RESUMEN
The advent of modular porous metal augments has ushered in a new form of treatment for acetabular bone loss. The function of an augment can be seen as reducing the size of a defect or reconstituting the anterosuperior/posteroinferior columns and/or allowing supplementary fixation. Depending on the function of the augment, the surgeon can decide on the sequence of introduction of the hemispherical shell, before or after the augment. Augments should always, however, be used with cement to form a unit with the acetabular component. Given their versatility, augments also allow the use of a hemispherical shell in a position that restores the centre of rotation and biomechanics of the hip. Progressive shedding or the appearance of metal debris is a particular finding with augments and, with other radiological signs of failure, should be recognized on serial radiographs. Mid- to long-term outcomes in studies reporting the use of augments with hemispherical shells in revision total hip arthroplasty have shown rates of survival of > 90%. However, a higher risk of failure has been reported when augments have been used for patients with chronic pelvic discontinuity.
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Artroplastia de Reemplazo de Cadera , Enfermedades Óseas Metabólicas , Prótesis de Cadera , Humanos , Artroplastia de Reemplazo de Cadera/efectos adversos , Prótesis de Cadera/efectos adversos , Porosidad , Acetábulo/cirugía , Reoperación , Metales , Falla de Prótesis , Estudios Retrospectivos , Estudios de SeguimientoRESUMEN
BACKGROUND: Necrotizing otitis externa is an invasive infection, affecting older patients, with significant associated morbidity. Despite this, there are no randomized controlled trials that address management, and therefore, treatment approaches may vary considerably. We describe the management and outcomes of 37 patients managed using a multidisciplinary treatment pathway for necrotizing otitis externa over a 5-year period. The pathway is based on a standardized antibiotic regime of 3 weeks of intravenous ceftazidime plus oral ciprofloxacin, followed by a further 3 weeks of ciprofloxacin. METHODS: This is a retrospective review of all patients diagnosed with necrotizing otitis externa since the introduction of our pathway in 2016. We include data on patient demographics, comorbidities, microbiology, length of stay, and length of antimicrobial treatment. Outcome data, including mortality, relapse and treatment failure, and adverse effects of treatment, are presented. RESULTS: The median age of our patients was 82 years. About 54% of patients had diabetes mellitus or another cause of immunocompromise. Pseudomonas aeruginosa was isolated in 68%. The median duration of inpatient stay was 9 days, and median treatment duration was 6 weeks. Of 37 patients, 32 were cured (86%), and of the remaining 5 patients, there were 2 mortalities unrelated to necrotizing otitis externa and 3 patients with recurrent infections due to anatomical abnormalities. CONCLUSION: We note favorable treatment outcomes when using a standardized multidisciplinary pathway and a 6-week course of antibiotic therapy.
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Otitis Externa , Infecciones por Pseudomonas , Humanos , Anciano de 80 o más Años , Otitis Externa/tratamiento farmacológico , Otitis Externa/microbiología , Estudios Retrospectivos , Ciprofloxacina/uso terapéutico , Antibacterianos/uso terapéutico , Ceftazidima/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/complicacionesRESUMEN
