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BACKGROUND: Arthroscopic arthrodesis is an accepted technique for the ankle but less commonly reported for multiple hindfoot joints. We present a case series review to establish the feasibility of this surgery. METHODS: In a consecutive series of 112 arthroscopic hindfoot arthrodeses, 18 involved decortication and fusion of 2 or 3 hindfoot joints. These were reviewed to identify complications, union rates and improvement over preoperative state. RESULTS: Mean age was 62 (45-78). Mean follow-up was 4.4 (1.75-7.5) years. There were no perioperative complications. The four patients with triple fusions united with good or excellent outcomes. Of 14 patients with subtalar and talonavicular arthrodeses there were three talonavicular non-unions. CONCLUSIONS: Arthroscopic double and triple arthrodeses appear feasible salvage options for pain and deformity. Decortication of all three joints and rotatory correction of deformity is possible whilst preserving the soft tissue envelope. Late adjacent joint pain and arthrosis can occur.
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Artritis/cirugía , Artrodesis/métodos , Articulaciones del Pie/cirugía , Anciano , Artroscopía , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Despite the numerous concepts of caregiving discussed in the literature, there is still no agreed definition and concept of family caregiving from the perspective of Islam. This study aims to comprehensively define family caregiving from Islamic religious and Muslim cultural perspectives. Rodger's evolutionary model was used to generate content by analyzing and redefining concepts. A thorough examination of the relevant literature using Scopus, PubMed, Medline, and CINAHL databases also trusted sources offered a total of 52 articles and 8 books to be reviewed. Our study reveals that family caregiving is viewed as God's gift as important as an essential religious and cultural obligation in Islam, where humans are expected to deliver care for their families although they are unprepared. This can be motivated by aspirations for respect, love, responsibility, and a desire to recompense parents, as well as the belief that by doing so they will be rewarded in the hereafter. The provision of family caregiving leads to positive consequences such as living with hope, gaining rewards and achievement, but at the same time, it also causes devastated life. This research contributes to a new discourse on family caregiving based on Islamic literature which helps in the comprehension of the practices of Muslim communities worldwide.
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The Ocean Carbon and Acidification Data System (OCADS) is a data management system at the National Oceanic and Atmospheric Administration (NOAA) National Centers for Environmental Information (NCEI). It manages a wide range of ocean carbon and acidification data, including chemical, physical, and biological observations collected from research vessels, ships of opportunity, and uncrewed platforms, as well as laboratory experiment results, and model outputs. Additionally, OCADS serves as a repository for related Global Ocean Observing System (GOOS) biogeochemistry Essential Ocean Variables (EOVs), e.g., oxygen, nutrients, transient tracers, and stable isotopes. OCADS endeavors to be one of the world's leading providers of ocean carbon and acidification data, information, products, and services. To provide the best data management services to the ocean carbon and acidification research community, OCADS prioritizes adopting a customer-centric approach and gathering knowledge and expertise from the research community to improve its data management practices. OCADS aims to make all ocean carbon and acidification data accessible via a single portal, and welcomes submissions from around the world: https://www.ncei.noaa.gov/products/ocean-carbon-acidification-data-system/.
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Gamma-ray bursts (GRBs) are known to come in two duration classes, separated at approximately 2 s. Long-duration bursts originate from star-forming regions in galaxies, have accompanying supernovae when these are near enough to observe and are probably caused by massive-star collapsars. Recent observations show that short-duration bursts originate in regions within their host galaxies that have lower star-formation rates, consistent with binary neutron star or neutron star-black hole mergers. Moreover, although their hosts are predominantly nearby galaxies, no supernovae have been so far associated with short-duration GRBs. Here we report that the bright, nearby GRB 060614 does not fit into either class. Its approximately 102-s duration groups it with long-duration GRBs, while its temporal lag and peak luminosity fall entirely within the short-duration GRB subclass. Moreover, very deep optical observations exclude an accompanying supernova, similar to short-duration GRBs. This combination of a long-duration event without an accompanying supernova poses a challenge to both the collapsar and the merging-neutron-star interpretations and opens the door to a new GRB classification scheme that straddles both long- and short-duration bursts.
