Fibroblast growth factor 21 is expressed and secreted from skeletal muscle following electrical stimulation via extracellular ATP activation of the PI3K/Akt/mTOR signaling pathway.

Fibroblast growth factor 21 (FGF21) is a hormone involved in the regulation of lipid, glucose, and energy metabolism. Although it is released mainly from the liver, in recent years it has been shown that it is a "myokine", synthesized in skeletal muscles after exercise and stress conditions through an Akt-dependent pathway and secreted for mediating autocrine and endocrine roles. To date, the molecular mechanism for the pathophysiological regulation of FGF21 production in skeletal muscle is not totally understood. We have previously demonstrated that muscle membrane depolarization controls gene expression through extracellular ATP (eATP) signaling, by a mechanism defined as "Excitation-Transcription coupling". eATP signaling regulates the expression and secretion of interleukin 6, a well-defined myokine, and activates the Akt/mTOR signaling pathway. This work aimed to study the effect of electrical stimulation in the regulation of both production and secretion of skeletal muscle FGF21, through eATP signaling and PI3K/Akt pathway. Our results show that electrical stimulation increases both mRNA and protein (intracellular and secreted) levels of FGF21, dependent on an extracellular ATP signaling mechanism in skeletal muscle. Using pharmacological inhibitors, we demonstrated that FGF21 production and secretion from muscle requires the activation of the P2YR/PI3K/Akt/mTOR signaling pathway. These results confirm skeletal muscle as a source of FGF21 in physiological conditions and unveil a new molecular mechanism for regulating FGF21 production in this tissue. Our results will allow to identify new molecular targets to understand the regulation of FGF21 both in physiological and pathological conditions, such as exercise, aging, insulin resistance, and Duchenne muscular dystrophy, all characterized by an alteration in both FGF21 levels and ATP signaling components. These data reinforce that eATP signaling is a relevant mechanism for myokine expression in skeletal muscle.

Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway.

Muscle and bone are tightly integrated through mechanical and biochemical signals. Osteoclasts are cells mostly related to pathological bone loss; however, they also start physiological bone remodeling. Therefore, osteoclast signals released during bone remodeling could improve both bone and skeletal muscle mass. Extracellular ATP is an autocrine/paracrine signaling molecule released by bone and muscle cells. Then, in the present work, it was hypothesized that ATP is a paracrine mediator released by osteoclasts and leads to skeletal muscle protein synthesis. RAW264.7-derived osteoclasts were co-cultured in Transwell® chambers with flexor digitorum brevis (FDB) muscle isolated from adult BalbC mice. The osteoclasts at the upper chamber were mechanically stimulated by controlled culture medium perturbation, resulting in a two-fold increase in protein synthesis in FDB muscle at the lower chamber. Osteoclasts released ATP to the extracellular medium in response to mechanical stimulation, proportional to the magnitude of the stimulus and partly dependent on the P2X7 receptor. On the other hand, exogenous ATP promoted Akt phosphorylation (S473) in isolated FDB muscle in a time- and concentration-dependent manner. ATP also induced phosphorylation of proteins downstream Akt: mTOR (S2448), p70S6K (T389) and 4E-BP1 (T37/46). Exogenous ATP increased the protein synthesis rate in FDB muscle 2.2-fold; this effect was blocked by Suramin (general P2X/P2Y antagonist), LY294002 (phosphatidylinositol 3 kinase inhibitor) and Rapamycin (mTOR inhibitor). These blockers, as well as apyrase (ATP metabolizing enzyme), also abolished the induction of FDB protein synthesis evoked by mechanical stimulation of osteoclasts in the co-culture model. Therefore, the present findings suggest that mechanically stimulated osteoclasts release ATP, leading to protein synthesis in isolated FDB muscle, by activating the P2-PI3K-Akt-mTOR pathway. These results open a new area for research and clinical interest in bone-to-muscle crosstalk in adaptive processes related to muscle use/disuse or in musculoskeletal pathologies.

Evaluation of air pollution tolerance index and anticipated performance index of six plant species, in an urban tropical valley: Medellin, Colombia.

