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1.
Immunity ; 46(1): 148-161, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-27986455

RESUMO

Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.


Assuntos
Citometria de Fluxo/métodos , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Humanos , Imunidade Inata , Fenótipo
2.
Immunity ; 45(2): 442-56, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27521270

RESUMO

Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body.


Assuntos
Sangue/imunologia , Movimento Celular , Tecido Linfoide/imunologia , Espectrometria de Massas/métodos , Especificidade de Órgãos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Biodiversidade , Biomarcadores/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Citocinas/metabolismo , Humanos , Ativação Linfocitária , Camundongos , Receptores de Retorno de Linfócitos/metabolismo , Transcriptoma
3.
J Hepatol ; 81(1): 42-61, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38423478

RESUMO

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC. METHODS: We combined single-cell transcriptomics (single-cell RNA sequencing) with multiparametric flow cytometry-based immune phenotyping, and multiplexed immunofluorescence to elucidate the immunopathological cell states associated with CHB vs. FC. RESULTS: We found that the intrahepatic environment in CHB and FC displays specific cell identities and molecular signatures that are distinct from those found in matched PBMCs. FC is associated with the emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes, and an activated innate response represented by liver-resident natural killer cells, specific Kupffer cell subtypes and marginated neutrophils. Surprisingly, we found MHC class II-expressing hepatocytes in patients achieving FC, as well as low but persistent levels of covalently closed circular DNA and pregenomic RNA, which may play an important role in FC. CONCLUSIONS: Our study provides conceptually novel insights into the immuno-pathological control of HBV cure, and opens exciting new avenues for clinical management, biomarker discovery and therapeutic development. We believe that the discoveries from this study, as it relates to the activation of an innate and altered immune response that may facilitate sustained, low-grade inflammation, may have broader implications in the resolution of chronic viral hepatitis. IMPACT AND IMPLICATIONS: This study dissects the immuno-pathological cell states associated with functionally cured chronic hepatitis B (defined by the loss of HBV surface antigen or HBsAg). We identified the sustained presence of very low viral load, accessory antigen-presenting hepatocytes, adaptive-memory-like natural killer cells, and the emergence of helper CD4 T cells with cytotoxic or effector-like signatures associated with functional cure, suggesting previously unsuspected alterations in the adaptive immune response, as well as a key role for the innate immune response in achieving or maintaining functional cure. Overall, the insights generated from this study may provide new avenues for the development of alternative therapies as well as patient surveillance for better clinical management of chronic hepatitis B.


Assuntos
Imunidade Adaptativa , Hepatite B Crônica , Imunidade Inata , Análise de Célula Única , Humanos , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Imunidade Inata/imunologia , Imunidade Adaptativa/imunologia , Análise de Célula Única/métodos , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/genética , Masculino , Feminino , Linfócitos T Citotóxicos/imunologia , Adulto , Fígado/imunologia , Fígado/patologia , Antígenos de Superfície da Hepatite B/imunologia , Pessoa de Meia-Idade , Células Matadoras Naturais/imunologia
4.
Rheumatology (Oxford) ; 63(2): 414-422, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37184855

RESUMO

OBJECTIVE: To study whether multimodal brain MRI comprising permeability and perfusion measures coupled with machine learning can predict neurocognitive function in young patients with SLE without neuropsychiatric manifestations. METHODS: SLE patients and healthy controls (HCs) (≤40 years of age) underwent multimodal structural brain MRI that comprised voxel-based morphometry (VBM), magnetization transfer ratio (MTR) and dynamic contrast-enhanced (DCE) MRI in this cross-sectional study. Neurocognitive function assessed by Automated Neuropsychological Assessment Metrics was reported as the total throughput score (TTS). Olfactory function was assessed. A machine learning-based model (i.e. glmnet) was constructed to predict TTS. RESULTS: Thirty SLE patients and 10 HCs were studied. Both groups had comparable VBM, MTR, olfactory bulb volume (OBV), olfactory function and TTS. While after correction for multiple comparisons the uncorrected increase in the blood-brain barrier (BBB) permeability parameters compared with HCs did not remain evident in SLE patients, DCE-MRI perfusion parameters, notably an increase in right amygdala perfusion, was positively correlated with TTS in SLE patients (r = 0.636, false discovery rate P < 0.05). A machine learning-trained multimodal MRI model comprising alterations of VBM, MTR, OBV and DCE-MRI parameters mainly in the limbic system regions predicted TTS in SLE patients (r = 0.644, P < 0.0005). CONCLUSION: Multimodal brain MRI demonstrated increased right amygdala perfusion that was associated with better neurocognitive performance in young SLE patients without statistically significant BBB leakage and microstructural abnormalities. A machine learning-constructed multimodal model comprising microstructural, perfusion and permeability parameters accurately predicted neurocognitive performance in SLE patients.