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Six phosphate glass formulations (in the system P(2)O(5)-CaO-MgO-Na(2)O-Fe(2)O(3)) were produced with fixed magnesium and calcium content at 24 and 16 mol%, respectively. P(2)O(5) and Fe(2)O(3) were varied between 40-50 and 0-4 mol% respectively, with the balance being Na(2)O. EDX analyses confirmed the final composition of the glasses investigated to within a 1-2 % error margin. Thermal analyses showed a linear increase in T(g) with increasing Fe(2)O(3) and P(2)O(5) contents, with Fe(2)O(3) showing a greater effect than P(2)O(5). This was proposed to be due to the formation of Fe-O-P bonds and an increase in the cross-link density of the glass network enhancing the durability of the glass. The glasses that were investigated revealed a decrease in degradation rate with increasing Fe(2)O(3) and P(2)O(5) contents and again the effect of Fe(2)O(3) was greater. All the above characteristics correlated well with structural changes measured by IR and XPS analyses. Cytocompatibility studies showed good cellular (MG63) response to the glasses up to 168 h in terms of cell viability, proliferation and differentiation. Statistical analysis revealed that all the formulations with the exception of P50Fe4 gave a comparable response to the control (TCP), which suggested that after a threshold level of glass durability is achieved the degradation rate has no or minimal effect on biocompatibility. However, it was seen that the glass chemistry can also affect cellular response, since increasing the P(2)O(5) content promoted phenotypic expression that was not related to degradation rate but to the degradation products. This was supported using an elution assay.
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Materiales Biocompatibles , Vidrio , Fosfatasa Alcalina/metabolismo , Línea Celular Tumoral , Humanos , Espectrometría por Rayos X , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
High-sugar grass varieties have received considerable attention for their potential ability to decrease N excretion in cattle. However, feeding high-sugar grasses alters the pattern of rumen fermentation, and no in vivo studies to date have examined this strategy with respect to another environmental pollutant: methane (CH(4)). Modeling allows us to examine potential outcomes of feeding strategies under controlled conditions, and can provide a useful framework for the development of future experiments. The purpose of the present study was to use a modeling approach to evaluate the effect of high-sugar grasses on simulated CH(4) emissions in dairy cattle. An extant dynamic, mechanistic model of enteric fermentation and intestinal digestion was used for this evaluation. A simulation database was constructed and analysis of model behavior was undertaken to simulate the effect of (1) level of water-soluble carbohydrate (WSC) increase in dietary dry matter, (2) change in crude protein (CP) and neutral detergent fiber (NDF) content of the plant with an increased WSC content, (3) level of N fertilization, and (4) presence or absence of grain feeding. Simulated CH(4) emissions tended to increase with increased WSC content when CH(4) was expressed as megajoules per day or percent of gross energy intake, but when CH(4) was expressed in terms of grams per kilogram of milk, results were much more variable due to the potential increase in milk yield. As a result, under certain conditions, CH(4) (g/kg of milk) decreased. The largest increases in CH(4) emissions (MJ/d or % gross energy intake) were generally seen when WSC increased at the expense of CP in the diet and this can largely be explained by the representation in the model of the type of volatile fatty acid produced. Effects were lower when WSC increased at the expense of NDF, and intermediary when WSC increased at the expense of a mixture of CP and NDF. When WSC increased at the expense of NDF, simulated milk yield increased and, therefore, CH(4) (g/kg of milk) tended to decrease. Diminished increases of CH(4) (% gross energy intake or g/kg of milk) were simulated when DMI was increased with elevated WSC content. Simulation results suggest that high WSC grass, as a strategy to mitigate N emission, may increase CH(4) emissions, but that results depend on the grass composition, DMI, and the units chosen to express CH(4). Overall, this project demonstrates the usefulness of modeling for hypothesis testing in the absence of observed experimental results.
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Dieta/veterinaria , Metano/biosíntesis , Poaceae , Animales , Bovinos , Ácidos Grasos Volátiles/metabolismo , Femenino , Fermentación , Lactancia , Modelos Biológicos , Rumen/metabolismoRESUMEN
The prompt optical emission that arrives with the gamma-rays from a cosmic gamma-ray burst (GRB) is a signature of the engine powering the burst, the properties of the ultra-relativistic ejecta of the explosion, and the ejecta's interactions with the surroundings. Until now, only GRB 990123 had been detected at optical wavelengths during the burst phase. Its prompt optical emission was variable and uncorrelated with the prompt gamma-ray emission, suggesting that the optical emission was generated by a reverse shock arising from the ejecta's collision with surrounding material. Here we report prompt optical emission from GRB 041219a. It is variable and correlated with the prompt gamma-rays, indicating a common origin for the optical light and the gamma-rays. Within the context of the standard fireball model of GRBs, we attribute this new optical component to internal shocks driven into the burst ejecta by variations of the inner engine. The correlated optical emission is a direct probe of the jet isolated from the medium. The timing of the uncorrelated optical emission is strongly dependent on the nature of the medium.
