Reversal of Soleus Muscle Atrophy in Older Adults: A Non-Volitional Exercise Intervention for a Changing Climate.

The World Health Organization recommends that older adults undertake at least 150 minutes of moderate intensity physical activity over the course of each week in order to maintain physical, mental, and social health. This goal turns out to be very difficult for most community dwelling older adults to achieve, due to both actual and perceived barriers. These barriers include personal health limitations, confinement issues, and self-imposed restrictions such as fear of injury. Climate change exacerbates the confinement issues and injury fears among the elderly. To assist older adults in obtaining the benefits of increased physical activity under increasingly challenging climate conditions, we propose a targeted non-volitional intervention which could serve as a complement to volitional physical activity. Exogenous neuro-muscular stimulation of the soleus muscles is a non-invasive intervention capable of significantly increasing cardiac output in sedentary individuals. Long-term daily use has been shown to improve sleep, reduce bone loss, and reverse age-related cognitive decline, all of which are significant health concerns for older adults. These outcomes support the potential benefit of exogenous neuro-muscular stimulation as a complementary form of physical activity which older adults may find convenient to incorporate into their daily life when traditional forms of exercise are difficult to achieve due to barriers to completing traditional physical activities as a result of in-home or in-bed confinement, perceptual risks, or real environmental risks such as those arising from climate change.

Pulsed shortwave electromagnetic field therapy increases quality of life in canines with symptoms of osteoarthritics.

BACKGROUND: Joint stiffness, lameness and reduced activity levels are common inflammatory responses observed in canines and have significant impact on quality of life (QOL). The symptoms are often ascribed to osteoarthritis (OA), for which the standard treatment is systemic anti-inflammatories, but pharmacologic intervention can have significant short-term and long-term side effects. OBJECTIVES: Test the efficacy of a Food and Drug Administration (FDA)-cleared pulsed shortwave therapy (PSWT) device as a means to modulate vagus nerve activity and initiate a systemic anti-inflammatory response to determine its ability to improve functionality and the QOL of canines with inflammatory symptoms commonly associated with OA. METHODS: A randomized, double-blinded, placebo-controlled 14-day study of 60 dogs with a presumptive prior diagnosis of OA in at least one limb joint. Two outcomes assessing changes in the dog's QOL and functionality were measured: subjectively determined changes in eight behaviours associated with discomfort and objectively determined changes in passive range of motion (PROM). The device was secured near the cervico-thoracic region of the dog's spine. PROM measures were taken at baseline and at the end of study. Behavioural measures were taken daily. RESULTS: Forty-nine animals completed the study. No negative side effects were reported. Average subjective discomfort scores for the treatment group (N = 26) were reduced from 3.74 to 2.10 (44%), compared to no improvement in the placebo group (N = 23) over the study period (p = 0.0001). Average PROM scores increased by 5.51 (4.59-6.23) degrees relative to the placebo group (p < 0.01). Ninety-six per cent of the treatment group showed either increased PROM or improved behavioural changes or both, compared to 4% for the placebo group (p < 0.01). Most changes occurred within the first 8 days of treatment. CONCLUSIONS: PSWT applied at the level of the cervico-thoracic spine to target the vagus nerve may have the potential to improve QOL in dogs manifesting behaviours commonly associated with OA.

The impact of tritium phytoremediation on plant health as measured by fluorescence.

Phytoremediation, using plants for soil, sediment, or water contaminant clean-up, is an established technology dependent on plant health. Tritium (3H), a radioactive isotope of hydrogen that is generally found in the environment as tritiated water (HTO), is a low-level beta emitter with a half-life of 12.32 years. Chlorophyll fluorescence (CF) for monitoring risk assessment of tritium to plant health was conducted at the Tritium Irrigation Facility (TIF) located on the US Department of Energy's Savannah River Site (SRS) near Aiken, SC. Two fluorometers were evaluated in conjunction with phytoremediation at the 25 -acre TIF where tritiated groundwater is being spray-irrigated on a mixed coniferous/deciduous forested watershed as a means of reducing tritium release to a nearby stream that serves as a tributary to the Savannah River. Tritium activity in irrigated water averaged 104 + 42 pCi mL-1 during the 2003 project. Fluorescence parameters measured by the two fluorometers were well correlated with each other (p < 0.0001). Tritium in water respired from oak leaves ranged up to 1845.13 pCi ml-1 and 2138.22 pCi ml-1 in pine needles. Trees in both the test and control sites were approximately 15 years old. Here we demonstrated that fluorescence parameters provide an effective way to estimate the impact of HTO on plant health in a noninvasive, extremely rapid, and cost-effective manner. In the current study applying fluorometry, plants within the TIF phytoremediation site exposed to the site tritiated water were not significantly impacted by the tritium phytoremediation based on CF parameters as compared to the control, a nascent non-irrigated site.

