Examination of Akt and GSK3ß in BDNF-mediated reductions in BACE1 activity in neuronal cells.

Brain-derived neurotrophic factor (BDNF) content and signaling has been identified as one potential regulator of amyloid precursor protein (APP) processing. Recently published work has demonstrated that BDNF reduces BACE1 activity while also elevating the inhibition of GSK3ß in the prefrontal cortex of male C57BL/6J mice. These results provide evidence that BDNF alters APP processing by reducing BACE1 activity, which may act through GSK3ß inhibition. The purpose of this study was to further explore the role of GSK3ß in BDNF-induced regulation on BACE1 activity. We utilized a cell culture and an in vitro activity assay model to pharmacologically target BDNF and GSK3ß signaling to confirm its involvement in the BDNF response. Treatment of differentiated SH-SY5Y neuronal cells with 75 ng/mL BDNF resulted in elevated pTrkB content, pAkt content, pGSK3ß content, and reduced BACE1 activity. An in vitro BACE1 activity assay utilizing mouse prefrontal cortex (n = 6/group) supplemented with BDNF, BDNF + ANA12 (Trkb antagonist), or BDNF + wortmannin (Akt inhibitor) demonstrated that BDNF reduced BACE1 activity; however, in the presence of TrkB or Akt inhibition, this effect was abolished. An in vitro ADAM10 activity assay utilizing mouse prefrontal cortex (n = 6/group) supplemented with BDNF, BDNF + ANA12 (Trkb antagonist), or BDNF + wortmannin (Akt inhibitor) demonstrated that BDNF did not alter ADAM10 activity. However, inhibiting BDNF signaling reduced ADAM10 activity. Collectively these studies suggest that GSK3ß inhibition may be necessary for BDNF-induced reductions in BACE1 activity. These findings will allow for the optimization of future therapeutic strategies by selectively targeting TrkB activation and GSK3ß inhibition.

Gestational physical activity alters offspring brain APP processing in an age-specific manner.

Maternal exercise is beneficial for offspring brain development. Amyloid precursor protein (APP) influences neurogenesis and synaptic plasticity. Cleavage products of APP are implicated in the proliferation of neural progenitor cells and neuronal network development. Our study aimed to investigate differences in APP processing in active or sedentary offspring of dams who were exposed to voluntary wheel running with and without a western diet throughout gestation. Female Wistar rats (7-8 weeks old) were fed a normal chow or western diet and randomized into voluntary wheel run or sedentary conditions. Dams returned to sedentary conditions post-parturition. The pups were weaned at 6 weeks after which point half of the samples were collected, while the rest of the pups remained on a normal diet, separated into sedentary or voluntary wheel run groups, and collected 12 weeks later. In utero exposure to maternal exercise was associated with higher neuronal nuclear protein, higher soluble APPα and lower soluble APPß in offspring prefrontal cortex tissue at 6, but not 18 weeks of age. Neuronal nuclear protein is exclusive to mature neurons implying that offspring of mothers who exercised could have more neuron maturation potentially influenced by the higher APPα content at this early developmental stage. The voluntary wheel run offspring groups had a higher mature/pro brain derived neurotrophic factor ratio compared to the sedentary counterparts. The maternal effects were isolated to the juvenile 6-week-old pups, while the differences in the adult offspring were caused by their own exercise status.

Creatine and low-dose lithium supplementation separately alter energy expenditure, body mass, and adipose metabolism for the promotion of thermogenesis.

Nutraceutical approaches to promote adipose tissue thermogenesis may help to prevent obesity onset. Creatine is a critical regulator of adipose metabolic function and low-dose lithium supplementation has been shown to promote adipose thermogenesis. In the present study, we sought to directly compare the two supplements for their effects on adipose metabolism and thermogenesis. We show that both supplements increase daily energy expenditure (EE) and reduce body mass in male Sprague-Dawley rats. Lithium increased brown adipose tissue (BAT) mitochondrial and lipolytic proteins that are associated with thermogenesis, while creatine increased BAT UCP1 and mitochondrial respiration. The BAT thermogenic findings were not observed in females. White adipose tissue and skeletal muscle markers of thermogenesis were unaltered with the supplements. Together, the data show that low-dose lithium and creatine have diverging effects on markers of BAT thermogenesis and that each increase daily EE and lower body mass in a sex-dependent manner.