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The explosion that results in a cosmic gamma-ray burst (GRB) is thought to produce emission from two physical processes: the central engine gives rise to the high-energy emission of the burst through internal shocking, and the subsequent interaction of the flow with the external environment produces long-wavelength afterglows. Although observations of afterglows continue to refine our understanding of GRB progenitors and relativistic shocks, gamma-ray observations alone have not yielded a clear picture of the origin of the prompt emission nor details of the central engine. Only one concurrent visible-light transient has been found and it was associated with emission from an external shock. Here we report the discovery of infrared emission contemporaneous with a GRB, beginning 7.2 minutes after the onset of GRB 041219a (ref. 8). We acquired 21 images during the active phase of the burst, yielding early multi-colour observations. Our analysis of the initial infrared pulse suggests an origin consistent with internal shocks.
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Two classes of rotating neutron stars-soft gamma-ray repeaters (SGRs) and anomalous X-ray pulsars-are magnetars, whose X-ray emission is powered by a very strong magnetic field (B approximately 10(15) G). SGRs occasionally become 'active', producing many short X-ray bursts. Extremely rarely, an SGR emits a giant flare with a total energy about a thousand times higher than in a typical burst. Here we report that SGR 1806-20 emitted a giant flare on 27 December 2004. The total (isotropic) flare energy is 2 x 10(46) erg, which is about a hundred times higher than the other two previously observed giant flares. The energy release probably occurred during a catastrophic reconfiguration of the neutron star's magnetic field. If the event had occurred at a larger distance, but within 40 megaparsecs, it would have resembled a short, hard gamma-ray burst, suggesting that flares from extragalactic SGRs may form a subclass of such bursts.
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Internal fixation for bone fractures with rigid metallic plates, screws and pins is a proven operative technique. However, refracture's have been observed after rigid internal fixation with metal plates and plate fixation has been known to cause localised osteopenia under and near the plate. In the present study, resorbable composites comprising a PLA matrix reinforced with iron doped phosphate glass fibres were investigated. Non-woven random mat laminates of approximately 30% and 45% fibre volume fraction (V(f)) were produced, along with unidirectional and 0°-90° samples of approximately 20% V(f). The non-woven composite laminates achieved maximum values of 10 GPa modulus and 120 MPa strength. The 0-90º samples showed unexpectedly low strengths close to matrix value (~50 MPa) although with a modulus of 7 GPa. The UD specimens exhibited values of 130 MPa and 11.5 GPa for strength and modulus respectively. All the modulus values observed were close to that expected from the rule of mixtures. Samples immersed in deionised water at 37°C revealed rapid mechanical property loss, more so for the UD and 0-90º samples. It was suggested that continuous fibres wicked the degradation media into the composite plates which sped up the deterioration of the fibre-matrix interface. The effect was less pronounced in the non-woven random mat laminates due to the discontinuous arrangement of fibres within the composite, making it less prone to wicking. Random mat composites revealed a higher mass loss than the UD and 0°-90° specimens, it was suggested this was due to the higher fibre volume fractions of these composites and SEM studies revealed voidage around the fibres by day 3. Studies of pH of the degradation media showed similar profiles for all the composites investigated. An initial decrease in pH was attributed to the release of phosphate ions into solution followed by a gradual return back to neutral.
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Vidrio , Fijadores Internos , Ácido Láctico/química , Fosfatos/química , Polímeros/química , Ensayo de Materiales , Microscopía Electrónica de Rastreo , PoliésteresRESUMEN
High-sugar grass varieties have received considerable attention for their potential to reduce nitrogen (N) excretion and increase milk yield in cattle. However, considerable variation exists in the magnitude of response in published results. The purpose of this study is to explain the variation in response using a dynamic mechanistic model to predict observed N and milk yield results from the literature, and from simulated data. Examined effects were (1) water-soluble carbohydrate [WSC; g/kg of dry matter (DM)] increase; (2) change in crude protein (CP) and neutral detergent fiber (NDF) content of the plant with WSC increase; and (3) the level of N fertilization. The database for evaluation of model N and milk yield predictions consisted of 4 published studies with 28 treatment means for which high-sugar grasses were being evaluated. Water-soluble carbohydrate content of the diets ranged from 95 to 248 g/kg of DM, CP content ranged from 115 to 263 g/kg of DM, and the NDF content ranged from 400 to 568 g/kg of DM. Urine N, milk N, and total N excretion were predicted well by the model and followed the directional pattern of observed values within each study. Simulation results showed that the N utilization ratio increased as the WSC content of the diet increased, but to varying degrees depending on the grass scenario examined. The greatest benefit in terms of N utilization ratio and urine N levels were seen when the WSC content of grass increased at the expense of CP, followed by a 50:50 CP and NDF mix, followed by a trade for NDF. Simulated milk yield decreased slightly when WSC increased at the expense of CP, increased slightly when it increased at the expense of a CP and NDF mix, and increased most when WSC increased at the expense of NDF. Results were amplified slightly under conditions of low-N fertilization and in the absence of grain feeding. Overall, modeling is useful as an explanatory tool. The variation from results in the literature with high-WSC grass feeding may be, at least in part, the result of the level of WSC (g/kg of DM) increase, concurrent changes occurring within the CP and NDF fractions of the plant, and the plane of nutrition of the diet (grain feeding and N fertilization levels).
