Aging, neurogenesis, and caloric restriction in different model organisms

Brain aging is a multifactorial process that is occurring across multiple cognitive domains. A significant complaint that occurs in the elderly is a decrement in learning and memory ability. Both rodents and zebrafish exhibit a similar problem with memory during aging. The neurobiological changes that underlie this cognitive decline are complex and undoubtedly influenced by many factors. Alterations in the birth of new neurons and neuron turnover may contribute to age-related cognitive problems. Caloric restriction is the only non-genetic intervention that reliably increases life span and healthspan across multiple organisms although the molecular mechanisms are not well-understood. Recently the zebrafish has become a popular model organism for understanding the neurobiological consequences but to date very little work has been performed. Similarly, few studies have examined the effects of dietary restriction in zebrafish. Here we review the literature related to memory decline, neurogenesis, and caloric restriction across model organisms and suggest that zebrafish has the potential to be an important animal model for understanding the complex interactions between age, neurobiological changes in the brain, and dietary regimens or their mimetics as interventions

Supergravity Inflation on the Brane

We study N=1 Supergravity inflation in the context of the braneworld scenario. Particular attention is paid to the problem of the onset of inflation at sub-Planckian field values and the ensued inflationary observables. We find that the so-called $\eta$-problem encountered in supergravity inspired inflationary models can be solved in the context of the braneworld scenario, for some range of the parameters involved. Furthermore, we obtain an upper bound on the scale of the fifth dimension, M_5 \lsim 10^{-3} M_P, in case the inflationary potential is quadratic in the inflaton field, $\phi$. If the inflationary potential is cubic in $\phi$, consistency with observational data requires that $M_5 \simeq 9.2 \times 10^{-4} M_P$.Comment: 6 pages, 1 figure, to appear in Phys. Rev.

Factors related to tinnitus and hyperacusis handicap in older people.

OBJECTIVE: The aim was to assess factors related to tinnitus and hyperacusis handicap in older people. DESIGN: Retrospective cross-sectional. STUDY SAMPLE: Data were gathered for 184 patients with an average age of 69 years. RESULTS: Tinnitus handicap as measured via the Tinnitus Handicap Inventory (THI) was significantly predicted by tinnitus annoyance as measured via the visual analogue scale (VAS) (regression coefficient, b = 2.9, p < 0.001) and the effect of tinnitus on the patient's life as measured via the VAS (b = 3.9, p < 0.001). Hyperacusis handicap as measured via the Hyperacusis Questionnaire (HQ) was significantly predicted by the score on the depression subscale of the Hospital Anxiety and Depression Scale (HADS) (b = 0.8, p < 0.001) and to a small extent by the THI score (b = 0.07, p = 0.048). Insomnia scores as measured via the Insomnia Severity Index (ISI) were significantly predicted by scores on the depression subscale of the HADS (b = 0.46, p = 0.007). CONCLUSIONS: Since tinnitus annoyance significantly predicts tinnitus handicap, it is important to explore factors associated with annoyance that may be useful in designing appropriate rehabilitative interventions aimed at reducing tinnitus handicap in older people. Future studies should explore whether hyperacusis and insomnia in older people with tinnitus need to be managed in conjunction with treatment for depression

Network Analysis Reveals Distinct Clinical Syndromes Underlying Acute Mountain Sickness

Acute mountain sickness (AMS) is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS), we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject-days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25). These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes

Latent classes of DSM-5 acute stress disorder symptoms in children after single-incident trauma: findings from an international data archive

Background: After a potentially traumatic event (PTE), children often show symptoms of acute stress disorder (ASD), which may evolve into posttraumatic stress (PTS) disorder. A growing body of literature has employed latent class analysis (LCA) to disentangle the complex structure underlying PTS symptomatology, distinguishing between homogeneous subgroups based on PTS presentations. So far, little is known about subgroups or classes of ASD reactions in trauma-exposed children. Objective: Our study aimed to identify latent classes of ASD symptoms in children exposed to a single-incident PTE and to identify predictors of class membership (gender, age, cultural background, parental education, trauma type, and trauma history). Method: A sample of 2287 children and adolescents (5–18 years) was derived from the Prospective studies of Acute Child Trauma and Recovery (PACT/R) Data Archive, an international archive including studies from the USA, UK, Australia, and Switzerland. LCA was used to determine distinct subgroups based on ASD symptoms. Predictors of class membership were examined using a three-step approach. Results: Our LCA yielded a three-class solution: low (42%), intermediate (43%) and high (15%) ASD symptom severity that differed in terms of impairment and number of endorsed ASD symptoms. Compared to the low symptoms class, children in the intermediate or high severity class were more likely to be of female gender, be younger of age, have parents who had not completed secondary education, and be exposed to a road traffic accident or interpersonal violence (vs. an unintentional injury). Conclusions: These findings provide new information on children at risk for ASD after single-incident trauma,

Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn''s disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 × 10-3), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 × 10-4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated

Primeval Corrections to the CMB Anisotropies

We show that deviations of the quantum state of the inflaton from the thermal vacuum of inflation may leave an imprint in the CMB anisotropies. The quantum dynamics of the inflaton in such a state produces corrections to the inflationary fluctuations, which may be observable. Because these effects originate from IR physics below the Planck scale, they will dominate over any trans-Planckian imprints in any theory which obeys decoupling. Inflation sweeps away these initial deviations and forces its quantum state closer to the thermal vacuum. We view this as the quantum version of the cosmic no-hair theorem. Such imprints in the CMB may be a useful, independent test of the duration of inflation, or of significant features in the inflaton potential about 60 e-folds before inflation ended, instead of an unlikely discovery of the signatures of quantum gravity. The absence of any such substructure would suggest that inflation lasted uninterrupted much longer than ${\cal O}(100)$ e-folds.Comment: 17 pages, latex, no figures; v3: added references and comments, final version to appear in Phys. Rev.

Restricted and Repetitive Behavior and Brain Functional Connectivity in Infants at Risk for Developing Autism Spectrum Disorder

Background: Restricted and repetitive behaviors (RRBs), detectable by 12 months in many infants in whom autism spectrum disorder (ASD) is later diagnosed, may represent some of the earliest behavioral markers of ASD. However, brain function underlying the emergence of these key behaviors remains unknown. Methods: Behavioral and resting-state functional connectivity (fc) magnetic resonance imaging data were collected from 167 children at high and low familial risk for ASD at 12 and 24 months (n = 38 at both time points). Twenty infants met criteria for ASD at 24 months. We divided RRBs into four subcategories (restricted, stereotyped, ritualistic/sameness, self-injurious) and used a data-driven approach to identify functional brain networks associated with the development of each RRB subcategory. Results: Higher scores for ritualistic/sameness behavior were associated with less positive fc between visual and control networks at 12 and 24 months. Ritualistic/sameness and stereotyped behaviors were associated with less positive fc between visual and default mode networks at 12 months. At 24 months, stereotyped and restricted behaviors were associated with more positive fc between default mode and control networks. Additionally, at 24 months, stereotyped behavior was associated with more positive fc between dorsal attention and subcortical networks, whereas restricted behavior was associated with more positive fc between default mode and dorsal attention networks. No significant network-level associations were observed for self-injurious behavior. Conclusions: These observations mark the earliest known description of functional brain systems underlying RRBs, reinforce the construct validity of RRB subcategories in infants, and implicate specific neural substrates for future interventions targeting RRBs

Walking, Gross Motor Development, and Brain Functional Connectivity in Infants and Toddlers

Infant gross motor development is vital to adaptive function and predictive of both cognitive outcomes and neurodevelopmental disorders. However, little is known about neural systems underlying the emergence of walking and general gross motor abilities. Using resting state fcMRI, we identified functional brain networks associated with walking and gross motor scores in a mixed cross-sectional and longitudinal cohort of infants at high and low risk for autism spectrum disorder, who represent a dimensionally distributed range of motor function. At age 12 months, functional connectivity of motor and default mode networks was correlated with walking, whereas dorsal attention and posterior cingulo-opercular networks were implicated at age 24 months. Analyses of general gross motor function also revealed involvement of motor and default mode networks at 12 and 24 months, with dorsal attention, cingulo-opercular, frontoparietal, and subcortical networks additionally implicated at 24 months. These findings suggest that changes in network-level brain-behavior relationships underlie the emergence and consolidation of walking and gross motor abilities in the toddler period. This initial description of network substrates of early gross motor development may inform hypotheses regarding neural systems contributing to typical and atypical motor outcomes, as well as neurodevelopmental disorders associated with motor dysfunction