Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs

Assessing Thyroid Size as an Independent Risk Factor in Thyroidectomy

Abstract: Background: Rates of complications of thyroidectomy, mainly hypocalcemia and recurrent laryngeal nerve injury, can be higher in certain patient groups. There are several risk factors for complications published in the literature, among them are malignancy, bilateral resection, younger age, and Graves disease.4,5 To our knowledge,there is not a study that examines the role of thyroid size as an independent risk factor in total thyroidectomy. Methods: A case-control study carried out at a tertiary, academic medical center involving patients who underwent total thyroidectomy between August, 2001 and March 2005. Pathology reports were reviewed for gland weight, size and histology, and anesthesiology reports were reviewed for estimated blood loss (EBL), American Society of Anesthesiologist score (ASA) classification and duration of surgery. Hard copies of charts were reviewed for calcium replacement as well as for length of hospital stay. Results: Thyroid size had a positive correlation of 0.34 (N = 49) (P = 0.02) with length of surgery and 0.32 correlation (P = 0.04) between increasing thyroid size and increased hospital stay. Thyroid weight (N = 50) had a positive correlation of 0.47 (P\u3c0.001) with estimated blood loss as did thyroid volume (N = 51) with a similar correlation of 0.49 (P\u3c0.001). The correlation with calcium nadirs was found to be —0.27 (P= 0.05). Hypocalcemia symptoms occurred in 13.4% of patients (N=7), all of which were female, otherwise age, BMI and thyroid weight and dimensions were statistically insignificant. Drain output is positively correlated as well with thyroid weight and dimension, 0.39 for weight (P=0.008) and 0.40 for dimension (P=0.006). Overall, 40 % of patients (N=21) had ionized calcium values below 1.0 mmol/L. Recurrent laryngeal nerve injury (N=2) occurred in 3.9%. Conclusion: Increased thyroid size does appear to portend and increase in peri-operative complications including increased blood loss, lower hypocalcemia nadirs and overall number of complications. There is also a positive correlation with time spent in surgery,and days spent in the hospital.\u2

The design, fabrication, installation & evaluation of the Balance Probe Monitor for large centrifuges at a national laboratory facility

Balance Probe Monitors were designed, fabricated, installed, and evaluated at Sandia National Laboratories (SNL) for the 22,600 g kg (50,000 g lb) direct drive electromotor driven large centrifuges. These centrifuges provide a high onset/decay rate g environment. The Balance Probe Monitor is physically located near a centrifuge’s Capacitance Probe, a crucial sensor for the centrifuge’s sustainability. The Balance Probe Monitor will validate operability of the centrifuge. Most importantly, it is used for triggering a kill switch under the condition that the centrifuge displacement value exceeds allowed tolerances. During operational conditions, the Capacitance Probe continuously detects the structural displacement of the centrifuge and an adjoining AccuMeasure 9000 translates this displacement into an output voltage. [1]Electrical and Computer Engineerin

Delayed protection by ESAT-6–specific effector CD4+ T cells after airborne M. tuberculosis infection

Mycobacterium tuberculosis infection induces complex CD4 T cell responses that include T helper type 1 (Th1) cells and regulatory T cells. Although Th1 cells control infection, they are unable to fully eliminate M. tuberculosis, suggesting that Th1-mediated immunity is restrained from its full sterilizing potential. Investigation into T cell–mediated defense is hindered by difficulties in expanding M. tuberculosis–specific T cells. To circumvent this problem, we cloned CD4+ T cells from M. tuberculosis–infected B6 mice and generated transgenic mice expressing a T cell receptor specific for the immunodominant antigen early secreted antigenic target 6 (ESAT-6). Adoptively transferred naive ESAT-6–specific CD4+ T cells are activated in pulmonary lymph nodes between 7 and 10 d after aerosol infection and undergo robust expansion before trafficking to the lung. Adoptive transfer of activated ESAT-6–specific Th1 cells into naive recipients before aerosol M. tuberculosis infection dramatically enhances resistance, resulting in 100-fold fewer bacteria in infected lungs. However, despite large numbers of Th1 cells in the lungs of mice at the time of M. tuberculosis challenge, protection was not manifested until after 7 d following infection. Our results demonstrate that pathogen-specific Th1 cells can provide protection against inhaled M. tuberculosis, but only after the first week of infection

Dysfunctional grief related to COVID-19 in Latin America

The characteristics associated with COVID-19-related dysfunctional grief suggest that we are most likely facing a “dysfunctional grief pandemic” due to COVID-19. Thus this preliminary study reports frequencies of dysfunctional grief in ten Latin American countries that varied between 7.3% in Brazil and 14.6% in El Salvador. This highlights a greater need for Latin American countries to work together to improve the accessibility of treatment for dysfunctional grief

