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The objective was to determine the effects of ad libitum-fed roughage-based diets or limit-fed high-energy diets on growth performance, behavior, health, and digestion in newly received growing cattle and subsequent implications on feedlot growth performance and carcass characteristics. In experiment 1, 409 crossbred heifers (initial body weight [BW]â =â 279â ±â 24 kg) in 32 pens were used in a randomized block design. Heifers were fed one of two dietary treatments: a total mixed ration with 0.99 Mcal net energy for gain (NEg)/kg dry matter (DM) fed ad libitum (0.99AL) or 1.32 Mcal NEg/kg DM limit-fed at 85% of intake of heifers fed 0.99AL (1.32LF85%). Both diets contained 40% DM as a branded wet corn gluten feed. In experiment 2, 370 crossbred heifers (initial BWâ =â 225â ±â 20 kg) were used in a randomized block design and were fed a diet formulated to contain 0.99 Mcal of NEg/kg DM for ad libitum intake or a diet formulated to contain 1.32 Mcal of NEg/kg DM and fed at 2.2% of BW daily (DM basis; 1.32LF2.2). For experiments 1 and 2, treatment integrity was maintained through the finishing phase where cattle were fed a common diet. Cattle were sorted by BW into heavy and light groups prior to finishing, with light cattle fed longer than heavy cattle to reach similar harvest BW. In experiment 3, eight ruminally cannulated heifers (average BWâ =â 305â ±â 23 kg) were used in a 2-period cross-over design and fed treatments from experiment 1 to assess digestibility and ruminal fermentation characteristics. Gain:feed was 47% and 35% greater (Pâ <â 0.01) in experiments 1 and 2, respectively, for limit-fed heifers compared with 0.99AL heifers. Rumination time was greater (Pâ <â 0.01) for 0.99AL compared with limit-fed treatments in experiments 1 and 2. Activity was greater (Pâ <â 0.01) for 1.32LF2.2 than for 0.99AL in experiment 2. In experiment 1, more (Pâ =â 0.03) carcasses from light-sort heifers than carcasses from heavy-sort heifers had livers with large, active abscesses. In experiment 2, finishing phase morbidity was greater (Pâ <â 0.01) for 1.32LF2.2 than for 0.99AL. Light-sort groups had fewer (Pâ <â 0.01) edible livers than heavy-sort groups, suggesting that greater number of days on feed may increase the risk of liver abscess prevalence and condemnation. In experiment 3, apparent total-tract DM and organic matter digestibilities were greater (Pâ <â 0.01) for 1.32LF85% than for 0.99AL. Overall, dietary treatments during the growing phase had little carryover effect on feedlot growth performance, carcass characteristics, or liver abscesses prevalence at harvest.
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Objective: Physician-directed point-of-care ultrasound (PoCUS) is routinely used to identify the etiology of shock and guide therapy in the ICU. We performed a preclinical study to determine what changes are manifested in the femoral vessels during hemorrhagic shock on Duplex imaging and to generate a femoral vessel sonographic profile over the time course of shock. Design & setting: A preclinical study in swine was performed using a convenience sample of animals that were being used in a Trauma Surgery training lab. The animals developed progressive unregulated hemorrhage during the lab. Subjects: Six anesthetized swine underwent Duplex studies of the femoral vessels prior to any hemorrhage and at two time points after the start of hemorrhage. Interventions: N/A. Measurements: Femoral vessel imaging was performed using a portable ultrasound (Sonosite and Clarius). Main results: Femoral arterial peak systolic velocity decreased in all animals with hemorrhage, from a mean (SD) of 77 (27) cm/s pre-hemorrhage to 42 (17) and 32 (16) cm/s at the two post-hemorrhage time points. There were also changes to the arterial waveform morphology. Mean venous velocities also decreased with hemorrhage (20, 11, 7 cm/s). Animals with severe hemorrhage had a cessation of venous flow during positive pressure ventilation. Conclusion: In this preclinical study, both femoral peak systolic velocity and venous velocity decreased with hemorrhage. Femoral vessels represent an easily accessible target for non-invasive hemodynamic monitoring. Changes in femoral vessel Duplex waveforms and velocities should be studied both in a larger sample of animals with controlled hemorrhage and in human trauma patients to determine whether changes appear in early hemorrhage, before the onset of clinically evident hemorrhagic shock.
