Reasons and risk: factors underlying women's perceptions of susceptibility to osteoporosis

OBJECTIVES: To assess women's perceptions of risk for osteoporosis and to identify factors that shape those perceptions. METHODS: A community sample of 358 women (aged 40-86) rated their perceived risk of osteoporosis and provided detailed information about factors underlying their risk perceptions. Their open-ended responses were content analysed. RESULTS: On average, participants believed they were less likely to develop osteoporosis than other women their age. In all, 63% perceived their risk as lower than other women their age; only 16% as higher. In explaining their risk, women mentioned more risk-decreasing factors than risk-increasing factors. Women who rated their risk as low attributed their risk primarily to their own preventive behaviors (e.g. taking calcium, exercising), whereas women who rated their risk as high attributed their risk primarily to their family history. Risk-increasing and risk-decreasing personal actions, hereditary factors, and physiological factors accounted for 53% of the variance in perceived risk for osteoporosis. Only one-half and one-third of all women, however, mentioned calcium consumption and exercise, respectively, as protective factors employed to reduce osteoporosis risk. Women also held misconceptions about osteoporosis risk and protective factors. CONCLUSIONS: The current findings yield a detailed portrait of women's risk perceptions for osteoporosis. Increasing awareness of osteoporosis should be a priority for future osteoporosis prevention campaigns. Interventions should address misconceptions women may hold about their risk for the disease and promote specific behavioral strategies for osteoporosis prevention.     

Using an asthma control questionnaire and administrative data to predict health-care utilization

OBJECTIVE: To examine the merits of the Asthma Therapy Assessment Questionnaire (ATAQ) control index together with prior asthma health-care utilization from administrative data in predicting future acute asthma health-care utilization. DESIGN: Prospective cohort study. POPULATION: A total of 4,788 adult asthma patients aged 17 to 93 years who completed a baseline evaluation and had at least 6 months of follow-up data. STATISTICAL METHODS: Classification and regression tree methodology to predict future risk of acute health-care utilization events. RESULTS: These results show that the ATAQ control index and administrative data are jointly useful for predicting future health-care utilization. The utility of the ATAQ control index in the presence of information about prior health-care utilization is to further stratify risk among the subset of younger individuals who did not have any prior acute health-care utilization. While administrative health-care utilization data served as the strongest predictor of future health-care utilization, the ATAQ control index helped to identify 1% of individuals without recent acute care that had approximately a sixfold elevated risk (95% confidence interval, 4.2 to 8.4) of future acute health-care utilization. This is an important result since only a small fraction of individuals with acute events in a given year will have had acute events in the previous year. CONCLUSION: These findings should assist the practicing clinician and organizations interested in population-based asthma disease management.     

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor

Ciliary neurotrophic factor (CNTF) exerts anorectic effects by overcoming leptin resistance via activation of hypothalamic neurons. However, the exact site of CNTF action in the hypothalamus has not yet been identified. Using Cre-loxP-mediated recombination in vivo, we have selectively ablated the common cytokine signaling chain gp130, which is required for functional CNTF signaling, in proopiomelanocortin (POMC)-expressing neurons. POMC-specific gp130 knockout mice exhibit unaltered numbers of POMC cells and normal energy homeostasis under standard and high fat diet. Endotoxin (LPS) and stress-induced anorexia and adrenocorticotropin regulation were unaffected in these animals. Strikingly, the anorectic effect of centrally administered CNTF was abolished in POMC-specific gp130 knockout mice. Correspondingly, in these animals, CNTF failed to activate STAT3 phosphorylation in POMC neurons and to induce c-Fos expression in the paraventricular nucleus. These data reveal POMC neurons as a critical site of CNTF action in mediating its anorectic effect.     

ProNGF,a cytokine induced after myocardial infarction in humans,targets pericytes to promote microvascular damage and activation

Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro–nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75^NTR) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75^NTR in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75^NTR by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75^NTR in proNGF-expressing mice rescues the phenotype, confirming the importance of p75^NTR-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75^NTR limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.The primary therapeutic goal after acute myocardial infarction (MI) is to limit the duration of ischemia and to establish reperfusion using angioplasty or thrombolysis. However, even with improved arterial flow, a significant proportion of patients experience microvascular damage that leads to decreased microvascular perfusion and chronically impaired heart function (Eltzschig and Collard, 2004; Bekkers et al., 2010). At this time, the proinflammatory cytokines induced by ischemia that mediate microvascular dysfunction or apoptosis after cardiac ischemia remain largely unknown.We considered whether nerve growth factor (NGF), and specifically its uncleaved precursor proNGF, could act as a potential proapoptotic and proinflammatory cytokine in the ischemic heart. NGF is initially synthesized as proNGF, which is normally cleaved intracellularly to release mature NGF (Heymach and Shooter, 1995). Mature NGF binds to the TrkA receptor tyrosine kinase to mediate survival and differentiative effects in neurons (Reichardt, 2006). Under pathological conditions, proNGF is secreted and acts as a distinct ligand to promote neuronal apoptosis by binding to the p75 neurotrophin receptor (p75^NTR), a member of the tumor necrosis factor receptor family, and the transmembrane receptor sortilin (Lee et al., 2001; Nykjaer et al., 2004). This receptor complex activates stress and apoptotic signaling molecules, such as JNK (c-Jun N-terminal kinase) and caspase-3 (Nykjaer et al., 2005; Jansen et al., 2007; Volosin et al., 2008; Hempstead, 2009).ProNGF and p75^NTR are present at low to undetectable levels in normal, uninjured adult tissues (Fanburg-Smith and Miettinen, 2001; Harrington et al., 2004; Lommatzsch et al., 2005; Hempstead, 2009). However, they are rapidly induced after acute neuronal injury and mediate cell death or degeneration after seizures or axotomy (Harrington et al., 2004; Volosin et al., 2008). In addition, proNGF is up-regulated in neurodegenerative diseases and aging (Pedraza et al., 2005; Jansen et al., 2007). However, ngf mRNA is expressed in many organs, and secreted mature NGF promotes sympathetic innervation during development and regulates sympathetic tone in the adult (Donovan et al., 1995; Glebova and Ginty, 2005; Habecker et al., 2008). In the adult heart, mature NGF is secreted tonically by cardiac myocytes to modulate synaptic transmission by sympathetic neurons (Luther and Birren, 2006). Additionally, within hours of cardiac ischemia-reperfusion (I-R) injury in rodents, ngf mRNA is induced (Hiltunen et al., 2001), and immunoreactivity to the mature NGF domain increases in human hearts after acute MI (Meloni et al., 2010). These studies, however, do not distinguish whether mature NGF or proNGF is induced after cardiac ischemia. P75^NTR expression is also induced in the vasculature after acute injury to the aorta (Donovan et al., 1995), and p75^NTR activation promotes vascular smooth muscle and endothelial cell death in vitro (Wang et al., 2000; Kim et al., 2004). Genetic deletion of p75^NTR in mice (p75^−/−) results in reduced apoptosis of vascular smooth muscle cells after vascular injury, suggesting that locally produced neurotrophins regulate this response (Kraemer, 2002).The induction of ngf mRNA by cardiomyocytes and of p75^NTR by vascular cells after injury suggests a potential paracrine role for NGF or proNGF in modulating vascular integrity. Microvascular endothelial survival depends on reciprocal interactions with neighboring pericytes during development, and pericytes maintain microvascular structure and function in the adult animal (Gaengel et al., 2009). Disruption of endothelial cell–pericyte communication during development leads to vascular hemorrhage and embryonic death, as is readily observed in platelet-derived growth factor B (Pdgfb)– or platelet-derived growth factor receptor β (Pdgfrb)–deficient mice, where pericyte recruitment to specific vascular beds is impaired (Lindahl et al., 1997; Hellström et al., 1999; Bjarnegård et al., 2004). In adult mice, TGF-β and bone morphogenetic proteins play critical roles in maintaining pericyte survival and promoting microvascular integrity (El-Bizri et al., 2008; Walshe et al., 2009). These observations suggest that disruption of endothelial cell–pericyte interactions during cardiac microvascular maturation may lead to cardiac dysfunction later in life.In this study, we examined the expression of proNGF and its receptors, p75^NTR and sortilin-related VPS10 domain containing receptor 2 (SorCS2), a sortilin family member (Willnow et al., 2008), in the infarcted myocardium after cardiac ischemia in human autopsy material and in an established mouse model of I-R injury. We observed the induction of proNGF by cardiac myocytes and arterioles, and of p75^NTR and SorCS2 by mural cells of arterioles in the peri-infarct region of individuals who died after a recent MI. Comparable induction patterns were observed in mouse tissue after I-R injury. To investigate the consequences of proNGF expression on the cardiac vasculature, we generated and analyzed a knockin mouse that expresses one allele of cleavage-resistant proNGF (proNgf-hemagglutinin [HA]/⁺). We found that proNGF overexpression targets p75^NTR- and SorCS2-immunoreactive pericytes in the perinatal period, leading to a reduction of pericyte processes, microvascular endothelial activation, and increased vascular permeability in young adulthood, culminating in a dilated cardiomyopathy and premature lethality. This phenotype is rescued in mice that are deficient in p75^NTR. Furthermore, deficiency in p75^NTR limits the infarct size expansion after myocardial I-R injury, when compared with infarct size in wild-type mice. These observations identify proNGF and p75^NTR as potential therapeutic targets to limit microvascular dysfunction in the ischemic heart.     

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+ CD4+ T cells

1α,25‐Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL‐10‐secreting CD4⁺ T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3⁺ regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3⁺ and IL‐10⁺ CD4⁺T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL‐10 at more moderate levels, with little coexpression of these molecules. The Foxp3⁺ and IL‐10⁺ T‐cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL‐10. 1α25VitD3 enables the selective expansion of Foxp3⁺ Treg cells over their Foxp3^? T‐cell counterparts. Equally, 1α25VitD3 maintains Foxp3⁺ expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4⁺Foxp3⁺ T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL‐10⁺ and Foxp3⁺ Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.