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Exploitable or potentially exploitable deposits of critical metals, such as rare-earth (REE) and high-field-strength elements (HFSE), are commonly associated with alkaline or peralkaline igneous rocks. However, the origin, transport and concentration of these metals in peralkaline systems remains poorly understood. This study presents the results of a mineralogical and geochemical investigation of the Na-metasomatism of alkali amphiboles and clinopyroxenes from a barren peralkaline granite pluton in NE China, to assess the remobilization and redistribution of REE and HFSE during magmatic-hydrothermal evolution. Alkali amphiboles and aegirine-augites from the peralkaline granites show evolutionary trends from sodic-calcic to sodic compositions, with increasing REE and HFSE concentrations as a function of increasing Na-index [Na#, defined as molar Na/(Na+Ca) ratios]. The Na-amphiboles (i.e., arfvedsonite) and aegirine-augites can be subsequently altered, or breakdown, to form hydrothermal aegirine during late- or post-magmatic alteration. Representative compositions analyzed by in-situ LA-ICPMS show that the primary aegirine-augites have high and variable REE (2194-3627 ppm) and HFSE (4194-16,862 ppm) contents, suggesting that these critical metals can be scavenged by alkali amphiboles and aegirine-augites. Compared to the primary aegirine-augites, the presentative early replacement aegirine (Aeg-I, Na# = 0.91-0.94) has notably lower REE (1484-1972) and HFSE (4351-5621) contents. In contrast, the late hydrothermal aegirine (Aeg-II, Na# = 0.92-0.96) has significantly lower REE (317-456 ppm) and HFSE (6.44-72.2 ppm) contents. Given that the increasing Na# from aegirine-augites to hydrothermal aegirines likely resulted from Na-metasomatism, a scavenging-release model can explain the remobilization of REE and HFSE in peralkaline granitic systems. The scavenging and release of REE and HFSE by Na-metasomatism provides key insights into the genesis of globally significant REE and HFSE deposits. The high Na-index of the hydrothermal aegirine might be useful as a geochemical indicator in the exploration for these critical-metals.
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Current influenza vaccines could be augmented by including recombinant neuraminidase (rNA) protein antigen to broaden protective immunity and improve efficacy. Toward this goal, we investigated formulation conditions to optimize rNA physicochemical stability. When rNA in sodium phosphate saline buffer (NaPBS) was frozen and thawed (F/T), the tetrameric structure transitioned from a "closed" to an "open" conformation, negatively impacting functional activity. Hydrogen deuterium exchange experiments identified differences in anchorage binding sites at the base of the open tetramer, offering a structural mechanistic explanation for the change in conformation and decreased functional activity. Change to the open configuration was triggered by the combined stresses of acidic pH and F/T. The desired closed conformation was preserved in a potassium phosphate buffer (KP), minimizing pH drop upon freezing and including 10% sucrose to control F/T stress. Stability was further evaluated in thermal stress studies where changes in conformation were readily detected by ELISA and size exclusion chromatography (SEC). Both tests were suitable indicators of stability and antigenicity and considered potential critical quality attributes (pCQAs). To understand longer-term stability, the pCQA profiles from thermally stressed rNA at 6 months were modeled to predict stability of at least 24-months at 5°C storage. In summary, a desired rNA closed tetramer was maintained by formulation selection and monitoring of pCQAs to produce a stable rNA vaccine candidate. The study highlights the importance of understanding and controlling vaccine protein structural and functional integrity.