Assuntos
Encéfalo , Lúpus Eritematoso Sistêmico , Humanos , Estudos Transversais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Neuroimagem , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/patologia
5.
Rheumatology (Oxford) ; 63(2): 551-562, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37341646

RESUMO

OBJECTIVES: Platelets and low-density neutrophils (LDNs) are major players in the immunopathogenesis of SLE. Despite evidence showing the importance of platelet-neutrophil complexes (PNCs) in inflammation, little is known about the relationship between LDNs and platelets in SLE. We sought to characterize the role of LDNs and Toll-like receptor 7 (TLR7) in clinical disease. METHODS: Flow cytometry was used to immunophenotype LDNs from SLE patients and controls. The association of LDNs with organ damage was investigated in a cohort of 290 SLE patients. TLR7 mRNA expression was assessed in LDNs and high-density neutrophils (HDNs) using publicly available mRNA sequencing datasets and our own cohort using RT-PCR. The role of TLR7 in platelet binding was evaluated in platelet-HDN mixing studies using TLR7-deficient mice and Klinefelter syndrome patients. RESULTS: SLE patients with active disease have more LDNs, which are heterogeneous and more immature in patients with evidence of kidney dysfunction. LDNs are platelet bound, in contrast to HDNs. LDNs settle in the peripheral blood mononuclear cell (PBMC) layer due to the increased buoyancy and neutrophil degranulation from platelet binding. Mixing studies demonstrated that this PNC formation was dependent on platelet-TLR7 and that the association results in increased NETosis. The neutrophil:platelet ratio is a useful clinical correlate for LDNs, and a higher NPR is associated with past and current flares of LN. CONCLUSIONS: LDNs sediment in the upper PBMC fraction due to PNC formation, which is dependent on the expression of TLR7 in platelets. Collectively, our results reveal a novel TLR7-dependent crosstalk between platelets and neutrophils that may be an important therapeutic opportunity for LN.


Assuntos
Nefrite Lúpica , Neutrófilos , Animais , Humanos , Camundongos , Leucócitos Mononucleares , Nefrite Lúpica/patologia , Neutrófilos/metabolismo , RNA Mensageiro/metabolismo , Receptor 7 Toll-Like/genética
6.
Allergy ; 78(3): 752-766, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36445014

RESUMO

BACKGROUND: Atopic diseases are characterized by IgE antibody responses that are dependent on cognate CD4 T cell help and T cell-produced IL-4 and IL-13. Current models of IgE cell differentiation point to the role of IgG memory B cells as precursors of pathogenic IgE plasma cells. The goal of this work was to identify intrinsic features of memory B cells that are associated with IgE production in atopic diseases. METHODS: Peripheral blood B lymphocytes were collected from individuals with physician diagnosed asthma or atopic dermatitis (AD) and from non-atopic individuals. These samples were analyzed by spectral flow cytometry, single cell RNA sequencing (scRNAseq), and in vitro activation assays. RESULTS: We identified a novel population of IgG memory B cells characterized by the expression of IL-4/IL-13 regulated genes FCER2/CD23, IL4R, IL13RA1, and IGHE, denoting a history of differentiation during type 2 immune responses. CD23+ IL4R+ IgG+ memory B cells had increased occurrence in individuals with atopic disease. Importantly, the frequency of CD23+ IL4R+ IgG+ memory B cells correlated with levels of circulating IgE. Consistently, in vitro stimulated B cells from atopic individuals generated more IgE+ cells than B cells from non-atopic subjects. CONCLUSIONS: These findings suggest that CD23+ IL4R+ IgG+ memory B cells transcribing IGHE are potential precursors of IgE plasma cells and are linked to pathogenic IgE production.


