Reduced dengue incidence following city-wide wMel Wolbachia mosquito releases throughout three Colombian cities: Interrupted time series analysis and a prospective case-control study.

BACKGROUND: The introduction of Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Randomised and non-randomised studies in multiple countries have shown significant reductions in dengue incidence following field releases of wMel-infected Ae. aegypti. We report the public health outcomes from phased, large-scale releases of wMel-Ae. aegypti mosquitoes throughout three contiguous cities in the Aburrá Valley, Colombia. METHODOLOGY/PRINCIPAL FINDINGS: Following pilot releases in 2015-2016, staged city-wide wMel-Ae. aegypti deployments were undertaken in the cities of Bello, Medellín and Itagüí (3.3 million people) between October 2016 and April 2022. The impact of the Wolbachia intervention on dengue incidence was evaluated in two parallel studies. A quasi-experimental study using interrupted time series analysis showed notified dengue case incidence was reduced by 95% in Bello and Medellín and 97% in Itagüí, following establishment of wMel at ≥60% prevalence, compared to the pre-intervention period and after adjusting for seasonal trends. A concurrent clinic-based case-control study with a test-negative design was unable to attain the target sample size of 63 enrolled virologically-confirmed dengue (VCD) cases between May 2019 and December 2021, consistent with low dengue incidence throughout the Aburrá Valley following wMel deployments. Nevertheless, VCD incidence was 45% lower (OR 0.55 [95% CI 0.25, 1.17]) and combined VCD/presumptive dengue incidence was 47% lower (OR 0.53 [95% CI 0.30, 0.93]) among participants resident in wMel-treated versus untreated neighbourhoods. CONCLUSIONS/SIGNIFICANCE: Stable introduction of wMel into local Ae. aegypti populations was associated with a significant and sustained reduction in dengue incidence across three Colombian cities. These results from the largest contiguous Wolbachia releases to-date demonstrate the real-world effectiveness of the method across large urban populations and, alongside previously published results, support the reproducibility of this effectiveness across different ecological settings. TRIAL REGISTRATION: NCT03631719.

Large-scale releases and establishment of wMel Wolbachia in Aedes aegypti mosquitoes throughout the Cities of Bello, Medellín and Itagüí, Colombia.

BACKGROUND: The wMel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and has been shown to reduce the transmission of dengue and other Aedes-borne viruses. Here we report the entomological results from phased, large-scale releases of Wolbachia infected Ae. aegypti mosquitoes throughout three contiguous cities located in the Aburrá Valley, Colombia. METHODOLOGY/PRINCIPAL FINDINGS: Local wMel Wolbachia-infected Ae. aegypti mosquitoes were generated and then released in an initial release pilot area in 2015-2016, which resulted in the establishment of Wolbachia in the local mosquito populations. Subsequent large-scale releases, mainly involving vehicle-based releases of adult mosquitoes along publicly accessible roads and streets, were undertaken across 29 comunas throughout Bello, Medellín and Itagüí Colombia between 2017-2022. In 9 comunas these were supplemented by egg releases that were undertaken by staff or community members. By the most recent monitoring, Wolbachia was found to be stable and established at consistent levels in local mosquito populations (>60% prevalence) in the majority (67%) of areas. CONCLUSION: These results, from the largest contiguous releases of wMel Wolbachia mosquitoes to date, highlight the operational feasibility of implementing the method in large urban settings. Based on results from previous studies, we expect that Wolbachia establishment will be sustained long term. Ongoing monitoring will confirm Wolbachia persistence in local mosquito populations and track its establishment in the remaining areas.

Zn-Salphen Acrylic Films Powered by Aggregation-Induced Enhanced Emission for Sensing Applications.

Zn(II) complexes possess attractive characteristics for supramolecular chemistry, catalysis, and optoelectronic applications, while Zn-Salphen counterparts are also suitable as chemical sensors, although limited by solution-based to date. In this study, we report the synthesis of new polymers from methyl methacrylate, n-butyl acrylate, and a non-symmetrical Zn-Salphen complex. We show that this low-fluorescent complex exhibits aggregation-induced emission enhancement (AIEE) properties and that, the incorporation of AIEE complexes into a polymeric matrix make it possible to achieve fluorescent films with enhanced fluorescence suitable for sensing applications. As a proof of concept, these films could detect acetic acid, showing a decrease of up to 73% in the original fluorescence. Host/guest studies showed a subtle disruption of the emission in aggregates upon treatment with anion guests. These results indicate that an interaction between the guest and Zn-Salphen complex may occur, stabilizing or destabilizing the complex and causing a concomitant increase or decrease in emission.

Prevalence and antimicrobial resistance of Escherichia coli and Salmonella spp. in animal feed in Colombia.

