NEDD4-1 deficiency impairs satellite cell function during skeletal muscle regeneration.

BACKGROUND: Satellite cells are tissue-specific stem cells primarily responsible for the regenerative capacity of skeletal muscle. Satellite cell function and maintenance are regulated by extrinsic and intrinsic mechanisms, including the ubiquitin-proteasome system, which is key for maintaining protein homeostasis. In this context, it has been shown that ubiquitin-ligase NEDD4-1 targets the transcription factor PAX7 for proteasome-dependent degradation, promoting muscle differentiation in vitro. Nonetheless, whether NEDD4-1 is required for satellite cell function in regenerating muscle remains to be determined. RESULTS: Using conditional gene ablation, we show that NEDD4-1 loss, specifically in the satellite cell population, impairs muscle regeneration resulting in a significant reduction of whole-muscle size. At the cellular level, NEDD4-1-null muscle progenitors exhibit a significant decrease in the ability to proliferate and differentiate, contributing to the formation of myofibers with reduced diameter. CONCLUSIONS: These results indicate that NEDD4-1 expression is critical for proper muscle regeneration in vivo and suggest that it may control satellite cell function at multiple levels.

NEDD4-1 deficiency impairs satellite cell function during skeletal muscle regeneration

BACKGROUND: Satellite cells are tissue-specific stem cells primarily responsible for the regenerative capacity of skeletal muscle. Satellite cell function and maintenance are regulated by extrinsic and intrinsic mechanisms, including the ubiquitin-proteasome system, which is key for maintaining protein homeostasis. In this context, it has been shown that ubiquitin-ligase NEDD4-1 targets the transcription factor PAX7 for proteasome-dependent degradation, promoting muscle differentiation in vitro. Nonetheless, whether NEDD4-1 is required for satellite cell function in regenerating muscle remains to be determined. RESULTS: Using conditional gene ablation, we show that NEDD4-1 loss, specifically in the satellite cell population, impairs muscle regeneration resulting in a significant reduction of whole-muscle size. At the cellular level, NEDD4-1-null muscle progenitors exhibit a significant decrease in the ability to proliferate and differentiate, contributing to the formation of myofibers with reduced diameter. CONCLUSIONS: These results indicate that NEDD4-1 expression is critical for proper muscle regeneration in vivo and suggest that it may control satellite cell function at multiple levels.

Zoonosis virales emergentes de impacto global / Emerging viral zoonoses of global impact

Objetivo: Analizar las principales zoonosis virales emergentes y su impacto a nivel global en la presentación de epidemias y pandemias que afectan la salud humana. Método: Se desarrolló una revisión sistemática de 15 artículos de la base de datos PubMed. Análisis de los resultados: Considerando que, en la inmensa mayoría de los casos, la intervención o control en la fuente animal podría evitar problemas ulteriores de salud pública, se hace necesario considerar y desarrollar intervenciones integradas, que tengan en cuenta las causas que interactúan y son responsables de los problemas intersectoriales de salud. Conclusión: El impacto humano en la ecología y el clima, junto con un transporte más rápido entre países y regiones, han acelerado la aparición o reaparición de patógenos zoonóticos.

Objective: To analyze the main emerging viral zoonoses and their global impact on the occurrence of epidemics and pandemics affecting human health. Methods: A systematic review of 15 articles from the PubMed database was carried out. Analysis of results: Considering that, in the vast majority of cases, intervention or control at the animal source could prevent further public health problems, it is necessary to consider and develop integrated interventions that take into account the interacting causes responsible for intersectoral health problems. Conclusion: Human impact on ecology and climate, together with more rapid transport between countries and regions, have accelerated the emergence or re-emergence of zoonotic pathogens.

USP7-dependent control of myogenin stability is required for terminal differentiation in skeletal muscle progenitors.

