Complete diabetes protection despite delayed thymic tolerance in NOD8.3 TCR transgenic mice due to antigen-induced extrathymic deletion of T cells

Prevention of autoimmunity requires the elimination of self-reactive T cells during their development in the thymus and maturation in the periphery. Transgenic NOD mice that overexpress islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP) in antigen-presenting cells (NOD-IGRP mice) have no IGRP-specific T cells. To study the relative contribution of central and peripheral tolerance mechanisms to deletion of antigen-specific T cells, we crossed NOD-IGRP mice to highly diabetogenic IGRP206-214 T-cell receptor transgenic mice (NOD8.3 mice) and studied the frequency and function of IGRP-specific T cells in the thymus and periphery. Peripheral tolerance was extremely efficient and completely protected NOD-IGRP/NOD8.3 mice from diabetes. Peripheral tolerance was characterized by activation of T cells in peripheral lymphoid tissue where IGRP was expressed followed by activation-induced cell death. Thymectomy showed that thymic output of IGRP-specific transgenic T cells compensated for peripheral deletion to maintain peripheral T-cell numbers. Central tolerance was undetectable until 10 weeks and complete by 15 weeks. These in vivo data indicate that peripheral tolerance alone can protect NOD8.3 mice from autoimmune diabetes and that profound changes in T-cell repertoire can follow subtle changes in thymic antigen presentation.     

Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation

Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1β. We postulated that blockade of IL-1β would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F(ab')(2) fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti-IL-1β mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-1RA showed a more rapid rate of remission of diabetes than mice treated with anti-CD3 mAb or IL-1RA alone. Combination-treated mice had increased IL-5, IL-4, and interferon (IFN)-γ levels in circulation. There were reduced pathogenic NOD-relevant V7 peptide-V7(+) T cells in the pancreatic lymph nodes. Their splenocytes secreted more IL-10, had increased arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-γ, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies indicate that the combination of anti-CD3 mAb with IL-1RA is synergistic in reversal of diabetes through a combination of mechanisms. The combination causes persistent remission from islet inflammation.     

Back pain and restricted daily physical activity in the Spanish adult population

Background. Low back pain is a widespread health problem that affects a great part of the Spanish adult population; it also places a constraint on developing activities of daily living. The aim of this paper is to estimate the association between daily physical activity and chronic back pain in Spain. Material and methods. This paper analyses data from the European Health Survey in Spain 2009; it presents a cross sectional epidemiological study designed to assess the health of the Spanish population, in which 22,188 people participated (10,876 men and 11,312 women over 16 years ), representative of the total Spanish population. The variables studied are: back pain indicators obtained from the European Health Status Module and the European Health Care Module included in this survey, and the daily physical activity pattern obtained from the European Module of Health Determinants. Results. The total volume of daily physical activity is similar in healthy people and those who have back pain, but a pattern of low or moderate intensity in people with chronic back pain in the last twelve months (p <0.01) was observed with greater frequency. Conclusions. People with chronic back pain do not show a lower volume of physical activity, but their physical activity pattern is often low or moderate. Developing a vigorous pattern of physical activity should be considered not only as a strategy to prevent this disease, but also as a therapeutic target in these patients.     

Cystadenoma of the liver with high levels of ACE and CA 19-9 in the cyst

The development of a cystadenocarcinoma from previously benign cystadenoma is controversial. Neither clinical nor biological factors have been described to explain this transformation. High levels of serum and cystic CEA and CA 19-9 seem to help in the diagnosis of cystadenoma but not cystadenocarcinoma. Definitive histological evaluation is the only means to discriminate malignant from benign cysts. We report a case of cystadenoma of the liver with very high cystic levels and normal serum levels of CEA and CA 19-9.     

Autosomal dominant arthropathy in a French family

We studied a French family in which 18 adult members had destructive arthropathy and enthesopathic changes. In 16 patients, the diagnosis was verified radiologically, and in the 2 other patients, the clinical history was consistent with familial arthropathy. The disease predominantly affects the wrists, fingers, shoulders, and peripheral entheses, and its onset occurs after age 18. Genetic transmission is autosomal dominant, with 100% penetrance, and is not related to the HLA system. The clinical and radiologic features are strikingly similar in all patients in successive generations and different branches of the genealogic tree, and this suggests monogenic transmission.     

Prevalence and short-term mortality of acute-on-chronic liver failure: A national cohort study from the USA

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