Clarification of Governance Relevant to the Sustainable Management of Marine Species and Habitats within the United Kingdom: An Overview of Regional, National and International Authorities, Advisories, Legislation and Designation Types with Summary Schematic Tool.

Marine management developments are occurring across the United Kingdom with the major aim to ensure economic growth and security of marine resources via the provision of legislative guidelines for sustainable management of activities within the marine environment. Many of these directives also provide guidance for maintaining ecologically valuable and/or endangered species and habitats that exist alongside, and may also support, marine activities/use. Marine governance is largely guided by several key directives laid out and implemented by governing authorities of Europe, the United Kingdom and those countries comprising the United Kingdom, and in line with several international conventions. The directives set out by each authority or convention may act discretely but more often tend to overlap, which can lead to confusion about the relevant marine conservation requirements and objectives that must be fulfilled for a given region, site or feature. Additionally, management objectives driven by the same legislation may oppose one another, adding further complexity to the matter. This article aims to provide an overview of governance that holds relevance to managing marine habitats and species, especially those deemed sensitive, ecologically valuable and/or endangered. A general overview and summary schematic tool of the marine governance, legislation and designations within each level of authority for the United Kingdom are provided. Additional consideration of the implications for legislation upon the United Kingdom leaving the EU is briefly discussed and a comparative case study of two marine habitats of high conservation value is provided to demonstrate how different sites/features may have considerably different management requirements.

Roundness of grains in cellular microstructures.

Many physical systems are composed of polyhedral cells of varying sizes and shapes. These structures are simple in the sense that no more than three faces meet at an edge and no more than four edges meet at a vertex. This means that individual cells can usually be considered as simple, three-dimensional polyhedra. This paper is concerned with determining the distribution of combinatorial types of such polyhedral cells. We introduce the terms fundamental and vertex-truncated types and apply these concepts to the grain growth microstructure as a testing ground. For these microstructures, we demonstrate that most grains are of particular fundamental types, whereas the frequency of vertex-truncated types decreases exponentially with the number of truncations. This can be explained by the evolutionary process through which grain growth structures are formed and in which energetically unfavorable surfaces are quickly eliminated. Furthermore, we observe that these grain types are "round" in a combinatorial sense: there are no "short" separating cycles that partition the polyhedra into two parts of similar sizes. A particular microstructure derived from the Poisson-Voronoi initial condition is identified as containing an unusually large proportion of round grains. This microstructure has an average of 14.036 faces per grain and is conjectured to be more resistant to topological change than the steady-state grain growth microstructure.

Adenomatous-Dominant Benign Prostatic Hyperplasia (AdBPH) as a Predictor for Clinical Success Following Prostate Artery Embolization: An Age-Matched Case-Control Study.

PURPOSE: To investigate the clinical impact of performing prostate artery embolization (PAE) on patients with adenomatous-dominant benign prostatic hyperplasia (AdBPH). MATERIALS AND METHODS: Twelve patients from the ongoing proSTatic aRtery EmbolizAtion for the treatMent of benign prostatic hyperplasia (STREAM) trial were identified as having AdBPH; defined as two or more adenomas within the central gland of ≥1 cm diameter on multi-parametric MRI (MP-MRI). These patients were age-matched with patients from the STREAM cohort, without AdBPH. Patients were followed up with repeat MP-MRI at 3 months and 1 year. International prostate symptom score (IPSS), international index for erectile function (IIEF), and quality of life assessment from the IPSS and EQ-5D-5S questionnaires were recorded pre-PAE and at 6 weeks, 3 months, and 1 year. RESULTS: The mean age of patients was 68 (61-76). All patients had PAE as a day-case procedure. The technical success in the cohort was 23/24 (96%). There was a significant reduction in prostate volume following embolization with a median reduction of 34% (30-55) in the AdBPH group, compared to a mean volume reduction of 22% (9-44) in the non-AdBPH group (p = 0.04). There was a significant reduction in IPSS in the AdBPH group following PAE when compared with the control group [AdBPH median IPSS 8 (3-15) vs. non-AdBPH median IPSS 13 (8-18), p = 0.01]. IPSS QOL scores significantly improved in the AdBPH group (p = 0.007). There was no deterioration in sexual function in either group post-PAE. CONCLUSIONS: This is the first time that AdBPH has been identified as being a predictor of clinical success following PAE.

