Question: Participating in six months of physical activity improves cognitive functioning.

Title: Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. Content: CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606.

Title: INTRANASAL INSULIN IMPROVES COGNITION AND MODULATES β-AMYLOID IN EARLY AD Content: Background: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes. Objective: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, β-amyloid, and cortisol. Methods: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment. Results: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group ( p = 0.0374). Insulin-treated subjects also showed improved attention ( p = 0.0108) and functional status ( p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the β-amyloid peptide (Aβ40; p = 0.0471) without affecting the longer isoform (Aβ42), resulting in an increased Aβ40/42 ratio ( p = 0.0207). Conclusions: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

Title: Cognitive predictors of young children's readiness for powered mobility. Content: Independent mobility in early childhood has been associated with the development of various cognitive and psychosocial skills. However, children with physical disabilities are not always able to move independently and may be at risk for delays in these areas. Early provision of powered mobility can offer young children an opportunity for independent mobility. Despite this, there is little information to help determine when a young child has the cognitive skills necessary to operate a powered wheelchair safely. This current research aims to identify these skills. A cognitive assessment battery and a wheelchair mobility training and assessment program were developed. Twenty-six children with physical disabilities between the ages of 20 and 36 months were evaluated on the cognitive assessment and participated in the wheelchair training and assessment program. A stepwise regression analysis was used to determine which of the cognitive skills predicted wheelchair mobility performance. The cognitive domains of spatial relations and problem solving were found to be significant and accounted for 57% of the variance in wheelchair skills. Developmental cut-off points on these scales as they relate to wheelchair skills are presented and clinical applications are discussed.

Title: Physical activity at 36 years: patterns and childhood predictors in a longitudinal study. Content: OBJECTIVE The aim was to describe the sex and socioeconomic differences in patterns of physical activity at work and in leisure time of men and women aged 36 years, and to investigate factors in childhood and adolescence which predict high rates of participation in sports and recreational activities in later life. DESIGN Data collected in childhood, adolescence, and at 36 years on members of a national prospective birth cohort study were used. SETTING The population sample was resident in England, Scotland, and Wales. SUBJECTS A stratified sample of about 3500 men and women was studied regularly from birth until 43 years. MEASUREMENTS AND MAIN RESULTS More men than women reported high rates of sports and recreational activities, gardening, and do-it-yourself. In contrast women reported higher rates of bicycling and walking. Higher levels of education were associated with frequent participation in sports. Individuals often engaged in one type of activity without necessarily engaging in other types. Those who were most active in sport had been above average at sports in school, more outgoing socially in adolescence, had fewer health problems in childhood, were better educated, and had more mothers with a secondary education than those who were less active. CONCLUSIONS Studies that examine the relationship between physical activity and chronic disease should consider a broad range of pursuits rather than extrapolating from only one area of physical activity, and in their explanations should take account of the possible role of childhood characteristics. The findings suggest the importance of developing skills and habits in childhood as well as of encouraging healthier exercise habits in adults who may have had few opportunities or low motivation previously.

Title: High-intensity functional exercise program and protein-enriched energy supplement for older persons dependent in activities of daily living: a randomised controlled trial. Content: The aims of this randomised controlled trial were to determine if a high-intensity functional exercise program improves balance, gait ability, and lower-limb strength in older persons dependent in activities of daily living and if an intake of protein-enriched energy supplement immediately after the exercises increases the effects of the training. One hundred and ninety-one older persons dependent in activities of daily living, living in residential care facilities, and with a Mini-Mental State Examination (MMSE) score of ? 10 participated. They were randomised to a high-intensity functional exercise program or a control activity, which included 29 sessions over 3 months, as well as to protein-enriched energy supplement or placebo. Berg Balance Scale, self-paced and maximum gait speed, and one-repetition maximum in lower-limb strength were followed-up at three and six months and analysed by 2 x 2 factorial ANCOVA, using the intention-to-treat principle. At three months, the exercise group had improved significantly in self-paced gait speed compared with the control group (mean difference 0.04 m/s, p = 0.02). At six months, there were significant improvements favouring the exercise group for Berg Balance Scale (1.9 points, p = 0.05), self-paced gait speed (0.05 m/s, p = 0.009), and lower-limb strength (10.8 kg, p = 0.03). No interaction effects were seen between the exercise and nutrition interventions. In conclusion, a high-intensity functional exercise program has positive long-term effects in balance, gait ability, and lower-limb strength for older persons dependent in activities of daily living. An intake of protein-enriched energy supplement immediately after the exercises does not appear to increase the effects of the training.

Title: Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. Content: IMPORTANCE The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. OBJECTIVE To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. DESIGN, SETTING, AND PARTICIPANTS We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. EXPOSURES Leisure time moderate- to vigorous-intensity physical activity. MAIN OUTCOMES AND MEASURES The upper limit of mortality benefit from high levels of leisure time physical activity. RESULTS Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. CONCLUSIONS AND RELEVANCE Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

Title: Are expert athletes 'expert' in the cognitive laboratory? A meta-analytic review of cognition and sport expertise Content: SUMMARY Recent literature has demonstrated the usefulness of fitness and computer-based cognitive training as a means to enhance cognition and brain function. However, it is unclear whether the combination of fitness and cognitive training that results from years of extensive sport training also results in superior performance on tests of cognitive processes. In this study we examine, in a quantitative meta-analysis (k ¼20), the relationship between expertise in sports and laboratory-based measures of cognition. We found that athletes performed better on measures of processing speed and a category of varied attentionalparadigms, andathletesfrominterceptive sporttypesandmalesshowedthelargesteffects. Based on our results, more research should be done with higher-level cognitive tasks, such as tasks of executive function and more varied sub-domains of visual attention. Furthermore, future studies should incorporate more female athletes and use a diverse range of sport types and levelsof expertise.

Title: Downloaded from Content: Physical activity induces a subclinical inflammatory response, mediated in part by leukocytes, and manifested by elevated concentrations of circulating proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). However, the source of the cytokines that appear during exercise remains unknown. In this study, we examined exercise-induced changes in plasma cytokine concentrations and their corresponding mRNA expression in peripheral blood mononuclear cells. Ten healthy [peak oxygen uptake = 48.8 ± 6.5 (SD) ml · kg−1 · min−1] but untrained men [age = 25 ± 5 (SD) yr] undertook 3 h of exercise (cycling and inclined walking) at 60–65% peak oxygen uptake. Circulating leukocyte subset counts were elevated during and 2 h postexercise but returned to normal within 24 h. Plasma concentrations of IL-1β, IL-6, and TNF-α peaked at the end of exercise and remained elevated at 2 h (IL-6) and up to 24 h (IL-1β and TNF-α) postexercise. Cytokine gene expression in circulating mononucl...

Title: Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish population based cohort study. Content: OBJECTIVE To determine whether exposure to low doses of ionising radiation in infancy affects cognitive function in adulthood. DESIGN Population based cohort study. SETTING Sweden. PARTICIPANTS 3094 men who had received radiation for cutaneous haemangioma before age 18 months during 1930-59. MAIN OUTCOME MEASURES Radiation dose to frontal and posterior parts of the brain, and association between dose and intellectual capacity at age 18 or 19 years based on cognitive tests (learning ability, logical reasoning, spatial recognition) and high school attendance. RESULTS The proportion of boys who attended high school decreased with increasing doses of radiation to both the frontal and the posterior parts of the brain from about 32% among those not exposed to around 17% in those who received > 250 mGy. For the frontal dose, the multivariate odds ratio was 0.47 (95% confidence interval 0.26 to 0.85, P for trend 0.0003) and for the posterior dose it was 0.59 (0.23 to 1.47, 0.0005). A negative dose-response relation was also evident for the three cognitive tests for learning ability and logical reasoning but not for the test of spatial recognition. CONCLUSIONS Low doses of ionising radiation to the brain in infancy influence cognitive abilities in adulthood.

Title: Effect of specific exercise strategy on need for surgery in patients with subacromial impingement syndrome: randomised controlled study Content: OBJECTIVE To evaluate if a specific exercise strategy, targeting the rotator cuff and scapula stabilisers, improves shoulder function and pain more than unspecific exercises in patients with subacromial impingement syndrome, thereby decreasing the need for arthroscopic subacromial decompression. DESIGN Randomised, participant and single assessor blinded, controlled study. SETTING Department of orthopaedics in a Swedish university hospital. PARTICIPANTS 102 patients with long standing (over six months) persistent subacromial impingement syndrome in whom earlier conservative treatment had failed, recruited through orthopaedic specialists. INTERVENTIONS The specific exercise strategy consisted of strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers in combination with manual mobilisation. The control exercise programme consisted of unspecific movement exercises for the neck and shoulder. Patients in both groups received five to six individual guided treatment sessions during 12 weeks. In between these supervised sessions the participants performed home exercises once or twice a day for 12 weeks. MAIN OUTCOME MEASURES The primary outcome was the Constant-Murley shoulder assessment score evaluating shoulder function and pain. Secondary outcomes were patients' global impression of change because of treatment and decision regarding surgery. RESULTS Most (97, 95%) participants completed the 12 week study. There was a significantly greater improvement in the Constant-Murley score in the specific exercise group than in the control exercise group (24 points (95% confidence interval 19 to 28.0) v 9 points (5 to 13); mean difference between group: 15 points (8.5 to 20.6)). Significantly more patients in the specific exercise group reported successful outcome (defined as large improvement or recovered) in the patients' global assessment of change because of treatment: 69% (35/51) v 24% (11/46); odds ratio 7.6, 3.1 to 18.9; P<0.001. A significantly lower proportion of patients in the specific exercise group subsequently chose to undergo surgery: 20% (10/51) v 63% (29/46); odds ratio 7.7, 3.1 to 19.4; P<0.001). CONCLUSION A specific exercise strategy, focusing on strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers, is effective in reducing pain and improving shoulder function in patients with persistent subacromial impingement syndrome. By extension, this exercise strategy reduces the need for arthroscopic subacromial decompression within the three month timeframe used in the study. TRIAL REGISTRATION Clinical trials NCT01037673.