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Vacunas contra la Influenza , Gripe Humana , Humanos , Gripe Humana/prevención & control , Neuraminidasa/genética , Vacunas Sintéticas/genética , ARNRESUMEN
Background: Significant advances in managing congenital heart disease (CHD) have occurred over the past few decades, resulting in a fast-growing adult patient population with distinct needs requiring urgent attention. Research has recently highlighted the prevalence of neurocognitive differences among adults living with CHD. Yet, there is a lack of knowledge about the perspectives of people living with CHD and family members/caregivers on brain health. We sought to explore their perspectives to guide future research and clinical endeavours. Methods: Using the principles of integrated knowledge translation and qualitative interpretive description, we conducted 2 focus groups with 7 individuals with CHD and their family members as part of a virtual forum on brain health in CHD. Data analysis followed the principles of interpretive description. Results: A lack of understanding about overall brain health and neurocognitive differences in adult CHD was identified. To increase overall knowledge about brain health, initiatives should (1) focus on the individual living with CHD, involving family members and peers; (2) use social media and health care encounters for knowledge exchange; and (3) ensure a "balancing act" in the information provided to avoid feelings of worry and uncertainty about the future while simultaneously empowering people living with CHD. Conclusions: There is a pressing need for better education about brain health among individuals living with CHD. Our findings can guide clinicians in developing programmes of care and (re)design health services that address the brain-heart axis and neurocognitive differences in CHD.
Contexte: Des progrès significatifs ont été réalisés au cours des dernières décennies dans la prise en charge des cardiopathies congénitales, et il en résulte une croissance rapide de la population des patients adultes dont les besoins distincts requièrent une attention urgente. Des études récentes ont mis en évidence la prévalence des différences neurocognitives chez les adultes atteints de cardiopathies congénitales (CC). À ce jour, les connaissances sur les points de vue des personnes qui vivent avec la CC, des membres de leurs familles et de leurs aidants au sujet de la santé du cerveau sont insuffisantes. Notre objectif était d'explorer ces points de vue afin d'orienter les recherches à venir et les initiatives cliniques. Méthodologie: En nous basant sur les approches d'application des connaissances intégrées et de description interprétative (DI) qualitative, nous avons organisé deux groupes de discussion avec 7 personnes atteintes de CC et les membres de leur famille, dans le cadre d'un forum virtuel sur la santé du cerveau dans les CC. L'analyse des données a été réalisée selon les principes de la DI. Résultats: Un manque de connaissances au sujet de la santé du cerveau en général et des différences neurocognitives chez les personnes atteintes de CC a été observé. Afin d'améliorer le niveau des connaissances générales sur la santé du cerveau, les initiatives doivent : (1) être centrées sur les personnes qui vivent avec la CC, avec la participation des membres de leur famille et d'autres patients; (2) tirer profit des médias sociaux et des rencontres en contexte de soins de santé pour le partage de connaissances; et (3) veiller à maintenir un équilibre, puisqu'il convient d'outiller les personnes atteintes de CC sans toutefois causer de sentiment d'inquiétude ou d'incertitude quant à l'avenir. Conclusions: Nous avons constaté le besoin urgent d'améliorer les connaissances des personnes qui vivent avec une CC au sujet de la santé du cerveau. Les résultats obtenus pourront guider les cliniciens dans l'élaboration de programmes de soins et la conception (ou la refonte) de services de soins de santé qui intègrent l'axe cerveau-cÅur et les différences neurocognitives associées aux CC.
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Accurate estimation of photovoltaic (PV) system performance is crucial for determining its feasibility as a power generation technology and financial asset. PV-based energy solutions offer a viable alternative to traditional energy resources due to their superior Levelized Cost of Energy (LCOE). A significant challenge in assessing the LCOE of PV systems lies in understanding the Performance Loss Rate (PLR) for large fleets of PV systems. Estimating the PLR of PV systems becomes increasingly important in the rapidly growing PV industry. Precise PLR estimation benefits PV users by providing real-time monitoring of PV module performance, while explainable PLR estimation assists PV manufacturers in studying and enhancing the performance of their products. However, traditional PLR estimation methods based on statistical models have notable drawbacks. Firstly, they require user knowledge and decision-making. Secondly, they fail to leverage spatial coherence for fleet-level analysis. Additionally, these methods inherently assume the linearity of degradation, which is not representative of real world degradation. To overcome these challenges, we propose a novel graph deep learning-based decomposition method called the Spatio-Temporal Graph Neural Network for fleet-level PLR estimation (PV-stGNN-PLR). PV-stGNN-PLR decomposes the power timeseries data into aging and fluctuation components, utilizing the aging component to estimate PLR. PV-stGNN-PLR exploits spatial and temporal coherence to derive PLR estimation for all systems in a fleet and imposes flatness and smoothness regularization in loss function to ensure the successful disentanglement between aging and fluctuation. We have evaluated PV-stGNN-PLR on three simulated PV datasets consisting of 100 inverters from 5 sites. Experimental results show that PV-stGNN-PLR obtains a reduction of 33.9% and 35.1% on average in Mean Absolute Percent Error (MAPE) and Euclidean Distance (ED) in PLR degradation pattern estimation compared to the state-of-the-art PLR estimation methods.
