The Small GTP-Binding Protein RhoA Regulates a Delayed Rectifier Potassium Channel

AbstractTyrosine kinases activated by G protein–coupled receptors can phosphorylate and thereby suppress the activity of the delayed rectifier potassium channel Kv1.2. Using a yeast two-hybrid screen, we identified the small GTP-binding protein RhoA as a necessary component in this process. Coimmunoprecipitation experiments confirmed that RhoA associates with Kv1.2. Electrophysiological analyses revealed that overexpression of RhoA markedly reduced the basal current generated by Kv1.2 expressed in Xenopus oocytes. Furthermore, in 293 cells expressing Kv1.2 and m1 muscarinic acetylcholine receptors, inactivating RhoA using C3 exoenzyme blocked the ability of m1 receptors to suppress Kv1.2 current. Therefore, these results demonstrate that RhoA regulates Kv1.2 activity and is a central component in the mechanism of receptor-mediated tyrosine kinase–dependent suppression of Kv1.2

Cholinergic suppression: A postsynaptic mechanism of long-term associative learning

Food avoidance learning in the mollusc Pleurobranchaea entails reduction in the responsiveness of key brain interneurons in the feeding neural circuitry, the paracerebral feeding command interneurons (PCNs), to the neurotransmitter acetylcholine (AcCho). Food stimuli applied to the oral veil of an untrained animal depolarize the PCNs and induce the feeding motor program (FMP). Atropine (a muscarinic cholinergic antagonist) reversibly blocks the food-induced depolarization of the PCNs, implicating AcCho as the neurotransmitter mediating food detection. AcCho applied directly to PCN somata depolarizes them, indicating that the PCN soma membrane contains AcCho receptors and induces the FMP in the isolated central nervous system preparation. The AcCho response of the PCNs is mediated by muscariniclike receptors, since comparable depolarization is induced by muscarinic agonists (acetyl-ß -methylcholine, oxotremorine, pilocarpine), but not nicotine, and blocked by muscarinic antagonists (atropine, trifluoperazine). The nicotinic antagonist hexamethonium, however, blocked the AcCho response in four of six cases. When specimens are trained to suppress feeding behavior using a conventional food-avoidance learning paradigm (conditionally paired food and shock), AcCho applied to PCNs in the same concentration as in untrained animals causes little or no depolarization and does not initiate the FMP. Increasing the concentration of AcCho 10-100 times, however, induces weak PCN depolarization in trained specimens, indicating that learning diminishes but does not fully abolish AcCho responsiveness of the PCNs. This study proposes a cellular mechanism of long-term associative learning -- namely, postsynaptic modulation of neurotransmitter responsiveness in central neurons that could apply also to mammalian species

Feasibility of an Aerobic Exercise Intervention in Rectal Cancer Patients During and After Neoadjuvant Chemoradiotherapy

Background: Standard treatment for locally advanced rectal cancer includes long-course neoadjuvant chemoradiotherapy (NACRT) followed by definitive surgery. NACRT improves outcomes but it is also associated with significant toxicities and declines in physical fitness that may impede treatment response, symptom management, and post-surgical recovery. Exercise may improve these outcomes but the feasibility of exercise during NACRT has not been established. Purpose: The primary objective of this phase I study was to assess the safety and feasibility of an aerobic exercise intervention in rectal cancer patients during and immediately after NACRT. Changes in objective health-related fitness and patient-reported outcomes were also tracked. Methods: Rectal cancer patients scheduled to receive long-course NACRT followed by definitive surgery were recruited from the Cross Cancer Institute in Edmonton Alberta. All participants received a supervised moderate-intensity aerobic exercise program 3 days/week during NACRT followed by unsupervised aerobic exercise for ≥ 150 minutes/week after NACRT. Feasibility was determined by eligibility rate, recruitment rate, follow-up rate, exercise adherence and adverse events. Health-related fitness outcomes and patient-reported outcomes were assessed pre-NACRT, post-NACRT and pre-surgery. Results: Of 45 rectal cancer patients screened, 32 (71%) were eligible and 18 (56%) of those were recruited. Follow-up post-NACRT was 83% for health-related fitness outcomes and 94% for patient-reported outcomes. Attendance for the supervised exercise sessions was 74%. The mean total aerobic exercise minutes/week was 222 ± 155 minutes for the unsupervised exercise. There were no adverse events resulting from the exercise intervention. Most health-related fitness outcomes and patient-reported outcomes declined during NACRT and recovered from post-NACRT to pre-surgery. For example, estimated VO2 max declined from pre- to post-NACRT (mean change, -1.3 ml/kg/min; 95% CI, -3.6 to 1.7) and then increased from post-NACRT to pre-surgery (mean change +2.4 ml/kg/min; 95% CI, -0.9 to 5.7). Conclusion: Aerobic exercise is safe and feasible for rectal cancer patients during and after NACRT. Phase II randomized trials to establish the harms and benefits of aerobic exercise in this patient population are warranted