Objective: To determine the prevalence and antimicrobial resistance of Escherichia coli and Salmonella spp. in animal feed samples collected between 2018 and 2021 in Colombia. Methods: This was a laboratory-based cross-sectional study using routine data from the program for inspection, surveillance, and control of animal feed at the Colombian Agriculture Institute. Samples of animal feed for swine, poultry, canine, feline, leporine, piscine, and equine species were processed for detection of E. coli and Salmonella spp. using enrichment and selective culture methods. Isolates were tested for antimicrobial susceptibility using an automated microdilution method. Results: Of 1 748 animal feed samples analyzed, 83 (4.7%) were positive for E. coli and 66 (3.8%) for Salmonella spp. The presence of E. coli and Salmonella spp. was highest in feed for poultry (6.4% and 5.5%) and swine (6.1% and 4.3%). Antimicrobial resistance testing was performed in 27 (33%) E. coli isolates and 26 (39%) Salmonella isolates. Among E. coli, resistance was most frequently observed to ampicillin (44.5%) followed by cefazolin (33.3%), ciprofloxacin (29.6%), ampicillin/sulbactam (26%), and ceftriaxone (11.1%). The highest resistance levels in Salmonella spp. isolates were against cefazolin (7.7%) and piperacillin/tazobactam (7.7%). Conclusions: This is the first study from Colombia reporting on the prevalence and antimicrobial resistance of E. coli and Salmonella spp. in animal feed samples. Its results establish a baseline over a wide geographical distribution in Colombia. It highlights the need to integrate antimicrobial resistance surveillance in animal feed due to the emergence of resistant bacteria in this important stage of the supply chain.

Prevalence and antimicrobial resistance of Escherichia coli and Salmonella spp. in animal feed in Colombia

[ABSTRACT]. Objective. To determine the prevalence and antimicrobial resistance of Escherichia coli and Salmonella spp. in animal feed samples collected between 2018 and 2021 in Colombia. Methods. This was a laboratory-based cross-sectional study using routine data from the program for inspec- tion, surveillance, and control of animal feed at the Colombian Agriculture Institute. Samples of animal feed for swine, poultry, canine, feline, leporine, piscine, and equine species were processed for detection of E. coli and Salmonella spp. using enrichment and selective culture methods. Isolates were tested for antimicrobial susceptibility using an automated microdilution method. Results. Of 1 748 animal feed samples analyzed, 83 (4.7%) were positive for E. coli and 66 (3.8%) for Salmonella spp. The presence of E. coli and Salmonella spp. was highest in feed for poultry (6.4% and 5.5%) and swine (6.1% and 4.3%). Antimicrobial resistance testing was performed in 27 (33%) E. coli isolates and 26 (39%) Salmonella isolates. Among E. coli, resistance was most frequently observed to ampicillin (44.5%) followed by cefazolin (33.3%), ciprofloxacin (29.6%), ampicillin/sulbactam (26%), and ceftriaxone (11.1%). The highest resistance levels in Salmonella spp. isolates were against cefazolin (7.7%) and piperacillin/tazobactam (7.7%). Conclusions. This is the first study from Colombia reporting on the prevalence and antimicrobial resistance of E. coli and Salmonella spp. in animal feed samples. Its results establish a baseline over a wide geographical distribution in Colombia. It highlights the need to integrate antimicrobial resistance surveillance in animal feed due to the emergence of resistant bacteria in this important stage of the supply chain.

[RESUMEN]. Objetivo. Determinar la prevalencia y resistencia a los antimicrobianos de Escherichia coli y Salmonella spp. en muestras de piensos para animales tomadas entre el 2018 y el 2021 en Colombia. Métodos. Se trata de un estudio transversal realizado en el laboratorio a partir de los datos regulares del programa de inspección, vigilancia y control de alimentos para animales del Instituto Colombiano Agropec- uario. Se procesaron muestras de alimentos utilizados en la cría de cerdos, aves de corral, cánidos, félidos, lepóridos, peces y equinos con el fin de detectar E. coli y Salmonella spp. por medio de métodos de enriquec- imiento y cultivo selectivo. Se analizó la sensibilidad a los antimicrobianos de las cepas aisladas mediante microdilución automatizada. Resultados. De 1748 muestras de alimentos analizadas, 83 (4,7%) resultaron positivas para E. coli y 66 (3,8%) para Salmonella spp. La presencia de E. coli y Salmonella spp. fue mayor en los alimentos para aves de corral (6,4% y 5,5%) y cerdos (6,1% y 4,3%). Se realizaron pruebas de resistencia a los antimicrobianos en 27 (33%) cepas de E. coli y 26 (39%) de Salmonella. En las cepas de E. coli, se observó una mayor resis- tencia a la ampicilina (44,5%), seguida de la resistencia a la cefazolina (33,3%), la ciprofloxacina (29,6%), la ampicilina/sulbactam (26%) y la ceftriaxona (11,1%). En el caso de las cepas de Salmonella spp., los niveles de resistencia más elevados fueron para la cefazolina (7,7%) y piperacilina/tazobactam (7,7%). Conclusiones. Este es el primer estudio realizado en Colombia en el que se informa sobre la prevalencia y la resistencia a los antimicrobianos de E. coli y Salmonella spp. en muestras de alimentos para animales. Sus resultados establecen una línea de base para una zona geográfica mucho mayor dentro de Colombia. Se subraya la necesidad de integrar la vigilancia de la resistencia a los antimicrobianos en los alimentos para animales debido a la aparición de bacterias resistentes en esta importante etapa de la cadena de suministro.

