Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis.

Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.

Alterações sistêmicas e bucais em pacientes usuários de cocaína: uma revisão integrativa da literatura / Cambios sistémicos y orales em pacientes consumidores de cocaína: una revisión bibliográfica integradora / Systemic and oral changes in cocaína-using patients: an integrative literature review

Introdução: A utilização de cocaína é bastante associada ao surgimento de algumas manifestações sistêmicas e também de algumas alterações orais. Objetivo: Identificaras alterações sistêmicas e bucais mais comuns a pacientes usuários de cocaína. Metodologia: Trata-se de uma revisão sistemática da literatura, considerando artigos com texto completo, com restrição de idioma em Português ou Inglês e que tenham sido publicados entre os anos de 2017 a 2022. Usou-se as bases de dados LiLaCS, MedLine e BBO, por via portal Biblioteca Virtual de Saúde, e SciELO. Os artigos excluídosf oram aqueles que não apresentaram relação explícita do uso de cocaína com alguma manifestação sistêmica e/ou bucal. Resultados: Após o processo de triagem,10 artigos foram salvos para serem analisados e 111 foram descartados por não atenderem aos critérios de inclusão. Dos 10 artigosselecionados,40% deles (n=4) trouxeram informações identificando possíveis riscos de desenvolvimento de doenças cardiovasculares sofridas pelos usuários de cocaína, 10%(n=1) identificou problemas cognitivos associados ao uso da cocaína,30% dos artigos (n=3) mostrou as alterações bucais associadas à utilização abusiva de cocaína. Conclusões: Houve a predominância de algumas manifestações sistêmicas e bucais nos indivíduos usuários de cocaína, como doenças cardiovasculares, xerostomia, perfurações no palato, etc. A partir disso, há algumas alterações sistêmicas e bucais provocadas por esse uso. Mediante o risco considerável, faz-se necessário que o Cirurgião-Dentista se atualize sobre essas alterações em pacientes usuários de cocaína visando promover um trabalho transdisciplinare multiprofissional para atender adequadamente às suas necessidades (AU).

Introduction: The use of cocaine is closely associated with the appearance of some systemic manifestations and also some oral alterations.Objective: To identify the most common systemic and oral alterations in cocaine-using patients.Methodology:This is a systematic review of the literature, considering full-text articles, with a language restriction of "Portuguese" or "English" and published between 2017 and 2022. We used the LiLaCS, MedLine and BBO databases, via the Virtual Health Library (VHL) portal, and SciELO.The articles excluded were those that did not explicitly relate cocaine use to some systemic and/or oral manifestation.Results: After the screening process, 10 articles were saved for analysis and 111 were discarded because they did not meet the inclusion criteria. Of the 10 articles selected, 40% (n=4) provided information identifying possible risks of developing cardiovascular diseases suffered by cocaine users, 10% (n=1)identified cognitive problems associated with cocaine use, 30% of the articles (n=3) showed oral alterations associated with cocaine abuse.Conclusions: There has been a predominance of some systemic and oral manifestations in cocaine users, such as cardiovascular diseases, xerostomia, perforations in the palate, etc. Based on this, there are some systemic and oral alterations caused by this use. Given the considerable risk, it is necessary for dentists to be up-to-date on these alterations in cocaine-using patients in order to promote transdisciplinary and multi-professional work to adequately meet their needs (AU).