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Modelos Estadísticos , Redes Neurales de la ComputaciónRESUMEN
Mouse models are central to studying and understanding the genotypic-to-phenotypic outcomes of Down syndrome (DS), a complex condition caused by an extra copy of the long arm of human chromosome 21. The recently developed TcMAC21-a transchromosomic mouse strain with comparable gene dosage to human chromosome 21 (Hsa21)-includes more Hsa21 genes than any other model of DS. Recent studies on TcMAC21 have provided valuable insight into the molecular, physiological, and neuroanatomical aspects of the model. However, relatively little is known about the craniofacial phenotype of TcMAC21 mice, particularly as it compares to the widely studied Ts65Dn model. Here we conducted a quantitative study of the cranial morphology of TcMAC21 and Ts65Dn mice and their respective unaffected littermates. Our comparative data comprise forty three-dimensional cranial measurements taken on micro-computed tomography scans of the heads of TcMAC21 and Ts65Dn mice. Our results show that TcMAC21 exhibit similar patterns of craniofacial change to Ts65Dn. However, the DS-specific morphology is more pronounced in Ts65Dn mice. Specifically, Ts65Dn present with more medio-lateral broadening and retraction of the snout compared to TcMAC21. Our findings reveal the complexity of potential gene interaction in the production of craniofacial phenotypes.
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Modelos Animales de Enfermedad , Síndrome de Down , Cráneo , Síndrome de Down/patología , Síndrome de Down/genética , Animales , Ratones , Cráneo/diagnóstico por imagen , Microtomografía por Rayos X , Masculino , FenotipoRESUMEN
The failure to consult with the public in policymaking can result in less sound and supportable policies. The Crosscurrents Dialogue Model (CDM) was developed to explore if Americans with different political perspectives could have useful policy conversations. To date, the CDM participants have addressed 10 separate topics such as health care and immigration and reached agreements each time. CDM provides evidence that the divide between politically diverse Americans can be bridged adequately to agree on specific recommendations for action. (Am J Public Health. 2023;113(10):1099-1101. https://doi.org/10.2105/AJPH.2023.307359).
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Comunicación , Formulación de Políticas , Atención a la Salud , Emigración e InmigraciónRESUMEN
Children with Down syndrome (DS, trisomy of chromosome 21) have an increased risk of infantile spasms (IS). As an epileptic encephalopathy, IS may further impair cognitive function and exacerbate neurodevelopmental delays already present in children with DS. To investigate the pathophysiology of IS in DS, we induced IS-like epileptic spasms in a genetic mouse model of DS that carries human chromosome 21q, TcMAC21, the animal model most closely representing gene dosage imbalance in DS. Repetitive extensor/flexor spasms were induced by the GABAB receptor agonist γ-butyrolactone (GBL) and occurred predominantly in young TcMAC21 mice (85%) but also in some euploid mice (25%). During GBL application, background electroencephalographic (EEG) amplitude was reduced, and rhythmic, sharp-and-slow wave activity or high-amplitude burst (epileptiform) events emerged in both TcMAC21 and euploid mice. Spasms occurred only during EEG bursts, but not every burst was accompanied by a spasm. Electrophysiological experiments revealed that basic membrane properties (resting membrane potential, input resistance, action-potential threshold and amplitude, rheobase, input-output relationship) of layer V pyramidal neurons were not different between TcMAC21 mice and euploid controls. However, excitatory postsynaptic currents (EPSCs) evoked at various intensities were significantly larger in TcMAC21 mice than euploid controls, while inhibitory postsynaptic currents (IPSCs) were similar between the two groups, resulting in an increased excitation-inhibition (E-I) ratio. These data show that behavioral spasms with epileptic EEG activity can be induced in young TcMAC21 DS mice, providing proof-of-concept evidence for increased IS susceptibility in these DS mice. Our findings also show that basic membrane properties are similar in TcMAC21 and euploid mice, while the neocortical E-I balance is altered to favor increased excitation in TcMAC21 mice, which may predispose to IS generation.
