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The Covid pandemic took the world by surprise in late 2019 and the need for rapid development of vaccines became paramount. The challenge was how to accelerate standard vaccine development times as much as possible. With knowledge of the genetic code of SARsCOV2, vaccine manufacturers throughout the world have risen to the challenge and several new vaccines were rapidly developed for emergency use. In March 2020, global Regulatory Authorities met to consider how to start early clinical trials and accept rolling submissions. Before use in clinical trials or any mass vaccination campaigns, the safety of the candidate vaccine needs to be evaluated. Non-clinical toxicology studies are required as an important part of vaccine safety evaluation. The extent of the toxicology evaluation prior to the start of clinical trials depended on several factors, including: the type of the candidate vaccine as well as already available supportive information with the candidate vaccine or similar vaccine types. For vaccine candidates with pre-existing data, this would save valuable time whilst a full toxicology evaluation was completed in parallel. For vaccines with more limited data, toxicology data was required before clinical development could start. This workshop examined the nonclinical toxicology studies for new Covid vaccines from the perspectives of: Vaccine manufacturers with different vaccine technologies, managing global regulatory submissions/responses; CROs, managing the urgency of conducting and reporting studies and supporting new players in the vaccine world; and Regulatory Authorities, in supporting the review process, juggling the need for safety and quality with mounting pressure to approve vaccines.
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Vacunas contra la COVID-19 , COVID-19 , Vacunas , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , ARN Viral , SARS-CoV-2RESUMEN
Post Tuberculosis Lung Disease (PTLD) affects millions of tuberculosis survivors and is a global health burden. The immune mechanisms that drive PTLD are complex and have historically been under investigated. Here, we discuss two immune-mediated paradigms that could drive human PTLD. We review the characteristics of a fibrotic granuloma that favors the development of PTLD via an abundance of T-helper-2 and T-regulatory cells and an upregulation of TGF-ß mediated collagen deposition. Next, we discuss the post-primary tuberculosis paradigm and the complex mixture of caseous pneumonia, cavity formation and fibrosis that can also lead to PTLD. We review the delicate balance between cellular subsets and cytokines of the innate and adaptive immune system in conjunction with host-derived proteases that can perpetuate the parenchymal lung damage seen in PTLD. Next, we discuss the role of novel host directed therapies (HDT) to limit the development of PTLD and in particular, the recent repurposing of established medications such as statins, metformin and doxycycline. Finally, we review the emerging role of novel imaging techniques as a non-invasive modality for the early recognition of PTLD. While access to computed tomography imaging is unlikely to be available widely in countries with a high TB burden, its use in research settings can help phenotype PTLD. Due to a lack of disease-specific biomarkers and controlled clinical trials, there are currently no evidence-based recommendations for the management of PTLD. It is likely that an integrated antifibrotic strategy that could simultaneously target inflammatory and pro-fibrotic pathways will probably emerge as a successful way to treat this complex condition. In a disease spectrum as wide as PTLD, a single immunologic or radiographic marker may not be sufficient and a combination is more likely to be a successful surrogate that could aid in the development of successful HDTs.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Enfermedades Pulmonares , Metformina , Mycobacterium tuberculosis , Tuberculosis , Biomarcadores , Colágeno/uso terapéutico , Mezclas Complejas/uso terapéutico , Citocinas , Doxiciclina/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pulmón/diagnóstico por imagen , Metformina/uso terapéutico , Mycobacterium tuberculosis/genética , Péptido Hidrolasas/uso terapéutico , Factor de Crecimiento Transformador beta/uso terapéuticoRESUMEN
The potential systemic toxicity of Oligopin®, a French Maritime Pine Bark extract (FMPBE) rich in procyanidolic oligomers, was evaluated in an acute oral limit test and a 90-day repeated dose oral toxicity study with Sprague Dawley rats. The potential mutagenicity was assessed in a bacterial reverse mutation assay and in vitro mammalian chromosome aberration assay with human lymphocytes. The results indicate that Oligopin® was nongenotoxic in both bacterial and human cell assays, was not acutely toxic via oral administration at up to 2000â¯mg/kg and was well tolerated following 90 days of oral administration to SD rats, with a no observed adverse effect level of 1000â¯mg/kg/day. The lack of significant adverse systemic effects in the 90 day study is concordant with findings from several human clinical trials. The acute toxicity and mutagenicity data are consistent with data reported by AFSSA in a summary of FMPBE safety, in which a NOAEL of 100â¯mg/kg/day was established. In contrast, the NOAEL derived from the 90-day study with Oligopin® was 1000â¯mg/kg/day, suggesting that it is less systemically toxic than other FMPBE previously evaluated in subchronic studies, and comparable to proanthocyanidins extracted from grape seeds, which are widely used as nutritional supplement ingredients.
