RESUMEN
Ribosome profiling (Ribo-seq) is a powerful method for the deep analysis of translation mechanisms and regulatory circuits during gene expression. Extraction and sequencing of ribosome-protected fragments (RPFs) and parallel RNA-seq yields genome-wide insight into translational dynamics and post-transcriptional control of gene expression. Here, we provide details on the Ribo-seq method and the subsequent analysis with the unicellular model alga Chlamydomonas reinhardtii (Chlamydomonas) for generating high-resolution data covering more than 10 000 different transcripts. Detailed analysis of the ribosomal offsets on transcripts uncovers presumable transition states during translocation of elongating ribosomes within the 5' and 3' sections of transcripts and characteristics of eukaryotic translation termination, which are fundamentally distinct for chloroplast translation. In chloroplasts, a heterogeneous RPF size distribution along the coding sequence indicates specific regulatory phases during protein synthesis. For example, local accumulation of small RPFs correlates with local slowdown of psbA translation, possibly uncovering an uncharacterized regulatory step during PsbA/D1 synthesis. Further analyses of RPF distribution along specific cytosolic transcripts revealed characteristic patterns of translation elongation exemplified for the major light-harvesting complex proteins, LHCs. By providing high-quality datasets for all subcellular genomes and attaching our data to the Chlamydomonas reference genome, we aim to make ribosome profiles easily accessible for the broad research community. The data can be browsed without advanced bioinformatic background knowledge for translation output levels of specific genes and their splice variants and for monitoring genome annotation.
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Chlamydomonas , Perfilado de Ribosomas , Chlamydomonas/genética , Chlamydomonas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribosomas/genética , Ribosomas/metabolismo , Biosíntesis de Proteínas , Perfilación de la Expresión GénicaRESUMEN
The Genetic Counseling Outcome Scale (GCOS-24) is a 24-item patient-reported outcome measure (PROM) that was developed to evaluate genetic counseling and testing services by measuring the construct of empowerment. The Genomics Outcome Scale (GOS) is a 6-item version of GCOS-24 that was designed to provide a PROM for use both within and outside clinical genetics services and reduce respondent burden. However, unlike GCOS-24, the sensitivity to change of the GOS has not yet been assessed in appropriate clinical settings. We carried out pre- and post-clinic surveys using the GOS to assess sensitivity to change of the GOS and produce before-and-after GOS data as part of a service evaluation. The survey was sent to patients attending the genetic counseling clinic for a first appointment at the All Wales Medical Genetic Service from 8 April 2019 to 18 September 2019. Patients attending disease management clinics, where genetic issues were not the primary concern, were excluded from this study. A total of 138 respondents were included in the final analysis. The result shows that empowerment scores, measured using the GOS, were significantly higher (p<0.05) after clinic attendance. The GOS shows good sensitivity to change, with a medium-to-large effect size (Cohen's d = 0.73). The result also shows that the service is delivering measurable benefits for its service users.