Reversal of cognitive impairment in a hypotensive elderly population using a passive exercise intervention.

BACKGROUND: Cognitive decline in the elderly is strongly associated with cerebral hypoperfusion, a condition that can be reversed with exercise. Adhering to a traditional exercise regimen, however, is challenging for this population. OBJECTIVE: In a pilot clinical study, we evaluated the ability of a "passive" exercise regimen (noninvasive calf muscle pump stimulation) to normalize blood pressure in a chronically hypotensive elderly population and enhance cognitive function. PARTICIPANTS AND METHODS: Ten elderly (82.5±7.5 years) men and women volunteers, residing in a senior living facility in upstate New York, were divided into control (N=5) and intervention (N=5) groups based on initial diastolic blood pressure (DBP); participants with initial DBP <65 mmHg became intervention participants, and those with initial DBP >65 mmHg enrolled in the control group. Body mass, blood pressure, and executive function (using incongruent Stroop and Trailmaking B test) were evaluated weekly for 4 months. RESULTS: At initiation of the study, time to complete the executive function tests in the hypotensive group was almost twice that of the control group. Daily calf muscle pump stimulation (passive exercise) for 1 hour/day, or less, was found to be sufficient to normalize DBP and significantly improve performance on the executive function tests.

Postural Hypotension and Cognitive Function in Older Adults.

Background: Cognitive decline in the elderly is associated with chronic cerebral hypoperfusion. While many forms of exercise can slow or reverse cognitive decline, compliance in unsupervised exercise programs is poor. Objective: We address whether passive exercise, that is, muscle stimulation, is capable of reversing postural hypotension in an older adult population sufficiently to significantly improve cognitive function as measured by executive function tests. Subjects and Methods: In this study, 50- to 80-year-old women underwent cognitive testing, long-duration cardiac hemodynamic recordings during quiet sitting, and 60 min of soleus muscle stimulation with continued hemodynamic recording. Results: Two thirds of our subjects were hypotensive (diastolic blood pressure [DBP] < 70 mmHg) after 30 min of quiet sitting. Cognitive performance was significantly better in individuals with higher DBPs (0.79 s per 1-mmHg increase in DBP). Soleus muscle stimulation resulted in an average increase in DBP of 6.1 mmHg, which could translate into a 30% or greater improvement in cognitive performance. Conclusions: Incongruent Stroop testing provides high statistical power for distinguishing differential cognitive responses to resting DBP levels. These results set the stage to investigate whether regular use of calf muscle pump stimulation could effectively reverse age-related cognitive impairment.

The 'straight mouse': defining anatomical axes in 3D embryo models.

A primary objective of the eMouseAtlas Project is to enable 3D spatial mapping of whole embryo gene expression data to capture complex 3D patterns for indexing, visualization, cross-comparison and analysis. For this we have developed a spatio-temporal framework based on 3D models of embryos at different stages of development coupled with an anatomical ontology. Here we introduce a method of defining coordinate axes that correspond to the anatomical or biologically relevant anterior-posterior (A-P), dorsal-ventral (D-V) and left-right (L-R) directions. These enable more sophisticated query and analysis of the data with biologically relevant associations, and provide novel data visualizations that can reveal patterns that are otherwise difficult to detect in the standard 3D coordinate space. These anatomical coordinates are defined using the concept of a 'straight mouse-embryo' within which the anatomical coordinates are Cartesian. The straight embryo model has been mapped via a complex non-linear transform onto the standard embryo model. We explore the utility of this anatomical coordinate system in elucidating the spatial relationship of spatially mapped embryonic ' Fibroblast growth factor ' gene expression patterns, and we discuss the importance of this technology in summarizing complex multimodal mouse embryo image data from gene expression and anatomy studies. Database URL: www.emouseatlas.org.