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Omalizumab (Xolair® ) is an anti-IgE monoclonal antibody, which may benefit adults with systemic mastocytosis. We report effective treatment with omalizumab in two toddlers with severe diffuse cutaneous mastocytosis. Our cases offer preliminary evidence to support the safe use of omalizumab in paediatric patients with cutaneous mastocytosis.
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Antialérgicos/uso terapéutico , Mastocitosis Cutánea/tratamiento farmacológico , Omalizumab/uso terapéutico , Preescolar , Humanos , MasculinoRESUMEN
Islet transplantation can potentially cure type 1 diabetes mellitus, but it is limited by a shortage of human donors as well as by islet graft destruction by inflammatory and thrombotic mechanisms. A possible solution to these problems is to use genetically modified pig islets. Endothelial protein C receptor (EPCR) enhances protein C activation and regulates coagulation, inflammation, and apoptosis. We hypothesized that human EPCR (hEPCR) expression on donor islets would improve graft survival and function. Islets from an hEPCR transgenic mouse line strongly expressed the transgene, and hEPCR expression was maintained after islet isolation. Islets were transplanted from hEPCR mice and wild-type (WT) littermates into diabetic mice in a marginal-dose syngeneic intraportal islet transplantation model. The blood glucose level normalized within 5 days in 5 of 7 recipients of hEPCR islets, compared with only 2 of 7 recipients of WT islets (P < .05). Transplanted hEPCR islets had better preserved morphology and more intense insulin staining than WT grafts, and they retained transgene expression. The improved engraftment compared with WT islets suggests that inflammation and coagulation associated with the transplant process can be reduced by hEPCR expression on donor tissue.
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Antígenos CD/metabolismo , Diabetes Mellitus Experimental/cirugía , Diabetes Mellitus Tipo 1/cirugía , Trasplante de Islotes Pancreáticos , Receptores de Superficie Celular/metabolismo , Trasplantes/metabolismo , Animales , Apoptosis , Glucemia/análisis , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 1/sangre , Receptor de Proteína C Endotelial , Supervivencia de Injerto , Humanos , Insulina/análisis , Masculino , Ratones , Ratones Transgénicos , Sustancias Protectoras/metabolismo , Proteína C/metabolismo , PorcinosRESUMEN
Stroke is a leading cause of death and disability. Effects of stroke include significant deficits in sensory-motor skills and cognitive abilities. At present, there are limited effective interventions for postacute stroke patients. In this preliminary research we studied a new noninvasive, very low intensity, low frequency, electromagnetic field treatment (VLIFE), targeting a neural network, on an in vivo stroke rat model. Eighteen rats were divided into three groups: sham (M1) and two treatment groups which were exposed to VLIFE treatment for 4 weeks, one using theta waves (M2) and another using beta waves (M3); all groups were followed up for an additional month. Results indicate that the M2 and M3 treated groups showed recovery of sensorimotor functional deficits, as demonstrated by Modified Neurological Severity Score and forelimb placement tests. Brain MRI imaging results show a decrease in perilesional edema and lateral ventricle widening in the treated groups. Fiber tracts' imaging, following VLIFE treatment, showed a higher white matter integrity compared to control. Histological findings support neural regeneration processes. Our data suggest that VLIFE treatment, targeting a specific functional neural network by frequency rather than location, promotes neuronal plasticity after stroke and, as a result, improves clinical recovery. Further studies will investigate the full potential of the treatment.