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Síndrome de Down , Epilepsia , Neocórtex , Espasmos Infantiles , Humanos , Niño , Ratones , Animales , Espasmos Infantiles/genética , Síndrome de Down/genética , Espasmo , Agonistas de Receptores GABA-B , Electroencefalografía , Modelos Animales de EnfermedadRESUMEN
The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.
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Músculo Esquelético , Termogénesis , Ratones , Humanos , Animales , Músculo Esquelético/metabolismo , Termogénesis/genética , Metabolismo Energético/fisiología , Proteolípidos/metabolismo , Citoplasma/metabolismo , Cromosomas Humanos/metabolismo , Calcio/metabolismoRESUMEN
PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens. METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient's weekly dose. RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy. CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.
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Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Adulto , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Estudios Prospectivos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Infusiones Subcutáneas , Inmunoglobulina G/uso terapéutico , Enfermedades de Inmunodeficiencia Primaria/tratamiento farmacológico , Evaluación del Resultado de la Atención al PacienteRESUMEN
Streams in urbanizing watersheds are threatened by economic development that can lead to excessive sediment erosion and surface runoff. These anthropogenic stressors diminish valuable ecosystem services and result in pervasive degradation commonly referred to as "urban stream syndrome." Understanding how the public perceives and values improvements in stream conditions is necessary to support efforts to quantify the economic benefits of water quality improvements. We develop an ecological production framework that translates measurable indicators of stream water quality into ecological endpoints. Our interdisciplinary approach integrates a predictive hierarchical water quality model that is well suited for sparse data environments, an expert elicitation that translates measurable water quality indicators into ecological endpoints that focus group participants identified as most relevant, and a stated preference survey that elicits the public's willingness to pay for changes in these endpoints. To illustrate our methods, we develop an application to the Upper Neuse River Watershed located in the rapidly developing Triangle region of North Carolina (the United States). Our results suggest, for example, that residents are willing to pay roughly $127 per household and $54 million per year in aggregate (2021 US$) for water quality improvements resulting from a stylized intervention that increases stream bank canopy cover by 25% and decreases runoff from impervious surfaces, leading to improvements in water quality and ecological endpoints for local streams. Although the three components of our analysis are conducted with data from North Carolina, we discuss how our findings are generalizable to urban and urbanizing areas across the larger Piedmont ecoregion of the Eastern United States.
