Background: Transgenic expression of human thrombomodulin (hTBM), which has the potential to solve the problem of coagulation dysregulation in pig-to-primate xenotransplantation, may have additional benefits by neutralizing the proinflammatory cytokine high-mobility group box 1 (HMGB1). The aim of this study was to investigate HMGB1-mediated effects on porcine aortic endothelial cells (PAEC) from wild-type (WT) and hTBM transgenic pigs. Methods: Porcine aortic endothelial cells were treated with HMGB1, human (h)TNF[alpha] or lipopolysaccharide (LPS). Procoagulant and proinflammatory responses were assessed by measuring expression of cell surface markers (adhesion molecules, fibrinogen-like protein 2, plasminogen activator inhibitor (PAI)-1), secretion of porcine cytokines and chemokines (HMGB1, TNF[alpha], IL-8, monocyte chemotactic protein-1), and formation of PAI-1/tissue plasminogen activator complexes. Thrombin-mediated degradation of HMGB1 in the presence of PAEC was examined by Western blot and functional assay. Results: High-mobility group box 1 potently activated WT PAEC, increasing the expression of E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, fibrinogen-like protein 2, and PAI-1, the secretion of TNF[alpha], IL-8, and monocyte chemotactic protein-1 and the formation of PAI-1/tissue plasminogen activator complexes. Human TNF[alpha]- or LPS-induced activation of WT PAEC was inhibited by treatment with rabbit anti-HMGB1 antibody. Transgenic expression of hTBM significantly reduced the activation of PAEC by HMGB1 or hTNF[alpha], and significantly enhanced thrombin-induced HMGB1 cleavage. Chemically induced shedding of the lectin-like domain of TBM resulted in significantly increased HMGB1-induced PAEC activation. Conclusions: High-mobility group box 1 exerts powerful proinflammatory and procoagulant effects on WT PAEC, and appears to be an important downstream mediator for the actions of hTNF[alpha] and LPS. Human thrombomodulin transgenic PAECs are less sensitive to activation by either HMGB1 or hTNF[alpha], an effect that appears to be dependent on the lectin-like domain of TBM. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Σάββατο 30 Ιουλίου 2016
Donor-Reactive Regulatory T-Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts.
Background: Acute cellular rejection is a major cause of morbidity after lung transplantation. Because regulatory T (Treg) cells limit rejection of solid organs, we hypothesized that donor-reactive Treg increase after transplantation with development of partial tolerance and decrease relative to conventional CD4+ (Tconv) and CD8+ T cells during acute cellular rejection. Methods: To test these hypotheses, we prospectively collected 177 peripheral blood mononuclear cell specimens from 39 lung transplant recipients at the time of transplantation and during bronchoscopic assessments for acute cellular rejection. We quantified the proportion of Treg, CD4+ Tconv, and CD8+ T cells proliferating in response to donor-derived, stimulated B cells. We used generalized estimating equation-adjusted regression to compare donor-reactive T-cell frequencies with acute cellular rejection pathology. Results: An average of 16.5 +/- 9.0% of pretransplantation peripheral blood mononuclear cell Treg cell were donor-reactive, compared with 3.8% +/- 2.9% of CD4+ Tconv and 3.4 +/- 2.6% of CD8+ T cells. These values were largely unchanged after transplantation. Donor-reactive CD4+ Tconv and CD8+ T-cell frequencies both increased 1.5-fold (95% confidence interval [95% CI], 1.3-1.6; P
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Transgenic Expression of Human Thrombomodulin Inhibits HMGB1-Induced Porcine Aortic Endothelial Cell Activation.
Background: Transgenic expression of human thrombomodulin (hTBM), which has the potential to solve the problem of coagulation dysregulation in pig-to-primate xenotransplantation, may have additional benefits by neutralizing the proinflammatory cytokine high-mobility group box 1 (HMGB1). The aim of this study was to investigate HMGB1-mediated effects on porcine aortic endothelial cells (PAEC) from wild-type (WT) and hTBM transgenic pigs. Methods: Porcine aortic endothelial cells were treated with HMGB1, human (h)TNF[alpha] or lipopolysaccharide (LPS). Procoagulant and proinflammatory responses were assessed by measuring expression of cell surface markers (adhesion molecules, fibrinogen-like protein 2, plasminogen activator inhibitor (PAI)-1), secretion of porcine cytokines and chemokines (HMGB1, TNF[alpha], IL-8, monocyte chemotactic protein-1), and formation of PAI-1/tissue plasminogen activator complexes. Thrombin-mediated degradation of HMGB1 in the presence of PAEC was examined by Western blot and functional assay. Results: High-mobility group box 1 potently activated WT PAEC, increasing the expression of E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, fibrinogen-like protein 2, and PAI-1, the secretion of TNF[alpha], IL-8, and monocyte chemotactic protein-1 and the formation of PAI-1/tissue plasminogen activator complexes. Human TNF[alpha]- or LPS-induced activation of WT PAEC was inhibited by treatment with rabbit anti-HMGB1 antibody. Transgenic expression of hTBM significantly reduced the activation of PAEC by HMGB1 or hTNF[alpha], and significantly enhanced thrombin-induced HMGB1 cleavage. Chemically induced shedding of the lectin-like domain of TBM resulted in significantly increased HMGB1-induced PAEC activation. Conclusions: High-mobility group box 1 exerts powerful proinflammatory and procoagulant effects on WT PAEC, and appears to be an important downstream mediator for the actions of hTNF[alpha] and LPS. Human thrombomodulin transgenic PAECs are less sensitive to activation by either HMGB1 or hTNF[alpha], an effect that appears to be dependent on the lectin-like domain of TBM. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Donor-Reactive Regulatory T-Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts.
