Grey and white matter correlates of recent and remote autobiographical memory retrieval:Insights from the dementias

The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the contribution of discrete regions in mediating successful retrieval of distant versus recently experienced events

The cost effectiveness of REACH-HF and home-based cardiac rehabilitation compared with the usual medical care for heart failure with reduced ejection fraction:a decision model-based analysis

This is the final version. Available from Sage Publications via the DOI in this record.Background The REACH-HF (Rehabilitation EnAblement in CHronic Heart Failure) trial found that the REACH-HF home-based cardiac rehabilitation intervention resulted in a clinically meaningful improvement in disease-specific health-related quality of life in patients with reduced ejection fraction heart failure (HFrEF). The aims of this study were to assess the long-term cost-effectiveness of the addition of REACH-HF intervention or home-based cardiac rehabilitation to usual care compared with usual care alone in patients with HFrEF. Design and methods A Markov model was developed using a patient lifetime horizon and integrating evidence from the REACH-HF trial, a systematic review/meta-analysis of randomised trials, estimates of mortality and hospital admission and UK costs at 2015/2016 prices. Taking a UK National Health and Personal Social Services perspective we report the incremental cost per quality-adjusted life-year (QALY) gained, assessing uncertainty using probabilistic and deterministic sensitivity analyses. Results In base case analysis, the REACH-HF intervention was associated with per patient mean QALY gain of 0.23 and an increased mean cost of £400 compared with usual care, resulting in a cost per QALY gained of £1720. Probabilistic sensitivity analysis indicated a 78% probability that REACH-HF is cost effective versus usual care at a threshold of £20,000 per QALY gained. Results were similar for home-based cardiac rehabilitation versus usual care. Sensitivity analyses indicate the findings to be robust to changes in model assumptions and parameters. Conclusions Our cost-utility analyses indicate that the addition of the REACH-HF intervention and home-based cardiac rehabilitation programmes are likely to be cost-effective treatment options versus usual care alone in patients with HFrEF.National Institute for Health Research (NIHR

Specific gene expression profiles and chromosomal abnormalities are associated with infant disseminated neuroblastoma

Background: Neuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. Clinical distinction of stage 4s from lethal stage 4 can be difficult, but critical for therapeutic decisions. The aim of this study was to investigate chromosomal alterations and differential gene expression amongst infant disseminated NB subgroups. Methods: Thirty-five NB tumours from patients diagnosed at < 18 months (25 stage 4 and 10 stage 4s), were evaluated by allelic and gene expression analyses. Results: All stage 4s patients underwent spontaneous remission, only 48% stage 4 patients survived despite combined modality therapy. Stage 4 tumours were 90% near-diploid/tetraploid, 44% MYCN amplified, 77% had 1p LOH (50% 1p36), 23% 11q and/or 14q LOH (27%) and 47% had 17q gain. Stage 4s were 90% near-triploid, none MYCN amplified and LOH was restricted to 11q. Initial comparison analyses between stage 4s and 4 < 12 months tumours revealed distinct gene expression profiles. A significant portion of genes mapped to chromosome 1 (P < 0.0001), 90% with higher expression in stage 4s, and chromosome 11 (P = 0.0054), 91% with higher expression in stage 4. Less definite expression profiles were observed between stage 4s and 4 < 18m, yet, association with chromosomes 1 (P < 0.0001) and 11 (P = 0.005) was maintained. Distinct gene expression profiles but no significant association with specific chromosomal region localization was observed between stage 4s and stage 4 < 18 months without MYCN amplification. Conclusion: Specific chromosomal aberrations are associated with distinct gene expression profiles which characterize spontaneously regressing or aggressive infant NB, providing the biological basis for the distinct clinical behaviour

Adaptive hypermedia driven serious game design and cognitive style in school settings: an exploratory study

