RESUMO
Neurons in the primary visual cortex respond selectively to simple features of visual stimuli, such as orientation and spatial frequency. Simple cells, which have phase-sensitive responses, can be modeled by a single receptive field filter in a linear-nonlinear model. However, it is challenging to analyze phase-invariant complex cells, which require more elaborate models having a combination of nonlinear subunits. Estimating parameters of these models is made additionally more difficult by cortical neurons' trial-to-trial response variability. We develop a simple convolutional neural network method to estimate receptive field models for both simple and complex visual cortex cells from their responses to natural images. The model consists of a spatiotemporal filter, a parameterized rectifier unit (PReLU), and a two-dimensional Gaussian "map" of the receptive field envelope. A single model parameter determines the simple vs. complex nature of the receptive field, capturing complex cell responses as a summation of homogeneous subunits, and collapsing to a linear-nonlinear model for simple type cells. The convolutional method predicts simple and complex cell responses to natural image stimuli as well as grating tuning curves. The fitted models yield a continuum of values for the PReLU parameter across the sampled neurons, showing that the simple/complex nature of cells can vary in a continuous manner. We demonstrate that complex-like cells respond less reliably than simple-like cells. However, compensation for this unreliability with noise ceiling analysis reveals predictive performance for complex cells proportionately closer to that for simple cells. Most spatial receptive field structures are well fit by Gabor functions, whose parameters confirm well-known properties of cat A17/18 receptive fields.
Assuntos
Biologia Computacional , Modelos Neurológicos , Redes Neurais de Computação , Neurônios , Córtex Visual , Animais , Neurônios/fisiologia , Córtex Visual/fisiologia , Córtex Visual/citologia , Biologia Computacional/métodos , Estimulação Luminosa , Campos Visuais/fisiologia , Gatos , Córtex Visual Primário/fisiologiaRESUMO
INTRODUCTION: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level. AIM: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency. METHODS: Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT). RESULTS: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤ 4.9 $ \le 4.9$ , AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR. CONCLUSION: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment.
Assuntos
Hemofilia A , Hemofilia B , Hemorragia , Lipoproteínas , Trombina , Humanos , Hemofilia A/complicações , Hemofilia A/sangue , Trombina/metabolismo , Hemofilia B/complicações , Hemofilia B/sangue , Hemorragia/etiologia , Hemorragia/sangue , Masculino , Lipoproteínas/sangue , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Adolescente , Estudos Retrospectivos , Feminino , Criança , Índice de Gravidade de Doença , Pré-Escolar , IdosoRESUMO
Excess soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble inhibitor of vascular endothelial growth factor pathway, has been demonstrated to promote endothelial dysfunction. Here, we demonstrate that sFlt-1 plasma levels correlate with respiratory symptom severity, expression of endothelial dysfunction biomarker, and incidence of organ failure in coronavirus disease 2019 patients. Clinical Trials Registration: NCT04394195.
Assuntos
COVID-19 , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Estado Terminal , Humanos , SARS-CoV-2 , Fator A de Crescimento do Endotélio VascularRESUMO
Peripheral arterial disease occurs more frequently and has a worse prognosis in patients with chronic kidney disease (CKD). The receptor for advanced glycation end products (RAGE) is involved in multiple aspects of uremia-associated vasculopathy. Previous data suggest that the RAGE pathway may promote soluble fms-like tyrosine kinase 1 (sFlt1) production, an anti-angiogenic molecule. Thus, we tested the hypothesis that the deletion of AgeR would decrease sFlt1 production and improve post-ischemic revascularization in uremic condition. We used a well-established CKD model (5/6 nephrectomy) in WT and AgeR-/- C57/Bl6 mice. Hindlimb ischemia was induced by femoral artery ligation. Revascularization was evaluated by complementary approaches: ischemic limb retraction, LASCA imagery, and capillary density. The production of sFlt1 was assessed at both RNA and protein levels. After hindlimb ischemia, uremic mice showed slower functional recovery (p < 0.01), decreased reperfusion (p < 0.01), lower capillary density (p = 0.02), and increased circulating sFlt1 levels (p = 0.03). AgeR deletion restored post-ischemic angiogenesis and was protective from sFlt1 increase in uremic mice. These findings show the main role of RAGE in post-ischemic angiogenesis impairment associated with CKD. RAGE may represent a key target for building new therapeutic approaches to improve the outcome of CKD patients with PAD.