[RESUMO]. Objetivo. Determinar a prevalência e a resistência a antimicrobianos de Escherichia coli e Salmonela spp. em amostras de ração animal coletadas entre 2018 e 2021 na Colômbia. Métodos. Estudo transversal de base laboratorial, usando dados de rotina do programa de inspeção, vig- ilância e controle de ração animal do Instituto Colombiano de Agricultura. Amostras de ração animal para as espécies suína, avícola, canina, felina, leporina, piscina e equina foram processadas para detecção de E. coli e Salmonella spp., usando métodos de enriquecimento e cultura seletiva. Os isolados foram testados quanto à suscetibilidade a antimicrobianos usando um método automatizado de microdiluição. Resultados. Das 1.748 amostras de ração animal analisadas, 83 (4,7%) foram positivas para E. coli e 66 (3,8%) para Salmonella spp. A presença de E. coli e Salmonella spp. foi maior em rações para aves (6,4% e 5,5%) e suínos (6,1% e 4,3%). O teste de resistência a antimicrobianos foi realizado em 27 (33%) isolados de E. coli e 26 (39%) isolados de Salmonella. Em E. coli, a resistência observada com maior frequência foi à ampicilina (44,5%), seguida da cefazolina (33,3%), ciprofloxacino (29,6%), ampicilina/sulbactam (26%) e ceftriaxona (11,1%). Os maiores níveis de resistência em isolados de Salmonella spp. foram contra cefazolina (7,7%) e piperacilina/tazobactam (7,7%). Conclusões. Este é o primeiro estudo da Colômbia a notificar a prevalência e resistência a antimicrobianos de E. coli e Salmonella spp. em amostras de ração animal. Os resultados estabelecem uma linha de base com ampla distribuição geográfica na Colômbia. Destaca-se a necessidade de integrar a vigilância da resistência a antimicrobianos na ração animal, devido ao surgimento de bactérias resistentes nesta importante etapa da cadeia de abastecimento.

Prevalence and antimicrobial resistance of Escherichia coli and Salmonella spp. in animal feed in Colombia / Prevalencia y resistencia a los antimicrobianos de Escherichia coli y Salmonella spp. en los alimentos para animales en Colombia / Prevalência e resistência a antimicrobianos de Escherichia coli e Salmonella spp. em ração animal na Colômbia

ABSTRACT Objective. To determine the prevalence and antimicrobial resistance of Escherichia coli and Salmonella spp. in animal feed samples collected between 2018 and 2021 in Colombia. Methods. This was a laboratory-based cross-sectional study using routine data from the program for inspection, surveillance, and control of animal feed at the Colombian Agriculture Institute. Samples of animal feed for swine, poultry, canine, feline, leporine, piscine, and equine species were processed for detection of E. coli and Salmonella spp. using enrichment and selective culture methods. Isolates were tested for antimicrobial susceptibility using an automated microdilution method. Results. Of 1 748 animal feed samples analyzed, 83 (4.7%) were positive for E. coli and 66 (3.8%) for Salmonella spp. The presence of E. coli and Salmonella spp. was highest in feed for poultry (6.4% and 5.5%) and swine (6.1% and 4.3%). Antimicrobial resistance testing was performed in 27 (33%) E. coli isolates and 26 (39%) Salmonella isolates. Among E. coli, resistance was most frequently observed to ampicillin (44.5%) followed by cefazolin (33.3%), ciprofloxacin (29.6%), ampicillin/sulbactam (26%), and ceftriaxone (11.1%). The highest resistance levels in Salmonella spp. isolates were against cefazolin (7.7%) and piperacillin/tazobactam (7.7%). Conclusions. This is the first study from Colombia reporting on the prevalence and antimicrobial resistance of E. coli and Salmonella spp. in animal feed samples. Its results establish a baseline over a wide geographical distribution in Colombia. It highlights the need to integrate antimicrobial resistance surveillance in animal feed due to the emergence of resistant bacteria in this important stage of the supply chain.