Satellite cells (SCs) are myogenic progenitors responsible for skeletal muscle regeneration and maintenance. Upon activation, SCs enter a phase of robust proliferation followed by terminal differentiation. Underlying this myogenic progression, the sequential expression of muscle regulatory transcription factors (MRFs) and the downregulation of transcription factor paired box gene 7 (Pax7) are key steps regulating SC fate. In addition to transcriptional regulation, post-translational control of Pax7 and the MRFs provides another layer of spatiotemporal control to the myogenic process. In this context, previous work showed that Pax7 is ubiquitinated by the E3 ligase neural precursor cell-expressed developmentally downregulated protein 4 and interacts with several proteins related to the ubiquitin-proteasome system, including the deubiquitinase ubiquitin-specific protease 7 (USP7). Although USP7 functions in diverse cellular contexts, its role(s) during myogenesis remains poorly explored. Here, we show that USP7 is transiently expressed in adult muscle progenitors, correlating with the onset of myogenin expression, while it is downregulated in newly formed myotubes/myofibers. Acute inhibition of USP7 activity upon muscle injury results in persistent expression of early regeneration markers and a significant reduction in the diameter of regenerating myofibers. At the molecular level, USP7 downregulation or pharmacological inhibition impairs muscle differentiation by affecting myogenin stability. Co-immunoprecipitation and in vitro activity assays indicate that myogenin is a novel USP7 target for deubiquitination. These results suggest that USP7 regulates SC myogenic progression by enhancing myogenin stability.

Osteonecrosis de los maxilares asociada a medicamentos (ONMM): guía redactada por expertos invitados por la Asociación Argentina de Osteología y Metabolismo Mineral y por la Sociedad Argentina de Osteoporosis / Medication-related osteonecrosis of the jaw (MRONJ): guideline prepared by experts invited by the Argentine Association of Osteology and Mineral Metabolism, and the Argentine Society for Osteoporosis

La osteonecrosis maxilar asociada a medicamentos (ONMM=MRONJ como se conoce en la literatura en inglés) se define como un área ósea expuesta al medio bucal con más de ocho semanas de permanencia, en pacientes tratados con antirresortivos y/o antiangiogénicos y sin antecedentes de radioterapia en cabeza y cuello. Las fracturas ocasionan una morbimortalidad significativa y los antirresortivos son drogas eficaces y seguras para prevenirlas. Se utilizan principalmente en osteoporosis, pero también en enfermedades oncológicas como mieloma múltiple o metástasis óseas de tumores sólidos. La posología varía según el contexto clínico, siendo mayor la dosis y frecuencia de administración en oncología. Los antirresortivos actualmente más utilizados son los bifosfonatos (BF) y el denosumab (Dmab). Si bien los BF persisten largo tiempo en el tejido óseo, el Dmab tiene un mecanismo de acción reversible y su suspensión abrupta conlleva importante pérdida de masa ósea y riesgo aumentado de fracturas vertebrales múltiples. Ninguna droga puede ser suspendida ni espaciada sin autorización médica, dado que no es de competencia del odontólogo. El diagnóstico presuntivo de ONMM debe ser confirmado clínicamente por un odontólogo, quien solicitará imágenes radiológicas para establecer el estadio de la lesión. La anamnesis correcta permite establecer un diagnóstico diferencial entre ONMM, osteomielitis y osteorradionecrosis. La presentación clínica es variable y puede mostrar distintos estadios. La mayoría de los casos están precedidos por un procedimiento quirúrgico odontológico. Suele ser asintomática, aunque puede haber dolor si se localiza cerca de una estructura neuronal. La localización es variable: 62,3% se produce en el maxilar inferior. La incidencia de ONMM es baja, en un rango de 0,001 a 0,01% y tiene relación con las dosis y el tiempo de administración. La remoción de caries, la operatoria dental, la endodoncia y la rehabilitación protética fija o removible no se asocian a riesgo de ONMM. Con menos de 3 años de tratamiento antirresortivo se pueden efectuar terapéuticas quirúrgicas como exodoncias, apicectomías, cistectomías, tratamientos periodontales de raspaje y alisado subgingival sin riesgo. Con más de 3 años se aconseja evitar la realización de exodoncias y manipulación de tejido óseo. Ante la necesidad de realizar un procedimiento odontológico, no hay evidencia que avale que la suspensión transitoria del tratamiento antirresortivo pueda reducir el riesgo. Tampoco la medición de marcadores de remodelado óseo aporta datos de utilidad. Existen pocos datos en la literatura sobre la colocación de implantes dentales en pacientes que reciben drogas antirresortivas en dosis bajas; si bien existe ONMM asociada, su incidencia sería baja. Antes de iniciar un tratamiento antirresortivo se recomienda realizar interconsulta con el odontólogo para evaluar potenciales necesidades quirúrgicas. Quienes reciben antirresortivos deben realizar controles orales periódicos (semestrales) y, ante cualquier síntoma compatible con un estadio incipiente de ONMM, deben consultar a su odontólogo. El trabajo conjunto del médico y el odontólogo puede prevenir la aparición de la ONMM, un evento infrecuente, pero que puede generar elevada morbilidad en los pacientes. La comunicación fluida entre profesionales tenderá a evitar no solo la incertidumbre y desconfianza de los pacientes, sino también que se produzcan lesiones con la consecuente necesidad de tratamientos de mayor complejidad. (AU)

