Neuregulin-1 Regulates Cell Adhesion via an ErbB2/Phosphoinositide-3 Kinase/Akt-Dependent Pathway: Potential Implications for Schizophrenia and Cancer

Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer.Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063).Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion

Evaluation of risk of falls and orthostatic hypotension in older, long-term topical beta-blocker users

Background: Falls are a serious problem in the elderly, and have recently been described as cardiovascular-mediated side effects of beta-blocker eye drops. Therefore, we investigated the possible association between the long-term use of beta-blockers, prostaglandins and their combinations in eye drops, and falls, dizziness and orthostatic hypotension in older patients. Methods: All participants were long-term users of eye drops containing beta-blockers, prostaglandins or their combinations. They underwent a structured falls interview and blood pressure measurement for testing of orthostatic hypotension. The odds ratio for presence of orthostatic hypotension or a positive falls history according to use of beta-blocker eye drops was calculated with a binary logistic regression analysis. The main outcome measures were a positive falls history and the presence of orthostatic hypotension. Results: In total, 148 of 286 subjects participated. After adjustment for age, gender, and use of fall-risk-increasing drugs other than beta-blocker eye drops, we found no significant difference in fall risk [odds ratio (OR): 0.60; 95% confidence interval (CI): 0.268-1.327] between patients using ophthalmic beta-blockers or a combination of ophthalmic beta-blockers and prostaglandins, and patients using ophthalmic prostaglandins only. Although prevalence of orthostatic hypotension was higher in the beta-blocker group (OR: 1.67; 95% CI: 0.731-3.793) compared to the prostaglandin group, this was a non-significant difference. Conclusions: In our study, we did not find a significant association between long-term use of beta-blockers eye drops and falls, dizziness or orthostatic hypotension in older ophthalmic outpatients, compared to long-term use of prostaglandin eye drops

V-TIME: a treadmill training program augmented by virtual reality to decrease fall risk in older adults: study design of a randomized controlled trial

Contains fulltext : 115437.pdf (publisher's version ) (Open Access)BACKGROUND: Recent work has demonstrated that fall risk can be attributed to cognitive as well as motor deficits. Indeed, everyday walking in complex environments utilizes executive function, dual tasking, planning and scanning, all while walking forward. Pilot studies suggest that a multi-modal intervention that combines treadmill training to target motor function and a virtual reality obstacle course to address the cognitive components of fall risk may be used to successfully address the motor-cognitive interactions that are fundamental for fall risk reduction. The proposed randomized controlled trial will evaluate the effects of treadmill training augmented with virtual reality on fall risk. METHODS/DESIGN: Three hundred older adults with a history of falls will be recruited to participate in this study. This will include older adults (n=100), patients with mild cognitive impairment (n=100), and patients with Parkinson's disease (n=100). These three sub-groups will be recruited in order to evaluate the effects of the intervention in people with a range of motor and cognitive deficits. Subjects will be randomly assigned to the intervention group (treadmill training with virtual reality) or to the active-control group (treadmill training without virtual reality). Each person will participate in a training program set in an outpatient setting 3 times per week for 6 weeks. Assessments will take place before, after, and 1 month and 6 months after the completion of the training. A falls calendar will be kept by each participant for 6 months after completing the training to assess fall incidence (i.e., the number of falls, multiple falls and falls rate). In addition, we will measure gait under usual and dual task conditions, balance, community mobility, health related quality of life, user satisfaction and cognitive function. DISCUSSION: This randomized controlled trial will demonstrate the extent to which an intervention that combines treadmill training augmented by virtual reality reduces fall risk, improves mobility and enhances cognitive function in a diverse group of older adults. In addition, the comparison to an active control group that undergoes treadmill training without virtual reality will provide evidence as to the added value of addressing motor cognitive interactions as an integrated unit. TRIAL REGISTRATION: (NIH)-NCT01732653

Fatores preditores de resultados no tratamento do transtorno obsessivo-compulsivo com as terapias comportamental e cognitivo-comportamental: uma revisão sistemática Outcome predictor factors in the treatment of obsessive-compulsive disorder using behavior and cognitive-behavior therapies: a systematic review

INTRODUÇÃO: As terapias comportamental e cognitivo-comportamental reduzem os sintomas do transtorno obsessivo-compulsivo em mais de 70% dos pacientes. Entretanto, cerca de 30% não obtêm nenhuma melhora. Conhecer fatores associados a esses desfechos poderia auxiliar numa melhor indicação do tratamento, incrementando sua eficácia. MÉTODO: Foram revisados trabalhos que investigaram fatores preditivos de resultados nos tratamentos do transtorno obsessivo-compulsivo, nas fontes PubMed, PsycINFO e LILACS. Termos utilizados na busca: predictive factors OR prediction AND obsessive-compulsive disorder AND exposure response prevention OR ritual prevention OR behav* therapy OR cognitive behav* therapy, resultando em 104 artigos. As referências dos artigos foram analisadas, possibilitando maior número de trabalhos revisados. Excluíram-se artigos que utilizaram apenas farmacoterapia e aqueles que não abordavam o tema, resultando em 29 artigos. DISCUSSÃO: As variáveis demográficas parecem exercer papel indireto, destacando-se sexo masculino e ausência de companheiro(a) como fatores de pior prognóstico. Maior gravidade e início precoce dos sintomas indicariam piores resultados. O transtorno esquizotípico comórbido é potencialmente negativo. Sintomas relacionados ao colecionismo e com conteúdo sexual/religioso indicam pior prognóstico. Maior nível de insight, motivação e colaboração com o tratamento são características favoráveis. Maior intensidade da melhora e a remissão completa são preditores para a não-recaída. CONCLUSÃO: A identificação de fatores preditores de resultados está longe de ser esclarecida. É possível que múltiplos fatores, cujas associações são complexas, atuem em conjunto. Os resultados podem depender de fatores não-específicos, ainda não abordados pelos estudos. A heterogeneidade do transtorno obsessivo-compulsivo e das pesquisas e o uso associado de medicamentos dificultam o estabelecimento de conclusões mais definidas.<br>INTRODUCTION: Behavioral and cognitive-behavioral therapies reduce symptoms of obsessive-compulsive disorder in over 70% of patients. However, about 30% do not show any improvement. The knowledge of factors associated with these outcomes may inform better treatment indications and improve treatment efficacy. METHOD: Review of studies that investigated predictors of obsessive-compulsive disorder treatment results in PubMed, PsychoINFO and LILACS databases. Terms used in the search were predictive factors OR prediction AND obsessive-compulsive disorder AND exposure response prevention OR ritual prevention OR behav* therapy OR cognitive behav* therapy." The search retrieved 104 studies. The references of retrieved studies were also analyzed to ensure that all relevant studies were included. Studies that used only pharmacotherapy or did not discuss the topic under analysis were excluded, and 29 studies met inclusion criteria. DISCUSSION: Demographic variables seem to play an indirect role in treatment results; male sex and not having partner are factors associated with poor prognosis. Greater severity and early symptom onset also indicate poor outcomes. Comorbid schizotypal disorder is potentially negative. Symptoms associated with hoarding and sexual/religious obsessions predict poor prognosis. Greater insight, motivation and collaboration with treatment are favorable characteristics. Greater improvement and complete remission of symptoms are predictors of no relapse. CONCLUSION: The identification of outcome predictors is still far from complete. Multiple factors may contribute to results, and their associations are complex. Results may depend on unspecific factors not yet investigated. Definite conclusions are difficult to reach because of the heterogeneity of obsessive-compulsive disorder and of the studies investigating it and the combined use of drugs