Introducción: El consumo de cocaína está estrechamente asociado a la aparición de algunas manifestaciones sistémicas y también de algunas alteraciones orales. Objetivo:Identificar las alteraciones sistémicas y bucales más frecuentes en los consumidores de cocaína. Metodología: Se trata de una revisión sistemática de la literatura, considerando artículos a texto completo, con restricción de idioma en "portugués" o "inglés" y publicados entre 2017 y 2022. Se utilizaron las bases de datos LiLaCS, MedLine y BBO, a través del portal Biblioteca Virtual en Salud (BVS) y SciELO. Los artículos excluidos fueron aquellos que no mostraban una relación explícita entre el consumo de cocaína y alguna manifestación sistémica y/o oral. Resultados: Tras el proceso de cribado, se guardaron10 artículos para el análisis y se descartaron 111 por no cumplir los criterios de inclusión. De los 10 artículos seleccionados, el 40% (n=4) proporcionaba información que identificaba posibles riesgos de desarrollar enfermedades cardiovasculares sufridaspor consumidores de cocaína, el 10% (n=1) identificaba problemas cognitivos asociados al consumo de cocaína, el 30% de los artículos (n=3) mostraban alteraciones orales asociadas al abuso de cocaína.Conclusiones:Ha habido un predominio de algunas manifestaciones sistémicas y orales en los consumidores de cocaína, como enfermedades cardiovasculares, xerostomía, perforaciones en el paladar, etc. De acuerdo con esto, existen algunas alteraciones sistémicas y orales causadas por este uso. Dado el considerable riesgo, es necesario que los odontólogos estén al día sobre estas alteraciones en los pacientes consumidores de cocaína, con el fin de promover el trabajo transdisciplinar y multiprofesional para atender adecuadamente sus necesidades (AU).

Targeting of neuroblastoma cells through Kynurenine-AHR pathway inhibition.

Neuroblastoma poses significant challenges in clinical management. Despite its relatively low incidence, this malignancy contributes disproportionately to cancer-related childhood mortality. Tailoring treatments based on risk stratification, including MYCN oncogene amplification, remains crucial, yet high-risk cases often confront therapeutic resistance and relapse. Here, we explore the aryl hydrocarbon receptor (AHR), a versatile transcription factor implicated in diverse physiological functions such as xenobiotic response, immune modulation, and cell growth. Despite its varying roles in malignancies, AHR's involvement in neuroblastoma remains elusive. Our study investigates the interplay between AHR and its ligand kynurenine (Kyn) in neuroblastoma cells. Kyn is generated from tryptophan (Trp) by the activity of the enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). We found that neuroblastoma cells displayed sensitivity to the TDO2 inhibitor 680C91, exposing potential vulnerabilities. Furthermore, combining TDO2 inhibition with retinoic acid or irinotecan (two chemotherapeutic agents used to treat neuroblastoma patients) revealed synergistic effects in select cell lines. Importantly, clinical correlation analysis using patient data established a link between elevated expression of Kyn-AHR pathway genes and adverse prognosis, particularly in older children. These findings underscore the significance of the Kyn-AHR pathway in neuroblastoma progression, emphasizing its potential role as a therapeutic target.

Hypercapnia in hospitalized children and adolescents with anorexia nervosa as a predictive marker for readmission: a prospective study.

PURPOSE: To determine whether hypercapnia is associated with risk of hospital readmission related to anorexia nervosa (AN) in children and adolescents. METHODS: We performed a prospective study of patients ≤ 18 years old admitted due to AN decompensation from November 2018 to October 2019. Both subtypes of AN, restricting subtype (AN-R) and binge-eating/purging subtype (AN-BP), were included. Study participants were evaluated upon admission, at discharge and six months after discharge. T-tests or Mann-Whitney U tests was used to compare means values. Pearson or Spearman correlations were used to measure the association between two variables. Logistic regression models were developed to evaluate the relationship between scoring methods and readmission. RESULTS: Of the 154 persons admitted during the study period, 131 met the inclusion criteria. Median age was 15.1 years. At admission, 71% of participants were malnourished and 33 (25%) had been previously admitted. We observed a marked decrease in venous pH and stable pCO2 elevation during follow-up period. Hypercapnia at discharge was associated with a twofold increased likelihood of readmission and the odds of readmission increased as discharge pCO2 rose. These findings did not depend on AN subtype or participant sex. Electrolytes persisted within the normal range. CONCLUSION: Hypercapnia and respiratory acidosis are common alterations in children and adolescents hospitalized due to AN decompensation. Hypercapnia persists for at least 6 months after discharge despite clinical improvement and is associated with higher odds of readmission. This is the first study to identify an abnormal laboratory finding as a potential predictor of readmission in AN. LEVEL OF EVIDENCE: IV: Multiple time series without intervention.