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Manejo de la Enfermedad , Asesoramiento Genético , Genómica , Humanos , Encuestas y Cuestionarios , GalesRESUMEN
KEY MESSAGE: We show that the calcium sensor, CML39, is important in various developmental processes from seeds to mature plants. This study bridges previous work on CML39 as a stress-induced gene and highlights the importance of calcium signalling in plant development. In addition to the evolutionarily-conserved Ca2+ sensor, calmodulin (CaM), plants possess a large family of CaM-related proteins (CMLs). Using a cml39 loss-of-function mutant, we investigated the roles of CML39 in Arabidopsis and discovered a range of phenotypes across developmental stages and in different tissues. In mature plants, loss of CML39 results in shorter siliques, reduced seed number per silique, and reduced number of ovules per pistil. We also observed changes in seed development, germination, and seed coat properties in cml39 mutants in comparison to wild-type plants. Using radicle emergence as a measure of germination, cml39 mutants showed more rapid germination than wild-type plants. In marked contrast to wild-type seeds, the germination of developing, immature cml39 seeds was not sensitive to cold-stratification. In addition, germination of cml39 seeds was less sensitive than wild-type to inhibition by ABA or by treatments that impaired gibberellic acid biosynthesis. Tetrazolium red staining indicated that the seed-coat permeability of cml39 seeds is greater than that of wild-type seeds. RNA sequencing analysis of cml39 seedlings suggests that changes in chromatin modification may underlie some of the phenotypes associated with cml39 mutants, consistent with previous reports that orthologs of CML39 participate in gene silencing. Aberrant ectopic expression of transcripts for seed storage proteins in 7-day old cml39 seedlings was observed, suggesting mis-regulation of early developmental programs. Collectively, our data support a model where CML39 serves as an important Ca2+ sensor during ovule and seed development, as well as during germination and seedling establishment.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/embriología , Arabidopsis/metabolismo , Calmodulina/metabolismo , Frutas/embriología , Germinación , Semillas/embriología , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Calmodulina/genética , Flores/embriología , Flores/genética , Frutas/genética , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Germinación/genética , Giberelinas/metabolismo , Mutación/genética , Permeabilidad , Latencia en las Plantas , Regiones Promotoras Genéticas/genética , Semillas/genética , Transcripción GenéticaRESUMEN
Phosphoenolpyruvate carboxylase (PEPC) is an important regulatory enzyme situated at a key branch point of central plant metabolism. Plant genomes encode several plant-type PEPC (PTPC) isozymes, along with a distantly related bacterial-type PEPC (BTPC). BTPC is expressed at high levels in developing castor oil seeds where it tightly interacts with co-expressed PTPC polypeptides to form unusual hetero-octameric Class-2 PEPC complexes that are desensitized to allosteric inhibition by L-malate. Analysis of RNA-Seq and microarray transcriptome datasets revealed two distinct patterns of tissue-specific BTPC expression in vascular plants. Species such as Arabidopsis thaliana, strawberry, rice, maize, and poplar mainly exhibited pollen- or floral-specific BTPC expression. By contrast, BTPC transcripts were relatively abundant in developing castor, cotton, and soybean seeds, cassava tubers, as well as immature tomato, cucumber, grape, and avocado fruit. Immunoreactive 118 kDa BTPC polypeptides were detected on immunoblots of cucumber and tomato fruit extracts. Co-immunoprecipitation established that as in castor, BTPCs physically interact with endogenous PTPCs to form Class-2 PEPC complexes in tomato and cucumber fruit. We hypothesize that Class-2 PEPCs simultaneously maintain rapid anaplerotic PEP carboxylation and respiratory CO2 refixation in diverse, biosynthetically active sinks that accumulate high malate levels.
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Magnoliopsida/genética , Malatos/metabolismo , Fosfoenolpiruvato Carboxilasa/genética , Proteínas de Plantas/genética , Transcriptoma/genética , Perfilación de la Expresión Génica , Magnoliopsida/metabolismo , Fosfoenolpiruvato Carboxilasa/metabolismo , Proteínas de Plantas/metabolismoRESUMEN
BACKGROUND: Fetal mesenchymal stem/stromal cells (MSC) represent a developmentally-advantageous cell type with translational potential.To enhance adult MSC migration, studies have focussed on the role of the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12), but more recent work implicates an intricate system of CXCR4 receptor dimerization, intracellular localization, multiple ligands, splice variants and nuclear accumulation. We investigated the intracellular localization of CXCR4 in fetal bone marrow-derived MSC and role of intracellular trafficking in CXCR4 surface expression and function. RESULTS: We found that up to 4% of human fetal MSC have detectable surface-localized CXCR4. In the majority of cells, CXCR4 is located not at the cell surface, as would be required for 'sensing' migratory cues, but intracellularly. CXCR4 was identified in early endosomes, recycling endosomes, and lysosomes, indicating only a small percentage of CXCR4 travelling to the plasma membrane. Notably CXCR4 was also found in and around the nucleus, as detected with an anti-CXCR4 antibody directed specifically against CXCR4 isoform 2 differing only in N-terminal sequence. After demonstrating that endocytosis of CXCR4 is largely independent of endogenously-produced SDF-1, we next applied the cytoskeletal inhibitors blebbistatin and dynasore to inhibit endocytotic recycling. These increased the number of cells expressing surface CXCR4 by 10 and 5 fold respectively, and enhanced the number of cells migrating to SDF1 in vitro (up to 2.6 fold). These molecules had a transient effect on cell morphology and adhesion, which abated after the removal of the inhibitors, and did not alter functional stem cell properties. CONCLUSIONS: We conclude that constitutive endocytosis is implicated in the regulation of CXCR4 membrane expression, and suggest a novel pharmacological strategy to enhance migration of systemically-transplanted cells.