Medication-Related Osteonecrosis of the Jaw (MRONJ) is defined as a bone area exposed to the oral environment lasting more than eight weeks, in patients treated with antiresorptive and/or antiangiogenic drugs and without a history radiation therapy to the head and neck. Fractures cause significant morbidity and mortality, and antiresorptives are effective and safe drugs to prevent them. They are used to treat not only osteoporosis but also oncological diseases such as multiple myeloma or bone metastases from solid tumors. The dosage varies according to the clinical context; doses and frequencies of administration are higher in oncology. The most commonly used antiresorptive medications are bisphosphonates (BP) and denosumab (Dmab). Whereas BP persist for a long time in bone tissue, Dmab has a reversible mechanism of action and its discontinuation leads to significant loss of bone mass and an increased risk of multiple vertebral fractures. No drug can be suspended or spaced without medical authorization. Dentists should not take decisions about antiresorptive prescription. The presumptive diagnosis of MRONJ must be clinically confirmed by a dentist, who will order radiological studies to establish the stage of the injury. The correct anamnesis helps differentiate MRONJ from osteomyelitis and osteoradionecrosis. Clinical presentation is variable and can present different stages. Most of the cases are preceded by a dental surgical procedure. Usually MRONJ is asymptomatic although patients may feel pain if it is located near a neuronal structure. The location is variable: 62.3% occurs in the lower jaw. The incidence of MRONJ is low, in the range of 0.001 to 0.01%, and is related to the dose and time of administration. Caries removal, dental surgery, endodontics, fixed or removable prosthetic rehabilitation are not associated with risk of MRONJ. With less than 3 years of antiresorptive treatment, surgical therapies such as extractions, apicectomies, cystectomies, periodontal scaling treatments and subgingival smoothing can be performed without risk. With more than 3 years, it is advisable to avoid performing extractions and manipulating bone tissue. Given the need to perform a dental procedure, there is no evidence to support that the temporary suspension of antiresorptive treatment can reduce the risk. Nor does the measurement of bone turnover markers provide useful information. There are few data in the literature on the placement of dental implants in patients receiving antiresorptive drugs at low doses; although there might be an associated risk of MRONJ, its incidence appears to be low. Before starting antiresorptive treatment, consultation with the dentist is recommended to evaluate potential surgical needs. Patients receiving treatment with antiresorptive agents should undergo periodic oral controls (every six months) and in the event of any symptoms compatible with an early MRONJ stage, they should consult their dentists. The collaboration between physician and dentist can prevent the appearance of MRONJ, that is an infrequent event, but can generate high morbidity in patients. Fluid communication between professionals will tend to avoid, not only the uncertainty and distrust of patients, but also the occurrence of injuries needing complex treatments. (AU)

Atención de los pacientes con trauma grave durante los primeros días: evolución entre la urgencia, el pabellón y la unidad de cuidados intensivos / Features of patients with trauma admitted to an emergency room of a general hospital

Background: Trauma is the main cause of death among people aged 5 to 44 years. Aim: To describe features, treatment and evolution of trauma patients admitted to an emergency room. Material and Methods: Adult patients admitted in the emergency department of a public hospital due to severe trauma were studied and followed during their hospital stay. Results: We included 114 patients aged 40 ± 17 years (78%men) with an injury severity score of 21 ± 11. Trauma was penetrating in 43%. Traumatic brain injury (TBI) was the most common diagnosis in 46%. In the emergency room, 8% had hypotension, 5% required vasopressors and 23% required mechanical ventilation. The initial lactate was 3.6 ± 2.9 mmol/L. Sixty-five patients (57%) required emergency surgery. The intraoperative lactate was 3 ± 1.7 mmol/L and 20% required vasopressors. Sixty-four patients (56%) were admitted to the ICU, with APACHEII and SOFA scores of 16 ± 8 and 5 ± 3, respectively. ICU lactate was 3.2±1.5 mmol/L. In the ICU 40% required vasopressors and 63% mechanical ventilation. Thirty two percent had coagulopathy, 43% received transfusions and 10% required massive transfusions. The hospital stay was 13 (6-32) days, being significantly longer in patients with TBI. ICU and hospital mortalities were 12.5 and 18.4% respectively. The only predictor for mortality was the APACHEII score (Hazard Ratio 1.18, 95% confidence intervals 1.03-1.36). Conclusions: APACHE score was a predictor of mortality in this group of patients.