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Bovinos/fisiología , Leche/metabolismo , Modelos Biológicos , Nitrógeno/análisis , Poaceae/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Bovinos/metabolismo , Simulación por Computador , Dieta/veterinaria , Heces/química , Femenino , Lactancia , Leche/química , Nitrógeno/orinaRESUMEN
INTRODUCTION: Specific patterns of blood test results are associated with COVID-19 infection. The aim of this study was to identify which blood tests could be used to assist in diagnosing COVID-19. METHOD: A retrospective review was performed on consecutive patients referred to hospital with a clinical suspicion of COVID-19 over a period of four weeks. The patient's clinical presentation and severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction (SARS-CoV-2 RT-PCR) were recorded. The patients were divided by diagnosis into COVID (COVID-19 infection) or CONTROL (an alternate diagnosis). A retrospective review of consecutive patients over a further two-week period was used for the purposes of validation. RESULTS: Overall, 399 patients (53% COVID, 47% CONTROL) were analysed. White cell count, neutrophils and lymphocytes were significantly lower, while lactate dehydrogenase and ferritin were significantly higher, in the COVID group in comparison to CONTROL. Combining the white cell count, lymphocytes and ferritin results into a COVID Combined Blood Test (CCBT) had an area under the curve of 0.79. Using a threshold CCBT of -0.8 resulted in a sensitivity of 0.85 and a specificity of 0.63. Analysing this against a further retrospective review of 181 suspected COVID-19 patients, using the same CCBT threshold, resulted in a sensitivity of 0.73 and a specificity of 0.75. The sensitivity was comparable to the SARS-CoV-2 RT PCR. DISCUSSION: Mathematically combining the blood tests has the potential to assist clinical acumen allowing for rapid streaming and more accurate patient flow pending definitive diagnosis. This may be of particular use in low-resource settings.
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Prueba de Ácido Nucleico para COVID-19 , COVID-19 , Ferritinas/sangre , L-Lactato Deshidrogenasa/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2 , Anciano , Anciano de 80 o más Años , COVID-19/sangre , COVID-19/diagnóstico , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The IETA (International Endometrial Tumor Analysis group) statement is a consensus statement on terms, definitions and measurements that may be used to describe the sonographic features of the endometrium and uterine cavity on gray-scale sonography, color flow imaging and sonohysterography. The relationship between the ultrasound features described and the presence or absence of pathology is not known. However, the IETA terms and definitions may form the basis for prospective studies to predict the risk of different endometrial pathologies based on their ultrasound appearance.
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Consenso , Neoplasias Uterinas/diagnóstico por imagen , Útero/diagnóstico por imagen , Endometrio/diagnóstico por imagen , Estudios de Evaluación como Asunto , Femenino , Humanos , Guías de Práctica Clínica como Asunto , Terminología como Asunto , Ultrasonografía Doppler en Color , Neoplasias Uterinas/clasificaciónRESUMEN
In Saccharomyces cerevisiae, more than 80% of the approximately 6200 predicted genes are nonessential, implying that the genome is buffered from the phenotypic consequences of genetic perturbation. To evaluate function, we developed a method for systematic construction of double mutants, termed synthetic genetic array (SGA) analysis, in which a query mutation is crossed to an array of approximately 4700 deletion mutants. Inviable double-mutant meiotic progeny identify functional relationships between genes. SGA analysis of genes with roles in cytoskeletal organization (BNI1, ARP2, ARC40, BIM1), DNA synthesis and repair (SGS1, RAD27), or uncharacterized functions (BBC1, NBP2) generated a network of 291 interactions among 204 genes. Systematic application of this approach should produce a global map of gene function.
