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Background Vaccine injections are the most common painful needle procedure experienced throughout the lifespan. Many strategies are available to mitigate this pain; however, they are uncommonly utilized, leading to unnecessary pain and suffering. Some individuals develop a high level of fear and subsequent needle procedures are associated with significant distress. Objective The present work is part of an update and expansion of a 2009 knowledge synthesis to include the management of vaccine-related pain across the lifespan and the treatment of individuals with high levels of needle fear. This article will provide a conceptual foundation for understanding: (a) painful procedures and their role in the development and maintenance of high levels of fear; (b) treatment strategies for preventing or reducing the experience of pain and the development of fear; and (c) interventions for mitigating high levels of fear once they are established. Results First, the general definitions, lifespan development and functionality, needle procedure-related considerations, and assessment of the following constructs are provided: pain, fear, anxiety, phobia, distress, and vasovagal syncope. Second, the importance of unmitigated pain from needle procedures is highlighted from a developmental perspective. Third, the prevalence, course, etiology, and consequences of high levels of needle fear are described. Finally, the management of needle-related pain and fear are outlined to provide an introduction to the series of systematic reviews in this issue. Discussion Through the body of work in this supplement, the authors aim to provide guidance in how to treat vaccination-related pain and its sequelae, including high levels of needle fear.

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic beta-cell function are very limited. In the present study, we investigated the effect of genistein on beta-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet beta-cell proliferation after 24 h of incubation, with 5 mu M genistein inducing a maximal 27% increase. The effect of genistein on beta-cell proliferation was neither dependent on estrogen receptors nor shared by 17 beta-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated beta-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for beta-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet beta-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic beta-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway. (Endocrinology 151: 3026-3037, 2010) American Diabetes Association Virginia Commonwealth Health Research Board National Institutes of Health 1R21AT004694, R01 DK55240

International audience; Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel ␣-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patchclamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg 2؉-sensitive current observed only in infected cells, which was thus identified as the CNG current (I CNG). The ␤-adrenergic agonist isoprenaline (ISO) also activated I CNG , although the maximal efficiency was Ϸ5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca 2؉ current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO-and L-85-stimulated I CNG. A similar potentiation of ␤-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation of I CNG. This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE. Recent evidence indicates that multimolecular signaling complexes between cell surface receptors and intracellular tar