Minimally Invasive Surgery for Gallbladder Cancer.

There is consensus that oncologic extended resection should be performed for resectable incidental and nonincidental gallbladder cancer. The safety and feasibility of a minimally invasive approach to oncologic extended resection of gallbladder cancer has been demonstrated and is performed in centers of expertise worldwide. In this article, a systematic approach to the indications and techniques for a minimally invasive approach to extended resection for gallbladder cancer is detailed.

Positive cystic duct margin at index cholecystectomy in incidental gallbladder cancer is an important negative prognosticator.

BACKGROUND: Prognostic factors following index-cholecystectomy in patients with incidental gallbladder cancer (IGBC) are poorly understood. The aim of this study was to assess the value of the initial cystic duct margin status as a prognosticator factor and to aid in clinical decision making to move forward with curative intent oncologic extended resection (OER). METHODS: This retrospective study included patients with IGBC who underwent subsequent OER with curative intent at 2 centers (USA and Chile) between 1999 and 2016., Patients with and without evidence of residual cancer (RC) at OER were included. Pathologic features were examined, and predictors of overall survival (OS) were analyzed. RESULTS: The study included 179 patients. Thirty-three patients (17%) had a positive cystic duct margin at the index cholecystectomy. Forty-two patients (23%) underwent resection of the common bile duct. OS was significantly worse in the patients with a positive cystic duct margin at index cholecystectomy (OS rates at 5 years, 34% vs 57%; p = 0.032). Following multivariate analysis, only a positive cystic duct margin at index cholecystectomy was predictive of worse OS in patients with no evidence of residual cancer (RC) at OER (hazard ratio, 1.7 95%CI 1.04-2.78; p = 0.034). CONCLUSIONS: A positive cystic duct margin at index-cholecystectomy is a strong independent predictor of worse OS even if no further cancer is found at OER. In patients with positive cystic duct margin and no RC at OER common bile duct resection leads to improved outcomes.

Incidental versus non-incidental gallbladder cancer: index cholecystectomy before oncologic re-resection negatively impacts survival in T2b tumors.

BACKGROUND: Conflicting data exists whether non-oncologic index cholecystectomy (IC) leading to discovery of incidental gallbladder cancer (IGBC) negatively impacts survival. This study aimed to determine whether a subgroup of patients derives a disadvantage from IC. METHODS: Patients with IGBC and non-IGBC treated at an academic USA and Chilean center during 1999-2016 were compared. Patients with T1, T4 tumor or preoperative jaundice were excluded. T2 disease was classified into T2a (peritoneal-side tumor) and T2b (hepatic-side tumor). Disease-specific survival (DSS) and its predictors were analyzed. RESULTS: Of the 196 patients included, 151 (77%) had IGBC. One hundred thirty-six (90%) patients of whom 118 (87%) had IGBC had T2 disease. Three-year DSS rates were similar between IGBC and non-IGBC for all patients. However, for T2b patients, 3-year survival rate was worse for IGBC (31% vs 85%; p = 0.019). In multivariate analysis of T2 patients, predictors of poor DSS were hepatic-side tumor hazard ratio [HR], 2.9; 95% CI, 1.6-5.4; p = 0.001) and N1 status (HR, 2.4; 95% CI, 1.6-3.6; p < 0.001). CONCLUSIONS: Patients with T2b gallbladder cancer specifically benefit from a single operation. These patients should be identified preoperatively and referred to hepatobiliary center.

[Features of patients with trauma admitted to an emergency room of a general hospital]. / Atención de los pacientes con trauma grave durante los primeros días: evolución entre la urgencia, el pabellón y la unidad de cuidados intensivos.

BACKGROUND: Trauma is the main cause of death among people aged 5 to 44 years. AIM: To describe features, treatment and evolution of trauma patients admitted to an emergency room. MATERIAL AND METHODS: Adult patients admitted in the emergency department of a public hospital due to severe trauma were studied and followed during their hospital stay. RESULTS: We included 114 patients aged 40 ± 17 years (78%men) with an injury severity score of 21 ± 11. Trauma was penetrating in 43%. Traumatic brain injury (TBI) was the most common diagnosis in 46%. In the emergency room, 8% had hypotension, 5% required vasopressors and 23% required mechanical ventilation. The initial lactate was 3.6 ± 2.9 mmol/L. Sixty-five patients (57%) required emergency surgery. The intraoperative lactate was 3 ± 1.7 mmol/L and 20% required vasopressors. Sixty-four patients (56%) were admitted to the ICU, with APACHEII and SOFA scores of 16 ± 8 and 5 ± 3, respectively. ICU lactate was 3.2±1.5 mmol/L. In the ICU 40% required vasopressors and 63% mechanical ventilation. Thirty two percent had coagulopathy, 43% received transfusions and 10% required massive transfusions. The hospital stay was 13 (6-32) days, being significantly longer in patients with TBI. ICU and hospital mortalities were 12.5 and 18.4% respectively. The only predictor for mortality was the APACHEII score (Hazard Ratio 1.18, 95% confidence intervals 1.03-1.36). CONCLUSIONS: APACHE score was a predictor of mortality in this group of patients.