Sarcoma de Kaposi, sífilis e neurocriptococose em paciente HIV positivo / Kaposi's sarcoma, syphilis and neurocryptococcosis in an HIV-positive patient

A infecção pelo vírus da imunodeficiência humana (HIV) tornou-se um problema de saúde pública em todo o mun-do nas últimas décadas. A principal característica do HIV é a supressão do sistema imunológico pelo ataque aos linfócitos T CD4+ que enfraquece o sistema imunológico e torna o indivíduo suscetível a infecções oportunistas, neoplasias secundárias e doenças neurológicas. Este estudo objetiva relatar e discutir o caso de um paciente HIV positivo que apresentou concomitantemente Sarcoma de Kaposi (SK), sífilis e neurocriptococose, todas doenças relacionadas ao HIV. Trata-se de um paciente masculino, 31 anos, que procurou o serviço do hospital de referência com lesões cutâneas violáceas em face, membros superiores e tórax, com três meses de evolução. Ao exame dermatológico exibiu placas eritematovioláceas infiltrativas, com bordas regulares, elevadas, descamativas e com diâmetros variáveis. Obteve sorologia positiva para anticorpos anti-HIV e VDRL, iniciando protocolos de terapia antirretroviral (TARV) e de tratamento para sífilis. O paciente retornou ao serviço 30 dias após alta hospitalar, com queixa de cefaleia de forte intensidade, refratária à analgesia com opioides, associada a vômitos persistentes. Re-alizada tomografia computadorizada de crânio, sem alterações, e, posteriormente, punção liquórica que evidenciou a presença de criptococo. Iniciado esquema terapêutico para neurocriptococose e realizadas outras duas punções liquóricas para alívio do quadro álgico. Este relato está de acordo com o que presume a literatura médica, reafirmando que pacientes HIV positivos apresentam maior predisposição para condições como o SK, a sífilis e a neurocriptococose. Dessa forma, o estudo ilustra com ineditismo a ocorrência simultânea de complexas manifestações clínicas no mesmo paciente imunossuprimido (AU).

Human immunodeficiency virus (HIV) infection has become a worldwide public health problem in recent decades. The main characteristic of HIV is the suppression of the immune system by attacking CD4+ T lymphocytes, which weakens the immune system and makes the individual susceptible to opportunistic infections, secondary neoplasms, and neurological diseases. This study aims to report and discuss the case of an HIV-positive patient who presented concomitantly Kaposi's Sarcoma (KS), primary syphilis, and neurocryptococcosis, all HIV-related. This is a 31-year-old male patient who sought care at the reference hospital with violaceous skin lesions on the face, upper limbs and chest, with a three-month evolution. Dermatological examination showed infiltrative erythematous-violet plaques, with regular, elevated, scaly edges and varying diameters. He obtained positive serology for anti-HIV and VDRL antibodies, initiating antiretroviral therapy (ART) and treatment protocols for primary syphilis. The patient re-turned to the service 30 days after hospital discharge, complaining of severe headache, refractory to analgesia with opioids, associated with persistent vomiting. Cranial computed tomography was performed and did not demonstrate alterations; later CSF puncture showed the presence of cryptococcus. A therapeutic scheme for neurocryptococcosis was started, and two other CSF punctures were performed to relieve the pain. This report agrees with the medical literature, reaffirming that HIV-positive patients present a greater predisposition to conditions such as KS, syphilis, and neurocryptococcosis. Thus, the study illustrates with uniqueness the simultaneous occurrence of complex clinical manifestations in the same immunosuppressed patient (AU),

Abandoned, lost or otherwise discarded fishing gear (ALDFG) as part of marine litter at the seafloor of the Baltic Sea - Characterization, quantification, polymer composition and possible impact.