Assuntos
Células B de Memória , Receptores de IgE , Humanos , Receptores de IgE/metabolismo , Interleucina-13 , Interleucina-4 , Imunoglobulina E , Imunoglobulina G , Subunidade alfa de Receptor de Interleucina-4 , Lectinas Tipo C
8.
Arterioscler Thromb Vasc Biol ; 41(10): 2598-2615, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34348488

RESUMO

Objective: Hypercholesterolemia-induced NETosis and accumulation of neutrophil extracellular traps (NETs) in the atherosclerotic lesion exacerbates inflammation and is causally implicated in plaque progression. We investigated whether hypercholesterolemia additionally impairs the clearance of NETs mediated by endonucleases such as DNase1 and DNase1L3 and its implication in advanced atherosclerotic plaque progression. Approach and Results: Using a mouse model, we demonstrate that an experimental increase in the systemic level of NETs leads to a rapid increase in serum DNase activity, which is critical for the prompt clearance of NETs and achieving inflammation resolution. Importantly, hypercholesterolemic mice demonstrate an impairment in this critical NET-induced DNase response with consequent delay in the clearance of NETs and defective inflammation resolution. Administration of tauroursodeoxycholic acid, a chemical chaperone that relieves endoplasmic reticulum stress, rescued the hypercholesterolemia-induced impairment in the NET-induced DNase response suggesting a causal role for endoplasmic reticulum stress in this phenomenon. Correction of the defective DNase response with exogenous supplementation of DNase1 in Apoe-/- mice with advanced atherosclerosis resulted in a decrease in plaque NET content and significant plaque remodeling with decreased area of plaque necrosis and increased collagen content. From a translational standpoint, we demonstrate that humans with hypercholesterolemia have elevated systemic extracellular DNA levels and decreased plasma DNase activity. Conclusions: These data suggest that hypercholesterolemia impairs the NET-induced DNase response resulting in defective clearance and accumulation of NETs in the atherosclerotic plaque. Therefore, strategies aimed at rescuing this defect could be of potential therapeutic benefit in promoting inflammation resolution and atherosclerotic plaque stabilization.


Assuntos
Doenças da Aorta/etiologia , Aterosclerose/etiologia , Armadilhas Extracelulares/metabolismo , Hipercolesterolemia/complicações , Mediadores da Inflamação/metabolismo , Inflamação/etiologia , Neutrófilos/metabolismo , Placa Aterosclerótica , Animais , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Células CACO-2 , Desoxirribonuclease I/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Endodesoxirribonucleases/metabolismo , Estresse do Retículo Endoplasmático , Feminino , Células HL-60 , Células Hep G2 , Humanos , Hipercolesterolemia/imunologia , Hipercolesterolemia/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Necrose , Neutrófilos/imunologia , Transdução de Sinais , Células THP-1
9.
Environ Sci Technol ; 55(22): 15351-15360, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34570480

RESUMO

With the COVID-19 pandemic surging, the demand for masks is challenging, especially in less-developed areas across the world. Billions of used masks are threatening the environment as a new source of plastic pollution. In this paper, corona discharge (CD) was explored as a safe and reliable method for mask reuse to alleviate the situation. CD can disinfect masks and simultaneously restore electrostatic charges to prevent filtration efficiency deterioration. Electric field, ions, and reactive species generated by CD cause DNA damage and protein denaturation to effectively disinfect N95 respirators. Log reduction of 2-3 against Escherichia coli can be easily reached within 7.5 min. Log reduction of up to 6 can be reached after three cycles of treatment with optimized parameters. CD disinfection is a broad spectrum with log reduction >1 against yeast and >2.5 against spores. N95 respirators can be recharged within 30 s of treatment and the charges can be retained at a higher level than brand-new masks for at least 5 days. The filtration efficiency of masks was maintained at ∼95% after 15 cycles of treatment. CD can provide at least 10 cycles of safe reuse with benefits of high safety, affordability, accessibility, and device scalability/portability.


