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N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate receptors critical for synaptic transmission and plasticity, and for the development of neural circuits. Rare or de-novo variants in GRIN genes encoding NMDAR subunits have been associated with neurodevelopmental disorders characterized by intellectual disability, developmental delay, autism, schizophrenia, or epilepsy. In recent years, some disease-associated variants in GRIN genes have been characterized using recombinant receptors expressed in non-neuronal cells, and a few variants have also been studied in neuronal preparations or animal models. Here we review the current literature on the functional evaluation of human disease-associated variants in GRIN1, GRIN2A and GRIN2B genes at all levels of analysis. Focusing on the impact of different patient variants at the level of receptor function, we discuss effects on receptor agonist and co-agonist affinity, channel open probability, and receptor cell surface expression. We consider how such receptor-level functional information may be used to classify variants as gain-of-function or loss-of-function, and discuss the limitations of this classification at the synaptic, cellular, or system level. Together this work by many laboratories worldwide yields valuable insights into NMDAR structure and function, and represents significant progress in the effort to understand and treat GRIN disorders. Keywords: NMDA receptor , GRIN genes, Genetic variants, Electrophysiology, Synapse, Animal models.
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BACKGROUND: Immune checkpoint blockade (ICB) in combination with chemotherapy improves outcome of patients with triple-negative breast cancer (TNBC) in metastatic and early settings. The identification of predictive biomarkers able to guide treatment decisions is challenging and currently limited to programmed death-ligand 1 (PD-L1) expression and high tumor mutational burden (TMB) in the advanced setting, with several limitations. MATERIALS AND METHODS: We carried out a retrospective analysis of clinical-pathological and molecular characteristics of tumor samples from 11 patients with advanced TNBC treated with single-agent pembrolizumab participating in two early-phase clinical trials: KEYNOTE-012 and KEYNOTE-086. Clinical, imaging, pathological [i.e. tumor-infiltrating lymphocytes (TILs), PD-L1 status], RNA sequencing, and whole-exome sequencing data were analyzed. We compared our results with publicly available transcriptomic data from TNBC cohorts from TCGA and METABRIC. RESULTS: Response to pembrolizumab was heterogeneous: two patients experienced exceptional long-lasting responses, six rapid progressions, and three relatively slower disease progression. Neither PD-L1 nor stromal TILs were significantly associated with response to treatment. Increased TMB values were observed in tumor samples from exceptional responders compared to the rest of the cohort (P = 3.4 × 10-4). Tumors from exceptional responders were enriched in adaptive and innate immune cell signatures. Expression of regulatory T-cell markers (FOXP3, CCR4, CCR8, TIGIT) was mainly observed in tumors from responders except for glycoprotein-A repetitions predominant (GARP), which was overexpressed in tumors from rapid progressors. GARP RNA expression in primary breast tumors from the public dataset was significantly associated with a worse prognosis. CONCLUSIONS: The wide spectrum of clinical responses to ICB supports that TNBC is a heterogeneous disease. Tumors with high TMB respond better to ICB. However, the optimal cut-off of 10 mutations (mut)/megabase (Mb) may not reflect the complexity of all tumor subtypes, despite its approval as a tumor-agnostic biomarker. Further studies are required to better elucidate the relevance of the tumor microenvironment and its components as potential predictive biomarkers in the context of ICB.
