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Background: Approximately 20% of adults in Vietnam have hypertension, and management of this chronic condition remains challenging. This study aimed to assess the effectiveness of a multicomponent intervention in reducing blood pressure (BP) in adults with uncontrolled hypertension. Methods: This cluster randomised controlled trial was conducted in sixteen communities (8 intervention and 8 comparison) in a rural setting in Vietnam (2017-2022). Consenting adults (aged ≥ 18 years) with uncontrolled hypertension were enrolled. Sixteen communities were equally randomised to an intervention or comparison group stratified by district. Consenting adults were assigned to study groups by community. The comparison arm received training sessions about hypertension prevention and management for health workers, and patient education materials. The intervention arm received training sessions about hypertension prevention and management for health workers, and patient education materials and three enhancement components including a storytelling intervention, home BP self-monitoring, and expanded community health worker services. The primary outcome was the difference in changes in patient's levels of systolic BP between the study groups over a 12-month follow-up period. Patients and outcome assessors were masked. Findings: A total of 671 patients (340: intervention, 331: comparison) were enrolled in the trial. The mean age was 66 years and 45% were men. At the 12-month follow-up, the mean systolic BP declined by 18.4 mmHg in the intervention group and 3.7 mmHg in the comparison group (differential decline of 14.7 mmHg [95% CI: 11.8-17.6]). The intervention group also achieved better BP control and medication adherence than the comparison group. There were no serious adverse events related to study participation. Interpretation: The results of this trial demonstrate that a multicomponent intervention can effectively reduce elevated BP in individuals with uncontrolled hypertension in Vietnam. Trial registration: This trial was registered at ClinicalTrials.gov, NCT03590691. Funding: National Heart, Lung, and Blood Institute.
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Introduction: Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is rare condition that has a negative impact on quality of life because affected women lack a uterus and vagina, and are therefore unable to engage in sexual intercourse and experience natural pregnancy. This study evaluated perceptions of surrogacy in Vietnamese women with MRKH who have started families. Method: Women with MRKH who had undergone successful vaginal reconstruction, were married, and had started families participated in a semi-structured, in-depth, one-on-one online video interview with an experienced female psychologist. Open-ended questions were used to encourage participants to express their perceptions of surrogacy; prominent themes were discussed, compared, and combined. Results: Twenty women (mean age 31 years) agreed to participate. Key themes identified from interviews were the importance of having genetic offspring, consideration of surrogacy as a preferred solution to infertility, the barriers to surrogacy in Vietnam, lack of reproductive information and counselling, individuals concealing their health condition, the impact of religion on the possibility of surrogacy, the economic cost of surrogacy, and the difficulty in finding a surrogate under the restrictions imposed by Vietnamese law. Discussion: Based on the perceptions of women from MRKH from Vietnam, there is an opportunity to improve how infertility is managed in these people, including information about surrogacy. These data show that individuals with MRKH should be provided with information about the possibility of surrogacy, encouraged to be open and seek support, and be managed by a multidisciplinary team that includes psychological support; the provision of economic support for fertility treatments in women with MRKH should also be considered.
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BACKGROUND: Metastasis is the leading cause of death in breast cancer patients. For metastasis to occur, tumor cells must invade locally, intravasate, and colonize distant tissues and organs, all steps that require tumor cell migration. The majority of studies on invasion and metastasis rely on human breast cancer cell lines. While it is known that these cells have different properties and abilities for growth and metastasis, the in vitro morphological, proliferative, migratory, and invasive behavior of these cell lines and their correlation to in vivo behavior is poorly understood. Thus, we sought to classify each cell line as poorly or highly metastatic by characterizing tumor growth and metastasis in a murine model of six commonly used human triple-negative breast cancer xenografts, as well as determine which in vitro assays commonly used to study cell motility best predict in vivo metastasis. METHODS: We evaluated the liver and lung metastasis of human TNBC cell lines MDA-MB-231, MDA-MB-468, BT549, Hs578T, BT20, and SUM159 in immunocompromised mice. We characterized each cell line's cell morphology, proliferation, and motility in 2D and 3D to determine the variation in these parameters between cell lines. RESULTS: We identified MDA-MB-231, MDA-MB-468, and BT549 cells as highly tumorigenic and metastatic, Hs578T as poorly tumorigenic and metastatic, BT20 as intermediate tumorigenic with poor metastasis to the lungs but highly metastatic to the livers, and SUM159 as intermediate tumorigenic but poorly metastatic to the lungs and livers. We showed that metrics that characterize cell morphology are the most predictive of tumor growth and metastatic potential to the lungs and liver. Further, we found that no single in vitro motility assay in 2D or 3D significantly correlated with metastasis in vivo. CONCLUSIONS: Our results provide an important resource for the TNBC research community, identifying the metastatic potential of 6 commonly used cell lines. Our findings also support the use of cell morphological analysis to investigate the metastatic potential and emphasize the need for multiple in vitro motility metrics using multiple cell lines to represent the heterogeneity of metastasis in vivo.
