Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes.

Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single pro-inflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could well be explained by the widespread gene expression dysregulation known as "genomic storm" in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this "storm". Licensed pooled intravenous immunoglobulin preparations seemed to be a promising candidate but they have also failed in their present form to prevent sepsis-related death. We report here the protective effect of a single dose of intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of sepsis and aseptic systemic inflammation. The modification of the pooled immunoglobulin G molecules by exposure to ferrous ions resulted in their newly acquired ability to bind some pro-inflammatory molecules, complement components and endogenous "danger" signals. The improved survival in endotoxemia was associated with serum levels of pro-inflammatory cytokines, diminished complement consumption and normalization of the coagulation time. We suggest that intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in sepsis and related systemic inflammatory syndromes.

Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.

Different Kinds of Paraneoplastic Syndromes in Childhood Neuroblastoma

Background: Clinical presentations of paraneoplastic syndromes in neuroblastoma may multiply. Review of the clinical data and the literature on this syndrome may help in the diagnosis of neuroblastoma. Objectives: In order to make more accurate diagnosis, we reviewed the clinical data and the literature on this syndrome. Patients and Methods: Between April 2007 and April 2012, 68 children were diagnosed with neuroblastoma or ganglioneuroblastoma in our institution, 9 of which presented exclusively with paraneoplastic syndromes and were not treated with chemotherapy prior to diagnosis. After the diagnosis, all patients received chemotherapy and operation on NB97 protocol. Results: Among 68 pediatric patients with neuroblastoma or ganglioneuroblastoma, 4 (5.9%) patients suffered from neurological complications at diagnosis, 2 (2.9%) patients had digestive tract disorders, 2 (2.9%) patients had immune diseases, and 1 (1.5%) suffered from hematological disorder (without bone marrow involvement). All paraneoplastic syndrome patients achieved complete remission on paraneoplastic syndrome before completion of chemotherapy. Conclusions: Neuroblastoma may present with a range of non-specific neurologic symptoms in addition to the well-known opsoclonus-myoclonus syndrome and cerebellar ataxia. In any case, the presence of unexplained neurologic manifestations and other common clinical presentations such as rash, constipation, diarrhea, and especially immune disorders in an otherwise healthy child had raised the possibility of paraneoplastic syndrome due to the presence of an undiagnosed tumor.

Comparison of 3D finite element analysis derived stiffness and BMD to determine the failure load of the excised proximal femur

Introduction: Bone mineral density (BMD) is currently the preferred surrogate for bone strength in clinical practice. Finite element analysis (FEA) is a computer simulation technique that can predict the deformation of a structure when a load is applied, providing a measure of stiffness (Nmm−1). Finite element analysis of X-ray images (3D-FEXI) is a FEA technique whose analysis is derived froma single 2D radiographic image. Methods: 18 excised human femora had previously been quantitative computed tomography scanned, from which 2D BMD-equivalent radiographic images were derived, and mechanically tested to failure in a stance-loading configuration. A 3D proximal femur shape was generated from each 2D radiographic image and used to construct 3D-FEA models. Results: The coefficient of determination (R2%) to predict failure load was 54.5% for BMD and 80.4% for 3D-FEXI. Conclusions: This ex vivo study demonstrates that 3D-FEXI derived from a conventional 2D radiographic image has the potential to significantly increase the accuracy of failure load assessment of the proximal femur compared with that currently achieved with BMD. This approach may be readily extended to routine clinical BMD images derived by dual energy X-ray absorptiometry. Crown Copyright © 2009 Published by Elsevier Ltd on behalf of IPEM. All rights reserved

Social change grant-making : a failure of innovation?

Focusing primarily on Anglophone countries, this article begins by looking at the changing environment of foundations, the pressures on foundations and some responses to those pressures. It then focuses on the potential of a structural change approach - often known as 'social change' or 'social justice' grant-making - as a solution to some of the modern dilemmas of foundations, and considers why this approach has, with some exceptions, gained relatively little support. This raises the wider issues of why and how resource-independent, endowed foundations change when conventional explanations of organisational change do not easily apply. Researching a 'lack' is clearly difficult; this article adopts an analytic perspective, examining the characteristics of the structural change approach as a mimetic model, and draws on the work of Rogers (2003) on the characteristics required for the successful diffusion of innovations. It suggests that the structural change approach suffers from some fundamental weaknesses as a mimetic model, failing to meet some key characteristics for the diffusion of innovations. In conclusion, the article looks at conditions under which these weaknesses may be overcome.

Prognosis of bearing failure based on health state estimation

This paper proposes a new prognosis model based on the technique for health state estimation of machines for accurate assessment of the remnant life. For the evaluation of health stages of machines, the Support Vector Machine (SVM) classifier was employed to obtain the probability of each health state. Two case studies involving bearing failures were used to validate the proposed model. Simulated bearing failure data and experimental data from an accelerated bearing test rig were used to train and test the model. The result obtained is very encouraging and shows that the proposed prognostic model produces promising results and has the potential to be used as an estimation tool for machine remnant life prediction.