Assuntos
COVID-19 , Desinfecção , Humanos , Respiradores N95 , Pandemias , SARS-CoV-2 , Eletricidade Estática
11.
Am J Respir Crit Care Med ; 199(7): 842-853, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30265843

RESUMO

RATIONALE: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear. OBJECTIVES: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis. METHODS: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined. MEASUREMENTS AND MAIN RESULTS: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome. CONCLUSIONS: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.


Assuntos
Alérgenos/efeitos adversos , Alérgenos/imunologia , Aspergillus , Asma/etiologia , Asma/imunologia , Bronquiectasia/complicações , Bronquiectasia/imunologia , Pyroglyphidae , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Coortes , Feminino , Humanos , Hipersensibilidade/imunologia , Imunização , Masculino , Pessoa de Meia-Idade
12.
J Biomech Eng ; 142(6)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633169

RESUMO

In this work, we provide a quantitative assessment of the biomechanical and geometric features that characterize abdominal aortic aneurysm (AAA) models generated from 19 Asian and 19 Caucasian diameter-matched AAA patients. 3D patient-specific finite element models were generated and used to compute peak wall stress (PWS), 99th percentile wall stress (99th WS), and spatially averaged wall stress (AWS) for each AAA. In addition, 51 global geometric indices were calculated, which quantify the wall thickness, shape, and curvature of each AAA. The indices were correlated with 99th WS (the only biomechanical metric that exhibited significant association with geometric indices) using Spearman's correlation and subsequently with multivariate linear regression using backward elimination. For the Asian AAA group, 99th WS was highly correlated (R2 = 0.77) with three geometric indices, namely tortuosity, intraluminal thrombus volume, and area-averaged Gaussian curvature. Similarly, 99th WS in the Caucasian AAA group was highly correlated (R2 = 0.87) with six geometric indices, namely maximum AAA diameter, distal neck diameter, diameter-height ratio, minimum wall thickness variance, mode of the wall thickness variance, and area-averaged Gaussian curvature. Significant differences were found between the two groups for ten geometric indices; however, no differences were found for any of their respective biomechanical attributes. Assuming maximum AAA diameter as the most predictive metric for wall stress was found to be imprecise: 24% and 28% accuracy for the Asian and Caucasian groups, respectively. This investigation reveals that geometric indices other than maximum AAA diameter can serve as predictors of wall stress, and potentially for assessment of aneurysm rupture risk, in the Asian and Caucasian AAA populations.


Assuntos
Aneurisma da Aorta Abdominal , Análise de Elementos Finitos , Fenômenos Biomecânicos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares
14.
Ann Vasc Surg ; 46: 331-336, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28743653

RESUMO

BACKGROUND: To analyze the outcomes of arteriovenous fistulae (AVFs) creation in octogenarians. METHODS: A retrospective study of 47 AVFs created in patients aged 80 years and above from 2008 to 2014. Patient and AVF characteristics and outcomes were evaluated. Predictors of patency were analyzed with multivariate analysis and Kaplan-Meier patency, and survival analysis was performed. RESULTS: Forty-seven of 1,259 AVFs created were for octogenarians (4%). Mean age was 83 years old (range: 80-91 years), with 27 male (57%) and 35 with tunneled dialysis catheters in situ (75%). There were a total of 15 (32%) radiocephalic AVFs, 30 (64%) brachial-cephalic AVFs, and 2 (4%) brachial-basilic transposition AVFs. At 12 months, assisted primary patency rate was 28% (13 patients) while primary failure rate was 72% (34 patients). Subset analysis showed brachial-cephalic AVFs to have the highest assisted primary patency rate at 33%. Within 24 months, tunneled dialysis catheter-related sepsis rate was 31% (11 patients). Multivariate analysis did not reveal any factor to be statistically significant in predicting AVF patency. Kaplan-Meier survival curve showed a 50% survival rate at 63 months after AVF creation. CONCLUSIONS: In view of high AVF primary failure rate and relatively low tunneled dialysis catheter bacteremia rate, long-term tunneled dialysis catheters as the main form of hemodialysis renal access may be a viable option. However, with 50% of end-stage renal failure patients surviving up to 63 months after AVF creation, the risks and benefits of long-term tunneled dialysis catheters must be balanced against those of AVF creation.