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Endocitosis , Feto/citología , Células Madre Mesenquimatosas/citología , Receptores CXCR4/análisis , Receptores CXCR4/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Diferenciación Celular , Movimiento Celular , Núcleo Celular/metabolismo , Células Cultivadas , Endosomas/metabolismo , Femenino , Humanos , Lisosomas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Transporte de ProteínasRESUMEN
BACKGROUND: To report a case of Multiple Evanescent White Dot Syndrome (MEWDS) one month after a COVID-19 infection in a female patient at an age unusual for the occurrence of this disease. CASE PRESENTATION: A 69-year-old Caucasian female reported the presence of floaters, photopsia, and enlarging vision loss in her left eye following the COVID-19 infection. Clinical and multimodal imaging was consistent with the MEWDS diagnosis. Fluorescein angiography examination revealed characteristic hyperfluorescent spots around the fovea in a wreath-like pattern. An extensive lab workup to rule out other autoimmune and infectious etiologies was inconclusive. Visual acuity and white dots resolved after a course of corticosteroids, which was confirmed on follow-up dilated fundus exam and multimodal imaging. CONCLUSIONS: MEWDS is a rare white dot syndrome that may occur following COVID-19 infection in addition to other reported ophthalmic disorders following this infection.
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COVID-19 , Angiografía con Fluoresceína , Humanos , Femenino , COVID-19/complicaciones , Anciano , SARS-CoV-2 , Tomografía de Coherencia Óptica , Síndromes de Puntos Blancos , Agudeza Visual , Enfermedades de la Retina/virología , Enfermedades de la Retina/etiología , Trastornos de la Visión/etiología , Trastornos de la Visión/virologíaRESUMEN
The chloroplast genomes of most plants and algae contain a large inverted repeat (IR) region that separates two single-copy regions and harbours the ribosomal RNA operon. We have addressed the functional importance of the IR region by removing an entire copy of the 25.3-kb IR from the tobacco plastid genome. Using plastid transformation and subsequent selectable marker gene elimination, we precisely excised the IR, thus generating plants with a substantially reduced plastid genome size. We show that the lack of the IR results in a mildly reduced plastid ribosome number, suggesting a gene dosage benefit from the duplicated presence of the ribosomal RNA operon. Moreover, the IR deletion plants contain an increased number of plastid genomes, suggesting that genome copy number is regulated by measuring total plastid DNA content rather than by counting genomes. Together, our findings (1) demonstrate that the IR can enhance the translation capacity of the plastid, (2) reveal the relationship between genome size and genome copy number, and (3) provide a simplified plastid genome structure that will facilitate future synthetic biology applications.
