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Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11's role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina's Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28). This DNAm signature was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.
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Anomalías Múltiples , Proteínas Represoras , Niño , Femenino , Humanos , Anomalías Múltiples/sangre , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Enfermedades del Desarrollo Óseo/sangre , Enfermedades del Desarrollo Óseo/diagnóstico , Enfermedades del Desarrollo Óseo/genética , Deleción Cromosómica , Metilación de ADN/genética , Epigénesis Genética/genética , Facies , Discapacidad Intelectual/sangre , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Aprendizaje Automático , Mutación , Fenotipo , Proteínas Represoras/genética , Anomalías Dentarias/sangre , Anomalías Dentarias/diagnóstico , Anomalías Dentarias/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND AND PURPOSE: The US Headache Consortium developed evidence-based guidelines for the treatment of migraine and found grade A evidence in support of behavior therapy (BT). Understanding the mechanisms of BT may improve the management of migraine and reduce its burden. METHODS: We performed a narrative review to define the current evidence of BT and determine its usefulness in migraine management. RESULTS: The information was obtained from 116 publications, with 56 of them retrieved through direct searches in PubMed (2011-2020) and the remainder selected by the authors to complete the content. BT might reduce migraine impact by decreasing the sympathetic nervous system's response to stress and increasing pain tolerance. Acting in headache-related surroundings can be improved, together with headache duration and self-efficacy. Applications such as mobile health and electronic health applications can help to carry out healthier lifestyle patterns. Regarding medication overuse, BT seems to be a good choice, with similar results to pharmacological prophylaxis. Advantages of using BT are the lack of adverse effects and the unrestricted use in children, where BT is postulated to be even more effective than the standardized pharmacopeia. CONCLUSIONS: BT is an interesting tool that can be used as an add-on therapy in migraine. Through BT, the autonomy and empowerment of migraine patients is enhanced. BT may not cure migraine, but it could help to reduce pain severity perception, disability, and migraine impact, adding an emotive and cognitive approach to the perceptive role of pharmacopeia. Thus, a better approach in migraine, implementing specific therapeutic management, can improve migraine control.
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BACKGROUND: Robust evidence to inform best transfusion management after major oncologic surgery, where postoperative recovery might impact treatment regimens for cancer, is lacking. We conducted a study to validate the feasibility of a larger trial comparing liberal versus restrictive red blood cells (RBC) transfusion strategies after major oncologic surgery. STUDY DESIGN AND METHODS: This was a two-center, randomized, controlled, study of patients admitted to the intensive care unit after major oncologic surgery. Patients whose hemoglobin level dropped below 9.5 g/dL, were randomly assigned to immediately receive a 1-unit RBC transfusion (liberal) or delayed until the hemoglobin level dropped below 7.5 g/dL (restrictive). The primary outcome was the median hemoglobin level between randomization to day 30 post-surgery. Disability-free survival was evaluated by the WHODAS 2.0 questionnaire. RESULTS: 30 patients were randomized (15 patients/group) in 15 months with a mean recruitment rate of 1.8 patients per month. The median hemoglobin level was significantly higher in the liberal group than in the restrictive group: 10.1 g/dL (IQR 9.6-10.5) versus 8.8 g/dL (IQR 8.3-9.4), p < .001, and RBC transfusion rates were 100% versus 66.7%, p = .04. The disability-free survival was similar between groups: 26.7% versus 20%, p = 1. DISCUSSION: Our results support the feasibility of a phase 3 randomized controlled trial comparing the impact of liberal versus restrictive transfusion strategies on the functional recovery of critically ill patients following major oncologic surgery.