Assuntos
Deleção de Genes , Isquemia/complicações , Neovascularização Fisiológica , Receptor para Produtos Finais de Glicação Avançada/deficiência , Uremia/complicações , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Animais , Biomarcadores/sangue , Linhagem Celular , Humanos , Ligantes , Masculino , Camundongos Endogâmicos C57BL , RNA/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Solubilidade , Regulação para CimaRESUMO
In paediatric acute lymphoblastic leukaemia (ALL), focus has shifted towards preventing treatment-related complications, including venous thromboembolism, the cause of significant mortality and morbidity. To better understand thrombogenic mechanisms during induction treatment, we studied the number, origin and procoagulant activity of extracellular vesicles (EVs) and P-selectin level throughout the induction course in 24 paediatric patients. EVs were mainly of platelet origin. We observed a significant increase in EV number, in platelet EV number and P-selectin level throughout the induction course. There was a correlation between higher EV and platelet EV number, P-selectin level, higher platelet count and leucocyte count. We also observed a correlation between higher EV procoagulant activity and higher platelet count and leucocyte count and higher P-selectin level. Older age and T phenotype were associated with a higher EV procoagulant activity. Platelet EV generation may play a role in thrombogenic complications in ALL patients and could serve as a biomarker to identify patients with a high risk of thrombosis. As a marker of platelet activation, P-selectin may be another relevant marker with the advantage of being easier to analyse in clinical practice.
Assuntos
Asparaginase/uso terapêutico , Vesículas Extracelulares , Quimioterapia de Indução , Selectina-P/sangue , Contagem de Plaquetas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tromboembolia Venosa , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Plaquetas/metabolismo , Plaquetas/patologia , Criança , Correlação de Dados , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Indução/métodos , Contagem de Leucócitos/métodos , Contagem de Leucócitos/estatística & dados numéricos , Masculino , Projetos Piloto , Ativação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas/métodos , Contagem de Plaquetas/estatística & dados numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tromboembolia Venosa/sangue , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiologiaRESUMO
COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 µg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.
Assuntos
Infecções por Coronavirus/terapia , Hemostasia/fisiologia , Hospitalização , Pneumonia Viral/terapia , Trombose/prevenção & controle , COVID-19 , Infecções por Coronavirus/fisiopatologia , Humanos , Monitorização Fisiológica , Pandemias , Pneumonia Viral/fisiopatologia , RiscoRESUMO
BACKGROUND: Cell therapy has been proposed for patients with critical limb ischemia (CLI). Autologous bone marrow derived cells (BMCs) have been mostly used, mesenchymal stem cells (MSCs) being an alternative. The aim of this study was to characterize two types of MSCs and evaluate their efficacy. METHODS: MSCs were obtained from CLI-patients BMCs. Stimulated- (S-) MSCs were cultured in endothelial growth medium. Cells were characterized by the expression of cell surface markers, the relative expression of 6 genes, the secretion of 10 cytokines and the ability to form vessel-like structures. The cell proangiogenic properties was analysed in vivo, in a hindlimb ischemia model. Perfusion of lower limbs and functional tests were assessed for 28 days after cell infusion. Muscle histological analysis (neoangiogenesis, arteriogenesis and muscle repair) was performed. RESULTS: S-MSCs can be obtained from CLI-patients BMCs. They do not express endothelial specific markers but can be distinguished from MSCs by their secretome. S-MSCs have the ability to form tube-like structures and, in vivo, to induce blood flow recovery. No amputation was observed in S-MSCs treated mice. Functional tests showed improvement in treated groups with a superiority of MSCs and S-MSCs. In muscles, CD31+ and αSMA+ labelling were the highest in S-MSCs treated mice. S-MSCs induced the highest muscle repair. CONCLUSIONS: S-MSCs exert angiogenic potential probably mediated by a paracrine mechanism. Their administration is associated with flow recovery, limb salvage and muscle repair. The secretome from S-MSCs or secretome-derived products may have a strong potential in vessel regeneration and muscle repair. Trial registration NCT00533104.