Title: Moderate regular exercise increases basal production of nitric oxide in elderly women. Content: Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and is thought to have antiatherosclerotic properties. Therefore, it has also been proposed that NO may be useful to regulate vascular tonus and prevent progression of atherosclerosis. On the other hand, NO activity reduces with aging. We previously reported that the plasma nitrite/nitrate (NOx: the stable end product of NO) concentration was significantly increased by intense aerobic exercise training in healthy young humans. We hypothesized that lifestyle modification (e.g., even mild regular exercise training) can increase NO production in previously sedentary older humans. We measured the plasma NOx concentration before and after a mild aerobic exercise training regimen (cycling on a leg ergometer at 80% ventilatory threshold for 30 min, 5 days/week) for 3 months in elderly women. In addition, we assessed the plasma concentration of cyclic guanosine monophosphate (cGMP), a second messenger of NO, in the same samples. The individual ventilatory threshold increased significantly after the 3-month exercise training. The blood pressure at rest significantly decreased after exercise training. These results suggest that the 3-month exercise training in the older women produced favorable physiological effects. The plasma concentration of NOx significantly increased by the exercise training, and the plasma concentration of cGMP also increased by the exercise training. The present study suggests that even a mild regular aerobic-endurance exercise increases NO production in previously sedentary older humans, which may have beneficial effects (i.e., antihypertensive and antiatherosclerotic effects by endogenous NO) on the cardiovascular system.

Title: Effects of a High-Intensity Functional Exercise Program on Dependence in Activities of Daily Living and Balance in Older Adults with Dementia Content: OBJECTIVES To investigate the effects of a high-intensity functional exercise program on independence in activities of daily living (ADLs) and balance in older people with dementia and whether exercise effects differed between dementia types. DESIGN Cluster-randomized controlled trial: Umeå Dementia and Exercise (UMDEX) study. SETTING Residential care facilities, Umeå, Sweden. PARTICIPANTS Individuals aged 65 and older with a dementia diagnosis, a Mini-Mental State Examination score of 10 or greater, and dependence in ADLs (N=186). INTERVENTION Ninety-three participants each were allocated to the high-intensity functional exercise program, comprising lower limb strength and balance exercises, and 93 to a seated control activity. MEASUREMENTS Blinded assessors measured ADL independence using the Functional Independence Measure (FIM) and Barthel Index (BI) and balance using the Berg Balance Scale (BBS) at baseline and 4 (directly after intervention completion) and 7 months. RESULTS Linear mixed models showed no between-group effect on ADL independence at 4 (FIM=1.3, 95% confidence interval (CI)=-1.6-4.3; BI=0.6, 95% CI=-0.2-1.4) or 7 (FIM=0.8, 95% CI=-2.2-3.8; BI=0.6, 95% CI=-0.3-1.4) months. A significant between-group effect on balance favoring exercise was observed at 4 months (BBS=4.2, 95% CI=1.8-6.6). In interaction analyses, exercise effects differed significantly between dementia types. Positive between-group exercise effects were found in participants with non-Alzheimer's dementia according to the FIM at 7 months and BI and BBS at 4 and 7 months. CONCLUSION In older people with mild to moderate dementia living in residential care facilities, a 4-month high-intensity functional exercise program appears to slow decline in ADL independence and improve balance, albeit only in participants with non-Alzheimer's dementia.

Title: Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Content: OBJECTIVE To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

Title: Ankle brachial index as a predictor of cognitive impairment in the general population: ten-year follow-up of the Edinburgh Artery Study. Content: OBJECTIVES To determine whether the ankle brachial index (ABI, a marker of generalized atherosclerosis) is associated with cognitive impairment after 10 years in older people. DESIGN Cohort study (Edinburgh Artery Study). SETTING Eleven general practices in Edinburgh, Scotland. PARTICIPANTS Seven hundred seventeen men and women aged 55 to 74 from the general population, followed for 10 years. MEASUREMENTS ABI measured at baseline and major cognitive functions (including premorbid function using the National Adult Reading Test, NART) tested after 10 years. RESULTS After adjustment for age and sex, a low ABI was associated with lower scoring (bottom tertile vs top tertile) on Raven's Matrices (odds ratio (OR)=1.6, 95% confidence interval (CI) =1.0-2.6), Verbal Fluency (OR =1.8, 95% CI =1.1-3.0), and Digit Symbol Test (OR =2.3, 95% CI =1.3-4.2), suggesting that the ABI is predictive of poorer performance in nonverbal reasoning, verbal fluency, and information processing speed. The association between ABI and the Digit Symbol Test remained significant after further adjustment for premorbid cognitive function (tested using the NART), suggesting that the ABI is also predictive of decline in information processing speed (from premorbid ability to that measured here in older age). CONCLUSION The ABI may be useful in identifying older individuals at higher risk of cognitive impairment. In the future, preventive measures developed to target individuals with a low ABI should consider measures to reduce vascular-related cognitive decline as well as cardiovascular events, in an effort to reduce the incidence and consequences of subsequent cognitive impairment and dementia.

Title: Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Content: Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110alpha isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exercise-induced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110alpha) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiac-specific transgenic mice with increased or decreased PI3K(p110alpha) activity to the DCM model, and subjected PI3K(p110alpha) transgenics to acute pressure overload (ascending aortic constriction). Life-span, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110alpha) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110alpha) activity drastically shortened lifespan by approximately 50%. Increased PI3K(p110alpha) activity had a favorable effect on cardiac function and fibrosis in the pressure-overload model and attenuated pathological growth. PI3K(p110alpha) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110gamma) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110alpha) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.

Title: Nutrition and physical activity guidelines for cancer survivors. Content: Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplements to improve their treatment outcomes, quality of life, and overall survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer survivorship to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information with which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity guidelines during the continuum of cancer care, briefly highlighting important issues during cancer treatment and for patients with advanced cancer, but focusing largely on the needs of the population of individuals who are disease free or who have stable disease following their recovery from treatment. It also discusses select nutrition and physical activity issues such as body weight, food choices, food safety, and dietary supplements; issues related to selected cancer sites; and common questions about diet, physical activity, and cancer survivorship.

Title: Relationship of physical activity and television watching with body weight and level of fatness among children: results from the Third National Health and Nutrition Examination Survey. Content: CONTEXT Physical inactivity contributes to weight gain in adults, but whether this relationship is true for children of different ethnic groups is not well established. OBJECTIVE To assess participation in vigorous activity and television watching habits and their relationship to body weight and fatness in US children. DESIGN Nationally representative cross-sectional survey with an in-person interview and medical examination. SETTING AND PARTICIPANTS Between 1988 and 1994, 4063 children aged 8 through 16 years were examined as part of the National Health and Nutrition Examination Survey III. Mexican Americans and non-Hispanic blacks were oversampled to produce reliable estimates for these groups. MAIN OUTCOME MEASURES Episodes of weekly vigorous activity and daily hours of television watched, and their relationship to body mass index and body fatness. RESULTS Eighty percent of US children reported performing 3 or more bouts of vigorous activity each week. This rate was lower in non-Hispanic black and Mexican American girls (69% and 73%, respectively). Twenty percent of US children participated in 2 or fewer bouts of vigorous activity perweek, and the rate was higher in girls (26%) than in boys (17%). Overall, 26% of US children watched 4 or more hours of television per day and 67% watched at least 2 hours per day. Non-Hispanic black children had the highest rates of watching 4 or more hours of television per day (42%). Boys and girls who watch 4 or more hours of television each day had greater body fat (P<.001) and had a greater body mass index (P<.001) than those who watched less than 2 hours per day. CONCLUSIONS Many US children watch a great deal of television and are inadequately vigorously active. Vigorous activity levels are lowest among girls, non-Hispanic blacks, and Mexican Americans. Intervention strategies to promote lifelong physical activity among US children are needed to stem the adverse health consequences of inactivity.

Title: Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Content: BACKGROUND Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH. METHODS AND RESULTS Thirty patients with PH (21 women; mean age, 50+/-13 years; mean pulmonary artery pressure, 50+/-15 mm Hg; mean World Health Organization [WHO] class, 2.9+/-0.5; pulmonary arterial hypertension, n=23; chronic thromboembolic PH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and a primary training (n=15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P<0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61+/-18 to 54+/-18 mm Hg) within the training group. CONCLUSIONS This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.

Title: The Combination of Exercise and Respiratory Training Improves Respiratory Muscle Function in Pulmonary Hypertension Content: Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients. Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation. Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001). Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings.

