Citations

AbstractTNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), is mutated in 10% of patients with common variable immune deficiency (CVID). One of the 2 most common TACI mutations in CVID, A181E, introduces a negative charge into the transmembrane domain. To define the consequence of the A181E mutation on TACI function, we studied the effect of its murine equivalent, mTACI A144E, on TACI signaling in transfected cells and on TACI function in transgenic mice. The mTACI A144E mutant, like its human TACI A181E counterpart, was expressed on the surface of 293T transfectants and was able to bind ligand, but exhibited impaired constitutive and ligand-induced NFκB signaling. In addition, constitutive and ligand-induced clustering of the intracellular domain was deficient for A144E as measured by fluorescence resonance energy transfer. Transgenic mice expressing the A144E mutant on TACI−/− background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll. B cells from A144E transgenic mice were impaired in their capacity to proliferate and secrete IgG1 and IgA in response to TACI ligation. These results suggest that mTACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions.

Objective: The aim of the study was to assess adding vs. switching to teriparatide 20μg/d in patients on alendronate or raloxifene. Design: We conducted a randomized, open-label trial. Patients and Interventions: Postmenopausal women with osteoporosis on alendronate or raloxifene for at least 18 months added teriparatide (Add groups) or switched to teriparatide (Switch groups) for 18 months. Main Outcome Measures: We measured bone turnover markers (BTM) and bone mineral density (BMD). Results: In the alendronate stratum, increases in BTM were smaller in the Add vs. Switch group [6-month PINP (64 vs. 401%); bone ALP (15 vs. 71%); βCTX (27 vs. 250%); all P < 0.001]. However, at 6 months, total hip BMD increased more in the Add vs. Switch group (1.4 vs. −0.8%; P = 0.002). In the Add vs. Switch group, 18-month BMD increments were higher in lumbar spine (8.4 vs. 4.8%; P = 0.003) and total hip (3.2 vs. 0.9%; P = 0.02), but not in femoral neck (2.7 vs. 2.3%; P = 0.75). In the raloxifene stratum, increases in BTM were also smaller in the Add vs. Switch group [6-month PINP (131 vs. 259%; P < 0.001), bone ALP (31 vs. 44%; P = 0.035), and βCTX (67 vs. 144%; P = 0.001)]. At 6 months, total hip BMD increase was greater in the Add vs. Switch group (1.8 vs. 0.5%; P = 0.028). At 18 months, increases in lumbar spine (9.2 vs. 8.1%), total hip (2.8 vs. 1.8%), and femoral neck (3.8 vs. 2.2%) were not significantly different between groups. Conclusions: In women with osteoporosis treated with antiresorptives, greater bone turnover increases were achieved by switching to teriparatide, whereas greater BMD increases were achieved by adding teriparatide. In patients treated with alendronate or raloxifene, adding teriparatide results in a greater bone mineral density response, and appears to be at least as safe as switching to teriparatide.

Abstract Hip fracture incidence appears to be declining in the United States, but changes in bone mineral density (BMD) of the population have not been evaluated. We used femur BMD data from the National Health and Nutrition Examination Survey (NHANES) 2005–2006 to estimate the prevalence of low femoral BMD in adults age 50 years and older and compared it with estimates from NHANES III (1988–1994). Dual-energy X-ray absorptiometry systems (pencil-beam geometry in NHANES III, fan-beam geometry in NHANES 2005–2006) were used to measure femur BMD, and World Health Organization (WHO) definitions of low BMD were used to categorize skeletal status. In 2005–2006, 49% of older US women had osteopenia and 10% had osteoporosis at the femur neck. In men, 30% had femur neck osteopenia and 2% had femur neck osteoporosis. An estimated 5.3 million older men and women had osteoporosis at the femur neck, and 34.5 million more had osteopenia in 2005–2006. When compared with NHANES III, the age-adjusted prevalence of femur neck osteoporosis in NHANES 2005–2006 was lower in men (by 3 percentage units) and women (by 7 percentage units) overall and among non-Hispanic whites. Changes in body mass index or osteoporosis medication use between surveys did not fully explain the decline in osteoporosis. Owing to the increase in the number of older adults in the US population, however, more older adults had low femur neck BMD (osteoporosis + osteopenia) in 2005–2006 than in 1988–1994. Thus, despite the decline in prevalence, the estimated number of affected older adults in 2005–2006 remained high. Copyright © 2010 American Society for Bone and Mineral Research

Abstract This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels < 200 mU/mL vs ≥ 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein+ CD34+ marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

Patients treated by pediatric interventional cardiologists and cardiac surgeons often have unmet medical device needs that pose a challenge to the current regulatory evaluation and approval process in the United States. In this report we review current US Food and Drug Administration regulatory processes, review some unique aspects of pediatric cardiology and cardiac surgery that pose challenges to these processes, and discuss possible alternate pathways to cardiac device evaluation and approval for children. Children deserve to benefit from new and refined cardiac devices and technology designed explicitly for their conditions.