The potential value of adaptive hypermedia and game based learning to education and training has long been recognised, numerous studies have been undertaken in both those areas investigating its potential to improve learner performance. In particular research has indicated that tailoring content to match the prior knowledge of the user has the power to increase the effectiveness of learning systems. Recent studies have begun to indicate that Adaptive Hypermedia Learning Systems (AHLS) based on cognitive styles have the power to improve learner performance. Recent examples of research exploring avenues for effectively incorporating serious games into AHLS indicated that integrating serious games into a personalized learning environment has the potential educational benefits of combining a personalized delivery with increased learner motivation. The exploratory study presented in this paper here developed an Adaptive Hypermedia Driven Serious Game (AHDSG) based around Pask’s Holist-Serialist dimension of cognitive style. A prototype AHDSG was designed and developed to teach students about Sutton Hoo and archaeological methods. Sixty-six secondary school students participated in this study. Overall the findings of this study show that there was an improvement in performance among all participants. Although the participants that used the system which adapted to their preferred cognitive style achieved a higher mean gain score, the difference was not significant

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The Mechanism of Antifungal Action of Essential Oil from Dill (Anethum graveolens L.) on Aspergillus flavus

The essential oil extracted from the seeds of dill (Anethum graveolens L.) was demonstrated in this study as a potential source of an eco-friendly antifungal agent. To elucidate the mechanism of the antifungal action further, the effect of the essential oil on the plasma membrane and mitochondria of Aspergillus flavus was investigated. The lesion in the plasma membrane was detected through flow cytometry and further verified through the inhibition of ergosterol synthesis. The essential oil caused morphological changes in the cells of A. flavus and a reduction in the ergosterol quantity. Moreover, mitochondrial membrane potential (MMP), acidification of external medium, and mitochondrial ATPase and dehydrogenase activities were detected. The reactive oxygen species (ROS) accumulation was also examined through fluorometric assay. Exposure to dill oil resulted in an elevation of MMP, and in the suppression of the glucose-induced decrease in external pH at 4 µl/ml. Decreased ATPase and dehydrogenase activities in A. flavus cells were also observed in a dose-dependent manner. The above dysfunctions of the mitochondria caused ROS accumulation in A. flavus. A reduction in cell viability was prevented through the addition of L-cysteine, which indicates that ROS is an important mediator of the antifungal action of dill oil. In summary, the antifungal activity of dill oil results from its ability to disrupt the permeability barrier of the plasma membrane and from the mitochondrial dysfunction-induced ROS accumulation in A. flavus

Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: a systematic review

Transcranial magnetic stimulation (TMS) was introduced as a non-invasive tool for the investigation of the motor cortex. The repetitive application (rTMS), causing longer lasting effects, was used to study the influence on a variety of cerebral functions. High-frequency (>1 Hz) rTMS is known to depolarize neurons under the stimulating coil and to indirectly affect areas being connected and related to emotion and behavior. Researchers found selective cognitive improvement after high-frequency (HF) stimulation specifically over the left dorsolateral prefrontal cortex (DLPFC). This article provides a systematic review of HF-rTMS studies (1999–2009) stimulating over the prefrontal cortex of patients suffering from psychiatric/neurological diseases or healthy volunteers, where the effects on cognitive functions were measured. The cognitive effect was analyzed with regard to the impact of clinical status (patients/healthy volunteers) and stimulation type (verum/sham). RTMS at 10, 15 or 20 Hz, applied over the left DLPFC, within a range of 10–15 successive sessions and an individual motor threshold of 80–110%, is most likely to cause significant cognitive improvement. In comparison, patients tend to reach a greater improvement than healthy participants. Limitations concern the absence of healthy groups in clinical studies and partly the absence of sham groups. Thus, future investigations are needed to assess cognitive rTMS effects in different psychiatric disorders versus healthy subjects using an extended standardized neuropsychological test battery. Since the pathophysiological and neurobiological basis of cognitive improvement with rTMS remains unclear, additional studies including genetics, experimental neurophysiology and functional brain imaging are necessary to explore stimulation-related functional changes in the brain

The Nature of Knowledge in Composition and Literary Understanding: The Question of Specificity

↵PETER SMAGORINSKY is Assistant Professor, College of Education, University of Oklahoma, 820 Van Vleet Oval, Norman, OK 73019-0. He specializes in classroom literacy.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline