Objective. Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Trans cutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. This study was undertaken to investigate if using TENS during activity would improve movement evoked pain and other patient reported outcomes in women with FM.Methods. Participants were randomly assigned to receive active TENS (n = 103), placebo TENS (n = 99), or no TENS (n = 99) and instructed to use it at home during activity 2 hours each day for 4 weeks. TENS was applied to the lumbar and cervicothoracic regions using a modulated frequency (2-125 Hz) at the highest tolerable intensity. Participants rated movement evoked pain (primary outcome measure) and fatigue on an 11 point scale before and during application of TENS. The primary outcome measure and secondary patient reported outcomes were assessed at baseline (time of randomization) and at 4 weeks.Results. After 4 weeks, a greater reduction in movement evoked pain was reported in the active TENS group versus the placebo TENS group (group mean difference -1.0 [95% confidence interval -1.8, -0.2]; P = 0.008) and ver sus the no TENS group (group mean difference -1.8 [95% confidence interval -2.6, -1.0]; P < 0.0001). A reduction in movement evoked fatigue was also reported in the active TENS group versus the placebo TENS group (group mean difference -1.4 [95% confidence interval -2.4, -0.4]; P = 0.001) and versus the no TENS group (group mean difference -1.9 [95% confidence interval -2.9, -0.9]; P = <0.0001). A greater percentage of the patients in the active TENS group reported improvement on the global impression of change compared to the placebo TENS group (70% versus 31%; P < 0.0001) and the no TENS group (9%; P < 0.0001). There were no TENS related serious adverse events, and <5% of participants experienced minor adverse events from TENS.Conclusion. Among women who had FM and were on a stable medication regimen, 4 weeks of active TENS use compared to placebo TENS or no TENS resulted in a significant improvement in movement evoked pain and other clinical outcomes. Further research is needed to examine effectiveness in a real world setting to establish the clinical importance of these findings.

This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a subset expressing autoantibodies associated with the early stages of T1D. RESEARCH DESIGN AND METHODS MRI was performed in individuals with recent-onset stage 3 T1D (n = 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants (n = 57) and in autoantibody-positive individuals without diabetes (n = 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition. RESULTS Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL; P < 0.001), including when normalized by individual weight (P < 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis (P < 0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than that of the T1D cohort (P = 0.017) but smaller than that of the control cohort (P = 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient (P = 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution. CONCLUSIONS These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes. Reduced pancreas size has been noted in individuals with long-standing type 1 diabetes (T1D) (1-3). Because pancreatic islets comprise only 1-2% of the pancreatic mass, the reason for the smaller pancreas in T1D is not known, but changes in the exocrine pancreas are implicated. More recently, studies in adults with recent-onset

Effective central tolerance is required to control the large extent of autoreactivity normally present in the developing B cell repertoire. Insulin-reactive B cells are required for T1D in the NOD mouse, as engineered mice lacking this population are protected from disease. The VH125Tg model is used to define this population, which is found with increased frequency in the periphery of NOD vs. non-autoimmune C57BL/6 VH125Tg mice, but the ontogeny of this disparity is unknown. To better understand the origins of these pernicious B cells, anti-insulin B cells were tracked during development in the polyclonal repertoire of VH125Tg mice. An increased proportion of insulin-binding B cells is apparent in NOD mice at the earliest point of antigen commitment in the bone marrow. Two predominant light chains were identified in B cells that bind heterologous insulin. Interestingly, Vκ4-57-1 polymorphisms that confer a CDR3 Pro-Pro motif enhance self-reactivity in VH125Tg/NOD mice. Despite binding circulating autoantigen in vivo, anti-insulin B cells transition from the parenchyma to the sinusoids in the bone marrow of NOD mice and enter the periphery unimpeded. Anti-insulin B cells expand at the site of autoimmune attack in the pancreas and correlate with increased numbers of IFN-γ producing cells in the repertoire. These data identify failure to cull autoreactive B cells in the bone marrow as the primary source of anti-insulin B cells in NOD mice, and suggest that dysregulation of central tolerance permits escape into the periphery to promote disease.

B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoAbs that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL/6 mice that harbor anti-insulin VDJH-125 site-directed to the native Ig H chain locus (VH125SD). Class switch-competent anti-insulin B cells fail to produce IgG Abs following T cell-dependent (TD) immunization of VH125SD mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, co-stimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Further, VH125SD mice produce both IgM and IgG2a anti-insulin Abs following immunization with a conjugate of insulin to type 1 T cell-independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM+ and IgM− GL7+ Fas+ germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Igκ genes in VH125SD mice immunized with insulin-BRT reveals that anti-insulin Vκ from the pre-immune repertoire are selected into GCs. These data demonstrate that class switch-competent anti-insulin B cells remain functionally silent in TD immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet under-appreciated role in driving loss of tolerance and promoting autoimmune disease.

A 27-year-old woman with essential thrombocythaemia (ET) had three miscarriages. She was treated with alpha interferon which was continued after she became pregnant again. The platelet count remained well controlled and at term she delivered a healthy baby with normal blood counts. The case demonstrates the effectiveness of IFN in preventing recurrent miscarriage associated with ET and the safety of IFN with respect to fertility and fetal development.