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BACKGROUND: Unfavourable clot microstructure is associated with adverse outcomes in ST elevation myocardial infarction (STEMI). We investigated the effect of comorbidities and anti-platelet treatment on clot microstructure in STEMI patients using fractal dimension (df), a novel biomarker of clot microstructure derived from the visco-elastic properties of whole blood. METHODS: Patients with STEMI (n = 187) were recruited sequentially receiving aspirin with Clopidogrel (n = 157) then Ticagrelor (n = 30). Patient characteristics and blood for rheological analysis obtained. We quantified df using sequential frequency sweep tests to obtain the phase angle of the Gel Point which is synonymous with the clot microstructure. RESULTS: Higher df was observed in males (1.755 ± 0.068) versus females (1.719 ± 0.061, p = .001), in patients with diabetes (1.786 ± 0.067 vs 1.743 ± 0.046, p < .001), hypertension (1.760 ± 0.065 vs 1.738 ± 0.069, p = .03) and previous MI (1.787 ± 0.073 vs 1.744 ± 0.066, p = .011) compared to without. Patients receiving Ticagrelor had lower df than those receiving Clopidogrel (1.708 ± 0.060 vs 1.755 ± 0.067, p < .001). Significant correlation with df was found with haematocrit (r = 0.331, p < .0001), low-density lipoprotein (LDL) (r = 0.155, p = .046) and fibrinogen (r = 0.182, p = .014). Following multiple regression analysis, diabetes, LDL, fibrinogen and haematocrit remained associated with higher df while treatment with Ticagrelor remained associated with lower df. CONCLUSIONS: The biomarker df uniquely evaluates the effect of interactions between treatment and underlying disease on clot microstructure. STEMI patients with diabetes and elevated LDL had higher df, indicating denser clot. Ticagrelor resulted in a lower df than Clopidogrel signifying a less compact clot.
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Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Trombosis , Masculino , Femenino , Humanos , Ticagrelor/uso terapéutico , Clopidogrel/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Infarto del Miocardio con Elevación del ST/etiología , Trombosis/etiología , Biomarcadores , Fibrinógeno , Resultado del Tratamiento , Intervención Coronaria Percutánea/efectos adversosRESUMEN
Elucidating the mechanisms of resistance to immunotherapy and developing strategies to improve its efficacy are challenging goals. Bioinformatics analysis demonstrates that high CDK6 expression in melanoma is associated with poor progression-free survival of patients receiving single-agent immunotherapy. Depletion of CDK6 or cyclin D3 (but not of CDK4, cyclin D1, or D2) in cells of the tumor microenvironment inhibits tumor growth. CDK6 depletion reshapes the tumor immune microenvironment, and the host anti-tumor effect depends on cyclin D3/CDK6-expressing CD8+ and CD4+ T cells. This occurs by CDK6 phosphorylating and increasing the activities of PTP1B and T cell protein tyrosine phosphatase (TCPTP), which, in turn, decreases tyrosine phosphorylation of CD3ζ, reducing the signal transduction for T cell activation. Administration of a PTP1B and TCPTP inhibitor prove more efficacious than using a CDK6 degrader in enhancing T cell-mediated immunotherapy. Targeting protein tyrosine phosphatases (PTPs) might be an effective strategy for cancer patients who resist immunotherapy treatment.
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Quinasa 6 Dependiente de la Ciclina , Neoplasias , Humanos , Ciclina D3/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Transducción de Señal , Fosforilación , Inmunoterapia , Quinasa 4 Dependiente de la Ciclina/metabolismo , Microambiente TumoralRESUMEN
Trisomy 21 and mutations in the Sonic hedgehog (SHH) signaling pathway cause overlapping and pleiotropic phenotypes including cerebellar hypoplasia, craniofacial abnormalities, congenital heart defects and Hirschsprung disease. Trisomic cells derived from individuals with Down syndrome possess deficits in SHH signaling, suggesting that overexpression of human chromosome 21 genes may contribute to SHH-associated phenotypes by disrupting normal SHH signaling during development. However, chromosome 21 does not encode any known components of the canonical SHH pathway. Here, we sought to identify chromosome 21 genes that modulate SHH signaling by overexpressing 163 chromosome 21 cDNAs in a series of SHH-responsive mouse cell lines. We confirmed overexpression of trisomic candidate genes using RNA sequencing in the cerebella of Ts65Dn and TcMAC21 mice, model systems for Down syndrome. Our findings indicate that some human chromosome 21 genes, including DYRK1A, upregulate SHH signaling, whereas others, such as HMGN1, inhibit SHH signaling. Individual overexpression of four genes (B3GALT5, ETS2, HMGN1 and MIS18A) inhibits the SHH-dependent proliferation of primary granule cell precursors. Our study prioritizes dosage-sensitive chromosome 21 genes for future mechanistic studies. Identification of the genes that modulate SHH signaling may suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.