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Transfusión Sanguínea , Hemoglobinas , Humanos , Proyectos Piloto , Hemoglobinas/análisis , Transfusión de Eritrocitos/métodos , Unidades de Cuidados IntensivosRESUMEN
Rationale: Streptococcus pneumoniae serotype 3 (SPN3) is a cause of invasive pneumococcal disease and associated with low carriage rates. Following the introduction of pediatric 13-valent pneumococcal conjugate vaccine (PCV13) programs, SPN3 declines are less than other vaccine serotypes and incidence has increased in some populations coincident with a shift in predominant circulating SPN3 clade, from I to II. A human challenge model provides an effective means for assessing the impact of PCV13 on SPN3 in the upper airway. Objectives: To establish SPN3's ability to colonize the nasopharynx using different inoculum clades and doses, and the safety of an SPN3 challenge model. Methods: In a human challenge study involving three well-characterized and antibiotic-sensitive SPN3 isolates (PFESP306 [clade Ia], PFESP231 [no clade], and PFESP505 [clade II]), inoculum doses (10,000, 20,000, 80,000, and 160,000 cfu/100 µl) were escalated until maximal colonization rates were achieved, with concurrent acceptable safety. Measurement and Main Results: Presence and density of experimental SPN3 nasopharyngeal colonization in nasal wash samples, assessed using microbiological culture and molecular methods, on Days 2, 7, and 14 postinoculation. A total of 96 healthy participants (median age 21, interquartile range 19-25) were inoculated (n = 6-10 per dose group, 10 groups). Colonization rates ranged from 30.0-70.0% varying with dose and isolate. 30.0% (29/96) reported mild symptoms (82.8% [24/29] developed a sore throat); one developed otitis media requiring antibiotics. No serious adverse events occurred. Conclusions: An SPN3 human challenge model is feasible and safe with comparable carriage rates to an established Serotype 6B human challenge model. SPN3 carriage may cause mild upper respiratory symptoms.
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Infecciones Neumocócicas , Streptococcus pneumoniae , Humanos , Niño , Lactante , Adulto Joven , Adulto , Serogrupo , Portador Sano , Vacunas Neumococicas/uso terapéutico , Infecciones Neumocócicas/prevención & control , Nasofaringe/microbiología , Antibacterianos/uso terapéutico , Antibacterianos/farmacologíaRESUMEN
BACKGROUND: The diagnosis of a life-limiting condition of a child in the perinatal or neonatal period is a threat to parental hopes. Hope is an interactional and multidimensional construct, and in palliative care, it is a determinant of quality of life, survival, acceptance and peaceful death. OBJECTIVE: To map scientific evidence on parents' hope in perinatal and neonatal palliative care contexts. METHOD: a scoping review theoretically grounded on Dufault and Martocchio's Framework, following the Joanna Briggs Institute methodological recommendations. Searches were performed until May 2023 in the MEDLINE, CINAHL and PsycINFO databases. The searches returned 1341 studies. RESULTS: Eligible papers included 27 studies, most of which were carried out in the United States under a phenomenological or literature review approach. The centrality of women's perspectives in the context of pregnancy and perinatal palliative care was identified. The parental hope experience is articulated in dealing with the uncertainty of information and diagnosis, an approach to which interaction with health professionals is a determinant and potentially distressful element. Hope was identified as one of the determinants of coping and, consequently, linked to autonomy and parenthood. Cognitive and affiliative dimensions were the hope dimensions that predominated in the results, which corresponded to the parents' ability to formulate realistic goals and meaningful interpersonal relationships, respectively. CONCLUSION: Hope is a force capable of guiding parents along the path of uncertainties experienced through the diagnosis of a condition that compromises their child's life. Health professionals can manage the family's hope by establishing sensitive therapeutic relationships that focus on the dimension of hope. The need for advanced research and intervention in parental and family hope are some of the points made in this study. PROTOCOL REGISTRATION: https://osf.io/u9xr5/ .
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Cuidados Paliativos , Calidad de Vida , Femenino , Humanos , Recién Nacido , Embarazo , Relaciones Interpersonales , Cuidados Paliativos/psicología , Padres/psicología , IncertidumbreRESUMEN
PURPOSE: Rare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation. METHODS: We obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine-based classifier distinguishing CDK13-RD and non-CDK13-RD samples. RESULTS: We reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance. CONCLUSION: We describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Proteína Quinasa CDC2/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
Bisphenols, endocrine disrupting chemicals, have frequently been used for producing food packaging materials. The best-known member, bisphenol A (BPA), has been linked to impaired foetal development in animals. Possible negative effects of BPA on human health have resulted in the production of novel, so-called next-generation (NextGen) bisphenols whose effects on humans are much less explored or even missing. This review aimed to summarise and critically assess the main findings and shortages in current bisphenol research in relation to their potential impact on the cardiovascular system in real biological exposure. Because of the common presence of bisphenols in daily use products, humans are clearly exposed to these compounds. Most data are available on BPA, where total serum levels (i.e. included conjugated metabolite) can reach up to â¼430 nM, while free bisphenol levels have been reported up to â¼80 nM. Limited data are available for other bisphenols, but maximal serum levels of bisphenol S have been reported (680 nM). Such levels seem to be negligible, although in vitro studies have showed effects on ion channels, and thyroid, oestrogenic and androgenic receptors in low micromolar concentrations. Ex vivo studies suggest vasodilatory effects of bisphenols. This stays in clear contrast to the elevation of arterial blood pressure documented in vivo and in observatory cross-sectional human studies. Bisphenols are also claimed to have a negative effect on lipidic spectrum and coronary artery disease. Regardless, the reported data are generally inconsistent and unsatisfactory. Hence novel well-designed studies, testing in particular NextGen bisphenols, are needed.
