Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase

Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg−1) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2α phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-κB (NF-κB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia

Can a lifestyle intervention be offered through NHS breast cancer screening?:Challenges and opportunities identified in a qualitative study of women attending screening

Background: Around one third of breast cancers in post-menopausal women could be prevented by decreasing body fatness and alcohol intake and increasing physical activity. This study aimed to explore views and attitudes on lifestyle intervention approaches in order to inform the proposed content of a lifestyle intervention programme amongst women attending breast cancer screening. Methods: Women attending breast cancer screening clinics in Dundee and Glasgow, were invited to participate in focus group discussions (FGD) by clinic staff. The groups were convened out with the clinic setting and moderated by an experienced researcher who attained brief details on socio-demographic background and audio-recorded the discussions. Data analysis was guided by the framework approach. The main topics of enquiry were: Understanding of risk of breast cancer and its prevention, views on engaging with a lifestyle intervention programme offered through breast cancer screening and programme design and content. Results: Thirty one women attended 5 focus groups. Participant ages ranged from 51 to 78 years and 38 % lived in the two most deprived quintiles of residential areas. Women were generally positive about being offered a programme at breast cancer screening but sceptical about lifestyle associated risk, citing genetics, bad luck and knowing women with breast cancer who led healthy lifestyles as reasons to query the importance of lifestyle. Engagement via clinic staff and delivery of the programme by lifestyle coaches out with the screening setting was viewed favourably. The importance of body weight, physical activity and alcohol consumption with disease was widely known although most were surprised at the association with breast cancer. They were particularly surprised about the role of alcohol and resistant to thinking about themselves having a problem. They expressed frustration that lifestyle guidance was often conflicting and divergent over time. The concept of focussing on small lifestyle changes, which were personalised, supported socially and appropriate to age and ability were welcomed. Conclusions: Offering access to a lifestyle programme through breast screening appears acceptable. Explaining the relevance of the target behaviours for breast cancer health, endorsing and utilising consistent messages and identifying personalised, mutually agreed, behaviour change goals provides a framework for programme development

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-κB activation

The potential for inhibitors of nuclear factor-κB (NF-κB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-κB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-κB inhibitor SN50 (18 μM) attenuated the expression of 205 proteasome α-subunits, two subunits of the 195 regulator MSSI and p42, and the ubiquitin-conjugating enzyme, E214k, as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-κB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 μM) and resveratrol (30 μM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin-proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2 14k. However, curcumin (150 and 300 mg kg-1) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg-1) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-κB DNA-binding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-κB may prove useful for the treatment of muscle wasting in cancer cachexia

Predicting the onset of anxiety syndromes at 12 months in primary care attendees. The PredictA-Spain study

Background: There are no risk algorithms for the onset of anxiety syndromes at 12 months in primary care. We aimed to develop and validate internally a risk algorithm to predict the onset of anxiety syndromes at 12 months. Methods: A prospective cohort study with evaluations at baseline, 6 and 12 months. We measured 39 known risk factors and used multilevel logistic regression and inverse probability weighting to build the risk algorithm. Our main outcome was generalized anxiety, panic and other non-specific anxiety syndromes as measured by the Primary Care Evaluation of Mental Disorders, Patient Health Questionnaire (PRIME-MD-PHQ). We recruited 3,564 adult primary care attendees without anxiety syndromes from 174 family physicians and 32 health centers in 6 Spanish provinces. Results: The cumulative 12-month incidence of anxiety syndromes was 12.2%. The predictA-Spain risk algorithm included the following predictors of anxiety syndromes: province; sex (female); younger age; taking medicines for anxiety, depression or stress; worse physical and mental quality of life (SF-12); dissatisfaction with paid and unpaid work; perception of financial strain; and the interactions sex*age, sex*perception of financial strain, and age*dissatisfaction with paid work. The C-index was 0.80 (95% confidence interval = 0.78–0.83) and the Hedges' g = 1.17 (95% confidence interval = 1.04–1.29). The Copas shrinkage factor was 0.98 and calibration plots showed an accurate goodness of fit. Conclusions: The predictA-Spain risk algorithm is valid to predict anxiety syndromes at 12 months. Although external validation is required, the predictA-Spain is available for use as a predictive tool in the prevention of anxiety syndromes in primary care.This study was supported by the Spanish Ministry of Health (grant FIS references: PI041980, PI041771, PI042450 and PI06/1442) and the Andalusian Council of Health (grant references: 05/403 and 06/278); as well as the Spanish Network of Primary Care Research ‘redIAPP’ (RD06/0018), the ‘Aragón group’ (RD06/0018/0020), the ‘Baleares group’ (RD07/0018/0033), and the ‘SAMSERAP group’ (RD06/0018/0039)

