Psychosocial Predictors of Self-reported Medical Adherence in Patients With Heart Failure Over 6 Months: An Examination of the Influences of Depression, Self-efficacy, Social Support, and Their Changes.

Background: Poor adherence to medical regimens is a serious problem that interferes with heart failure (HF) patients' disease management and contributes to poor clinical outcomes. Few prospective studies have examined the psychosocial predictors of adherence over time in HF patients. Purpose: This study examined the influences of depression, self-efficacy, social support, and their changes on self-reported medical adherence over 6 months in HF patients. Methods: Participants were 252 HF outpatients, among whom 168 completed follow-up assessments. Hierarchical multiple regression analyses were conducted to examine whether psychosocial variables and their changes prospectively predicted adherence at 6 months, after adjusting for baseline adherence, age, gender, ethnicity, marital status, education, HF severity, medical comorbidity, and mental health treatment. Results: Baseline self-efficacy (ß = .22, p < .05), increase in self-efficacy (ß = .34, p < .001), and decrease in depression (ß = -.15, p = .05) predicted improved adherence over 6 months, but social support did not. In the combined model that included all significant psychosocial predictors from previous analyses, baseline self-efficacy (ß = .37, p = .001) and its increase (ß = .35, p < .001) emerged as independent predictors of improved adherence at 6 months. Conclusions: Promoting self-efficacy and reducing depressive symptoms may be promising targets of behavioral interventions to facilitate long-term disease management in HF patients.

Self-efficacy mediates the associations of social support and depression with treatment adherence in heart failure patients.

BACKGROUND: Nonadherence to treatment recommendations is a leading preventable cause of rehospitalization and premature mortality in chronic heart failure (HF) patients. PURPOSE: This study examined whether self-efficacy mediates the contributions of social support and depression to treatment adherence. METHODS: A sample of 252 HF outpatients with a mean age of 54 years completed self-report questionnaires assessing depression, perceived social support, self-efficacy, and treatment adherence. RESULTS: Self-efficacy mediated the associations of social support and depression with treatment adherence after adjusting for demographic (age, gender, marital status, education, and ethnicity) and medical (New York Heart Association Classification and comorbidity) covariates. CONCLUSION: Self-efficacy explains the influence of social support and depression on treatment adherence and may be a key target for interventions to improve disease management and self-care behaviors in HF patients.

Depression and anxiety predict decline in physical health functioning in patients with heart failure.

BACKGROUND: Few studies have examined the prospective influences of depression and anxiety on physical health functioning in heart failure (HF) patients. Prior studies were also limited by employing psychological measures containing somatic items confounded with HF symptoms. PURPOSE: This study examined whether depression, anxiety, social support, and their changes predicted the decline of physical functioning in HF patients over 6 months. METHODS: Participants were 238 HF patients among whom 164 provided follow-up data. The depression and anxiety measures did not contain somatic items. RESULTS: After controlling for baseline physical functioning and demographic and medical covariates, baseline depression and its increase, as well as baseline anxiety and its increase, independently predicted greater decline in physical functioning at 6 months. Social support and its change were not associated with either concurrent or follow-up physical functioning. CONCLUSIONS: Depression, anxiety, and their changes independently predicted the decline of physical health functioning over 6 months.

The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation.

The anesthetic isoflurane has been reported to induce apoptosis and increase Abeta generation and aggregation. However, the molecular mechanism underlying these effects remains unknown. We therefore set out to assess whether the effects of isoflurane on apoptosis are linked to amyloid beta-protein (Abeta) generation and aggregation. For this purpose, we assessed the effects of isoflurane on beta-site amyloid beta precursor protein (APP)-cleaving enzyme (BACE) and gamma-secretase, the proteases responsible for Abeta generation. We also tested the effects of inhibitors of Abeta aggregation (iAbeta5, a beta-sheet breaker peptide; clioquinol, a copper-zinc chelator) on the ability of isoflurane to induce apoptosis. All of these studies were performed on naive human H4 neuroglioma cells as well as those overexpressing APP (H4-APP cells). Isoflurane increased the levels of BACE and gamma-secretase and secreted Abeta in the H4-APP cells. Isoflurane-induced Abeta generation could be blocked by the broad-based caspase inhibitor Z-VAD. The Abeta aggregation inhibitors, iAbeta5 and clioquinol, selectively attenuated caspase-3 activation induced by isoflurane. However, isoflurane was able to induce caspase-3 activation in the absence of any detectable alterations of Abeta generation in naive H4 cells. Finally, Abeta potentiated the isoflurane-induced caspase-3 activation in naive H4 cells. Collectively, these findings suggest that isoflurane can induce apoptosis, which, in turn, increases BACE and gamma-secretase levels and Abeta secretion. Isoflurane also promotes Abeta aggregation. Accumulation of aggregated Abeta in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, Abeta generation and aggregation, and additional rounds of apoptosis, leading to cell death.

Isoflurane-induced apoptosis: a potential pathogenic link between delirium and dementia.