BACKGROUND: Approximately half the patients with ulcerative colitis who undergo restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) will subsequently have pouchitis, and among those patients, one fifth will have chronic pouchitis. METHODS: We conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab in adult patients in whom chronic pouchitis had developed after undergoing IPAA for ulcerative colitis. Patients were assigned (in a 1:1 ratio) to receive vedolizumab intravenously at a dose of 300 mg or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All the patients received concomitant ciprofloxacin from weeks 1 to 4. The primary end point was modified Pouchitis Disease Activity Index (mPDAI)-defined remission (an mPDAI score of ≤4 and a reduction from baseline of ≥2 points in the mPDAI total score; scores range from 0 to 12, with higher scores indicating more severe pouchitis) at week 14. The mPDAI is based on clinical symptoms and endoscopic findings. Other efficacy end points included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction from baseline of ≥2 points in the mPDAI score) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of ≤6 and a reduction from baseline of ≥3 points; scores range from 0 to 18, with higher scores indicating more severe pouchitis) at weeks 14 and 34. The PDAI is based on clinical symptoms, endoscopic findings, and histologic findings. RESULTS: Among the 102 patients who underwent randomization, the incidence of mPDAI-defined remission at week 14 was 31% (16 of 51 patients) with vedolizumab and 10% (5 of 51 patients) with placebo (difference, 21 percentage points; 95% confidence interval [CI], 5 to 38; P = 0.01). Differences in favor of vedolizumab over placebo were also seen with respect to mPDAI-defined remission at week 34 (difference, 17 percentage points; 95% CI, 0 to 35), mPDAI-defined response at week 14 (difference, 30 percentage points; 95% CI, 8 to 48) and at week 34 (difference, 22 percentage points; 95% CI, 2 to 40), and PDAI-defined remission at week 14 (difference, 25 percentage points; 95% CI, 8 to 41) and at week 34 (difference, 19 percentage points; 95% CI, 2 to 37). Serious adverse events occurred in 3 of 51 patients (6%) in the vedolizumab group and in 4 of 51 patients (8%) in the placebo group. CONCLUSIONS: Treatment with vedolizumab was more effective than placebo in inducing remission in patients who had chronic pouchitis after undergoing IPAA for ulcerative colitis. (Funded by Takeda; EARNEST ClinicalTrials.gov number, NCT02790138; EudraCT number, 2015-003472-78.).
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Colitis Ulcerosa , Fármacos Gastrointestinales , Reservoritis , Proctocolectomía Restauradora , Adulto , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ciprofloxacina/administración & dosificación , Ciprofloxacina/uso terapéutico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/cirugía , Reservoritis/tratamiento farmacológico , Reservoritis/etiología , Enfermedad Crónica , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Proctocolectomía Restauradora/efectos adversos , Método Doble Ciego , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Administración Intravenosa , Quimioterapia CombinadaRESUMEN
This is the first study to investigate the relationship between neighborhood walkability and cardiovascular (CV) risk factors in the United States using a large population-based database. Cross-sectional study using data from 1.1 million patients over the age of 18 in the Houston Methodist Learning Health System Outpatient Registry (2016-2022). Using the 2019 WalkScore, patients were assigned to one of the 4 neighborhood walkability categories. The burden of CV risk factors (hypertension, diabetes, obesity, dyslipidemia, and smoking) was defined as poor, average, or optimal (>3, 1-2, 0 risk factors, respectively). We included 887,654 patients, of which 86% resided in the two least walkable neighborhoods. The prevalence of CV risk factors was significantly lower among participants in the most walkable neighborhoods irrespective of ASCVD status. After adjusting for age, sex, race/ethnicity, and socioeconomic factors, we found that adults living in the most walkable neighborhoods were more likely to have optimal CV risk profile than those in the least walkable ones (RRR 2.77, 95% CI 2.64-2.91). We observed an inverse association between neighborhood walkability and the burden of CV risk factors. These findings support multilevel health system stakeholder engagements and investments in walkable neighborhoods as a viable tool for mitigating the growing burden of modifiable CV risk factors.