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Combination of tumor antigens with immunostimulants is a promising approach in cancer immunotherapy. We assessed animal model toxicity of AS15 combined with various tumor antigens: WT1 (rabbits), or p501, dHER2 and recPRAME (cynomolgus monkeys), administered in seven or 20 dose regimens versus a saline control. Clinical and ophthalmological examinations, followed by extensive post-mortem pathological examinations, were performed on all animals. Blood hematology and biochemistry parameters were also assessed. Antigen-specific antibody titers were determined by enzyme-linked immunosorbent assay. Additional assessments in monkeys included electrocardiography and immunohistochemical evaluations of the p501 expression pattern. Transient increases in body temperature were observed 4 h or 24 h after injections of recPRAME + AS15 and dHER2 + AS15. Edema and erythema were observed up to 1 week after most injections of recPRAME + AS15 and all injections of dHER2 + AS15. No treatment-related effects were observed for electrocardiography parameters. Mean fibrinogen levels were significantly higher in all treated groups compared to controls, but no differences could be observed at the end of the treatment-free period. Transient but significant differences in biochemistry parameters were observed post-injection: lower albumin/globulin ratios (p501 + AS15), and higher bilirubin, urea and creatinine (dHER2 + AS15). Pathology examinations revealed significant increases in axillary lymph node mean weights (recPRAME + AS15) compared to controls. A 100% seroconversion rate was observed in all treated groups, but not in controls. p501 protein expression was observed in prostates of all monkeys from studies assessing p501 + AS15. These results suggest a favorable safety profile of the AS15-containing candidate vaccines, supporting the use of AS15 for clinical development of potential anticancer vaccines.
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Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Antígenos de Neoplasias/administración & dosificación , Antígenos de Neoplasias/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Adyuvantes Inmunológicos/toxicidad , Animales , Antígenos de Neoplasias/toxicidad , Femenino , Haplorrinos , Inyecciones Intramusculares , Masculino , Modelos Animales , ConejosRESUMEN
We assessed potential toxic effects of the MAGE-A3 Cancer Immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. Three groups of 48 female (Study 1) or 22 male (Study 2) CD rats received 5 or 3 injections of 100µL of saline, AS15 immunostimulant, or MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 recombinant protein combined with AS15) at various timepoints pre- or post-mating. Male Cynomolgus monkeys (Study 3) received 8 injections of 500µL of saline (n=2) or the MAGE-A3 Cancer Immunotherapeutic (n=6) every 2 weeks. Rats were sacrificed on gestation day 20 or lactation day 25 (Study 1) or 9 weeks after first injection (Study 2) and monkeys, 3 days or 8 weeks after last injection. Injections were well tolerated. Female rat mating performance or fertility, pre- and post-natal survival, offspring development up to 25 days of age, and male mating performance (rats) or fertility parameters (rats and monkeys) were unaffected.
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Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/farmacología , Desarrollo Embrionario/efectos de los fármacos , Fertilidad/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Proteínas de Neoplasias/inmunología , Reproducción/efectos de los fármacos , Animales , Anticuerpos/sangre , Femenino , Inmunoterapia , Macaca fascicularis , Masculino , RatasRESUMEN
Differential protein glycosylation in the donor and recipient can have profound consequences for transplanted organs, as evident in ABO-incompatible transplantation and xenotransplantation. In this study, we investigated the impact of altered fucosylation on graft acceptance by using donor mice overexpressing human α1,2-fucosyltransferase (HTF). Skin and heart grafts from HTF transgenic mice were rapidly rejected by otherwise completely matched recipients (median survival times 16 and 14 days, respectively). HTF skin transplanted onto mice lacking T and B cells induced an natural killer cell-mediated innate rejection crisis that affected 50-95% of the graft at 10-20 days. However, in the absence of adaptive immunity, the residual graft recovered and survived long-term (>100 days). Experiments using "parked" grafts or MHC class II-deficient recipients suggested that indirect rather than direct antigen presentation plays a role in HTF skin graft rejection, although the putative antigen(s) was not identified. We conclude that altered glycosylation patterns on donor tissue can trigger a powerful rejection response comprising both innate and adaptive components. This has potential implications for allotransplantation, in light of increasing recognition of the variability of the human glycome, and for xenotransplantation, where carbohydrate remodeling has been a lynchpin of donor genetic modification.