Title: The association between common physical impairments and dementia in low and middle income countries, and, among people with dementia, their association with cognitive function and disability. A 10/66 Dementia Research Group population-based study. Content: OBJECTIVE Chronic physical comorbidity is common in dementia. However, there is an absence of evidence to support good practice guidelines for attention to these problems. We aimed to study the extent of this comorbidity and its impact on cognitive function and disability in population-based studies in low and middle income countries, where chronic diseases and impairments are likely to be both common and undertreated. METHODS A multicentre cross-sectional survey of all over 65 year old residents (n = 15 022) in 11 catchment areas in China, India, Cuba, Dominican Republic, Venezuela, Mexico and Peru. We estimated the prevalence of pain, incontinence, hearing and visual impairments, mobility impairment and undernutrition according to the presence of dementia and its severity, and, among those with dementia, the independent contribution of these impairments to cognitive function and disability, adjusting for age, gender, education and dementia severity. RESULTS Incontinence, hearing impairment, mobility impairment and undernutrition were consistently linearly associated with the presence of dementia and its severity across regions. Among people with dementia, incontinence, hearing impairment and mobility impairment were independently associated with disability in all regions while the contributions of pain, visual impairment and undernutrition were inconsistent. Only hearing impairment made a notable independent contribution to cognitive impairment. CONCLUSIONS There is an urgent need for clinical trials of the feasibility, efficacy and cost-effectiveness of regular physical health checks and remediation of identified pathologies, given the considerable comorbidity identified in our population based studies, and the strong evidence for independent impact upon functioning.

Title: Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study. Content: RATIONALE Physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD). COPD has a systemic component that includes significant extrapulmonary effects that may contribute to its severity in individual patients. OBJECTIVES To investigate the association of extrapulmonary effects of the disease and its comorbidities with reduced physical activity in patients with COPD. METHODS In a cross-sectional study, 170 outpatients with COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages I-IV; BODE [body mass index, airway obstruction, dyspnea, and exercise capacity] score 0-10) underwent a series of tests. Physical activity was assessed over 5 to 6 consecutive days by using a multisensor accelerometer armband that records steps per day and the physical activity level (total daily energy expenditure divided by whole-night sleeping energy expenditure). Cardiovascular status was assessed by echocardiography, vascular Doppler sonography, and levels of N-terminal pro-B-type natriuretic peptide. Mental status, metabolic/muscular status, systemic inflammation, and anemia were assessed by Beck Depression Inventory, bioelectrical impedance analysis, handgrip strength, high-sensitivity C-reactive protein/fibrinogen, and hemoglobin, respectively. MEASUREMENTS AND MAIN RESULTS In a multivariate linear regression analysis using either steps per day or physical activity level as a dependent variable, the extrapulmonary parameters that were associated with reduced physical activity in patients with COPD independently of GOLD stages or BODE score were N-terminal pro-B-type natriuretic peptide levels, echocardiographically measured left ventricular diastolic function, and systemic inflammation. CONCLUSIONS Higher values of systemic inflammation and left cardiac dysfunction are associated with reduced physical activity in patients with COPD.

Title: Body mass index and magnetic resonance markers of brain integrity in adults. Content: OBJECTIVE Obesity and being overweight during adulthood have been consistently linked to increased risk for development of dementia later in life, especially Alzheimer's disease. They have also been associated with cognitive dysfunction and brain structural alterations in otherwise healthy adults. Although proton magnetic resonance spectroscopy may distinguish between neuronal and glial components of the brain and may point to neurobiological mechanisms underlying brain atrophy and cognitive changes, no spectroscopic studies have yet assessed the relationships between adiposity and brain metabolites. METHODS We have utilized magnetic resonance imaging and proton magnetic resonance spectroscopic imaging data from 50 healthy middle-aged participants (mean age, 41.7 +/- 8.5 years; 17 women), who were scanned as control subjects for another study. RESULTS After adjustment for age and sex, greater body mass indices (BMIs) correlated with: (1) lower concentrations of N-acetylaspartate (spectroscopic marker of neuronal viability) in frontal (p = 0.001), parietal (p = 0.006), and temporal (p = 0.008) white matter; (2) lower N-acetylaspartate in frontal gray matter (p = 0.01); and (3) lower concentrations of choline-containing metabolites (associated with membrane metabolism) in frontal white matter (p = 0.05). INTERPRETATION These results suggest that increased BMI at midlife is associated with neuronal and/or myelin abnormalities, primarily in the frontal lobe. Because white matter in the frontal lobes is more prone to the effects of aging than in other lobes, our results may reflect accelerated aging in individuals with high levels of adiposity. Thus, greater BMI may increase the odds of developing an age-related disease, such as Alzheimer's disease.

Title: Insulin Signaling and Dietary Restriction Differentially Influence the Decline of Learning and Memory with Age Content: Of all the age-related declines, memory loss is one of the most devastating. While conditions that increase longevity have been identified, the effects of these longevity-promoting factors on learning and memory are unknown. Here we show that the C. elegans Insulin/IGF-1 receptor mutant daf-2 improves memory performance early in adulthood and maintains learning ability better with age but, surprisingly, demonstrates no extension in long-term memory with age. By contrast, eat-2 mutants, a model of Dietary Restriction (DR), exhibit impaired long-term memory in young adulthood but maintain this level of memory longer with age. We find that crh-1, the C. elegans homolog of the CREB transcription factor, is required for long-term associative memory, but not for learning or short-term memory. The expression of crh-1 declines with age and differs in the longevity mutants, and CREB expression and activity correlate with memory performance. Our results suggest that specific longevity treatments have acute and long-term effects on cognitive functions that decline with age through their regulation of rate-limiting genes required for learning and memory.

Title: Endothelium-mediated relaxation of porcine collateral-dependent arterioles is improved by exercise training. Content: BACKGROUND Endothelium-dependent modulation of coronary tone is impaired in the collateral-dependent coronary microcirculation. We used a porcine model of chronic coronary occlusion and collateral development to evaluate the hypothesis that exercise training enhances endothelium-mediated relaxation and increases endothelial nitric oxide synthase (ecNOS) mRNA levels of collateral-dependent microvasculature. METHODS AND RESULTS Adult female miniature swine were subjected to chronic, progressive ameroid occlusion of the proximal left circumflex coronary artery (LCx); after 2 months, animals were randomly exposed to 16-week exercise-training (EX group; treadmill running) or sedentary (SED group; cage confinement) protocols. After completion of EX or SED programs, coronary arterioles ( approximately 100 microm in diameter) were isolated from collateral-dependent LCx (distal to occlusion) and nonoccluded left anterior descending coronary artery (LAD) regions of each heart. Arterioles were studied by in vitro videomicroscopy or frozen for ecNOS mRNA analysis (RT-PCR techniques). Relaxation to the endothelium-dependent vasodilator bradykinin was decreased (P<0.05) in arterioles isolated from collateral-dependent LCx versus nonoccluded LAD regions of SED animals. Bradykinin-mediated relaxation, however, was not different in LCx versus LAD arterioles isolated from EX animals. Nitroprusside-induced relaxation was unaffected by either chronic occlusion or exercise. Importantly, ecNOS mRNA expression was significantly decreased in arterioles isolated from LCx versus LAD regions of SED animals. After training, ecNOS mRNA expression was not different between LAD and LCx arterioles. CONCLUSIONS These data indicate that exercise training enhances bradykinin-mediated relaxation of collateral-dependent LCx arterioles isolated after chronic coronary occlusion, most likely because of effects on ecNOS mRNA expression and increased production of NO.

Title: Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. Content: CONTEXT Insomnia is a common condition in older adults and is associated with a number of adverse medical, social, and psychological consequences. Previous research has suggested beneficial outcomes of both psychological and pharmacological treatments, but blinded placebo-controlled trials comparing the effects of these treatments are lacking. OBJECTIVE To examine short- and long-term clinical efficacy of cognitive behavioral therapy (CBT) and pharmacological treatment in older adults experiencing chronic primary insomnia. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blinded, placebo-controlled trial of 46 adults (mean age, 60.8 y; 22 women) with chronic primary insomnia conducted between January 2004 and December 2005 in a single Norwegian university-based outpatient clinic for adults and elderly patients. INTERVENTION CBT (sleep hygiene, sleep restriction, stimulus control, cognitive therapy, and relaxation; n = 18), sleep medication (7.5-mg zopiclone each night; n = 16), or placebo medication (n = 12). All treatment duration was 6 weeks, and the 2 active treatments were followed up at 6 months. MAIN OUTCOME MEASURES Ambulant clinical polysomnographic data and sleep diaries were used to determine total wake time, total sleep time, sleep efficiency, and slow-wave sleep (only assessed using polysomnography) on all 3 assessment points. RESULTS CBT resulted in improved short- and long-term outcomes compared with zopiclone on 3 out of 4 outcome measures. For most outcomes, zopiclone did not differ from placebo. Participants receiving CBT improved their sleep efficiency from 81.4% at pretreatment to 90.1% at 6-month follow-up compared with a decrease from 82.3% to 81.9% in the zopiclone group. Participants in the CBT group spent much more time in slow-wave sleep (stages 3 and 4) compared with those in other groups, and spent less time awake during the night. Total sleep time was similar in all 3 groups; at 6 months, patients receiving CBT had better sleep efficiency using polysomnography than those taking zopiclone. CONCLUSION These results suggest that interventions based on CBT are superior to zopiclone treatment both in short- and long-term management of insomnia in older adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00295386.

