Parameters of injury reporting in skiing

An injury survey of 505 skiers from the 1971-72 and 5,459 skiers from thh 1972-73 season collected 601 time loss injries for a rate of 9.31000 skier days. Forty percent of these injuries were reported to a ski patrol and almost 60 to physicians. Fractures and lacerations were reported to the patrol more frequently than other injury types, bruises and strains less commonly. Injuries not reported to patrols and physicians were primarily bruises, sprains and strains. Although fractures were almost invariably reported to physicians, one in four was not seen by the ski patrol. Patrol-only or physician only reported injuries thus do not represent the full spectrum of time loss skiing injuries.     

HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/γc(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells

OBJECTIVE

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes.

RESEARCH DESIGN AND METHODS

We adoptively transferred HLA-A2–matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc^null/HLA-A*0201 (NOD-scid/γc^null/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γc^null/A2 mice after transfer.

RESULTS

Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γc^null/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γc^null/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2–matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8⁺ T cells among the islet infiltrates.

CONCLUSIONS

We show that insulitis is transferred to NOD-scid/γc^null/A2 mice that received HLA-A2–matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8⁺ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γc^null/A2 mice transferred with HLA-A2–matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell–mediated responses in patients with type 1 diabetes.NOD mice develop spontaneous diabetes due to autoimmune destruction of pancreatic β-cells. These mice have served as a useful tool for understanding many aspects of type 1 diabetes (1,2). For example, the identification of certain pathogenic epitopes were originally found in NOD mice and subsequently observed in the blood of type 1 diabetic patients (3). The major shortcoming of these studies is their inability to evaluate the human autoreactive effector cells directly. Researchers have identified a number of pathogenic autoreactive epitopes of CD4⁺ and CD8⁺ T cells that recognize and result in β-cell killing. Epitopes for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), insulin, and preproinsulin have been identified in the islets of NOD mice (4). T cells specific for epitopes from these proteins and other islet proteins, including islet amyloid polypeptide (IAPP), have been found in the blood of type 1 diabetic patients (5). At the same time, however, many of the findings in NOD mice have not directly translated to human type 1 diabetes. Importantly, a large number of therapies appear to “cure” diabetes in NOD mice, but these therapies have not readily translated to humans. Anti-CD3 antibody therapy, which is extremely effective in NOD mice (6,7), is less effective in patients (8,9). These immunomodulatory therapies still leave concerns about their effects, as discussed by Santamaria (10). Other immune therapies aimed at targeting B cells, such as anti-CD20 monoclonal antibody treatment, also offer short-term CD19⁺ B-cell depletion and partially preserve β-cell function (11).Development of humanized mice in which HLA-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients are adoptively transferred into immune-deficient mice would provide a means of studying human immune cells without the restrictions inherent to human studies (12). Specifically, it would be possible to identify human autoreactive epitope-specific T cells that infiltrate the islets directly ex vivo. A small-animal model that recapitulates the clinical manifestations of type 1 diabetes would also assist in identifying novel therapeutic targets and in developing and testing novel immunotherapeutic agents. Furthermore, we would be able to investigate the mechanisms involved in disease pathogenesis of many other autoimmune diseases, especially those with disease-associated epitopes, shared between humans and mice (13,14).During the past several years, many investigators have used human hematopoietic stem cells (HSCs) for engraftment into immunodeficient mice (15–17). These studies have attempted to develop a complete human immune system in a murine host. In many cases, successful engraftment and cell differentiation was observed. Most recently, investigators showed that functional human CD4⁺ and CD8⁺ T cells developed after being transferred into immune-deficient HLA transgenic mice and that these T cells demonstrated HLA-restricted responses (18). In contrast, our goal was not to recapitulate the entire autoimmune process; rather, we sought to develop a humanized mouse model that would be useful for identifying pre-existing autoreactive diabetogenic circulating T cells from type 1 diabetic patients that are important in the direct pathogenesis of type 1 diabetes.In NOD mice, β-cell–specific CD8⁺ T-cell clones are found in the peripheral blood and pancreatic islets (19). In patients with type 1 diabetes, epitope-specific T cells display T-lymphocyte cytotoxic activity toward human β-cells (20). Humans and mice also share many of the protein sequences of identified epitopes (21). Therefore, because it is likely that lymphocytes that have been exposed to islet antigens circulate within the blood of patients with type 1 diabetes, we adoptively transferred peripheral blood mononuclear cells (PBMCs) from HLA-A2–matched type 1 diabetic patients into transgenic NOD-scid/γc^null/HLA-A*0201 (NOD-scid/γc^null/A2) mice (22).

