The epidemiology and pathogenesis of type 1 diabetes mellitus in Africa

Type 1 diabetes is a serious, debilitating disease, with life-threatening complications, and the financial burden associated with the management of this disease is enormous. Early diagnosis and intervention can improve morbidity and mortality. Unfortunately, in Africa, type 1 diabetes is poorly characterised, and there is sparse information regarding the aetiology and epidemiology of this disease. However, there is some evidence of a later age of onset in African type 1 diabetic patients, compared to European diabetics, and it is thought that the prevalence of type 1 diabetes is lower in African populations than in the Western world.Keywords: type 1 diabetes, Africa, epidemiology, autoimmunity, susceptibilit

Hydration level is an internal variable for computing motivation to obtain water rewards in monkeys

In the process of motivation to engage in a behavior, valuation of the expected outcome is comprised of not only external variables (i.e., incentives) but also internal variables (i.e., drive). However, the exact neural mechanism that integrates these variables for the computation of motivational value remains unclear. Besides, the signal of physiological needs, which serves as the primary internal variable for this computation, remains to be identified. Concerning fluid rewards, the osmolality level, one of the physiological indices for the level of thirst, may be an internal variable for valuation, since an increase in the osmolality level induces drinking behavior. Here, to examine the relationship between osmolality and the motivational value of a water reward, we repeatedly measured the blood osmolality level, while 2 monkeys continuously performed an instrumental task until they spontaneously stopped. We found that, as the total amount of water earned increased, the osmolality level progressively decreased (i.e., the hydration level increased) in an individual-dependent manner. There was a significant negative correlation between the error rate of the task (the proportion of trials with low motivation) and the osmolality level. We also found that the increase in the error rate with reward accumulation can be well explained by a formula describing the changes in the osmolality level. These results provide a biologically supported computational formula for the motivational value of a water reward that depends on the hydration level, enabling us to identify the neural mechanism that integrates internal and external variables

Long-Lived Plasma Cells and Memory B Cells Produce Pathogenic Anti-GAD65 Autoantibodies in Stiff Person Syndrome

Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic twins suffering from SPS, who were treated with the B cell-depleting monoclonal anti-CD20 antibody rituximab, we found that the humoral autoimmune response in SPS is composed of a rituximab-sensitive part that is rapidly cleared after treatment, and a rituximab-resistant component, which persists and acts as a reservoir for autoantibodies inhibiting GAD65 enzyme activity. Our data show that these potentially pathogenic anti-GAD65 autoantibodies are secreted by long-lived plasma cells, which may either be persistent or develop from rituximab-resistant memory B lymphocytes. Both subsets represent only a fraction of anti-GAD65 autoantibody secreting cells. Therefore, the identification and targeting of this compartment is a key factor for successful treatment planning of SPS and of similar autoimmune diseases

Multiplicity of the antibody response to GAD65 in Type I diabetes

Type I diabetes (TID) is an autoimmune disease characterized in part by the presence of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65), among other pancreatic islet antigens. We investigated the independent epitope specificities of these GAD65 antibodies (GAD65Ab) and their combinations in the sera of new onset TID patients and first-degree relatives positive for GAD65Ab. For our analysis, we used four GAD65-specific recombinant Fabs (rFabs) that recognize different conformational determinants of GAD65 located throughout the molecule, including the N-terminal, the middle and the C-terminal regions. We used these epitope-specific rFabs in competition assays to determine the binding specificity of the autoantibodies found in patient sera. Among the 61 sera from newly diagnosed GAD65Ab-positive TID patients GAD65 binding was competed for 23 sera by all four rFabs, 29 by at least two rFabs, and in nine sera were displaced by one or no rFab. In contrast, none of the 24 sera from GAD65Ab-positive first-degree relatives of TID patients were displaced by all four rFabs. When using all four rFabs simultaneously to compete with GAD65Ab binding, binding of sera from TID patients was reduced by an average of 70%. A significantly weaker competition was observed when evaluating sera of GAD65Ab-positive first-degree relatives (P < 0·0001)

Longitudinal epitope analysis of insulin-binding antibodies in type 1 diabetes

Autoantibodies to insulin (IAA) are one of the first markers of the autoimmune process leading to type 1 diabetes (T1D). While other autoantibodies in T1D have been studied extensively, relatively little is known about IAA and their binding specificities, especially after insulin treatment is initiated. We hypothesize that insulin antibodies (IA) that develop upon initiation of insulin treatment differ in their epitope specificities from IAA. We analysed insulin antibody binding specificities in longitudinal samples of T1D patients (n = 49). Samples were taken at clinical diagnosis of disease and after insulin treatment was initiated. The epitope specificities were analysed using recombinant Fab (rFab) derived from insulin-specific monoclonal antibodies AE9D6 and CG7C7. Binding of radiolabelled insulin by samples taken at onset of the disease was significantly reduced in the presence of rFab CG7C7 and AE9D6. rFab AE9D6 competed sera binding to insulin significantly better than rFab CG7C7 (P = 0·02). Binding to the AE9D6-defined epitope in the initial sample was correlated inversely with age at onset (P = 0·005). The binding to the AE9D6-defined epitope increased significantly (P < 0·0001) after 3 months of insulin treatment. Binding to the CG7C7-defined epitope did not change during the analysed period of 12 months. We conclude that epitopes recognized by insulin binding antibodies can be identified using monoclonal insulin-specific rFab as competitors. Using this approach we observed that insulin treatment is accompanied by a change in epitope specificities in the emerging IA

Financial Stability, Regulation, Supervision, and Modern Central Banking

A discussion of the relationship between central banking and financial regulation and supervision, at the theoretical and policy leve