Topological similarity of random cell complexes and applications.

Although random cell complexes occur throughout the physical sciences, there does not appear to be a standard way to quantify their statistical similarities and differences. The various proposals in the literature are usually motivated by the analysis of particular physical systems and do not necessarily apply to general situations. The central concepts in this paper-the swatch and the cloth-provide a description of the local topology of a cell complex that is general (any physical system that can be represented as a cell complex is admissible) and complete (any statistical question about the local topology can be answered from the cloth). Furthermore, this approach allows a distance to be defined that measures the similarity of the local topology of two cell complexes. The distance is used to identify a steady state of a model grain boundary network, quantify the approach to this steady state, and show that the steady state is independent of the initial conditions. The same distance is then employed to show that the long-term properties in simulations of a specific model of a dislocation network do not depend on the implementation of dislocation intersections.

Recovery practice in community mental health teams: national survey.

BACKGROUND: There is consensus about the importance of 'recovery' in mental health services, but the link between recovery orientation of mental health teams and personal recovery of individuals has been underresearched. AIMS: To investigate differences in team leader, clinician and service user perspectives of recovery orientation of community adult mental health teams in England. METHOD: In six English mental health National Health Service (NHS) trusts, randomly chosen community adult mental health teams were surveyed. A random sample of ten patients, one team leader and a convenience sample of five clinicians were surveyed from each team. All respondents rated the recovery orientation of their team using parallel versions of the Recovery Self Assessment (RSA). In addition, service users also rated their own personal recovery using the Questionnaire about Processes of Recovery (QPR). RESULTS: Team leaders (n = 22) rated recovery orientation higher than clinicians (n = 109) or patients (n = 120) (Wald(2) = 7.0, P = 0.03), and both NHS trust and team type influenced RSA ratings. Patient-rated recovery orientation was a predictor of personal recovery (b = 0.58, 95% CI 0.31-0.85, P<0.001). Team leaders and clinicians with experience of mental illness (39%) or supporting a family member or friend with mental illness (76%) did not differ in their RSA ratings from other team leaders or clinicians. CONCLUSIONS: Compared with team leaders, frontline clinicians and service users have less positive views on recovery orientation. Increasing recovery orientation may support personal recovery.

The effect of adjuvant remifentanil with propofol or thiopentone on seizure quality during electroconvulsive therapy.

In order to optimise outcome to Electro Convulsive therapy (ECT), there has been a trend to utilise remifentanil as an adjunct to standard intravenous induction agents. This has allowed a reduction in the dose of anaesthetic agent, and usually an improved response to stimulation. However there have been no previous studies to ascertain whether this improvement is simply as a result of the reduced dose of anaesthetic agent or whether remifentanil itself might possess epileptogenic properties. This retrospective case-controlled study examined ECT outcomes, determined by EEG quality analysis, in patients who received ECT with or without remifentanil, where there was no dose reduction in the anaesthetic agent. There were no improvements seen in the measurements of any EEG parameter, including seizure duration. These observations suggest that remifentanil does not possess any intrinsic pro-convulsant activity and that any improvement in outcome seen with its use is as a result of dose reduction in the IV anaesthetic agent.

Reduced cortical BACE1 content with one bout of exercise is accompanied by declines in AMPK, Akt, and MAPK signaling in obese, glucose-intolerant mice.