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The goal of this protocol is to develop a standardized method for acquiring images of the optic nerve sheath and measuring the optic nerve sheath diameter (ONSD). Diagnostic ultrasound of the ONSD to detect intracranial hypertension has traditionally faced many problems because of methodologic discrepancies. Due to inconsistencies in the measuring techniques, the potential for ONSD to become a non-invasive bedside monitoring tool for ICP has been hampered. However, establishing a transparent, consistent methodology for measuring the ONSD would support its use as a valid and reliable method of identifying intracranial hypertension. This is important as it has both high sensitivity and specificity in acute care settings. This narrative review describes ONSD POCUS image acquisition, including patient positioning, transducer selection, probe placement, the acquisition sequence, and image optimization. Further, visual aids are provided to assist in real-time during image acquisition. This method should be considered for patients for whom there are concerns regarding intracranial hypertension but who do not have an intracranial monitor in place.
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Hipertensión Intracraneal , Sistemas de Atención de Punto , Humanos , Hipertensión Intracraneal/diagnóstico por imagen , Cuidados Críticos , Ultrasonografía , Nervio Óptico/diagnóstico por imagenRESUMEN
The COVID-19 pandemic has resulted in the exposure of many surgeons and healthcare providers (HCPs) to disease given high patient loads and limited availability of negative pressure rooms. For these reasons we pursued the development of a portable patient isolation system (COVIAGE™ by iSolace, Inc.) that can be used to contain patients with respiratory illness and minimize the exposure of HCPs. COVIAGE™ is comprised of a reusable aluminum frame, a disposable thermoplastic polyurethane tent and a HEPA filtration/ventilation system (HVAC) utilizing two inline filters. The efficacy of filtration was tested by comparing particulate concentration inside and outside of the device by an independent third party. Additionally, physician, nursing, and respiratory tasks were performed initially on simulated patients and then on intubated patients in the ICU. The system attained a verified filtration efficiency greater than 99.999% for an average 0.3-µm size particulates. Simulation testing revealed that most common physician, nursing, and respiratory tasks could be completed in the device, including endotracheal intubation. Emergency removal of the device can be accomplished in 8.8 ± 2.8 seconds. The reusable aluminum frame allows for simple attachment to the bed, and adaptability to different types and sizes of beds/stretchers. An emergency use authorization was granted by the FDA. The device created results in a portable negative pressure isolation system that can be placed over the patient's bed to contain aerosols during high aerosol generating procedures, transportation of patients or for total patient care in environments where negative pressure rooms are not available.
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COVID-19 , Pandemias , Aerosoles , Aluminio , Personal de Salud , Humanos , Pandemias/prevención & control , Aislamiento de PacientesRESUMEN
Two growth performance studies and two digestibility trials were conducted to evaluate the effects of feeding Enogen Feed Corn silage and corn grain to growing cattle. In Exp. 1, there were a total of four diets offered for ad libitum intake. The four diets consisted of two varieties of corn (Enogen Feed Corn [EFC] vs. yellow #2 corn [CON]) with two different methods of corn processing (dry-rolled [DR] vs. whole-shelled [WS]) and were formulated to provide 1.13 Mcal NEg/kg dry matter (DM); corn grain was 28.6% of diet DM. Average daily gain (ADG) and ending body weight tended to be greater for calves fed EFC than for those fed CON (Pâ <â 0.10). Gain:feed (G:F) was better for calves fed EFC (Pâ <â 0.01), improving by 5.5% over calves fed CON. In Exp. 2, a digestibility trial was conducted using seven cannulated Holstein steers fed the same diets from Exp. 1. Ruminal pH was not affected by corn variety (Pâ >â 0.82). Liquid passage rate was greater for CON-fed calves and associated with lower digestibility. Total tract DM and organic matter (OM) digestibilities were greater for EFC-fed calves (Pâ <â 0.04). In Exp. 3, there were four diets offered for ad libitum intake. Dietary factors were arranged as a 2â ×â 2 factorial and consisted of two hybrids of corn silage (EFC silage [EFC-S] vs. control silage [CON-S]) and two varieties of corn grain (EFC grain [EFC-G] vs. control [CON-G]; both were dry-rolled). Diets were formulated to provide 1.11 Mcal NEg/kg DM; corn grain was 38.5% of diet DM, and corn silage was 40% of diet DM. ADG was 6.0% greater (Pâ <â 0.01) and G:F was numerically (Pâ <â 0.14) 3.3% greater for calves fed EFC-S than for those fed CON-S, but substituting EFC-G for CON-G did not affect ADG or G:F. In Exp. 4, a digestibility trial was conducted using eight cannulated beef steers fed the same diets as Exp. 3. Liquid passage rate (Pâ >â 0.20), ruminal pH (Pâ >â 0.23), and ruminal total volatile fatty acid concentrations (Pâ >â 0.27) were unaffected by treatment. Total tract digestibilities of DM and OM were numerically greater by 2.5% and 2.2%, respectively, for calves fed the EFC-S compared with those fed CON-S. Feeding a corn hybrid containing alpha-amylase enzyme improved G:F of growing calves. Feeding EFC can benefit the beef industry by allowing less processing of grain without sacrificing performance.