Agerelated quantitative and qualitative changes in decision making ability

Abstract. The "frontal aging hypothesis" predicts that brain senescence affects predominantly the prefrontal regions. Preliminary evidence has recently been gathered in favour of an age-related change in a typically frontal process, i.e. decision making, using the Iowa Gambling Task (IGT), but overall findings have been conflicting. Following the traditional scoring method, coupled with a qualitative analysis, in the present study we compared IGT performance of 40 young (mean age: 27.9 ± 4.7) and 40 old (mean age: 65.4 ± 8.6) healthy adults and of 18 patients affected by frontal lobe dementia of mild severity (mean age: 65.1 ± 7.4, mean MMSE score: 24.1 ± 3.9). Quantitative findings support the notion that decision making ability declines with age; moreover, it approximates the impairment observed in executive dysfunction due to neurodegeneration. Results of the qualitative analysis did not reach statistical significance for the motivational and learning decision making components considered, but approached significance for the attentional component for elderly versus young normals, suggesting a possible decrease in the ability to maintain sustained attention during complex and prolonged tasks as the putative deficit underlying impaired decision making in normal aging

Age-Related Quantitative and Qualitative Changes in Decision Making Ability

Abstract. The "frontal aging hypothesis" predicts that brain senescence affects predominantly the prefrontal regions. Preliminary evidence has recently been gathered in favour of an age-related change in a typically frontal process, i.e. decision making, using the Iowa Gambling Task (IGT), but overall findings have been conflicting. Following the traditional scoring method, coupled with a qualitative analysis, in the present study we compared IGT performance of 40 young (mean age: 27.9 ± 4.7) and 40 old (mean age: 65.4 ± 8.6) healthy adults and of 18 patients affected by frontal lobe dementia of mild severity (mean age: 65.1 ± 7.4, mean MMSE score: 24.1 ± 3.9). Quantitative findings support the notion that decision making ability declines with age; moreover, it approximates the impairment observed in executive dysfunction due to neurodegeneration. Results of the qualitative analysis did not reach statistical significance for the motivational and learning decision making components considered, but approached significance for the attentional component for elderly versus young normals, suggesting a possible decrease in the ability to maintain sustained attention during complex and prolonged tasks as the putative deficit underlying impaired decision making in normal aging

Study on the short-term effects of increased alcohol and cigarette consumption in healthy young men's seminal quality

Many studies have reported a negative impact of lifestyle factors on testicular function, spermatozoa parameters and pituitary-gonadal axis. However, conclusions are difficult to draw, since studies in the general population are rare. In this study we intended to address the early and late short-term impact of acute lifestyle alterations on young men's reproductive function. Thirty-six healthy male students, who attended the Portuguese academic festivities, provided semen samples and answered questionnaires at three time-points. The consumption of alcohol and cigarette increased more than 8 and 2 times, respectively, during the academic festivities and resulted in deleterious effects on semen quality: one week after the festivities, a decrease on semen volume, spermatozoa motility and normal morphology was observed, in parallel with an increase on immotile spermatozoa, head and midpiece defects and spermatozoa oxidative stress. Additionally, three months after the academic festivities, besides the detrimental effect on volume, motility and morphology, a negative impact on spermatozoa concentration was observed, along with a decrease on epididymal, seminal vesicles and prostate function. This study contributed to understanding the pathophysiology underlying semen quality degradation induced by acute lifestyle alterations, suggesting that high alcohol and cigarette consumption are associated with decreased semen quality in healthy young men.publishe

