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1.
Sci Data ; 11(1): 884, 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39143096

RESUMEN

AI image classification algorithms have shown promising results when applied to skin cancer detection. Most public skin cancer image datasets are comprised of dermoscopic photos and are limited by selection bias, lack of standardization, and lend themselves to development of algorithms that can only be used by skilled clinicians. The SLICE-3D ("Skin Lesion Image Crops Extracted from 3D TBP") dataset described here addresses those concerns and contains images of over 400,000 distinct skin lesions from seven dermatologic centers from around the world. De-identified images were systematically extracted from sensitive 3D Total Body Photographs and are comparable in optical resolution to smartphone images. Algorithms trained on lower quality images could improve clinical workflows and detect skin cancers earlier if deployed in primary care or non-clinical settings, where photos are captured by non-expert physicians or patients. Such a tool could prompt individuals to visit a specialized dermatologist. This dataset circumvents many inherent limitations of prior datasets and may be used to build upon previous applications of skin imaging for cancer detection.


Asunto(s)
Neoplasias Cutáneas , Neoplasias Cutáneas/diagnóstico por imagen , Humanos , Algoritmos , Imagenología Tridimensional , Piel/diagnóstico por imagen
2.
Australas J Dermatol ; 65(5): 409-422, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38693690

RESUMEN

In recent years, there has been a surge in the development of AI-based Software as a Medical Device (SaMD), particularly in visual specialties such as dermatology. In Australia, the Therapeutic Goods Administration (TGA) regulates AI-based SaMD to ensure its safe use. Proper labelling of these devices is crucial to ensure that healthcare professionals and the general public understand how to use them and interpret results accurately. However, guidelines for labelling AI-based SaMD in dermatology are lacking, which may result in products failing to provide essential information about algorithm development and performance metrics. This review examines existing labelling guidelines for AI-based SaMD across visual medical specialties, with a specific focus on dermatology. Common recommendations for labelling are identified and applied to currently available dermatology AI-based SaMD mobile applications to determine usage of these labels. Of the 21 AI-based SaMD mobile applications identified, none fully comply with common labelling recommendations. Results highlight the need for standardized labelling guidelines. Ensuring transparency and accessibility of information is essential for the safe integration of AI into health care and preventing potential risks associated with inaccurate clinical decisions.


Asunto(s)
Dermatología , Aplicaciones Móviles , Etiquetado de Productos , Australia , Humanos , Aplicaciones Móviles/normas , Etiquetado de Productos/normas , Inteligencia Artificial , Guías como Asunto , Programas Informáticos
3.
J Thromb Haemost ; 22(8): 2331-2344, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38754782

RESUMEN

BACKGROUND: Ischemic stroke is characterized by a necrotic lesion in the brain surrounded by an area of dying cells termed the penumbra. Salvaging the penumbra either with thrombolysis or mechanical retrieval is the cornerstone of stroke management. At-risk neuronal cells release extracellular adenosine triphosphate, triggering microglial activation and causing a thromboinflammatory response, culminating in endothelial activation and vascular disruption. This is further aggravated by ischemia-reperfusion injury that follows all reperfusion therapies. The ecto-enzyme CD39 regulates extracellular adenosine triphosphate by hydrolyzing it to adenosine, which has antithrombotic and anti-inflammatory properties and reverses ischemia-reperfusion injury. OBJECTIVES: The objective off the study was to determine the efficacy of our therapeutic, anti-VCAM-CD39 in ischaemic stroke. METHODS: We developed anti-VCAM-CD39 that targets the antithrombotic and anti-inflammatory properties of recombinant CD39 to the activated endothelium of the penumbra by binding to vascular cell adhesion molecule (VCAM)-1. Mice were subjected to 30 minutes of middle cerebral artery occlusion and analyzed at 24 hours. Anti-VCAM-CD39 or control agents (saline, nontargeted CD39, or anti-VCAM-inactive CD39) were given at 3 hours after middle cerebral artery occlusion. RESULTS: Anti-VCAM-CD39 treatment reduced neurologic deficit; magnetic resonance imaging confirmed significantly smaller infarcts together with an increase in cerebrovascular perfusion. Anti-VCAM-CD39 also restored blood-brain barrier integrity and reduced microglial activation. Coadministration of anti-VCAM-CD39 with thrombolytics (tissue plasminogen activator [tPA]) further reduced infarct volumes and attenuated blood-brain barrier permeability with no associated increase in intracranial hemorrhage. CONCLUSION: Anti-VCAM-CD39, uniquely targeted to endothelial cells, could be a new stroke therapy even when administered 3 hours postischemia and may further synergize with thrombolytic therapy to improve stroke outcomes.