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

Loss of skeletal muscle in cancer cachexia has a negative effect on both morbidity and mortality. The role of nuclear factor-κB (NF-κB) in regulating muscle protein degradation and expression of the ubiquitin–proteasome proteolytic pathway in response to a tumour cachectic factor, proteolysis-inducing factor (PIF), has been studied by creating stable, transdominant-negative, muscle cell lines. Murine C2C12 myoblasts were transfected with plasmids with a CMV promoter that had mutations at the serine phosphorylation sites required for degradation of I-κBα, an NF-κB inhibitory protein, and allowed to differentiate into myotubes. Proteolysis-inducing factor induced degradation of I-κBα, nuclear accumulation of NF-κB and an increase in luciferase reporter gene activity in myotubes containing wild-type, but not mutant, I-κBα proteins. Proteolysis-inducing factor also induced total protein degradation and loss of the myofibrillar protein myosin in myotubes containing wild-type, but not mutant, plasmids at the same concentrations as those causing activation of NF-κB. Proteolysis-inducing factor also induced increased expression of the ubiquitin–proteasome pathway, as determined by ‘chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the β-subunits of the proteasome, protein expression of 20S α-subunits and the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme, E214k, in cells containing wild-type, but not mutant, I-κBα. The ability of mutant I-κBα to inhibit PIF-induced protein degradation, as well as expression of the ubiquitin–proteasome pathway, confirms that both of these responses depend on initiation of transcription by NF-κB

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

Previous studies suggest that the activation (autophosphorylation) of dsRNA-dependent protein kinase (PKR) can stimulate protein degradation, and depress protein synthesis in skeletal muscle through phosphorylation of the translation initiation factor 2 (eIF2) on the α-subunit. To understand whether these mediators are important in muscle wasting in cancer patients, levels of the phospho forms of PKR and eIF2α have been determined in rectus abdominus muscle of weight losing patients with oesophago-gastric cancer, in comparison with healthy controls. Levels of both phospho PKR and phospho eIF2α were significantly enhanced in muscle of cancer patients with weight loss irrespective of the amount and there was a linear relationship between phosphorylation of PKR and phosphorylation of eIF2α (correlation coefficient 0.76, P=0.005). This suggests that phosphorylation of PKR led to phosphorylation of eIF2α. Myosin levels decreased as the weight loss increased, and there was a linear relationship between myosin expression and the extent of phosphorylation of eIF2α (correlation coefficient 0.77, P=0.004). These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer patients

Ipsilesional trajectory control is related to contralesional arm paralysis after left hemisphere damage

We have recently shown ipsilateral dynamic deficits in trajectory control are present in left hemisphere damaged (LHD) patients with paresis, as evidenced by impaired modulation of torque amplitude as response amplitude increases. The purpose of the current study is to determine if these ipsilateral deficits are more common with contralateral hemiparesis and greater damage to the motor system, as evidenced by structural imaging. Three groups of right-handed subjects (healthy controls, LHD stroke patients with and without upper extremity paresis) performed single-joint elbow movements of varying amplitudes with their left arm in the left hemispace. Only the paretic group demonstrated dynamic deficits characterized by decreased modulation of peak torque (reflected by peak acceleration changes) as response amplitude increased. These results could not be attributed to lesion volume or peak velocity as neither variable differed across the groups. However, the paretic group had damage to a larger number of areas within the motor system than the non-paretic group suggesting that such damage increases the probability of ipsilesional deficits in dynamic control for modulating torque amplitude after left hemisphere damage