Obesity and type 2 diabetes are significant risk factors in the development of neurodegenerative diseases, such as Alzheimer's disease. A variety of cellular mechanisms, such as altered Akt and AMPK and increased inflammatory signaling, contribute to neurodegeneration. Exercise training can improve markers of neurodegeneration, but the underlying mechanisms remain unknown. The purpose of this study was to determine the effects of a single bout of exercise on markers of neurodegeneration and inflammation in brains from mice fed a high-fat diet. Male C57BL/6 mice were fed a low (LFD; 10% kcal from lard)- or a high-fat diet (HFD; 60% kcal from lard) for 7 wk. HFD mice underwent an acute bout of exercise (treadmill running: 15 m/min, 5% incline, 120 min) followed by a recovery period of 2 h. The HFD increased body mass and glucose intolerance (both P < 0.05). This was accompanied by an approximately twofold increase in the phosphorylation of Akt, ERK, and GSK in the cortex (P < 0.05). Following exercise, there was a decrease in beta-site amyloid precursor protein cleaving enzyme 1 (BACE1; P < 0.05) and activity (P < 0.001). This was accompanied by a reduction in AMPK phosphorylation, indicative of a decline in cellular stress (P < 0.05). Akt and ERK phosphorylation were decreased following exercise in HFD mice to a level similar to that of the LFD mice (P < 0.05). This study demonstrates that a single bout of exercise can reduce BACE1 content and activity independent of changes in adiposity. This effect is associated with reductions in Akt, ERK, and AMPK signaling in the cortex.

Changes in mitochondrial perilipin 3 and perilipin 5 protein content in rat skeletal muscle following endurance training and acute stimulated contraction.

NEW FINDINGS: What is the central question of this study? The aim was to determine whether mitochondrial protein content of perilipin 3 (PLIN3) and perilipin 5 (PLIN5) is increased following endurance training and whether mitochondrial PLIN5 protein is increased to a greater extent in endurance-trained rats when compared with sedentary rats following acute contraction. What is the main finding and its importance? Mitochondrial PLIN3 but not PLIN5 protein was increased in endurance-trained compared with sedentary rats, suggesting a mitochondrial role for PLIN3 due to chronic exercise. Contrary to our hypothesis, acute mitochondrial PLIN5 protein was similar in both sedentary and endurance-trained rats. Endurance training results in an increased association between skeletal muscle lipid droplets and mitochondria. This association is likely to be important for the expected increase in intramuscular fatty acid oxidation that occurs with endurance training. The perilipin family of lipid droplet proteins, PLIN(2-5), are thought to play a role in skeletal muscle lipolysis. Recently, results from our laboratory demonstrated that skeletal muscle mitochondria contain PLIN3 and PLIN5 protein. Furthermore, 30 min of stimulated contraction induces an increased mitochondrial PLIN5 content. To determine whether mitochondrial content of PLIN3 and PLIN5 is altered with endurance training, Sprague-Dawley rats were randomized into sedentary or endurance-trained groups for 8 weeks of treadmill running followed by an acute (30 min) sciatic nerve stimulation to induce lipolysis. Mitochondrial PLIN3 protein was ∼1.5-fold higher in red gastrocnemius of endurance-trained rats compared with sedentary animals, with no change in mitochondrial PLIN5 protein. In addition, there was an increase in plantaris intramuscular lipid storage. Acute electrically stimulated contraction in red gastrocnemius from sedentary and endurance-trained rats resulted in a similar increase of mitochondrial PLIN5 between these two groups, with no net change in PLIN3 in either group. Plantaris intramuscular lipid content decreased to a similar extent in sedentary and endurance-trained rats. These results suggest that while total mitochondrial PLIN5 content is not altered by endurance training, PLIN5 does have an acute role in the mitochondrial fraction during muscle contraction. Conversely, mitochondrial PLIN3 does not change acutely with muscle contraction, but PLIN3 content was increased following endurance training, indicating a role in chronic adaptations of skeletal muscle.

Sprint interval exercise elicits near maximal peak VO2 during repeated bouts with a rapid recovery within 2 minutes.