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Fucosiltransferasas/metabolismo , Rechazo de Injerto/etiología , Trasplante de Corazón/efectos adversos , Complejo Mayor de Histocompatibilidad/fisiología , Trasplante de Piel/efectos adversos , Trasplante Heterólogo/efectos adversos , Animales , Presentación de Antígeno/inmunología , Femenino , Fucosiltransferasas/genética , Glicosilación , Rechazo de Injerto/mortalidad , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Técnicas para Inmunoenzimas , Células Asesinas Naturales/inmunología , Depleción Linfocítica , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Pronóstico , Factores de Riesgo , Tasa de Supervivencia , Linfocitos T/inmunología , Donantes de Tejidos , Trasplante Homólogo , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
Non-communicable diseases (NCD) are a major and increasing contributor to morbidity and mortality in developed and developing countries. Much of the chronic disease burden is preventable through modification of lifestyle behaviours, and increased attention is being focused on identifying and implementing effective preventative health strategies. Nutrition has been identified as a major modifiable determinant of NCD. The recent merging of health economics and nutritional sciences to form the nascent discipline of nutrition economics aims to assess the impact of diet on health and disease prevention, and to evaluate options for changing dietary choices, while incorporating an understanding of the immediate impacts and downstream consequences. In short, nutrition economics allows for generation of policy-relevant evidence, and as such the discipline is a crucial partner in achieving better population nutritional status and improvements in public health and wellness. The objective of the present paper is to summarise presentations made at a satellite symposium held during the 11th European Nutrition Conference, 28 October 2011, where the role of nutrition and its potential to reduce the public health burden through alleviating undernutrition and nutrition deficiencies, promoting better-quality diets and incorporating a role for functional foods were discussed.
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Enfermedad Crónica/prevención & control , Dieta , Alimentos , Fenómenos Fisiológicos de la Nutrición/fisiología , Salud Pública/economía , Adulto , Niño , Preescolar , Países en Desarrollo , Femenino , Alimentos Funcionales , Costos de la Atención en Salud , Prioridades en Salud , Promoción de la Salud , Humanos , Lactante , Recién Nacido , Masculino , Desnutrición/economía , Trastornos Nutricionales/economía , Ciencias de la Nutrición , Estado Nutricional , EmbarazoRESUMEN
BACKGROUND: Recently, the dual-energy X-ray absorptiometry (DXA) diagnostic cut-off (T-score) for Australian Pharmaceutical Benefits Scheme (PBS) supported primary fracture prevention therapy with alendronate for older women (>70 years) has been changed from -3.0 to -2.5. AIM: To examine the impact of the expanded criteria for PBS-supported fracture prevention therapy in older women on case finding and cost. METHODS: One thousand, nine hundred and eighty-three women, median age 76 years, not previously known to have low bone mineral density by DXA or a vertebral fracture underwent DXA scanning and a thoracolumbar X-ray. A woman was considered eligible for fracture prevention therapy if she had a T-score ≤-2.5 at the femoral neck and/or the lumbar vertebrae (two to four) or at least one vertebral fracture of ≥20% deformity. RESULTS: Seven hundred and forty-six women (37.6%) met the new criteria as a case for PBS-subsidised fracture prevention therapy. Four hundred and thirty-one (21.7%) had a T-score ≤-2.5 on DXA compared with 10.6% (n = 210) with a T-score ≤-3.0. Four hundred and eighty-three (24.4%) had at least one vertebral fracture. Only 8.5% (n = 168) had both a T-score ≤-2.5 and a prevalent vertebral fracture. The cost per case found by DXA equated to $460 compared with $398 for screening by thoracolumbar X-ray. CONCLUSIONS: The use of either DXA or X-ray will identify approximately two-thirds of women aged 70 years and over who would be eligible for fracture prevention. The use of X-ray would identify a marginally larger number of women and at lower financial cost but involve substantially greater radiation exposure.