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Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Proliferación Celular , Xenoinjertos , Trasplante Heterólogo , Movimiento CelularRESUMEN
[This corrects the article DOI: 10.1021/acssuschemeng.3c03030.].
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In the context of transitioning toward a more sustainable use of natural resources, the application of lignin to substitute commonly utilized petroleum-based plastics can play a key role. Although lignin is highly available at low cost and presents interesting properties, such as antioxidant and UV barrier activities, its application is limited by its low reactivity, which is a consequence of harsh conditions normally used to extract lignin from biomass. In this work, the use of glyoxylic acid lignin (GA lignin), rich in carboxylic acid groups and hence highly reactive toward epoxy cross-linkers, is presented. GA lignin, which is directly extracted from biomass via a one-step aldehyde-assisted fractionation process, allowed the preparation of thermoset films and coatings via a simple reaction with sustainable poly(ethylene glycol) diglycidyl ether and glycerol diglycidyl ether cross-linkers. This allows one to prepare freestanding films containing up to 70 wt % lignin with tunable mechanical properties and covalently surface-attached coatings containing up to 90 wt % lignin with high solvent resistance. Both films and coatings display antioxidant properties and combine excellent UV barrier activity with high visible transparency, which is attractive for applications in sustainable food packaging.
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Background: Metastasis is the leading cause of death in breast cancer patients. For metastasis to occur, tumor cells must invade locally, intravasate, and colonize distant tissues and organs, all steps that require tumor cell migration. The majority of studies on invasion and metastasis rely on human breast cancer cell lines. While it is known that these cells have different properties and abilities for growth and metastasis, the in vitro morphological, proliferative, migratory, and invasive behavior of these cell lines and their correlation to in vivo behavior is poorly understood. Thus, we sought to classify each cell line as poorly or highly metastatic by characterizing tumor growth and metastasis in a murine model of six commonly used human triple-negative breast cancer xenografts, as well as determine which in vitro assays commonly used to study cell motility best predict in vivo metastasis. Methods: We evaluated the liver and lung metastasis of human TNBC cell lines MDA-MB-231, MDA-MB-468, BT549, Hs578T, BT20, and SUM159 in immunocompromised mice. We characterized each cell line's cell morphology, proliferation, and motility in 2D and 3D to determine the variation in these parameters between cell lines. Results: We identified MDA-MB-231, MDA-MB-468, and BT549 cells as highly tumorigenic and metastatic, Hs578T as poorly tumorigenic and metastatic, BT20 as intermediate tumorigenic with poor metastasis to the lungs but highly metastatic to the livers, and SUM159 as intermediate tumorigenic but poorly metastatic to the lungs and livers. We showed that metrics that characterize cell morphology are the most predictive of tumor growth and metastatic potential to the lungs and liver. Further, we found that no single in vitro motility assay in 2D or 3D significantly correlated with metastasis in vivo. Conclusions: Our results provide an important resource for the TNBC research community, identifying the metastatic potential of 6 commonly used cell lines. Our findings also support the use of cell morphological analysis to investigate the metastatic potential and emphasize the need for multiple in vitro motility metrics using multiple cell lines to represent the heterogeneity of metastasis in vivo.