Assuntos
Derivação Arteriovenosa Cirúrgica , Falência Renal Crônica/terapia , Diálise Renal , Extremidade Superior/irrigação sanguínea , Fatores Etários , Idoso de 80 Anos ou mais , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Derivação Arteriovenosa Cirúrgica/mortalidade , Cateterismo Venoso Central , Distribuição de Qui-Quadrado , Tomada de Decisão Clínica , Feminino , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Longevidade , Masculino , Análise Multivariada , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular
15.
Ann Vasc Surg ; 49: 9-16, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29428535

RESUMO

BACKGROUND: To review patient characteristics and outcomes of in-patient diabetic foot limb salvage and identify risk factors predicting for endovascular limb salvage failure. METHODS: Retrospective study of limb salvage attempts in 809 patients between August 2013 and July 2015. RESULTS: Sixty-eight percent of our study population were male with mean age at 65 years and 73% presented with Rutherford grade 6 critical limb ischemia, with the remaining 27% Rutherford grade 5. Eighty-one percent had toe pressures of less than 50 mm Hg, 64% had infrainguinal trans-Atlantic inter-society consensus (TASC II) C or D lesions while 78% had infrapopliteal TASC II C or D lesions. Seven hundred seventy-seven patients (96%) underwent endovascular-first approach limb salvage, with 95% requiring infrapopliteal angioplasty, with 84% of them requiring 2-vessel or 3-vessel revascularization. Thirty-two patients (4%) underwent surgical bypass limb salvage, with 63% performed as salvage procedures for failed angioplasties. The mean in-patient stay was 12.3 days within the endovascular group and 31.1 days within the bypass group (P < 0.01). One-year limb salvage was successful in 88% of endovascular group, as compared with 72% in bypass group (P = 0.01). Overall 1-year survival was 93% within the endovascular group and 88% within the bypass group (P = 0.27). The mean in-patient cost was SGD$5,518 within the endovascular group and SGD$15,141 within the bypass group (P < 0.01). Multivariate analysis showed that independent predictors for failure of endovascular limb salvage include end-stage renal failure (ESRF) (odds ratio [OR] 2.04, P = 0.01), toe pressures <50 mm Hg (OR 2.15, P = 0.01), infrainguinal TASC II patterns C or D (OR 1.99, P = 0.03), and indirect angiosome revascularization (OR 2.03, P = 0.02). CONCLUSIONS: Within our study population of Asian ethnicity, most in-patient diabetic foot peripheral arterial disease presented with Rutherford grade 6 disease, with mostly TASC II C or D lesions and required infrapopliteal revascularization. As most patients had multiple comorbidities and were poor surgical candidates, the majority underwent endovascular-first approach revascularization. Independent predictors of endovascular limb salvage failure include ESRF, toe pressures <50 mm Hg, infrainguinal TASC II patterns C or D, and indirect angiosome revascularization.


Assuntos
Angioplastia , Pé Diabético/terapia , Salvamento de Membro/métodos , Enxerto Vascular , Idoso , Idoso de 80 Anos ou mais , Amputação Cirúrgica , Angioplastia/efeitos adversos , Angioplastia/mortalidade , Comorbidade , Pé Diabético/diagnóstico , Pé Diabético/mortalidade , Pé Diabético/cirurgia , Feminino , Humanos , Salvamento de Membro/efeitos adversos , Salvamento de Membro/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento , Enxerto Vascular/efeitos adversos , Enxerto Vascular/mortalidade
16.
Ann Vasc Surg ; 45: 264.e1-264.e4, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28689945