Title: A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children. Content: Because children are becoming overweight, unhealthy, and unfit, understanding the neurocognitive benefits of an active lifestyle in childhood has important public health and educational implications. Animal research has indicated that aerobic exercise is related to increased cell proliferation and survival in the hippocampus as well as enhanced hippocampal-dependent learning and memory. Recent evidence extends this relationship to elderly humans by suggesting that high aerobic fitness levels in older adults are associated with increased hippocampal volume and superior memory performance. The present study aimed to further extend the link between fitness, hippocampal volume, and memory to a sample of preadolescent children. To this end, magnetic resonance imaging was employed to investigate whether higher- and lower-fit 9- and 10-year-old children showed differences in hippocampal volume and if the differences were related to performance on an item and relational memory task. Relational but not item memory is primarily supported by the hippocampus. Consistent with predictions, higher-fit children showed greater bilateral hippocampal volumes and superior relational memory task performance compared to lower-fit children. Hippocampal volume was also positively associated with performance on the relational but not the item memory task. Furthermore, bilateral hippocampal volume was found to mediate the relationship between fitness level (VO(2) max) and relational memory. No relationship between aerobic fitness, nucleus accumbens volume, and memory was reported, which strengthens the hypothesized specific effect of fitness on the hippocampus. The findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.

Title: Beta-band oscillations--signalling the status quo? Content: In this review, we consider the potential functional role of beta-band oscillations, which at present is not yet well understood. We discuss evidence from recent studies on top-down mechanisms involved in cognitive processing, on the motor system and on the pathophysiology of movement disorders that suggest a unifying hypothesis: beta-band activity seems related to the maintenance of the current sensorimotor or cognitive state. We hypothesize that beta oscillations and/or coupling in the beta-band are expressed more strongly if the maintenance of the status quo is intended or predicted, than if a change is expected. Moreover, we suggest that pathological enhancement of beta-band activity is likely to result in an abnormal persistence of the status quo and a deterioration of flexible behavioural and cognitive control.

Title: Cardiorespiratory fitness and body mass index as predictors of cardiovascular disease mortality among men with diabetes. Content: BACKGROUND Questions remain as to whether higher levels of cardiorespiratory fitness, a measure of regular physical activity, are associated with lower risk of cardiovascular disease (CVD) mortality in overweight and obese individuals with diabetes. Our objective was to quantify the independent and joint relations of cardiorespiratory fitness (hereafter, fitness) and body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) with CVD mortality in men with diabetes. METHODS This study was conducted using prospective observational data from the Aerobics Center Longitudinal Study. Study participants comprised 2316 men with no history of stroke or myocardial infarction and who were diagnosed as having diabetes (mean [SD] age, 50 [10] years); had a medical examination, including a maximal exercise test during 1970 to 1997 with mortality surveillance to December 31, 1998; and had a BMI of 18.5 or greater and less than 35.0. The main outcome measure was CVD mortality across levels of fitness with stratification by BMI. RESULTS We identified 179 CVD deaths during a mean (SD) follow-up of 15.9 (7.9) years and 36,710 man-years of exposure. In a model containing age, examination year, fasting glucose level, systolic blood pressure, parental history of premature CVD, total cholesterol level, cigarette smoking, abnormal resting, and exercise electrocardiograms, a significantly higher adjusted risk of mortality was observed in men with a low fitness level who were normal weight (hazard ratio, 2.7 [95% confidence interval, 1.3-5.7]), overweight (hazard ratio, 2.7 [95% confidence interval, 1.4-5.1]), and class 1 obese (hazard ratio, 2.8 [95% confidence interval, 1.4-5.1]) compared with normal weight men with a high fitness level. CONCLUSION In this cohort of men with diabetes, low fitness level was associated with increased risk of CVD mortality within normal weight, overweight, and class 1 obese weight categories.

Title: Prevalence and cardiovascular disease correlates of low cardiorespiratory fitness in adolescents and adults. Content: CONTEXT Population surveys indicate that physical activity levels are low in the United States. One consequence of inactivity, low cardiorespiratory fitness, is an established risk factor for cardiovascular disease (CVD) morbidity and mortality, but the prevalence of cardiorespiratory fitness has not been quantified in representative US population samples. OBJECTIVES To describe the prevalence of low fitness in the US population aged 12 through 49 years and to relate low fitness to CVD risk factors in this population. DESIGN, SETTING, AND PARTICIPANTS Inception cohort study using data from the cross-sectional nationally representative National Health and Nutrition Examination Survey 1999-2002. Participants were adolescents (aged 12-19 years; n = 3110) and adults (aged 20-49 years; n = 2205) free from previously diagnosed CVD who underwent submaximal graded exercise treadmill testing to achieve at least 75% to 90% of their age-predicted maximum heart rate. Maximal oxygen consumption (VO2max) was estimated by measuring the heart rate response to reference levels of submaximal work. MAIN OUTCOME MEASURES Low fitness defined using percentile cut points of estimated VO2max from existing external referent populations; anthropometric and other CVD risk factors measured according to standard methods. RESULTS Low fitness was identified in 33.6% of adolescents (approximately 7.5 million US adolescents) and 13.9% of adults (approximately 8.5 million US adults); the prevalence was similar in adolescent females (34.4%) and males (32.9%) (P = .40) but was higher in adult females (16.2%) than in males (11.8%) (P = .03). Non-Hispanic blacks and Mexican Americans were less fit than non-Hispanic whites. In all age-sex groups, body mass index and waist circumference were inversely associated with fitness; age- and race-adjusted odds ratios of overweight or obesity (body mass index > or =25) ranged from 2.1 to 3.7 (P<.01 for all), comparing persons with low fitness with those with moderate or high fitness. Total cholesterol levels and systolic blood pressure were higher and levels of high-density lipoprotein cholesterol were lower among participants with low vs high fitness. CONCLUSION Low fitness in adolescents and adults is common in the US population and is associated with an increased prevalence of CVD risk factors.

Title: Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 in ob/ob mice Content: Objective:Consumption of high-fat diet exerts adverse effects on learning and memory formation, which is linked to impaired hippocampal function. Activation of glucagon-like peptide-1 (GLP-1) signalling ameliorates detrimental effects of obesity-diabetes on cognitive function; however, mechanisms underlying these beneficial actions remain unclear. This study examined effects of daily subcutaneous treatment with GLP-1 mimetic, Liraglutide, on synaptic plasticity, hippocampal gene expression and metabolic control in adult obese diabetic (ob/ob) mice. Results:Long-term potentiation (LTP) induced by area CA1 was completely abolished in ob/ob mice compared with lean controls. Deleterious effects on LTP were rescued (P<0.001) with Liraglutide. Indeed, Liraglutide-treated mice exhibited superior LTP profile compared with lean controls (P<0.01). Expression of hippocampal brain-derived neurotropic factor and neurotrophic tyrosine kinase receptor-type 2 were not significantly different, but synaptophysin and Mash1 were decreased in ob/ob mice. Treatment with Liraglutide over 21 days increased expression of Mash1 in ob/ob mice (2.0-fold; P<0.01). These changes were associated with significantly reduced plasma glucose (21% reduction; P<0.05) and markedly improved plasma insulin concentrations (2.1- to 3.3-fold; P<0.05 to P<0.01). Liraglutide also significantly reduced the glycaemic excursion following an intraperitonal glucose load (area under curve (AUC) values: 22%; P<0.05) and markedly enhanced the insulin response to glucose (AUC values: 1.6-fold; P<0.05). O2 consumption, CO2 production, respiratory exchange ratio and energy expenditure were not altered by Liraglutide therapy. On day 21, accumulated food intake (32% reduction; P<0.05) and number of feeding bouts (32% reduction; P<0.05) were significantly reduced but simple energy restriction was not responsible for the beneficial actions of Liraglutide. Conclusion:Liraglutide elicits beneficial effects on metabolic control and synaptic plasticity in mice with severe obesity and insulin resistance mediated in part through increased expression of Mash1 believed to improve hippocampal neurogenesis and cell survival.

Title: A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches. Content: Forty-one recurrent tension headache sufferers were randomly assigned to either cognitive-behavioral therapy (administered in a primarily home-based treatment protocol) or to amitriptyline therapy (with dosage individualized at 25, 50, or 75 mg/day). Cognitive-behavioral therapy and amitriptyline each yielded clinically significant improvements in headache activity, both when improvement was assessed with patient daily recordings (56% and 27% reduction in headache index, respectively), and when improvement was assessed with neurologist ratings of clinical improvement (94% and 69% of patients rated at least moderately improved, respectively). In instances where differences in treatment effectiveness were observed (headache index, somatic complaints, perceptions of control of headache activity), cognitive-behavioral therapy yielded somewhat more positive outcomes than did amitriptyline. Neither treatment, however, eliminated headache problems.