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The peripheral nervous system plays an important role in cancer progression. Studies in multiple cancer types have shown that higher intratumoral nerve density is associated with poor outcomes. Peripheral nerves have been shown to directly regulate tumor cell properties, such as growth and metastasis, as well as affect the local environment by modulating angiogenesis and the immune system. In this Review, we discuss the identity of nerves in organs in the periphery where solid tumors grow, the known mechanisms by which nerve density increases in tumors, and the effects these nerves have on cancer progression. We also discuss the strengths and weaknesses of current in vitro and in vivo models used to study nerve-cancer interactions. Increased understanding of the mechanisms by which nerves impact tumor progression and the development of new approaches to study nerve-cancer interactions will facilitate the discovery of novel treatment strategies to treat cancer by targeting nerves.
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Neoplasias , Tejido Nervioso , Humanos , Neoplasias/patologíaRESUMEN
In breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis, yet the mechanisms by which different types of peripheral nerves drive tumor progression remain poorly understood. In this study, we identified sensory nerves as more abundant in human triple-negative breast cancer (TNBC) tumors. Co-injection of sensory neurons isolated from the dorsal root ganglia (DRG) of adult female mice with human TNBC cells in immunocompromised mice increased the number of lung metastases. Direct in vitro co-culture of human TNBC cells with the dorsal root ganglia (DRG) of adult female mice revealed that TNBC cells adhere to sensory neuron fibers leading to an increase in migration speed. Species-specific RNA sequencing revealed that co-culture of TNBC cells with sensory nerves upregulates the expression of genes associated with cell migration and adhesion in cancer cells. We demonstrated that lack of the semaphorin receptor PlexinB3 in cancer cells attenuate their adhesion to and migration on sensory nerves. Together, our results identify a mechanism by which nerves contribute to breast cancer migration and metastasis by inducing a shift in TNBC cell gene expression and support the rationale for disrupting neuron-cancer cell interactions to target metastasis.
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INTRODUCTION: Contemporary data on the epidemiology of acute myocardial infarction (AMI) in Vietnam are extremely limited. METHODS: We established population-based registries of residents from 2 provinces in a northern urban (Hai Phong), and a central rural (Thanh Hoa), province of Vietnam hospitalized with a validated first AMI in 2018. We described patient characteristics, in-hospital management and clinical complications, and estimated incidence rates of AMI in these two registries. RESULTS: A total of 785 patients (mean age = 71.2 years, 64.7% men) were admitted to the two hospitals with a validated first AMI. Approximately 64% of the AMI cases were ST-segment-elevation AMI. Patients from Thanh Hoa compared with Hai Phong were more likely to delay seeking acute hospital care. The incidence rates (per 100,000 population) of initial AMI in Thanh Hoa and Hai Phong were 16 and 30, respectively. Most patients were treated with aspirin (Thanh Hoa: 96%; Hai Phong: 90%) and statins (both provinces: 91%) during their hospitalization. A greater proportion of patients in Hai Phong (69%) underwent percutaneous revascularization than those in Thanh Hoa (58%). The most common in-hospital complications were heart failure (both provinces:12%), cardiogenic shock (Thanh Hoa: 10%; Hai phong: 7%); and cardiac arrest (both provinces: 9%). The in-hospital case-fatality rates for patients from Thanh Hoa and Hai Phong were 6.8% and 3.8%, respectively. CONCLUSIONS: The incidence and hospital case-fatality rates of AMI were low in two Vietnamese provinces. Extent of pre-hospital delay and in-hospital use of evidence-based therapies were suboptimal, being more prominent in the rural province.
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Infarto del Miocardio , Infarto del Miocardio con Elevación del ST , Anciano , Femenino , Mortalidad Hospitalaria , Hospitales , Humanos , Masculino , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/terapia , Infarto del Miocardio con Elevación del ST/epidemiología , Choque Cardiogénico/terapia , Vietnam/epidemiologíaRESUMEN
BACKGROUND: There is a critical need to better understand the mechanisms that drive local cell invasion and metastasis to develop new therapeutics targeting metastatic disease. Bioelectricity is an important mediator of cellular processes and changes in the resting membrane potential (RMP) are associated with increased cancer cell invasion. However, whether the RMP can be used to target invading cancer cells is unknown. METHODS: We employed both genetic and pharmacological manipulation of potassium channel activity and characterized the effects on breast cancer cell migration and invasion in vitro, and metastasis in an animal model of breast cancer. FINDINGS: Our data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channel expression increases in vitro invasion, in vivo tumour growth and metastasis, and is accompanied by changes in gene expression associated with cell adhesion. INTERPRETATION: We describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new strategy to target metastatic TNBC in vivo by repurposing an FDA-approved potassium channel blocker. Our results demonstrate that bioelectricity regulates cancer cell invasion and metastasis which could lead to a new class of therapeutics for patients with metastatic disease. FUNDING: This work was supported by the National Institutes of Health (R00-CA207866 to M.J.O.), Tufts University (Start-up funds from the School of Engineering to M.J.O., Tufts Collaborates Award to M.J.O. and M.L.), Allen Discovery centre program (Paul G. Allen Frontiers Group (12,171) to M.L.), and Breast Cancer Alliance Young Investigator Grant to M.J.O, Laidlaw Scholar funding to D.S. M.L. also gratefully acknowledges support of the Barton Family Foundation.