Asunto(s)
Antígenos CD , Apirasa , Barrera Hematoencefálica , Infarto de la Arteria Cerebral Media , Accidente Cerebrovascular Isquémico , Molécula 1 de Adhesión Celular Vascular , Animales , Humanos , Masculino , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antígenos CD/metabolismo , Apirasa/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Fibrinolíticos/uso terapéutico , Fibrinolíticos/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Ratones Endogámicos C57BL , Proteínas Recombinantes/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo
4.
Australas J Dermatol ; 65(3): e21-e29, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38419186

RESUMEN

BACKGROUND/OBJECTIVES: Artificial intelligence (AI) holds remarkable potential to improve care delivery in dermatology. End users (health professionals and general public) of AI-based Software as Medical Devices (SaMD) require relevant labelling information to ensure that these devices can be used appropriately. Currently, there are no clear minimum labelling requirements for dermatology AI-based SaMDs. METHODS: Common labelling recommendations for AI-based SaMD identified in a recent literature review were evaluated by an Australian expert panel in digital health and dermatology via a modified Delphi consensus process. A nine-point Likert scale was used to indicate importance of 10 items, and voting was conducted to determine the specific characteristics to include for some items. Consensus was achieved when more than 75% of the experts agreed that inclusion of information was necessary. RESULTS: There was robust consensus supporting inclusion of all proposed items as minimum labelling requirements; indication for use, intended user, training and test data sets, algorithm design, image processing techniques, clinical validation, performance metrics, limitations, updates and adverse events. Nearly all suggested characteristics of the labelling items received endorsement, except for some characteristics related to performance metrics. Moreover, there was consensus that uniform labelling criteria should apply across all AI categories and risk classes set out by the Therapeutic Goods Administration. CONCLUSIONS: This study provides critical evidence for setting labelling standards by the Therapeutic Goods Administration to safeguard patients, health professionals, consumers, industry, and regulatory bodies from AI-based dermatology SaMDs that do not currently provide adequate information about how they were developed and tested.


Asunto(s)
Inteligencia Artificial , Consenso , Dermatología , Etiquetado de Productos , Programas Informáticos , Humanos , Dermatología/normas , Etiquetado de Productos/normas , Técnica Delphi , Australia
5.
BMJ Open ; 13(9): e072788, 2023 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-37770274

RESUMEN

INTRODUCTION: Three-dimensional (3D) total body photography may improve early detection of melanoma and facilitate surveillance, leading to better prognosis and lower healthcare costs. The Australian Centre of Excellence in Melanoma Imaging and Diagnosis (ACEMID) cohort study will assess long-term outcomes from delivery of a precision strategy of monitoring skin lesions using skin surface imaging technology embedded into health services across Australia. METHODS AND ANALYSIS: A prospective cohort study will enrol 15 000 participants aged 18 years and above, across 15 Australian sites. Participants will attend study visits according to their melanoma risk category: very high risk, high risk or low/average risk, every 6, 12 and 24 months, respectively, over 3 years. Participants will undergo 3D total body photography and dermoscopy imaging at study visits. A baseline questionnaire will be administered to collect sociodemographic, phenotypic, quality of life and sun behaviour data. A follow-up questionnaire will be administered every 12 months to obtain changes in sun behaviour and quality of life. A saliva sample will be collected at the baseline visit from a subsample. ETHICS AND DISSEMINATION: The ACEMID cohort study was approved by the Metro South Health Human Research Ethics Committee (approval number: HREC/2019/QMS/57206) and the University of Queensland Human Research Ethics Committee (approval number: 2019003077). The findings will be reported through peer-reviewed and lay publications and presentations at conferences. TRIAL REGISTRATION NUMBER: ACTRN12619001706167.