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Dosificación de Gen , Genoma de Plastidios , Secuencias Invertidas Repetidas , Nicotiana , Nicotiana/genética , Secuencias Invertidas Repetidas/genética , Plastidios/genética , Tamaño del Genoma , Variaciones en el Número de Copia de ADN , Genoma de PlantaAsunto(s)
Prolapso de Órgano Pélvico , Prolapso Uterino , Femenino , Humanos , Mallas Quirúrgicas , Estados Unidos , VaginaRESUMEN
Circadian clocks are endogenous timing mechanisms that allow an organism to adapt cellular processes in anticipation of predictable changes in the environment. Luciferase reporters are well utilized as an effective, nondestructive method to measure circadian rhythms of promoter activity in Arabidopsis. Obtaining stable transgenic reporter lines can be laborious. Here, we report a protocol for Agrobacterium-mediated seedling transformation tailored for plant circadian studies. We show that period estimates generated from wild-type and clock-mutant seedlings transformed with circadian luciferase reporters are similar to rhythms obtained from equivalent stable transgenic seedlings. These experiments demonstrate the versatility and robustness of the protocol for testing new constructs or quickly assessing circadian effects in any genotype of interest.
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Arabidopsis , Relojes Circadianos , Ritmo Circadiano , Agrobacterium/genética , Agrobacterium/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Relojes Circadianos/genética , Ritmo Circadiano/genética , Regulación de la Expresión Génica de las Plantas , Luciferasas/genética , Plantones/genética , Plantones/metabolismoRESUMEN
BACKGROUND: Our study aimed to describe the incidence, epidemiology of respiratory viruses and outcomes in hospital acquired viral respiratory infections (HAVRI). METHODS: We conducted a retrospective observational study on all adults and children with hospital acquired viral respiratory infections between July 2012 and April 2019. Clinical and microbiological data were collected in a major tertiary level hospital in North Queensland. Morbidity indicators were the length of stay, need for intensive care and mechanical ventilation. Length of stay was analyzed with the Kruskal-Wallis test and mortality with the Chi-Square test. RESULTS: A total of 283 patients tested positive for a respiratory virus and fulfilled the criteria for a hospital acquired infection. Individuals in the younger age group were more likely to be admitted to intensive care and need mechanical ventilation. A higher mortality was found with individuals in the older age category. The morbidity and mortality did not differ based on the virus type. Influenza A was the most common respiratory virus associated with hospital acquired viral respiratory infections. CONCLUSION: Hospital acquired viral respiratory infections contribute significantly to morbidity and mortality regardless of the virus species.
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Infección Hospitalaria/epidemiología , Virus de la Influenza A/aislamiento & purificación , Gripe Humana/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Adolescente , Adulto , Anciano , Infección Hospitalaria/etiología , Hospitalización , Humanos , Incidencia , Gripe Humana/etiología , Gripe Humana/virología , Persona de Mediana Edad , Queensland/epidemiología , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/virología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Pulmonary vein (PV) -encircling radiofrequency ablation frequently is effective in vagal atrial fibrillation (AF), and there is evidence that PVs may be particularly prone to cholinergically induced arrhythmia mechanisms. However, PV ablation procedures also can affect intracardiac autonomic ganglia. The present study examined the relative role of PVs versus peri-PV autonomic ganglia in an experimental vagal AF model. METHODS AND RESULTS: Cholinergic AF was studied under carbachol infusion in coronary perfused canine left atrial PV preparations in vitro and with cervical vagal stimulation in vivo. Carbachol caused dose-dependent AF promotion in vitro, which was not affected by excision of all PVs. Sustained AF could be induced easily in all dogs during vagal nerve stimulation in vivo both before and after isolation of all PVs with encircling lesions created by a bipolar radiofrequency ablation clamp device. PV elimination had no effect on atrial effective refractory period or its responses to cholinergic stimulation. Autonomic ganglia were identified by bradycardic and/or tachycardic responses to high-frequency subthreshold local stimulation. Ablation of the autonomic ganglia overlying all PV ostia suppressed the effective refractory period-abbreviating and AF-promoting effects of cervical vagal stimulation, whereas ablation of only left- or right-sided PV ostial ganglia failed to suppress AF. Dominant-frequency analysis suggested that the success of ablation in suppressing vagal AF depended on the elimination of high-frequency driver regions. CONCLUSIONS: Intact PVs are not needed for maintenance of experimental cholinergic AF. Ablation of the autonomic ganglia at the base of the PVs suppresses vagal responses and may contribute to the effectiveness of PV-directed ablation procedures in vagal AF.
