Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). OBJECTIVES: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer’s disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers). METHODS: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. RESULTS: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. CONCLUSION: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study

Massive Schwinger model and its confining aspects on curved space-time

Using a covariant method to regularize the composite operators, we obtain the bosonized action of the massive Schwinger model on a classical curved background. Using the solution of the bosonic effective action, the energy of two static external charges with finite and large distance separation on a static curved space-time is obtained. The confining behavior of this model is also explicitly discussed.Comment: A disscussion about the infrared regularization and also two references are added. Accepted for publication in Phys. Rev. D (2001

Interface modification of clay and graphene platelets reinforced epoxy nanocomposites: a comparative study

The interface between the matrix phase and dispersed phase of a composite plays a critical role in influencing its properties. However, the intricate mecha-nisms of interface are not fully understood, and polymer nanocomposites are no exception. This study compares the fabrication, morphology, and mechanical and thermal properties of epoxy nanocomposites tuned by clay layers (denoted as m-clay) and graphene platelets (denoted as m-GP). It was found that a chemical modification, layer expansion and dispersion of filler within the epoxy matrix resulted in an improved interface between the filler mate-rial and epoxy matrix. This was confirmed by Fourier transform infrared spectroscopy and transmission electron microscope. The enhanced interface led to improved mechanical properties (i.e. stiffness modulus, fracture toughness) and higher glass transition temperatures (Tg) compared with neat epoxy. At 4 wt% m-GP, the critical strain energy release rate G1c of neat epoxy improved by 240 % from 179.1 to 608.6 J/m2 and Tg increased from 93.7 to 106.4 �C. In contrast to m-clay, which at 4 wt%, only improved the G1c by 45 % and Tg by 7.1 %. The higher level of improvement offered by m-GP is attributed to the strong interaction of graphene sheets with epoxy because the covalent bonds between the carbon atoms of graphene sheets are much stronger than silicon-based clay

Paraphrases and summaries: A means of clarification or a vehicle for articulating a preferred version of student accounts?

The use of group discussions as a means to facilitate learning from experiences is well documented in adventure education literature. Priest and Naismith (1993) assert that the use of the circular discussion method, where the leader poses questions to the participants, is the most common form of facilitation in adventure education. This paper draws on transcripts of facilitation sessions to argue that the widely advocated practice of leader summaries or paraphrases of student responses in these sessions functions as a potential mechanism to control and sponsor particular knowledge(s). Using transcripts from recorded facilitation sessions the analysis focuses on how the leader paraphrases the students’ responses and how these paraphrases or ‘formulations’ function to modify or exclude particular aspects of the students’ responses. I assert that paraphrasing is not simply a neutral activity that merely functions to clarify a student response, it is a subtle means by which the leader of the session can, often inadvertently or unknowingly, alter the student’s reply with the consequence of favouring particular knowledge(s). Revealing the subtle work that leader paraphrases perform is of importance for educators who claim to provide genuine opportunities for students to learn from their experience

Submerged in the mainstream? A case study of an immigrant learner in a New Zealand primary classroom

Immigrant children from diverse language backgrounds face not only linguistic challenges when enrolled in mainstream English-medium classrooms, but also difficulties adjusting to an unfamiliar learning community. The culture of primary school classrooms in New Zealand typically reflects conventions across three dimensions: interactional, instructional task performance and cognitive-academic development. All three dimensions are underpinned by the culturally specific discourse conventions involved in language socialisation. New learners may be helped by classmates or their teacher to understand and successfully use these conventions, but left on their own they may sink rather than swim. This is a case study of one Taiwanese 11-year old boy, 'John', who entered a New Zealand primary classroom midway through the school year. John's basic conversational ability was sound, but he did not possess the interactive classroom skills needed to operate in the new culture of learning. Selected from a wider study of the classroom, transcript data from audio-recorded excerpts of John's interactions over several months with his teacher and classmates are interpreted from perspectives derived from sociocultural and language socialisation theories. The article concludes with a brief consideration of the extent to which John constructed, or was constrained from constructing meaningful learning experiences, and suggestions for further research and reflection

HE0107-5240, A Chemically Ancient Star.I. A Detailed Abundance Analysis

We report a detailed abundance analysis for HE0107-5240, a halo giant with [Fe/H]_NLTE=-5.3. This star was discovered in the course of follow-up medium-resolution spectroscopy of extremely metal-poor candidates selected from the digitized Hamburg/ESO objective-prism survey. On the basis of high-resolution VLT/UVES spectra, we derive abundances for 8 elements (C, N, Na, Mg, Ca, Ti, Fe, and Ni), and upper limits for another 12 elements. A plane-parallel LTE model atmosphere has been specifically tailored for the chemical composition of {\he}. Scenarios for the origin of the abundance pattern observed in the star are discussed. We argue that HE0107-5240 is most likely not a post-AGB star, and that the extremely low abundances of the iron-peak, and other elements, are not due to selective dust depletion. The abundance pattern of HE0107-5240 can be explained by pre-enrichment from a zero-metallicity type-II supernova of 20-25M_Sun, plus either self-enrichment with C and N, or production of these elements in the AGB phase of a formerly more massive companion, which is now a white dwarf. However, significant radial velocity variations have not been detected within the 52 days covered by our moderate-and high-resolution spectra. Alternatively, the abundance pattern can be explained by enrichment of the gas cloud from which HE0107-5240 formed by a 25M_Sun first-generation star exploding as a subluminous SNII, as proposed by Umeda & Nomoto (2003). We discuss consequences of the existence of HE0107-5240 for low-mass star formation in extremely metal-poor environments, and for currently ongoing and future searches for the most metal-poor stars in the Galaxy.Comment: 60 pages, 16 figures. Accepted for publication in Ap