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Sistema Cardiovascular , Disruptores Endocrinos , Animales , Compuestos de Bencidrilo/toxicidad , Estudios Transversales , Disruptores Endocrinos/toxicidad , Femenino , Fenoles , EmbarazoRESUMEN
About 11% of all human disease-associated gene lesions are nonsense mutations, resulting in the introduction of an in-frame premature translation-termination codon (PTC) into the protein-coding gene sequence. When translated, PTC-containing mRNAs originate truncated and often dysfunctional proteins that might be non-functional or have gain-of-function or dominant-negative effects. Therapeutic strategies aimed at suppressing PTCs to restore deficient protein function-the so-called nonsense suppression (or PTC readthrough) therapies-have the potential to provide a therapeutic benefit for many patients and in a broad range of genetic disorders, including cancer. These therapeutic approaches comprise the use of translational readthrough-inducing compounds that make the translational machinery recode an in-frame PTC into a sense codon. However, most of the mRNAs carrying a PTC can be rapidly degraded by the surveillance mechanism of nonsense-mediated decay (NMD), thus decreasing the levels of PTC-containing mRNAs in the cell and their availability for PTC readthrough. Accordingly, the use of NMD inhibitors, or readthrough-compound potentiators, may enhance the efficiency of PTC suppression. Here, we review the mechanisms of PTC readthrough and their regulation, as well as the recent advances in the development of novel approaches for PTC suppression, and their role in personalized medicine.
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Codón sin Sentido , Enfermedades Genéticas Congénitas/terapia , Degradación de ARNm Mediada por Codón sin Sentido , Biosíntesis de Proteínas , Enfermedades Genéticas Congénitas/genética , HumanosRESUMEN
The largest ever recorded epidemic of the Chikungunya virus (CHIKV) broke out in 2004 and affected four continents. Acute symptomatic infections are typically associated with the onset of fever and often debilitating polyarthralgia/polyarthritis. In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. Among these genes, the putative role of the Eukaryotic Initiation Factor (eIF) family genes and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3A) in the CHIKV replication process were displayed. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation. The observations provided valuable insights into virus-host interactions during the acute phase and can be instrumental in the investigation of new and effective therapeutic interventions.
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Artritis/inmunología , Fiebre Chikungunya/inmunología , Virus Chikungunya/fisiología , Citidina Desaminasa/inmunología , Proteínas/inmunología , Replicación Viral/inmunología , Adulto , Animales , Artritis/patología , Artritis/virología , Fiebre Chikungunya/patología , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Femenino , Fiebre/inmunología , Fiebre/patología , Fiebre/virología , Estudios de Seguimiento , Humanos , Interleucina-1beta/inmunología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/inmunologíaRESUMEN
PURPOSE: Within this study, we aimed to discover novel gene-disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS). METHODS: We followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene-disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients. RESULTS: We propose six novel gene-disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral-facial-digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia. CONCLUSION: Our results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene-disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.