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Proteínas del Citoesqueleto , Eliminación de Gen , Genes Fúngicos/fisiología , Técnicas Genéticas , Proteínas de Microfilamentos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/fisiología , Proteínas Portadoras/genética , Proteínas Portadoras/fisiología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiología , Polaridad Celular , Biología Computacional , Cruzamientos Genéticos , Citoesqueleto/fisiología , ADN Helicasas/genética , ADN Helicasas/fisiología , Reparación del ADN , ADN de Hongos/biosíntesis , Bases de Datos Genéticas , Endodesoxirribonucleasas/genética , Endodesoxirribonucleasas/fisiología , Endonucleasas de ADN Solapado , Proteínas Fúngicas/genética , Proteínas Fúngicas/fisiología , Genes Esenciales , Marcadores Genéticos , Genoma Fúngico , Proteínas de Microtúbulos/genética , Proteínas de Microtúbulos/fisiología , Mitosis , RecQ Helicasas , Recombinación Genética , Robótica , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/fisiologíaRESUMEN
INTRODUCTION: Research over the last decade has identified both strengths and limitations in the use of routinely prescribed psychological therapies for depression. More recently, a focus on how creative art therapies and 'arts on prescription' are developing a growing recognition of their potential additional therapeutic mechanisms for depression. AIM: In an attempt to develop a new therapeutic intervention for depression, this research aligned both the evidence base surrounding the arts on prescription movement, collating these with client-reported helpful factors and preferences for therapeutic interventions. METHODS: We developed a framework for a new pluralistic 'meta-approach' of therapy for depression, based on; an interdisciplinary thematic synthesis of active ingredients, considered specific features implemented in therapy, and client-reported helpful factors considered to be the broad features or experiences in therapy from both talking therapies and creative approaches. This framework contributed to the development of a pilot workshop entitled Arts for the Blues - A New Creative Psychological Therapy for Depression. An outline of, and evaluation from this workshop is presented in this article. Workshop participants were recruited via a voluntary workshop taking place at a North West Higher Education Institution Arts and Health conference ( N = 15). RESULTS: The workshop was evaluated using quantitative measures, with results indicating around a 70% overall satisfaction, followed up with qualitative commentary around areas of good practice and areas for development. These included the positive reflection on the application of creative arts and the multimodal nature of the approach, while others reflected on the potential overwhelming nature of utilising multimodal methods for individuals with depression. CONCLUSION: Overall feedback from the pilot workshop is discussed in relation to prior research, giving credence to the potential for incorporating arts into therapy.
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Arteterapia , Depresión/terapia , Humanos , Satisfacción del Paciente , Proyectos Piloto , Evaluación de Programas y Proyectos de SaludRESUMEN
Mice with gene-targeted deletion of the Kv1.3 channel were generated to study its role in olfactory function. Potassium currents in olfactory bulb mitral cells from Kv1.3 null mice have slow inactivation kinetics, a modified voltage dependence, and a dampened C-type inactivation and fail to be modulated by activators of receptor tyrosine signaling cascades. Kv1.3 deletion increases expression of scaffolding proteins that normally regulate the channel through protein-protein interactions. Kv1.3-/- mice have a 1,000- to 10,000-fold lower threshold for detection of odors and an increased ability to discriminate between odorants. In accordance with this heightened sense of smell, Kv1.3-/- mice have glomeruli or olfactory coding units that are smaller and more numerous than those of wild-type mice. These data suggest that Kv1.3 plays a far more reaching role in signal transduction, development, and olfactory coding than that of the classically defined role of a potassium channel-to shape excitability by influencing membrane potential.