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Anticuerpos Monoclonales Humanizados , Biomarcadores de Tumor , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Estudios Retrospectivos , Femenino , Biomarcadores de Tumor/metabolismo , Persona de Mediana Edad , Inmunoterapia/métodos , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Anciano , Adulto , Linfocitos Infiltrantes de Tumor/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVE: Large intestinal fermentation of dietary fiber may control meal-related glycemia and appetite via the production of short-chain fatty acids (SCFA) and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). We investigated whether this mechanism contributes to the efficacy of the Roux-en-Y gastric bypass (RYGB) by assessing the effect of oligofructose-enriched inulin (inulin) vs. maltodextrin (MDX) on breath hydrogen (a marker of intestinal fermentation), plasma SCFAs, gut hormones, insulin and blood glucose concentrations as well as appetite in RYGB patients. METHOD: Eight RYGB patients were studied on two occasions before and ~8 months after surgery using a cross-over design. Each patient received 300 ml orange juice containing 25 g inulin or an equicaloric load of 15.5 g MDX after an overnight fast followed by a fixed portion snack served 3 h postprandially. Blood samples were collected over 5 h and breath hydrogen measured as well as appetite assessed using visual analog scales. RESULTS: Surgery increased postprandial secretion of GLP-1 and PYY (P ≤ 0.05); lowered blood glucose and plasma insulin increments (P ≤ 0.05) and reduced appetite ratings in response to both inulin and MDX. The effect of inulin on breath hydrogen was accelerated after surgery with an increase that was earlier in onset (2.5 h vs. 3 h, P ≤ 0.05), but less pronounced in magnitude. There was, however, no effect of inulin on plasma SCFAs or plasma GLP-1 and PYY after the snack at 3 h, neither before nor after surgery. Interestingly, inulin appeared to further potentiate the early-phase glucose-lowering and second-meal (3-5 h) appetite-suppressive effect of surgery with the latter showing a strong correlation with early-phase breath hydrogen concentrations. CONCLUSION: RYGB surgery accelerates large intestinal fermentation of inulin, however, without measurable effects on plasma SCFAs or plasma GLP-1 and PYY. The glucose-lowering and appetite-suppressive effects of surgery appear to be potentiated with inulin.
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Derivación Gástrica , Insulinas , Humanos , Inulina/farmacología , Apetito , Proyectos Piloto , Glucemia , Estudios Cruzados , Estudios Prospectivos , Péptido YY , Péptido 1 Similar al Glucagón , PercepciónRESUMEN
Cyclodextrin-based nanosponges are promising materials for heterogeneous catalysis due to their inherent synthetic versatility, tunable porosity and nontoxicity. In this work, a primary amine-rich ß-cyclodextrin nanosponge was synthesized via click imine condensation reaction between 1,6-hexamethylamine-functionalized ß-cyclodextrin (CDAM) and glutaraldehyde (GLT) to afford CDGLAM, in mild conditions. The crosslinked polymer exhibited a BET surface area of 36.39 m2 g-1, an average pore diameter of 3.09 nm (as assessed by the BJH method), and thermal stability up to 253 °C. CDGLAM was tested as heterogeneous catalyst for the metal-free Henry and Knoevenagel reactions, between aromatic aldehydes and nitromethane or ethyl cyanoacetate, respectively, affording the products in moderate to very high yields. These results show the ease of preparation of ß-CD-based nanosponges from a green chemistry perspective, as well as their potential for future use in catalytic systems.
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Objective.MamoRef is an mammography device that uses near-infrared light, designed to provide clinically relevant information for the screening of diseases of the breast. Using low power continuous wave lasers and a high sensitivity CCD (Charge-coupled device) that captures a diffusely reflected image of the tissue, MamoRef results in a versatile diagnostic tool that aims to fulfill a complementary role in the diagnosis of breast cancer providing information about the relative hemoglobin concentrations as well as oxygen saturation.Approach.We present the design and development of an initial prototype of MamoRef. To ensure its effectiveness, we conducted validation tests on both the theoretical basis of the reconstruction algorithm and the hardware design. Furthermore, we initiated a clinical feasibility study involving patients diagnosed with breast disease, thus evaluating the practical application and potential benefits of MamoRef in a real-world setting.Main results.Our study demonstrates the effectiveness of the reconstruction algorithm in recovering relative concentration differences among various chromophores, as confirmed by Monte Carlo simulations. These simulations show that the recovered data correlates well with the ground truth, with SSIMs of 0.8 or more. Additionally, the phantom experiments validate the hardware implementation. The initial clinical findings exhibit highly promising outcomes regarding MamoRef's ability to differentiate between lesions.Significance.MamoRef aims to be an advancement in the field of breast pathology screening and diagnostics, providing complementary information to standard diagnostic techniques. One of its main advantages is the ability of determining oxy/deoxyhemoglobin concentrations and oxygen saturation; this constitutes valuable complementary information to standard diagnostic techniques. Besides, MamoRef is a portable and relatively inexpensive device, intended to be not only used in specific medical imaging facilities. Finally, its use does not require external compression of the breast. The findings of this study underscore the potential of MamoRef in fulfilling this crucial role.