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Enfermedades Cardiovasculares , Prestación Integrada de Atención de Salud , Aprendizaje del Sistema de Salud , Adulto , Humanos , Persona de Mediana Edad , Caminata , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Pacientes Ambulatorios , Estudios Transversales , Protestantismo , Factores de Riesgo , Factores de Riesgo de Enfermedad Cardiaca , Sistema de RegistrosRESUMEN
OBJECTIVES: Magnetic resonance fingerprinting (MRF) is a novel, quantitative, and noninvasive technique to measure brain tissue properties. We aim to use MRF for characterizing normal-appearing thalamic and basal ganglia nuclei in the epileptic brain. METHODS: A three-dimensional (3D) MRF protocol (1 mm3 isotropic resolution) was acquired from 48 patients with unilateral medically intractable focal epilepsy and 39 healthy controls (HCs). Whole-brain T1 and T2 maps (containing T1 and T2 relaxation times) were reconstructed for each subject. Ten subcortical nuclei in the thalamus and basal ganglia were segmented as regions of interest (ROIs), within which the mean T1 and T2 values, as well as their coefficient of variation (CV) were compared between the patients and HCs at the group level. Subgroup and correlation analyses were performed to examine the relationship between significant MRF measures and various clinical characteristics. Using significantly abnormal MRF measures from the group-level analyses, support vector machine (SVM) and logistic regression machine learning models were built and tested with 5-fold and 10-fold cross-validations, to separate patients from HCs, and to separate patients with left-sided and right-sided epilepsy, at the individual level. RESULTS: MRF revealed increased T1 mean value in the ipsilateral thalamus and nucleus accumbens; increased T1 CV in the bilateral thalamus, bilateral pallidum, and ipsilateral caudate; and increased T2 CV in the ipsilateral thalamus in patients compared to HCs (p < .05, false discovery rate [FDR] corrected). The SVM classifier produced 78.2% average accuracy to separate individual patients from HCs, with an area under the curve (AUC) of 0.83. The logistic regression classifier produced 67.4% average accuracy to separate patients with left-sided and right-sided epilepsy, with an AUC of 0.72. SIGNIFICANCE: MRF revealed bilateral tissue-property changes in the normal-appearing thalamus and basal ganglia, with ipsilateral predominance and thalamic preference, suggesting subcortical involvement/impairment in patients with medically intractable focal epilepsy. The individual-level performance of the MRF-based machine-learning models suggests potential opportunities for predicting lateralization.
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Epilepsia Refractaria , Epilepsias Parciales , Epilepsia , Ganglios Basales/diagnóstico por imagen , Epilepsia Refractaria/diagnóstico por imagen , Epilepsias Parciales/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Tálamo/diagnóstico por imagenRESUMEN
BACKGROUND: Obesity is a global pandemic that threatens the health of the population and the sustainability of publicly funded health care. This randomised controlled trial addresses the gap in the literature surrounding unconscious persuasion and its use in weight loss and weight management. The Slimpod® tool is unlike any of those currently available on the market. Using breakthrough research in 'nudge' thinking, it is designed to retrain an adult's habitual and emotional response to foodstuffs. This therapeutic model allows unconscious thought to be shaped into a manner more consistent with a healthy lifestyle. Candidates can then take control of their eating behaviours to induce a holistic state of wellbeing. AIM: To assess the effectiveness of an audio unconscious-persuasion weight loss/weight management intervention (Slimpod®) compared with audio relaxation (control). METHOD: Eighty-two overweight adults were randomised to intervention (n = 41) and control groups (n = 41). Weight was assessed at trial commencement, mid-trial (12 weeks), and trial end (24 weeks). Secondary outcomes were assessed using the Eating Self-Efficacy Scale (ESES), Exercise Confidence Scale (ECS), and Quality of Life Index Generic Version III (QLI-G3) at the start and end of the trial. RESULTS: Reports found a statistically significant difference in mean weight loss between intervention group (1.7 kg at 12 weeks and 4.3 kg at 24 weeks) versus control (0.6 kg and 1.2 kg respectively) at P<0.001. ESES scores showed greater self-efficacy (P = 0.008) in intervention at 24 weeks. No significant differences in ESES negative affect sub-scale score or ECS were observed. CONCLUSION: Slimpod® was effective at reducing weight and increasing eating self-efficacy in overweight adults.
RESUMEN
There are huge gaps in evidence-based cardiovascular care at the national, organizational, practice, and provider level that can be attributed to variation in provider attitudes, lack of incentives for positive change and care standardization, and observed uncertainty in clinical decision making. Big data analytics and digital application platforms-such as patient care dashboards, clinical decision support systems, mobile patient engagement applications, and key performance indicators-offer unique opportunities for value-based healthcare delivery and efficient cardiovascular population management. Successful implementation of big data solutions must include a multidisciplinary approach, including investment in big data platforms, harnessing technology to create novel digital applications, developing digital solutions that can inform the actions of clinical and policy decision makers and relevant stakeholders, and optimizing engagement strategies with the public and information-empowered patients.