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Exoma , Discapacidad Intelectual , Secuencia de Bases , Exoma/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso , Fenotipo , Secuenciación del ExomaRESUMEN
OBJECTIVES: To describe the first outbreak of Candida auris in Brazil, including epidemiological, clinical and microbiological data. METHODS: After the first Candida auris-colonised patient was diagnosed in a COVID-19 ICU at a hospital in Salvador, Brazil, a multidisciplinary team conducted a local C. auris prevalence investigation. Screening cultures for C. auris were collected from patients, healthcare workers and inanimate surfaces. Risk factors for C. auris colonisation were evaluated, and the fungemia episodes that occurred after the investigation were also analysed and described. Antifungal susceptibility of the C. auris isolates was determined, and they were genotyped with microsatellite analysis. RESULTS: Among body swabs collected from 47 patients, eight (n = 8/47, 17%) samples from the axillae were positive for C. auris. Among samples collected from inanimate surfaces, digital thermometers had the highest rate of positive cultures (n = 8/47, 17%). Antifungal susceptibility testing showed MICs of 0.5 to 1 mg/L for AMB, 0.03 to 0.06 mg/L for voriconazole, 2 to 4 mg/L for fluconazole and 0.03 to 0.06 mg/L for anidulafungin. Microsatellite analysis revealed that all C. auris isolates belong to the South Asian clade (Clade I) and had different genotypes. In multivariate analysis, having a colonised digital thermometer was the only independent risk factor associated with C. auris colonisation. Three episodes of C. auris fungemia occurred after the investigation, with 30-day attributable mortality of 33.3%. CONCLUSIONS: Emergence of C. auris in Salvador, Brazil, may be related to local C. auris clade I closely related genotypes. Contaminated axillary monitoring thermometers may facilitate the dissemination of C. auris reinforcing the concept that these reusable devices should be carefully cleaned with an effective disinfectant or replaced by other temperature monitoring methods.
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Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis/diagnóstico , Candidiasis/tratamiento farmacológico , Candidiasis/epidemiología , Transmisión de Enfermedad Infecciosa , Termómetros/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Anidulafungina/uso terapéutico , Brasil/epidemiología , COVID-19/complicaciones , COVID-19/microbiología , Cuidados Críticos , Brotes de Enfermedades , Femenino , Fluconazol/uso terapéutico , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Prevalencia , SARS-CoV-2 , Voriconazol/uso terapéuticoRESUMEN
EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.
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Anomalías Musculoesqueléticas/genética , N-Acetilglucosaminiltransferasas/genética , Osteocondrodisplasias/genética , Alelos , Línea Celular , Línea Celular Tumoral , Condroitín/sangre , Condroitín/orina , Variaciones en el Número de Copia de ADN , Estudio de Asociación del Genoma Completo , Glicosaminoglicanos/metabolismo , Humanos , Anomalías Musculoesqueléticas/diagnóstico , Mutación Missense , Osteocondrodisplasias/diagnóstico , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genéticaRESUMEN
The choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are fundamental to neurophysiological functions of the central cholinergic system. We confirmed and quantified the presence of extracellular ChAT protein in human plasma and also characterized ChAT and VAChT polymorphisms, protein and activity levels in plasma of Alzheimer's disease patients (AD; N = 112) and in cognitively healthy controls (EC; N = 118). We found no significant differences in plasma levels of ChAT activity and protein between AD and EC groups. Although no differences were observed in plasma ChAT activity and protein concentration among ChEI-treated and untreated AD patients, ChAT activity and protein levels variance in plasma were higher among the rivastigmine-treated group (ChAT protein: p = 0.005; ChAT activity: p = 0.0002). Moreover, AD patients homozygous for SNP rs1880676 A allele exhibited higher levels of ChAT activity. Considering this is the first study to report the influence of genetic variability of CHAT locus over ChAT activity in AD patients plasma, it opens a new set of important questions on peripheral cholinergic signaling in AD.
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Chagas disease (CD), caused by the protozoa Trypanosoma cruzi, is a chronic illness in which parasites persist in the host-infected tissues for years. T. cruzi invasion in cardiomyocytes elicits the production of pro-inflammatory mediators [TNF-α, IL-1ß, IFN-γ; nitric oxide (·NO)], leading to mitochondrial dysfunction with increased superoxide radical (O2·-), hydrogen peroxide (H2O2) and peroxynitrite generation. We hypothesize that these redox mediators may control parasite proliferation through the induction of intracellular amastigote programmed cell death (PCD). In this work, we show that T. cruzi (CL-Brener strain) infection in primary cardiomyocytes produced an early (24â h post infection) mitochondrial dysfunction with H2O2 generation and the establishment of an oxidative stress evidenced by FoxO3 activation and target host mitochondrial protein expression (MnSOD and peroxiredoxin 3). TNF-α/IL-1ß-stimulated cardiomyocytes were able to control intracellular amastigote proliferation compared with unstimulated cardiomyocytes. In this condition leading to oxidant formation, an enhanced number of intracellular apoptotic amastigotes were detected. The ability of H2O2 to induce T. cruzi PCD was further confirmed in the epimastigote stage of the parasite. H2O2 treatment induced parasite mitochondrial dysfunction together with intra-mitochondrial O2·- generation. Importantly, parasites genetically engineered to overexpress mitochondrial Fe-superoxide dismutase (Fe-SODA) were more infective to TNF-α/IL-1ß-stimulated cardiomyocytes with less apoptotic amastigotes; this result underscores the role of this enzyme in parasite survival. Our results indicate that cardiomyocyte-derived diffusible mediators are able to control intracellular amastigote proliferation by triggering T. cruzi PCD and that parasite Fe-SODA tilts the process toward survival as part of an antioxidant-based immune evasion mechanism.