Title: Relationship of collegiate football experience and concussion with hippocampal volume and cognitive outcomes. Content: IMPORTANCE Concussion and subconcussive impacts have been associated with short-term disrupted cognitive performance in collegiate athletes, but there are limited data on their long-term neuroanatomic and cognitive consequences. OBJECTIVE To assess the relationships of concussion history and years of football experience with hippocampal volume and cognitive performance in collegiate football athletes. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study conducted between June 2011 and August 2013 at a US psychiatric research institute specializing in neuroimaging among collegiate football players with a history of clinician-diagnosed concussion (n = 25), collegiate football players without a history of concussion (n = 25), and non-football-playing, age-, sex-, and education-matched healthy controls (n = 25). EXPOSURES History of clinician-diagnosed concussion and years of football experience. MAIN OUTCOMES AND MEASURES High-resolution anatomical magnetic resonance imaging was used to quantify brain volumes. Baseline scores on a computerized concussion-related cognitive battery were used for cognitive assessment in athletes. RESULTS Players with and without a history of concussion had smaller hippocampal volumes relative to healthy control participants (with concussion: t48 = 7.58; P < .001; mean difference, 1788 μL; 95% CI, 1317-2258 μL; without concussion: t48 = 4.35; P < .001, mean difference, 1027 μL; 95% CI, 556-1498 μL). Players with a history of concussion had smaller hippocampal volumes than players without concussion (t48 = 3.15; P < .001; mean difference, 761 μL; 95% CI, 280-1242 μL). In both athlete groups, there was a statistically significant inverse relationship between left hippocampal volume and number of years of football played (t46 = -3.62; P < .001; coefficient = -43.54; 95% CI, -67.66 to -19.41). Behavioral testing demonstrated no differences between athletes with and without a concussion history on 5 cognitive measures but did show an inverse correlation between years of playing football and reaction time (ρ42 = -0.43; 95% CI, -0.46 to -0.40; P = .005). CONCLUSIONS AND RELEVANCE Among a group of collegiate football athletes, there was a significant inverse relationship of concussion and years of football played with hippocampal volume. Years of football experience also correlated with slower reaction time. Further research is needed to determine the temporal relationships of these findings.

Title: Antioxidants attenuate the plasma cytokine response to exercise in humans. Content: Exercise increases plasma TNF-alpha, IL-1beta, and IL-6, yet the stimuli and sources of TNF-alpha and IL-1beta remain largely unknown. We tested the role of oxidative stress and the potential contribution of monocytes in this cytokine (especially IL-1beta) response in previously untrained individuals. Six healthy nonathletes performed two 45-min bicycle exercise sessions at 70% of Vo(2 max) before and after a combination of antioxidants (vitamins E, A, and C for 60 days; allopurinol for 15 days; and N-acetylcysteine for 3 days). Blood was drawn at baseline, end-exercise, and 30 and 120 min postexercise. Plasma cytokines were determined by ELISA and monocyte intracellular cytokine level by flow cytometry. Before antioxidants, TNF-alpha increased by 60%, IL-1beta by threefold, and IL-6 by sixfold secondary to exercise (P < 0.05). After antioxidants, plasma IL-1beta became undetectable, the TNF-alpha response to exercise was abolished, and the IL-6 response was significantly blunted (P < 0.05). Exercise did not increase the percentage of monocytes producing the cytokines or their mean fluorescence intensity. We conclude that in untrained humans oxidative stress is a major stimulus for exercise-induced cytokine production and that monocytes play no role in this process.

Title: Behavioral treatment of obesity in patients encountered in primary care settings: a systematic review. Content: IMPORTANCE In 2011, the Centers for Medicare & Medicaid Services (CMS) approved intensive behavioral weight loss counseling for approximately 14 face-to-face, 10- to 15-minute sessions over 6 months for obese beneficiaries in primary care settings, when delivered by physicians and other CMS-defined primary care practitioners. OBJECTIVE To conduct a systematic review of behavioral counseling for overweight and obese patients recruited from primary care, as delivered by primary care practitioners working alone or with trained interventionists (eg, medical assistants, registered dietitians), or by trained interventionists working independently. EVIDENCE REVIEW We searched PubMed, CINAHL, and EMBASE for randomized controlled trials published between January 1980 and June 2014 that recruited overweight and obese patients from primary care; provided behavioral counseling (ie, diet, exercise, and behavioral therapy) for at least 3 months, with at least 6 months of postrandomization follow-up; included at least 15 participants per treatment group and objectively measured weights; and had a comparator, an intention-to-treat analysis, and attrition of less than 30% at 1 year or less than 40% at longer follow-up. FINDINGS Review of 3304 abstracts yielded 12 trials, involving 3893 participants, that met inclusion-exclusion criteria and prespecified quality ratings. No studies were found in which primary care practitioners delivered counseling that followed the CMS guidelines. Mean 6-month weight changes from baseline in the intervention groups ranged from a loss of 0.3 kg to 6.6 kg. In the control group, mean change ranged from a gain of 0.9 kg to a loss of 2.0 kg. Weight loss in both groups generally declined with longer follow-up (12-24 months). Interventions that prescribed both reduced energy intake (eg, ≥ 500 kcal/d) and increased physical activity (eg, ≥150 minutes a week of walking), with traditional behavioral therapy, generally produced larger weight loss than interventions without all 3 specific components. In the former trials, more treatment sessions, delivered in person or by telephone by trained interventionists, were associated with greater mean weight loss and likelihood of patients losing 5% or more of baseline weight. CONCLUSIONS AND RELEVANCE Intensive behavioral counseling can induce clinically meaningful weight loss, but there is little research on primary care practitioners providing such care. The present findings suggest that a range of trained interventionists, who deliver counseling in person or by telephone, could be considered for treating overweight or obesity in patients encountered in primary care settings.

Title: The use of mouse models to understand and improve cognitive deficits in Down syndrome Content: Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development.

Title: Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study Content: OBJECTIVE To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition. DESIGN Population based, cross sectional study. SETTING Epidemiology of Vascular Ageing study, Nantes, France. PARTICIPANTS 780 participants (mean age 69, 58.5% women) with detailed headache assessment. MAIN OUTCOME MEASURES Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination. RESULTS 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions. CONCLUSIONS In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.

Title: Swim training suppresses tumor growth in mice. Content: The present study was designed to determine the effects of physical training on the development of cancer induced by the injection of Ehrlich tumor cells in mice. Male Swiss mice were subjected to a swim training protocol (5 days/wk for 6 wk, 1 h at 50% of maximal capacity-trained groups) or remained sedentary in their cages (sedentary groups). The inoculation of Ehrlich tumor cells was performed at the end of the fourth week, and animals were killed after 6 wk of training. Heart and solid tumor weights were recorded, and tumor volumes were calculated. Portions of the tumors were used for the evaluation of macrophages and neutrophil accumulation or fixed in neutral 10% buffered formalin for histological analysis. The tumor volume and weight were, respectively, approximately 270% and 280% greater in sedentary mice than in trained mice. Macrophage infiltration in the tumor tissue was significantly lower in trained mice (0.65 +/- 0.16 vs. 1.78 +/- 0.43 macrophages x 10(3) in the sedentary group). Moreover, neutrophil accumulation in tumors was slightly reduced after exercise training, and the amount of tumor cells was reduced in trained mice. Exercise capacity was substantially increased in trained mice, as determined by a 440% increase in the exercise time at 50% of maximal capacity. In summary, swim training retarded the development of Ehrlich tumors in mice, accompanied by a reduction in macrophage infiltration and neutrophil accumulation. These findings provide conceptual support for clinical observations that controlled physical activities may be a therapeutically important approach to preventing cancer progression and may improve the outcome of cancer treatment.

Title: Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preference. Content: Brain-derived neurotrophic factor (BDNF) regulates synaptic activity and behavioral flexibility, and reduction of BDNF strongly predicts psychiatric disorders and cognitive dysfunction. Restoration of BDNF-dependent activity could alleviate these impairments, but BDNF has limited clinical utility due to its pharmacokinetics. Here we demonstrate that activation of a primary BDNF target, the tropomyosin-related kinase B (TrkB) receptor, enhances the amplitude and prolongs the decay kinetics of N-methyl-d-aspartate receptor (NMDAR) currents in male rat infralimbic prefrontal pyramidal neurons. Moreover, these effects were prevented and reversed by blockade of NMDARs containing the GluN2B subunit. Our results show that this signaling cascade bidirectionally regulates extinction of a cocaine-induced conditioned place preference (CPP), a task that requires behavioral flexibility. Blockade of infralimbic TrkB receptors or GluN2B-containing NMDARs disrupted consolidation of extinction of the CPP. In contrast, extinction was strengthened by potentiation of TrkB receptor activity with infralimbic infusions of BDNF or systemic injections of 7,8 dihydroxyflavone (7,8DHF), the newly synthesized TrkB receptor agonist. The 7,8DHF-induced enhancement of extinction was prevented by infralimbic infusions of a GluN2B-specific receptor antagonist, demonstrating that TrkB receptor activation enhances extinction of cocaine-CPP via GluN2B-containing NMDARs. Together, infralimbic TrkB receptor activation strengthens GluN2B-containing NMDAR currents to support extinction learning. TrkB receptor agonists would therefore be useful as pharmacological adjuncts for extinction-based therapies for treatment of psychiatric disorders associated with reduced BDNF activity.