TABLE 1

Type 1 diabetic and nondiabetic haplotype-matched PBMC donors used in transfer experiments^*

Polycomb eviction as a new distant enhancer function

Remote distal enhancers may be located tens or thousands of kilobases away from their promoters. How they control gene expression is still poorly understood. Here, we analyze the influence of a remote enhancer on the balance between repression (Polycomb-PcG) and activation (Trithorax-TrxG) of a developmentally regulated gene associated with a CpG island. We reveal its essential, nonredundant role in clearing the PcG complex and H3K27me3 from the CpG island. In the absence of the enhancer, the H3K27me3 demethylase (JMJD3) is not recruited to the CpG island. We propose a new role of long-range regulatory elements in removing repressive PcG complexes.     

Banking for the future: an Australian experience in brain banking

The New South Wales (NSW) Tissue Resource Centre (TRC) has been set up to provide Australian and international researchers with fixed and frozen brain tissue from cases that are well characterised, both clinically and pathologically, for projects related to neuropsychiatric and alcohol-related disorders. A daily review of the Department of Forensic Medicine provides initial information regarding a potential collection. If the case adheres to the strict inclusion criteria, the pathologist performing the postmortem examination is approached regarding retention of the brain tissue. The next of kin of the deceased is then contacted requesting permission to retain the brain for medical research. Cases are also obtained through donor programmes, where donors are assessed and consent to donate their brain during life. Once the brain is removed at autopsy, the brain is photographed, weighed and the volume determined, the brainstem and cerebellum are removed. The two hemispheres are divided, one hemisphere is fresh frozen and one fixed (randomised). Prior to freezing, the hemisphere is sliced into 1-cm coronal slices and a set of critical area blocks is taken. All frozen tissues are kept bagged at -80 degrees C. The other hemisphere is fixed in 15% buffered formalin for 2 weeks, embedded in agar and sliced at 3-mm intervals in the coronal plane. Tissue blocks from these slices are used for neuropathological analysis to exclude any other pathology. The TRC currently has 230 cases of both fixed and frozen material that has proven useful in a range of techniques in many research projects. These techniques include quantitative analyses of brain regions using neuropathological, neurochemical, neuropharmacological and gene expression assays.     

Wireless Body Area Network (WBAN) Design Techniques and Performance Evaluation

In recent years interest in the application of Wireless Body Area Network (WBAN) for patient monitoring applications has grown significantly. A WBAN can be used to develop patient monitoring systems which offer flexibility to medical staff and mobility to patients. Patients monitoring could involve a range of activities including data collection from various body sensors for storage and diagnosis, transmitting data to remote medical databases, and controlling medical appliances, etc. Also, WBANs could operate in an interconnected mode to enable remote patient monitoring using telehealth/e-health applications. A WBAN can also be used to monitor athletes’ performance and assist them in training activities. For such applications it is very important that a WBAN collects and transmits data reliably, and in a timely manner to a monitoring entity. In order to address these issues, this paper presents WBAN design techniques for medical applications. We examine the WBAN design issues with particular emphasis on the design of MAC protocols and power consumption profiles of WBAN. Some simulation results are presented to further illustrate the performances of various WBAN design techniques.     

Hepatitis C virus entry: beyond receptors

HCV is a blood-borne pathogen that affects approximately 3% of the global population and leads to progressive liver disease. Recent advances have identified an essential role for host cell molecules: tetraspanin CD81, scavenger receptor B1 and the tight junction proteins claudin-1 and occludin in HCV entry, suggesting a complex multi-step process. The conserved nature of this receptor-dependent step in the viral life cycle offers an attractive target for therapeutic intervention. Evidence is emerging that additional factors other than classical receptors, such as inflammatory mediators regulate the ability of hepatocytes to support HCV entry, and as such may provide potential avenues for drug design and development. In this review, we summarise the recent literature on HCV entry mechanisms with a view to realising the future potential of therapeutically targeting this process.     

Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139

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