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Enfermedades de la Mama , Neoplasias de la Mama , Humanos , Femenino , Mamografía/métodos , Mama/diagnóstico por imagen , Mama/patología , Neoplasias de la Mama/patología , Enfermedades de la Mama/patología , Fantasmas de ImagenAsunto(s)
Humanos , Masculino , Femenino , Higiene Bucal , Clorhexidina/administración & dosificación , Boca , XerostomíaRESUMEN
AIMS: The aim of this research was to map available healthy planning frameworks to discover the range, composition, design, and implementation of healthy planning frameworks. METHODS: A systematic scoping review with date, location, and usability limitations was augmented by a grey literature search. Data were extracted on key details, design, outcomes considered, and implementation features of the final 61 frameworks. RESULTS: Data extracted indicated that most frameworks tend to focus on one element of the built environment, with active mobility, active environments, and transport being the most prevalent ones (34%). Most frameworks (40) stated their intended outcomes on health in general terms, rather than targeting specific health outcomes. Very few frameworks (12%) were aimed at the public, and only 11% of frameworks included an evaluation. CONCLUSIONS: While there are a wide variety and number of frameworks available in the field of healthy urban planning, they are generally siloed, focusing on highly specific individual urban determinants, and rarely consider health outcomes in detail. There is significantly less provision available for citizen and community use. Frameworks tend to offer limited updating mechanisms and very rarely include ongoing evaluation processes, making their success difficult to assess.
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Functional near infrared spectroscopy has been used in recent decades to sense and quantify changes in hemoglobin concentrations in the human brain. This noninvasive technique can deliver useful information concerning brain cortex activation associated with different motor/cognitive tasks or external stimuli. This is usually accomplished by considering the human head as a homogeneous medium; however, this approach does not explicitly take into account the detailed layered structure of the head, and thus, extracerebral signals can mask those arising at the cortex level. This work improves this situation by considering layered models of the human head during reconstruction of the absorption changes in layered media. To this end, analytically calculated mean partial pathlengths of photons are used, which guarantees fast and simple implementation in real-time applications. Results obtained from synthetic data generated by Monte Carlo simulations in two- and four-layered turbid media suggest that a layered description of the human head greatly outperforms typical homogeneous reconstructions, with errors, in the first case, bounded up to â¼20% maximum, while in the second case, the error is usually larger than 75%. Experimental measurements on dynamic phantoms support this conclusion.
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Encéfalo , Espectroscopía Infrarroja Corta , Humanos , Espectroscopía Infrarroja Corta/métodos , Cabeza/fisiología , Fotones , Método de MontecarloRESUMEN
INTRODUCTION: Chronic inflammation can remain many years after the completion of cancer treatment and is associated with cancer recurrence. The purpose of this study was to examine how a 16-week therapeutic yoga program (TYP) modulates the cytokine profile in heterogeneous cancer survivors. METHODS: Eligible participants were 18 years of age or older and clinically diagnosed with cancer. Consenting participants were asked to attend three, 75-min sessions weekly of TYP with meditation. Seventeen patients provided blood samples at baseline and end of study. Eight cytokines (interferon (IFN)-γ; interleukin (IL)-1b, IL-1ra, IL-4, IL-6, IL-8, IL-10; and tumor necrosis factor (TNF)-α), three receptors (sIL-6R, sTNFRI, sTNFRII), and C-reactive protein (CRP) were quantified. RESULTS: Patients were 59.6 ± 7.3 years old; over half (56%) were overweight or obese BMI ≥ 25 kg/m2); majority were female (71%) and breast cancer survivors (65%), of which 44% were Hispanic. Marked reductions were observed in all cytokines except IL-4, with significant reductions (p < 0.05) found in IL-1b (- 13%) and IL-1ra (- 13%). No significant changes were observed in soluble cytokine receptors or CRP. CONCLUSIONS: TYP led to significant reduction in circulating cytokines associated with chronic inflammation in a heterogeneous sample of cancer survivors.
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Supervivientes de Cáncer , Meditación , Yoga , Humanos , Femenino , Masculino , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Citocinas , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-4 , Recurrencia Local de Neoplasia , Factor de Necrosis Tumoral alfa , Proteína C-Reactiva/metabolismo , InflamaciónRESUMEN
This work presents a method for constructing phantoms suitable for diffuse optical mammography. They are based on Polydimethylsiloxane silicones, with the characteristic of being anthropomorphic, and having similar mechanical and optical properties as a real breast. These phantoms are useful for testing the performance of diffuse optical imaging devices in the near infrared, both in transmittance and reflectance geometries, since they can be constructed containing inclusions, to simulate breast tumors. An alternative component to be used as scattering agent, that is easier to handle than traditional scattering agents, is also studied. The optical properties of the phantoms were tested varying the concentration of scattering and absorbing agents, while their mechanical properties were modified by adding a silicone fluid to the basic mixture. Finally, the phantoms were tested by Diffuse Optical Imaging experiments, and these images were compared to the ones obtained by conventional ultrasound techniques. Results show that the constructed anthropomorphic phantoms properly reproduce the optical and mechanical characteristics of human breasts, and are suitable to be used in Diffuse Optical Imaging.
