Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

A CST program based on patient preferences is effective for both oncologists and patients with cancer. Oncologists should consider CST as an approach to enhancing their communication skills.

The literature on multivariate stochastic volatility (MSV) models has developed significantly over the last few years. This paper reviews the substantial literature on specification, estimation, and evaluation of MSV models. A wide range of MSV models is presented according to various categories, namely, (i) asymmetric models, (ii) factor models, (iii) time-varying correlation models, and (iv) alternative MSV specifications, including models based on the matrix exponential transformation, the Cholesky decomposition, and the

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We investigated the effects of interleukin-1 beta (IL-1 beta), administered directly into the rat anterior hypothalamus (AHY), on monoamine release in the same region by using a brain microdialysis technique and an HPLC-electrochemical detection system. First, to study the local effects of IL-1 beta, we used a microdialysis probe equipped with a microinjection tube for administering IL-1 beta in the same region into which the probe had been inserted. IL-1 beta (1 ng) injected directly into the AHY elicited release of norepinephrine (NE), dopamine (DA), and 5-HT, as well as increases in their metabolites, 4-hydroxy-3-methoxyphenylglycol, 3,4-dihydroxyphenylacetic acid, 4-hydroxy-3-methoxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid, in the AHY. Vehicle alone exerted no effect on monoamine release. Although the elevated levels of NE and DA persisted for more than 6 hr after injection of IL-1 beta, the elevated levels of 5-HT were transient. Second, in order to investigate whether this effect of IL-1 beta is a direct action in the AHY, we performed in vitro experiments using hypothalamus slices. IL-1 beta (0.1 and 1 nM) increased the levels of each monoamine released from hypothalamic slices in a dose-dependent manner. These findings suggest that IL-1 beta acts directly on the hypothalamus to induce release of NE, DA, and 5-HT. Third, the roles of prostaglandins (PGs) in NE release in the AHY elicited by direct injection of IL-1 beta were examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid b peptide (Ab), is generated from amyloid precursor protein (APP) by b-and c-secretase-mediated cleavage. Because b-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Ab and grow normally, a b-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel b-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits b-secretase activity in cultured cells in a dosedependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced Ab production in vivo in the soluble fraction compared with vehicle, but the level of Ab in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wildtype mice remarkably reduced Ab production in both the soluble and insoluble fractions. Our results indicate that the b-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD. Keywords: Alzheimer's disease, amyloid b peptide, b-secretase inhibitor, beta-site APP cleaving enzyme 1, hydroxymethylcarbonyl isostere, KMI inhibitor. Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose primary pathogenic event is the extracellular accumulation of amyloid b peptide (Ab), followed by oxidative damage to neurons that ultimately results in

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