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Effects of dietary energy level and intake of corn by-product-based diets on antibody production, acute phase protein response, stress, and immunocompetency of healthy and morbid newly received growing cattle were evaluated. Four dietary treatments were formulated to supply 0.99, 1.10, 1.21, and 1.32 Mcal NEg/ kg DM and were offered at 100%, 95%, 90%, and 85% of ad libitum based on 0.99/100 treatment intake, respectively. Thirty-two pens were utilized with approximately 12 animals/pen. Four animals from each pen (32/dietary treatment) were randomly selected and used to serve as a subset to monitor immune function and acute phase proteins following a split-plot design. In addition, two animals were randomly and independently selected from each pen (16/dietary treatment) and used to measure fecal cortisol metabolite. Additionally, animals removed from the pen one (M1), two (M2), or three (M3) times and classified as morbid were bled in conjunction with a healthy control (H) removed at the same time and the serum analyzed for the same parameters. A quadratic response to time (P < 0.01) was detected for haptoglobin concentrations and for antibody titers for bovine viral diarrhea type 1 (BVD-I) and infectious bovine rhinotracheitis (IBR; P < 0.01). Haptoglobin was lowest on arrival, highest on day 14, and similar to baseline levels by day 27. Titer levels for BVD-I and IBR were lowest on arrival, higher on day 14, and significantly higher on day 27. Titers for bovine viral diarrhea type 2 (BVD-II) responded linearly (P < 0.05) with lower levels on arrival and highest levels on day 27. Haptoglobin was elevated in morbid animals compared to healthy pen mates (P < 0.05). Titer levels for BVD-I and IBR were also higher in healthy animals compared to animals pulled for morbidity (P < 0.01). Fecal cortisol was higher on arrival than on day 14 (P < 0.05). Dietary treatment had no effect on any of the parameters investigated. In summary, high-energy receiving diets based on fermentable fiber from by-products can be fed to newly received growing cattle without negative effects on antibody production toward vaccines, inflammation, or overall stress. In addition, haptoglobin concentrations and titer levels for BVD-I and IBR viruses are higher in healthy animals compared to sick animals.
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Reacción de Fase Aguda/inmunología , Alimentación Animal/análisis , Virus de la Diarrea Viral Bovina Tipo 1/inmunología , Ingestión de Energía , Metabolismo Energético , Rinotraqueítis Infecciosa Bovina/inmunología , Proteínas de Fase Aguda/análisis , Animales , Formación de Anticuerpos , Bovinos , Dieta/veterinaria , Femenino , Glucocorticoides/metabolismo , Haptoglobinas/análisis , Estrés Fisiológico , Zea maysRESUMEN
Central line placement is a common procedure, routinely performed by junior residents in medical and surgical departments. Before this project, no standardized instructional course on the insertion of central lines existed at our institution, and few interns had received formal ultrasound training. Interns from five departments participated in a simulation-based central line insertion course. Intern familiarity with the procedure and with ultrasound, as well as their prior experience with line placement and their level of comfort, was assessed. Of the 99 interns in participating departments, 45 per cent had been trained as of October 2015. Forty-one per cent were female. The majority (59.5%) had no prior formal ultrasound training, and 46.0 per cent had never placed a line as primary operator. Scores increased significantly, from a precourse score mean of 13.7 to a postcourse score mean of 16.1, P < 0.001. All three of the self-reported measures of comfort with ultrasound also improved significantly. All interns reported the course was "very much" helpful, and 100 per cent reported they felt "somewhat" or "much" more comfortable with the procedure after attendance. To our knowledge, this is the first hospital-wide, standardized, simulation-based central line insertion course in the United States. Preliminary results indicate overwhelming satisfaction with the course, better ultrasound preparedness, and improved comfort with central line insertion.