Differential Roles for L-Type Calcium Channel Subtypes in Alcohol Dependence

It has previously been shown that the inhibition of L-type calcium channels (LTCCs) decreases alcohol consumption, although the contribution of the central LTCC subtypes Cav1.2 and Cav1.3 remains unknown. Here, we determined changes in Cav1.2 (Cacna1c) and Cav1.3 (Cacna1d) mRNA and protein expression in alcohol-dependent rats during protracted abstinence and naive controls using in situ hybridization and western blot analysis. Functional validation was obtained by electrophysiological recordings of calcium currents in dissociated hippocampal pyramidal neurons. We then measured alcohol self-administration and cue-induced reinstatement of alcohol seeking in dependent and nondependent rats after intracerebroventricular (i.c.v.) injection of the LTCC antagonist verapamil, as well as in mice with an inducible knockout (KO) of Cav1.2 in Ca2+/calmodulin-dependent protein kinase parallel to alpha (CaMKII alpha)-expressing neurons. Our results show that Cacna1c mRNA concentration was increased in the amygdala and hippocampus of alcohol-dependent rats after 21 days of abstinence, with no changes in Cacna1d mRNA. This was associated with increased Cav1.2 protein concentration and L-type calcium current amplitudes. Further analysis of Cacna1c mRNA in the CA1, basolateral amygdala (BLA), and central amygdala (CeA) revealed a dynamic regulation over time during the development of alcohol dependence. The inhibition of central LTCCs via i. c. v. administration of verapamil prevented cue-induced reinstatement of alcohol seeking in alcohol-dependent rats. Further studies in conditional Cav1.2-KO mice showed a lack of dependence-induced increase of alcohol-seeking behavior. Together, our data indicate that central Cav1.2 channels, rather than Cav1.3, mediate alcohol-seeking behavior. This finding may be of interest for the development of new antirelapse medications

Transport Coefficients for Granular Media from Molecular Dynamics Simulations

Under many conditions, macroscopic grains flow like a fluid; kinetic theory pred icts continuum equations of motion for this granular fluid. In order to test the theory, we perform event driven molecular simulations of a two-dimensional gas of inelastic hard disks, driven by contact with a heat bath. Even for strong dissipation, high densities, and small numbers of particles, we find that continuum theory describes the system well. With a bath that heats the gas homogeneously, strong velocity correlations produce a slightly smaller energy loss due to inelastic collisions than that predicted by kinetic theory. With an inhomogeneous heat bath, thermal or velocity gradients are induced. Determination of the resulting fluxes allows calculation of the thermal conductivity and shear viscosity, which are compared to the predictions of granular kinetic theory, and which can be used in continuum modeling of granular flows. The shear viscosity is close to the prediction of kinetic theory, while the thermal conductivity can be overestimated by a factor of 2; in each case, transport is lowered with increasing inelasticity.Comment: 14 pages, 17 figures, 39 references, submitted to PRE feb 199

Binge-Like Alcohol Exposure During Adolescence Disrupts Dopaminergic Neurotransmission in the Adult Prelimbic Cortex

Repeated binge-like exposure to alcohol during adolescence has been reported to perturb prefrontal cortical development, yet the mechanisms underlying these effects are unknown. Here we report that adolescent intermittent ethanol exposure induces cellular and dopaminergic abnormalities in the adult prelimbic cortex (PrL-C). Exposing rats to alcohol during early-mid adolescence (PD28–42) increased the density of long/thin dendritic spines of layer 5 pyramidal neurons in the adult PrL-C. Interestingly, although AIE exposure did not alter the expression of glutamatergic proteins in the adult PrL-C, there was a pronounced reduction in dopamine (DA) D1 receptor modulation of both intrinsic firing and evoked NMDA currents in pyramidal cells, whereas D2 receptor function was unaltered. Recordings from fast-spiking interneurons also revealed that AIE reduced intrinsic excitability, glutamatergic signaling, and D1 receptor modulation of these cells. Analysis of PrL-C tissue of AIE-exposed rats further revealed persistent changes in the expression of DA-related proteins, including reductions in the expression of tyrosine hydroxylase and catechol-O-methyltransferase (COMT). AIE exposure was associated with hypermethylation of the COMT promoter at a conserved CpG site in exon II. Taken together, these findings demonstrate that AIE exposure disrupts DA and GABAergic transmission in the adult medial prefrontal cortex (mPFC). As DA and GABA work in concert to shape and synchronize neuronal ensembles in the PFC, these alterations could contribute to deficits in behavioral control and decision-making in adults who abused alcohol during adolescence

Soft systems methodology: a context within a 50-year retrospective of OR/MS

Soft systems methodology (SSM) has been used in the practice of operations research and management science OR/MS) since the early 1970s. In the 1990s, it emerged as a viable academic discipline. Unfortunately, its proponents consider SSM and traditional systems thinking to be mutually exclusive. Despite the differences claimed by SSM proponents between the two, they have been complementary. An extensive sampling of the OR/MS literature over its entire lifetime demonstrates the richness with which the non-SSM literature has been addressing the very same issues as does SSM