Asunto(s)
Melanoma , Calidad de Vida , Humanos , Estudios de Cohortes , Australia/epidemiología , Estudios Prospectivos , Melanoma/diagnóstico por imagen , Fotograbar
6.
Purinergic Signal ; 18(4): 409-419, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35947229

RESUMEN

Pulmonary arterial hypertension (PAH) is a devastating progressive disease characterised by pulmonary arterial vasoconstriction and vascular remodelling. Endothelial dysfunction has emerged as a contributing factor in the development of PAH. However, despite progress in the understanding of the pathophysiology of this disease, current therapies fail to impact upon long-term outcomes which remain poor in most patients. Recent observations have suggested the disturbances in the balance between ATP and adenosine may be integral to the vascular remodelling seen in PAH. CD39 is an enzyme important in regulating these nucleos(t)ides which may also provide a novel pathway to target for future therapies. This review summarises the role of adenosine signalling in the development and progression of PAH and highlights the therapeutic potential of CD39 for treatment of PAH.


Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Remodelación Vascular , Adenosina/uso terapéutico , Inmunosupresores
7.
Blood Adv ; 6(18): 5505-5515, 2022 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-35580335

RESUMEN

Hemophilic arthropathy (HA) is characterized by joint damage following recurrent joint bleeds frequently observed in patients affected by the clotting disorder hemophilia. Joint bleeds or hemarthroses trigger inflammation in the synovial tissue, which promotes damage to the articular cartilage. The plasminogen activation system is integral to fibrinolysis, and the urokinase plasminogen activator, or uPA in particular, is strongly upregulated following hemarthroses. uPA is a serine protease that catalyzes the production of plasmin, a broad-spectrum protease that can degrade fibrin as well as proteins of the joint extracellular matrix and cartilage. Both uPA and plasmin are able to proteolytically generate active forms of matrix metalloproteinases (MMPs). The MMPs are a family of >20 proteases that are secreted as inactive proenzymes and are activated extracellularly. MMPs are involved in the degradation of all types of collagen and proteoglycans that constitute the extracellular matrix, which provides structural support to articular cartilage. The MMPs have an established role in joint destruction following rheumatoid arthritis (RA). They degrade cartilage and bone, indirectly promoting angiogenesis. MMPs are also implicated in the pathology of osteoarthritis (OA), characterized by degradation of the cartilage matrix that precipitates joint damage and deformity. HA shares a number of overlapping pathological characteristics with RA and OA. Here we discuss how the plasminogen activation system and MMPs might exacerbate joint damage in HA, lending insight into novel possible therapeutic targets to reduce the comorbidity of hemophilia.


Asunto(s)
Artritis Reumatoide , Hemofilia A , Osteoartritis , Artritis Reumatoide/metabolismo , Colágeno , Precursores Enzimáticos , Fibrina , Fibrinolisina , Hemartrosis , Hemofilia A/complicaciones , Humanos , Metaloproteinasas de la Matriz/metabolismo , Péptido Hidrolasas , Plasminógeno , Proteoglicanos , Activador de Plasminógeno de Tipo Uroquinasa
8.
Biomolecules ; 11(7)2021 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-34356618

RESUMEN

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood-brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.