Assuntos
Meios de Cultura/farmacologia , Células Endoteliais/citologia , Extremidades/irrigação sanguínea , Isquemia/terapia , Células-Tronco Mesenquimais/citologia , Adulto , Idoso , Animais , Artérias/crescimento & desenvolvimento , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Extremidades/patologia , Feminino , Membro Posterior/irrigação sanguínea , Humanos , Isquemia/patologia , Masculino , Transplante de Células-Tronco Mesenquimais , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Músculos/irrigação sanguínea , Músculos/patologia , Neovascularização Fisiológica , Organogênese , Fluxo Sanguíneo RegionalAssuntos
Hemofilia A , Qualidade de Vida , Irmãos , Humanos , Hemofilia A/psicologia , Adolescente , Irmãos/psicologia , Masculino , Feminino , Criança , Inquéritos e QuestionáriosRESUMO
We have investigated the development of murine hindlimb ischemia from day 1 to day 55 after femoral artery ligation (FAL) using blood flow analysis, functional tests, histopathological staining, and in vivo Raman spectroscopy. FAL resulted in hindlimb blood deprivation and the loss of functionality as attested by the blood flow analysis and functional tests, respectively. The limbs recovered a normal circulation progressively without recovering complete functionality. Histological analysis showed changes in the morphology of muscle fibers with intense inflammation. From day 22 to day 55 post-ischemia, regeneration of the myofibers was observed. Raman spectroscopic results related to subcutaneous analysis made the identification of modification in the biochemical constituents of hindlimb muscles possible during disease progression. Ischemia was characterized by a quantitative increase in the lipid content and a decrease in the protein content. The lipid to protein ratio can be used as a spectroscopic marker to score the severity of ischemia. Multivariate statistical analysis PC-LDA (Principal Component-Linear Discriminant Analysis) was used to classify all the data measured for the normal and ischemic tissues. This classification illustrated an excellent separation between the control and ischemic tissues at any time during the course of ischemic development. In vivo Raman spectroscopy was then applied to assess the potential of this technique as a screening tool to explore an ischemic disease non-invasively (transcutaneously). For this purpose, the influence of skin on the diagnostic accuracy was evaluated; transcutaneous analysis revealed the accuracy of this technique, indicating its potential in the in situ monitoring of muscle structural changes during ischemia.
Assuntos
Membro Posterior/metabolismo , Isquemia/diagnóstico , Isquemia/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Pele/metabolismo , Animais , Circulação Sanguínea/fisiologia , Análise Discriminante , Membro Posterior/irrigação sanguínea , Masculino , Camundongos Endogâmicos BALB C , Análise Multivariada , Fibras Musculares Esqueléticas/patologia , Análise Espectral Raman/métodosRESUMO
Thromboembolic events are frequent and serious complications of acute lymphoblastic leukaemia treatment. The importance of chemotherapy in the pathogenesis of this increased risk is enhanced by the fact that thrombosis rarely occurs at diagnosis. Our study aims at investigating the effect of chemotherapy on pro-coagulant activity (PCA), phosphatidylserine (PS) exposure, tissue factor (TF) activity and derived extracellular vesicles (EV) of Jurkat cells. Jurkat cells were treated with two commonly used chemotherapeutics: Vincristine (VCR) or Daunorubicin (DNR), at relevant concentrations. PCA of cells and derived EV were evaluated using Thrombin generation Assay (TGA). Cells or EV were incubated with annexin V or anti TF antibodies to assess the respective contribution of TF and PS. PS exposure on cells was analysed by flow cytometry. Derived EV were evaluated in fluorescence microscopy and flow cytometry. Untreated Jurkat cells and EV support thrombin generation. Thrombin generation was abolished when PS activity was inhibited by annexin V. VCR treatment resulted in a time dependent increase of thrombin generation. After VCR exposure, TF activity increased as well as PS exposure increased on the cell surface. The increase in TF activity was abolished by annexin V indicating that PS was required. A spontaneous release of EV from Jurkat cells was observed and VCR treatment increased the number of generated EV. Our results indicate that VCR increased the PCA of Jurkat cells predominantly through PS exposure and increased EV generation. Lymphoid blasts derived EV could be biomarkers to determine high thrombotic risk ALL patients.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Vincristina/farmacologia , Anexina A5/farmacologia , Antineoplásicos Fitogênicos , Citometria de Fluxo , Humanos , Células Jurkat , Fosfatidilserinas/metabolismo , Tromboplastina/metabolismoRESUMO
