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

Hornblendite delineates zones of mass transfer through the lower crust

Geochemical signatures throughout the layered Earth require significant mass transfer through the lower crust, yet geological pathways are under-recognized. Elongate bodies of basic to ultrabasic rocks are ubiquitous in exposures of the lower crust. Ultrabasic hornblendite bodies hosted within granulite facies gabbroic gneiss of the Pembroke Valley, Fiordland, New Zealand, are typical occurrences usually reported as igneous cumulate hornblendite. Their igneous features contrast with the metamorphic character of their host gabbroic gneiss. Both rock types have a common parent; field relationships are consistent with modification of host gabbroic gneiss into hornblendite. This precludes any interpretation involving cumulate processes in forming the hornblendite; these bodies are imposter cumulates. Instead, replacement of the host gabbroic gneiss formed hornblendite as a result of channeled high melt flux through the lower crust. High melt/rock ratios and disequilibrium between the migrating magma (granodiorite) and its host gabbroic gneiss induced dissolution (grain-scale magmatic assimilation) of gneiss and crystallization of mainly hornblende from the migrating magma. The extent of this reaction-replacement mechanism indicates that such hornblendite bodies delineate significant melt conduits. Accordingly, many of the ubiquitous basic to ultrabasic elongate bodies of the lower crust likely map the ‘missing’ mass transfer zones

The effect of short-term intermittent hypoxic exposure on heart rate variability in a sedentary population

While the effects of instantaneous, single-bout exposure to hypoxia have been well researched, little is known about the autonomic response during, or as an adaptation to, repeated intermittent hypoxic exposure (IHE) in a sedentary population. Resting heart rate variability (HRV) and exercise capacity was assessed in 16 participants (8 receiving IHE, [Hyp] and 8 receiving a placebo treatment [C]) before and after a 4-week IHE intervention. Heart rate variability was also measured during an IHE session in the last week of the intervention. Post-intervention, the root mean squared successive difference (rMSSD) increased substantially in Hyp (71.6 ± 52.5%, mean change ± 90% confidence limits) compared to C suggesting an increase in vagal outflow. However, aside from a likely decrease in submaximal exercise heart rate in the Hyp group (–5.0 ± 6.4%) there was little evidence of improved exercise capacity. During the week 4 IHE measurement, HRV decreased during the hypoxic exposure (reduced R-R interval: –7.5 ± 3.2%; and rMSSD: –24.7 ± 17.3%) suggesting a decrease in the relative contribution of vagal activity. In summary, while 4 weeks of IHE is unlikely to improve maximal exercise capacity, it may be a useful means of increasing HRV in people unable to exercise

Issues potentially affecting quality of life arising from long-term medicines use: a qualitative study

Background Polypharmacy is increasing and managing large number of medicines may create a burden for patients. Many patients have negative views of medicines and their use can adversely affect quality of life. No studies have specifically explored the impact of general long-term medicines use on quality of life. Objective To determine the issues which patients taking long-term medicines consider affect their day-to-day lives, including quality of life. Setting Four primary care general practices in North West England Methods Face-to-face interviews with adults living at home, prescribed four or more regular medicines for at least 1 year. Interviewees were identified from primary care medical records and purposively selected to ensure different types of medicines use. Interviews were recorded, transcribed and analysed thematically. Results Twenty-one interviews were conducted and analysed. Patients used an average of 7.8 medicines, 51 % were preventive, 40 % for symptom relief and 9 % treatment. Eight themes emerged: relationships with health professionals, practicalities, information, efficacy, side effects, attitudes, impact and control. Ability to discuss medicines with health professionals varied and many views were coloured by negative experiences, mainly with doctors. All interviewees had developed routines for using multiple medicines, some requiring considerable effort. Few felt able to exert control over medicines routines specified by health professionals. Over half sought additional information about medicines whereas others avoided this, trusting in doctors to guide their medicines use. Patients recognised their inability to assess efficacy for many medicines, notably those used for prophylaxis. All were concerned about possible side effects and some had poor experiences of discussing concerns with doctors. Medicines led to restrictions on social activities and personal life to the extent that, for some, life can revolve around medicines. Conclusion There is a multiplicity and complexity of issues surrounding medicines use, which impact on day-to-day lives for patients with long-term conditions. While most patients adapt to long-term medicines use, others did so at some cost to their quality of life