RESUMEN Objetivo. Determinar la prevalencia y resistencia a los antimicrobianos de Escherichia coli y Salmonella spp. en muestras de piensos para animales tomadas entre el 2018 y el 2021 en Colombia. Métodos. Se trata de un estudio transversal realizado en el laboratorio a partir de los datos regulares del programa de inspección, vigilancia y control de alimentos para animales del Instituto Colombiano Agropecuario. Se procesaron muestras de alimentos utilizados en la cría de cerdos, aves de corral, cánidos, félidos, lepóridos, peces y equinos con el fin de detectar E. coli y Salmonella spp. por medio de métodos de enriquecimiento y cultivo selectivo. Se analizó la sensibilidad a los antimicrobianos de las cepas aisladas mediante microdilución automatizada. Resultados. De 1748 muestras de alimentos analizadas, 83 (4,7%) resultaron positivas para E. coli y 66 (3,8%) para Salmonella spp. La presencia de E. coli y Salmonella spp. fue mayor en los alimentos para aves de corral (6,4% y 5,5%) y cerdos (6,1% y 4,3%). Se realizaron pruebas de resistencia a los antimicrobianos en 27 (33%) cepas de E. coli y 26 (39%) de Salmonella. En las cepas de E. coli, se observó una mayor resistencia a la ampicilina (44,5%), seguida de la resistencia a la cefazolina (33,3%), la ciprofloxacina (29,6%), la ampicilina/sulbactam (26%) y la ceftriaxona (11,1%). En el caso de las cepas de Salmonella spp., los niveles de resistencia más elevados fueron para la cefazolina (7,7%) y piperacilina/tazobactam (7,7%). Conclusiones. Este es el primer estudio realizado en Colombia en el que se informa sobre la prevalencia y la resistencia a los antimicrobianos de E. coli y Salmonella spp. en muestras de alimentos para animales. Sus resultados establecen una línea de base para una zona geográfica mucho mayor dentro de Colombia. Se subraya la necesidad de integrar la vigilancia de la resistencia a los antimicrobianos en los alimentos para animales debido a la aparición de bacterias resistentes en esta importante etapa de la cadena de suministro.

RESUMO Objetivo. Determinar a prevalência e a resistência a antimicrobianos de Escherichia coli e Salmonela spp. em amostras de ração animal coletadas entre 2018 e 2021 na Colômbia. Métodos. Estudo transversal de base laboratorial, usando dados de rotina do programa de inspeção, vigilância e controle de ração animal do Instituto Colombiano de Agricultura. Amostras de ração animal para as espécies suína, avícola, canina, felina, leporina, piscina e equina foram processadas para detecção de E. coli e Salmonella spp., usando métodos de enriquecimento e cultura seletiva. Os isolados foram testados quanto à suscetibilidade a antimicrobianos usando um método automatizado de microdiluição. Resultados. Das 1.748 amostras de ração animal analisadas, 83 (4,7%) foram positivas para E. coli e 66 (3,8%) para Salmonella spp. A presença de E. coli e Salmonella spp. foi maior em rações para aves (6,4% e 5,5%) e suínos (6,1% e 4,3%). O teste de resistência a antimicrobianos foi realizado em 27 (33%) isolados de E. coli e 26 (39%) isolados de Salmonella. Em E. coli, a resistência observada com maior frequência foi à ampicilina (44,5%), seguida da cefazolina (33,3%), ciprofloxacino (29,6%), ampicilina/sulbactam (26%) e ceftriaxona (11,1%). Os maiores níveis de resistência em isolados de Salmonella spp. foram contra cefazolina (7,7%) e piperacilina/tazobactam (7,7%). Conclusões. Este é o primeiro estudo da Colômbia a notificar a prevalência e resistência a antimicrobianos de E. coli e Salmonella spp. em amostras de ração animal. Os resultados estabelecem uma linha de base com ampla distribuição geográfica na Colômbia. Destaca-se a necessidade de integrar a vigilância da resistência a antimicrobianos na ração animal, devido ao surgimento de bactérias resistentes nesta importante etapa da cadeia de abastecimento.

Archivos comunitarios y de derechos humanos como una apuesta por la memoria, la verdad y la resistencia / Community and Human Rights Archives as a Commitment to Memory, Truth, and Resistance

Resumen La reconstrucción de saberes sobre archivos comunitarios de derechos humanos y memoria es de vital importancia para los procesos de transición en países marcados por el conflicto armado como Colombia. Es preciso dar cuenta de procesos pedagógicos realizados por organizaciones de víctimas que diseñaron de manera participativa planes de gestión de archivos comunitarios y que contribuyeron a potenciar las nuevas narrativas de paz y preparar a las organizaciones y comunidades para articular sus experiencias territoriales como una manera de narrar para sus propios territorios, así como para establecer un diálogo con las instancias de justicia y de memoria en Colombia en los escenarios de justicia transicional en ámbitos rurales y urbanos. Se han tomado los casos: Comuna 3 en Medellín y los municipios de Granada e Ituango (Antioquia).

Abstract The reconstruction of knowledge on community archives of human rights and memory is of vital importance for transition processes in countries marked by armed conflict, such as Colombia. It is necessary to account for pedagogical processes carried out by victims' organizations, which designed, in a participatory manner, community archives management plans and that contributed to enhance new peace narratives and to prepare organizations and communities to articulate their territorial experiences as a way of narrating for their own territories, as well as to establish a dialogue with the instances of justice and memory in Colombia in transitional justice scenarios in both rural and urban settings. The cases, which have been taken are Commune 3 in Medellin and the municipalities of Granada and Ituango, Antioquia.