BACKGROUND: Vascular endothelial injury during ischemia generates apoptotic cell death and precedes apoptosis of underlying tissues. We aimed at studying the role of extracellular adenosine triphosphate (ATP) on endothelial cells protection against hypoxia injury. METHODS: In a hypoxic model on endothelial cells, we quantified the extracellular concentration of ATP and adenosine. The expression of mRNA (ectonucleotidases, adenosine, and P2 receptors) was measured. Apoptosis was evaluated by the expression of cleaved caspase 3. The involvement of P2 and adenosine receptors and signaling pathways was investigated using selective inhibitors. RESULTS: Hypoxic stress induced a significant increase in extracellular ATP and adenosine. After a 2-h hypoxic injury, an increase of cleaved caspase 3 was observed. ATP anti-apoptotic effect was prevented by suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and CGS15943, as well as by selective A2A, A2B, and A3 receptor antagonists. P2 receptor-mediated anti-apoptotic effect of ATP involved phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases (ERK1/2), mitoKATP, and nitric oxide synthase (NOS) pathways whereas adenosine receptor-mediated anti-apoptotic effect involved ERK1/2, protein kinase A (PKA), and NOS. CONCLUSIONS: These results suggest a complementary role of P2 and adenosine receptors in ATP-induced protective effects against hypoxia injury of endothelial. This could be considered therapeutic targets to limit the development of ischemic injury of organs such as heart, brain, and kidney.
Assuntos
Trifosfato de Adenosina/metabolismo , Apoptose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hipóxia/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2/metabolismo , Adenosina/metabolismo , Apoptose/genética , Biomarcadores , Espaço Extracelular/metabolismo , Expressão Gênica , Humanos , Hipóxia/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/genética , Receptores Purinérgicos P1/genética , Receptores Purinérgicos P2/genética , Transdução de Sinais , Estresse Fisiológico/genéticaRESUMO
BACKGROUND: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). In spite of the fact that clinical trials found some efficacy, the mechanism of action remains elusive. The objective of this study was to characterize two autologous cell therapy products (CTPs) obtained from patients with advanced peripheral arterial disease. METHODS: Bone marrow (BM-CTPs) (n = 20) and CTPs obtained by non-mobilized cytapheresis (peripheral blood [PB]-CTPs) (n = 20) were compared. CTPs were characterized by their cell composition, by the quantification of endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs) and by transcriptomic profiling. The angiogenic profile and the 6-month outcome of CLI patients are described. RESULTS: Patients presented inflammation syndrome and high levels of CXCL12, soluble stem cell factor and granulocyte colony-stimulating factor, whereas granulocyte macrophage colony-stimulating factor was low. Circulating CD34+ cells represented rare events. BM and PB-CTPs were heterogeneous. Mature cells and colony-forming unit-endothelial cells were in higher concentration in PB-CTPs, whereas CD34+ stem cells and EPCs were more abundant in BM-CTPs. MSCs were identified in both CTPs. Transcriptomic profiling revealed the strong angiogenic potential of BM-CTPs. Transcutaneous partial pressure of oxygen, C-reative protein and neutrophil content in CTPs are predictive of the clinical outcome at 6 months. DISCUSSION: Transcriptomic allows an accurate characterization of CTPs. BM-CTPs have the richest content in terms of stem cells and transcriptome. The high content of mature cells in PB-CTPs means that they work via a paracrine mechanism. The clinical outcome indicates the deleterious influence the patients' status and the limits of an autologous approach. In this respect, MSCs may allow an allogenic strategy.