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Fibrilación Atrial/terapia , Ablación por Catéter/métodos , Ganglios Autónomos/cirugía , Venas Pulmonares/fisiopatología , Nervio Vago/fisiopatología , Animales , Carbacol , Agonistas Colinérgicos , Modelos Animales de Enfermedad , PerrosRESUMEN
The application that motivates this paper is molecular imaging at the atomic level. When discretized at subatomic distances, the volume is inherently sparse. Noiseless measurements from an imaging technology can be modeled by convolution of the image with the system point spread function (psf). Such is the case with magnetic resonance force microscopy (MRFM), an emerging technology where imaging of an individual tobacco mosaic virus was recently demonstrated with nanometer resolution. We also consider additive white Gaussian noise (AWGN) in the measurements. Many prior works of sparse estimators have focused on the case when H has low coherence; however, the system matrix H in our application is the convolution matrix for the system psf. A typical convolution matrix has high coherence. This paper, therefore, does not assume a low coherence H. A discrete-continuous form of the Laplacian and atom at zero (LAZE) p.d.f. used by Johnstone and Silverman is formulated, and two sparse estimators derived by maximizing the joint p.d.f. of the observation and image conditioned on the hyperparameters. A thresholding rule that generalizes the hard and soft thresholding rule appears in the course of the derivation. This so-called hybrid thresholding rule, when used in the iterative thresholding framework, gives rise to the hybrid estimator, a generalization of the lasso. Estimates of the hyperparameters for the lasso and hybrid estimator are obtained via Stein's unbiased risk estimate (SURE). A numerical study with a Gaussian psf and two sparse images shows that the hybrid estimator outperforms the lasso.
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Algoritmos , Procesamiento de Imagen Asistido por Computador/métodos , Microscopía de Fuerza Atómica , Simulación por Computador , Espectroscopía de Resonancia Magnética , Modelos Estadísticos , Proteínas/química , Virus/químicaRESUMEN
BACKGROUND: Pace mapping has been used to identify the site of origin of focal ventricular arrhythmias. The spatial resolution of pace mapping has not been adequately quantified using currently available three-dimensional mapping systems. OBJECTIVE: The purpose of this study was to determine the spatial resolution of pace mapping in patients with idiopathic ventricular tachycardia or premature ventricular contractions originating in the right ventricular outflow tract. METHODS: In 16 patients with idiopathic ventricular tachycardia/ectopy from the right ventricular outflow tract, comparisons and classifications of pace maps were performed by two observers (good pace map: match >10/12 leads; inadequate pace map: match < or =10/12 leads) and a customized MATLAB 6.0 program (assessing correlation coefficient and normalized root mean square of the difference (nRMSd) between test and template signals). With an electroanatomic mapping system, the correlation coefficient of each pace map was correlated with the distance between the pacing site and the effective ablation site. The endocardial area within the 10-ms activation isochrone was measured. RESULTS: The ablation procedure was effective in all patients. Sites with good pace maps had a higher correlation coefficient and lower nRMSd than sites with inadequate pace maps (correlation coefficient: 0.96 +/- 0.03 vs 0.76 +/- 0.18, P <.0001; nRMSd: 0.41 +/- 0.16 vs 0.89 +/- 0.39, P <.0001). Using receiver operating characteristic curves, appropriate cutoff values were >0.94 for correlation coefficient (sensitivity 81%, specificity 89%) and < or =0.54 for nRMSd (sensitivity 76%, specificity 80%). Good pace maps were located a mean of 7.3 +/- 5.0 mm from the effective ablation site and had a mean activation time of -24 +/- 7 ms. However, in 3 (18%) of 16 patients, the best pace map was inadequate at the effective ablation site, with an endocardial activation time at these sites of -25 +/- 12 ms. Pace maps with correlation coefficient > or =0.94 were confined to an area of 1.8 +/- 0.6 cm2. The 10-ms isochrone measured 1.2 +/- 0.7 cm2. CONCLUSION: The spatial resolution of a good pace map for targeting ventricular tachycardia/ectopy is 1.8 cm2 in the right ventricular outflow tract and therefore is inferior to the spatial resolution of activation mapping as assessed by isochronal activation. In approximately 20% of patients, pace mapping is unreliable in identifying the site of origin, possibly due a deeper site of origin and preferential conduction via fibers connecting the focus to the endocardial surface.