The impact of city-wide deployment of Wolbachia-carrying mosquitoes on arboviral disease incidence in Medellín and Bello, Colombia: study protocol for an interrupted time-series analysis and a test-negative design study.

Background: Dengue, chikungunya and Zika are viral infections transmitted by Aedes aegypti mosquitoes, and present major public health challenges in tropical regions. Traditional vector control methods have been ineffective at halting disease transmission. The World Mosquito Program has developed a novel approach to arbovirus control using Ae. aegypti stably transfected with the Wolbachia bacterium, which have significantly reduced ability to transmit dengue, Zika and chikungunya in laboratory experiments. Field releases in eight countries have demonstrated Wolbachia establishment in local Ae. aegypti populations. Methods: We describe a pragmatic approach to measuring the epidemiological impact of city-wide Wolbachia deployments in Bello and Medellín, Colombia. First, an interrupted time-series analysis will compare the incidence of dengue, chikungunya and Zika case notifications before and after Wolbachia releases, across the two municipalities. Second, a prospective case-control study using a test-negative design will be conducted in one quadrant of Medellín. Three of the six contiguous release zones in the case-control area were allocated to receive the first Wolbachia deployments in the city and three to be treated last, approximating a parallel two-arm trial for the >12-month period during which Wolbachia exposure remains discordant. Allocation, although non-random, aimed to maximise balance between arms in historical dengue incidence and demographics. Arboviral disease cases and arbovirus-negative controls will be enrolled concurrently from febrile patients presenting to primary care, with case/control status classified retrospectively following laboratory diagnostic testing. Intervention effect is estimated from an aggregate odds ratio comparing Wolbachia-exposure odds among test-positive cases versus test-negative controls. Discussion: The study findings will add to an accumulating body of evidence from global field sites on the efficacy of the Wolbachia method in reducing arboviral disease incidence, and can inform decisions on wider public health implementation of this intervention in the Americas and beyond. Trial registration: ClinicalTrials.gov: NCT03631719. Registered on 15 August 2018.

Prospective assessment of diagnostic tests for pediatric penicillin allergy: From clinical history to challenge tests.

BACKGROUND: Diagnostic guidelines for penicillin allergy in children recommend cumbersome protocols based partially on data from adults, which may be suboptimal for pediatric use. OBJECTIVE: To assess the accuracy of tools for diagnosis of penicillin allergy in children. METHODS: A prospective, multicenter study was conducted in children with reported adverse events related to penicillin, excluding severe reactions. All patients underwent a uniform diagnostic protocol that consisted of clinical history, skin tests, serum specific IgE (sIgE), and, regardless of these results, drug provocation tests (DPTs). RESULTS: A total of 732 children (mean age, 5.5 years; 51.2% males) completed the allergy workup, including DPTs. Amoxicillin triggered 96.9% of all reactions. None of the patients with an immediate index reaction (IR) developed a reaction on DPT. Penicillin allergy was confirmed in 35 children (4.8%): 6 immediate reactions (17%) and 29 nonimmediate reactions (83%) on the DPT. No severe reactions were recorded. The allergist diagnosis based on the clinical history was not associated with the DPT final outcome. In 30 of 33 allergic patients (91%), the results of all skin tests and sIgE tests were negative. A logistic regression model identified the following to be associated with penicillin allergy: a family history of drug allergy (odds ratio [OR], 3.03; 95% confidence interval [CI], 1.33-6.89; P = .008), an IR lasting more than 3 days vs 24 hours or less (OR, 8.96; 95% CI, 2.01-39.86; P = .004), and an IR treated with corticosteroids (OR, 2.68; 95% CI, 1.30-5.54; P = .007). CONCLUSION: Conventional predictors of allergy to penicillin performed weakly. The authors propose straightforward penicillin provocation testing in controlled, experienced centers for the diagnosis of nonsevere penicillin allergy in children.

Liquid Biopsy: From Basic Research to Clinical Practice.

Liquid biopsy refers to the molecular analysis in biological fluids of nucleic acids, subcellular structures, especially exosomes, and, in the context of cancer, circulating tumor cells. In the last 10 years, there has been an intensive research in liquid biopsy to achieve a less invasive and more precise personalized medicine. Molecular assessment of these circulating biomarkers can complement or even surrogate tissue biopsy. Because of this research, liquid biopsy has been introduced in clinical practice, especially in oncology, prenatal screening, and transplantation. Here we review the biology, methodological approaches, and clinical applications of the main biomarkers involved in liquid biopsy.

Phase I Trial of DNX-2401 for Diffuse Intrinsic Pontine Glioma Newly Diagnosed in Pediatric Patients.

