Spinal Palpation Error and Its Impact on Skin Marker-Based Spinal Alignment Measurement in Adult Spinal Deformity

Spinal alignment measurement in spinal deformity research has recently shifted from using mainly two-dimensional static radiography toward skin marker-based motion capture approaches, allowing three-dimensional (3D) assessments during dynamic conditions. The validity and accuracy of such skin marker-based methods is highly depending on correct marker placement. In this study we quantified, for the first time, the 3D spinal palpation error in adult spinal deformity (ASD) and compared it to the error in healthy spines. Secondly, the impact of incorrect marker placement on the accuracy of marker-based spinal alignment measurement was investigated. 3D, mediolateral and inferosuperior palpation errors for thoracolumbar and lumbar vertebral levels were measured on biplanar images by extracting 3D positions of skin-mounted markers and their corresponding anatomical landmarks in 20 ASD and 10 healthy control subjects. Relationships were investigated between palpation error and radiographic spinal alignment (lordosis and scoliosis), as well as body morphology [BMI and soft tissue (ST) thickness]. Marker-based spinal alignment was measured using a previously validated method, in which a polynomial is fit through the marker positions of a motion trial and which allows for radiograph-based marker position correction. To assess the impact of palpation error on spinal alignment measurement, the agreement was investigated between lordosis and scoliosis measured by a polynomial fit through, respectively, (1) the uncorrected marker positions, (2) the palpation error-corrected (optimal) marker positions, and (3) the anatomically corrected marker positions (toward the vertebral body), and their radiographic equivalents expressed as Cobb angles (ground truth), using Spearman correlations and root mean square errors (RMSE). The results of this study showed that, although overall accuracy of spinal level identification was similar across groups, mediolateral palpation was less accurate in the ASD group (ASDmean: 6.8 mm; Controlmean: 2.5 mm; p = 0.002). Significant correlations with palpation error indicated that determining factors for marker misplacement were spinal malalignment, in particular scoliotic deformity (r = 0.77; p < 0.001), in the ASD group and body morphology [i.e., increased BMI (rs = 0.78; p = 0.008) and ST thickness (rs = 0.66; p = 0.038)] in healthy spines. Improved spinal alignment measurements after palpation error correction, shows the need for radiograph-based marker correction methods, and therefore, should be considered when interpreting spinal kinematics

Human multipotent adult progenitor cells enhance islet function and revascularisation when co-transplanted as a composite pellet in a mouse model of diabetes

AIMS/HYPOTHESIS: Hypoxia in the initial days after islet transplantation leads to considerable loss of islet mass and contributes to disappointing outcomes in the clinical setting. The aim of the present study was to investigate whether co-transplantation of human non-endothelial bone marrow-derived multipotent adult progenitor cells (MAPCs), which are non-immunogenic and can secrete angiogenic growth factors during the initial days after implantation, could improve islet engraftment and survival.METHODS: Islets (150) were co-transplanted, with or without human MAPCs (2.5 × 105) as separate or composite pellets, under the kidney capsule of syngeneic alloxan-induced diabetic C57BL/6 mice. Blood glucose levels were frequently monitored and IPGTTs were carried out. Grafts and serum were harvested at 2 and 5 weeks after transplantation to assess outcome.RESULTS: Human MAPCs produced high amounts of angiogenic growth factors, including vascular endothelial growth factor, in vitro and in vivo, as demonstrated by the induction of neo-angiogenesis in the chorioallantoic membrane assay. Islet-human MAPC co-transplantation as a composite pellet significantly improved the outcome of islet transplantation as measured by the initial glycaemic control, diabetes reversal rate, glucose tolerance and serum C-peptide concentration compared with the outcome following transplantation of islets alone. Histologically, a higher blood vessel area and density in addition to a higher vessel/islet ratio were detected in recipients of islet-human MAPC composites.CONCLUSIONS/INTERPRETATION: The present data suggest that co-transplantation of mouse pancreatic islets with human MAPCs, which secrete high amounts of angiogenic growth factors, enhance islet graft revascularisation and subsequently improve islet graft function

Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate, characterized by reduced frequencies of effector memory CD4+ T cells and a modest reduction in the frequency of IFNγ-producing CD4+ and CD8+ T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes

Spinal Palpation Error and Its Impact on Skin Marker-Based Spinal Alignment Measurement in Adult Spinal Deformity

Spinal alignment measurement in spinal deformity research has recently shifted from using mainly two-dimensional static radiography toward skin marker-based motion capture approaches, allowing three-dimensional (3D) assessments during dynamic conditions. The validity and accuracy of such skin marker-based methods is highly depending on correct marker placement. In this study we quantified, for the first time, the 3D spinal palpation error in adult spinal deformity (ASD) and compared it to the error in healthy spines. Secondly, the impact of incorrect marker placement on the accuracy of marker-based spinal alignment measurement was investigated. 3D, mediolateral and inferosuperior palpation errors for thoracolumbar and lumbar vertebral levels were measured on biplanar images by extracting 3D positions of skin-mounted markers and their corresponding anatomical landmarks in 20 ASD and 10 healthy control subjects. Relationships were investigated between palpation error and radiographic spinal alignment (lordosis and scoliosis), as well as body morphology [BMI and soft tissue (ST) thickness]. Marker-based spinal alignment was measured using a previously validated method, in which a polynomial is fit through the marker positions of a motion trial and which allows for radiograph-based marker position correction. To assess the impact of palpation error on spinal alignment measurement, the agreement was investigated between lordosis and scoliosis measured by a polynomial fit through, respectively, (1) the uncorrected marker positions, (2) the palpation error-corrected (optimal) marker positions, and (3) the anatomically corrected marker positions (toward the vertebral body), and their radiographic equivalents expressed as Cobb angles (ground truth), using Spearman correlations and root mean square errors (RMSE). The results of this study showed that, although overall accuracy of spinal level identification was similar across groups, mediolateral palpation was less accurate in the ASD group (ASDmean: 6.8 mm; Controlmean: 2.5 mm; p = 0.002). Significant correlations with palpation error indicated that determining factors for marker misplacement were spinal malalignment, in particular scoliotic deformity (r = 0.77; p &lt; 0.001), in the ASD group and body morphology [i.e., increased BMI (rs = 0.78; p = 0.008) and ST thickness (rs = 0.66; p = 0.038)] in healthy spines. Improved spinal alignment measurements after palpation error correction, shows the need for radiograph-based marker correction methods, and therefore, should be considered when interpreting spinal kinematics

Prevention of primary non-function of islet xenografts in autoimmune diabetic NOD mice by anti-inflammatory agents

El libro Libertad e igualdad en el Caribe colombiano de la profesora Aline Helg, muestra la pretensión en Colombia de instaurar una nación blanca. Inicialmente con la aceptación de una nación mestiza en aras de blanqueamiento y cómo en este contexto, las comunidades negras se desdibujaron e invisibilizaron; términos utilizados por la autora para abordar el fenómeno en el Caribe colombiano entre 1770 a 1835. Buena parte de la tesis acerca de la invisibilización afro en la región, sugiere la autora, fue la ausencia de una identidad negra, que les permitiera tener una acción política colectiva, donde lo racial fuera central, como sí sucedió en Haití

Inhibitory effects of interleukin-10 plasmid DNA on the development of atopic dermatitis-like skin lesions in NC/Nga mice

Interleukin (IL)-10 exerts potent anti-inflammatory effects by suppression of both T-help (Th) 1 and Th2 cells. Previous studies have reported that IL-10 can ameliorate various inflammatory disorders. The present study was performed to examine whether IL-10 plasmid DNA could suppress development of atopic dermatitis (AD)-like skin lesions in NC/Nga mice, as an initial step towards the development of an appliance for use in dogs with AD. Intradermal injection of IL-10 plasmid DNA markedly inhibited the development of AD-like skin lesions, as evidenced by a marked decrease in skin symptoms and reduced inflammation within the skin lesions. Efficacy was confirmed by significant decreases in eosinophil ratio and serum IgE concentration, and a reduction in the number of Staphylococcus aureus recovered from the ear. Moreover, relative mRNA expression levels of IL-4 and interferon-γ in the skin lesions of mice injected with IL-10 plasmid DNA were also decreased compared with those of control mice. Of note, higher serum IL-10 levels in mice injected with IL-10 plasmid DNA were maintained compared with those in control mice. Taken together, the results indicate that IL-10 plasmid DNA can suppress the development of AD-like skin lesions by suppressing both Th1 and Th2 cell responses. Beneficial effects of IL-10 plasmid DNA may be expected in dogs with AD

