Primary progressive aphasia: six questions in search of an answer

Here, we review recent progress in the diagnosis and management of primary progressive aphasia—the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there—and is syndromic diagnosis even useful? Are these truly ‘language-led’ dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies

The impact of submaximal exercise during heat and/or hypoxia on the cardiovascular and monocyte HSP72 responses to subsequent (post 24 h) exercise in hypoxia

BACKGROUND: The aims of this study were to describe the cellular stress response to prolonged endurance exercise in acute heat, hypoxia and the combination of heat and hypoxia and to determine whether prior acute exposure to these stressors improved cellular tolerance to a subsequent exercise bout in hypoxia 24 h later. METHODS: Twelve males (age 22 ± 4 years, height 1.77 ± 0.05 m, mass 79 ± 12.9 kg, VO(2) max 3.57 ± 0.7 L · min(-1)) completed four trials (30-min rest, 90-min cycling at 50% normoxic VO(2) max) in normothermic normoxia (NORM; 18°C, F(I)O(2) = 0.21), heat (HEAT; 40°C, 20% RH), hypoxia (HYP; F(I)O(2) = 0.14) or a combination of heat and hypoxia (COM; 40°C, 20% RH, F(I)O(2) = 0.14) separated by at least 7 days. Twenty-four hours after each trial, participants completed a hypoxic stress test (HST; 15-min rest, 60-min cycling at 50% normoxic VO(2) max, F(I)O(2) = 0.14). Monocyte heat shock protein 72 (mHSP72) was assessed immediately before and after each exercise bout. RESULTS: mHSP72 increased post exercise in NORM (107% ± 5.5%, p > 0.05), HYP (126% ± 16%, p < 0.01), HEAT (153% ± 14%, p < 0.01) and COM (161% ± 32%, p < 0.01). mHSP72 had returned to near-resting values 24 h after NORM (97% ± 8.6%) but was elevated after HEAT (130% ± 19%), HYP (118% ± 17%) and COM (131% ± 19%) (p < 0.05). mHSP72 increased from baseline after HST(NORM) (118% ± 12%, p < 0.05), but did not increase further in HST(HEAT), HST(HYP) and HST(COM). CONCLUSIONS: The prior induction of mHSP72 as a result of COM, HEAT and HYP attenuated further mHSP72 induction after HST and was indicative of conferred cellular tolerance

Markers of physiological stress during exercise under conditions of normoxia, normobaric hypoxia, hypobaric hypoxia and genuine high altitude.

Purpose To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH) and normobaric normoxia (NN). Method Markers of sympathoadrenal and adrenocortical function (plasma normetanephrine [PNORMET], metanephrine [PMET], cortisol), myocardial injury (highly sensitive cardiac troponin T [hscTnT]) and function (N-terminal brain natriuretic peptide [NT-proBNP]) were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 hours {15 minute warm-up, 105 minutes at 55% Wmax (maximal workload)} with venous blood samples taken prior (T0), immediately following (T120) and 2 hours post-exercise (T240). Results Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET. Conclusion Biochemical markers that reflect sympathoadrenal, adrenocortical and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia while NH and HH appear to induce broadly similar responses to GHA and may therefore be reasonable surrogates

The Healthy Steps Study: A randomized controlled trial of a pedometer-based Green Prescription for older adults. Trial protocol

Background: Graded health benefits of physical activity have been demonstrated for the reduction of coronary heart disease, some cancers, and type-2 diabetes, and for injury reduction and improvements in mental health. Older adults are particularly at risk of physical inactivity, and would greatly benefit from successful targeted physical activity interventions. Methods/Design: The Healthy Steps study is a 12-month randomized controlled trial comparing the efficacy of a pedometer-based Green Prescription with the conventional time-based Green Prescription in increasing and maintaining physical activity levels in low-active adults over 65 years of age. The Green Prescription interventions involve a primary care physical activity prescription with 3 follow-up telephone counselling sessions delivered by trained physical activity counsellors over 3 months. Those in the pedometer group received a pedometer and counselling based around increasing steps that can be monitored on the pedometer, while those in the standard Green Prescription group received counselling using time-based goals. Baseline, 3 month (end of intervention), and 12 month measures were assessed in face-to-face home visits with outcomes measures being physical activity (Auckland Heart Study Physical Activity Questionnaire), quality of life (SF-36 and EQ-5D), depressive symptoms (Geriatric Depression Scale), blood pressure, weight status, functional status (gait speed, chair stands, and tandem balance test) and falls and adverse events (self-report). Utilisation of health services was assessed for the economic evaluation carried out alongside this trial. As well, a process evaluation of the interventions and an examination of barriers and motives for physical activity in the sample were conducted. The perceptions of primary care physicians in relation to delivering physical activity counselling were also assessed. Discussion: The findings from the Healthy Steps trial are due in late 2009. If successful in improving physical activity in older adults, the pedometer-based Green Prescription could assist in reducing utilisation of health services and improve cardiovascular health and reduction of risk for a range of non-communicable lifestyles diseases