Background: Acute cellular rejection is a major cause of morbidity after lung transplantation. Because regulatory T (Treg) cells limit rejection of solid organs, we hypothesized that donor-reactive Treg increase after transplantation with development of partial tolerance and decrease relative to conventional CD4+ (Tconv) and CD8+ T cells during acute cellular rejection. Methods: To test these hypotheses, we prospectively collected 177 peripheral blood mononuclear cell specimens from 39 lung transplant recipients at the time of transplantation and during bronchoscopic assessments for acute cellular rejection. We quantified the proportion of Treg, CD4+ Tconv, and CD8+ T cells proliferating in response to donor-derived, stimulated B cells. We used generalized estimating equation-adjusted regression to compare donor-reactive T-cell frequencies with acute cellular rejection pathology. Results: An average of 16.5 +/- 9.0% of pretransplantation peripheral blood mononuclear cell Treg cell were donor-reactive, compared with 3.8% +/- 2.9% of CD4+ Tconv and 3.4 +/- 2.6% of CD8+ T cells. These values were largely unchanged after transplantation. Donor-reactive CD4+ Tconv and CD8+ T-cell frequencies both increased 1.5-fold (95% confidence interval [95% CI], 1.3-1.6; P
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Obstructive sleep apnoea in patients with epilepsy: a meta-analysis
Abstract
Purpose
The aim of this study was to accurately determine the prevalence of obstructive sleep apnoea (OSA) in patients with epilepsy (PWE) and to evaluate the efficacy of seizure control after treating OSA.
Methods
Articles were identified through a search of both MEDLINE and Embase. The articles were collected and data were extracted independently by two authors. OSA was described using the following terms: Apnoea/hypopnoea index (AHI) and respiratory disturbance index (RDI). The variables were calculated using DerSimonian and Laird's random-effects model and odds ratio (OR).
Results
The prevalence of mild-to-severe OSA in PWE was determined to be 33.4 % (95 % CI 20.8–46.1 %), and PWE are more susceptible to OSA as compared to healthy controls (OR 2.36; 95 % CI 1.33–4.18). Males were shown to be more susceptible to OSA than females (OR 3.00; 95 % CI 2.25–3.99). The results also indicated that the prevalence of OSA in patients with refractory epilepsy is not higher than the prevalence of OSA in PWE overall (17.5 vs 33.4 %). The prevalence of OSA was not found to be significantly different for different seizure types or in the number of antiepileptic drugs (AEDs). Patients that had been treated with continuous positive airway pressure (CPAP) were shown to have better seizure control than those untreated (OR 5.26; 95 % CI 2.04–13.5).
Conclusions
The prevalence of OSA in PWE is higher than in the general population. Additionally, the results of our study suggest that CPAP treatment results in a reduction of seizures.
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Obstructive sleep apnoea in patients with epilepsy: a meta-analysis
Abstract
Purpose
The aim of this study was to accurately determine the prevalence of obstructive sleep apnoea (OSA) in patients with epilepsy (PWE) and to evaluate the efficacy of seizure control after treating OSA.
Methods
Articles were identified through a search of both MEDLINE and Embase. The articles were collected and data were extracted independently by two authors. OSA was described using the following terms: Apnoea/hypopnoea index (AHI) and respiratory disturbance index (RDI). The variables were calculated using DerSimonian and Laird's random-effects model and odds ratio (OR).
Results
The prevalence of mild-to-severe OSA in PWE was determined to be 33.4 % (95 % CI 20.8–46.1 %), and PWE are more susceptible to OSA as compared to healthy controls (OR 2.36; 95 % CI 1.33–4.18). Males were shown to be more susceptible to OSA than females (OR 3.00; 95 % CI 2.25–3.99). The results also indicated that the prevalence of OSA in patients with refractory epilepsy is not higher than the prevalence of OSA in PWE overall (17.5 vs 33.4 %). The prevalence of OSA was not found to be significantly different for different seizure types or in the number of antiepileptic drugs (AEDs). Patients that had been treated with continuous positive airway pressure (CPAP) were shown to have better seizure control than those untreated (OR 5.26; 95 % CI 2.04–13.5).