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Enfermedad de Chagas/parasitología , Interacciones Huésped-Parásitos , Hierro/metabolismo , Mitocondrias/patología , Miocitos Cardíacos/patología , Estrés Oxidativo , Superóxido Dismutasa/metabolismo , Animales , Apoptosis , Células Cultivadas , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/patología , Ratones , Ratones Endogámicos BALB C , Mitocondrias/metabolismo , Mitocondrias/parasitología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/parasitología , Oxidación-Reducción , Ratas , Superóxido Dismutasa/genética , Superóxidos , Trypanosoma cruzi/patogenicidadRESUMEN
This study was aimed to microencapsulate fish oil (FO) in two biocompatible polymeric blends: gum arabic (GA)-maltodextrin (MD) and casein-pectin (CP)-MD. GA-MD microparticles and CP-MD microparticles were produced by spray-drying and complex coacervation and spray-drying, respectively. Encapsulation efficiency, particle size, moisture content, oxidative stability, and morphological properties were analysed. Encapsulation efficiencies of 51.2-56.8% (w/v) for GA and 64.7-67.9% (w/v) for CP preparations were found. GA particle sizes varied from 2 to 100 µm and from 2 to 120 µm for CP microparticles. Spherical forms with depressions in the topography of both systems were evidenced by scanning electron microscopy. Confocal microscopy evidenced surface oil on GA microparticles, corroborating encapsulation efficiency. CP was more efficient than GA to reduce oxidation, with maximum peroxide values (PVs) of 17.40 mmol/kg oil after 28 d at 40 °C/75% relative humidity (RH). Thus, CP is a promising biopolymeric blend for encapsulation of FO that provides protection against lipid oxidation.
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Caseínas/química , Excipientes/química , Aceites de Pescado/administración & dosificación , Goma Arábiga/química , Pectinas/química , Cápsulas , Composición de Medicamentos , Aceites de Pescado/química , Oxidación-Reducción , Polisacáridos/químicaRESUMEN
Oxygen is commonly administered in hospitals, with poor adherence to treatment recommendations.We conducted a multicentre randomised controlled study in patients admitted to the emergency department requiring O2 ≥3â L·min-1 Patients were randomised to automated closed-loop or manual O2 titration during 3â h. Patients were stratified according to arterial carbon dioxide tension (PaCO2 ) (hypoxaemic PaCO2 ≤45â mmHg; or hypercapnic PaCO2 >45-≤55â mmHg) and study centre. Arterial oxygen saturation measured by pulse oximetry (SpO2 ) goals were 92-96% for hypoxaemic, or 88-92% for hypercapnic patients. Primary outcome was % time within SpO2 target. Secondary endpoints were hypoxaemia and hyperoxia prevalence, O2 weaning, O2 duration and hospital length of stay.187 patients were randomised (93 automated, 94 manual) and baseline characteristics were similar between the groups. Time within the SpO2 target was higher under automated titration (81±21% versus 51±30%, p<0.001). Time with hypoxaemia (3±9% versus 5±12%, p=0.04) and hyperoxia under O2 (4±9% versus 22±30%, p<0.001) were lower with automated titration. O2 could be weaned at the end of the study in 14.1% versus 4.3% patients in the automated and manual titration group, respectively (p<0.001). O2 duration during the hospital stay was significantly reduced (5.6±5.4 versus 7.1±6.3â days, p=0.002).Automated O2 titration in the emergency department improved oxygenation parameters and adherence to guidelines, with potential clinical benefits.