Asunto(s)
Adenosina Trifosfato/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Endotelio Vascular/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Transducción de Señal , Trombosis/metabolismo , Animales , Enfermedades de los Pequeños Vasos Cerebrales/patología , Endotelio Vascular/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Accidente Cerebrovascular Isquémico/patología , Trombosis/patología
9.
Front Immunol ; 12: 708554, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34421913

RESUMEN

Allogenic hematopoietic stem cell transplant (allo-HSCT) can lead to sinusoidal obstruction syndrome (SOS) and graft-versus-host disease (GvHD) in some individuals. GvHD is characterised by an immune triggered response that arises due to donor T cells recognizing the recipient tissue as "foreign". SOS results in impaired liver function due to microvascular thrombosis and consequent obstruction of liver sinusoids. Endothelial damage occurs following chemotherapy and allo-HSCT and is strongly associated with GvHD onset as well as hepatic SOS. Animal models of GvHD are rarely clinically relevant, and endothelial dysfunction remains uncharacterised. Here we established and characterised a clinically relevant model of GvHD wherein Balb/C mice were subjected to myeloablative chemotherapy followed by transplantation of bone marrow (BM) cells± splenic T-cells from C57Bl6 mice, resulting in a mismatch of major histocompatibility complexes (MHC). Onset of disease indicated by weight loss and apoptosis in the liver and intestine was discovered at day 6 post-transplant in mice receiving BM+T-cells, with established GvHD detectable by histology of the liver within 3 weeks. Together with significant increases in pro-inflammatory cytokine gene expression in the liver and intestine, histopathological signs of GvHD and a significant increase in CD4+ and CD8+ effector and memory T-cells were seen. Endothelial activation including upregulation of vascular cell adhesion molecule (VCAM)- 1 and downregulation of endothelial nitric oxide synthase (eNOS) as well as thrombosis in the liver indicated concomitant hepatic SOS. Our findings confirm that endothelial activation is an early sign of acute GvHD and SOS in a clinically relevant mouse model of GvHD based on myeloablative chemotherapy. Preventing endothelial activation may be a viable therapeutic strategy to prevent GvHD.


Asunto(s)
Células Endoteliales/metabolismo , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfocitos T/trasplante , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Agonistas Mieloablativos/toxicidad , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos
10.
Stroke ; 52(5): 1895-1904, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33794655

RESUMEN

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.


Asunto(s)
Isquemia Encefálica/complicaciones , Encéfalo/fisiopatología , COVID-19/complicaciones , Células Endoteliales/citología , Accidente Cerebrovascular Isquémico/complicaciones , Enzima Convertidora de Angiotensina 2/metabolismo , Coagulación Sanguínea , Isquemia Encefálica/fisiopatología , COVID-19/fisiopatología , Citocinas/metabolismo , Fibrina/química , Productos de Degradación de Fibrina-Fibrinógeno/química , Hemostasis , Humanos , Hipoxia , Incidencia , Inflamación , Accidente Cerebrovascular Isquémico/fisiopatología , Infarto del Miocardio/fisiopatología , Pandemias , Pronóstico
11.
Sci Rep ; 10(1): 18170, 2020 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-33097782

RESUMEN

Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia-reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood-brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.


Asunto(s)
Circulación Cerebrovascular/fisiología , Accidente Cerebrovascular Hemorrágico/patología , Accidente Cerebrovascular Isquémico/patología , Prosencéfalo/irrigación sanguínea , Daño por Reperfusión/patología , Animales , Antiinflamatorios/uso terapéutico , Apoptosis/inmunología , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Arterias Carótidas/fisiopatología , Circulación Cerebrovascular/efectos de los fármacos , Colagenasas/administración & dosificación , Colagenasas/efectos adversos , Citocinas/genética , Citocinas/inmunología , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Accidente Cerebrovascular Hemorrágico/tratamiento farmacológico , Accidente Cerebrovascular Hemorrágico/inmunología , Accidente Cerebrovascular Hemorrágico/fisiopatología , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/inmunología , Accidente Cerebrovascular Isquémico/fisiopatología , Ligadura , Locomoción/fisiología , Imagen por Resonancia Magnética , Masculino , Ratones , Arteria Cerebral Media/fisiopatología , Prosencéfalo/diagnóstico por imagen , Prosencéfalo/efectos de los fármacos , Prosencéfalo/patología , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/inmunología , Daño por Reperfusión/fisiopatología , Receptores Toll-Like/genética , Activación Transcripcional/inmunología
12.
J Thromb Haemost ; 18(10): 2658-2671, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32668057

