Plasma REST: a novel candidate biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population.

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain's stress response. It is reduced in conditions of stress and Alzheimer's disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention-mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Plasma REST: A novel candidate biomarker of Alzheimer\u27s disease is modified by psychological intervention in an at-risk population

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain’s stress response. It is reduced in conditions of stress and Alzheimer’s disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention—mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Characterization of the 1st and 2nd EF-hands of NADPH oxidase 5 by fluorescence, isothermal titration calorimetry, and circular dichroism

<p>Abstract</p> <p>Background</p> <p>Superoxide generated by non-phagocytic NADPH oxidases (NOXs) is of growing importance for physiology and pathobiology. The calcium binding domain (CaBD) of NOX5 contains four EF-hands, each binding one calcium ion. To better understand the metal binding properties of the 1^stand 2^ndEF-hands, we characterized the N-terminal half of CaBD (NCaBD) and its calcium-binding knockout mutants.</p> <p>Results</p> <p>The isothermal titration calorimetry measurement for NCaBD reveals that the calcium binding of two EF-hands are loosely associated with each other and can be treated as independent binding events. However, the Ca²⁺binding studies on NCaBD(E31Q) and NCaBD(E63Q) showed their binding constants to be 6.5 × 10⁵and 5.0 × 10²M^-1with ΔHs of -14 and -4 kJ/mol, respectively, suggesting that intrinsic calcium binding for the 1^stnon-canonical EF-hand is largely enhanced by the binding of Ca²⁺to the 2^ndcanonical EF-hand. The fluorescence quenching and CD spectra support a conformational change upon Ca²⁺binding, which changes Trp residues toward a more non-polar and exposed environment and also increases its α-helix secondary structure content. All measurements exclude Mg²⁺-binding in NCaBD.</p> <p>Conclusions</p> <p>We demonstrated that the 1^stnon-canonical EF-hand of NOX5 has very weak Ca²⁺binding affinity compared with the 2^ndcanonical EF-hand. Both EF-hands interact with each other in a cooperative manner to enhance their Ca²⁺binding affinity. Our characterization reveals that the two EF-hands in the N-terminal NOX5 are Ca²⁺specific.</p> <p>Graphical abstract</p> <p><display-formula><graphic file="1752-153X-6-29-i1.gif"/></display-formula></p

A randomized, controlled clinical trial: the effect of mindfulness-based cognitive therapy on generalized anxiety disorder among Chinese community patients: protocol for a randomized trial

&lt;b&gt;Background&lt;/b&gt; Research suggests that an eight-week Mindfulness-Based Cognitive Therapy (MBCT) program may be effective in the treatment of generalized anxiety disorders. Our objective is to compare the clinical effectiveness of the MBCT program with a psycho-education programme and usual care in reducing anxiety symptoms in people suffering from generalized anxiety disorder.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods and Design&lt;/b&gt; A three armed randomized, controlled clinical trial including 9-month post-treatment follow-up is proposed. Participants screened positive using the Structure Clinical Interview for DSM-IV (SCID) for general anxiety disorder will be recruited from community-based clinics. 228 participants will be randomly allocated to the MBCT program plus usual care, psycho-education program plus usual care or the usual care group. Validated Chinese version of instruments measuring anxiety and worry symptoms, depression, quality of life and health service utilization will be used. Our primary end point is the change of anxiety and worry score (Beck Anxiety Inventory and Penn State Worry Scale) from baseline to the end of intervention. For primary analyses, treatment outcomes will be assessed by ANCOVA, with change in anxiety score as the baseline variable, while the baseline anxiety score and other baseline characteristics that significantly differ between groups will serve as covariates.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Discussion&lt;/b&gt; This is a first randomized controlled trial that compare the effectiveness of MBCT with an active control, findings will advance current knowledge in the management of GAD and the way that group intervention can be delivered and inform future research