Conclusions
The prevalence of OSA in PWE is higher than in the general population. Additionally, the results of our study suggest that CPAP treatment results in a reduction of seizures.
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Correlation of cognitive and masticatory function in Alzheimer’s disease
Abstract
Objectives
This study investigated chewing function in elderly individuals with Alzheimer's disease (AD) and correlated chewing function with cognitive status.
Materials and methods
Sixteen elderly individuals with mild AD (mean age 76.7 ± 6.3 years; 8 men, 8 women) and 16 age and gender-matched healthy controls (mean age 75.23 ± 4.4 years; 8 men, 8 women) were included in this study. All volunteers wore removable prostheses: 11 were totally edentulous and five were partially edentulous in each group. Chewing function was evaluated via masticatory performance (MP) using Optocal chewable test material and a sieve fractionation method. Cognitive functioning was assessed by the Mini Mental State Exam (MMSE), administered by a trained examiner. Data were analyzed by non-paired t test and Pearson's correlation with α = 0.05.
Results
Compared to controls, mild AD patients had decreased MP (P < 0.01) and MMSE (P = 0.01). MP showed a moderate negative correlation with MMSE (r = −0.69).
Conclusions
Mild AD was associated with impaired chewing function.
Clinical relevance
Knowledge that mild AD has an impact on chewing is important for dental professionals in decision-making related to prosthetics and general dental treatment.
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Correlation of cognitive and masticatory function in Alzheimer’s disease
Abstract
Objectives
This study investigated chewing function in elderly individuals with Alzheimer's disease (AD) and correlated chewing function with cognitive status.
Materials and methods
Sixteen elderly individuals with mild AD (mean age 76.7 ± 6.3 years; 8 men, 8 women) and 16 age and gender-matched healthy controls (mean age 75.23 ± 4.4 years; 8 men, 8 women) were included in this study. All volunteers wore removable prostheses: 11 were totally edentulous and five were partially edentulous in each group. Chewing function was evaluated via masticatory performance (MP) using Optocal chewable test material and a sieve fractionation method. Cognitive functioning was assessed by the Mini Mental State Exam (MMSE), administered by a trained examiner. Data were analyzed by non-paired t test and Pearson's correlation with α = 0.05.
Results
Compared to controls, mild AD patients had decreased MP (P < 0.01) and MMSE (P = 0.01). MP showed a moderate negative correlation with MMSE (r = −0.69).
Conclusions
Mild AD was associated with impaired chewing function.
Clinical relevance
Knowledge that mild AD has an impact on chewing is important for dental professionals in decision-making related to prosthetics and general dental treatment.
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Παρασκευή 29 Ιουλίου 2016
Review of perforator flaps in head and neck cancer surgery.
Purpose of review: Perforator flaps are increasingly being used to reconstruct head and neck defects. They offer several advantages over nonperforator-based flaps with lower donor site morbidity and a versatile range of reconstructive options. The anterolateral thigh flap is well established in the head and neck and is a good example of a reliable perforator free flap. With the increasing use of both free and regional perforator-based flaps, it is timely to review their anatomy, clinical applications, and role in head and neck reconstruction. We also discuss increasingly popular perforator flaps such as the submental flap for the head and neck. Recent findings: The anterolateral thigh flap is now commonly used to reconstruct a wide variety of head and neck defects. The submental flap fills a niche role for reconstruction of intraoral defects. Summary: Perforator flaps are now mainstream reconstructive options in the head and neck surgeon's armamentarium. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Review of perforator flaps in head and neck cancer surgery.
Purpose of review: Perforator flaps are increasingly being used to reconstruct head and neck defects. They offer several advantages over nonperforator-based flaps with lower donor site morbidity and a versatile range of reconstructive options. The anterolateral thigh flap is well established in the head and neck and is a good example of a reliable perforator free flap. With the increasing use of both free and regional perforator-based flaps, it is timely to review their anatomy, clinical applications, and role in head and neck reconstruction. We also discuss increasingly popular perforator flaps such as the submental flap for the head and neck. Recent findings: The anterolateral thigh flap is now commonly used to reconstruct a wide variety of head and neck defects. The submental flap fills a niche role for reconstruction of intraoral defects. Summary: Perforator flaps are now mainstream reconstructive options in the head and neck surgeon's armamentarium. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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CD45RA distinguishes CD4+CD25+CD127-/low TSDR demethylated regulatory T cell subpopulations with differential stability and susceptibility to tacrolimus mediated inhibition of suppression.