Eficacia analgésica y complicaciones a corto plazo de catéteres peridurales lumbares y torácicos en pacientes pediátricos: una evaluación retrospectiva / Analgesic efficacy and short-term complications of lumbar peridural catheters and thoracic in pediatric patients: a retrospective evaluation

Introducción: la analgesia peridural postoperatoria en niños es efectiva con catéteres insertados al nivel del sitio quirúrgico. Objetivo:comparar la eficacia y las complicaciones de catéteres insertados a nivel lumbar y torácico para analgesia postoperatoria. Método:revisamos la base de datos del Servicio de dolor agudo. Extrajimos información de pacientes de 0-18 años, con analgesia peridural postoperatoria. Los pacientes fueron divididos en grupo lumbar y torácico y, en cada grupo, por edades. Recopilamos información de: variables demográficas, tipo de cirugía, nivel de inserción del catéter peridural, solución de anestésico local administrada, analgésicos sistémicos, coadyuvantes peridurales, dolor postoperatorio y complicaciones. Dividimos las complicaciones según gravedad. Resultados: se analizaron 221 pacientes, 123 con catéter lumbar y 98 con catéter torácico. Catéteres peridurales lumbares y torácicos fueron principalmente insertados en niños de 1-3 años y mayores de 4 años respectivamente. Se utilizó bupivacaína 0,1-0,125 por ciento. Las cirugías fueron urológicas, intraabdominales, ortopédicas, torácicas y cardiovasculares. Los niños con catéteres torácicos tuvieron más dolor (mediana (rango): 3 (0-6) vs. 2 (0-4)) y necesitaron sus catéteres por más días (promedio (DE): 2,96 (1,06) vs. 2,53 (1,09) que aquellos con catéter lumbar. Los requerimientos analgésicos fueron similares en ambos grupos. Hubo 60 complicaciones (27,1 por ciento), principalmente menores (92 por ciento), sin diferencias entre los grupos lumbar y torácica (30 por ciento vs 23 por ciento) ni entre las diferentes edades. Conclusión: los catéteres peridurales insertados en relación al sitio quirúrgico, a nivel lumbar o torácico, proporcionarían analgesia postoperatoria clínicamente aceptable y comparable, con similar incidencia de complicaciones.(AU)

Introduction: postoperative epidural analgesia in children is effective with catheters inserted at the level of the surgical site. Objective: compare the efficacy and complications of epidural catheters inserted at the lumbar and thoracic level for postoperative analgesia in this population. Methods: we review the Acute Pain Service Database. We extracted information of patient from 0 to 18 years with postoperative epidural analgesia. Patients were divided into lumbar and thoracic groups and, in each group, by age. Collected data included: demographic, type of surgery, details of epidural catheters insertion, the local anesthetic administered, systemic analgesics and epidural adjuvant used, postoperative pain and complications. We divide complications according severity. Results: 221 patients were analyzed, 123 with lumbar and 98 with thoracic epidurals catheters. Lumbar and thoracic epidural catheters were mainly placed in patients 1-3 years and older than four years respectively. Bupivacaine 0.1-0.125 percent was the analgesic solution used. Performed surgeries were urological, intraabdominal, orthopedic, thoracic and cardiovascular. Children with thoracic catheters had more pain (median (IQR): 3 (0-6) vs. 2 (0-4)) and needed their catheters more days (mean (SD): 2.96 (1.06) vs. 2.53 (1.09)) than children with lumbar catheters.Analgesic requirements were similar between both groups. There were 60 complications (27.1 percent), mainly minors (92 percent), with no differences between lumbar and thoracic groups (30 percent vs. 23 percent respectively), and among age categories. Conclusion: the epidural catheters inserted about the surgical site, at the lumbar or the thoracic level would provide clinically acceptable and comparable postoperative analgesia with a similar rate of complications.(AU)