RESUMEN

BACKGROUND: Tranexamic acid (TXA) is an anti-fibrinolytic agent used to reduce bleeding in various conditions including traumatic brain injury (TBI). As the fibrinolytic system also influences the central nervous system and the immune response, TXA may also modulate these parameters following TBI. OBJECTIVES: To determine the effect of TXA on blood-brain barrier (BBB) integrity and changes in immune and motor function in male and female mice subjected to TBI. METHODS: Wild-type and plasminogen deficient (plg-/-) mice were subjected to TBI then administered either TXA/vehicle. The degree of BBB breakdown, intracerebral hemorrhage (ICH), motor dysfunction, and changes in inflammatory subsets in blood and brain were determined. RESULTS AND CONCLUSIONS: Tranexamic acid significantly reduced BBB breakdown, and increased blood neutrophils in male mice 3 hours post-TBI. In contrast, TXA treatment of female mice increased BBB permeability and ICH but had no effect on blood neutrophils at the same time-point. TXA improved motor function in male mice but still increased BBB breakdown in female mice 24 hours post-TBI. Brain urokinase-type plasminogen activator (u-PA) antigen and activity levels were significantly higher in injured females compared to males. Because TXA can promote a pro-fibrinolytic effect via u-PA, these sex differences may be related to brain u-PA levels. TXA also increased monocyte subsets and dendritic cells in the injured brain of wild-type male mice 1 week post-TBI. Plg-/- mice of both sexes had reduced BBB damage and were protected from TBI irrespective of treatment indicating that TXA modulation of the BBB is plasmin-dependent. In conclusion, TXA is protective post-TBI but only in male mice.


Asunto(s)
Antifibrinolíticos , Lesiones Traumáticas del Encéfalo , Ácido Tranexámico , Animales , Antifibrinolíticos/farmacología , Barrera Hematoencefálica , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Femenino , Inmunidad , Masculino , Ratones , Permeabilidad , Ácido Tranexámico/farmacología
13.
Cell Rep ; 29(5): 1178-1191.e6, 2019 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-31665632

RESUMEN

Traumatic brain injury (TBI) leaves many survivors with long-term disabilities. A prolonged immune response in the brain may cause neurodegeneration, resulting in chronic neurological disturbances. In this study, using a TBI mouse model, we correlate changes in the local immune response with neurodegeneration/neurological dysfunction over an 8-month period. Flow cytometric analysis reveals a protracted increase in effector/memory CD8+ T cells (expressing granzyme B) in the injured brain. This precedes interleukin-17+CD4+ T cell infiltration and is associated with progressive neurological/motor impairment, increased circulating brain-specific autoantibodies, and myelin-related pathology. Genetic deficiency or pharmacological depletion of CD8+ T cells, but not depletion of CD4+ T cells, improves neurological outcomes and produces a neuroprotective Th2/Th17 immunological shift, indicating a persistent detrimental role for cytotoxic T cells post-TBI. B cell deficiency results in severe neurological dysfunction and a heightened immune reaction. Targeting these adaptive immune cells offers a promising approach to improve recovery following TBI.