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Neoplasias de la Mama Triple Negativas , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Humanos , Metástasis de la Neoplasia , Canales de Potasio , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Cardiac fibroblasts are responsible for extracellular matrix turnover and repair in the cardiac environment and serve to help facilitate immune responses. However, it is well established that they have a significant phenotypic heterogeneity with respect to location, physiological conditions, and developmental age. The goal of this study was to provide an in-depth transcriptomic profile of cardiac fibroblasts derived from rat hearts at fetal, neonatal, and adult developmental ages to ascertain variations in gene expression that may drive functional differences in these cells at these specific stages of development. We performed RNA sequencing (RNA-seq) of cardiac fibroblasts isolated from fetal, neonatal, and adult rats and compared with the rat genome. Principal component analysis of RNA-seq data suggested that data variance was predominantly due to developmental age. Differential expression and gene set enrichment analysis against Gene Ontology and Kyoto Encyclopedia of Genes and Genomes datasets indicated an array of differences across developmental ages, including significant decreases in cardiac development and cardiac function-associated genes with age and a significant increase in immune- and inflammatory-associated functions, particularly immune cell signaling and cytokine and chemokine production, with respect to increasing developmental age. These results reinforce established evidence of diverse phenotypic heterogeneity of fibroblasts with respect to developmental age. Furthermore, based on our analysis of gene expression, age-specific alterations in cardiac fibroblasts may play a crucial role in observed differences in cardiac inflammation and immune response observed across developmental ages.
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Fibroblastos/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Corazón/crecimiento & desarrollo , ARN/genética , Transcriptoma/genética , Animales , Matriz Extracelular/genética , Matriz Extracelular/fisiología , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Ratas , Análisis de Secuencia de ARN/métodos , Transducción de Señal/genética , Transducción de Señal/fisiología , Secuenciación del Exoma/métodosRESUMEN
BACKGROUND: Even though dragon fruit peel has more health benefits than its pulp, it is considered to be waste after fruit processing. In this study, dragon fruit peel was explored as an additional ingredient in winemaking. METHODS: The contents of total phenolic compounds, betacyanins and ascorbic acid, the antioxidant capacity by DPPHz method, and the level of consumer acceptability of the wines prepared from two species with and without peel were compared. RESULTS: The wines of the H. polyrhizus species contained much higher total phenolics (1.4-1.6 times), betacyanins (75-81 times), and vitamin C (2.8-3.8 times), as well as higher 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (1.2 times) than the wines of H. undatus. Although the fermentation process led to the degradation of betacyanins, it increased the total phenolics (up to 17%), vitamin C (up to 24%), and DPPHz scavenging activity (up to 19%) as compared with the control when fermentation was conducted at 25°C, which was found as the most suitable fermentation temperature to produce wines with the highest quality in terms of antioxidant content and activity. At this temperature, peel inclusion also increased these values in the wine. In addition, the sensory properties in terms of appearance and aroma could be improved in the final fermented product. CONCLUSIONS: H. polyrhizus wine might have higher antioxidant properties than H. undatus wine. With a suitable fermentation temperature, peel inclusion as an ingredient could enhance these characteristics of the wine without compromising its sensory quality. This study may provide insights into fruit winemaking with higher health benefits.