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Cateterismo Venoso Central/normas , Educación Basada en Competencias/métodos , Educación de Postgrado en Medicina , Cirugía General/educación , Relaciones Interdepartamentales , Internado y Residencia/normas , Entrenamiento Simulado , Adulto , Educación de Postgrado en Medicina/métodos , Evaluación Educacional , Femenino , Humanos , Venas Yugulares/cirugía , Masculino , Maniquíes , Entrenamiento Simulado/métodos , Vena Subclavia/cirugía , Estados UnidosRESUMEN
BACKGROUND: Simulation is quickly becoming vital to resident education, but commercially available central line models are costly and little information exists to evaluate their realism. This study compared an inexpensive homemade simulator to three commercially available simulators and rated model characteristics. MATERIALS AND METHODS: Seventeen physicians, all having placed >50 lines in their lifetime, completed blinded central line insertions on three commercial and one homemade model (made of silicone, tubing, and a pressurized pump system). Participants rated each model on the realism of its ultrasound image, cannulation feel, manometry, and overall. They then ranked the models based on the same variables. Rankings were assessed with Friedman's and post hoc Conover's tests, using alphas 0.05 and 0.008 (Bonferroni corrected), respectively. RESULTS: The models significantly differed (P < 0.0004) in rankings across all dimensions. The homemade model was ranked best on ultrasound image, manometry measurement, cannulation feel, and overall quality by 71%, 67%, 53%, and 77% of raters, respectively. It was found to be statistically superior to the second rated model in all (P < 0.003) except cannulation feel (P = 0.134). Ultrasound image and manometry measurement received the lowest ratings across all models, indicating less realistic simulation. The cost of the homemade model was $400 compared to $1000-$8000 for commercial models. CONCLUSIONS: Our data suggest that an inexpensive, homemade central line model is as good or better than commercially available models. Areas for potential improvement within models include the ultrasound image and ability to appropriately measure manometry of accessed vessels.
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Cateterismo Venoso Central , Internado y Residencia/métodos , Modelos Anatómicos , Entrenamiento Simulado/métodos , Cateterismo Venoso Central/economía , Cateterismo Venoso Central/métodos , Humanos , Internado y Residencia/economía , Entrenamiento Simulado/economía , Método Simple Ciego , Ultrasonografía Intervencional , Estados UnidosRESUMEN
BACKGROUND: The focused ultrasound examination has become increasingly recognized as a safe and valuable diagnostic tool for the bedside assessment of the critically ill patient. We implemented a dedicated on-site critical care ultrasonography curriculum with the goal of developing a model for teaching ultrasound skills to pulmonary and critical care medicine fellows. METHODS: The program was comprised of blended didactic and bedside sessions in the following topic domains: fundamentals; vascular access and diagnosis; and abdominal, thoracic, and cardiac ultrasonography. Formal knowledge and image acquisition assessments were performed before and after the program to assess success in meeting predefined learning objectives. Participants completed surveys (on Likert scale 1-5) before and after the program to assess their confidence in ultrasonography knowledge and skills as well as their perception as to training effectiveness. RESULTS: The preintervention knowledge and bedside image acquisition scores were 71 and 32%, respectively. The global preintervention score was 51%. All postintervention measures demonstrated significant improvement: 89% (P < 0.01), 86% (P < 0.0001), and 87% (P < 0.0001). Preintervention participant confidence in their ultrasound knowledge and skill was 2.9/5, which improved to 4.3/5 (P = 0.007) after intervention. Participants rated the curriculum as meeting course objectives at a mean of 4.8/5. CONCLUSIONS: At one academic medical center, the knowledge of eight adult pulmonary and critical care fellowship trainees regarding critical care ultrasound was high at baseline; however, bedside image acquisition skills were poor. A dedicated 6-week educational intervention resulted in highly significant improvements in subject knowledge and image acquisition skills. These preliminary results warrant validation studies at other medical centers.