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Síndrome de Down , Proteína HMGN1 , Ratones , Humanos , Animales , Síndrome de Down/genética , Proteínas Hedgehog/metabolismo , Cromosomas Humanos Par 21/genética , Proteína HMGN1/genética , Proteína HMGN1/metabolismo , Transducción de SeñalRESUMEN
The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are due to sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.
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OBJECTIVE: Trisomy 21 is one of the most complex genetic perturbations compatible with postnatal survival. Dosage imbalance arising from the triplication of genes on human chromosome 21 (Hsa21) affects multiple organ systems. Much of Down syndrome (DS) research, however, has focused on addressing how aneuploidy dysregulates CNS function leading to cognitive deficit. Although obesity, diabetes, and associated sequelae such as fatty liver and dyslipidemia are well documented in the DS population, only limited studies have been conducted to determine how gene dosage imbalance affects whole-body metabolism. Here, we conduct a comprehensive and systematic analysis of key metabolic parameters across different physiological states in the Ts65Dn trisomic mouse model of DS. METHODS: Ts65Dn mice and euploid littermates were subjected to comprehensive metabolic phenotyping under basal (chow-fed) state and the pathophysiological state of obesity induced by a high-fat diet (HFD). RNA sequencing of liver, skeletal muscle, and two major fat depots were conducted to determine the impact of aneuploidy on tissue transcriptome. Pathway enrichments, gene-centrality, and key driver estimates were performed to provide insights into tissue autonomous and non-autonomous mechanisms contributing to the dysregulation of systemic metabolism. RESULTS: Under the basal state, chow-fed Ts65Dn mice of both sexes had elevated locomotor activity and energy expenditure, reduced fasting serum cholesterol levels, and mild glucose intolerance. Sexually dimorphic deterioration in metabolic homeostasis became apparent when mice were challenged with a high-fat diet. While obese Ts65Dn mice of both sexes exhibited dyslipidemia, male mice also showed impaired systemic insulin sensitivity, reduced mitochondrial activity, and elevated fibrotic and inflammatory gene signatures in the liver and adipose tissue. Systems-level analysis highlighted conserved pathways and potential endocrine drivers of adipose-liver crosstalk that contribute to dysregulated glucose and lipid metabolism. CONCLUSIONS: A combined alteration in the expression of trisomic and disomic genes in peripheral tissues contribute to metabolic dysregulations in Ts65Dn mice. These data lay the groundwork for understanding the impact of aneuploidy on in vivo metabolism.
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Síndrome de Down , Intolerancia a la Glucosa , Femenino , Masculino , Ratones , Animales , Humanos , Síndrome de Down/genética , Aneuploidia , Obesidad/genética , Obesidad/complicaciones , Metabolismo de los Lípidos/genéticaRESUMEN
INTRODUCTION: Human immunoglobulin (IG) administered intravenously (IVIG) or subcutaneously (SCIG) is used to prevent infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. AREAS COVERED: This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. EXPERT OPINION: Individualized treatment for PIDD in children is necessary given the different factors that affect administration of SCIG. Variables such as the dose, dosing interval, administration sites, and ancillary equipment can be adjusted to impact the long-term satisfaction with SCIG administration in pediatric patients. The successful work that has been conducted by both professional and patient organizations to increase awareness of PIDD, especially in pediatric patients, is substantial and ongoing. The importance of early diagnosis and treatment in the pediatric patient population cannot be overstated. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.