Association of Calf Muscle Pump Stimulation With Sleep Quality in Adults.

Prevention of lower extremity fluid pooling (LEFP) is associated with improved sleep quality. Physical activity and compression stockings are non-invasive methods used to manage LEFP, but both are associated with low adherence. Calf muscle pump (CMP) stimulation is an alternative and more convenient approach. Convenience sampling was used to recruit 11 participants between ages 45 and 65 with poor sleep quality. A within-person single-group pre-test-post-test design was used to evaluate changes in sleep quality, daytime sleepiness, and functional outcomes sensitive to impaired sleep as measured by the Pittsburgh Sleep Quality Index (PSQI), Functional Outcomes of Sleep Questionnaire, and Epworth Sleepiness Scale after 4 weeks of CMP stimulation. Statistical analysis included effect size (ES) calculations. After daily use of CMP stimulation, participants demonstrated improvement in overall sleep quality (ES = -.97) and a large reduction in daily disturbance from poor sleep (ES = -1.25). Moderate improvements were observed in daytime sleepiness (ES = -.53) and functional outcomes sensitive to sleepiness (ES = .49). Although causality could not be determined with this study design, these results support further research to determine whether CMP stimulation can improve sleep quality. © 2016 Wiley Periodicals, Inc.

PhenoImageShare: an image annotation and query infrastructure.

BACKGROUND: High throughput imaging is now available to many groups and it is possible to generate a large quantity of high quality images quickly. Managing this data, consistently annotating it, or making it available to the community are all challenges that come with these methods. RESULTS: PhenoImageShare provides an ontology-enabled lightweight image data query, annotation service and a single point of access backed by a Solr server for programmatic access to an integrated image collection enabling improved community access. PhenoImageShare also provides an easy to use online image annotation tool with functionality to draw regions of interest on images and to annotate them with terms from an autosuggest-enabled ontology-lookup widget. The provenance of each image, and annotation, is kept and links to original resources are provided. The semantic and intuitive search interface is species and imaging technology neutral. PhenoImageShare now provides access to annotation for over 100,000 images for 2 species. CONCLUSION: The PhenoImageShare platform provides underlying infrastructure for both programmatic access and user-facing tools for biologists enabling the query and annotation of federated images. PhenoImageShare is accessible online at http://www.phenoimageshare.org .

Calf muscle pump stimulation as a means to reduce symptoms of fibromyalgia syndrome.

Fibromyalgia (FM) is a debilitating chronic condition that often affects women in midlife with widespread pain that interrupts attempts to exercise. The purpose of this pilot study was to test the efficacy of calf muscle pump (CMP) stimulation as an adjuvant therapy for FM by (1) assessing the correlation of the level of symptoms, as measured by the revised Fibromyalgia Impact Questionnaire (FIQR), and blood pressure (BP), (2) measuring change in mean FIQR scores for subjects who use a CMP-stimulation device for 12 weeks, and (3) measuring the correlation of total device usage and the level of symptoms as measured by the FIQR. The 29 male and female participants (mean age = 47.3 years) were screened using the Widespread Pain Index (WPI), Symptom Severity (SS) score, and the FIQR. Participants were contacted weekly, and progress was assessed using the WPI, SS score, and the FIQR as well as general questions regarding responses to CMP stimulation. The attrition rate was high, which is not uncommon in studies of patients with FM. We found that diastolic BP was significantly inversely correlated with baseline FIQR scores during quiet sitting. Further, 12 weeks of CMP stimulation was associated with significant improvement in average FIQR scores at a rate of approximately -1.5 points per week (R (2) = .9; p ≤ .0001). Total device usage was strongly and inversely correlated with baseline FIQR scores (R (2) = .43; p = .02). These findings suggest that CMP stimulation may provide an additional treatment option for individuals with FM who are challenged to perform traditional forms of exercise.

Elevation of heat shock gene expression from static magnetic field exposure in vitro.