RESUMO

PURPOSE: To report a rare case of concurrent inferior mesenteric artery (IMA) aneurysm and infrarenal abdominal aortic aneurysm (AAA) with a novel indication for the use of chimney stent-graft technique in this patient. CASE REPORT: An 82-year-old man with an asymptomatic 4.4-cm fusiform AAA and 3.6-cm IMA aneurysm, coupled with chronic occlusion of celiac artery and superior mesenteric artery at the ostia, underwent endovascular repair of both aneurysms. Preservation of the IMA and treatment of both aneurysms were achieved with IMA aneurysm stenting, aortic aneurysm stenting and IMA chimney stenting. At 1, 6, and 12 months surveillance, the grafts remained patent without endoleak. CONCLUSIONS: The IMA chimney with aortic stenting technique may be safely used in patients who require preservation of the IMA during AAA and IMA aneurysm repairs.


Assuntos
Aneurisma/cirurgia , Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Procedimentos Endovasculares/instrumentação , Artéria Mesentérica Inferior/cirurgia , Stents , Idoso de 80 Anos ou mais , Aneurisma/diagnóstico por imagem , Aneurisma/fisiopatologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/fisiopatologia , Aortografia/métodos , Implante de Prótese Vascular/métodos , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/métodos , Humanos , Masculino , Artéria Mesentérica Inferior/diagnóstico por imagem , Artéria Mesentérica Inferior/fisiopatologia , Desenho de Prótese , Fluxo Sanguíneo Regional , Resultado do Tratamento , Grau de Desobstrução Vascular
17.
Curr Top Microbiol Immunol ; 388: 1-19, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25553792

RESUMO

The generation of long-lived plasma cells and memory B cells producing high-affinity antibodies depends on the maturation of B cell responses in germinal centers. These processes are essential for long-lasting antibody-mediated protection against infections. IgE antibodies are important for defense against parasites and toxins and can also mediate anti-tumor immunity. However, high-affinity IgE is also the main culprit responsible for the manifestations of allergic disease, including life-threatening anaphylaxisAnaphylaxis . Thus, generation of high-affinity IgE must be tightly regulated. Recent studies of IgE B cell biology have unveiled two mechanisms that limit high-affinity IgE memory responses: First, B cells that have recently switched to IgE production are programmed to rapidly differentiate into plasma cells,Plasma cells and second, IgE germinal centerGerminal center cells are transient and highly apoptotic. Opposing these processes, we now know that germinal center-derived IgG B cells can switch to IgE production, effectively becoming IgE-producing plasma cells. In this chapter, we will discuss the unique molecular and cellular pathways involved in the generation of IgE antibodies.


Assuntos
Diferenciação Celular , Imunoglobulina E/biossíntese , Memória Imunológica , Animais , Linfócitos B/imunologia , Humanos , Switching de Imunoglobulina , Imunoglobulina E/genética
18.
J Immunol ; 189(2): 587-97, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22675200

RESUMO

We find that the cell surface receptor Toso is dramatically downregulated by in vitro stimulation of human T and NK cells with IL-2 in a STAT5-dependent manner. The fact that IL-2 is known to prime NK and T cells for Fas/TNF-mediated activation-induced cell death (AICD) fits nicely with the original and recent descriptions of Toso as an inhibitor of Fas/TNF-induced apoptosis. In support of this possibility, effector memory T cells express markedly lower levels of Toso than those of naive T cells, indicating that activation in vivo correlates with the downregulation of Toso. Moreover, in vitro activation of memory T cells through TCR dramatically downregulates Toso expression compared with that of naive CD4 T cells. However, overexpression of Toso in human NK cells and Jurkat T cells does not inhibit Fas-mediated apoptosis, and, in agreement with other recent reports, Toso clearly functions as an IgM receptor. Unlike CD16, Toso expression by NK cells does not convey cytotoxic potential, but its ligation does trigger intracellular signaling in NK cells. In summary, our data indicate that Toso is a functional IgM receptor that is capable of activating signaling molecules, is regulated by IL-2, and is not inherently an antiapoptotic molecule.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Interleucina-2/fisiologia , Células Matadoras Naturais/imunologia , Proteínas de Membrana/metabolismo , Receptores Fc/metabolismo , Subpopulações de Linfócitos T/imunologia , Apoptose/imunologia , Células HEK293 , Humanos , Células Jurkat , Células Matadoras Naturais/metabolismo , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptor fas/antagonistas & inibidores , Receptor fas/fisiologia
19.
Sci Adv ; 10(1): eadi6470, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38170763