Assuntos
Células da Medula Óssea/citologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Estado Terminal/terapia , Extremidades/irrigação sanguínea , Isquemia/terapia , Salvamento de Membro/métodos , Células-Tronco de Sangue Periférico/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transplante de Medula Óssea , Citaferese/métodos , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Doença Arterial Periférica/terapia , Transplante de Células-Tronco de Sangue PeriféricoRESUMO
BACKGROUND: Cell therapy is a therapeutic option for patients presenting with nonrevascularizable critical limb ischemia (CLI). However there is a lack of firm evidence on its efficacy because of the paucity of randomized controlled trials.MethodsâandâResults:The BALI trial was a multicenter, randomized, controlled, double-blind clinical trial that included 38 patients. For all of them, 500 mL of bone marrow were collected for preparation of a BM-MNC product that was implanted in patients assigned to active treatment. For the placebo group, a placebo cell-free product was implanted. Within 6 months after inclusion, major amputations had to be performed in 5 of the 19 placebo-treated patients and in 3 of the 17 BM-MNC-treated patients. According to a classical logistic regression analysis there was no significant difference. However, when using the jackknife analysis, 6 months after inclusion BM-MNC implantation was associated with a lower risk of major amputation (odds ratio (OR): 0.55; 95% confidence interval (CI): 0.52-0.58; P<0.0001) and of occurrence of any event (major or minor amputation, or revascularization) (OR: 0.30; 95% CI: 0.29-0.31; P<0.0001). The secondary endpoints (i.e., pain, ulcers, TcPO2, and ankle-brachial index value) were not statistically different between groups. CONCLUSIONS: Our results suggested that cell therapy reduced the risk of major amputation in patients presenting with nonrevascularizable CLI.
Assuntos
Transplante de Medula Óssea/métodos , Isquemia/terapia , Monócitos/transplante , Idoso , Amputação Cirúrgica/estatística & dados numéricos , Arteriopatias Oclusivas , Estado Terminal , Método Duplo-Cego , Extremidades/patologia , Extremidades/cirurgia , Feminino , Humanos , Isquemia/cirurgia , Masculino , Pessoa de Meia-Idade , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: Cell therapy is an emerging potential biotherapy for critical limb ischaemia (CLI) patients who are not eligible for revascularization. However, the findings on this technique's efficacy are inconsistent. Trials investigating this topic focused on the more severe CLI patients who were often beyond any therapy. Therefore, identifying those who may truly benefit from cell transplantation is now warranted. To this end, we studied the prognostic value of tcPO2 for major amputation after 1 year in patients treated with bone marrow-derived cells. PATIENTS AND METHODS: CLI patients ineligible for revascularization were included in a cell-therapy pilot study. On inclusion, patients underwent tcPO2 measurement in supine and sitting positions. For a tcPO2 < 10 mmHg in the supine position, the vascular reserve was defined by tcPO2 > 30 mmHg in the sitting position. Patients were administered intramuscular injections of mononuclear cells derived from aspirated bone marrow. RESULTS: In total, 25 patients (a lower limbs) were included for analysis. At inclusion, 11 lower limbs had tcPO2 at rest > 10 mmHg, and 16 lower limbs had a tcPO2 < 10 mmHg. The success probability for cell therapy was 0.79 (95 % CI 0.38-0.94) and 0.44 (95 % CI 0.18-0.67), respectively (p = 0.1). Of the 16 limbs with tcPO2 < 10 mmHg, the success rate was considerably higher in patients demonstrating a tcPO2 increase in a sitting position of over 30 mmHg (6/8, success probability 0.71, 95 % CI 0.26-0.92) compared to those without (2/8, success probability 0.15, 95 % CI 0.01-0.48, p = 0.03). CONCLUSIONS: For patients with chronic CLI for whom cellular therapy is a therapeutic option, a tcPO2 < 10 mmHg at rest, without vascular reserve (i. e. < 30 mmHg when sitting), is a prognostic indicator for poor outcome.â©.