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Macrodatos , Enfermedades Cardiovasculares/terapia , Prestación Integrada de Atención de Salud , Medicina Basada en la Evidencia , Gestión de la Salud Poblacional , Telemedicina , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , HumanosRESUMEN
Importance: Many studies have investigated the imaging findings showing sequelae of repetitive head trauma, with mixed results. Objective: To determine whether fighters (boxers and mixed martial arts fighters) with cavum septum pellucidum (CSP) and cavum vergae (CV) have reduced volumes in various brain structures or worse clinical outcomes on cognitive and mood testing. Design, Setting, and Participants: This cohort study assessed participants from the Professional Fighters Brain Health Study. Data were collected from April 14, 2011, to January 17, 2018, and were analyzed from September 1, 2018, to May 23, 2019. This study involved a referred sample of 476 active and retired professional fighters. Eligible participants were at least 18 years of age and had at least a fourth-grade reading level. Healthy age-matched controls with no history of trauma were also enrolled. Exposures: Presence of CSP, CV, and their total (additive) length (CSPV length). Main Outcomes and Measures: Information regarding depression, impulsivity, and sleepiness among study participants was obtained using the Patient Health Questionnaire depression scale, Barrett Impulsiveness Scale, and the Epworth Sleepiness Scale. Cognition was assessed using raw scores from CNS Vital Signs. Volumes of various brain structures were measured via magnetic resonance imaging. Results: A total of 476 fighters (440 men, 36 women; mean [SD] age, 30.0 [8.2] years [range, 18-72 years]) and 63 control participants (57 men, 6 women; mean [SD] age, 30.8 [9.6] years [range, 18-58 years]) were enrolled in the study. Compared with fighters without CV, fighters with CV had significantly lower mean psychomotor speed (estimated difference, -11.3; 95% CI, -17.4 to -5.2; P = .004) and lower mean volumes in the supratentorium (estimated difference, -31â¯191 mm3; 95% CI, -61â¯903 to -479 mm3; P = .05) and other structures. Longer CSPV length was associated with lower processing speed (slope, -0.39; 95% CI, -0.49 to -0.28; P < .001), psychomotor speed (slope, -0.43; 95% CI, -0.53 to -0.32; P < .001), and lower brain volumes in the supratentorium (slope, -1072 mm3 for every 1-mm increase in CSPV length; 95% CI, -1655 to -489 mm3; P < .001) and other structures. Conclusions and Relevance: This study suggests that the presence of CSP and CV is associated with lower regional brain volumes and cognitive performance in a cohort exposed to repetitive head trauma.
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Boxeo/lesiones , Encéfalo/patología , Traumatismos Cerrados de la Cabeza/complicaciones , Traumatismos Cerrados de la Cabeza/patología , Artes Marciales/lesiones , Adolescente , Adulto , Afecto/fisiología , Anciano , Cognición/fisiología , Trastornos del Conocimiento/etiología , Estudios de Cohortes , Femenino , Traumatismos Cerrados de la Cabeza/etiología , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/etiología , Tabique Pelúcido/patología , Adulto JovenRESUMEN
IMPACT STATEMENT: The timing and rate of release of pharmaceuticals from advanced drug delivery systems is an important property that has received considerable attention in the scientific literature. Broadly, these mostly fall into two classes: controlled release with a prolonged release rate or triggered release where the drug is rapidly released in response to an environmental stimulus. This review aims to highlight the potential for developing adaptive release systems that more subtlety modulate the drug release profile through continuous communication with its environment facilitated through feedback control. By reviewing the key elements of this approach in one place (fundamental principles of nanomedicine, enzymatic nanoreactors for medical therapies and feedback-controlled chemical systems) and providing additional motivating case studies in the context of chronobiology, we hope to inspire innovative development of novel "chrononanomedicines."