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Water pollution due to global economic activity is one of the greatest environmental concerns, and many efforts are currently being made toward developing materials capable of selectively and efficiently removing pollutants and contaminants. A series of ß-ketoenamine covalent organic frameworks (COFs) have been synthesized, by reacting 1,3,5-triformylphloroglucinol (TFP) with different C2-functionalized and nonfunctionalized diamines, in order to evaluate the influence of wall functionalization and pore size on the adsorption capacity toward dye and heavy metal pollutants. The obtained COFs were characterized by different techniques. The adsorption of methylene blue (MB), which was used as a model for the adsorption of pharmaceuticals and dyes, was initially evaluated. Adsorption studies showed that -NO2 and -SO3H functional groups were favorable for MB adsorption, with TpBd(SO3H)2-COF [100%], prepared between TFP and 4,4'-diamine- [1,1'-biphenyl]-2,2'-disulfonic acid, achieving the highest adsorption capacity (166 ± 13 mg g-1). The adsorption of anionic pollutants was less effective and decreased, in general, with the increase in -SO3H and -NO2 group content. The effect of ionic interactions on the COF performance was further assessed by carrying out adsorption experiments involving metal ions. Isotherms showed that nonfunctionalized and functionalized COFs were better described by the Langmuir and Freundlich sorption models, respectively, confirming the influence of functionalization on surface heterogeneity. Sorption kinetics experiments were better adjusted according to a second-order rate equation, confirming the existence of surface chemical interactions in the adsorption process. These results confirm the influence of selective COF functionalization on adsorption processes and the role of functional groups on the adsorption selectivity, thus clearly demonstrating the potential of this new class of materials in the efficient and selective capture and removal of pollutants in aqueous solutions.
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There have been a number of pharmaceutical and non-pharmaceutical interventions associated with COVID-19 over the past two years. Various non-pharmaceutical interventions were proposed and implemented to control the spread of the COVID-19 pandemic. Most common of these were partial and complete lockdowns that were used in an attempt to minimize the costs associated with mortality, economic losses and social factors, while being subject to constraints such as finite hospital capacity. Here, we use a minimal model posed in terms of optimal control theory to understand the costs and benefits of such strategies. This allows us to determine top-down policies for how to restrict social contact rates given an age-structured model for the dynamics of the disease. Depending on the relative weights allocated to mortality and socioeconomic losses, we see that the optimal strategies range from long-term social-distancing only for the most vulnerable, partial lockdown to ensure not over-running hospitals, and alternating-shifts, all of which lead to significant reduction in mortality and/or socioeconomic losses. Crucially, commonly used strategies that involve long periods of broad lockdown are almost never optimal, as they are highly unstable to reopening and entail high socioeconomic costs. Using parameter estimates from data available for Germany and the USA early in the pandemic, we quantify these policies and use sensitivity analysis in the relevant model parameters and initial conditions to determine the range of robustness of our policies. Finally we also discuss how bottom-up behavioral changes affect the dynamics of the pandemic and show how they can work in tandem with top-down control policies to mitigate pandemic costs even more effectively.
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COVID-19 , Pandemias , COVID-19/epidemiología , COVID-19/prevención & control , Control de Enfermedades Transmisibles , Humanos , Pandemias/prevención & control , PolíticasRESUMEN
BACKGROUND AND PURPOSE: Neurologic manifestations in hereditary hemorrhagic telangiectasia include an increased incidence of brain abscesses and ischemic strokes due to paradoxic embolization in addition to a wide spectrum of symptoms and complications due to typical brain vascular malformations. Intracranial aneurysms are not part of this brain vascular malformation spectrum. The aim of this study was to determine their prevalence in patients with hereditary hemorrhagic telangiectasia. MATERIALS AND METHODS: This was a single-center, retrospective study. Adult patients from the institutional Hereditary Hemorrhagic Telangiectasia registry with a definitive diagnosis of hereditary hemorrhagic telangiectasia and an available report or angiographic imaging study were included and reviewed to determine the intracranial aneurysm prevalence. In addition, the morphologic characteristics of intracranial aneurysms and possible associated risk factors were collected. RESULTS: Two hundred twenty-eight patients were analyzed. Thirty-seven aneurysms in 33 patients (14.5%; 95% CI, 9.9%-19%) were found. The median diameter of intracranial aneurysms was 3.2 mm (interquartile range, 2.6-4.4 mm). No association between intracranial aneurysm and sex, age, or genetic background was noted. There were no subarachnoid hemorrhagic events due to intracranial aneurysm rupture. CONCLUSIONS: Due to the high prevalence of intracranial aneurysms in adult patients with hereditary hemorrhagic telangiectasia, further studies regarding bleeding risks and monitoring should be addressed.