Title: Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 Dementia Research Group population-based cohort study Content: BACKGROUND Results of the few cohort studies from countries with low incomes or middle incomes suggest a lower incidence of dementia than in high-income countries. We assessed incidence of dementia according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, the effect of dementia at baseline on mortality, and the independent effects of age, sex, socioeconomic position, and indicators of cognitive reserve. METHODS We did a population-based cohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident 10/66 and DSM-IV dementia 3-5 years after cohort inception. We used questionnaires to obtain information about age in years, sex, educational level, literacy, occupational attainment, and number of household assets. We obtained information about mortality from all sites. For participants who had died, we interviewed a friend or relative to ascertain the likelihood that they had dementia before death. FINDINGS 12,887 participants were interviewed at baseline. 11,718 were free of dementia, of whom 8137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Incidence for 10/66 dementia varied between 18·2 and 30·4 per 1000 person-years, and were 1·4-2·7 times higher than were those for DSM-IV dementia (9·9-15·7 per 1000 person-years). Mortality hazards were 1·56-5·69 times higher in individuals with dementia at baseline than in those who were dementia-free. Informant reports suggested a high incidence of dementia before death; overall incidence might be 4-19% higher if these data were included. 10/66 dementia incidence was independently associated with increased age (HR 1·67; 95% CI 1·56-1·79), female sex (0·72; 0·61-0·84), and low education (0·89; 0·81-0·97), but not with occupational attainment (1·04; 0·95-1·13). INTERPRETATION Our results provide supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer substantial protection against the onset of dementia. FUNDING Wellcome Trust Health Consequences of Population Change Programme, WHO, US Alzheimer's Association, FONACIT/ CDCH/ UCV.

Title: High-performance neuroprosthetic control by an individual with tetraplegia. Content: BACKGROUND Paralysis or amputation of an arm results in the loss of the ability to orient the hand and grasp, manipulate, and carry objects, functions that are essential for activities of daily living. Brain-machine interfaces could provide a solution to restoring many of these lost functions. We therefore tested whether an individual with tetraplegia could rapidly achieve neurological control of a high-performance prosthetic limb using this type of an interface. METHODS We implanted two 96-channel intracortical microelectrodes in the motor cortex of a 52-year-old individual with tetraplegia. Brain-machine-interface training was done for 13 weeks with the goal of controlling an anthropomorphic prosthetic limb with seven degrees of freedom (three-dimensional translation, three-dimensional orientation, one-dimensional grasping). The participant's ability to control the prosthetic limb was assessed with clinical measures of upper limb function. This study is registered with ClinicalTrials.gov, NCT01364480. FINDINGS The participant was able to move the prosthetic limb freely in the three-dimensional workspace on the second day of training. After 13 weeks, robust seven-dimensional movements were performed routinely. Mean success rate on target-based reaching tasks was 91·6% (SD 4·4) versus median chance level 6·2% (95% CI 2·0-15·3). Improvements were seen in completion time (decreased from a mean of 148 s [SD 60] to 112 s [6]) and path efficiency (increased from 0·30 [0·04] to 0·38 [0·02]). The participant was also able to use the prosthetic limb to do skilful and coordinated reach and grasp movements that resulted in clinically significant gains in tests of upper limb function. No adverse events were reported. INTERPRETATION With continued development of neuroprosthetic limbs, individuals with long-term paralysis could recover the natural and intuitive command signals for hand placement, orientation, and reaching, allowing them to perform activities of daily living. FUNDING Defense Advanced Research Projects Agency, National Institutes of Health, Department of Veterans Affairs, and UPMC Rehabilitation Institute.

Title: Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise Content: Pyruvate dehydrogenase (PDH) plays a key role in the regulation of skeletal muscle substrate utilization. IL-6 is produced in skeletal muscle during exercise in a duration dependent manner and has been reported to increase whole body fatty acid oxidation, muscle glucose uptake and decrease PDHa activity in skeletal muscle of fed mice. The aim of the present study was to examine whether muscle IL-6 contributes to exercise-induced PDH regulation in skeletal muscle. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) completed a single bout of treadmill exercise for 10, 60 or 120 min, with rested mice of each genotype serving as basal controls. The respiratory exchange ratio (RER) was overall higher (P<0.05) in IL-6 MKO than control mice during the 120 min of treadmill exercise, while RER decreased during exercise independent of genotype. AMPK and ACC phosphorylation also increased with exercise independent of genotype. PDHa activity was in control mice higher (P<0.05) at 10 and 60 min of exercise than at rest but remained unchanged in IL-6 MKO mice. In addition, PDHa activity was higher (P<0.05) in IL-6 MKO than control mice at rest and 60 min of exercise. Neither PDH phosphorylation nor acetylation could explain the genotype differences in PDHa activity. Together, this provides evidence that skeletal muscle IL-6 contributes to the regulation of PDH at rest and during prolonged exercise and suggests that muscle IL-6 normally dampens carbohydrate utilization during prolonged exercise via effects on PDH.

Title: Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Content: BACKGROUND AN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients. METHODS This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 microg plus the adjuvant QS-21 50 microg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale-Cognitive Subscale [ADAS-Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Abeta42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer > or = 1:2,200). RESULTS Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS-Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 +/- 0.37 vs -0.20 +/- 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p < 0.001). CONCLUSION Although interrupted, this trial provides an indication that Abeta immunotherapy may be useful in Alzheimer disease.

Title: Pyruvate dehydrogenase activity and acetyl group accumulation during exercise after different diets. Content: Pyruvate dehydrogenase activity (PDHa) and acetyl group accumulation were examined in human skeletal muscle at rest and during exercise after different diets. Five males cycled at 75% of maximal O2 uptake (VO2 max) to exhaustion after consuming a low-carbohydrate diet (LCD) for 3 days and again 1-2 wk later for the same duration after consuming a high-carbohydrate diet (HCD) for 3 days. Resting PDHa was lower after a LCD (0.20 +/- 0.04 vs. 0.69 +/- 0.05 mmol.min-1.kg wet wt-1; P < 0.05) and coincided with a greater intramuscular acetyl-CoA-to-CoASH ratio, acetyl-CoA content, and acetylcarnitine content. PDHa increased during exercise in both conditions but at a lower rate in the LCD condition compared with the HCD condition (1.46 +/- 0.25 vs. 2.65 +/- 0.23 mmol.min-1.kg wet wt-1 at 16 min and 1.88 +/- 0.20 vs. 3.11 +/- 0.14 at the end of exercise; P < 0.05). During exercise muscle acetyl-CoA and acetylcarnitine content and the acetyl-CoA-to-CoASH ratio decreased in the LCD condition but increased in the HCD condition. Under resting conditions PDHa was influenced by the availability of fat or carbohydrate fuels acting through changes in the acetyl-CoA-to-CoASH ratio. However, during exercise the activation of PDHa occurred independent of changes in the acetyl-CoA-to-CoASH ratio, suggesting that other factors are more important.

Title: Blood pressure, salivary cortisol, and inflammatory cytokine outcomes in senior female cancer survivors enrolled in a tai chi chih randomized controlled trial Content: Older cancer survivors are a vulnerable population due to an increased risk for chronic diseases (e.g., cardiovascular disease) compounded with treatment late-effects and declines in physical functioning. Therefore, interventions that reduce chronic disease risk factors (i.e., blood pressure, chronic inflammation, and cortisol) are important in this population. Tai chi chih (TCC) is a mind-body exercise associated with reductions in chronic disease risk factors, but has not been examined with older cancer survivors. In a feasibility randomized controlled trial of TCC, we examined secondary outcomes of blood pressure, salivary cortisol, and inflammatory cytokines (interleukin (IL)-6, IL-12, tumor necrosis factor-α, IL-10, IL-4) due to their implications in chronic diseases. Sixty-three senior female cancer survivors (M age = 67 years, SD = 7.15) with physical functioning limitations (SF-12 physical functioning ≤80 or role-physical ≤72) were randomized to 12-weeks (60-min, three times a week) of TCC or Health Education control (HEC) classes. Resting blood pressure, 1-day salivary cortisol samples, and fasting plasma samples for cytokine multiplex assays were collected at baseline and 1-week post-intervention. Controlling for baseline values, the TCC group had significantly lower systolic blood pressure (SBP, p = 0.002) and cortisol area-under-curve (AUC, p = 0.02) at post-intervention than the HEC group. There was no intervention effect on inflammatory cytokines (p’s > 0.05). This TCC feasibility trial was associated with significant reductions in SBP and cortisol AUC in senior female cancer survivors. Larger, definitive trials are needed to confirm these findings. Senior survivors’ have an increased risk for chronic diseases; however, TCC interventions may help reduce associated risk factors.

Title: Control of synapse development and plasticity by Rho GTPase regulatory proteins Content: Synapses are specialized cell-cell contacts that mediate communication between neurons. Most excitatory synapses in the brain are housed on dendritic spines, small actin-rich protrusions extending from dendrites. During development and in response to environmental stimuli, spines undergo marked changes in shape and number thought to underlie processes like learning and memory. Improper spine development, in contrast, likely impedes information processing in the brain, since spine abnormalities are associated with numerous brain disorders. Elucidating the mechanisms that regulate the formation and plasticity of spines and their resident synapses is therefore crucial to our understanding of cognition and disease. Rho-family GTPases, key regulators of the actin cytoskeleton, play essential roles in orchestrating the development and remodeling of spines and synapses. Precise spatio-temporal regulation of Rho GTPase activity is critical for their function, since aberrant Rho GTPase signaling can cause spine and synapse defects as well as cognitive impairments. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). We propose that Rho-family GEFs and GAPs provide the spatiotemporal regulation and signaling specificity necessary for proper Rho GTPase function based on the following features they possess: (i) existence of multiple GEFs and GAPs per Rho GTPase, (ii) developmentally regulated expression, (iii) discrete localization, (iv) ability to bind to and organize specific signaling networks, and (v) tightly regulated activity, perhaps involving GEF/GAP interactions. Recent studies describe several Rho-family GEFs and GAPs that uniquely contribute to spinogenesis and synaptogenesis. Here, we highlight several of these proteins and discuss how they occupy distinct biochemical niches critical for synaptic development.