AIM: We investigated the cardiorespiratory response during acute sprint interval exercise (SIE; 4 x 30 sec maximal efforts, each separated by 4 min recovery) vs. continuous endurance exercise (CEE; 30 min) at 70% VO2max. METHODS: Oxygen consumption (VO2) and heart rate were measured in 8 males (age: 23±2.3 y, height: 181±6.4 cm, body mass: 78±8.6 kg, VO2max: 52±3.1 ml·kg-1·min-1, mean±SD). Pre-exercise diet was controlled. RESULTS AND CONCLUSION: Total VO2 was greater with CEE vs. SIE (87.6±13.1 vs. 35.1±4.4 L O2) with small differences (P=0.06) in average heart rates (CEE: 157±10 bpm vs. SIE: 149±6 bpm) and peak heart rates (CEE: 166±10 vs. SIE: 173±6; P=0.14). VO2 increased during the sprint bouts (53-72% of VO2max) and attained near maximal values (84-96%) in the immediate recovery period (within 20 sec). Thereafter a rapid decrease occurred so that at 2 min of recovery VO2 was ~1.5 L/min (~38% VO2max). During the remaining 2 min of recovery VO2 declined more slowly to ~1.3 L/min or ~33% of VO2max. Similar heart rate responses with CEE and SIE and a greater VO2 during SIE suggest increased muscle oxygen extraction with SIE, which might explain the greater peripheral adaptations, observed previously with sprint vs. continuous training. The potential value of shorter recovery durations to SIE needs to be examined.

Trabectedin in Advanced High-Grade Uterine Leiomyosarcoma: A Case Report Illustrating the Value of (18)FDG-PET-CT in Assessing Treatment Response.

We report the case of a 60-year-old woman with metastatic high-grade uterine leiomyosarcoma who achieved a delayed response to second-line therapy with the marine-derived drug trabectedin (Yondelis(®), PharmaMar). We used 2-deoxy-2-[(18)F] fluorodeoxyglucose (FDG)-positron emission tomography (PET-CT) imaging as a tool for response monitoring in parallel with conventional re-staging according to Response Evaluation Criteria in Solid Tumours (RECIST) using computed tomography (CT). We illustrate the role of serial (18)FDG-PET-CT imaging in the functional assessment of tumour response. Three cycles after commencement of trabectedin treatment, a reduction of the maximum standardized uptake value (SUVmax) of the solid component of the pelvic mass was observed, indicating a cystic or necrotic response in the tumour to trabectedin. After 7 cycles of treatment, on (18)FDG-PET-CT there was clear evidence of ongoing disease improvement: the solid pelvic components were at worst stable, with an unchanged SUVmax, and possibly marginally reduced in size, while the pulmonary metastases had further reduced in size and become FDG negative; the bony metastases were stable. After a total of 13 cycles of treatment, administered over 13 months, the patient showed signs of progression on an (18)FDG-PET-CT scan. The safety profile of trabectedin remained manageable, showing no evidence of cumulative toxicity and being associated with a preserved quality of life. This report illustrates potential limitations of RECIST in response assessments and the critical role of serial (18)FDG-PET-CT imaging in assessing response to trabectedin treatment. Therefore, we propose that (18)FDG-PET-CT may improve the assessment of response to trabectedin in selected patients.

Individual care packages for people with severe mental illness: a description of their implementation in an English County.

BACKGROUND: This paper includes a brief review of the historical and policy background to a new form of supported accommodation, the Individual Care Package (ICP). This is a co-ordinated, individualised and flexible method to support people with complex mental health problems in the community. METHOD: The study aimed to describe the implementation of this new form of care in Gloucestershire, England, over a 5-year period. We aimed to audit the quality of care in the packages against six care standards, derived by a project steering group. Staff working in community mental health services and staff providing ICPs were asked to report their levels of satisfaction with care provision. RESULTS: A total of 35 ICPs were developed, mostly relating to service users with severe mental illness. Only 60% of the community mental health team key workers were aware of the expected level of care. In many cases, service users were accessing support from day services or family alongside the ICP. Four service users were admitted, and four moved accommodation after going into ICPs. Overall, levels of care provided within ICPs tended to remain static. Trust key workers were mostly satisfied with the support provided in ICPs, but a range of concerns were expressed. ICP staff reported mostly positive views about the support that they received from statutory services, but also reported some concerns. CONCLUSIONS: ICPs appeared to be successful in enabling a number of service users with complex difficulties to obtain and maintain tenancies in the community. There were some concerns about the quality of monitoring of the ICPs and some uncertainty about whether ICP staff would have the skills, support and training to promote recovery and increasing independence of service users. There was little evidence of service users moving on or reduction in care over time. There is a need for good inter-agency working for the successful deployment of this new form of service. There is also a need for more research, comparing ICPs with other forms of supported accommodation and considering the service user experience through qualitative research.

Statistical topology of cellular networks in two and three dimensions.