Asunto(s)
Lesiones Traumáticas del Encéfalo/inmunología , Encéfalo/patología , Linfocitos T CD8-positivos/inmunología , Activación de Linfocitos/inmunología , Inmunidad Adaptativa , Animales , Autoanticuerpos/sangre , Linfocitos B/inmunología , Conducta Animal , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/fisiopatología , Linfocitos T CD4-Positivos/inmunología , ADN/inmunología , Marcha , Memoria Inmunológica , Depleción Linfocítica , Masculino , Ratones Endogámicos C57BL , Vaina de Mielina/inmunología , Médula Espinal/patología , Células Th17/inmunología , Factores de Tiempo , Microglobulina beta-2/deficiencia , Microglobulina beta-2/metabolismo
14.
J Thromb Haemost ; 17(12): 2174-2187, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31393041

RESUMEN

BACKGROUND: Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. OBJECTIVE: To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild-type and plasminogen-deficient (plg-/- ) mice subjected to TBI. METHODS: Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme-linked Immunosorbent Spot (ELISpot) assay.  Fibrinolysis was determined by thromboelastography and measuring D-dimer and plasmin-antiplasmin complex levels. RESULTS: Plg-/-  mice, but not plg+/+  mice displayed increases in both the number and activation of various antigen-presenting cells and T cells in the cLN 1 week post TBI. Wild-type mice treated with TXA also displayed increased cellularity of the cLN 1 week post TBI together with increases in innate and adaptive immune cells. These changes occurred despite the absence of systemic hyperfibrinolysis or coagulopathy in this model of TBI. Importantly, neither plg deficiency nor TXA treatment enhanced the autoreactivity within the CNS. CONCLUSION: In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen-presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.


Asunto(s)
Antifibrinolíticos/farmacología , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Fibrinólisis/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Leucocitos/efectos de los fármacos , Ganglios Linfáticos/efectos de los fármacos , Ácido Tranexámico/farmacología , Animales , Encéfalo/inmunología , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/inmunología , Lesiones Traumáticas del Encéfalo/patología , Proliferación Celular/efectos de los fármacos , Quimiotaxis de Leucocito/efectos de los fármacos , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Leucocitos/inmunología , Ganglios Linfáticos/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Plasminógeno/deficiencia , Plasminógeno/genética
15.
J Neurotrauma ; 36(23): 3297-3308, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31140372

RESUMEN

The antifibrinolytic agent, tranexamic acid (TXA), an inhibitor of plasmin formation, currently is evaluated to reduce bleeding in various conditions, including traumatic brain injury (TBI). Because plasmin is implicated in inflammation and immunity, we investigated the effects of plasmin inhibition on the immune response after TBI in the presence or absence of induced pneumonia. Wild-type mice treated with vehicle or TXA or mice deficient in plasminogen (plg-/-) underwent TBI using the controlled cortical impact model. Mice were then subjected to Staphylococcus aureus induced pneumonia and the degree of immune competence determined. Significant baseline changes in the innate immune cell profile were seen in plg-/- mice with increases in spleen weight and white blood cell counts, and elevation in plasma interleukin-6 levels. The plg-/- mice subjected to TBI displayed no additional changes in these parameters at the 72 h or one week time point post-TBI. The plg-/- mice subjected to TBI did not exhibit any further increase in susceptibility to endogenous infection. Pneumonia was induced by intratracheal instillation of S. aureus. The TBI did not worsen pneumonia symptoms or delay recovery in plg-/- mice. Similarly, in wild type mice, treatment with TXA did not impact on the ability of mice to counteract pneumonia after TBI. Administration of TXA after TBI and subsequent pneumonia, however, altered the number and surface marker expression of several myeloid and lymphoid cell populations, consistent with enhanced immune activation at the 72 h time point. This investigation confirms the immune-modulatory properties of TXA, thereby highlighting its effects unrelated to inhibition of fibrinolysis.


Asunto(s)
Lesiones Traumáticas del Encéfalo/inmunología , Inmunidad Celular/inmunología , Depuración Mucociliar/inmunología , Neumonía Bacteriana/inmunología , Infecciones Estafilocócicas/inmunología , Ácido Tranexámico/uso terapéutico , Animales , Antifibrinolíticos/farmacología , Antifibrinolíticos/uso terapéutico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Inmunidad Celular/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Depuración Mucociliar/efectos de los fármacos , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/metabolismo , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus , Ácido Tranexámico/farmacología
16.
Blood Adv ; 3(10): 1598-1609, 2019 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-31126915