High atmospheric pollution levels in urban areas have become a global problem that threatens both human health and urban ecosystems. Trees that grow near areas with vehicular and industrial emissions can be highly affected, since they constitute the main barrier for emitted pollutants, with trees being either tolerant or sensitive to them. Different methodologies worldwide have been implemented to evaluate the tolerance and sensitivity of tree species to atmospheric pollutants. In this research, the air pollution tolerance index (APTI) and the anticipated performance index (API) are evaluated in order to determine both the degree of tolerance or sensitivity of trees to pollutants in the air and their performance in urban areas. To this end, six tree species found in four biomonitoring zones in the city of Medellín, Colombia, were selected: Mangifera indica, Tabebuia chrysantha-rosea, Erythrina fusca, Jacaranda mimosifolia, Fraxinus uhdei, and Spathodea campanulata. A total of 54 individual trees were evaluated by means of the APTI and API, and it was determined that the species with the highest tolerance (APTI≥16) and the best performance (81

Resistencia antimicrobiana en pacientes con Infección del Tracto Urinario / Antimicrobial resistance in patients with Urinary Tract Infection / Resistência antimicrobiana em pacientes coma infecção do trato urinário

RESUMEN El alarmante incremento de la resistencia bacteriana a los antibióticos, en pacientes con infección del tracto urinario, es uno de los mayores problemas actuales de la salud pública mundial; siendo la Escherichia coli, principal patógeno en esta infección, resistente a la mayoría de los antibióticos. Con el objetivo de determinar el patrón microbiológico de resistencia antimicrobiana de los gérmenes más frecuentemente aislados en urocultivos positivos, en el laboratorio de microbiología del Hospital Provincial Docente Celia Sánchez Manduley, Manzanillo, durante el año 2018, se realizó un estudio observacional, descriptivo de corte transversal a todos los urocultivos realizados a los pacientes con la orden de estudio bacteriológico, en la institución y período de tiempo declarados. Se evaluaron las variables: positividad del cultivo, gérmenes aislados, resistencia antimicrobiana de los microorganismos aislados en general y de la Escherichia coli en particular. Los datos fueron analizados utilizando la estadística descriptiva. Se analizaron 2482 urocultivos, 714 fueron positivos; como germen predominó Escherichia coli en 58.12% de los casos. El total de gérmenes aislados mostró resistencia a: cefotaxima (46.08 %), ciprofloxacino (44.67 %), ácido nalidíxico (44.11 %), cotrimoxazol (42.99 %) y ceftazidima (42.85 %).Para el caso de la Escherichia coli se mantuvo el mismo patrón de resistencia con valores discretamente superiores. La menor resistencia de estos microorganismos fue para la nitrofurantoina, alrededor de un1.44 %. Se determinó el patrón microbiológico de resistencia antimicrobiana de los gérmenes más frecuentes aislados en los urocultivos positivos de este estudio.

ABSTRACT The alarming increase in bacterial resistance to antibiotics in patients with urinary tract infection is one of the biggest current problems in world public health; being Escherichia coli, the main pathogen in this infection, resistant to most antibiotics. With the aim of determining the microbiological pattern of antimicrobial resistance of the germs most frequently isolated in positive urine cultures, in the microbiology laboratory of the Celia Sánchez Manduley Provincial Teaching Hospital, Manzanillo, during 2018, an observational, descriptive cut-off study was carried out. cross-sectional to all urine cultures performed on patients with the order of bacteriological study, in the institution and period of time declared. The variables were evaluated: positivity of the culture, isolated germs, antimicrobial resistance of isolated microorganisms in general and Escherichia coli in particular. The data were analyzed using descriptive statistics. 2482 urine cultures were analyzed, 714 were positive; As a germ, Escherichia coli predominated in 58.12% of the cases. The total of isolated germs showed resistance to: cefotaxime (46.08%), ciprofloxacin (44.67%), nalidixic acid (44.11%), cotrimoxazole (42.99%) and ceftazidime (42.85%). In the case of Escherichia coli, the same resistance pattern was maintained with slightly higher values. The lowest resistance of these microorganisms was for nitrofurantoin, around 1.44%. The microbiological pattern of antimicrobial resistance of the most frequent germs isolated in the positive urine cultures of this study was determined.

