found. CONCLUSION: The most common diseases responsible for the solitary constitutional syndrome were, by decreasing frequency, malignant tumors, psychiatric disorders, and non-malignant organic diseases located in the digestive tract. A better knowledge of the etiological spectrum of this syndrome might be useful for a more efficient management of these patients.