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Sistemas de Liberación de Medicamentos , Retroalimentación , Nanomedicina , Células Artificiales/citología , Biocatálisis , CronoterapiaRESUMEN
Small fringing marshes are ecologically important habitats often impacted by petroleum. We characterized the phylogenetic structure (16S rRNA) and petroleum hydrocarbon degrading alkane hydroxylase genes (alkB and CYP 153A1) in a sediment microbial community from a New Hampshire fringing marsh, using alkane-exposed dilution cultures to enrich for petroleum degrading bacteria. 16S rRNA and alkB analysis demonstrated that the initial sediment community was dominated by Betaproteobacteria (mainly Comamonadaceae) and Gammaproteobacteria (mainly Pseudomonas), while CYP 153A1 sequences predominantly matched Rhizobiales. 24â¯h of exposure to n-hexane, gasoline, dodecane, or dilution culture alone reduced functional and phylogenetic diversity, enriching for Gammaproteobacteria, especially Pseudomonas. Gammaproteobacteria continued to dominate for 10â¯days in the n-hexane and no alkane exposed samples, while dodecane and gasoline exposure selected for gram-positive bacteria. The data demonstrate that small fringing marshes in New England harbor petroleum-degrading bacteria, suggesting that petroleum degradation may be an important fringing marsh ecosystem function.
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Sedimentos Geológicos/microbiología , Microbiota/genética , Contaminación por Petróleo/análisis , Petróleo/análisis , Contaminantes Químicos del Agua/análisis , Humedales , Biodegradación Ambiental , Citocromo P-450 CYP4A/genética , New England , Filogenia , Proteobacteria/genética , ARN Ribosómico 16S/genética , UrbanizaciónRESUMEN
OBJECTIVE: To evaluate radiofrequency-induced temperature rises associated with performing lumbar and pelvic magnetic resonance imaging (MRI) studies with an implanted sacral neuromodulation device using a phantom model. MATERIALS AND METHODS: An accepted phantom model of radiofrequency-induced heating in human tissue was used to measure the temperature rise in the stimulator lead electrodes and impulse generator under the conditions used during routine clinical lumbar and pelvic MRIs in a 1.5Tesla MRI scanner. Testing configurations included an intact device (tined lead connected to generator), an intact lead, and a lead fragment (model of lead fracture). Variations in the position of the phantom relative to the scanner were also tested. RESULTS: During testing with the intact device or the lead fragment no significant heating was detected. In contrast, the isolated intact lead model showed heating up to 5°C. CONCLUSION: These tests provide preliminary evidence that the risk of heating is low for clinical lumbar and pelvic MRI at 1.5-Tesla with an intact sacral neuromodulation device system and with a fractured lead. However, there is a significant temperature change in the intact lead model.
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Terapia por Estimulación Eléctrica/instrumentación , Hipertermia Inducida/instrumentación , Síntomas del Sistema Urinario Inferior/terapia , Imagen por Resonancia Magnética/métodos , Fantasmas de Imagen , Electrodos Implantados , Diseño de Equipo , Humanos , Plexo LumbosacroRESUMEN
PURPOSE: We performed functional magnetic resonance imaging to identify changes in brain activity during sacral neuromodulation in women with overactive bladder who were responsive to therapy. MATERIALS AND METHODS: Women recruited into the study had nonneurogenic refractory overactive bladder, responded to sacral neuromodulation and had had a stable program for at least 3 months with no subsequent overactive bladder treatment. Enrolled patients completed validated symptom and quality of life instruments before functional magnetic resonance imaging. Stimulus settings were recorded, devices were switched off for a 5-day washout and instruments were repeated. Three functional magnetic resonance imaging scans with simultaneous sacral neuromodulation stimulation were performed below, at and above stimulus sensory threshold using a block design. This yielded brain activity maps represented by changes in blood oxygenation level dependence. A total of 5 stimulator off and 4 stimulator on cycles of 42 seconds each were imaged. Group analysis was done using a single voxel p value of 0.05 with a false-positive error of 0.05 on cluster analysis. RESULTS: Six of the 13 patients enrolled completed functional magnetic resonance imaging. Median age was 52 years (range 36 to 64). Urinary symptoms and voiding diary data worsened with washout. Overall brain activation generally progressed with increasing stimulation amplitude. However, activation of the right inferior frontal gyrus remained stable while deactivation of the pons and the periacqueductal gray matter only occurred with subsensory stimulation. Sensory stimulation activated the insula but deactivated the medial and superior parietal lobes. Suprasensory stimulation activated multiple structures and the expected S3 somatosensory region. All devices had normal impedance after functional magnetic resonance imaging. CONCLUSIONS: Functional magnetic resonance imaging confirmed that sacral neuromodulation influences brain activity in women with overactive bladder who responded to therapy. These changes varied with stimulus intensity.