Physical activity interventions for disease-related physical and mental health during and following treatment in people with non-advanced colorectal cancer

Background: Colorectal cancer is the third most commonly diagnosed cancer worldwide. A diagnosis of colorectal cancer and subsequent treatment can adversely affect an individuals physical and mental health. Benefits of physical activity interventions in alleviating treatment side effects have been demonstrated in other cancer populations. Given that regular physical activity can decrease the risk of colorectal cancer, and cardiovascular fitness is a strong predictor of all-cause and cancer mortality risk, physical activity interventions may have a role to play in the colorectal cancer control continuum. Evidence of the efficacy of physical activity interventions in this population remains unclear. Objectives: To assess the effectiveness and safety of physical activity interventions on the disease-related physical and mental health of individuals diagnosed with non-advanced colorectal cancer, staged as T1-4 N0-2 M0, treated surgically or with neoadjuvant or adjuvant therapy (i.e. chemotherapy, radiotherapy or chemoradiotherapy), or both. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 6), along with OVID MEDLINE, six other databases and four trial registries with no language or date restrictions. We screened reference lists of relevant publications and handsearched meeting abstracts and conference proceedings of relevant organisations for additional relevant studies. All searches were completed between 6 June and 14 June 2019. Selection criteria: We included randomised control trials (RCTs) and cluster-RCTs comparing physical activity interventions, to usual care or no physical activity intervention in adults with non-advanced colorectal cancer. Data collection and analysis: Two review authors independently selected studies, performed the data extraction, assessed the risk of bias and rated the quality of the studies using GRADE criteria. We pooled data for meta-analyses by length of follow-up, reported as mean differences (MDs) or standardised mean differences (SMDs) using random-effects wherever possible, or the fixed-effect model, where appropriate. If a meta-analysis was not possible, we synthesised studies narratively. Main results: We identified 16 RCTs, involving 992 participants; 524 were allocated to a physical activity intervention group and 468 to a usual care control group. The mean age of participants ranged between 51 and 69 years. Ten studies included participants who had finished active treatment, two studies included participants who were receiving active treatment, two studies included both those receiving and finished active treatment. It was unclear whether participants were receiving or finished treatment in two studies. Type, setting and duration of physical activity intervention varied between trials. Three studies opted for supervised interventions, five for home-based self-directed interventions and seven studies opted for a combination of supervised and self-directed programmes. One study did not report the intervention setting. The most common intervention duration was 12 weeks (7 studies). Type of physical activity included walking, cycling, resistance exercise, yoga and core stabilisation exercise. Most of the uncertainty in judging study bias came from a lack of clarity around allocation concealment and blinding of outcome assessors. Blinding of participants and personnel was not possible. The quality of the evidence ranged from very low to moderate overall. We did not pool physical function results at immediate-term follow-up due to considerable variation in results and inconsistency of direction of effect. We are uncertain whether physical activity interventions improve physical function compared with usual care. We found no evidence of effect of physical activity interventions compared to usual care on disease-related mental health (anxiety: SMD -0.11, 95% confidence interval (CI) -0.40 to 0.18; 4 studies, 198 participants; I2 = 0%; and depression: SMD -0.21, 95% CI -0.50 to 0.08; 4 studies, 198 participants; I2 = 0%; moderate-quality evidence) at short- or medium-term follow-up. Seven studies reported on adverse events. We did not pool adverse events due to inconsistency in reporting and measurement. We found no evidence of serious adverse events in the intervention or usual care groups. Minor adverse events, such as neck, back and muscle pain were most commonly reported. No studies reported on overall survival or recurrence-free survival and no studies assessed outcomes at long-term follow-up. We found evidence of positive effects of physical activity interventions on the aerobic fitness component of physical fitness (SMD 0.82, 95% CI 0.34 to 1.29; 7 studies, 295; I2 = 68%; low-quality evidence), cancer-related fatigue (MD 2.16, 95% CI 0.18 to 4.15; 6 studies, 230 participants; I2 = 18%; low-quality evidence) and health-related quality of life (SMD 0.36, 95% CI 0.10 to 0.62; 6 studies, 230 participants; I2 = 0%; moderate-quality evidence) at immediate-term follow-up. These positive effects were also observed at short-term follow-up but not medium-term follow-up. Only three studies reported medium-term follow-up for cancer-related fatigue and health-related quality of life. Authors' conclusions: The findings of this review should be interpreted with caution due to the low number of studies included and the quality of the evidence. We are uncertain whether physical activity interventions improve physical function. Physical activity interventions may have no effect on disease-related mental health. Physical activity interventions may be beneficial for aerobic fitness, cancer-related fatigue and health-related quality of life up to six months follow-up. Where reported, adverse events were generally minor. Adequately powered RCTs of high methodological quality with longer-term follow-up are required to assess the effect of physical activity interventions on the disease-related physical and mental health and on survival of people with non-advanced colorectal cancer. Adverse events should be adequately reported.</p

