Effect Size Analyses of Souvenaid in Patients with Alzheimer's Disease

Background: Souvenaid ® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. Objective: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. Methods: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations. Results: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD. Conclusions: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD

Fuelling conditions at staging sites can mitigate Arctic warming effects in a migratory bird

© 2018, The Author(s). Under climate warming, migratory birds should align reproduction dates with advancing plant and arthropod phenology. To arrive on the breeding grounds earlier, migrants may speed up spring migration by curtailing the time spent en route, possibly at the cost of decreased survival rates. Based on a decades-long series of observations along an entire flyway, we show that when refuelling time is limited, variation in food abundance in the spring staging area affects fitness. Bar-tailed godwits migrating from West Africa to the Siberian Arctic reduce refuelling time at their European staging site and thus maintain a close match between breeding and tundra phenology. Annual survival probability decreases with shorter refuelling times, but correlates positively with refuelling rate, which in turn is correlated with food abundance in the staging area. This chain of effects implies that conditions in the temperate zone determine the ability of godwits to cope with climate-related changes in the Arctic

Alternative splicing of exon 10 in the tau gene as a target for treatment of tauopathies

Tau aggregation is one of the major features in Alzheimer's disease and in several other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy (PSP). More than 35 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alters splicing of exon 10, resulting in an increase in exon 10 inclusion into tau mRNA. Abnormal splicing with inclusion of exon 10 into tau mRNA has also been observed in PSP and AD patients. These results indicate that abnormal splicing of exon 10, leading to the production of tau with exon 10, is probably one of the mechanisms by which tau accumulates and aggregates in tauopathic brains. Therefore, modulation of exon 10 splicing in the tau gene could potentially be targeted to prevent tauopathies. To identify small molecules or compounds that could potentially be developed into drugs to treat tauopathies, we established a cell-based high-throughput screening assay. In this review, we will discuss how realistic, specific biological molecules can be found to regulate exon 10 splicing in the tau gene for potential treatment of tauopathies

The Yin and Yang of Yeast Transcription: Elements of a Global Feedback System between Metabolism and Chromatin

When grown in continuous culture, budding yeast cells tend to synchronize their respiratory activity to form a stable oscillation that percolates throughout cellular physiology and involves the majority of the protein-coding transcriptome. Oscillations in batch culture and at single cell level support the idea that these dynamics constitute a general growth principle. The precise molecular mechanisms and biological functions of the oscillation remain elusive. Fourier analysis of transcriptome time series datasets from two different oscillation periods (0.7 h and 5 h) reveals seven distinct co-expression clusters common to both systems (34% of all yeast ORF), which consolidate into two superclusters when correlated with a compilation of 1,327 unrelated transcriptome datasets. These superclusters encode for cell growth and anabolism during the phase of high, and mitochondrial growth, catabolism and stress response during the phase of low oxygen uptake. The promoters of each cluster are characterized by different nucleotide contents, promoter nucleosome configurations, and dependence on ATP-dependent nucleosome remodeling complexes. We show that the ATP:ADP ratio oscillates, compatible with alternating metabolic activity of the two superclusters and differential feedback on their transcription via activating (RSC) and repressive (Isw2) types of promoter structure remodeling. We propose a novel feedback mechanism, where the energetic state of the cell, reflected in the ATP:ADP ratio, gates the transcription of large, but functionally coherent groups of genes via differential effects of ATP-dependent nucleosome remodeling machineries. Besides providing a mechanistic hypothesis for the delayed negative feedback that results in the oscillatory phenotype, this mechanism may underpin the continuous adaptation of growth to environmental conditions

The effects of Animal Assisted Therapy on autonomic and endocrine activity in adults with autism spectrum disorder:A randomized controlled trial

Objective:  Stress and its sequelae are very common in adults with autism spectrum disorder (ASD) without an intellectual disability (ID). Animal-assisted therapy (AAT) has shown physiological stress-reductive effects in children with ASD. The aim of the current study was to examine the acute psychophysiological response to an AAT session, and to examine the longer-term stress-physiological effects of the intervention, up until 10 weeks post-treatment, in comparison to waiting-list controls.  Method:  A randomized controlled trial with pre-intervention (T0), post-intervention (T1: 10 weeks) and followup (T2: 20 weeks) measurements of neuroendocrine and cardiovascular measures, was conducted in 53 adults with ASD (N = 27 in intervention arm; N = 26 in control arm). Within the intervention group, stressphysiological data were collected during the 5th therapy session (acute effects). Data were analyzed with mixed models for outcome measures cortisol, alpha-amylase, heart rate variability and sympathetic activity.  Results:  The AAT interventional session was significantly associated with reduced cortisol levels (beta = -0.41, p = .010), while parasympathetic and sympathetic cardiovascular activity remained unaltered. No significant changes were found for stress-physiological measures at post-treatment time points.  Conclusions:  Acute stress reduction, reflected in significant reduction in cortisol levels, was found during an AAT session in adults with ASD, without ID. More research is needed to explore to what extent the specific factors of AAT have contributed to the decrease in cortisol and whether stress reduction is possible for the longer-term

The effects of Animal Assisted Therapy on autonomic and endocrine activity in adults with autism spectrum disorder: A randomized controlled trial

Objective:  Stress and its sequelae are very common in adults with autism spectrum disorder (ASD) without an intellectual disability (ID). Animal-assisted therapy (AAT) has shown physiological stress-reductive effects in children with ASD. The aim of the current study was to examine the acute psychophysiological response to an AAT session, and to examine the longer-term stress-physiological effects of the intervention, up until 10 weeks post-treatment, in comparison to waiting-list controls.  Method:  A randomized controlled trial with pre-intervention (T0), post-intervention (T1: 10 weeks) and followup (T2: 20 weeks) measurements of neuroendocrine and cardiovascular measures, was conducted in 53 adults with ASD (N = 27 in intervention arm; N = 26 in control arm). Within the intervention group, stressphysiological data were collected during the 5th therapy session (acute effects). Data were analyzed with mixed models for outcome measures cortisol, alpha-amylase, heart rate variability and sympathetic activity.  Results:  The AAT interventional session was significantly associated with reduced cortisol levels (beta = -0.41, p = .010), while parasympathetic and sympathetic cardiovascular activity remained unaltered. No significant changes were found for stress-physiological measures at post-treatment time points.  Conclusions:  Acute stress reduction, reflected in significant reduction in cortisol levels, was found during an AAT session in adults with ASD, without ID. More research is needed to explore to what extent the specific factors of AAT have contributed to the decrease in cortisol and whether stress reduction is possible for the longer-term