Evaluación de score de hueso trabecular (TBS) en pacientes menopáusicas con fracturas y sin ellas / Trabecular bone score evaluation in postmenopausal women with or without fractures

El score de hueso trabecular (TBS, Trabecular Bone Score) es una medición de la textura de los grises derivada de la evaluación del raquis por DXA y proporciona un índice de la microarquitectura ósea. Se ha demostrado que los valores bajos presentan capacidad para predecir fracturas. Nuestro objetivo fue evaluar si existían diferencias entre los valores de TBS de pacientes con fracturas frente a no fracturadas. Materiales y métodos: se revisaron 159 historias clínicas de mujeres menopáusicas que consultaron para evaluación de su salud ósea. Se consideraron los antecedentes autorreferidos de fracturas (Fx), la DMO de raquis, cuello femoral y fémur total y TBS. Resultados: treinta pacientes (18,9%) presentaron fracturas y en ellas se observó menor TBS (con Fx: 1,295±83 vs. sin Fx: 1,366±84, p<0,0001), menor índice de masa corporal (IMC) (con Fx: 23,7±1,9 vs. sin Fx: 25,7±4,2, p=0,02), sin diferencias en la edad (p=0,39), ni en valores de DMO (L1-L4 p=0,11, cuello femoral p=0,20 y fémur total p= 0,12). Muchas de las fracturas ocurrieron en pacientes sin osteoporosis por DXA. Conclusiones: el TBS aumentaría la capacidad de DXA para identificar a mujeres argentinas en riesgo de padecer fracturas sin tener osteoporosis densitométrica. Este es el primer trabajo realizado en la Argentina con medición de TBS. (AU)

Trabecular Bone Score (TBS) is a measure of the grey scale derived from DXA lumbar image and provides information about microarchitecture. It has been shown that low TBS values can predict fractures. Our objective was to evaluate if there are any differences between the TBS values in patients with fractures vs. non-fractures. Materials and methods: We reviewed 159 medical records of menopausal women who consulted for evaluation of their bone health. Self-reported fractures (Fx), spine BMD, femoral neck and total femur and TBS were evaluated. Results: thirty patients (18.9%) presented fractures and they showed lower TBS (with Fx: 1,295±0,083 vs. without Fx: 1,366±0,084, p<0.0001), lower body mass index (BMI) (with Fx: 23.7±1.9 vs. without Fx 25.7±4.2, p=0.02), without differences in ages (p=0.39) or in BMD values (L1-L4 p=0.11, femoral neck p=0.20 and total femur p=0.12). Some fractures occurred in patients without osteoporosis, as determined by DXA. Conclusions: TBS would increase the ability of DXA to identify Argentine women at risk for fractures without densitometric osteoporosis. This is the first work done in Argentina with TBS measurement. (AU)

Incidental Gallbladder Cancer: Residual Cancer Discovered at Oncologic Extended Resection Determines Outcome: A Report from High- and Low-Incidence Countries.

BACKGROUND: Gallbladder cancer detected incidentally after cholecystectomy (IGBC) currently is the most common diagnosis of gallbladder cancer, and oncologic extended resection (OER) is recommended for tumors classified higher than T1b. However, the precise prognostic significance of residual cancer (RC) found at the time of OER has not been well established. This analysis aimed to determine the prognostic impact of RC found in patients with IGBC undergoing OER. METHODS: Outcomes for IGBC at a center for a low-incidence country (USA) and a high-incidence country (Chile) between January 1999 and June 2015 were analyzed. Residual cancer was defined as histologically proven cancer at OER. Predictors of disease-specific survival (DSS) were analyzed. RESULTS: Of 187 patients, 171 (91.4%) achieved complete resection (R0) at OER. The rates of surgical mortality and severe morbidity were respectively 1.1 and 9.6%. Of the 187 patients, 73 (39%) had RC. Perineural invasion and/or lymphovascular invasion and T3 stage were associated with the presence of RC. In both countries, RC was associated with a significantly shorter median survival (23% vs not reached; p < 0.001) and lower 5-year DSS rate (19% vs. 74%; p < 0.001) despite R0 resection. In the multivariable analysis, RC was an independent poor predictor of DSS (hazard ratio [HR], 4.00; 95% confidence interval [CI], 2.13-7.47; p < 0.001), as were lymphovascular and/or perineural invasion (HR, 1.95; 95% CI, 1.19-3.21; p = 0.008). CONCLUSIONS: The presence of RC in patients undergoing OER for IGBC is associated with poor DSS in both high- and low-incidence countries, even when R0 resection is achieved. Residual cancer defines a high-risk cohort for whom adjuvant therapy may be beneficial.