BACKGROUND: There are no effective treatments for diffuse intrinsic pontine gliomas (DIPGs); these tumors cannot be surgical resected, and diagnosis is based on magnetic resonance imaging. As a result, tumor tissues for molecular studies and pathologic diagnosis are infrequent. New clinical trials are investigating novel medications and therapeutic techniques in an effort to improve treatment of patients with DIPGs. OBJECTIVE: To determine the safety, tolerability, and toxicity of an oncolytic adenovirus, DNX-2401, injected into the cerebellar peduncle in pediatric subjects with DIPG and to collect tumor samples of this type of tumor. METHODS: Phase I, single-center, uncontrolled trial. A tumor biopsy will be performed through the cerebellar peduncle, and DNX-2401 will be injected immediately after the biopsy. Standard therapy consisting of radiotherapy and chemotherapy will follow in 2 to 6 wk. EXPECTED OUTCOMES: Improvement of overall survival and quality of life in patients with DIPG and collection of tumor specimens to study the molecular profiling of these tumors. DISCUSSION: The aims of this trial are to contribute to the sample collection of DIPG and to offer treatment during the tumor tissue biopsy using the virus. If this virus works as expected, it could kill the tumor cells with no damage to healthy tissue, functioning as a targeted therapy. It is important to note that edema has not been observed with this virus in all trials performed to date. The information obtained through this and other similar studies may be useful for developing or improving new therapies in the battle against DIPG.

A cumulative effect involving malfunction of the PTH1R and ATP4A genes explains a familial gastric neuroendocrine tumor with hypothyroidism and arthritis.

BACKGROUND: Type I gastric neuroendocrine tumors (gNETs) classically arise because of hypergastrinemia and involve destruction of parietal cells, which are responsible for gastric acid secretion through the ATP4A proton pump and for intrinsic factor production. METHODS: By whole exome sequencing, we studied a family with three members with gNETs plus hypothyroidism and rheumatoid arthritis to uncover their genetic origin. RESULTS: A heterozygous missense mutation in the ATP4A gene was identified. Carriers of this variant had low ferritin and vitamin B12 levels but did not develop gNETs. A second heterozygous mutation was also uncovered (PTH1R p.E546K). Carriers exhibited hypothyroidism and one of them had rheumatoid arthritis. Gastrin activates parathyroid hormone like hormone/parathyroid hormone 1 receptor (PTH1R) signaling, which is involved in gastric cell homeostasis. Activation of parathyroid hormone/PTH1R, which is upregulated by thyrotropin in the thyroid, is also involved in RANKL expression, which regulates bone homeostasis. Thyrotropin and RANKL expression were deregulated in PTH1R mutation carriers, suggesting a link between the PTH1R gene, hypothyroidism, rheumatoid arthritis, and gastric disease. Only patients with both mutations developed gNETs plus hypothyroidism and rheumatoid arthritis. CONCLUSION: Both mutations suggest that a collaborative mechanism is operative in this family, in which mutations in these genes affect the function and viability of parietal cells and lead to the achlorhydria that drives hypergastrinemia and the formation of gNETs.

The Oncolytic Adenovirus VCN-01 as Therapeutic Approach Against Pediatric Osteosarcoma.

PURPOSE: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Despite aggressive chemotherapy, more than 30% of patients do not respond and develop bone or lung metastasis. Oncolytic adenoviruses engineered to specifically destroy cancer cells are a feasible option for osteosarcoma treatment. VCN-01 is a replication-competent adenovirus specifically engineered to replicate in tumors with a defective RB pathway, presents an enhanced infectivity through a modified fiber and an improved distribution through the expression of a soluble hyaluronidase. The aim of this study is to elucidate whether the use of VCN-01 would be an effective therapeutic strategy for pediatric osteosarcoma. EXPERIMENTAL DESIGN: We used osteosarcoma cell lines established from patients with metastatic disease (531MII, 678R, 588M, and 595M) and a commercial cell line (143B). MTT assays were carried out to evaluate the cytotoxicity of VCN-01. Hexon assays were used to evaluate the replication of the virus. Western blot analysis was performed to assess the expression levels of viral proteins and autophagic markers. The antitumor effect of VCN-01 was evaluated in orthotopic and metastatic osteosarcoma murine animal models. RESULTS: This study found that VCN-01, a new generation genetically modified oncolytic adenovirus, administered locally or systemically, had a potent antisarcoma effect in vitro and in vivo in mouse models of intratibial and lung metastatic osteosarcoma. Moreover, VCN-01 administration showed a safe toxicity profile. CONCLUSIONS: These results uncover VCN-01 as a promising strategy for osteosarcoma, setting the bases to propel a phase I/II trial for kids with this disease. Clin Cancer Res; 22(9); 2217-25. ©2015 AACR.