As an important part of marine litter at the seafloor "Abandoned, lost, discarded or otherwise lost fishing gear" (ALDFG) is gaining increasing attention in environmental assessments. Within this study marine litter at the seafloor of the Baltic Sea was quantified and characterized with special regard to fishery as source. Litter items (LI) were collected within fishery catches by bottom trawling during three cruises in 2020 and 2021. The resulting mean litter abundance was 9.2 LI/km2. Approximately 56 % of all LI were plastic, with PE as the most frequently identified polymer. ALDFG was present in considerable amounts with a mean value of 2.2 LI/km2 (22.2 %). However, the absolute counts of fishery nets were low (0.4 LI/km2; 4.2 %). Regarding weight, fishery nets are the dominant part of litter at the Baltic seafloor. Threshold values for marine litter at the seafloor are missing and might be developed using quantitative data on ALDFG.

Visual quantification and identification of shallow seafloor marine litter in the southernmost North and Baltic seas using an epibenthic video sledge (EVS) - A comparison to bottom trawl data.

The quantification of the marine litter at the seafloor is a challenging process. Currently the majority of the data of marine litter at the seafloor is a by-product of bottom trawl fish stocks assessment. In the search for a new, less invasive and universally usable method, an epibenthic video sledge was used to make video recordings of the seafloor. With these videos a visual estimation of the marine litter in the southernmost North and Baltic seas was done. The estimated mean litter abundances with 526.8 litter items (LI)·km-2 in the Baltic Sea and 305.1 LI·km-2 in the North Sea are significantly higher compared to bottom trawl studies. Using both results conversion factors for marine litter catch efficiency of two fishing gears were calculated for the first-time. These new factors now allow obtaining more realistic quantitative data of seafloor litter abundance.

Correlations between oxidative DNA damage and formation of hepatic tumours in two flatfish species from contaminated environments.

Many species in aquatic environments face increased exposure to oncogenic pollution due to anthropogenic environmental change which can lead to higher cancer prevalence. The mechanistic relationship connecting environmental pollution and cancer is multi-factorial and poorly understood, and the specific mechanisms are so far still uncharacterized. One potential mediator between pollutant exposure and cancer is oxidative damage to DNA. We conducted a study in the field with two flatfish species, European flounder (Platichthys flesus L.) and common dab (Limanda limanda L.) with overlapping distribution and similar ecological niche, to investigate if the link between oncogenic pollutants and cancer described in ecotoxicological literature could be mediated by oxidative DNA damage. This was not the case for flounders as neither polycyclic aromatic hydrocarbon (PAH) bile metabolites nor metallic trace element concentrations were related to oxidative DNA damage measurements. However, dabs with higher PAH concentrations did exhibit increased oxidative damage. High oxidative DNA damage also did not predict neoplasm occurrence, rather, healthy individuals tended to have higher oxidative damage measurements compared to fishes with pre-neoplastic tumours. Our analyses showed that flounders had lower concentrations of PAH bile metabolites, suggesting that compared to dab this species is less exposed or better at eliminating these contaminants.

The orphan G protein-coupled receptor, GPR139, is expressed in the hypothalamus and is involved in the regulation of body mass, blood glucose, and insulin.

GPR139 is an orphan G-protein-coupled receptor that is expressed in restricted areas of the nervous system, including the hypothalamus. In this study, we hypothesized that GPR139 could be involved in the regulation of energy balance and metabolism. In the first part of the study, we confirmed that GPR139 is expressed in the hypothalamus and particularly in proopiomelanocortin and agouti-related peptide neurons of the mediobasal hypothalamus. Using a lentivirus with a short-hairpin RNA, we inhibited the expression of GPR139 bilaterally in the mediobasal hypothalamus of mice. The intervention promoted a 40% reduction in the hypothalamic expression of GPR139, which was accompanied by an increase in body mass, a reduction in fasting blood glucose levels, and an increase in insulin levels. In the hypothalamus, inhibition of GPR139 was accompanied by a reduction in the expression of orexin. As previous studies using a pharmacological antagonist of orexin showed a beneficial impact on type 2 diabetes and glucose metabolism, we propose that the inhibition of hypothalamic GPR139 could be acting indirectly through the orexin system to control systemic glucose and insulin. In conclusion, this study advances the characterization of GPR139 in the hypothalamus, demonstrating its involvement in the regulation of body mass, blood insulin, and glycemia.

Temporal trends of mercury levels in fish (dab, Limanda limanda) and sediment from the German Bight (North Sea) in the period 1995-2020.

As a toxic and harmful global pollutant, mercury (Hg) enters the marine environment through natural sources, and human activities. It bioaccumulates through the food chain and therefore, Hg is of great importance for environmental monitoring. This study aims to answer the question if Hg contamination in fish and sediment from the German Bight follows temporal trends. Therefore, 496 individual female dab (Limanda limanda) were analyzed. The Hg concentrations in the muscle of dab from the German Bight showed significant increase in function of time with an annual percental change of 1.4%, leading to a 41% increase in Hg contamination level within 25 years of monitoring. At the same time, Hg concentrations in sediment-analyzed in 86 samples-significantly decreased in the nearby North Sea environment. This surprising contradiction is shown in the present study and possible causes are discussed. It could be clearly shown that contamination in sediment and biota can follow completely different time courses and therefore, different environmental matrices should be considered in future monitoring studies. Age of the fish turned out to be a biological factor of particular importance for temporal trend analysis.

Decrease in the use of bronchodilators in the management of bronchiolitis after applying improvement initiatives.

INTRODUCTION: In the treatment of patients with acute bronchiolitis there is great variability in clinical practice. Treatments whose efficacy has not been demonstrated are frequently used despite the recommendations contained in the Clinical Practice Guidelines. MATERIAL AND METHODS: A quality improvement strategy is implemented in the care of patients with acute bronchiolitis in the Emergency Department, which is maintained for five years and is periodically updated to be increasingly restrictive regarding the use of bronchodilators. To evaluate the impact of the intervention, a retrospective study of the rates of prescription of bronchodilators in children diagnosed with acute bronchiolitis in the month of December of four epidemic periods (2012, 2014, 2016 and 2018) was carried out. RESULTS: 1767 children are included. There were no differences regarding age, respiratory rate, oxygen saturation or the estimated severity in each of the study seasons. The use of salbutamol in the Emergency Department decreased from 51.2% (95% CI: 46.6-55.8%) in 2012 to 7.8% (95% CI: 5.7%-10.5%) in 2018 (P < .001) and epinephrine prescription rates fell from 12.9% (95% CI: 10.1%-16.3%) to 0.2% (95% CI: 0-1.1%) (P < .001). At the same time, there was a decrease in the median time of attendance in the Emergency Department and in the admission rate without changing the readmission rate in 72 h. CONCLUSIONS: The systematic and continuous deployment over time of actions aimed at reducing the use of salbutamol and epinephrine in the treatment of bronchiolitis, prior to the epidemic period, seems an effective strategy to reduce the use of bronchodilators in the Emergency Department.

Metaphyseal sleeves in revision total knee arthroplasties: Computational analysis of bone remodeling.

BACKGROUND: Metaphyseal sleeves help maintain long term stability and reduce revision rate for aseptic loosening in total knee arthroplasty (TKA) revision. However, their performance regarding bone remodeling is still poorly known for the long term. This study aimed to investigate the impact of metaphyseal sleeves on the bone remodeling of the tibia. METHODS: Five finite element models of a female tibia with different implant configurations (regarding stem length and metaphyseal sleeve application) were developed. Loading conditions included joint reaction force, muscle, and tibia-fibula loads from 6 instances of the gait cycle. The bone remodeling model applied was adapted to the subject under analysis by selecting the bone remodeling parameters that best replicated the bone density distribution of the tibia estimated from the CT data. Changes in bone density after TKA were evaluated in 8 regions of interest. RESULTS: Global bone loss ranged from -31.16%, in 115 mm stemmed configurations, to -20.93%, in 75 mm stemmed configurations. Apart from the lateral and posterior regions in the proximal tibia, whose bone loss reduced and increased, respectively, due to the incorporation of a metaphyseal sleeve, changes in bone density were similar with and without a metaphyseal sleeve for each stem length. CONCLUSION: The results suggest that bone remodeling of the tibia is not critically affected by the incorporation of metaphyseal sleeves. Considering that sleeves are believed to present a favorable clinical outcome in stability and osseointegration, reducing the revision rate for aseptic loosening, their advantages seem to outweigh their disadvantages regarding bone remodeling.