Assuntos
Monitorização Transcutânea dos Gases Sanguíneos , Transplante de Medula Óssea , Isquemia/cirurgia , Extremidade Inferior/irrigação sanguínea , Oxigênio/sangue , Idoso , Amputação Cirúrgica , Biomarcadores/sangue , Transplante de Medula Óssea/efeitos adversos , Estado Terminal , Estudos de Viabilidade , Feminino , França , Humanos , Injeções Intramusculares , Isquemia/sangue , Isquemia/diagnóstico , Isquemia/fisiopatologia , Salvamento de Membro , Masculino , Pessoa de Meia-Idade , Pressão Parcial , Posicionamento do Paciente , Seleção de Pacientes , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Reoperação , Fatores de Risco , Decúbito Dorsal , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: A relationship between generalized anxiety disorder (GAD) and fear of falling (FOF) has long been proposed but never specifically studied. This study aimed at analyzing the relationship between FOF and GAD or anxiety symptoms, while controlling for major depressive episodes (MDE), depressive symptoms, fall risk, and sociodemographic variables. METHODS: Twenty-five older adults participated in this pilot study. Assessments included the following: Anxiety Disorder Interview Schedule, Geriatric Anxiety Inventory, Geriatric Depression Scale, Falls-Efficacy Scale-International. A multidisciplinary team evaluated fall risk. RESULTS: FOF was significantly correlated with GAD, MDE, anxiety and depressive symptoms, and fall risk, but not with sociodemographic variables. Multiple regression analyses indicated that GAD and anxiety symptoms were significantly and independently associated with FOF. CONCLUSION: Although the results of this pilot study should be replicated with larger samples, they suggest that FOF is associated with GAD and anxiety symptoms even when considering physical factors that increase the risk of falling. CLINICAL IMPLICATIONS: Treatment of FOF in patients with GAD may present a particular challenge because of the central role of intolerance of uncertainty, which may prevent patients from regaining confidence despite the reduction of fall risk. Clinicians should screen for GAD and anxiety symptoms in patients with FOF to improve detection and treatment.
Assuntos
Acidentes por Quedas , Transtornos de Ansiedade/psicologia , Ansiedade/psicologia , Medo/psicologia , Avaliação Geriátrica/estatística & dados numéricos , Idoso , Ansiedade/complicações , Transtornos de Ansiedade/complicações , Canadá/epidemiologia , Feminino , Avaliação Geriátrica/métodos , Humanos , Masculino , Projetos Piloto , Fatores de RiscoRESUMO
INTRODUCTION: Venous thromboembolism is common in cancer. Low-molecular weight heparins are recommended for prolonged treatment (3-6 months or more if the cancer is active) and prevention of recurrence of venous thromboembolism in cancer. Community pharmacists are often faced with questions from patients. The main objective of this study was to describe the organization, practices and knowledge of pharmacists in care of venous thromboembolism in cancer patients. METHODS: A descriptive survey was conducted electronically in October and November 2013 with pharmacists in the Champagne-Ardenne region. The questionnaire collected data on the general organization of the pharmacy, management of outpatients with cancer and thrombosis, and the level of knowledge regarding recommendations on the management of thrombosis in patients with cancer. RESULTS: The participation rate was 31.6%. In 93% of cases, pharmacists had no particular expertise in oncology and/or supportive care. In addition, 96% did not know the existence of recommendations for "thrombosis in cancer." Finally, 49% gave the correct answer to the case report (low-molecular weight heparins). CONCLUSION: Training sessions on the management of venous thromboembolism in cancer are currently available to pharmacists in the region. A new assessment of knowledge will be performed at the end of the year 2014. This regional experience is now extended to a national level (all French regions).