Asociación entre la conducta alimentaria y polimorfismos genéticos de la leptina y su receptor en niños obesos chilenos / Association between feeding behavior, and genetic polymorphism of leptin and its receptor in obese Chilean children

Introducción: La leptina (LEP) se produce principalmente en el tejido adiposo y actúa en el hipotálamo regulando la ingesta energética. Mutaciones en el gen LEP o en su receptor (LEPR) que generen obesidad monogénica son pocos frecuentes. Sin embargo, polimorfismos de LEP y LEPR han sido relacionados con la obesidad multifactorial, debido a la asociación encontrada con el peso corporal y la conducta alimentaria. Objetivo: Medir la asociación entre polimorfismos de LEP y LEPR con obesidad infantil y conducta alimentaria en niños obesos. Métodos: Se reclutaron 221 niños obesos Chilenos (IMC sobre el percentil 95). Los progenitores de 134 de esos niños también fueron reclutados, para determinar la asociación entre los polimorfismos de LEP y LEPR con la obesidad en un estudio de tríos caso-progenitor. La conducta alimentaria se midió a través del cuestionario de alimentación de tres factores versión progenitores (TFEQ-P19) y el de conducta alimentaria en niños (CEBQ). Resultados: No se observa una diferencia significativa entre los polimorfismos estudiados y la obesidad infantil, luego de la corrección por comparaciones múltiples. Por otro lado, se encontraron asociaciones significativas entre ciertos polimorfismos de LEP y LEPR con dimensiones de la conducta alimentaria tales como: 'lentitud para comer', 'alimentación emocional', 'disfrute de los alimentos' y 'alimentación sin control'. Conclusiones: Existiría una asociación entre polimorfismos de los genes LEP y LEPR con la conducta alimentaria en niños obesos Chilenos (AU)

Introduction: Leptin (LEP) is mainly produced in adipose tissue and acts in the hypothalamus to regulate energy intake. Mutations in the LEP gene or its receptor (LEPR) that produce monogenic obesity are infrequent. However, LEP and LEPR polymorphisms have been associated with obesity multifactorial, due to the association found with body weight and eating behavior. Aim: Measure the association between LEP and LEPR polymorphisms with childhood obesity and eating behavior. Methods: 221 Chilean obese children (BMI above the 95th percentile) were recruited. Parents of 134 of these children were also recruited to determine the association between LEP and LEPR polymorphisms with obesity in a case study-parent trio. Eating behavior was measured through the questionnaire of three factors progenitors’ version (TFEQ-P19) and eating behavior in children (CEBQ). Results: No significant difference between the studied polymorphisms and childhood obesity, after correction for multiple comparisons, was observed. The dimensions; 'Slow eating', 'emotional eating', 'enjoyment of food' and 'uncontrolling eating' were significant associated with certain polymorphisms of LEP and LEPR. Conclusions: There would be an association between polymorphisms of the LEP and LEPR genes with eating behavior in Chilean obese children (AU)

[Association between feeding behavior, and genetic polymorphism of leptin and its receptor in obese Chilean children]. / Asociación entre la conducta alimentaria y polimorfismos genéticos de la leptina y su receptor en niños obesos chilenos.

INTRODUCTION: Leptin (LEP) is mainly produced in adipose tissue and acts in the hypothalamus to regulate energy intake. Mutations in the LEP gene or its receptor (LEPR) that produce monogenic obesity are infrequent. However, LEP and LEPR polymorphisms have been associated with obesity multifactorial, due to the association found with body weight and eating behavior. AIM: Measure the association between LEP and LEPR polymorphisms with childhood obesity and eating behavior. METHODS: 221 Chilean obese children (BMI above the 95th percentile) were recruited. Parents of 134 of these children were also recruited to determine the association between LEP and LEPR polymorphisms with obesity in a case study-parent trio. Eating behavior was measured through the questionnaire of three factors progenitors' version (TFEQ-P19) and eating behavior in children (CEBQ). RESULTS: No significant difference between the studied polymorphisms and childhood obesity, after correction for multiple comparisons, was observed. The dimensions; "Slow eating", "emotional eating", "enjoyment of food" and "uncontrolling eating" were significant associated with certain polymorphisms of LEP and LEPR. CONCLUSIONS: There would be an association between polymorphisms of the LEP and LEPR genes with eating behavior in Chilean obese children.

Introducción: La leptina (LEP) se produce principalmente en el tejido adiposo y actúa en el hipotálamo regulando la ingesta energética. Mutaciones en el gen LEP o en su receptor (LEPR) que generen obesidad monogénica son pocos frecuentes. Sin embargo, polimorfismos de LEP y LEPR han sido relacionados con la obesidad multifactorial, debido a la asociación encontrada con el peso corporal y la conducta alimentaria. Objetivo: Medir la asociación entre polimorfismos de LEP y LEPR con obesidad infantil y conducta alimentaria en niños obesos. Métodos: Se reclutaron 221 niños obesos Chilenos (IMC sobre el percentil 95). Los progenitores de 134 de esos niños también fueron reclutados, para determinar la asociación entre los polimorfismos de LEP y LEPR con la obesidad en un estudio de tríos caso-progenitor. La conducta alimentaria se midió a través del cuestionario de alimentación de tres factores versión progenitores (TFEQ-P19) y el de conducta alimentaria en niños (CEBQ). Resultados: No se observa una diferencia significativa entre los polimorfismos estudiados y la obesidad infantil, luego de la corrección por comparaciones múltiples. Por otro lado, se encontraron asociaciones significativas entre ciertos polimorfismos de LEP y LEPR con dimensiones de la conducta alimentaria tales como: "lentitud para comer", "alimentación emocional", "disfrute de los alimentos" y "alimentación sin control". Conclusiones: Existiría una asociación entre polimorfismos de los genes LEP y LEPR con la conducta alimentaria en niños obesos Chilenos.