Persistent frequent attenders in primary care: costs, reasons for attendance, organisation of care and potential for cognitive behavioural therapeutic intervention

<p><b>Abstract</b></p> <p>Background</p> <p>The top 3% of frequent attendance in primary care is associated with 15% of all appointments in primary care, a fivefold increase in hospital expenditure, and more mental disorder and functional somatic symptoms compared to normal attendance. Although often temporary if these rates of attendance last more than two years, they may become persistent (persistent frequent or regular attendance). However, there is no long-term study of the economic impact or clinical characteristics of regular attendance in primary care. Cognitive behaviour formulation and treatment (CBT) for regular attendance as a motivated behaviour may offer an understanding of the development, maintenance and treatment of regular attendance in the context of their health problems, cognitive processes and social context.</p> <p>Methods/design</p> <p>A case control design will compare the clinical characteristics, patterns of health care use and economic costs over the last 10 years of 100 regular attenders (≥30 appointments with general practitioner [GP] over 2 years) with 100 normal attenders (6–22 appointments with GP over 2 years), from purposefully selected primary care practices with differing organisation of care and patient demographics. Qualitative interviews with regular attending patients and practice staff will explore patient barriers, drivers and experiences of consultation, and organisation of care by practices with its challenges. Cognitive behaviour formulation analysed thematically will explore the development, maintenance and therapeutic opportunities for management in regular attenders. The feasibility, acceptability and utility of CBT for regular attendance will be examined.</p> <p>Discussion</p> <p>The health care costs, clinical needs, patient motivation for consultation and organisation of care for persistent frequent or regular attendance in primary care will be explored to develop training and policies for service providers. CBT for regular attendance will be piloted with a view to developing this approach as part of a multifaceted intervention.</p

Association of sleep, screen time and physical activity with overweight and obesity in Mexico

PURPOSE: Approximately 70% of adults in Mexico are overweight or obese. Unhealthy lifestyle behaviors are also prevalent. We examined the association of three lifestyle behaviors with body mass index (BMI) categories in adults from Mexico. METHODS: We used publicly available data from the ENSANUT 2016 survey (n = 6419). BMI was used to categorize participants. Differences in sleep duration, suffering from symptoms of insomnia, TV watching time, time in front of any screen, vigorous physical activity (yes vs no), moderate physical activity (> 30 min/day-yes vs. no) and walking (> 60 min/day-yes vs. no) were compared across BMI groups using adjusted linear and logistic regression analyses. RESULTS: Thirty-nine percent of participants were overweight and 37% obese. Time in front of TV, in front of any screen, sleep duration and physical activity were significantly associated with overweight and obesity. Compared to normal weight participants, participants in the obese II category spend on average 0.60 h/day (95% CI 0.36-0.84, p = 0.001) and participants in the obese III category 0.54 h/day (95% CI 0.19-0.89, p < 0.001) more in front of any screen; participants in the obese II category reported 0.55 h/day less sleep (95% CI - 0.67 to - 0.43, p < 0.001); participants in the obese III category were less likely to engage in vigorous activity (OR = 0.60, 95% CI 0.43-0.84, p ≤ 0.003), or walking (OR = 0.65, 95% CI 0.49-0.88, p = 0.005). CONCLUSION: Screen time, sleeping hours, and physical activity were associated with overweight and obesity. However, these associations were not consistent across all BMI categories. Assuming established causal connections, overweight individuals and individuals with obesity would benefit from reduced screen time and engaging in moderate/vigorous physical activity. LEVEL OF EVIDENCE: Level III: observational case-control analytic study