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Antioxidantes/farmacología , Cactaceae/química , Comportamiento del Consumidor , Fermentación , Manipulación de Alimentos/métodos , Frutas , Vino/análisis , Antioxidantes/análisis , Ácido Ascórbico/análisis , Ácido Ascórbico/farmacología , Betacianinas/análisis , Betacianinas/farmacología , Compuestos de Bifenilo , Cactaceae/clasificación , Humanos , Fenoles/análisis , Fenoles/farmacología , Picratos , Epidermis de la Planta , Extractos Vegetales/análisis , Extractos Vegetales/farmacología , Especificidad de la Especie , Gusto , TemperaturaRESUMEN
BACKGROUND: Vietnam has been experiencing an epidemiologic transition to that of a lower-middle income country with an increasing prevalence of non-communicable diseases. The key risk factors for cardiovascular disease (CVD) are either on the rise or at alarming levels in Vietnam, particularly hypertension (HTN). Inasmuch, the burden of CVD will continue to increase in the Vietnamese population unless effective prevention and control measures are put in place. The objectives of the proposed project are to evaluate the implementation and effectiveness of two multi-faceted community and clinic-based strategies on the control of elevated blood pressure (BP) among adults in Vietnam via a cluster randomized trial design. METHODS: Sixteen communities will be randomized to either an intervention (8 communities) or a comparison group (8 communities). Eligible and consenting adult study participants with HTN (n = 680) will be assigned to intervention/comparison status based on the community in which they reside. Both comparison and intervention groups will receive a multi-level intervention modeled after the Vietnam National Hypertension Program including education and practice change modules for health care providers, accessible reading materials for patients, and a multi-media community awareness program. In addition, the intervention group only will receive three carefully selected enhancements integrated into routine clinical care: (1) expanded community health worker services, (2) home BP self-monitoring, and (3) a "storytelling intervention," which consists of interactive, literacy-appropriate, and culturally sensitive multi-media storytelling modules for motivating behavior change through the power of patients speaking in their own voices. The storytelling intervention will be delivered by DVDs with serial installments at baseline and at 3, 6, and 9 months after trial enrollment. Changes in BP will be assessed in both groups at several follow-up time points. Implementation outcomes will be assessed as well. DISCUSSION: Results from this full-scale trial will provide health policymakers with practical evidence on how to combat a key risk factor for CVD using a feasible, sustainable, and cost-effective intervention that could be used as a national program for controlling HTN in Vietnam. TRIAL REGISTRATION: ClinicalTrials.gov NCT03590691 . Registered on July 17, 2018. Protocol version: 6. Date: August 15, 2019.
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Enfermedades Cardiovasculares , Hipertensión , Adulto , Agentes Comunitarios de Salud , Análisis Costo-Beneficio , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Vietnam/epidemiologíaRESUMEN
Spinal muscular atrophy (SMA) is caused by mutation or deletion of survival motor neuron 1 (SMN1) and retention of SMN2 leading to SMN protein deficiency. We developed an immortalized mouse embryonic fibroblast (iMEF) line in which full-length wild-type Smn (flwt-Smn) can be conditionally deleted using Cre recombinase. iMEFs lacking flwt-Smn are not viable. We tested the SMA patient SMN1 missense mutation alleles A2G, D44V, A111G, E134K and T274I in these cells to determine which human SMN (huSMN) mutant alleles can function in the absence of flwt-Smn. All missense mutant alleles failed to rescue survival in the conditionally deleted iMEFs. Thus, the function lost by these mutations is essential to cell survival. However, co-expression of two different huSMN missense mutants can rescue iMEF survival and small nuclear ribonucleoprotein (snRNP) assembly, demonstrating intragenic complementation of SMN alleles. In addition, we show that a Smn protein lacking exon 2B can rescue iMEF survival and snRNP assembly in the absence of flwt-Smn, indicating exon 2B is not required for the essential function of Smn. For the first time, using this novel cell line, we can assay the function of SMN alleles in the complete absence of flwt-Smn.