Evaluación de la respuesta densitométrica en pacientes con osteoporosis posmenopáusica tratadas con ranelato de estroncio o denosumab / Densitometric response in postmenopausal osteoporosis treated with strontium ranelate or denosumab

Tanto el ranelato de estroncio (RSr) como el denosumab (Dmab) son eficaces en el tratamiento de la osteoporosis (OP) posmenopáusica (PM). El efecto de cada fármaco por separado sobre la densidad mineral ósea (DMO) ha sido estudiado recientemente. Con ambas drogas se observó, al año de tratamiento, un aumento significativo de la DMO en columna lumbar (CL), cuello femoral (CF) y cadera total (CT). En este trabajo comparamos la respuesta densitométrica al año de tratamiento con una y otra droga. Utilizamos los registros de 425 pacientes PMOP tratadas con Dmab y 441 tratadas con RSr. En cada paciente analizamos el porcentaje de cambio; se clasificaron como respondedoras aquellas que mostraron un cambio ≥3%. Adicionalmente se comparó la respuesta en pacientes no previamente tratadas con bifosfonatos (BF-naïve) en comparación con pacientes que habían recibido previamente un BF. Al analizar el grupo completo para Dmab, el porcentaje de pacientes respondedoras fue de 68,4% en CL, 63,3% en CF y 49,3% en CT. Por otro lado, en el grupo de pacientes tratadas con RSr, el porcentaje de respondedoras (53,8% en CL, 40,0% en CF y 35,6% en CT) fue estadísticamente menor. Cuando comparamos la respuesta entre las pacientes BF-naïve que recibieron RSr o Dmab, el Dmab indujo mayor respuesta en CL y CF que el grupo RSr, sin diferencias en CT. Cuando se analizaron los subgrupos BF-previo, las tratadas con Dmab mostraron mayor respuesta en todas las regiones. Conclusión: en pacientes con OP-PM, el tratamiento con Dmab produjo mayores incrementos densitométricos que el RSr, siendo el porcentaje de pacientes respondedoras mayor con Dmab que con RSr. (AU)

Both strontium ranelate (SrR) and denosumab (Dmab) are effective in the treatment of postmenopausal osteoporosis (PMOP). The effect of each drug on bone mineral density (BMD) has been studied separately by us. With both treatments, there was a significant increase after one year of treatment at the lumbar spine (LS) and hip. In this paper we compared the densitometric response after one year of treatment with both drugs used separately. We used the clinical records of 425 PM patients treated with Dmab and 441 treated with SrR. For each patient we analyzed the percentage of change; those who showed a change ≥3% were classified as responders. Additionally, the response was compared in patients not previously treated with bisphosphonates (BP-naïve) compared to patients who had previously received a BP. When analyzing the complete group for Dmab, the percentage of "responders" was 65.2% at the LS, 62.9% at the femoral neck (FN) and 47.4% at the total hip (TH). On the other hand, in the group of patients treated with SrR the percentage of responders (53.8% at the LS, 40.0% at the FN and 35.6% at the TH) was statistically lower. When comparing the response between in BF-naïve patients receiving RSr or Dmab, Dmab induced a greater response at the LS and FN than the RSr group, with no statistical differences at the TH. When the subgroups with prior BP treatment were analyzed, those treated with Dmab showed greater response in all regions. Conclusion: in patients with PMOP treatment with Dmab produced greater densitometric increments than SrR, and the percentage of responders was higher with Dmab than with SrR. (AU)

Ck2-Dependent Phosphorylation Is Required to Maintain Pax7 Protein Levels in Proliferating Muscle Progenitors.

Skeletal muscle regeneration and long term maintenance is directly link to the balance between self-renewal and differentiation of resident adult stem cells known as satellite cells. In turn, satellite cell fate is influenced by a functional interaction between the transcription factor Pax7 and members of the MyoD family of muscle regulatory factors. Thus, changes in the Pax7-to-MyoD protein ratio may act as a molecular rheostat fine-tuning acquisition of lineage identity while preventing precocious terminal differentiation. Pax7 is expressed in quiescent and proliferating satellite cells, while its levels decrease sharply in differentiating progenitors Pax7 is maintained in cells (re)acquiring quiescence. While the mechanisms regulating Pax7 levels based on differentiation status are not well understood, we have recently described that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4, thus promoting proteasome-dependent Pax7 degradation in differentiating satellite cells. Here we show that Pax7 levels are maintained in proliferating muscle progenitors by a mechanism involving casein kinase 2-dependent Pax7 phosphorylation at S201. Point mutations preventing S201 phosphorylation or casein kinase 2 inhibition result in decreased Pax7 protein in proliferating muscle progenitors. Accordingly, this correlates directly with increased Pax7 ubiquitination. Finally, Pax7 down regulation induced by casein kinase 2 inhibition results in precocious myogenic induction, indicating early commitment to terminal differentiation. These observations highlight the critical role of post translational regulation of Pax7 as a molecular switch controlling muscle progenitor fate.