Title: Disturbance in cerebral spinal fluid sphingolipid content is associated with memory impairment in subjects infected with the human immunodeficiency virus Content: Despite widespread use of antiretroviral therapies to control replication of the human immunodeficiency virus (HIV), dysfunctions of cognition that are collectively termed HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of those infected by the virus. Currently there is not a biomarker that can identify HIV-infected people who are at risk for the development of HAND. Previous studies have identified particular sphingolipid species that are dysregulated in HAND, but the neurocognitive correlates of these biochemical findings are not currently understood. To address this question, we compared cerebrospinal fluid (CSF) levels of sphingomyelin, ceramide, and sterol species with performance on standard neurological tests designed to assess the function of multiple cognitive and motor domains in HIV-infected subjects. We found that sphingomyelin:ceramide ratios for acyl chain lengths of C16∶0, C18∶0, C22∶0, and C24∶0 were associated with worse performance on several indices of memory. The most striking finding was for the acyl chain of C18∶0 that consistently associatedwith performance onmultiple tests of memory. These findings suggest that the sphingomyelin:ceramide ratio for C18∶0 may be a reasonable surrogate marker for memory dysfunction in HIV-infected subjects.

Title: Prevalence of attempting weight loss and strategies for controlling weight. Content: CONTEXT Overweight and obesity are increasing in the United States. Changes in diet and physical activity are important for weight control. OBJECTIVES To examine the prevalence of attempting to lose or to maintain weight and to describe weight control strategies among US adults. DESIGN The Behavioral Risk Factor Surveillance System, a random-digit telephone survey conducted in 1996 by state health departments. Setting The 49 states (and the District of Columbia) that participated in the survey. PARTICIPANTS Adults aged 18 years and older (N = 107 804). MAIN OUTCOME MEASURES Reported current weights and goal weights, prevalence of weight loss or maintenance attempts, and strategies used to control weight (eating fewer calories, eating less fat, or using physical activity) by population subgroup. RESULTS The prevalence of attempting to lose and maintain weight was 28.8% and 35.1 % among men and 43.6% and 34.4% among women, respectively. Among those attempting to lose weight, a common strategy was to consume less fat but not fewer calories (34.9% of men and 40.0% of women); only 21.5% of men and 19.4% of women reported using the recommended combination of eating fewer calories and engaging in at least 150 minutes of leisure-time physical activity per week. Among men trying to lose weight, the median weight was 90.4 kg with a goal weight of 81.4 kg. Among women, the median weight was 70.3 kg with a goal weight of 59.0 kg. CONCLUSIONS Weight loss and weight maintenance are common concerns for US men and women. Most persons trying to lose weight are not using the recommended combination of reducing calorie intake and engaging in leisure-time physical activity 150 minutes or more per week.

Title: Effectiveness of a diabetes education and self management programme (DESMOND) for people with newly diagnosed type 2 diabetes mellitus: three year follow-up of a cluster randomised controlled trial in primary care Content: OBJECTIVE To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years. DESIGN Three year follow-up of a multicentre cluster randomised controlled trial in primary care, with randomisation at practice level. SETTING 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS 731 of the 824 participants included in the original trial were eligible for follow-up. Biomedical data were collected on 604 (82.6%) and questionnaire data on 513 (70.1%) participants. INTERVENTION A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES The primary outcome was glycated haemoglobin (HbA(1c)) levels. The secondary outcomes were blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, emotional impact of diabetes, and drug use at three years. RESULTS HbA(1c) levels at three years had decreased in both groups. After adjusting for baseline and cluster the difference was not significant (difference -0.02, 95% confidence interval -0.22 to 0.17). The groups did not differ for the other biomedical and lifestyle outcomes and drug use. The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years (P<0.01). Depression scores and quality of life did not differ at three years. CONCLUSION A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs. TRIAL REGISTRATION Current Controlled Trials ISRCTN17844016.

Title: Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. Content: CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent. OBJECTIVE To test the effects of exercise training on health status among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007. INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models. MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle. RESULTS Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected. CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

Title: Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis. Content: OBJECTIVES Prevention of cognitive decline and dementia with blood pressure lowering treatments has shown inconsistent results. We compared the effects of different classes of antihypertensive drugs on the incidence of dementia, and on cognitive function. METHODS We conducted a systematic review and included 19 randomized trials (18 515 individuals) and 11 studies (831 674 individuals) analysing the effects of antihypertensive treatment on cognition and on the incidence of dementia, respectively, in hypertensive patients without prior cerebrovascular disorders. Network meta-analysis was used for the comparison of antihypertensive classes. RESULTS Antihypertensive treatment, regardless of the drug class, had benefits on overall cognition [effect size 0.05, 95% confidence interval (CI) 0.02-0.07] and all cognitive functions except language. Antihypertensive treatment reduced the risk of all-cause dementia by 9%, with reference to the control group (hazard ratio 0.91, 95% CI 0.89-0.94), when randomized trials and observationnal studies were combined (n = 15). Result was not significant with randomized trials alone (n = 4). Angiotensin II receptor blockers (ARBs) had larger benefits than placebo on overall cognition (adjusted effect size 0.60 ± 0.18, P = 0.02). ARBs were more effective than β-blockers (0.67 ± 0.18, P = 0.01), diuretics (0.54 ± 0.19, P = 0.04) and angiotensin-converting enzyme inhibitors (0.47 ± 0.17, P = 0.04) in rank. The mean change in blood pressure did not differ significantly between the different antihypertensive drug classes. CONCLUSION Our results support the notion that antihypertensive treatment has beneficial effects on cognitive decline and prevention of dementia, and indicate that these effects may differ between drug classes with ARBs possibly being the most effective.

Title: Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models Content: Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.

Title: Depressive symptoms and physical decline in community-dwelling older persons. Content: CONTEXT Significant symptoms of depression are common in the older community-dwelling population. Although depressive symptoms and disability may commonly occur in the same person, whether depressive symptoms contribute to subsequent functional decline has not been elucidated. OBJECTIVE To determine whether depressive symptoms in older persons increase the risk of subsequent decline in physical function as measured by objective performance-based tests. DESIGN A 4-year prospective cohort study. SETTING The communities of Iowa and Washington counties, Iowa. PARTICIPANTS A total of 1286 persons aged 71 years and older who completed a short battery of physical performance tests in 1988 and again 4 years later. MAIN OUTCOME MEASURES Baseline depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale. Physical performance tests included an assessment of standing balance, a timed 2.4-m (8-ft) walk, and a timed test of 5 repetitions of rising from a chair and sitting down. RESULTS After adjustment for baseline performance score, health status, and sociodemographic factors, increasing levels of depressive symptoms were predictive of greater decline in physical performance over 4 years (odds ratio for decline in those with depressed mood vs those without, 1.55; 95% confidence interval [CI], 1.02-2.34). Even among those at the high end of the functional spectrum, who reported no disability, the severity of depressive symptoms predicted subsequent decline in physical performance (odds ratio for decline, 1.03; 95% CI, 1.00-1.08). CONCLUSIONS This study provides evidence that older persons who report depressive symptoms are at higher risk of subsequent physical decline. These results suggest that prevention or reduction of depressed mood could play a role in reducing functional decline in older persons.

Title: p63 Regulates adult neural precursor and newly born neuron survival to control hippocampal-dependent Behavior. Content: The molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thus maintain adult neurogenesis, are not well defined. Here, we investigate the role of p63, a p53 family member, in adult NPC function in mice. Conditional ablation of p63 in adult NPCs or p63 haploinsufficiency led to reduced numbers of NPCs and newborn neurons in the neurogenic zones of the hippocampus and lateral ventricles and in the olfactory bulb. These reductions were attributable to enhanced apoptosis of NPCs and newborn neurons and were rescued by inhibition of caspase activity, p53, or the p53 apoptotic effector PUMA (p53-upregulated modulator of apoptosis). Moreover, these cellular deficits were functionally important because they led to perturbations in hippocampus-dependent memory formation. These results indicate that p63 regulates the numbers of adult NPCs and adult-born neurons as well as neural stem cell-dependent cognitive functions, and that it does so, at least in part, by inhibiting p53-dependent cell death.

Title: Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in a Spinocerebellar Ataxia Type 1 Mouse Model Content: Background Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) that replicates many features of the human disease. Methods and Findings Sca1154Q/2Q mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1154Q/2Q mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity. Conclusions The effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.

Title: Brief Internet-Based Intervention Reduces Posttraumatic Stress and Prolonged Grief in Parents after the Loss of a Child during Pregnancy: A Randomized Controlled Trial Content: Background: The loss of a child during pregnancy causes significant psychological distress for many women and their partners, and may lead to long-lasting psychiatric disorders. Internet-based interventions using exposure techniques and cognitive restructuring have proved effective for posttraumatic stress disorder (PTSD) and prolonged grief. This study compared the effects of an Internet-based intervention for parents after prenatal loss with a waiting list condition (WLC). Methods: The Impact of Event Scale - Revised assessed symptoms of PTSD; the Inventory of Complicated Grief and the Brief Symptom Inventory assessed depression, anxiety, and general mental health. The 228 participants (92% female) were randomly allocated to a treatment group (TG; n = 115) or a WLC group (n = 113). The TG received a 5-week cognitive behavioral intervention including (1) self-confrontation, (2) cognitive restructuring, and (3) social sharing. Results: The TG showed significantly reduced symptoms of posttraumatic stress, prolonged grief, depression, and anxiety relative to the WLC control group. Intention-to-treat analysis revealed treatment effects of between d = 0.84 and d = 1.02 for posttraumatic stress and prolonged grief from pre- to posttreatment time points. Further significant improvement in all symptoms of PTSD and prolonged grief was found from the posttreatment evaluation to the 12-month follow-up. The attrition rate of 14% was relatively low. Conclusions: The Internet-based intervention proved to be a feasible and cost-effective treatment, reducing symptoms of posttraumatic stress, grief, depression, anxiety, and general mental health after pregnancy loss. Low-threshold e-health interventions should be further evaluated and implemented routinely to improve psychological support after pregnancy loss.