Human immunoglobulin (IG) is extracted from the plasma of donors as a sterile, purified blood product that is administered intravenously (via a vein [IVIG]) or subcutaneously (under the skin [SCIG]) and is used for a variety of disorders, including the prevention of infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. The importance of early identification of PIDD, especially in pediatric patients, cannot be overstated to ensure prompt treatment. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Síndromes de Inmunodeficiencia , Humanos , Niño , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Infusiones Subcutáneas/métodos , Inmunoglobulina G , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéuticoRESUMEN
Interdisciplinary research teams can be extremely beneficial when addressing difficult clinical problems. The incorporation of conceptual and methodological strategies from a variety of research disciplines and health professions yields transformative results. In this setting, the long-term goal of team science is to improve patient care, with emphasis on population health outcomes. However, team principles necessary for effective research teams are rarely taught in health professional schools. To form successful interdisciplinary research teams in cardio-oncology and beyond, guiding principles and organizational recommendations are necessary. Cardiovascular disease results in annual direct costs of $220 billion (about $680 per person in the US) and is the leading cause of death for cancer survivors, including adult survivors of childhood cancers. Optimizing cardio-oncology research in interdisciplinary research teams has the potential to aid in the investigation of strategies for saving hundreds of thousands of lives each year in the United States and mitigating the annual cost of cardiovascular disease. Despite published reports on experiences developing research teams across organizations, specialties and settings, there is no single journal article that compiles principles for cardiology or cardio-oncology research teams. In this review, recurring threads linked to working as a team, as well as optimal methods, advantages, and problems that arise when managing teams are described in the context of career development and research. The worth and hurdles of a team approach, based on practical lessons learned from establishing our multidisciplinary research team and information gleaned from relevant specialties in the development of a successful team are presented.
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A prospective study and its long-term extension examined whether weekly treatment of patients with primary immunodeficiencies (PIDs) with a 16.5% subcutaneous immunoglobulin (SCIg; cutaquig®) confers acceptable efficacy, safety, and tolerability over a follow-up of up to 238 weeks (>4 years). Seventy-five patients received 4462 infusions during up to 70 weeks of follow-up in the main study and 27 patients received 2777 infusions during up to 168 weeks of follow-up in the extension. In the main study, there were no serious bacterial infections (SBIs), and the annual rate of other infections was 3.3 (95% CI 2.4, 4.5). One SBI was recorded in the extension, for an SBI rate of 0.02 (upper 99% CI 0.19). The annual rate of all infections over the duration of the extension study was 2.2 (95% CI 1.2, 3.9). Only 15.0% (1085) of 7239 infusions were associated with infusion site reactions (ISRs), leaving 85.0% (6153) of infusions without reactions. The majority of ISRs were mild and transient. ISR incidence decreased over time, from 36.9% to 16% during the main study and from 9% to 2.3% during the extension. The incidence of related systemic adverse events was 14.7% in the main study and 7.4% in the extension. In conclusion, this prospective, long-term study with cutaquig showed maintained efficacy and low rates of local and systemic adverse reactions in PID patients over up to 238 weeks of follow-up.
Asunto(s)
Infecciones Bacterianas , Síndromes de Inmunodeficiencia , Humanos , Estudios Prospectivos , Infusiones Subcutáneas , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Resultado del Tratamiento , Inmunoglobulinas Intravenosas/uso terapéuticoRESUMEN
Cymbopogon giganteus is a medicinal plant from Burkina Faso whose leaves are used in many traditional recipes to treat several diseases. However, no scientific studies have been reported on the analysis of bioactive molecules of the plant. It is therefore for the first time that flavonoids are isolated from the leaves of the Burkina Faso species. The aim was to quantify, isolate and characterize the major flavonoids in methanol extracts of the plant leaves by spectrophotometry, chromatography and NMR respectively. Flavonoid content analysis showed values ranging from 134 to 270 µg QE/mg extract. HPTLC-MS identified six peaks corresponding to phenolic compounds. By a succession of chromatography on column and by chemical, physicochemical and physical methods, we could isolate and characterize three flavonoids: epicatechin, luteolin 8-C-glucosid and luteolin 6-C-glucosid which structures were characterized by NMR. This study has provided relevant results to contribute to the knowledge of bio-active molecules of the local flora of Burkina Faso for their consideration as an alternative to synthetic products in various fields.