Computer simulation of syringomyelia in dogs

Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked

Assessment of a conduction-repolarisation metric to predict Arrhythmogenesis in right ventricular disorders

Background: The re-entry vulnerability index (RVI) is a recently proposed activation-repolarization metric designed to quantify tissue susceptibility to re-entry. This study aimed to test feasibility of an RVI-based algorithm to predict the earliest endocardial activation site of ventricular tachycardia (VT) during electrophysiological studies and occurrence of haemodynamically significant ventricular arrhythmias in follow-up. Methods: Patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (n = 11), Brugada Syndrome (BrS) (n = 13) and focal RV outflow tract VT (n = 9) underwent programmed stimulation with unipolar electrograms recorded from a non-contact array in the RV. Results: Lowest values of RVI co-localised with VT earliest activation site in ARVC/BrS but not in focal VT. The distance between region of lowest RVI and site of VT earliest site (D min ) was lower in ARVC/BrS than in focal VT (6.8 ± 6.7 mm vs 26.9 ± 13.3 mm, p = 0.005). ARVC/BrS patients with inducible VT had lower Global-RVI (RVI G ) than those who were non-inducible (−54.9 ± 13.0 ms vs −35.9 ± 8.6 ms, p = 0.005) or those with focal VT (−30.6 ± 11.5 ms, p = 0.001). Patients were followed up for 112 ± 19 months. Those with clinical VT events had lower Global-RVI than both ARVC and BrS patients without VT (−54.5 ± 13.5 ms vs −36.2 ± 8.8 ms, p = 0.007) and focal VT patients (−30.6 ± 11.5 ms, p = 0.002). Conclusions: RVI reliably identifies the earliest RV endocardial activation site of VT in BrS and ARVC but not focal ventricular arrhythmias and predicts the incidence of haemodynamically significant arrhythmias. Therefore, RVI may be of value in predicting VT exit sites and hence targeting of re-entrant arrhythmias

Understanding asthma phenotypes: the World Asthma Phenotypes (WASP) international collaboration.

The World Asthma Phenotypes (WASP) study started in 2016 and has been conducted in five centres, in the UK, New Zealand, Brazil, Ecuador and Uganda. The objectives of this study are to combine detailed biomarker and clinical information in order to 1) better understand and characterise asthma phenotypes in high-income countries (HICs) and low and middle-income countries (LMICs), and in high and low prevalence centres; 2) compare phenotype characteristics, including clinical severity; 3) assess the risk factors for each phenotype; and 4) assess how the distribution of phenotypes differs between high prevalence and low prevalence centres. Here we present the rationale and protocol for the WASP study to enable other centres around the world to carry out similar analyses using a standardised protocol. Large collaborative and integrative studies like this are essential to further our understanding of asthma phenotypes. The findings of this study will help elucidate the aetiological mechanisms of asthma and might potentially identify new causes and guide the development of new treatments, thereby enabling better management and prevention of asthma in both HICs and LMICs

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up

The internalization of social stigma among minor-attracted persons: Implications for treatment

In this article, we sought to build on existing stigmatization research by examining the extent to which internalized stigmatization (i.e., the personal adoption and incorporation of social views, operationalized as thought suppression – an avoidant coping strategy – and low psychological wellbeing) among minor-attracted persons (MAPs) may impact upon help-seeking behaviors and their avoidance of children. We adopted a cross-sectional anonymous survey design to recruit a sample of self-identified MAPs (N = 183) from prominent online support fora. We found that increased levels of suppression and lower levels of psychological wellbeing were associated with lower levels of hope about the future, but higher levels of both shame and guilt about having a sexual interest in minors. Thought suppression was not significantly associated with outcomes related to help-seeking behaviors, but did significantly higher rates of actively avoiding children, even after controlling for psychological wellbeing and other emotional variables. Independently, lower levels of self-reported psychological wellbeing was associated with a desire for more support and higher rates of actively avoiding children. We explore the potential implications of our data in relation to treating and supporting MAPs within the community, increasing their wellbeing, and encouraging help-seeking behavior