RESUMO O alarmante aumento da resistência bacteriana aos antibióticos em pacientes com infecção do trato urinário é um dos maiores problemas atuais de saúde pública mundial; sendo Escherichia coli, o principal patógeno dessa infecção, resistente à maioria dos antibióticos. Como objetivo de determinar o padrão microbiológico de resistência antimicrobiana dos germes mais freqüentemente isolados em uroculturas positivas, no laboratório de microbiologia do Hospital Universitário Provincial Celia Sánchez Manduley, Manzanillo, durante 2018, foi realizado um estudo observacional descritivo de corte. out. transversal a todas as culturas de urina realizadas em pacientes com a ordem de estudo bacteriológico, na instituição e período de tempo declarado. Foram avaliadas as variáveis: positividade da cultura, germes isolados, resistência antimicrobiana dos microrganismos isolados em geral e Escherichia coli em particular. Os dados foram analisados ​​por meio de estatística descritiva. 2.482 culturas de urina foram analisadas, 714 foram positivas; Como germe, a Escherichia coli predominou em 58,12% dos casos. O total de germes isolados apresentou resistência a: cefotaxima (46,08%), ciprofloxacina (44,67%), ácido nalidíxico (44,11%), cotrimoxazol (42,99%) e ceftazidima (42,85%). No caso da Escherichia coli, o mesmo padrão de resistência foi mantido com valores ligeiramente superiores. A menor resistência desses microrganismos foi para a nitrofurantoína, em torno de 1,44%. Foi determinado o padrão microbiológico de resistência antimicrobiana dos germes mais frequentes isolados unas uroculturas positivas deste estudo.

Ectopic Cushing syndrome in Colombia.

OBJECTIVE: The aim was to describe the clinical features of patients with ectopic Cushing syndrome (ECS) from Colombia and compare these findings with other series to provide the best management for these patients. METHODS: Records of patients with ECS from 1986 to 2017 were retrospectively reviewed; patients with a diagnosis of adrenal or pituitary Cushing syndrome (CS) were excluded. RESULTS: Fourteen patients with ECS were analyzed in this study. The mean age was 54.4 (SD 17.1) years, and the female to male ratio was 1.33:1. Regarding the etiology of ECS, four patients had lung carcinoids (28.6%), three had small-cell lung carcinoma (21.4%), three had pancreatic neuroendocrine tumors (21.4%), one had medullary thyroid cancer (7.1%), one had non-metastatic pheochromocytoma (7.1%), one had metastatic thymoma (7.1%) and one patient had an occult source of ACTH (7.1%). The most common clinical features at presentation were moon-face, muscle weakness, diabetes mellitus and hypertension. Hyperpigmentation was present in 36% of patients, and 12 patients had hypokalemia with a mean value of 2.3 mEq/L (SD 0.71). The median basal cortisol, 24-hour urinary free cortisol (UFC) and ACTH were 30.5 ug/dL (IQR 21-59 ug/dL), 2,600 ug/24 h (IQR 253-6,487 ug/24 h) and 91 pg/mL (IQR 31.9-141.9), respectively. Thirteen patients (92.8%) had the site of the primary lesion identified. Six patients had undergone a surgical intervention to address the primary tumor. Resection was curative in 28.5% of patients. Death occurred in 57.1% of patients, and the median overall survival was 27 months. Intrathoracic tumors had the most aggressive behavior. CONCLUSION: ECS is a rare disease; however, it is associated with high morbidity and mortality. A rapid intervention supported by an interdisciplinary group is required to improve overall survival and quality of life.

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.

ABSTRACT: This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.

Pelvic fractures and changes in bone mineral density after radiotherapy for cervical, endometrial, and vaginal cancer: A prospective study of 239 women.