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Centros Médicos Académicos , Competencia Clínica , Cuidados Críticos , Curriculum , Educación Médica Continua/métodos , Internado y Residencia/métodos , Desarrollo de Programa , Adulto , Evaluación Educacional , Femenino , Humanos , Masculino , UltrasonografíaRESUMEN
BACKGROUND: Up to 20% of all trauma patients admitted to an intensive care unit die from their injuries. End-of-life decision making is a variable process that involves prognosis, predicted functional outcomes, personal beliefs, institutional resources, societal norms, and clinician experience. The goal of this study was to better understand end-of-life processes after major injury by comparing clinician viewpoints from various countries and cultures. METHODS: A clinician-based, 38-question international survey was used to characterize the impacts of medical, religious, social, and system factors on end-of-life care after trauma. RESULTS: A total of 419 clinicians from the United States (49%), Canada (19%), South Africa (11%), Europe (9%), Asia (8%), and Australasia (4%) completed the survey. In America, the admitting surgeon guided most end-of-life decisions (51%), when compared with all other countries (0-27%). The practice structure of American respondents also varied from other regions. Formal medical futility laws are rarely available (14-38%). Ethical consultation services are often accessible (29-98%), but rarely used (0-29%), and typically unhelpful (<30%). End-of-life decision making for patients with traumatic brain injuries varied extensively across regions with regard to the impact of patient age, Glasgow Coma Scale score, and clinician philosophy. Similar differences were observed for spinal cord injuries (age and functional level). The availability and use of "donation after cardiac death" also varied substantially between countries. CONCLUSIONS: In this unique study, geographic differences in religion, practice composition, decision-maker viewpoint, and institutional resources resulted in significant variation in end-of-life care after injury. These disparities reflect competing concepts (patient autonomy, distributive justice, and religion).
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Cultura , Toma de Decisiones , Unidades de Cuidados Intensivos , Cuidado Terminal , Asia , Actitud del Personal de Salud , Australasia , Canadá , Europa (Continente) , Recursos en Salud , Humanos , Inutilidad Médica/legislación & jurisprudencia , Relaciones Médico-Paciente , Religión , Sudáfrica , Encuestas y Cuestionarios , Obtención de Tejidos y Órganos , Estados UnidosRESUMEN
BACKGROUND: Current recommendations for victims of penetrating trauma include prompt transportation to a trauma center. It remains unclear whether field intubation allows for improvements in mortality rate. METHODS: A retrospective review of the National Trauma Data Bank of adult victims of penetrating trauma was performed. Standard demographic data, method, and location of airway management were examined. Mortality rate was used as the primary outcome measure. RESULTS: There were 56,094 victims of penetrating trauma identified. A total of 1,925 patients required a prehospital airway. The mortality rate for patients who underwent airway management at the scene was 69.2%, compared with a rate of 35.9% for patients in whom airway management was deferred. The mortality rate for patients undergoing surgical airway management at the scene was only 23.9%. CONCLUSIONS: Victims of penetrating trauma who require any airway management have a high mortality rate. The cause of this difference awaits further prospective investigation.
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Intubación Intratraqueal , Traqueotomía , Heridas Penetrantes/terapia , Adulto , Femenino , Humanos , Masculino , Estudios Retrospectivos , Heridas Penetrantes/mortalidadRESUMEN
BACKGROUND: Most seriously wounded US Army casualties from the Iraqi theater of operations come through Walter Reed Army Medical Center on their return to the United States. General surgery and orthopaedic surgery services have developed a multidisciplinary team approach to triage and treatment of incoming casualties. STUDY DESIGN: Prospective database of returning casualties to Walter Reed Army Medical Center from Operation Iraqi Freedom (OIF) from March 1 to July 1, 2003. RESULTS: Of 294 casualties seen, 119 were triaged to inpatient status and treated within 1 hour of arrival; mean age 26.6 +/- 6.2 years (range 23 to 37). Time from original battlefield injury was a mean of 8 days (range 3 to 28 days). Forty-six (39%) sustained gunshot wounds, 37 (31%) sustained blast and shrapnel injuries, and 41 (34%) had blunt/motor vehicle collision mechanisms. There were a total of 184 wounded locations in these 119 casualties; of these, there were 29 head and neck, 25 chest, 20 abdomen, 74 lower extremity, and 36 upper extremity. Twenty-eight casualties (23%) required emergent surgical procedures on the night of arrival. Another 30 (25%) required an urgent surgical procedure within 48 hours of arrival. CONCLUSIONS: Followup surgical procedures were urgently or emergently required in 43% of admitted battlefield casualties from OIF on transfer to Level V care in the continental United States. The injury pattern of wounds from this engagement is described. The Walter Reed Army Medical Center system of incoming battlefield casualty evaluation using multidisciplinary teams is successful in expediting care and ensuring evaluation of the full range of potential injuries.