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Densidad Ósea , Fracturas Espontáneas/prevención & control , Vértebras Lumbares/diagnóstico por imagen , Osteoporosis Posmenopáusica/diagnóstico por imagen , Atención Primaria de Salud/métodos , Fracturas de la Columna Vertebral/prevención & control , Vértebras Torácicas/diagnóstico por imagen , Absorciometría de Fotón/economía , Anciano , Anciano de 80 o más Años , Alendronato/uso terapéutico , Australia/epidemiología , Conservadores de la Densidad Ósea/uso terapéutico , Femenino , Fracturas del Cuello Femoral/prevención & control , Cuello Femoral/diagnóstico por imagen , Fracturas Espontáneas/diagnóstico por imagen , Fracturas Espontáneas/economía , Fracturas Espontáneas/etiología , Humanos , Vértebras Lumbares/lesiones , Tamizaje Masivo , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoporosis Posmenopáusica/economía , Osteoporosis Posmenopáusica/epidemiología , Dosis de Radiación , Medición de Riesgo , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/economía , Fracturas de la Columna Vertebral/etiología , Vértebras Torácicas/lesionesAsunto(s)
Alérgenos/inmunología , Hipersensibilidad a los Alimentos/diagnóstico , Alimentos/efectos adversos , Alérgenos/administración & dosificación , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Modelos Inmunológicos , Sensibilidad y Especificidad , Pruebas CutáneasRESUMEN
Improving health through better nutrition of the population may contribute to enhanced efficiency and sustainability of healthcare systems. A recent expert meeting investigated in detail a number of methodological aspects related to the discipline of nutrition economics. The role of nutrition in health maintenance and in the prevention of non-communicable diseases is now generally recognised. However, the main scope of those seeking to contain healthcare expenditures tends to focus on the management of existing chronic diseases. Identifying additional relevant dimensions to measure and the context of use will become increasingly important in selecting and developing outcome measurements for nutrition interventions. The translation of nutrition-related research data into public health guidance raises the challenging issue of carrying out more pragmatic trials in many areas where these would generate the most useful evidence for health policy decision-making. Nutrition exemplifies all the types of interventions and policy which need evaluating across the health field. There is a need to start actively engaging key stakeholders in order to collect data and to widen health technology assessment approaches for achieving a policy shift from evidence-based medicine to evidence-based decision-making in the field of nutrition.
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Ensayos Clínicos como Asunto/economía , Dieta/economía , Trastornos Nutricionales/prevención & control , Tecnología Biomédica/economía , Costos y Análisis de Costo/métodos , Medicina Basada en la Evidencia/economía , Humanos , Trastornos Nutricionales/economía , Política NutricionalRESUMEN
Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 µmol/L vs. 78.5 ± 10.0 µmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplant-related thrombotic and inflammatory injury, without detrimental effects in the donor animal.
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Antígenos CD/metabolismo , Endotelio Vascular/metabolismo , Glicoproteínas/metabolismo , Modelos Animales , Receptores de Superficie Celular/metabolismo , Animales , Receptor de Proteína C Endotelial , Citometría de Flujo , Humanos , Inmunohistoquímica , Ratones , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Daño por Reperfusión/prevención & controlRESUMEN
The vascular ectonucleotidases CD39[ENTPD1 (ectonucleoside triphosphate diphosphohydrolase-1), EC 3.6.1.5] and CD73[EC 3.1.3.5] generate adenosine from extracellular nucleotides. CD39 activity is critical in determining the response to ischemia-reperfusion injury (IRI), and CD39 null mice exhibit heightened sensitivity to renal IRI. Adenosine has multiple mechanisms of action in the vasculature including direct endothelial protection, antiinflammatory and antithrombotic effects and is protective in several models of IRI. Mice transgenic for human CD39 (hCD39) have increased capacity to generate adenosine. We therefore hypothesized that hCD39 transgenic mice would be protected from renal IRI. The overexpression of hCD39 conferred protection in a model of warm renal IRI, with reduced histological injury, less apoptosis and preserved serum creatinine and urea levels. Benefit was abrogated by pretreatment with an adenosine A2A receptor antagonist. Adoptive transfer experiments showed that expression of hCD39 on either the vasculature or circulating cells mitigated IRI. Furthermore, hCD39 transgenic kidneys transplanted into syngeneic recipients after prolonged cold storage performed significantly better and exhibited less histological injury than wild-type control grafts. Thus, systemic or local strategies to promote adenosine generation and signaling may have beneficial effects on warm and cold renal IRI, with implications for therapeutic application in clinical renal transplantation.