RESUMEN

Tranexamic acid (TXA) is an antifibrinolytic agent that blocks plasmin formation. Because plasmin is known to promote inflammatory and immunosuppressive responses, we explored the possibility that plasmin-mediated immunosuppression in patients undergoing cardiac surgery can be directly reversed by TXA and decrease postoperative infection rates. The modulatory effect of TXA on inflammatory cytokine levels and on innate immune cell activation were evaluated with multiplex enzyme-linked immunosorbent assay and flow cytometry, respectively. Postoperative infection rates were determined in patients undergoing cardiac surgery and randomized to TXA (ACTRN12605000557639; http://www.anzca.edu.au). We demonstrate that TXA-mediated plasmin blockade modulates the immune system and reduces surgery-induced immunosuppression in patients following cardiac surgery. TXA enhanced the expression of immune-activating markers while reducing the expression of immunosuppressive markers on multiple myeloid and lymphoid cell populations in peripheral blood. TXA administration significantly reduced postoperative infection rates, despite the fact that patients were being administered prophylactic antibiotics. This effect was independent of the effect of TXA at reducing blood loss. TXA was also shown to exert an immune-modulatory effect in healthy volunteers, further supporting the fibrin-independent effect of TXA on immune function and indicating that baseline plasmin levels contribute to the regulation of the immune system in the absence of any comorbidity or surgical trauma. Finally, the capacity of TXA to reduce infection rates, modulate the innate immune cell profile, and generate an antifibrinolytic effect overall was markedly reduced in patients with diabetes, demonstrating for the first time that the diabetic condition renders patients partially refractory to TXA.


Asunto(s)
Antifibrinolíticos/uso terapéutico , Transmisión de Enfermedad Infecciosa/estadística & datos numéricos , Ácido Tranexámico/uso terapéutico , Adulto , Antifibrinolíticos/farmacología , Humanos , Periodo Posoperatorio , Estudios Prospectivos , Ácido Tranexámico/farmacología , Voluntarios
17.
Res Pract Thromb Haemost ; 3(2): 197-206, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31011704

RESUMEN

BACKGROUND: Arterial thrombosis models are important for preclinical evaluation of antithrombotics but how anesthetic protocol can influence experimental results is not studied. OBJECTIVES: We studied how three most commonly used rodent anesthetics affect the induction of thrombosis and thrombus resolution with antiplatelet agent integrilin (Eptifibatide). METHODS: The Folts, electrolytic, and FeCl3 models of carotid artery thrombosis were evaluated. The extent of blood flow reduction required to elicit cyclic flow reductions (CFR) was examined in the Folts model. The occlusion time and stability following electrolytic or FeCl3 injury was assessed. The efficacy of Eptifibatide was studied in each cohort and clot composition following FeCl3 application was assessed histologically. RESULTS: Isoflurane and ketamine-xylazine (ket-x) elicited higher basal blood flow velocities. For reliable CFR in the Folts model, a higher degree of blood flow reduction was required under ket-x and isoflurane. For the FeCl3 and electrolytic models, injury severity had to be increased in mice under ket-x anesthesia to achieve rapid occlusion. FeCl3-injured artery sections from ket-x and isoflurane-treated mice showed vessel dilatation and clots that were more fibrin/red-cell rich compared to pentobarbitone. Integrilin led to cycle abolishment for all three Folts-injury cohorts but for the electrolytic model a 2.5-fold higher dose was required to restore blood flow under pentobarbitone. Integrilin after FeCl3 arterial injury was partially ineffective in isoflurane-treated mice. CONCLUSIONS: Anesthesia impacts rodent carotid artery occlusion experiments and alters integrilin efficacy. It is important to consider anesthetic protocols in animal experiments involving pharmacological agents for treatment of atherothrombosis.