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Guerra , Heridas y Lesiones/clasificación , Accidentes de Tránsito , Adulto , Traumatismos por Explosión/clasificación , Traumatismos por Explosión/cirugía , Estudios de Cohortes , Traumatismos Craneocerebrales/clasificación , Traumatismos Craneocerebrales/cirugía , Urgencias Médicas , Femenino , Estudios de Seguimiento , Humanos , Irak , Extremidad Inferior/lesiones , Extremidad Inferior/cirugía , Masculino , Traumatismos del Cuello/clasificación , Traumatismos del Cuello/cirugía , Estudios Prospectivos , Traumatismos Torácicos/clasificación , Traumatismos Torácicos/cirugía , Factores de Tiempo , Triaje , Estados Unidos , Extremidad Superior/lesiones , Extremidad Superior/cirugía , Heridas y Lesiones/cirugía , Heridas por Arma de Fuego/clasificación , Heridas por Arma de Fuego/cirugía , Heridas no Penetrantes/clasificación , Heridas no Penetrantes/cirugíaRESUMEN
Anti-CD154 variably prolongs allograft survival in nonhuman primates. Rodent studies suggest that adding pretransplant donor-specific transfusion (DST) and/or rapamycin to anti-CD154 improves survival. The CD154-specific Ab IDEC-131 was tested alone and in combination with rapamycin for its ability to inhibit rhesus MLRs. The ability of the Ab to block endothelial activation was also assessed. IDEC-131 was then tested alone and in combination with DST and/or rapamycin for its ability to prevent rejection of full-thickness, MHC-mismatched rhesus skin allografts. Animals were monitored for donor-specific hyporesponsiveness by MLR and alloantibody determination. IDEC-131 modestly inhibited rhesus MLRs and inhibited CD154-dependent endothelial cell activation. Rapamycin combined with IDEC-131 additively inhibited MLRs. IDEC-131 modestly prolonged allograft survival when compared with no treatment, rapamycin alone, or DST plus rapamycin. Adding DST to IDEC-131 did not prolong survival beyond IDEC-131 alone. IDEC-131 plus rapamycin was effective in prolonging graft survival, although animals had episodes of acute rejection before graft demise. Therapy with IDEC-131, rapamycin, and DST induced long-term allograft survival without intermittent acute rejection. However, no evidence for MLR inhibition was seen, and most animals eventually developed alloantibody. All animals ultimately rejected their grafts after drug withdrawal. IDEC-131 modestly prolongs rhesus skin allograft survival. Rapamycin and rapamycin plus DST improves the efficacy of IDEC-131 in prolonging allograft survival. IDEC-131, rapamycin, and DST are a promising combination for clinical evaluation in allotransplantation.