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Atrofia Muscular Espinal/genética , Ribonucleoproteínas Nucleares Pequeñas/genética , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Alelos , Animales , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Exones/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Integrasas/genética , Ratones , Atrofia Muscular Espinal/patología , Mutación Missense/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
BACKGROUND: Multiple studies investigating the use of focused cardiac ultrasound (FCU) in lower and middle-income countries and in medically underserved areas of the United States have demonstrated utility in echocardiographic screening algorithms performed by a variety of operators at different levels of training. No study to date has employed previously untrained nurses in a medically underserved setting to identify older adults with cardiac disorders. The aim of this study was to assess the accuracy of nurse-performed FCU to screen adult subjects at a village health center in Vietnam. METHODS: Vietnamese nurses (N = 8) underwent structured training conducted by sonographers and physicians during an outreach event sponsored by the American Society of Echocardiography Education and Research Foundation. The nurses were trained to detect abnormalities from a single echocardiographic view (parasternal long-axis) with a laptop-sized device and underwent pre- and posttraining testing. Following training, cardiac ultrasound examinations were performed on subjects >50 years of age at a village health center. First, the nurses performed focused cardiac ultrasound using two-dimensional and color Doppler imaging in the parasternal long-axis view using the M7 device and recorded their assessments. Two-dimensional color and spectral Doppler echocardiography was thereafter performed using the same machine by a sonographer (n = 5) or a Vietnamese echocardiography-trained cardiologist (n = 1). Interviews and electrocardiography were performed at the time of FCU. RESULTS: Each nurse improved from pre- to posttraining (average improvement in correct answers, 21%; range, 2%-31%). During the scanning phase, nurses' sensitivity, specificity, and accuracy for identifying subjects with any abnormality were 51.5% (85 of 165), 78.1% (82 of 105) and 61.9%, respectively. There were 60 subjects with significant findings (22.2%); all of these subjects had significant abnormalities visible on parasternal long-axis images. Overall sensitivity, specificity, and accuracy for identifying subjects with major abnormalities were 83.3% (50 of 60), 78.1% (164 of 210), and 78.6%, respectively. Nurse-performed FCU demonstrated much higher sensitivity with lower specificity than electrocardiography alone. The combination of nurse-performed FCU plus ECG identified all of the significant findings on echocardiography and increased accuracy to 91.5%. CONCLUSIONS: Nurses with no prior echocardiographic experience and with limited training can identify patients with significant cardiac abnormalities using FCU with acceptable accuracy. Screening strategies involving FCU may play a role in improving access to health care and triage in underserved areas.
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Ecocardiografía/enfermería , Cardiopatías/diagnóstico , Tamizaje Masivo/enfermería , Pautas de la Práctica en Enfermería , Población Rural , Femenino , Cardiopatías/enfermería , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Spinal muscular atrophy (SMA) is caused by reduced levels of full-length SMN (FL-SMN). In SMA patients with one or two copies of the Survival Motor Neuron 2 (SMN2) gene there are a number of SMN missense mutations that result in milder-than-predicted SMA phenotypes. These mild SMN missense mutation alleles are often assumed to have partial function. However, it is important to consider the contribution of FL-SMN as these missense alleles never occur in the absence of SMN2. We propose that these patients contain a partially functional oligomeric SMN complex consisting of FL-SMN from SMN2 and mutant SMN protein produced from the missense allele. Here we show that mild SMN missense mutations SMND44V, SMNT74I or SMNQ282A alone do not rescue mice lacking wild-type FL-SMN. Thus, missense mutations are not functional in the absence of FL-SMN. In contrast, when the same mild SMN missense mutations are expressed in a mouse containing two SMN2 copies, functional SMN complexes are formed with the small amount of wild-type FL-SMN produced by SMN2 and the SMA phenotype is completely rescued. This contrasts with SMN missense alleles when studied in C. elegans, Drosophila and zebrafish. Here we demonstrate that the heteromeric SMN complex formed with FL-SMN is functional and sufficient to rescue small nuclear ribonucleoprotein assembly, motor neuron function and rescue the SMA mice. We conclude that mild SMN missense alleles are not partially functional but rather they are completely non-functional in the absence of wild-type SMN in mammals.