The feasibility of measuring the activation of the trunk muscles in healthy older adults during trunk stability exercises

<p>Abstract</p> <p>Background</p> <p>As the older adult population increases, the potential functional and clinical burden of trunk muscle dysfunction may be significant. An evaluation of risk factors including the impact of the trunk muscles in terms of their temporal firing patterns, amplitudes of activation, and contribution to spinal stability is required. Therefore, the specific purpose of this study was to assess the feasibility of measuring the activation of trunk muscles in healthy older adults during specific leg exercises with trunk stabilization.</p> <p>Methods</p> <p>12 asymptomatic adults 65 to 75 years of age were included in the study. Participants performed a series of trunk stability exercises, while bilateral activation of abdominal and back extensor muscles was recorded by 24 pairs of Meditrace™ surface electrodes. Maximal voluntary isometric contractions (MVIC) were performed for electromyographic (EMG) normalization purposes. EMG waveforms were generated and amplitude measures as a percentage of MVIC were calculated along with ensemble average profiles. 3D kinematics data were also recorded, using an electromagnetic sensor placed at the left lateral iliac crest. Furthermore, a qualitative assessment was conducted to establish the participant's ability to complete all experimental tasks.</p> <p>Results</p> <p>Excellent quality abdominal muscle activation data were recorded during the tasks. Participants performed the trunk stability exercises with an unsteady, intermittent motion, but were able to keep pelvic motion to less than 10°. The EMG amplitudes showed that during these exercises, on average, the older adults recruited their abdominal muscles from 15–34% of MVIC and back extensors to less than 10% of MVIC. There were similarities among the abdominal muscle profiles. No participants reported pain during the testing session, although 3 (25%) of the participants reported delayed onset muscle soreness during follow up that was not functionally limiting.</p> <p>Conclusion</p> <p>Older adults were able to successfully complete the trunk stability protocol that was developed for younger adults with some minor modifications. The collected EMG amplitudes were higher than those reported in the literature for young healthy adults. The temporal waveforms for the abdominal muscles showed a degree of synchrony among muscles, except for the early activation from the internal oblique prior to lifting the leg off the table.</p

Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals

<p>Abstract</p> <p>Background</p> <p>Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP) and congestive heart failure (CHF) as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R) agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting.</p> <p>Hypothesis</p> <p>We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals.</p> <p>Methods</p> <p>We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP.</p> <p>Results</p> <p>In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL) force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals.</p> <p>Conclusions</p> <p>These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production.</p

Regulation of High-Temperature Stress Response by Small RNAs

Temperature extremes constitute one of the most common environmental stresses that adversely affect the growth and development of plants. Transcriptional regulation of temperature stress responses, particularly involving protein-coding gene networks, has been intensively studied in recent years. High-throughput sequencing technologies enabled the detection of a great number of small RNAs that have been found to change during and following temperature stress. The precise molecular action of some of these has been elucidated in detail. In the present chapter, we summarize the current understanding of small RNA-mediated modulation of high- temperature stress-regulatory pathways including basal stress responses, acclimation, and thermo-memory. We gather evidence that suggests that small RNA network changes, involving multiple upregulated and downregulated small RNAs, balance the trade-off between growth/development and stress responses, in order to ensure successful adaptation. We highlight specific characteristics of small RNA-based tem- perature stress regulation in crop plants. Finally, we explore the perspectives of the use of small RNAs in breeding to improve stress tolerance, which may be relevant for agriculture in the near future

Eating disorders: the current status of molecular genetic research

Anorexia nervosa (AN) and bulimia nervosa (BN) are complex disorders characterized by disordered eating behavior where the patient’s attitude towards weight and shape, as well as their perception of body shape, are disturbed. Formal genetic studies on twins and families suggested a substantial genetic influence for AN and BN. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Hardly any of the positive findings achieved in these studies were unequivocally confirmed or substantiated in meta-analyses. This might be due to too small sample sizes and thus low power and/or the genes underlying eating disorders have not yet been analyzed. However, some studies that also used subphenotypes (e.g., restricting type of AN) led to more specific results; however, confirmation is as yet mostly lacking. Systematic genome-wide linkage scans based on families with at least two individuals with an eating disorder (AN or BN) revealed initial linkage regions on chromosomes 1, 3 and 4 (AN) and 10p (BN). Analyses on candidate genes in the chromosome 1 linkage region led to the (as yet unconfirmed) identification of certain variants associated with AN. Genome-wide association studies are under way and will presumably help to identify genes and pathways involved in these eating disorders. The elucidation of the molecular mechanisms underlying eating disorders might improve therapeutic approaches