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Antígenos CD/biosíntesis , Apirasa/biosíntesis , Daño por Reperfusión/prevención & control , Adenosina/metabolismo , Animales , Isquemia Fría , Humanos , Necrosis de la Corteza Renal/prevención & control , Ratones , Ratones Transgénicos , Modelos AnimalesRESUMEN
AIMS: Chronic disease management is increasingly informed by clinical practice guidelines (CPGs). However, their implementation requires not only knowledge of guideline content by clinicians and practice processes that support implementation, but also a health workforce with the capacity to deliver care consistent with CPGs. This has a health services planning as well as a health workforce dimension. However, it is not known whether CPGs are described in a way that can inform health services and health workforce planning and potentially drive better quality care. This study aimed to ascertain whether CPGs are useful for health service and health workforce planning. METHODS: This question was explored taking diabetes mellitus as a case study. A systematic search of Medline, EMBASE, CINAHL and Scopus was carried out to identify all CPGs relating to the management of diabetes mellitus in the primary healthcare setting. The search was limited to guidelines published in the English language between 2003 and 2009. The quality of guidelines was assessed against a subset of criteria set by the Appraisal of Guidelines for Research and Evaluation (AGREE) collaboration. RESULTS: Seventy-five diabetes-related CPGs were identified, of which 27 met the inclusion criteria. In terms of quality, many guidelines adopted evidence-based recommendations for diabetes care (59%) and most were endorsed by national authorities (70%). With regards to coverage of 17 identified subpopulations, guidelines were generally selective in the populations they covered. Whilst many provided adequate coverage of common complications and comorbidities, approaches to management for those with reduced capacity for effective diabetes self-care were largely absent, except for indigenous populations. CONCLUSIONS: Clinical practice guidelines are potentially useful for health services and health workforce planning, but would be more valuable for this purpose if they contained more detail about care protocols and specific skills and competencies, especially for subpopulations who would be expected to have reduced capacity for effective self-care. If service planning ignores these subgroups that tend to require more resource-intensive management, underprovision of services is likely.
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Atención a la Salud/organización & administración , Diabetes Mellitus/terapia , Planificación de Atención al Paciente , Admisión y Programación de Personal , Guías de Práctica Clínica como Asunto , Manejo de la Enfermedad , Medicina Basada en la Evidencia , Humanos , Calidad de la Atención de SaludRESUMEN
Thrombomodulin (TBM) is an important vascular anticoagulant that has species specific effects. When expressed as a transgene in pigs, human (h)TBM might abrogate thrombotic manifestations of acute vascular rejection (AVR) that occur when GalT-KO and/or complement regulator transgenic pig organs are transplanted to primates. hTBM transgenic mice were generated and characterized to determine whether this approach might show benefit without the development of deleterious hemorrhagic phenotypes. hTBM mice are viable and are not subject to spontaneous hemorrhage, although they have a prolonged bleeding time. They are resistant to intravenous collagen-induced pulmonary thromboembolism, stasis-induced venous thrombosis and pulmonary embolism. Cardiac grafts from hTBM mice to rats treated with cyclosporine in a model of AVR have prolonged survival compared to controls. hTBM reduced the inflammatory reaction in the vein wall in the stasis-induced thrombosis and mouse-to-rat xenograft models and reduced HMGB1 levels in LPS-treated mice. These results indicate that transgenic expression of hTBM has anticoagulant and antiinflammatory effects that are graft-protective in murine models.
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Antiinflamatorios/farmacología , Ciclosporina/farmacología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Ratas , Porcinos , Trombomodulina , Transgenes/efectos de los fármacosRESUMEN
The ability to mimic cell-matrix interactions in a way that closely resembles the natural environment is of a great importance for both basic neuroscience and for fabrication of potent scaffolding materials for nervous tissue engineering. Such scaffolding materials should not only facilitate cell attachment but also create a microenvironment that provides essential developmental and survival cues. We previously found that porous aragonite crystalline matrices of marine origin are an adequate and active biomaterial that promotes neural cell growth and tissue development. Here we studied the mechanism underlying these neural cell-material interactions, focusing on the three-dimensional (3D) surface architecture and matrix activity of these scaffolds. We introduced a new cloning technique of the hydrozoan Millepora dichotoma, through which calcein or (45)Ca(2+) were incorporated into the organism's growing skeleton and neuronal cells could then be cultured on the labelled matrices. Herein, we describe the role of matrix 3D architecture on neural cell type composition and survival in culture, and report for the first time on the capacity of neurons and astrocytes to exploit calcium ions from the supporting biomatrix. We found that hippocampal cells growing on the prelabelled aragonite lattice took up aragonite-derived Ca(2+), and even enhanced this uptake when extracellular calcium ions were chelated by EGTA. When the aragonite-derived Ca(2+) uptake was omitted by culturing the cells on coral skeletons coated with gold, cell survival was reduced but not arrested, suggesting a role for matrix architecture in neural survival. In addition, we found that the effects of scaffold architecture and chemistry on cell survival were more profound for neurons than for astrocytes. We submit that translocation of calcium from the biomaterial to the cells activates a variety of membrane-bound signalling molecules and leads to the subsequent cell behaviour. This kind of cell-material interaction possesses great potential for fabricating advanced biomaterials for neural tissue-engineering applications.