18.
J Neurotrauma ; 2018 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-29901412

RESUMEN

Initial studies have found some evidence for transactive response DNA-binding protein 43 (TDP-43) abnormalities after traumatic brain injury (TBI), and the presence of protein inclusions consisting of TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis (ALS), a condition associated with TBI. However, no study has characterized changes in TDP-43 phosphorylation, mislocalization, and fragmentation (i.e., abnormalities linked to hallmark TDP-43 pathology) after TBI, and how these relate to functional outcomes. Further, how TBI affects an individual with a known predisposition to TDP-43 pathology is unknown. Therefore, this study examined the effects of TBI on TDP-43 post-translational processing, localization, and behavioral outcomes in wild-type (WT) mice and mutant TDP-43A315T mice (i.e., mice predisposed to TDP-43 pathology) at 24 h and 1 week after TBI. Post-mortem brain tissue from human patients with acute TBI was also examined. Western blots found that WT mice given TBI had increased TDP-43 phosphorylation, mislocalization, and fragmentation compared with sham-injured WT mice. The TDP-43A315T mice given a TBI had exacerbated TDP-43 abnormalities, worse cell death, and cognitive deficits compared with all other groups. In the human TBI patients, the only significant finding was increased nuclear accumulation of phosphorylated TDP-43 fragments. The discrepancy between the robust mouse findings and the largely non-significant human findings may be due to factors including heterogeneity in clinical TBI, the small group sizes, and temporal complexities with TDP-43 abnormalities. These findings indicate that TBI can induce a number of TDP-43 abnormalities that may contribute to the neurological consequences of TBI, though further research is still needed.

19.
J Autoimmun ; 88: 131-138, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29103803

RESUMEN

OBJECTIVE: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preeclampsia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS. METHODS: We studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity. RESULTS: aPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression. CONCLUSION: We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.


Asunto(s)
Aborto Espontáneo/inmunología , Anticuerpos Antifosfolípidos/metabolismo , Antígenos CD/metabolismo , Síndrome Antifosfolípido/inmunología , Apirasa/metabolismo , Complicaciones del Embarazo/inmunología , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , Adulto , Animales , Antígenos CD/genética , Apirasa/genética , Complemento C3d/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunización Pasiva , Inflamación , Mediadores de Inflamación/metabolismo , Peroxidación de Lípido , Ratones , Ratones Noqueados , Ratones Transgénicos , Embarazo , Tromboplastina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
20.
Purinergic Signal ; 13(2): 259-265, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28343356

RESUMEN

Kidney ischemia-reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress. We designed a P-selectin targeted CD39 molecule (rsol.CD39-PSGL-1) consisting of recombinant soluble CD39 that incorporates 20 residues of PSGL-1 that bind P-selectin. We hypothesised that rsol.CD39-PSGL-1 would maintain endothelial integrity by focusing the ectonucleotidase platelet-inhibitory activity and reducing leukocyte adhesion at the injury site. The rsol.CD39-PSGL-1 displayed ADPase activity and inhibited platelet aggregation ex vivo, as well as bound with high specificity to soluble P-selectin and platelet surface P-selectin. Importantly, mice injected with rsol.CD39-PSGL-1 and subjected to renal IRI showed significantly less kidney damage both biochemically and histologically, compared to those injected with solCD39. Furthermore, the equivalent dose of rsol.CD39-PSGL-1 had no effect on tail template bleeding times. Hence, targeting recombinant CD39 to the injured vessel wall via PSGL-1 binding resulted in substantial preservation of renal function and morphology after IRI without toxicity. These studies indicate potential translational importance to clinical transplantation and nephrology.


Asunto(s)
Antígenos CD/farmacología , Apirasa/farmacología , Endotelio Vascular/efectos de los fármacos , Fibrinolíticos/farmacología , Riñón/efectos de los fármacos , Daño por Reperfusión , Animales , Plaquetas/efectos de los fármacos , Microambiente Celular/fisiología , Humanos , Riñón/irrigación sanguínea , Glicoproteínas de Membrana/farmacología , Ratones , Agregación Plaquetaria/efectos de los fármacos , Proteínas Recombinantes/farmacología
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