Charisma and the Clinic

Here we argue that ‘charisma’, a concept widely taken up within geography and the environmental humanities, is of utility to the social studies of medicine. Charisma, we suggest, draws attention to the affective dimensions of medical work, the ways in which these affective relations are structured, and the manner in which they are intimately tied to particular material-discursive contexts. The paper differentiates this notion of charisma from Weber’s analyses of the ‘charismatic leader’ before detailing three forms of charisma - ecological (which relates to the affordances an entity has), corporeal (related to bodily interaction) and aesthetic (pertaining to an entity’s initial visual and emotional impact). Drawing on interview data we then show how this framework can be used to understand the manner in which psychologists and neuroscientists have come to see and act on autism. We conclude the article by suggesting that examining charisma within healthcare settings furthers the concept, in particular by drawing attention to the discursive features of ecologies and the ‘non-innocence’ of charisma

Meditation on the Soles of the Feet Practice Provides Some Control of Aggression for Individuals with Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative condition that affects cognition, mental and physical health, and functionality of older people. As the disease progresses from the mild to moderate stage, there is a concomitant increase in several behavioral variables, chiefly agitation, anger, and aggression. Currently, there are no evidence-based treatments for these behaviors in this population. Three individuals with moderate Alzheimer’s disease were taught an informal mindfulness practice, meditation on the Soles of the Feet (SoF), as a self-management strategy within a multiple-baseline design across participants. All three were able to learn and use the SoF practice to manage their verbal and physical aggression. Their use of the SoF practice was correlated with decreased perceived psychological stress for their spouses and caregivers, as well as for the participants, but to a much smaller degree. In terms of social validity, the participants, their spouses, and caregivers rated the SoF practice as acceptable, effective, with no unintended effects, and indicated that they would recommend the practice to others. However, they also rated SoF as effortful for the participants because it involves the participants remembering to use the practice with rising anger, a requirement particularly challenging for those with memory problems. The SoF practice may enable individuals in the early stages of dementia to manage their anger and aggression. The data were derived from an internally valid experimental design, suggestive of initial proof-of-concept, but needs to be replicated before any clinical implications can be imputed from this study

The Relationship Between Homework Compliance and Therapy Outcomes: An Updated Meta-Analysis

The current study was an updated meta-analysis of manuscripts since the year 2000 examining the effects of homework compliance on treatment outcome. A total of 23 studies encompassing 2,183 subjects were included. Results indicated a significant relationship between homework compliance and treatment outcome suggesting a small to medium effect (r = .26; 95% CI = .19–.33). Moderator analyses were conducted to determine the differential effect size of homework on treatment outcome by target symptoms (e.g., depression; anxiety), source of homework rating (e.g., client; therapist), timing of homework rating (e.g., retroactive vs. contemporaneous), and type of homework rating (e.g., Likert; total homeworks completed). Results indicated that effect sizes were robust across target symptoms, but differed by source of homework rating, timing of homework rating, and type of homework rating. Specifically, studies utilizing combined client and therapist ratings of compliance had significantly higher mean effect size relative to those using therapist only assessments and those using objective assessments. Further, studies that rated the percentage of homeworks completed had a significantly lower mean effect size compared to studies using Likert ratings, and retroactive assessments had higher effect size than contemporaneous assessments

The G-Quadruplex Ligand Telomestatin Impairs Binding of Topoisomerase IIIα to G-Quadruplex-Forming Oligonucleotides and Uncaps Telomeres in ALT Cells

In Alternative Lengthening of Telomeres (ALT) cell lines, specific nuclear bodies called APBs (ALT-associated PML bodies) concentrate telomeric DNA, shelterin components and recombination factors associated with telomere recombination. Topoisomerase IIIα (Topo III) is an essential telomeric-associated factor in ALT cells. We show here that the binding of Topo III to telomeric G-overhang is modulated by G-quadruplex formation. Topo III binding to G-quadruplex-forming oligonucleotides was strongly inhibited by telomestatin, a potent and specific G-quadruplex ligand. In ALT cells, telomestatin treatment resulted in the depletion of the Topo III/BLM/TRF2 complex and the disruption of APBs and led to the segregation of PML, shelterin components and Topo III. Interestingly, a DNA damage response was observed at telomeres in telomestatin-treated cells. These data indicate the importance of G-quadruplex stabilization during telomere maintenance in ALT cells. The function of TRF2/Topo III/BLM in the resolution of replication intermediates at telomeres is discussed