¿Neumonía redonda o hallazgo casual? / Round pneumonia or incidental finding?

El diagnóstico diferencial de las neumonías redondas es amplio y engloba enfermedades infecciosas, neoplásicas y congénitas. La paciente que se presenta a continuación fue diagnosticada de una neumonía redonda con una clínica e imagen radiológica compatible. Sin embargo, el diagnóstico definitivo fue una malformación vascular. Este caso permite reflexionar sobre la importancia de valorar distintitos diagnósticos ante una condensación redondeada y sobre la necesidad o no de realizar una radiografía de control en estos casos. Además, lo más original del caso radica en el tratamiento que recibió para la malformación vascular, que no estaba descrito previamente: el propranolol (AU)

The differential diagnosis of round pneumonia is broad and includes infectious, malignant, and congenital diseases. The patient presented below received a diagnosis of round pneumonia based on compatible clinical and radiological findings; however, the definitive diagnosis was a vascular malformation. This case allows us to reflect on the importance of considering alternative diagnoses in the presence of round opacities in the lung and when performance of a follow-up X-ray is or not required in such cases. In addition, the most original aspect of this case lies in the treatment provided for the vascular malformation, which has not been previously described: propranolol. (AU)

Descenso del uso de broncodilatadores en el manejo de la bronquiolitis tras aplicar iniciativas de mejora / Decrease in the use of bronchodilators in the management of bronchiolitis after applying improvement initiatives

Introducción: En el tratamiento de los pacientes con bronquiolitis aguda existe una gran variabilidad de la práctica clínica y con frecuencia se utilizan de forma indiscriminada tratamientos cuya eficacia no está demostrada a pesar de las recomendaciones recogidas en las guías de práctica clínica. Material y métodos: Se implementó una estrategia de mejora de la calidad en la atención a los pacientes con bronquiolitis aguda en el Servicio de Urgencias que se mantuvo durante 5 años y se actualizó periódicamente para ser cada vez más restrictiva respecto al uso de tratamientos broncodilatadores. Para evaluar el impacto de la intervención se realizó un estudio descriptivo retrospectivo de las tasas de prescripción de broncodilatadores en los niños diagnosticados de bronquiolitis aguda en el mes de diciembre de 4 periodos epidémicos (2012, 2014, 2016 y 2018). Resultados: Se incluyó a 1.767 niños. No existieron diferencias respecto a edad, frecuencia respiratoria, saturación de oxígeno ni gravedad en cada una de las temporadas a estudio. El empleo de salbutamol en Urgencias descendió del 51,2% (IC del 95%: 46,6-55,8%) en 2012 al 7,8% (IC del 95%: 5,7-10,5%) en 2018 (p <0,001) y el de adrenalina del 12,9% (IC del 95%: 10,1-16,3%) al 0,2% (IC del 95%: 0-1,1%) (p <0,001). Se produjo a su vez un descenso en la mediana de tiempo de asistencia en Urgencias y en la tasa de ingreso sin que se modificase la tasa de readmisión en 72 h. Conclusiones: El despliegue sistemático y continuado en el tiempo de acciones dirigidas a la reducción del uso de fármacos en el tratamiento de la bronquiolitis, previo al periodo epidémico, parece una estrategia eficaz para reducir el uso de broncodilatadores en urgencias. (AU)