Assuntos
Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adulto , Idoso , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Farmacêuticos , Recidiva , Inquéritos e Questionários , Tromboembolia Venosa/etiologiaRESUMO
BACKGROUND: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). Autologous cell therapy products (CTP) are obtained from patients with advanced peripheral arterial disease to be injected at the site of ischemia. Thrombogenicity of CTPs has not yet been assessed. The objectives were: 1) to assess thrombotic risk in candidates for cell therapy, 2) to evaluate two different CTPs in terms of thrombogenic potential, and 3) to evaluate clinical thrombotic events. STUDY DESIGN AND METHODS: In this ancillary study of a Phase I and II clinical trial, bone marrow (BM)-CTPs (n = 20) and CTPs obtained by cytapheresis (peripheral blood [PB]-CTPs; n = 20) were compared. Inflammatory and coagulation markers were measured at baseline and 24 hours after CTP implantation. CTP cell content and tissue factor (TF) expression (mRNA and protein) were analyzed. Thrombin generation assessed CTP-related thrombogenicity. RESULTS: All patients presented cardiovascular risk factors. At baseline, the patients' biologic profile was characterized by high levels of fibrinogen, C-reactive protein (CRP), D-dimer, interleukin (IL)-6, and plasmatic TF, whereas IL-10 was low. Although different in terms of cell composition, both BM- and PB-CTPs support low thrombin generation. Twenty-four hours after implantation, biologic markers remained stable in the PB-CTP group, except for IL-6. In the BM-CTP group, a significant increase of IL-6 but also of CRP and D-dimer was observed. Clinically, one single patient developed deep vein thrombosis 24 hours after the implantation of autologous PB-CTP. CONCLUSION: CTPs supported low thrombin generation and were well tolerated after calf implantation.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Isquemia/diagnóstico , Perna (Membro)/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Isquemia/terapia , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional/fisiologiaRESUMO
OBJECTIVE: Elastin is the major structural extracellular matrix component of the arterial wall that provides the elastic recoil properties and resilience essential for proper vascular function. Elastin-derived peptides (EDP) originating from elastin fragmentation during vascular remodeling have been shown to play an important role in cell physiology and development of cardiovascular diseases. However, their involvement in thrombosis has been unexplored to date. In this study, we investigated the effects of EDP on (1) platelet aggregation and related signaling and (2) thrombus formation. We also characterized the mechanism by which EDP regulate thrombosis. APPROACH AND RESULTS: We show that EDP, derived from organo-alkaline hydrolysate of bovine insoluble elastin (kappa-elastin), decrease human platelet aggregation in whole blood induced by weak and strong agonists, such as ADP, epinephrine, arachidonic acid, collagen, TRAP, and U46619. In a mouse whole blood perfusion assay over a collagen matrix, kappa-elastin and VGVAPG, the canonical peptide recognizing the elastin receptor complex, significantly decrease thrombus formation under arterial shear conditions. We confirmed these results in vivo by demonstrating that both kappa-elastin and VGVAPG significantly prolonged the time for complete arteriole occlusion in a mouse model of thrombosis and increased tail bleeding times. Finally, we demonstrate that the regulatory role of EDP on thrombosis relies on platelets that express a functional elastin receptor complex and on the ability of EDP to disrupt plasma von Willebrand factor interaction with collagen. CONCLUSIONS: These results highlight the complex nature of the mechanisms governing thrombus formation and reveal an unsuspected regulatory role for circulating EDP in thrombosis.
Assuntos
Elastina/fisiologia , Trombose/etiologia , Animais , Plaquetas/fisiologia , Catepsina A/sangue , Bovinos , Colágeno/sangue , Elastina/sangue , Elastina/química , Humanos , Camundongos , Neuraminidase/sangue , Oligopeptídeos/sangue , Oligopeptídeos/química , Oligopeptídeos/fisiologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/fisiologia , Agregação Plaquetária/fisiologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Proteólise , Receptores de Superfície Celular/sangue , Transdução de Sinais , Trombose/sangue , Remodelação Vascular/fisiologia , Fator de von Willebrand/metabolismoRESUMO
Appropriate anticoagulation for hemodialysis (HD) requires a subtle balance between under- and over-heparinization to prevent extracorporeal circuit (ECC) clotting and bleeding, respectively. We discuss five key issues relating to anticoagulation therapy for chronic HD in adults following a review of relevant literature published since 2002: (i) options for standardization of anticoagulation in HD settings. The major nephrology societies have issued low evidence level recommendations on this subject. Interventional studies have generally investigated novel low-molecular weight heparins and provided data on safety of dosing regimens that cannot readily be extrapolated to clinical practice; (ii) identification of clinical and biological parameters to aid individualization of anticoagulation treatment. We find that use of clinical and biological monitoring of anticoagulation during HD sessions is currently not clearly defined in routine clinical practice; (iii) role of ECC elements (dialysis membrane and blood lines), dialysis modalities, and blood flow in clotting development; (iv) options to reduce or suppress systemic heparinization during HD sessions. Alternative strategies have been investigated, especially when the routine mode of anticoagulation was not suitable in patients at high risk of bleeding or was contraindicated; (v) optimization of anticoagulation therapy for the individual patient. We conclude by proposing a standardized approach to deliver anticoagulation treatment for HD based on an individualized prescription prepared according to the patient's profile and needs.