Investigation of linezolid resistance in staphylococci and enterococci

The objective of this study was to investigate an apparent increase in linezolid-nonsusceptible staphylococci and enterococci following a laboratory change in antimicrobial susceptibility testing from disk diffusion to an automated susceptibility testing system. Isolates with nonsusceptible results (n = 27) from Vitek2 were subjected to a battery of confirmatory testing which included disk diffusion, Microscan broth microdilution, Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution, gradient diffusion (Etest), 23S rRNA gene sequencing, and cfr PCR. Our results show that there is poor correlation between methods and that only 70 to 75% of isolates were confirmed as linezolid resistant with alternative phenotypic testing methods (disk diffusion, Microscan broth microdilution, CLSI broth microdilution, and Etest). 23S rRNA gene sequencing identified mutations previously associated with linezolid resistance in 16 (59.3%) isolates, and the cfr gene was detected in 3 (11.1%) isolates. Mutations located at positions 2576 and 2534 of the 23S rRNA gene were most common. In addition, two previously undescribed variants (at positions 2083 and 2345 of the 23S rRNA gene) were also identified and may contribute to linezolid resistance

Effects of a Home-Based Exercise Program on Inflammatory Cytokines and Functional Capacity in Men with Prostate Cancer Under Active Surveillance

Regular exercise can improve physical fitness, functional performance, and quality of life in men with prostate cancer (PCa); however, few men with PCa meet national physical activity guidelines. Structured, home-based exercise programs may bridge this gap and increase physical activity in men with PCa. PURPOSE: This pilot study aimed to investigate the impact of a home-based exercise program on cytokines associated with tumor progression in men with PCa. METHODS: A single group, self-controlled study design was used. Fifteen men with PCa under active surveillance were recruited to complete 24 weeks of a home-based exercise program, combining aerobic and body-weight based exercises. The aerobic portion of the intervention included 5 days of light-to-moderate intensity walking for 30 minutes at 40-60% of the participant’s heart rate reserve as calculated using the Karvonen formula. Body-weight based exercises were performed 3 times per week consisting of 3 sets of 15 reps of bodyweight squats, inclined push-ups, and hip thrusts. Serum was collected at baseline and end of study to measure circulating eotaxin, interferon (IFN)γ, interleukin (IL)-12, IL-1a, IL-5, IL-6, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) cytokines using an 8-protein multiplex (Millipore Sigma, Billerica, MA). A 6-minute walk test (MWT)was completed at the beginning and end of study to measure physical function. T-tests were performed with significance set to p \u3c0.05. RESULTS: A total of 15 men were consented with 9 men completing the intervention (40% attrition due to COVID). At baseline, participants were 70.11 ± 5.42 years of age, weighted 85.31 ± 6.41 kg with a body mass index of 27.77 ± 2.93 kg/m2. A non-significant tendency was observed for improved 6MWT distance (meters) (Pre: 382.7 ± 108.1; Post: 466.7 ± 73.78; p=0.08). Analysis of circulating cytokines showed tendencies for reduced circulating concentrations (pg/mL) of IFNγ (Pre: 152.9 ± 312.7; Post: 118.9 ± 258.8; p=0.08), and VEGF (Pre: 125.2 ± 198.7; Post: 80.29 ± 124.3; p=0.06) following the intervention. Several other biomarkers showed relevant, though not significant, decreases as well, including IL-12 (Pre: 28.69 ± 32.06; Post: 23.92 ± 19.38; -16.6%), IL-1a (Pre: 78.76 ± 183.3; Post: 65.55 ± 147.7; -16.8%), IL-6 (Pre: 23.71 ± 45.64; Post: 21.24 ± 45.18; -10.4%), and TNF-α (Pre: 24.58 ± 35.4; Post: 19.71 ± 20.76; -19.8%). CONCLUSION: Due to institutional COVID-19 protocols limiting in person research visits, six participants declined to continue the study. The small sample size likely accounts for the lack of statistically significant findings. Although the study did not yield statistically significant outcomes, the results of this study show promising indications that a home-based exercise program could be effective in reducing inflammatory cytokines and increasing functional capacity in men with PCa. Further investigation is needed to confirm these results with a powered sample

Mejoramiento de ICallbackEventHandler mediante una herramienta basada en Reflection y JavaScript