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Atrofia Muscular Espinal/genética , Ribonucleoproteínas Nucleares Pequeñas/genética , Proteínas del Complejo SMN/genética , Alelos , Animales , Caenorhabditis elegans/genética , Línea Celular , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Exones/genética , Humanos , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Mutación Missense , Ribonucleoproteínas Nucleares Pequeñas/química , Proteínas del Complejo SMN/química , Proteína 2 para la Supervivencia de la Neurona Motora/química , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Pez Cebra/genéticaRESUMEN
In France, the national breast cancer-screening program is based on mammography combined with clinical breast examination, and sometimes breast ultrasound for patients with high breast density. Digital breast tomosynthesis is a currently assessed 3D imaging technique in which angular projections of the stationary compressed breast are acquired automatically. When combined with mammography, clinicians can review both conventional (2D) as well as three-dimensional (3D) data. The purpose of this article is to review recent reports on this new breast imaging technique and complements this information with our personal experience. The main advantages of tomosynthesis are that it facilitates the detection and characterization of breast lesions, as well as the diagnosis of occult lesions in dense breasts. However, to do this, patients are exposed to higher levels of radiation than with 2D mammography. In France, the indications for tomosynthesis and its use in breast cancer-screening (individual and organized) are yet to be defined, as is its role in the diagnosis and staging of breast cancer (multiple lesions). Further studies assessing in particular the combined reconstruction of the 2D view using 3D tomosynthesis data acquired during a single breast compression event, and therefore reducing patient exposure to radiation, are expected to provide valuable insight.
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Neoplasias de la Mama/diagnóstico por imagen , Detección Precoz del Cáncer , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Mamografía/métodos , Intensificación de Imagen Radiográfica/métodos , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Biopsia con Aguja , Mama/patología , Densidad de la Mama , Neoplasias de la Mama/patología , Femenino , Humanos , Glándulas Mamarias Humanas/anomalías , Estadificación de Neoplasias , Dosis de Radiación , Sensibilidad y Especificidad , Ultrasonografía Mamaria/métodosRESUMEN
Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons.
Asunto(s)
Glicoproteínas de Membrana/fisiología , Proteínas de Microfilamentos/fisiología , Neuronas Motoras/metabolismo , Atrofia Muscular Espinal/terapia , Médula Espinal/metabolismo , Animales , Modelos Animales de Enfermedad , Embrión no Mamífero/anomalías , Embrión no Mamífero/química , Femenino , Genes Reporteros , Humanos , Masculino , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/biosíntesis , Proteínas de Microfilamentos/genética , Morfolinos/administración & dosificación , Morfolinos/genética , Atrofia Muscular Espinal/genética , Unión Neuromuscular/fisiopatología , Fenotipo , Priones/genética , Regiones Promotoras Genéticas , ARN Mensajero/administración & dosificación , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Proteínas Recombinantes/biosíntesis , Caracteres Sexuales , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Transgenes , Pez Cebra/embriologíaRESUMEN
OBJECTIVES: Influenza A/H1N1pdm09 virus was first detected in Vietnam on May 31, 2009, and continues to circulate in Vietnam as a seasonal influenza virus. This study has monitored genotypic and phenotypic changes in this group of viruses during 2010-2013 period. DESIGN AND SETTING: We sequenced hemagglutinin (HA) and neuraminidase (NA) genes from representative influenza A/H1N1pdm09 and compared with vaccine strain A/California/07/09 and other contemporary isolates from neighboring countries. Hemagglutination inhibition (HI) and neuraminidase inhibition (NAI) assays also were performed on these isolates. SAMPLE: Representative influenza A/H1N1pdm09 isolates (n = 61) from ILI and SARI surveillances in northern Vietnam between 2010 and 2013. MAIN OUTCOME MEASURES AND RESULTS: The HA and NA phylogenies revealed six and seven groups, respectively. Five isolates (8·2%) had substitutions G155E and N156K in the HA, which were associated with reduced HI titers by antiserum raised against the vaccine virus A/California/07/2009. One isolate from 2011 and one isolate from 2013 had a predicted H275Y substitution in the neuraminidase molecule, which was associated with reduced susceptibility to oseltamivir in a NAI assay. We also identified a D222N change in the HA of a virus isolated from a fatal case in 2013. CONCLUSIONS: Significant genotypic and phenotypic changes in A/ H1N1pdm09 influenza viruses were detected by the National Influenza Surveillance System (NISS) in Vietnam between 2010 and 2013 highlighting the value of this system to Vietnam and to the region. Sustained NISS and continued virological monitoring of seasonal influenza viruses are required for vaccine policy development in Vietnam. 3.