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Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Plexo Lumbosacro , Imagen por Resonancia Magnética , Estimulación Eléctrica Transcutánea del Nervio , Vejiga Urinaria Hiperactiva/fisiopatología , Vejiga Urinaria Hiperactiva/terapia , Adulto , Femenino , Humanos , Persona de Mediana Edad , Factores de Tiempo , Estimulación Eléctrica Transcutánea del Nervio/métodosRESUMEN
OBJECTIVES: Cumulative head trauma may alter brain structure and function. We explored the relationship between exposure variables, cognition and MRI brain structural measures in a cohort of professional combatants. METHODS: 224 fighters (131 mixed martial arts fighters and 93 boxers) participating in the Professional Fighters Brain Health Study, a longitudinal cohort study of licensed professional combatants, were recruited, as were 22 controls. Each participant underwent computerised cognitive testing and volumetric brain MRI. Fighting history including years of fighting and fights per year was obtained from self-report and published records. Statistical analyses of the baseline evaluations were applied cross-sectionally to determine the relationship between fight exposure variables and volumes of the hippocampus, amygdala, thalamus, caudate, putamen. Moreover, the relationship between exposure and brain volumes with cognitive function was assessed. RESULTS: Increasing exposure to repetitive head trauma measured by number of professional fights, years of fighting, or a Fight Exposure Score (FES) was associated with lower brain volumes, particularly the thalamus and caudate. In addition, speed of processing decreased with decreased thalamic volumes and with increasing fight exposure. Higher scores on a FES used to reflect exposure to repetitive head trauma were associated with greater likelihood of having cognitive impairment. CONCLUSIONS: Greater exposure to repetitive head trauma is associated with lower brain volumes and lower processing speed in active professional fighters.
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Boxeo/lesiones , Trastornos del Conocimiento/patología , Traumatismos Craneocerebrales/patología , Artes Marciales/lesiones , Procesos Mentales/fisiología , Enfermedades Talámicas/patología , Tálamo/patología , Adolescente , Adulto , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/fisiopatología , Traumatismos Craneocerebrales/fisiopatología , Humanos , Masculino , Tamaño de los Órganos , Enfermedades Talámicas/etiología , Enfermedades Talámicas/fisiopatología , Adulto JovenRESUMEN
TOP mRNAs encode components of the translational apparatus, and repression of their translation comprises one mechanism, by which cells encountering amino acid deprivation downregulate the biosynthesis of the protein synthesis machinery. This mode of regulation involves TSC as knockout of TSC1 or TSC2 rescued TOP mRNAs translation in amino acid-starved cells. The involvement of mTOR in translational control of TOP mRNAs is demonstrated by the ability of constitutively active mTOR to relieve the translational repression of TOP mRNA upon amino acid deprivation. Consistently, knockdown of this kinase as well as its inhibition by pharmacological means blocked amino acid-induced translational activation of these mRNAs. The signaling of amino acids to TOP mRNAs involves RagB, as overexpression of active RagB derepressed the translation of these mRNAs in amino acid-starved cells. Nonetheless, knockdown of raptor or rictor failed to suppress translational activation of TOP mRNAs by amino acids, suggesting that mTORC1 or mTORC2 plays a minor, if any, role in this mode of regulation. Finally, miR10a has previously been suggested to positively regulate the translation of TOP mRNAs. However, we show here that titration of this microRNA failed to downregulate the basal translation efficiency of TOP mRNAs. Moreover, Drosha knockdown or Dicer knockout, which carries out the first and second processing steps in microRNAs biosynthesis, respectively, failed to block the translational activation of TOP mRNAs by amino acid or serum stimulation. Evidently, these results are questioning the positive role of microRNAs in this mode of regulation.