Introduction: In the treatment of patients with acute bronchiolitis there is great variability in clinical practice. Treatments whose efficacy has not been demonstrated are frequently used despite the recommendations contained in the Clinical Practice Guidelines. Material and methods: A quality improvement strategy is implemented in the care of patients with acute bronchiolitis in the Emergency Department, which is maintained for five years and is periodically updated to be increasingly restrictive regarding the use of bronchodilators. To evaluate the impact of the intervention, a retrospective study of the rates of prescription of bronchodilators in children diagnosed with acute bronchiolitis in the month of December of four epidemic periods (2012, 2014, 2016 and 2018) was carried out. Results: 1767 children are included. There were no differences regarding age, respiratory rate, oxygen saturation or the estimated severity in each of the study seasons. The use of salbutamol in the Emergency Department decreased from 51.2% (95% CI: 46.6%–55.8%) in 2012 to 7.8% (95% CI: 5.7%–10.5%) in 2018 (P<.001) and epinephrine prescription rates fell from 12.9% (95% CI: 10.1%–16.3%) to 0.2% (95% CI: 0–1.1%) (P<.001). At the same time, there was a decrease in the median time of attendance in the Emergency Department and in the admission rate without changing the readmission rate in 72h. Conclusions: The systematic and continuous deployment over time of actions aimed at reducing the use of salbutamol and epinephrine in the treatment of bronchiolitis, prior to the epidemic period, seems an effective strategy to reduce the use of bronchodilators in the Emergency Department. (AU)

Metagenomic Analysis of the Gastrointestinal Microbiota of Gadus morhua callarias L. Originating from a Chemical Munition Dump Site.

Several hundred thousand tonnes of munitions containing chemical warfare agents (CWAs) are lying on the seafloor worldwide. CWAs have started leaking from corroded munitions, and their presence in the environment and in organisms inhabiting dump sites has been detected. The presence of CWAs in the water negatively affects fish, macrobenthos and free-living bacteria. It can be expected that the presence of CWAs would also affect the gut-associated bacteria in fish, which are vital for their condition. The main aim of this study was to test if the microbiota of cod collected in the Baltic Bornholm Deep (highly polluted with CWAs) is dysregulated. To investigate this, we conducted metagenomic studies based on 16S rRNA gene sequencing. We found that the microbiota of cod inhabiting the dump site was significantly less taxonomically diverse compared to those from a non-polluted reference site. Moreover, taxa associated with fish diseases (e.g., Vibrionaceae, Aeromonadaceae) were more prevalent, and probiotic taxa (e.g., Actinobacteriota, Rhodobacteraceae) were less frequent in the guts of individuals from the dump site, than those from the reference site. The differences in vulnerability of various bacterial taxa inhabiting cod gastrointestinal tracts to CWAs were hypothesised to be responsible for the observed microbiota dysregulation.

The orphan receptor GPR68 is expressed in the hypothalamus and is involved in the regulation of feeding.

Currently, up to 35% off all drugs approved for the treatment of human diseases belong to the G-protein-coupled receptor (GPCR) family. Out of the almost 800 existing GPCRs, 25% have no known endogenous ligands and are regarded as orphan receptors; many of these are currently under investigation as potential pharmacological targets. Here, we hypothesised that orphan GPCRs expressed in the hypothalamus could be targets for the treatment of obesity and other metabolic diseases. Using bioinformatic tools, we identified 78 class A orphan GPCRs that are expressed in the hypothalamus of mice. Initially, we selected two candidates and determined their responsivities to nutritional interventions: GPR162, the GPCR with highest expression in the hypothalamus, and GPR68, a GPCR with intermediate expression in the hypothalamus and that has never been explored for its potential involvement in metabolic regulation. GPR162 expression was not modified by fasting/feeding or by the consumption of a high-fat diet, and was therefore not subsequently evaluated. Conversely, GPR68 expression increased in response to the consumption of a high-fat diet and reduced under fasting conditions. Using immunofluorescence, GPR68 was identified in both proopiomelanocortin-expressing and agouti-related peptide-expressing neurons in the hypothalamic arcuate nucleus. Acute inhibition of GPR68 with an allosteric modulator promoted an increase in the expression of the orexigenic agouti-related peptide and neuropeptide Y, whereas 4- and 12-h inhibition of GPR68 resulted in increased caloric intake. Thus, GPR68 has emerged as an orphan GPCR that is expressed in the hypothalamus and is involved in the regulation of feeding.