NEDD4 Regulates PAX7 Levels Promoting Activation of the Differentiation Program in Skeletal Muscle Precursors.

The transcription factor Pax7 regulates skeletal muscle stem cell (satellite cells) specification and maintenance through various mechanisms, including repressing the activity of the muscle regulatory factor MyoD. Hence, Pax7-to-MyoD protein ratios can determine maintenance of the committed-undifferentiated state or activation of the differentiation program. Pax7 expression decreases sharply in differentiating myoblasts but is maintained in cells (re)acquiring quiescence, yet the mechanisms regulating Pax7 levels based on differentiation status are not well understood. Here we show that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4. Our results indicate that Nedd4 is expressed in quiescent and activated satellite cells, that Nedd4 and Pax7 physically interact during early muscle differentiation-correlating with Pax7 ubiquitination and decline-and that Nedd4 loss of function prevented this effect. Furthermore, even transient nuclear accumulation of Nedd4 induced a drop in Pax7 levels and precocious muscle differentiation. Consequently, we propose that Nedd4 functions as a novel Pax7 regulator, which activity is temporally and spatially controlled to modulate the Pax7 protein levels and therefore satellite cell fate.

Strontium ranelate effect on bone mineral density is modified by previous bisphosphonate treatment.

The aim of this study was to evaluate the effect of strontium ranelate (SrR) on bone mineral density (BMD) and bone turnover markers after 1 year of treatment. Additionally, the effect of SrR in bisphosphonate-naïve patients (BP-naïve) compared to patients previously treated with bisphosphonates (BP-prior) was analyzed. This retrospective study included 482 postmenopausal women treated with SrR (2 g/day) for 1 year in ten Argentine centers; 41 patients were excluded due to insufficient data, while 441 were included. Participants were divided according to previous bisphosphonate treatment in two groups: BP-naïve (n = 87) and BP-prior (n = 350). Data are expressed as mean ± SEM. After 1 year of treatment with SrR the bone formation markers total alkaline phosphatase and osteocalcin were increased (p < 0.0001), while the bone resorption marker s-CTX was decreased (p = 0.0579). Also increases in BMD at the lumbar spine (LS, 3.73%), femoral neck (FN, 2.00%) and total hip (TH, 1.54%) [p < 0.0001] were observed. These increments were significant (p < 0.0001) both among BP-naïve and BP-prior patients. Interestingly, the change in BMD after 1 year of SrR treatment was higher in BP-naïve patients: LS: BP-naïve = 4.58 ± 0.62%; BP-prior = 3.45 ± 0.28% (p = 0.078). FN: BP-naïve = 2.79 ± 0.56%; BP-prior = 2.13 ± 0.29% (p = 0.161). TH: BP-naïve = 3.01 ± 0.55%; BP-prior = 1.22 ± 0.27% (p = 0.0006). SrR treatment increased BMD and bone formation markers and decreased a bone resorption marker in the whole group, with better response in BP-naïve patients.

Investigations of biodeterioration by fungi in historic wooden churches of Chiloé, Chile.

The use of wood in construction has had a long history and Chile has a rich cultural heritage of using native woods for building churches and other important structures. In 2000, UNESCO designated a number of the historic churches of Chiloé, built entirely of native woods, as World Heritage Sites. These unique churches were built in the late 1700 s and throughout the 1800 s, and because of their age and exposure to the environment, they have been found to have serious deterioration problems. Efforts are underway to better understand these decay processes and to carryout conservation efforts for the long-term preservation of these important structures. This study characterized the types of degradation taking place and identified the wood decay fungi obtained from eight historic churches in Chiloé, seven of them designated as UNESCO World Heritage sites. Micromorphological observations identified white, brown and soft rot in the structural woods and isolations provided pure cultures of fungi that were identified by sequencing of the internal transcribed region of rDNA. Twenty-nine Basidiomycota and 18 Ascomycota were found. These diverse groups of fungi represent several genera and species not previously reported from Chile and demonstrates a varied microflora is causing decay in these historic buildings.