Problema de Investigación Hay mucha dificultad en implementar la interfaz ICallbackEventHandler cuando se desea agregar varias llamadas asíncronas en una misma página web. Existen una serie de pasos que se deben realizar cada vez que se quiera ejecutar un evento que tenga las características asíncronas utilizando ICallbackEventHandler, esto demanda un exceso de tiempo y esfuerzo que podría ser reducido. A continuación se describen los pasos: a) Implementar la interface b) Implementar los métodos de la interface c) Colocar el script del servidor d) Colocar el script del lado del cliente e) Modificar los métodos de la interface según el funcionamiento que se desea obtener. f) Realizar llamada asíncrona Este es justamente el problema que se ha encontrado y se atacará, para reducir los pasos y dar facilidad para implementar más eventos en una misma interfaz de una manera más fácil y rápida. Objetivo General Bajar la dificultad de uso de ICallbackEventHandler al desarrollar páginas Web. Se reduce la implementación a un mínimo de 4 pasos que además son más óptimos. Objetivos Específicos a) Usar varios métodos personalizables en la aplicación, ocultando los métodos en el lado del servidor: RaiseCallbackEvent y GetCallbackResult. b) Permitir que los métodos personalizables tengan varios parámetros de tipos numéricos y tipo String. c) Facilitar la tarea de implementar más de una llamada asíncrona. Se cuenta con métodos indefinidos en el servidor d) Permitir controlar las Excepciones e) Utilizar la función estándar “ICallBackFunction” para la comunicación con el servidorTesi

Impact of a Home-Based Exercise Program on Cardiovascular Disease Biomarkers in Men with Prostate Cancer

Patients with prostate cancer (PCa) tend to live a sedentary lifestyle and fail to meet national physical activity requirements putting them at a greater risk for developing weight-related co-morbidities and cancer recurrence. Physical activity after cancer diagnosis is known to improve body composition, physical function, and overall quality of life. The inclusion of a home-based exercise regimen may increase their physical activity and reduce the risk of weight-related illness. PURPOSE: To gather preliminary data regarding the impact of a home-based exercise program on body composition and cardiovascular disease (CVD) biomarkers. METHODS: A single group self-controlled study design was used to test the hypothesis that a home-based exercise program can reduce CVD risk in men with PCa. Fifteen men with PCa under active surveillance were recruited to complete a 24-week home-based exercise program consisting of both aerobic and strength-based exercises. Each week, participants were asked to complete 5 days of light-to-moderate intensity walking at a heart rate reserve of 40-60% and 3 days of bodyweight-based exercises including 3 sets of 15 reps of squats, incline push-ups, and hip thrusts. Serum was collected at baseline and end of study to quantify circulating CVD biomarkers: a-2 macroglobulin (A2M), C-reactive protein (CRP), fetuin-A, a-1 acid glycoprotein (AGP), fibrinogen, L-selectin, serum amyloid P (SAP), platelet factor 4 (PF4/CXCL4), and adipsin using an 8-protein multiplex (Millipore Sigma, Billerica, MA). T-tests were performed with significance established at pRESULTS: A total of 15 men consented and 9 men saw the trial to completion (Age: 72.0 ± 8.52; Weight: 85.31 ± 6.41 kg; BMI: 27.77 ± 2.93 kg/m2). There was a 40% rate of attrition observed due to COVID-19. No significant changes occurred in average weights and BMI from pre to post trial visits. Though not significant, tendencies for increased concentrations of the anticoagulant, A2M (Pre: 99.83 ± 81.19 pg/mL; Post: 126.7 ± 102.5; p=0.064) and the inflammatory protein, SAP (Pre: 0.63 ± 0.32 pg/mL; Post: 0.86 ± 0.46; p=0.09) were seen. We also observed a 1.5-fold increase in CRP (Pre: 0.47 ± 0.38 pg/mL; Post: 1.19 ± 2.209) perhaps, as a result of an increase in SAP, or indicative of increased levels of stress due to COVID-19. No other significant differences were found. CONCLUSION: The reduced sample size may have contributed to the lack of significance found in the analysis. Although there were no statistically significant findings, the tendencies seen in A2M suggest that a home-based exercise program may protect against certain facets of CVD in this overweight population. However, our enthusiasm is blunted by the observed increases in SAP and CRP. Further investigation is necessary to validate these results

LANSCE personnel access control system

The Radiation Security System (RSS) at the Los Alamos Neutron Science Center (LANSCE) provides personnel protection from prompt radiation due to accelerated beam. The Personnel Access Control System (PACS) is a component of the RSS that is designed to prevent personnel access to areas where prompt radiation is a hazard. PACS was designed to replace several older personnel safety systems (PSS) with a single modem unified design. Lessons learned from the operation over the last 20 years were incorporated into a redundant sensor, single-point failure safe, fault tolerant, and tamper-resistant system that prevents access to the beam areas by controlling the access keys and beam stoppers. PACS uses a layered philosophy to the physical and electronic design. The most critical assemblies are battery backed up, relay logic circuits; less critical devices use Programmable Logic Controllers (PLCs) for timing functions and communications. Outside reviewers have reviewed the operational safety of the design. The design philosophy, lessons learned, hardware design, software design, operation, and limitations of the device are described