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Eliminación de Gen , Neuronas/fisiología , Bulbo Olfatorio/citología , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/metabolismo , Proteínas 14-3-3 , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Conducta Animal , Western Blotting , Peso Corporal/genética , Factor Neurotrófico Derivado del Encéfalo/farmacología , Canales de Calcio/genética , Canales de Calcio/metabolismo , Células Cultivadas , Densitometría , Umbral Diferencial , Discriminación en Psicología , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/genética , Estimulación Eléctrica , Embrión de Mamíferos , Ingestión de Energía/genética , Conducta Exploratoria , Proteína Adaptadora GRB10 , Habituación Psicofisiológica/genética , Humanos , Insulina/farmacología , Riñón , Cinética , Canal de Potasio Kv1.3 , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Ratones , Ratones Noqueados , Actividad Motora/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neurotoxinas/farmacología , Proteínas Asociadas a Matriz Nuclear , Odorantes , Bulbo Olfatorio/metabolismo , Técnicas de Placa-Clamp/métodos , Canales de Potasio/deficiencia , Canales de Potasio/genética , Proteínas/genética , Proteínas/metabolismo , ARN Mensajero/biosíntesis , Receptor trkB/genética , Receptor trkB/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Venenos de Escorpión , Umbral Sensorial/fisiologíaRESUMEN
Composites comprising a biodegradable polymeric matrix and a bioactive filler show considerable promise in the field of regenerative medicine, and could potentially serve as degradable bone fracture fixation devices, depending on the properties obtained. Therefore, glass fibres from a binary calcium phosphate (50P(2)O(5)+50CaO) glass were used to reinforce polycaprolactone, at two different volume fractions (V(f)). As-drawn, non-treated and heat-treated fibres were assessed. Weight loss, ion release and the initial mechanical properties of the fibres and composites produced have been investigated. Single fibre tensile testing revealed a fibre strength of 474MPa and a tensile modulus of 44GPa. Weibull analysis suggested a scale value of 524. The composites yielded flexural strength and modulus of up to 30MPa and 2.5GPa, respectively. These values are comparable with human trabecular bone. An 8% mass loss was seen for the lower V(f) composite, whereas for the two higher V(f) composites an approximate 20% mass loss was observed over the course of the 5week study. A plateau in the degradation profile at 350h indicated that fibre dissolution was complete at this interval. This assertion was further supported via ion release studies. The leaching of fibres from the composite created a porous structure, including continuous channels within the polymer matrix. This offers further scope for tailoring scaffold development, as cells from the surrounding tissue may be induced to migrate into the resulting porous matrix.
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Materiales Biocompatibles/química , Pirofosfato de Calcio/química , Poliésteres/química , Absorción , Difusión , Elasticidad , Vidrio/química , Iones , Ensayo de Materiales , Peso Molecular , Porosidad , Estrés Mecánico , Resistencia a la TracciónRESUMEN
TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression. By drug-sensitivity testing of leukemic blasts from the index patient, control samples and TCF3-PBX1 positive and negative BCP-ALL cell lines, we identified the phosphatidylinositide 3-kinase delta (p110δ) inhibitor idelalisib as an effective treatment for TCF3-PBX1 BCP-ALL. This was further supported by evidence showing TCF3-PBX1 directly regulates expression of PIK3CD, the gene encoding p110δ. Other somatic mutations to TP53 and MTOR, as well as aberrant expression of CXCR4, may influence additional drug sensitivities specific to the index patient and accompanied progression of the disease. Our results suggest that idelalisib is a promising treatment option for patients with TCF3-PBX1 BCP-ALL, whereas other drugs could be useful depending on the genetic context of individual patients.
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Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Purinas/farmacología , Quinazolinonas/farmacología , Adulto , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de Fusión Oncogénica/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico , RecurrenciaRESUMEN
Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to ß2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.
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Antineoplásicos/farmacología , Regulación Leucémica de la Expresión Génica , Genes Homeobox , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Compuestos de Anilina/farmacología , Antineoplásicos/uso terapéutico , Biopsia , Médula Ósea/patología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Estudios de Casos y Controles , Línea Celular Tumoral , Análisis por Conglomerados , Resistencia a Antineoplásicos/genética , Exoma , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Familia de Multigenes , Mutación , Sulfonamidas/farmacología , Proteínas WT1/genética , Microglobulina beta-2/genéticaRESUMEN
Metallic bone plates are commonly used for arm bone fractures where conservative treatment (casts) cannot provide adequate support and compression at the fracture site. These plates, made of stainless steel or titanium alloys, tend to shield stress transfer at the fracture site and delay the bone healing rate. This study investigates the feasibility of adopting advanced composite materials to overcome stress shielding effects by optimising the geometry and mechanical properties of the plate to match more closely to the bone. An ulnar transverse fracture is characterised and finite element techniques are employed to investigate the feasibility of a composite-plated fractured bone construct over a stainless steel equivalent. Numerical models of intact and fractured bones are analysed and the mechanical behaviour is found to agree with experimental data. The mechanical properties are tailored to produce an optimised composite plate, offering a 25% reduction in length and a 70% reduction in mass. The optimised design may help to reduce stress shielding and increase bone healing rates.