Background: Adoptive transfer of FOXP3+ regulatory T cells (Treg) offers a promising strategy to reduce damage to an allograft by the recipient's immune system. Identification of cell surface markers sufficient to purify Treg expanded ex vivo to remove cellular contaminants requires optimisation. Furthermore, the expanded Treg must be able to survive, expand and suppress in allograft recipients exposed to immunosuppressants such as tacrolimus (TAC). Reduced CD127 expression enhances identification of Treg in the human CD4+CD25+ population. CD45RA expression identifies naive CD4+CD25+ Treg with an enhanced stability of Treg phenotype. Methods: We combine an analysis of CD45RA, CD25 and CD127 expression to identify subpopulations of CD4+CD127-/loCD25+ cells. Treg were sorted according to expression of CD25 and CD45RA and expanded in the presence of a physiological relevant concentration of tacrolimus. TSDR demethylation, FOXP3 expression and suppression were analysed. Results: CD4+CD127-/loCD25+CD45RA+ Treg had a stable TSDR demethylated FOXP3+ phenotype following expansion whilst CD4+CD127lo/-CD25+CD45RA- Treg lost the TSDR demethylated phenotype. CD45RA- Treg had a greater capacity to suppress following expansion with tacrolimus. Conclusions: Although CD45RA- Treg retained a greater suppressive capacity when expanded with TAC, the marked loss of the TSDR demethylated status highlights the potential for loss of stability of these cells in transplant recipients treated with TAC based immunosuppression. We show that a population of CD4+CD127-/loCD45RA+ Treg may offer the best compromise between susceptibility to loss of suppression when exposed to TAC and maintenance of a TSDR demethylated phenotype following in vitro expansion. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Donor-transmitted Atherosclerosis Associated with Worsening Cardiac Allograft Vasculopathy After Heart Transplantation: Serial Volumetric Intravascular Ultrasound Analysis.
Background: The influence of preexisting donor-transmitted atherosclerosis (DA) on cardiac allograft vasculopathy (CAV) development remains unclear. Methods: We performed 3-dimensional intravascular ultrasound (3D-IVUS) analysis in 42 heart transplant (HTx) recipients at 2.1+/-0.9 months (baseline) and 12.2+/-0.4 months post-HTx, as well as consecutive 3D-IVUS analyses up to 3 years post-HTx in 35 of the 42 recipients. DA was defined as a maximal intimal thickness (MIT) >=0.5 mm at baseline. Changes in volumetric IVUS parameters were compared in recipients with (DA group) and without DA (DA-free group) at baseline, 1 year and 3 years post-HTx. Results: DA was observed in 57.1% of 42 recipients. The DA group exhibited a significantly greater increase in plaque volume at 1 year post-HTx (P
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Increased CD40 ligation and reduced BCR signalling leads to higher IL-10 production in B cells from tolerant kidney transplant patients.
Background: An increased percentage of peripheral transitional B cells producing IL-10 has been observed in patients tolerant to kidney allografts. In healthy volunteers, the balance between the CD40 and B cell receptor (BCR) signalling modulated IL-10 production by B cells, with stimulation via the BCR decreasing CD40-mediated-IL-10 production. In this study, we evaluate whether in tolerant kidney transplant patients the increased IL-10 production by B cells was due to an altered CD40 and/or BCR signalling. Methods: B cells obtained from a new cohort of tolerant renal transplant recipients and those from age- and gender-matched healthy volunteers, were activated via CD40 and BCR, either alone or in combination. Results: In tolerant patients we observed higher percentages of B cells producing IL-10 after CD40 ligation and higher expression of CD40L on activated T cells, compared to healthy controls. Furthermore, B cells from tolerant recipients had reduced ERK signalling following BCR-mediated activation compared to healthy controls. In keeping with this, combining BCR signalling with CD40 ligation did not reduce IL-10 secretion as was observed in healthy control transitional B cells. Conclusion: Altogether our data suggests that the altered response of B cells in tolerant recipients may contribute to long-term stable graft acceptance. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Costimulation blockade in kidney transplantation: an update.
In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIsis associated with some degree of nephrotoxicity. This has led to exploring the blockadeof some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney-transplant patients is belatacept (Nulojix): a fusion protein that interferes with CTLA-4. Belatacep thas been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, i.e., no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, caused by the CTLA-4 pathway having an inhibitory effect on the allo-immune response. This has led to the development of antibodies that target CD28. The most advanced is FR104: it has shown promise in nonhuman primate models of autoimmune diseases and allo-transplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase-II studytesting ASK1240, i.e. anti-CD40 antibody has been completed and the results are pending. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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