Study protocol : Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes

Introduction Type 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing beta cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12-45 years is antithymocyte globulin (ATG), Thymoglobuline, encouraging further exploration in lower age groups. Methods and analysis Minimal effective low dose (MELD)-ATG is a phase 2, multicentre, randomised, double-blind, placebo-controlled, multiarm parallel-group trial in participants 5-25 years diagnosed with T1D within 3-9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12-15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over two consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test at 12 months for 2.5 mg/kg ATG arm vs the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on (1) stimulated C-peptide, (2) glycated haemoglobin, (3) daily insulin dose, (4) time in range by intermittent continuous glucose monitoring measures, (5) fasting and stimulated dry blood spot (DBS) C-peptide measurements. Ethics and dissemination MELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA (An innovative approach towards understanding and arresting Type 1 diabetes consortium) grant agreement (www.innodia.eu).Peer reviewe

PTPN2, a Candidate Gene for Type 1 Diabetes, Modulates Interferon-γ–Induced Pancreatic β-Cell Apoptosis

OBJECTIVE: The pathogenesis of type 1 diabetes has a strong genetic component. Genome-wide association scans recently identified novel susceptibility genes including the phosphatases PTPN22 and PTPN2. We hypothesized that PTPN2 plays a direct role in beta-cell demise and assessed PTPN2 expression in human islets and rat primary and clonal beta-cells, besides evaluating its role in cytokine-induced signaling and beta-cell apoptosis. RESEARCH DESIGN AND METHODS: PTPN2 mRNA and protein expression was evaluated by real-time PCR and Western blot. Small interfering (si)RNAs were used to inhibit the expression of PTPN2 and downstream STAT1 in beta-cells, allowing the assessment of cell death after cytokine treatment. RESULTS: PTPN2 mRNA and protein are expressed in human islets and rat beta-cells and upregulated by cytokines. Transfection with PTPN2 siRNAs inhibited basal- and cytokine-induced PTPN2 expression in rat beta-cells and dispersed human islets cells. Decreased PTPN2 expression exacerbated interleukin (IL)-1beta + interferon (IFN)-gamma-induced beta-cell apoptosis and turned IFN-gamma alone into a proapoptotic signal. Inhibition of PTPN2 amplified IFN-gamma-induced STAT1 phosphorylation, whereas double knockdown of both PTPN2 and STAT1 protected beta-cells against cytokine-induced apoptosis, suggesting that STAT1 hyperactivation is responsible for the aggravation of cytokine-induced beta-cell death in PTPN2-deficient cells. CONCLUSIONS: We identified a functional role for the type 1 diabetes candidate gene PTPN2 in modulating IFN-gamma signal transduction at the beta-cell level. PTPN2 regulates cytokine-induced apoptosis and may thereby contribute to the pathogenesis of type 1 diabetes

IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection

We have recently demonstrated that peripheral CD8 T cells require two separate activation hits to accumulate to high numbers in the lungs after influenza virus infection: a primary interaction with mature, antigen-bearing dendritic cells (DCs) in the lymph node, and a second, previously unrecognized interaction with MHC I–viral antigen–bearing pulmonary DCs in the lungs. We demonstrate that in the absence of lung-resident DC subsets, virus-specific CD8 T cells undergo significantly increased levels of apoptosis in the lungs; however, reconstitution with pulmonary plasmacytoid DCs and CD8α+ DCs promotes increased T cell survival and accumulation in the lungs. Further, our results show that the absence of DCs after influenza virus infection results in significantly reduced levels of IL-15 in the lungs and that pulmonary DC–mediated rescue of virus-specific CD8 T cell responses in the lungs requires trans-presentation of IL-15 via DC-expressed IL-15Rα. This study demonstrates a key, novel requirement for DC trans-presented IL-15 in promoting effector CD8 T cell survival in the respiratory tract after virus infection, and suggests that this trans-presentation could be an important target for the development of unique antiviral therapies and more effective vaccine strategies