RESUMO

The ability to predict the future based on past experience lies at the core of the brain's ability to adapt behavior. However, the neural mechanisms that participate in generating and updating predictions are not clearly understood. Further, the evolutionary antecedents and the prevalence of predictive processing among vertebrates are even less explored. Here, we show evidence of predictive processing via the involvement of cerebellar circuits in larval zebrafish. We presented stereotyped optic flow stimuli to larval zebrafish to evoke swims and discovered that lesioning the cerebellum abolished prediction-dependent modulation of swim latency. When expectations of optic flow direction did not match with reality, error signals arrive at Purkinje cells via the olivary climbing fibers, whereas granule cells and Purkinje cells encode signals of expectation. Strong neural representations of expectation correlate with faster swim responses and vice versa. In sum, our results show evidence for predictive processing in nonmammalian vertebrates with the involvement of cerebellum, an evolutionarily conserved brain structure.


Assuntos
Cerebelo , Peixe-Zebra , Animais , Peixe-Zebra/fisiologia , Larva/fisiologia , Cerebelo/fisiologia , Células de Purkinje/fisiologia , Neurônios/fisiologia
20.
J Vasc Surg Venous Lymphat Disord ; 12(6): 101901, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38677550

RESUMO

BACKGROUND: Pelvic venous disorders (PeVD) encompass a variety of conditions linked to chronic pelvic pain in women. However, PeVD remain underdiagnosed due to the absence of universally accepted diagnostic criteria. The complexity of PeVD classifications across specialties leads to delays in treatment. This scoping review aims to fill a gap in PeVD diagnosis and management by identifying all existing scoring or grading systems to lay the foundation for standardized clinical scoring tools for PeVD. METHODS: This scoping review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping reviews. Online databases were searched up to April 2023. Studies implementing a scoring or grading system for patients with confirmed or suspected PeVD were included. Scores or grading systems were classified into four main categories based on their use in the study: screening, diagnosis, measure of disease severity, and measure of response to treatment. RESULTS: Of the 2976 unique records identified, 82 were reviewed in full, and 20 were included in this study. The publication dates ranged from 1984 to 2023 (median, 2018; interquartile range, 2003-2022). A total of 21 scores and/or grading systems were identified. Of these 21 scores, 10 (47.6%) were clinical scores, and 10 (47.6%) were scores based on radiological findings; one study included a score that used both clinical and radiological findings. The identified scores were used in various settings. Of the 21 scores, 2 (9.52%) were used for screening in a tertiary care setting; 3 (14.3%) were used to establish the PeVD diagnosis; 8 (38.1%) were used to assess disease severity; and 8 (38.1%) were used as measures of response to treatment. Of the eight scores assessing disease severity, four (50.0%) assessed the degree of dilatation of pelvic veins and four (50%) assessed the severity of reflux. Only three of the scores were validated. CONCLUSIONS: This scoping review identified a range of scoring and grading systems for PeVD. We note a lack of a validated scoring system, both clinical and radiological, for screening and assessment of disease severity. This is an important first step in developing validated disease-specific scoring systems for patient screening, appropriate referral, assessment of symptom severity, and assessment of the response to treatment.


Assuntos
Dor Pélvica , Pelve , Índice de Gravidade de Doença , Humanos , Dor Pélvica/diagnóstico , Pelve/irrigação sanguínea , Feminino , Valor Preditivo dos Testes , Doenças Vasculares/diagnóstico , Doenças Vasculares/classificação , Doenças Vasculares/terapia , Doenças Vasculares/diagnóstico por imagem , Reprodutibilidade dos Testes , Veias/diagnóstico por imagem , Veias/fisiopatologia
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