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Servicio de Urgencia en Hospital/estadística & datos numéricos , Hiperoxia/epidemiología , Hipoxia/epidemiología , Terapia por Inhalación de Oxígeno/métodos , Oxígeno/administración & dosificación , Anciano , Anciano de 80 o más Años , Canadá , Dióxido de Carbono/sangre , Femenino , Francia , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Oximetría , Oxígeno/efectos adversos , Terapia por Inhalación de Oxígeno/efectos adversosRESUMEN
Q fever is a zoonotic infection caused by the pathogen Coxiella burnetii, and patients can present with a wide spectrum of clinical manifestations, depending on whether it is an acute or a chronic infection. We present the case of a 61-year-old male with fatigue, posterior thoracalgia, intermittent fever, night sweats and weight loss for a month. After an extensive workup, he was diagnosed with acute Q fever with large-vessel vasculitis. The FDG-PET/CT scan suggested an active vasculitis specifically in the thoracic aorta, proximal abdominal aorta, subclavian and carotid vessels, suggesting an immunologic response to acute Q fever infection, barely reported worldwide. LEARNING POINTS: Large-vessel vasculitis is a possible immunologic response to acute Q fever infection.There are few data about the management and treatment of patients with Q fever related large-vessel vasculitis.
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AIM: This study aims to explore the perceptions of feedback among undergraduate students and faculty members at a Brazilian private nursing school. BACKGROUND: Feedback plays a crucial role in the socioemotional development of learners, with its interpretation varying across different sociocultural contexts. Student evaluations frequently express dissatisfaction regarding both the quality and quantity of feedback received. Conversely, delivering feedback poses a challenge for faculty, requiring the establishment of an empathetic connection that fosters trust and credibility. Brazil, being a developing country characterized by social disparities and economic challenges, presents a unique backdrop for examining feedback dynamics. DESIGN: Qualitative research, employing Inductive Content Analysis, was used to understand feedback perceptions in Brazilian nursing education. Symbolic interactionism was adopted as methodological framework and guided data interpretation. METHODS: We carried out five virtual focus groups composed of a group of teachers (n=5) and four of students (n=34). Semi-structured interviews guided data collection. The recorded sessions were subsequently analyzed to identify key themes and codes. Symbolic interactionism was employed as a framework to derive meaning from qualitative data. RESULTS: Content analysis generated two categories that reveal the perception of teachers and students in the feedback process. The first, called "Feedback in Education: Sociocultural Influences for Students and Teachers", expresses the beliefs and interpretations of students and teachers within the shared feedback environment. The second called "Challenging resonance, transformative construction: Navigating the dualities of feedback for teachers and students", which elucidated how relational dynamics shape behaviors and attitudes, promoting the development of social skills and learning. Faculty's previous feedback experiences significantly influence their self-perception and behavior with students. As a result of the resonance of these past interactions, we recognize that the teaching self also plays a crucial role in the quality and perception of feedback. Furthermore, students construct social reality with similar beliefs and values, they believe in the learning potential generated by feedback. Our findings also corroborate that perceptions of feedback are deeply influenced by the sociocultural context and the narratives corroborate previous findings indicating that, in Brazil, honest feedback can be implicitly perceived as criticism rather than an opportunity for growth. CONCLUSIONS: Faculty members often draw on their past experiences when providing feedback, highlighting the adaptive nature of feedback interactions. Additionally, the feedback process is consistently influenced by the commitment to maintaining positive relationships with students. Students recognize the constructive dimension of feedback as a valuable tool for learning and personal growth.
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Flavonoids are considered as health-protecting food constituents. The testing of their biological effects is however hampered by their low oral absorption and complex metabolism. In order to investigate the direct effect(s) of unmetabolized flavonoid, a preparation in a biologically friendly solvent for intravenous administration is needed. Isorhamnetin, a natural flavonoid and a human metabolite of the most frequently tested flavonoid quercetin, has very low water solubility (<3.5 µg/mL). The aim of this study was to improve its solubility to enable intravenous administration and to test its pharmacokinetics in an animal model. By using polyvinylpyrrolidone (PVP10) and benzalkonium chloride, we were able to improve the solubility approximately 600 times to 2.1 mg/mL. This solution was then administered intravenously at a dose of 0.5 mg/kg of isorhamnetin to rats and its pharmacokinetics was analyzed. The pharmacokinetics of isorhamnetin corresponded to two compartmental model with a rapid initial distribution phase (t1/2α: 5.7 ± 4.3 min) and a slower elimination phase (t1/2ß: 61 ± 47.5 min). Two sulfate metabolites were also identified. PVP10 and benzalkonium did not modify the properties of isorhamnetin (iron chelation and reduction, and cell penetration) substantially. In conclusion, the novel preparation reported in this study is suitable for future testing of isorhamnetin effects under in vivo conditions.