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Estimulación Cardíaca Artificial , Técnicas Electrofisiológicas Cardíacas/métodos , Endocardio/fisiopatología , Taquicardia Ventricular/fisiopatología , Disfunción Ventricular Derecha/fisiopatología , Obstrucción del Flujo Ventricular Externo/fisiopatología , Complejos Prematuros Ventriculares/fisiopatología , Ablación por Catéter , Distribución de Chi-Cuadrado , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Taquicardia Ventricular/cirugía , Disfunción Ventricular Derecha/cirugía , Obstrucción del Flujo Ventricular Externo/cirugía , Complejos Prematuros Ventriculares/cirugíaRESUMEN
Regulatory error is an issue that has come to the fore following the withdrawal of rofecoxib (Vioxx; Merck) a year ago. Here, we provide a theoretical discussion of the factors that could influence regulatory error, drawing on the Vioxx episode in particular as a possible example of error, and consider the implications for future regulatory policy.
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Aprobación de Drogas/métodos , Lógica , Política , Proyectos de Investigación/estadística & datos numéricos , Aprobación de Drogas/legislación & jurisprudencia , Aprobación de Drogas/estadística & datos numéricos , Humanos , Lactonas/efectos adversos , Lactonas/uso terapéutico , Variaciones Dependientes del Observador , Sulfonas/efectos adversos , Sulfonas/uso terapéuticoRESUMEN
BACKGROUND: Adequate exposure of the proximal humerus is necessary to address atypical or complex proximal humerus fractures and orthopedic tumors. Surgical management may be difficult through existing approaches due to their limited nature and the delicate neurovascular anatomy of the shoulder. The deltoid lift, a previously described extensile approach, can be incorporated into the surgeon's armamentarium as an alternative exposure to the proximal humerus. The objective of this study was to quantify and compare the humeral exposure achieved through the deltoid lift with the standard direct lateral deltoid-splitting, anterolateral acromial, and deltopectoral approaches in terms of surface area and exposure of key anatomic landmarks. METHODS: Each approach was performed a minimum of 8 times on 18 cadaveric specimens. After identifying landmarks, exposure area of exposed humerus was quantified using digital images and ImageJ software. RESULTS: The deltoid lift yielded an average exposure area of 46 cm2. Comparison of the exposure area for the deltoid lift against each of the other approaches yielded statistical significance ( P < .01). The exposure provided was 2-folds greater than that of the next most extensive approach. All anatomic landmarks were directly visible through the deltoid lift as compared with the remaining approaches, through which only 1 landmark was directly visualized and only 2 of the 3 remaining were palpable through the approach. CONCLUSIONS: The deltoid lift extensile surgical exposure to the proximal humerus provides the largest humeral exposure with the greatest visibility of landmarks relative to the 3 most widely utilized standard approaches.