Assessing the prevalence and youth-directed marketing power of outdoor food and beverage advertisements around schools in six cities across Canada.

Recent policy initiatives in Canada propose to restrict the commercial advertising of foods containing sugars, sodium, or saturated fat to youth on digital and broadcast media. While there is abundant research on youth’s exposure to food and beverage advertising on digital and broadcast media, there is limited research exploring youth’s exposure to outdoor food and beverage advertisements (e.g., freestanding billboards, restaurant exteriors, bus shelters). To address this research gap and inform policy decisions, Manuscript 1 of this thesis describes the prevalence, content, and youth-directed marketing power of outdoor food and beverage advertisements near schools. Manuscript 2 of this thesis explores the association between outdoor F&B advertisement prevalence, food outlet density, degree of urbanization, neighbourhood deprivation, and ethnocultural composition near schools to understand how the built environment and neighbourhood characteristics influence outdoor advertising environments. For this research, data on outdoor advertisements and food outlets within 1000 m of elementary and secondary schools in six cities across Canada (Vancouver, BC; Calgary, AB; Winnipeg, MB; Ottawa, ON; Quebec City, QC; and Halifax, NS) was analyzed, along with Statistics Canada data on deprivation and ethnocultural composition (from the Canadian Index of Multiple Deprivation). Descriptive statistics, chi-square tests, and negative binomial regression models were used to analyze the data. Most (64.5%) outdoor F&B advertisements near schools promote “unhealthy” food and beverage products. The most common marketing techniques used to target youth were youth product/convenience (39.4%), sense of urgency/limited time offer/seasonal (18.4%), and price promotion/discount (13.1%). School areas with high food outlet counts contained 7.429 times more advertisements than those with low counts (CI: 4.805 – 11.486, p < 0.05). The mean count of outdoor advertisements on food outlet exteriors (M = 23.22, SD = 35.52) was 10.6 times higher than the mean count of freestanding outdoor advertisements (M = 2.18, SD = 3.94), revealing that most outdoor F&B advertisements around schools are located on food outlets. Measures for deprivation and ethnocultural composition were not found to have notable patterns of significance with outdoor advertisement, except for residential instability. School areas with a high degree of residential instability contained 1.707 times more advertisements than the school areas with a low degree of residential instability (CI:1.029 - 2.832, p < 0.05). These findings suggest outdoor F&B advertisements near schools primarily promote unhealthy food choices and advertisement prevalence is influenced by features of the built environment, such as food outlet density. Future research should explore the impact of planning and public health policy interventions to reduce outdoor food and beverage advertising to youth. Opportunities for these professions (as well as other relevant disciplines) to collaborate to create healthier food environments for youth should also be identified