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MicroARNs/genética , Complejos Multiproteicos/genética , Biosíntesis de Proteínas , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Proteínas Supresoras de Tumor/genética , Aminoácidos/genética , Animales , Regulación de la Expresión Génica , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Ratones Noqueados , Fosforilación , ARN Mensajero/genética , Proteína 1 del Complejo de la Esclerosis TuberosaRESUMEN
About half of patients with diffuse large B-cell lymphoma (DLBCL) do not respond to or relapse soon after the standard chemotherapy, indicating a critical need to better understand the specific pathways perturbed in DLBCL for developing effective therapeutic approaches. Mice deficient in the E3 ubiquitin ligase Smurf2 spontaneously develop B-cell lymphomas that resemble human DLBCL with molecular features of germinal centre or post-germinal centre B cells. Here we show that Smurf2 mediates ubiquitination and degradation of YY1, a key germinal centre transcription factor. Smurf2 deficiency enhances YY1-mediated transactivation of c-Myc and B-cell proliferation. Furthermore, Smurf2 expression is significantly decreased in primary human DLBCL samples, and low levels of Smurf2 expression correlate with inferior survival in DLBCL patients. The Smurf2-YY1-c-Myc regulatory axis represents a novel pathway perturbed in DLBCL that suppresses B-cell proliferation and lymphomagenesis, suggesting pharmaceutical targeting of Smurf2 as a new therapeutic paradigm for DLBCL.
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Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Proteínas Proto-Oncogénicas c-myc/genética , Ubiquitina-Proteína Ligasas/genética , Factor de Transcripción YY1/genética , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , Proliferación Celular , Centro Germinal/metabolismo , Centro Germinal/patología , Humanos , Activación de Linfocitos , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Noqueados , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Transcripción Genética , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Factor de Transcripción YY1/metabolismoRESUMEN
This study addresses the spatial relation between local Na(+) and K(+) imbalances in the ischemic core in a rat model of focal ischemic stroke. Quantitative [Na(+)] and [K(+)] brain maps were obtained by (23)Na MRI and histochemical K(+) staining, respectively, and calibrated by emission flame photometry of the micropunch brain samples. Stroke location was verified by diffusion MRI, by changes in tissue surface reflectivity and by immunohistochemistry with microtubule-associated protein 2 antibody. Na(+) and K(+) distribution within the ischemic core was inhomogeneous, with the maximum [Na(+)] increase and [K(+)] decrease typically observed in peripheral regions of the ischemic core. The pattern of the [K(+)] decrease matched the maximum rate of [Na(+)] increase ('slope'). Some residual mismatch between the sites of maximum Na(+) and K(+) imbalances was attributed to the different channels and pathways involved in transport of the two ions. A linear regression of the [Na(+)]br vs. [K(+)]br in the samples of ischemic brain indicates that for each K(+) equivalent leaving ischemic tissue, 0.8±0.1 Eq, on average, of Na(+) enter the tissue. Better understanding of the mechanistic link between the Na(+) influx and K(+) egress would validate the (23)Na MRI slope as a candidate biomarker and a complementary tool for assessing ischemic damage and treatment planning.