Cellular networks may be found in a variety of natural contexts, from soap foams to biological tissues to grain boundaries in a polycrystal, and the characterization of these structures is therefore a subject of interest to a range of disciplines. An approach to describe the topology of a cellular network in two and three dimensions is presented. This allows for the quantification of a variety of features of the cellular network, including a quantification of topological disorder and a robust measure of the statistical similarity or difference of a set of structures. The results of this analysis are presented for numerous simulated systems including the Poisson-Voronoi and the steady-state grain growth structures in two and three dimensions.

A proposed new imaging pathway for patients with suspected lung cancer.

AIMS: PET-CT scans are routinely performed in patients with lung cancer after investigation by chest x-ray (CXR) and CT scan, when these have demonstrated potentially curable disease. If the majority of patients with lung cancer potentially suitable for curative treatment could be identified earlier in the diagnostic pathway on the basis of CXR findings they could be referred for PET-CT imaging without a prior CT scan. We investigated the clinical and financial implications of adopting such a strategy. MATERIALS AND METHODS: The details of 1187 patients referred with suspected lung cancer between July 2006 and August 2009 were analysed. The initial CXR and subsequent imaging of patients fit for curative treatment (Performance Status 0/1, FEV1 > 1.0) were reviewed (n = 251). The clinical and financial implications of referring patients for first line PET-CT if deemed potentially curable based on CXR findings were assessed. RESULTS: 107 of 1187 patients had potentially curable lung cancer on PS, lung function, CT and PET-CT. 96 of these 107 patients (90%) were correctly identified on CXR. 149 patients overall were diagnosed as potentially curable on CXR. Referring suitable patients for an immediate PET-CT scan resulted in a reduction in the time to complete staging investigations. CONCLUSIONS: Early PET-CT scanning for patients with suspected lung cancer, potentially suitable for curative therapy could result in more efficient staging with little additional cost.

The use of CT angiography in acute subarachnoid haemorrhage in Eastern Scotland.

INTRODUCTION: Early confirmation of aneurysmal cause for SAH can expedite patient management and thus minimise rebleed risk. CT Angiography is the first-line method for diagnosing the cause of SAH in most UK regions. We wanted to assess the use of CTA in this context in the East of Scotland and determine how imaging delays contribute to overall delay from ictus to aneurysm treatment. METHODS: A prospective audit of aneurysmal SAH admissions over a three month period to the Neurosciences Unit in Edinburgh was performed. The time from diagnosis of SAH to aneurysm imaging with CTA and/or DSA and time from aneurysm confirmation to definitive treatment was ascertained. RESULTS: Twenty nine patients with aneurysmal SAH were admitted during the audit. Four patients had CTA expeditiously after SAH was diagnosed; the remaining 25 patients had a substantially greater wait for aneurysm imaging, involving transfer to a neuroscience centre. Average excess delay was 17 hours for CTA (72 hours for DSA). DISCUSSION: CTA widely available and accurate method of determining the cause of SAH. Performing immediate CTA after SAH is confirmed could reduce delays to aneurysm treatment by up to 64%. By thus reducing rebleeds post SAH, immediate CTA could reduce poor outcomes in the East of Scotland.

Non-small-cell lung cancer dimensions: CT-pathological correlation and interobserver variation.

The aim of the study was to identify the most accurate CT window level setting for the measurement of non-small-cell lung cancer to optimise CT planning for radiotherapy treatment. 27 patients who underwent resection for non-small-cell lung cancer in a single institution were studied. The maximal superior-inferior, anteroposterior and mediolateral dimensions of the resected tumours were measured by a consultant pathologist. Two radiologists made corresponding measurements using pre-operative CT scans independently of each other and of the pathologist's findings. The measurements were obtained using four different CT window settings. The mean pathological size of the superior-inferior tumours, the anteroposterior tumours and the mediolateral tumours was 32 mm, 28 mm and 25 mm, respectively. A total of 648 CT measurements were taken, of which 321 were within +/-5 mm of the pathological size (49.5%). There was significant interobserver variability between the two radiologists. There was poor correlation between the pathological and radiological measurements of tumour size. Significant interobserver variability was noted between the two radiologists and no window setting could be identified as being superior in accurately assessing the tumour size.