BACKGROUND: Advances in radiotherapy (RT) have led to improved oncologic outcomes for women with gynecologic cancers; however, the long-term effects and survivorship implications need further evaluation. The purpose of this study was to determine the incidence of pelvic fractures and changes in bone mineral density (BMD) after pelvic RT. METHODS: Two hundred thirty-nine women who had pelvic RT for cervical, endometrial, or vaginal cancer between 2008 and 2015 were prospectively studied. BMD scans and biomarkers of bone turnover were obtained at the baseline and 3 months, 1 year, and 2 years after RT. Imaging studies were assessed for pelvic fractures for up to 5 years. Patients with osteopenia, osteoporosis, or pelvic fractures at any point were referred to the endocrinology service for evaluation and treatment. RESULTS: The median age at diagnosis was 51 years; 132 patients (56%) were menopausal. The primary diagnoses were cervical (63.6%), endometrial (30.5%), and vaginal cancer (5.9%). Sixteen patients (7.8%; 95% confidence interval, 4.5%-12.4%) had pelvic fractures with actuarial rates of 3.6%, 12.7%, and 15.7% at 1, 2, and 3 years, respectively. Fractures were associated with baseline osteoporosis (P < .001), higher baseline bone-specific alkaline phosphatase (P < .001), and older age (P = .007). The proportion of patients with osteopenia/osteoporosis increased from 50% at the baseline to 58%, 59%, and 70% at 3 months, 1 year, and 2 years, respectively. CONCLUSIONS: A high proportion of women had significant decreases in BMD after pelvic RT, with 7.8% diagnosed with a pelvic fracture. BMD screening and pharmacologic intervention should be strongly considered for these high-risk women.

Variabilidad de la frecuencia cardiaca como factor predictor de las enfermedades cardiovasculares / Heart rate variability as a predictive factor of cardiovascular diseases

Resumen La variabilidad de la frecuencia cardiaca se conoce como la variación en el tiempo que transcurre entre los intervalos RR del electrocardiograma y refleja la actividad del sistema nervioso autónomo sobre la función cardiaca. Su aumento se considera un factor protector para el corazón y su medición podría ser una herramienta predictiva temprana o diagnóstica en enfermedades cardiovasculares. El sistema nervioso autónomo genera efectos inotrópicos y cronotrópicos en la función cardiaca, que pueden aumentar o disminuir esta variabilidad. Existen diversos métodos de medición de la variabilidad de la frecuencia cardiaca; el más común es el Holter seguido por el sistema POLAR, además se han desarrollado programas de software clínico (Kubios®, Sinus Core®) que han demostrado validez en estas mediciones. La variabilidad de la frecuencia cardiaca puede emplearse como factor predictor en la aparición de eventos coronarios, accidentes cerebrovasculares y muerte súbita, entre otros.

Abstract Heart rate variability is defined as the variation in time between the RR intervals of the electrocardiogram, and reflects the activity of the autonomous nervous system over cardiac function. Its increase is considered as a protective factor for the heart, and its measurement could be used as a tool for the early prediction or diagnosis of cardiovascular diseases. The autonomous nervous system generates inotropic and chronotropic effects on cardiac function, which can increase or decrease this variability. There are several methods for measuring heart rate variability. The most common is the Holter device, followed by the Polar system. Clinical computer programs have also been developed (Kubios®, Sinus Core®) that have shown to be valid in the measurements. Heart rate variability may be used as a predictive factor for the appearance of coronary events, including among others, cerebrovascular accidents and sudden death.

Impact of Surgical Resection of the Primary Tumor on Overall Survival in Patients With Metastatic Pheochromocytoma or Sympathetic Paraganglioma.

OBJECTIVE: To determine whether primary tumor resection in patients with metastatic pheochromocytoma or paraganglioma (PPG) is associated with longer overall survival (OS). BACKGROUND: Patients with metastatic PPG have poor survival outcomes. The impact of surgical resection of the primary tumor on OS is not known. METHODS: We retrospectively studied patients with metastatic PPG treated at the University of Texas, MD Anderson Cancer Center from January 2000 through January 2015. Kaplan-Meier analysis with log-rank tests was used to compare OS among patients undergoing primary tumor resection and patients not treated surgically. Propensity score method was applied to adjust for selection bias using demographic, clinical, biochemical, genetic, imaging, and pathologic information. RESULTS: A total of 113 patients with metastatic PPG were identified. Eighty-nine (79%) patients had surgery and 24 (21%) patients did not. Median OS was longer in patients who had surgery than in patients who did not [148 months, 95% confidence interval (CI) 112.8-183.2 months vs 36 months, 95% CI 27.2-44.8 months; P < 0.001].Fifty-three (46%) patients had synchronous metastases; of these patients, those who had surgery had longer OS than those who did not (85 months, 95% CI 64.5-105.4 months vs 36 months, 95% CI 29.7-42.3 months; P < 0.001). Patients who had surgery had a similar ECOG performance status to the ones who did not (P = 0.1798, two sample t test; P = 0.2449, Wilcoxon rank sum test). Univariate and propensity score analysis confirmed that patients treated with surgery had longer OS than those not treated surgically irrespective of age, race, primary tumor size and location, number of metastatic sites, and genetic background (log-rank P < 0.001).In patients with hormonally active tumors (70.8%), the symptoms of catecholamine excess improved after surgery. However, the tumor burden was a more important determinant of OS than hormonal secretion. CONCLUSIONS: Primary tumor resection in patients with metastatic PPG appeared to be associated with improved OS. In patients with hormonally active tumors, surgical resection led to better blood pressure control.

Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies.

Research on medullary thyroid carcinoma (MTC) over the last 55 years has led to a good understanding of the genetic defects and altered molecular pathways associated with its development. Currently, with the use of genetic testing, patients at high risk for MTC can be identified before the disease develops and offered prophylactic treatment. In cases of localized neck disease, surgery can be curative. However, once MTC has spread beyond the neck, systemic therapy may be necessary. Conventional chemotherapy has been shown to be ineffective; however, multikinase inhibitors have shown promise in stabilizing disease, and this year will probably see the approval of a drug (Vandetanib) for advanced unresectable or metastatic disease, which represents a new chapter in the history of MTC. In this paper, we explore newly understood molecular pathways and the most promising emerging therapies that may change the management of MTC.

Carcinoma corticosuprarrenal: estado actual de nuestro conocimiento / Adrenocortical carcinoma: state of the art

Una mujer de 22 años de edad consultó por presentar una masa en el seno izquierdo asociada con un tumor suprarrenal funcional de rápida evolución que, en 9 meses, la llevó a consultar por manifestaciones compatibles con un síndrome de Cushing y virilización, y con estudios bioquímicos que confirmaron hipercortisolismo e hiperandrogenismo. La tomografía abdominal mostró una masa suprarrenal de gran tamaño sugestiva de carcinoma corticosuprarrenal con compromiso metastásico de varios órganos. En este artículo revisamos y discutimos el diagnóstico y las opciones terapéuticas de esta entidad agresiva y poco frecuente, a la luz de los conocimientos actuales.

Neoplasia endocrina múltiple tipo 2: un ejemplo para la prevención del cáncer / Multiple endocrine neoplasia type 2: a model for cancer prevention

La Neoplasia endocrina múltiple tipo 2 es un síndrome caracterizado por carcinoma medular de tiroides y feocromocitomas. La identificación de mutaciones del proto-oncogén RET como responsables de este síndrome ha brindado un método preciso para la identificación de los individuos susceptibles de desarrollar esta enfermedad. Además, la identificación de estas mutaciones ha permitido caracterizar la expresión clínica y la gravedad del carcinoma medular de tiroides, su tratamiento preventivo y su seguimiento. Esta revisión presenta una discusión concisa sobre el uso de la evaluación genética en el manejo del carcinoma medular de tiroides hereditario con énfasis en la intervención primaria para prevenir la mortalidad y la morbilidad asociadas con esta enfermedad.

Hypercalcemia humoral maligna / Humoral hypercalcemia of malignancy

La hipercalcemia es el trastorno metabólico más común con las enfermedades neoplásicas y representa una complicación potencialmente mortal. Ocurre en el 10 por ciento al 20 por ciento al 20 por ciento de todos los adultos con cáncer y esta relacionada con mayor frecuencia a los tumores sólidos, entre otros el de mama y pulmón, al igual que a múltiples neoplasias hematológicas. La hipercalcemia maligna humoral resulta de la producción de múltiples factores que actúan sobre la matriz ósea ocasionando la liberación del calcio. El compromiso humoral es característico de ciertas neoplasias en las que no se encuentra enfermedad ósea metastásica. Uno de los medidores más importantes es la protéina relacionada con la hormona paratiroidea (PTHrP), que actúa sobre el transporte de calcio y en la bología deñ desarrollo. La PTHrP conparte una secuencia parcial de amino ácidos homólogos a la PTH normal y se une a los mismos rceptores localizados en los tejidos diana esqueléticos y renales, afectando la homeostasis del calcio y del fosfato. Algunos factores circulantes también puedenmediar la hipercalcemia; entre otros se encuentran el factor transformador de crecimiento, la interlucina 1 y 6, y el factor de necrosis tumoral