Previously, we found that extremely low frequency (ELF) electric fields were able to elicit an approximate 3.5-fold increase in heat shock gene expression, a response which may have applicability to cancer therapy. Based on recent studies demonstrating the ability of magnetic fields to influence gene expression, we hypothesized that low level static magnetic fields may be able to affect heat shock gene expression while avoiding some of the clinical difficulties that arise with electric fields. Transfected rat primary cells in monolayer were exposed to magnetic fields of 1 to 440 mT for 16, 24, or 48 h starting at 24 and 48 h post transfection. Heat shock protein (HSP70) expression, as indicated by a promoter linked luciferase reporter, was followed for up to 96 h and showed a dependence on flux density, exposure duration, and start time post transfection. A nonlinear response was observed for increasing flux density with a maximum of a 3.5-fold increase in expression for 48 h of exposure starting 48 h after transfection. These results demonstrate an enhancement of gene expression similar in magnitude to that observed with external electric field exposure, while eliminating many of the clinical complications.

Induction of heat shock gene expression in RAT1 primary fibroblast cells by ELF electric fields.

Recent studies have demonstrated that the Ku70 gene fragment can be placed in the anti-sense orientation under the control of a heat-inducible heat shock protein 70 (HSP70) promoter and activated through heat shock exposure. This results in attenuation of the Ku70 protein expression, inhibiting cellular repair processes, and sensitizing the transfected cells to exposures such as the ionizing radiation exposures used clinically. However, achieving the tissue temperatures necessary to thermally induce the HSP70 response presents significant limitations to the clinical application of this strategy. Previous findings suggest an alternative approach to inducing a heat shock response, specifically through the use of extremely low frequency (ELF) electrical field stimulation. To further pursue this approach, we investigated HSP70 responses in transfected rat primary fibroblast (RAT1) cells exposed to 10 Hz electric fields at intensities of 20-500 V/m. We confirmed that low frequency electric fields can induce HSP70 heat shock expression, with peak responses obtained at 8 h following a 2 h field exposure. However, the approximate threefold increase in expression is substantially lower than that obtained using thermal stimulation, raising questions of the clinical utility of the response.

Argudas: lessons for argumentation in biology based on a gene expression use case.

BACKGROUND: In situ hybridisation gene expression information helps biologists identify where a gene is expressed. However, the databases that republish the experimental information online are often both incomplete and inconsistent. Non-monotonic reasoning can help resolve such difficulties - one such form of reasoning is computational argumentation. Essentially this involves asking a computer to debate (i.e. reason about) the validity of a particular statement. Arguments are produced for both sides - the statement is true and, the statement is false - then the most powerful argument is used. In this work the computer is asked to debate whether or not a gene is expressed in a particular mouse anatomical structure. The information generated during the debate can be passed to the biological end-user, enabling their own decision-making process. RESULTS: This paper examines the evolution of a system, Argudas, which tests using computational argumentation in an in situ gene hybridisation gene expression use case. Argudas reasons using information extracted from several different online resources that publish gene expression information for the mouse. The development and evaluation of two prototypes is discussed. Throughout a number of issues shall be raised including the appropriateness of computational argumentation in biology and the challenges faced when integrating apparently similar online biological databases. CONCLUSIONS: From the work described in this paper it is clear that for argumentation to be effective in the biological domain the argumentation community need to develop further the tools and resources they provide. Additionally, the biological community must tackle the incongruity between overlapping and adjacent resources, thus facilitating the integration and modelling of biological information. Finally, this work highlights both the importance of, and difficulty in creating, a good model of the domain.

The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells.

Focal adhesion kinase (FAK) is upregulated in several epithelial tumours and there has been considerable interest in developing small molecule kinase inhibitors of FAK. However, FAK also has important adaptor functions within the cell, integrating signals from both integrins and growth factors. To investigate the role of FAKs kinase domain, we generated fak-deficient squamous cell carcinoma (SCC) cell lines. Re-expression of a wild type or kinase dead FAK allowed us to delineate its kinase dependent functions. In addition, we used the novel FAK kinase inhibitor PF-562,271. The kinase activity of FAK was important for tumour cell migration and polarity but more striking was its requirement for the anchorage independent 3 dimensional (3D) proliferation of SCC cells and their growth as xenografts in mice. Inhibition of FAK activity and prevention of growth in 3D correlated with Src inhibition. We further identified a mechanism whereby FAK regulates proliferation in 3D via regulation of the kinase activity of Src. This was dependent on the kinase activity of FAK and its resulting phosphorylation on Y397 that provides a high affinity binding site for Src. These data support the further development of FAK kinase inhibitors as agents that have the potential to inhibit both tumour cell migration and proliferation.

Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling.

Here we describe a mechanism that cancer cells use to survive when flux through the Src/FAK pathway is severely perturbed. Depletion of FAK, detachment of FAK-proficient cells or expression of non-phosphorylatable FAK proteins causes sequestration of active Src away from focal adhesions into intracellular puncta that co-stain with several autophagy regulators. Inhibition of autophagy results in restoration of active Src at peripheral adhesions, and this leads to cancer cell death. Autophagic targeting of active Src is associated with a Src-LC3B complex, and is mediated by c-Cbl. However, this is independent of c-Cbl E3 ligase activity, but is mediated by an LC3-interacting region. Thus, c-Cbl-mediated autophagic targeting of active Src can occur in cancer cells to maintain viability when flux through the integrin/Src/FAK pathway is disrupted. This exposes a previously unrecognized cancer cell vulnerability that may provide a new therapeutic opportunity.

Knowledge-driven enhancements for task composition in bioinformatics.

BACKGROUND: A key application area of semantic technologies is the fast-developing field of bioinformatics. Sealife was a project within this field with the aim of creating semantics-based web browsing capabilities for the Life Sciences. This includes meaningfully linking significant terms from the text of a web page to executable web services. It also involves the semantic mark-up of biological terms, linking them to biomedical ontologies, then discovering and executing services based on terms that interest the user. RESULTS: A system was produced which allows a user to identify terms of interest on a web page and subsequently connects these to a choice of web services which can make use of these inputs. Elements of Artificial Intelligence Planning build on this to present a choice of higher level goals, which can then be broken down to construct a workflow. An Argumentation System was implemented to evaluate the results produced by three different gene expression databases. An evaluation of these modules was carried out on users from a variety of backgrounds. Users with little knowledge of web services were able to achieve tasks that used several services in much less time than they would have taken to do this manually. The Argumentation System was also considered a useful resource and feedback was collected on the best way to present results. CONCLUSION: Overall the system represents a move forward in helping users to both construct workflows and analyse results by incorporating specific domain knowledge into the software. It also provides a mechanism by which web pages can be linked to web services. However, this work covers a specific domain and much co-ordinated effort is needed to make all web services available for use in such a way, i.e. the integration of underlying knowledge is a difficult but essential task.

Feasibility of treatment of lower limb edema with calf muscle pump stimulation in chronic heart failure.

BACKGROUND: Persons with chronic heart failure may exhibit a decrease in functional ability related to lower extremity edema in spite of optimal diuretic therapy and salt restrictions. AIM: The aim of this pilot prospective clinical study was to test the feasibility of using exogenous calf muscle pump stimulation to decrease lower leg edema and thus improve functional status and quality of life. METHODS: Six subjects entered into this study and agreed to use the intervention 30 min/day for one month. DXA was used to assess lower extremity composition. RESULTS: Device use averaged approximately 1 h/day and resulted in a reduction in the lean mass of the legs of 0.5 kg (range = 0.08-1.0 L; p = 0.03). Linear regression analysis of reduction of lower limb edema against daily usage suggests that increased utilization of calf muscle pump stimulation was associated with increased water losses, although this trend was not significant (R(2 = 0.4, p = 0.18). CONCLUSION: This pilot indicates that exogenous calf muscle pump stimulation could be a useful and safe addition to the patients' treatment regimes, but further studies testing a more typical population with heart failure is warranted.

Influence of seated rocking on blood pressure in the elderly: a pilot clinical study.