Biomecánica del hombro y bases fisiológicas de los ejercicios de Codman / Shoulder's biomechanics and physiological basis for the Codman exercise

El hombro se considera la articulación más móvil del cuerpo humano, pero también la más inestable. Ante la presencia de enfermedades en dicha articulación se han empleado técnicas de intervención fisioterapéuticas, entre ellas los ejercicios de Codman, con la finalidad de restablecer la integridad del hombro, sustentándose en sus efectos fisiológicos. El objetivo de esta revisión de tema es describir la biomecánica del hombro como base fundamental de los ejercicios de Codman y sus efectos fisiológicos.

Shoulder is considered the most mobile joint in the human body, but also the most unstable. In the presence of diseases in this joint has been used physiotherapy rehabilitation techniques, including Codman exercises with the aim of restore the integrity of the shoulder, sustained in their physiological effects. The objective of this review is to explain the biomechanics of the shoulder as the foundation of Codman exercises and their physiological effects.

ErbB3 silencing reduces osteosarcoma cell proliferation and tumor growth in vivo.

Osteosarcoma is the most common primary bone tumor in children and adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of osteosarcoma treatment. The identification of the molecular signals that contribute to the aberrant osteosarcoma cell growth may provide clues to develop new therapeutic strategies for chemoresistant osteosarcoma. Here we show that the expression of ErbB3 is increased in human osteosarcoma cells in vitro. Tissue microarray analysis of tissue cores from osteosarcoma patients further showed that the ErbB3 protein expression is higher in bone tumors compared to normal bone tissue, and is further increased in patients with recurrent disease or soft tissue metastasis. In murine osteosarcoma cells, silencing ErbB3 using shRNA decreased cell replication, cell migration and invasion, indicating that ErbB3 contributes to tumor cell growth and invasiveness. Furthermore, ErbB3 silencing markedly reduced tumor growth in a murine allograft model in vivo. Immunohistochemal analysis showed that the reduced tumor growth induced by ErbB3 silencing in this model resulted from decreased cell osteosarcoma cell proliferation, supporting a role of ErbB3 in bone tumor growth in vivo. Taken together, the results reveal that ErbB3 expression in human osteosarcoma correlates with tumor grade. Furthermore, silencing ErbB3 in a murine osteosarcoma model results in decreased cell growth and invasiveness in vitro, and reduced tumor growth in vivo, which supports the potential therapeutic interest of targeting ErbB3 in osteosarcoma.

CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis.

Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and the poor survival rate for patients. We showed previously that the HMGCoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor statin exhibits antitumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify Cyr61 as a new target of statins. Transcriptome and molecular analyses revealed that statins downregulate Cyr61 expression in human and murine osteosarcoma cells. Cyr61 silencing in osteosarcoma cell lines enhanced cell death and reduced cell migration and cell invasion compared with parental cells, whereas Cyr61 overexpression had opposite effects. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients. Tissue microarray analysis revealed that Cyr61 protein expression was higher in human osteosarcoma than in normal bone tissue and was further increased in metastatic tissues. Finally, tumor behavior and metastasis occurrence were analyzed by intramuscular injection of modified osteosarcoma cells into BALB/c mice. Cyr61 overexpression enhanced lung metastasis development, whereas cyr61 silencing strongly reduced lung metastases in mice. The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma.

Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potential effects in a 6-OHDA-induced model of Parkinson's disease.

The ability of aluminium to affect the oxidant status of specific areas of the brain (cerebellum, ventral midbrain, cortex, hippocampus, striatum) was investigated in rats intraperitoneally treated with aluminium chloride (10 mg Al3+/kg/day) for 10 days. The potential of aluminium to act as an etiological factor in Parkinson's disease (PD) was assessed by studying its ability to increase oxidative stress in ventral midbrain and striatum and the striatal dopaminergic neurodegeneration induced by 6-hydroxydopamine in an experimental model of PD.The results showed that aluminium caused an increase in oxidative stress (TBARS, protein carbonyl content, and protein thiol content) for most of the brain regions studied, which was accompanied by a decrease in the activity of some antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase). However, studies in vitro confirmed the inability of aluminium to affect the activity of those enzymes. The reported effects exhibited a regional-selective behaviour for all the cerebral structures studied. Aluminium also enhanced the ability of 6-hydroxydopamine to cause oxidative stress and neurodegeneration in the dopaminergic system, which confirms its potential as a risk factor in the development of PD.