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Malformaciones Vasculares del Sistema Nervioso Central , Embolización Terapéutica , Aneurisma Intracraneal , Telangiectasia Hemorrágica Hereditaria , Adulto , Malformaciones Vasculares del Sistema Nervioso Central/complicaciones , Humanos , Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/epidemiología , Prevalencia , Estudios Retrospectivos , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico por imagen , Telangiectasia Hemorrágica Hereditaria/epidemiologíaRESUMEN
El cuidado infantil de buena calidad atenúa los efectos de la adversidad social. La prevención en salud es parte de él. Se presenta un programa innovador de formación de referentes de salud en centros de cuidado infantil que atienden a poblaciones vulnerables en Buenos Aires, Argentina. Este consistió en una capacitación para personal de centros de cuidado infantil, seguido de la implementación, durante 4 meses, de un plan de mejoras elaborado por cada participante para su centro, con apoyo de consultoría permanente. Veintiséis participantes de 19centroscompletaron el programa. Se alcanzaron 35 de 49 objetivos planteados en los planes, incluida la certificación en reanimación cardiopulmonar, la capacitación del personal y las familias, el desarrollo de políticas del centro y la mejora de la gestión de recursos. Es posible mejorar los cuidados preventivos en los centros de cuidado infantil mediante una intervención sencilla y de bajo costo, incluso en condiciones desfavorables.
An adequate child care helps to mitigate the effects of social adversity. Health prevention is a part of it. This is an innovative training program for health referents in child care centers that cater to vulnerable populations in Buenos Aires, Argentina. It consisted in training child care center staff, followed by the implementation, over 4 months, of an improvement plan developed by each participant in their center, with ongoing advisory support. In total, 26 participants from 19 centers completed the program. In total, 35 out of 49 goals proposed in the plans were achieved, including the certification in cardiopulmonary resuscitation, staff and family training, development of center policies, and improved resource management. Preventive care offered in child care centers may be improved via a simple and inexpensive intervention, including in unfavorable conditions
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Humanos , Cuidado del Niño , Guarderías Infantiles , Argentina , Ingestión de AlimentosRESUMEN
An adequate child care helps to mitigate the effects of social adversity. Health prevention is a part of it. This is an innovative training program for health referents in child care centers that cater to vulnerable populations in Buenos Aires, Argentina. It consisted in training child care center staff, followed by the implementation, over 4 months, of an improvement plan developed by each participant in their center, with ongoing advisory support. In total, 26 participants from 19 centers completed the program. In total, 35 out of 49 goals proposed in the plans were achieved, including the certification in cardiopulmonary resuscitation, staff and family training, development of center policies, and improved resource management. Preventive care offered in child care centers may be improved via a simple and inexpensive intervention, including in unfavorable conditions.
El cuidado infantil de buena calidad atenúa los efectos de la adversidad social. La prevención en salud es parte de él. Se presenta un programa innovador de formación de referentes de salud en centros de cuidado infantil que atienden a poblaciones vulnerables en Buenos Aires, Argentina. Este consistió en una capacitación para personal de centros de cuidado infantil, seguido de la implementación, durante 4meses, de un plan de mejoras elaborado por cada participante para su centro, con apoyo de consultoría permanente. Veintiséis participantes de 19centros completaron el programa. Se alcanzaron 35 de 49 objetivos planteados en los planes, incluida la certificación en reanimación cardiopulmonar, la capacitación del personal y las familias, el desarrollo de políticas del centro y la mejora de la gestión de recursos. Es posible mejorar los cuidados preventivos en los centros de cuidado infantil mediante una intervención sencilla y de bajo costo, incluso en condiciones desfavorables.