Patients with Alzheimer's disease (AD) who rock for 1-2 hr per day in a rocking chair demonstrate significant improvements in depression, anxiety, and balance and a decrease in pain medication usage; however, the underlying basis for their responses remains unclear. Rocking with plantar flexion uses the calf muscles, enhancing lower limb fluid return to the heart, which should increase blood pressure (BP) and may, then, also increase cerebral perfusion. Accordingly, we tested the efficacy of rocking activity for increasing BP in healthy, older persons. In a pilot laboratory study of 24 healthy, White men and women aged 55-87 years, we observed that 30 min of steady rocking led to an average 12 mmHg increase in systolic blood pressure (SBP, p < .001) and a 3.6 mmHg average increase in diastolic blood pressure (DBP, p < .001). To determine the effect of using this intervention in a nonclinical setting, we tested a similar group of 7 participants at a senior center. In this setting, we observed an average increase in SBP of 27 mmHg (p < .001) and in DBP of 2.5 mmHg (p < .001) after 30 min of rocking. In a subgroup (n = 8) of hypotensive individuals (SBP < 110 mmHg after sitting quietly for 30 min) extracted from both settings, rocking raised the average SBP from <100 mmHg to approximately 120 mmHg. These results are consistent with the hypothesis that rocking can increase BP and, therefore, may enhance cerebral perfusion. This observation may play a fundamental role in designing nursing interventions focused on improvement of symptoms associated with AD.

Enhancing hemodialysis efficacy through neuromuscular stimulation.

Beat-to-beat blood pressure monitoring was used to assess the efficacy of reflex-mediated, calf muscle pump stimulation to enhance cardiovascular refilling in subjects in the supine and seated positions, with extension of this stimulation technology to dialysis evaluated in 2 dialysis patients. Micromechanical stimulation (50 mum at 45 Hz) of the plantar surface was found to significantly increase both the rate and volume of cardiovascular refilling relative to that observed for subjects in the supine position. During hemodialysis, calf muscle pump stimulation permitted significantly increased ultrafiltrate removal, specifically from 78 to 96% of clinical goal, while serving to maintain both blood pressure and blood volume.

Prevalence and etiology of delayed orthostatic hypotension in adult women.

OBJECTIVE: To evaluate the contributing roles of venous status, microvascular filtration, and calf muscle pump activity in the etiology of delayed orthostatic hypotension (OH). DESIGN: Unblinded within-subjects trial. SETTING: Academic clinical research center. PARTICIPANTS: Convenience sample of healthy adult women (N=30) with an age range of 30 to 65 years. INTERVENTION: Plantar micromechanical stimulation applied at a 45-Hz frequency and a 50-microm amplitude for a duration of 30 minutes during upright sitting. MAIN OUTCOME MEASURE: Diastolic blood pressure (DBP). RESULTS: White women (mean age, 51.8+/-1.3 y) were recruited and screened for delayed OH. About one quarter (9/33) of the screened subjects showed delayed OH as determined by a significant decrease in blood pressure after at least 15 minutes of quiet sitting. Air plethysmographic assessment provided no evidence of venous insufficiency (venous filling index, >2.5 mL/s; venous volume, >80 mL) or excessive microvascular filtration in the affected subjects, whereas activation of the calf muscle pump (CMP) through plantar-based micromechanical stimulation consistently resulted in a significant increase in systolic blood pressure (SBP) (DeltaSBP=22.8+/-3.9 mmHg, P=.003) and DBP (DeltaDBP=20.9+/-3.3 mmHg, P=.002). CONCLUSIONS: About 25% of the adult women studied showed delayed OH during quiet sitting and the proximate cause appears to be neuromuscular in origin, specifically inadequate calf muscle tone, because venous and microvascular filtration status is normative in the delayed OH subpopulation and CMP stimulation reverses the hypotension.

Towards the use of argumentation in bioinformatics: a gene expression case study.

MOTIVATION: Due to different experimental setups and various interpretations of results, the data contained in online bioinformatics resources can be inconsistent, therefore, making it more difficult for users of these resources to assess the suitability and correctness of the answers to their queries. This work investigates the role of argumentation systems to help users evaluate such answers. More specifically, it looks closely at a gene expression case study, creating an appropriate representation of the underlying data and series of rules that are used by a third-party argumentation engine to reason over the query results provided by the mouse gene expression database EMAGE. RESULTS: A prototype using the ASPIC argumentation engine has been implemented and a preliminary evaluation carried out. This evaluation suggested that argumentation can be used to deal with inconsistent data in biological resources. AVAILABILITY: The ASPIC argumentation engine is available from http://www.argumentation.org. EMAGE gene expression data can be obtained from http://genex.hgu.mrc.ac.uk. The argumentation rules for the gene expression example are available from the lead author upon request.