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

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

Understanding non-governmental organizations in world politics: the promise and pitfalls of the early ‘science of internationalism’

The years immediately preceding the First World War witnessed the development of a significant body of literature claiming to establish a ‘science of internationalism’. This article draws attention to the importance of this literature, especially in relation to understanding the roles of non-governmental organizations in world politics. It elaborates the ways in which this literature sheds light on issues that have become central to twenty-first century debates, including the characteristics, influence, and legitimacy of non-governmental organizations in international relations. Amongst the principal authors discussed in the article are Paul Otlet, Henri La Fontaine and Alfred Fried, whose role in the development of international theory has previously received insufficient attention. The article concludes with evaluation of potential lessons to be drawn from the experience of the early twentieth century ‘science of internationalism’

Glucagon-Like Peptide-1 Protects Human Islets against Cytokine-Mediated β-Cell Dysfunction and Death: A Proteomic Study of the Pathways Involved

Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against cytokine-induced dysfunction and destruction. The mechanisms through which GLP-1 exerts its effects are complex and still poorly understood. The aim of this study was to analyze the protein expression profiles of human islets of Langerhans treated with cytokines (IL-1β and IFN-γ) in the presence or absence of GLP-1 by 2D difference gel electrophoresis and subsequent protein interaction network analysis to understand the molecular pathways involved in GLP-1-mediated β-cell protection. Co-incubation of cytokine-treated human islets with GLP-1 resulted in a marked protection of β-cells against cytokine-induced apoptosis and significantly attenuated cytokine-mediated inhibition of glucose-stimulated insulin secretion. The cytoprotective effects of GLP-1 coincided with substantial alterations in the protein expression profile of cytokine-treated human islets, illustrating a counteracting effect on proteins from different functional classes such as actin cytoskeleton, chaperones, metabolic proteins, and islet regenerating proteins. In summary, GLP-1 alters in an integrated manner protein networks in cytokine-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic patients.status: publishe

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

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults

Aims/hypothesis: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual’s clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. Methods: Data were collected from the large INNODIA cohort of individuals (aged 1.0–45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10–17 years; and ≥18 years. Results: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0–382.0) pmol/l (AUC 749.3 [466.2–1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). Conclusions/interpretation: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline. Graphical Abstract

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