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Isquemia Encefálica/metabolismo , Imagen por Resonancia Magnética/métodos , Potasio/metabolismo , Sodio/metabolismo , Accidente Cerebrovascular/metabolismo , Animales , Isquemia Encefálica/complicaciones , Procesamiento de Imagen Asistido por Computador , Masculino , Potasio/análisis , Ratas , Ratas Sprague-Dawley , Sodio/análisis , Accidente Cerebrovascular/etiologíaRESUMEN
BACKGROUND: Malignant, or necrotising, otitis externa is a potentially fatal infection of the external ear canal and surrounding soft tissue and bone. It may be complicated by involvement of cranial nerves, principally the facial nerves and the contents of the jugular foramen. It is an uncommon condition mainly found in the elderly or in diabetics. OBJECTIVES: To assess the effectiveness of adjunctive hyperbaric oxygen treatment for malignant otitis externa. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 4 April 2013. SELECTION CRITERIA: Randomised controlled trials, involving adults, undergoing hyperbaric oxygen therapy in malignant otitis externa. DATA COLLECTION AND ANALYSIS: No identified articles described randomised controlled trials of hyperbaric oxygen therapy in the treatment of malignant otitis externa. MAIN RESULTS: Due to the lack of data we could present no results. AUTHORS' CONCLUSIONS: No clear evidence exists to demonstrate the efficacy of hyperbaric oxygen therapy when compared to treatment with antibiotics and/or surgery. We found no data to compare rates of complication between the different treatment modalities. Further research is required.
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Infecciones Bacterianas/terapia , Oxigenoterapia Hiperbárica , Otitis Externa/terapia , Humanos , Necrosis/terapiaRESUMEN
Repetitive head trauma is a risk factor for Alzheimer's disease and is the primary cause of chronic traumatic encephalopathy. However, little is known about the natural history of, and risk factors for, chronic traumatic encephalopathy or about means of early detection and intervention. The Professional Fighters Brain Health Study is a longitudinal study of active professional fighters (boxers and mixed martial artists), retired professional fighters, and controls matched for age and level of education. The main objective of the Professional Fighters Brain Health Study is to determine the relationships between measures of head trauma exposure and other potential modifiers and changes in brain imaging and neurological and behavioral function over time. The study is designed to extend over 5 years, and we anticipate enrollment of more than 400 boxers and mixed martial artists. Participants will undergo annual evaluations that include 3-tesla magnetic resonance imaging scanning, computerized cognitive assessments, speech analysis, surveys of mood and impulsivity, and blood sampling for genotyping and exploratory biomarker studies. Statistical models will be developed and validated to predict early and progressive changes in brain structure and function. A composite fight exposure index, developed as a summary measure of cumulative traumatic exposure, shows promise as a predictor of brain volumes and cognitive function.
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Boxeo/lesiones , Lesión Encefálica Crónica/etiología , Artes Marciales/lesiones , Traumatismos Ocupacionales/etiología , Proyectos de Investigación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Lesión Encefálica Crónica/diagnóstico , Lesión Encefálica Crónica/fisiopatología , Estudios de Casos y Controles , Protocolos Clínicos , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Traumatismos Ocupacionales/diagnóstico , Traumatismos Ocupacionales/fisiopatología , Pruebas Psicológicas , Tamaño de la Muestra , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECT: Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM). METHODS: Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation. RESULTS: Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose. CONCLUSIONS: NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. CLINICAL TRIAL REGISTRATION NO.: NCT00747253 ( ClinicalTrials.gov ).
Asunto(s)
Neoplasias Encefálicas/cirugía , Glioblastoma/cirugía , Terapia por Láser/efectos adversos , Terapia por Láser/métodos , Recurrencia Local de Neoplasia/cirugía , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Estimación de Kaplan-Meier , Terapia por Láser/instrumentación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estudios Prospectivos , Programas Informáticos , Termometría , Resultado del TratamientoRESUMEN
The concentrations of nine residual metals in some Jamaican foods were determined using inductively coupled plasma mass spectrometry technique. Cadmium concentration was highest in yellow yam (0.21 mg/kg). Sweet potato had the highest concentrations of lead (0.31 mg/kg), arsenic (0.70 mg/kg) and mercury (0.35 mg/kg). Samples from Grove Place exceeded the regulatory limits of 0.1 mg/kg for cadmium, lead and arsenic and 0.05 mg/kg for mercury. Significant correlations were found between soil and agricultural produce concentrations for cadmium and lead (r(2) ≥ 0.5). These results suggest that the elements were available in soluble forms in the soil for absorption by food crops.