BACKGROUND: Dementia and delirium have been postulated to share common pathophysiologic mechanisms; however, identification of these unifying mechanisms has remained elusive. The inhalation anesthetic isoflurane has been shown to enhance beta-amyloid protein (Abeta) oligomerization and generation, to potentiate the cytotoxicity of Abeta, and to induce apoptosis. To address the molecular mechanisms of dementia and delirium associated with anesthesia and surgery, we assessed whether the Abeta fibrillar aggregation inhibitor Congo red can attenuate isoflurane-induced caspase-3 activation in H4 human neuroglioma cells overexpressing human beta-amyloid precursor protein (APP). METHODS: H4 human neuroglioma cells stably transfected to express human full-length wild-type APP were exposed to 2% isoflurane for 6 hours. The cells were harvested at the end of the treatment. Caspase-3 activation was measured with quantitative Western blotting. RESULTS: We found that isoflurane induces cellular apoptosis in a dose-dependent manner, and that Congo red inhibits isoflurane-induced apoptosis in H4 human neuroglioma cells overexpressing APP. Interestingly, Congo red also inhibits staurosporine-induced apoptosis. CONCLUSION: The demonstration that isoflurane contributes to well-described mechanisms of Alzheimer's neuropathogenesis provides a plausible link between the acute effects of anesthesia, a well-described risk factor for delirium, and the more long-term sequelae of dementia. These findings suggest that isoflurane-induced Abeta oligomerization and apoptosis may contribute to the risk of postoperative cognitive dysfunction and provide a potential pathogenic link between delirium and dementia.

RNAi-mediated knock-down of Dab and Numb attenuate Aß levels via γ-secretase mediated APP processing.

Amyloid-ß-protein (Aß), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of ß-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aß production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aß levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided.

Standardized assessment of strategy use and working memory in early mental arithmetic performance.

Although children's use of a variety of strategies to solve arithmetic problems has been well documented, there is no agreed on standardized and validated method for assessing this mix. We examined the convergent validity of typically achieving (TA, N = 39) and low achieving (LA, N = 20) second and third grade children's strategy choices in simple addition using three different methods: child self-report, observer-report, and response time (RT). The high concordance between child and observer reports (Kappa = .948) in both groups suggests that the participants were aware of, and could accurately report, the strategies they used. The Receiver-Operator Characteristic (ROC) analysis showed that RT accurately differentiated between retrieval and counting (AUC = 82%). The specificity and sensitivity of the ROC profiles were significantly greater for the TA group than for LA group, even though the groups did not differ in the overall strategy mix. Our findings suggest that ROC analysis is more sensitive to group differences in the mechanisms governing strategy choice than observation or child report. Children's use of retrieval strategies as well as accuracy during both retrieval and counting trials were all related to the central executive, but not the phonological and visuospatial sketchpad, component of working memory. We discuss the implication of these findings for early mathematical learning.

RNA interference silencing of the adaptor molecules ShcC and Fe65 differentially affect amyloid precursor protein processing and Abeta generation.

The amyloid precursor protein (APP) and its pathogenic by-product amyloid-beta protein (Abeta) play central roles in Alzheimer disease (AD) neuropathogenesis. APP can be cleaved by beta-secretase (BACE) and alpha-secretase to produce APP-C99 and APP-C83. These C-terminal fragments can then be cleaved by gamma-secretase to produce Abeta and p3, respectively. p3 has been reported to promote apoptosis, and Abeta is the key component of senile plaques in AD brain. APP adaptor proteins with phosphotyrosine-binding domains, including ShcA (SHC1), ShcC (SHC3), and Fe65 (APBB1), can bind to and interact with the conserved YENPTY motif in the APP-C terminus. Here we have described for the first time the effects of RNA interference (RNAi) silencing of ShcA, ShcC, and Fe65 expression on APP processing and Abeta production. RNAi silencing of ShcC led to reductions in the levels of APP-C-terminal fragments (APP-CTFs) and Abeta in H4 human neuroglioma cells stably overexpressing full-length APP (H4-FL-APP cells) but not in those expressing APP-C99 (H4-APP-C99 cells). RNAi silencing of ShcC also led to reductions in BACE levels in H4-FL-APP cells. In contrast, RNAi silencing of the homologue ShcA had no effect on APP processing or Abeta levels. RNAi silencing of Fe65 increased APP-CTF levels, although also decreasing Abeta levels in H4-FL-APP cells. These findings suggest that pharmacologically blocking interaction of APP with ShcC and Fe65 may provide novel therapeutic strategies against AD.

The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels.

BACKGROUND: The common inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease-associated amyloid beta protein (Abeta), the principal peptide component of cerebral beta-amyloid deposits. METHODS: H4 human neuroglioma cells stably transfected to express human full-length wild-type amyloid precursor protein (APP) were exposed to 2% isoflurane for 6 h. The cells and conditioned media were harvested at the end of the treatment. Caspase-3 activation, processing of APP, cell viability, and Abeta levels were measured with quantitative Western blotting, cell viability kit, and enzyme-linked immunosorbent assay sandwich. The control condition consisted of 5% CO2 plus 21% O2 and balanced nitrogen, which did not affect caspase-3 activation, cell viability, APP processing, or Abeta generation. RESULTS: Two percent isoflurane caused apoptosis, altered processing of APP, and increased production of Abeta in H4 human neuroglioma cell lines. Isoflurane-induced apoptosis was independent of changes in Abeta and APP holoprotein levels. However, isoflurane-induced apoptosis was potentiated by increased levels of APP C-terminal fragments. CONCLUSION: A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases Abeta production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of Abeta is a key event in the pathogenesis of Alzheimer disease, these findings may have implications for use of this anesthetic agent in individuals with excessive levels of cerebral Abeta and elderly patients at increased risk for postoperative cognitive dysfunction.