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Músculo Deltoides/cirugía , Húmero/anatomía & histología , Anciano , Puntos Anatómicos de Referencia , Cadáver , Femenino , Fijación de Fractura/métodos , Humanos , Masculino , Fracturas del Hombro/cirugíaRESUMEN
The inflammatory response is characterized by increased endothelial permeability, which permits the passage of fluid and inflammatory cells into interstitial spaces. The Eph/ephrin receptor ligand system plays a role in inflammation through a signaling cascade, which modifies Rho-GTPase activity. We hypothesized that blocking Eph/ephrin signaling using an EphA4-Fc would result in decreased inflammation and tissue injury in a model of ischemia/reperfusion (I/R) injury. Mice undergoing intestinal I/R pretreated with the EphA4-Fc had significantly reduced intestinal injury compared to mice injected with the control Fc. This reduction in I/R injury was accompanied by significantly reduced neutrophil infiltration, but did not affect intestinal inflammatory cytokine generation. Using microdialysis, we identified that intestinal I/R induced a marked increase in systemic vascular leakage, which was completely abrogated in EphA4-Fc-treated mice. Finally, we confirmed the direct role of Eph/ephrin signaling in endothelial leakage by demonstrating that EphA4-Fc inhibited tumor necrosis factor-α-induced vascular permeability in human umbilical vein endothelial cells. This study identifies that Eph/ephrin interaction induces proinflammatory signaling in vivo by inducing vascular leak and neutrophil infiltration, which results in tissue injury in intestinal I/R. Therefore, therapeutic targeting of Eph/ephrin interaction using inhibitors, such as EphA4-Fc, may be a novel method to prevent tissue injury in acute inflammation by influencing endothelial integrity and by controlling vascular leak.
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Permeabilidad Capilar/efectos de los fármacos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Receptor EphA4/antagonistas & inhibidores , Daño por Reperfusión/tratamiento farmacológico , Animales , Línea Celular , Humanos , Masculino , Ratones , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Obtaining adequate exposure of the proximal humerus for anatomic reduction of complex intra-articular fractures or in the surgical treatment of tumor may be difficult. Here we describe a novel approach to the proximal humerus: the deltoid lift, and perform a cadaveric analysis objectively quantifying the exposure. The deltoid lift offers significantly greater exposure to the proximal humerus as compared with the deltopectoral approach.
Asunto(s)
Fijación Interna de Fracturas/métodos , Fracturas del Hombro/cirugía , Cadáver , Músculo Deltoides , Disección , HumanosRESUMEN
Cyanide toxicity is a rare complication of sodium nitroprusside that can be difficult to diagnose in critically ill patients. We describe a case of cyanide toxicity after cardiac surgery that presented as lactic acidosis after discontinuation of nitroprusside.
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Acidosis Láctica/diagnóstico , Lesión Renal Aguda/inducido químicamente , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Cianuros/envenenamiento , Insuficiencia Cardíaca/cirugía , Nitroprusiato/efectos adversos , Acidosis Láctica/etiología , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Anciano , Procedimientos Quirúrgicos Cardíacos/métodos , Enfermedad Crítica , Cianuros/metabolismo , Diagnóstico Tardío , Diagnóstico Diferencial , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/diagnóstico , Humanos , Infusiones Intravenosas , Nitroprusiato/administración & dosificación , Diálisis Renal , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Significant endeavor has been applied to identify functional therapeutic targets in glioblastoma (GBM) to halt the growth of this aggressive cancer. We show that the receptor tyrosine kinase EphA3 is frequently overexpressed in GBM and, in particular, in the most aggressive mesenchymal subtype. Importantly, EphA3 is highly expressed on the tumor-initiating cell population in glioma and appears critically involved in maintaining tumor cells in a less differentiated state by modulating mitogen-activated protein kinase signaling. EphA3 knockdown or depletion of EphA3-positive tumor cells reduced tumorigenic potential to a degree comparable to treatment with a therapeutic radiolabelled EphA3-specific monoclonal antibody. These results identify EphA3 as a functional, targetable receptor in GBM.