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Anticuerpos Monoclonales/uso terapéutico , Transfusión Sanguínea , Ligando de CD40/inmunología , Modelos Inmunológicos , Sirolimus/uso terapéutico , Trasplante de Piel/inmunología , Acondicionamiento Pretrasplante , Administración Oral , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Transfusión Sanguínea/métodos , Complejo CD3/inmunología , Ligando de CD40/biosíntesis , División Celular/efectos de los fármacos , División Celular/inmunología , Células Cultivadas , Quimioterapia Combinada , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Refuerzo Inmunológico de Injertos/métodos , Humanos , Tolerancia Inmunológica , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Inyecciones Intravenosas , Isoanticuerpos/biosíntesis , Prueba de Cultivo Mixto de Linfocitos , Macaca mulatta , Sirolimus/administración & dosificación , Trasplante de Piel/métodos , Trasplante de Piel/patología , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Acondicionamiento Pretrasplante/métodosRESUMEN
BACKGROUND: Antibodies and fusion proteins specific for CD80, CD86, and CD154 have shown promise as agents capable of inducing donor-specific tolerance in rodents. These agents have also been shown to be synergistic with one another in many settings of counter-adaptive immunity. In the nonhuman primate, monoclonal antibodies specific for CD80 and CD86 have prolonged the time to rejection of renal allografts but have not resulted in tolerance. A monoclonal antibody specific for CD154 has resulted in markedly prolonged survival of kidney, islet, cardiac, and skin allografts, but again most animals have eventually developed rejection after prolonged periods of rejection-free survival off therapy. METHODS: A combination of monoclonal antibodies specific for CD80, CD86, and CD154 were used in a mismatched nonhuman primate renal-allograft model. Doses used were based on optimized treatment protocols for each agent individually. RESULTS: Treatment of four rhesus macaques with this combination yielded a mean rejection-free survival of 565 days (311-911 days), significantly greater than untreated controls (mean survival=7.0 days, P=0.001) and animals treated with only a combination of anti-CD80 and CD86 (mean survival=191 days, P=0.01). The survival of animals treated with this combination of monoclonal antibodies was not significantly greater than those treated with anti-CD154 alone, but the production of alloantibody was delayed compared with monotherapy anti-CD154. CONCLUSION: These data suggest that a synergy exists between these agents, particularly with regard to T-dependent B-cell responses, but that they fail to induce durable tolerance in nonhuman primates.
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Anticuerpos Monoclonales/administración & dosificación , Antígenos CD/inmunología , Antígeno B7-1/inmunología , Ligando de CD40/inmunología , Trasplante de Riñón/inmunología , Glicoproteínas de Membrana/inmunología , Animales , Anticuerpos Monoclonales/efectos adversos , Formación de Anticuerpos , Antígeno B7-1/fisiología , Antígeno B7-2 , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Macaca mulatta , Ratones , Trasplante HomólogoRESUMEN
The anti-CD154 antibody hu5C8 prevents acute allograft rejection and prolongs allograft survival after withdrawal of therapy in nonhuman primates. This study describes the use of hu5C8 as a rescue agent for rejection developing after the withdrawal of hu5C8. Twelve rhesus monkeys that had received renal allografts under hu5C8 induction and subsequently rejected were studied. Rescue with hu5C8 was analyzed based on the histological character of the rejection (acute versus chronic) and whether conventional therapy was received at the time of rescue or induction. The diagnosis of rejection and response to therapy was based on allograft function and histology. Four monkeys that had acute rejection associated with conventional immunosuppression and hu5C8 were not reversed by hu5C8 rescue. Four animals with isolated chronic rejection following prolonged rejection-free survival after the withdrawal of hu5C8 did not respond to hu5C8 rescue therapy. Hu5C8 rescue therapy effectively reversed acute rejection occurring in two monkeys after hu5C8 withdrawal. One of two animals with combined acute on chronic rejection responded to hu5C8 rescue therapy. Hu5C8 effectively reverses acute but not chronic allograft rejection and appears to have no synergistic effect with conventional rescue agents.
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Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Ligando de CD40/inmunología , Rechazo de Injerto/tratamiento farmacológico , Trasplante de Riñón , Terapia Recuperativa , Enfermedad Aguda , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Biopsia , Enfermedad Crónica , Esquema de Medicación , Rechazo de Injerto/patología , Humanos , Terapia de Inmunosupresión , Riñón/patología , Macaca mulatta , Trasplante HomólogoRESUMEN
A regimen combining sirolimus, tacrolimus, and daclizumab has recently been shown to provide adequate immunosuppression for allogeneic islet transplantation in humans, but remains unproven for primarily vascularized allografts. We evaluated this regimen for renal allograft transplantation in mismatched nonhuman primates. Dosages of sirolimus and tacrolimus were adjusted for trough levels of 10-15 ng/mL and 4-6 ng/mL, respectively. Treated monkeys (n = 5) had significantly prolonged allograft survival, with a mean survival of 36 days vs. 7 days in untreated controls (n = 6, p = 0.008). Four of five treated animals, but none of the controls, developed fibrinoid vascular necrosis of the small intestine. A review of gut histology from animals on other immunosuppressive protocols performed by our laboratory suggested that these lesions were a result of sirolimus exposure. In summary, this regimen prolongs the survival of vascularized renal allografts, but is limited by profound GI toxicity in rhesus macaques.