Title: Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. Content: CONTEXT Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes. OBJECTIVE To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years. DESIGN, SETTING, AND PATIENTS A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California. MAIN OUTCOME MEASURE Hypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease. RESULTS At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55). CONCLUSIONS Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown.

Title: Exercise as a therapeutic approach to improve blood pressure in patients with peripheral arterial disease: current literature and future directions. Content: INTRODUCTION Patients with symptomatic peripheral artery disease (PAD) exhibit reduced functional capacity and increased mortality due to cardiovascular disease. Although exercise has been a cornerstone for clinical treatment to improve walking capacity in patients with symptomatic PAD, its effects on cardiovascular parameters have been poorly explored. Areas covered: This review examines the role of exercise in improving blood pressure in patients with symptomatic PAD and summarizes the current evidence on the acute (single bout of exercise) and chronic effects of walking and resistance exercise on blood pressure and its determinants. Expert commentary: In patients with symptomatic PAD, exercise promotes acute and chronic reductions in blood pressure. These effects were observed particularly after walking and resistance exercise. Future studies are necessary to investigate the effects of other exercise modalities, especially non-painful exercises, on cardiovascular function in patients with symptomatic PAD.

Title: Brief, four-session group CBT reduces binge eating behaviors among bariatric surgery candidates. Content: BACKGROUND The objective of this study was to evaluate the effectiveness of a brief, 4-session cognitive behavioral, group psychotherapy for binge eating among bariatric surgery candidates at an academic medical center. Binge eating behaviors have been linked to poorer outcomes among bariatric surgery patients, and binge eating disorder have be considered a contraindication in surgery programs, some of which have mandated preoperative binge eating treatment. However, no previous studies have examined whether a preoperative binge eating intervention could successfully reduce binge eating behaviors among severely obese bariatric surgery candidates. METHODS A total of 243 bariatric surgery candidates completed a brief cognitive behavioral group treatment for binge eating behaviors and were administered the Binge Eating Scale and reported the number of weekly binge eating episodes at the initial psychological evaluation and again after the group sessions. The study used a pre-post intervention design. RESULTS The results suggested significant reductions in both binge eating behaviors and cognitions and binge eating episodes after the group intervention. The intervention's effectiveness did not differ according to gender or ethnicity (black versus white). CONCLUSION A brief cognitive behavioral intervention can reduce binge eating behaviors among bariatric surgery candidates. Given the potential influence of binge eating on outcomes, bariatric surgery programs could benefit by treating binge eating before surgery.

Title: Lip movements entrain the observers’ low-frequency brain oscillations to facilitate speech intelligibility Content: During continuous speech, lip movements provide visual temporal signals that facilitate speech processing. Here, using MEG we directly investigated how these visual signals interact with rhythmic brain activity in participants listening to and seeing the speaker. First, we investigated coherence between oscillatory brain activity and speaker's lip movements and demonstrated significant entrainment in visual cortex. We then used partial coherence to remove contributions of the coherent auditory speech signal from the lip-brain coherence. Comparing this synchronization between different attention conditions revealed that attending visual speech enhances the coherence between activity in visual cortex and the speaker's lips. Further, we identified a significant partial coherence between left motor cortex and lip movements and this partial coherence directly predicted comprehension accuracy. Our results emphasize the importance of visually entrained and attention-modulated rhythmic brain activity for the enhancement of audiovisual speech processing.

Title: Immediate effects of droperidol Content: The subjective and behavioural responses of 20 healthy volunteers taking droperidol 5 mg as part of a cognitive challenge programme were catalogued. Some form of akathisia was universally experienced. Half of the subjects were dysphoric, but there appeared to be a number of different inputs to their dysphoria and a range of other effects were noted, including sedation, dissociative experiences, alterations in sensation and subtle changes in physiognomy. The duration of these effects varied from a few hours to over a week. In the acute phase, insight as to the origin of what was happening was mixed. The results have implications for the interpretation of cognitive challenge tests, the nature of akathisia, clinical therapeutics and drug development. © 1998 John Wiley & Sons, Ltd.

Title: Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides. Content: Insulin-regulated aminopeptidase (IRAP or oxytocinase) is a membrane-bound zinc-metallopeptidase that cleaves neuroactive peptides in the brain and produces memory enhancing effects when inhibited. We have determined the crystal structure of human IRAP revealing a closed, four domain arrangement with a large, mostly buried cavity abutting the active site. The structure reveals that the GAMEN exopeptidase loop adopts a very different conformation from other aminopeptidases, thus explaining IRAP's unique specificity for cyclic peptides such as oxytocin and vasopressin. Computational docking of a series of IRAP-specific cognitive enhancers into the crystal structure provides a molecular basis for their structure-activity relationships and demonstrates that the structure will be a powerful tool in the development of new classes of cognitive enhancers for treating a variety of memory disorders such as Alzheimer's disease.

Title: Casual blood pressure and neurocognitive function in children with chronic kidney disease: a report of the children with chronic kidney disease cohort study. Content: BACKGROUND AND OBJECTIVES Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on the potential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited. Our objective was to determine whether children with CKD and elevated BP (EBP) had decreased performance on neurocognitive testing compared with children with CKD and normal BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional analysis of the relation between auscultatory BP and neurocognitive test performance in children 6 to 17 years enrolled in the Chronic Kidney Disease in Children (CKiD) project. RESULTS Of 383 subjects, 132 (34%) had EBP (systolic BP and/or diastolic BP ≥90(th) percentile). Subjects with EBP had lower mean (SD) scores on Wechsler Abbreviated Scales of Intelligence (WASI) Performance IQ than those with normal BP (normal BP versus EBP, 96.1 (16.7) versus 92.4 (14.9), P = 0.03) and WASI Full Scale IQ (97.0 (16.2) versus 93.4 (16.5), P = 0.04). BP index (subject's BP/95(th) percentile BP) correlated inversely with Performance IQ score (systolic, r = -0.13, P = 0.01; diastolic, r = -0.19, P < 0.001). On multivariate analysis, the association between lower Performance IQ score and increased BP remained significant after controlling for demographic and disease-related variables (EBP, β = -3.7, 95% confidence interval [CI]: -7.3 to -0.06; systolic BP index, β = -1.16 to 95% CI: -2.1, -0.21; diastolic BP index, β = -1.17, 95% CI: -1.8 to -0.55). CONCLUSIONS Higher BP was independently associated with decreased WASI Performance IQ scores in children with mild-to-moderate CKD.

Title: A mental health intervention for schoolchildren exposed to violence: a randomized controlled trial. Content: CONTEXT No randomized controlled studies have been conducted to date on the effectiveness of psychological interventions for children with symptoms of posttraumatic stress disorder (PTSD) that has resulted from personally witnessing or being personally exposed to violence. OBJECTIVE To evaluate the effectiveness of a collaboratively designed school-based intervention for reducing children's symptoms of PTSD and depression that has resulted from exposure to violence. DESIGN A randomized controlled trial conducted during the 2001-2002 academic year. SETTING AND PARTICIPANTS Sixth-grade students at 2 large middle schools in Los Angeles who reported exposure to violence and had clinical levels of symptoms of PTSD. INTERVENTION Students were randomly assigned to a 10-session standardized cognitive-behavioral therapy (the Cognitive-Behavioral Intervention for Trauma in Schools) early intervention group (n = 61) or to a wait-list delayed intervention comparison group (n = 65) conducted by trained school mental health clinicians. MAIN OUTCOME MEASURES Students were assessed before the intervention and 3 months after the intervention on measures assessing child-reported symptoms of PTSD (Child PTSD Symptom Scale; range, 0-51 points) and depression (Child Depression Inventory; range, 0-52 points), parent-reported psychosocial dysfunction (Pediatric Symptom Checklist; range, 0-70 points), and teacher-reported classroom problems using the Teacher-Child Rating Scale (acting out, shyness/anxiousness, and learning problems; range of subscales, 6-30 points). RESULTS Compared with the wait-list delayed intervention group (no intervention), after 3 months of intervention students who were randomly assigned to the early intervention group had significantly lower scores on symptoms of PTSD (8.9 vs 15.5, adjusted mean difference, - 7.0; 95% confidence interval [CI], - 10.8 to - 3.2), depression (9.4 vs 12.7, adjusted mean difference, - 3.4; 95% CI, - 6.5 to - 0.4), and psychosocial dysfunction (12.5 vs 16.5, adjusted mean difference, - 6.4; 95% CI, -10.4 to -2.3). Adjusted mean differences between the 2 groups at 3 months did not show significant differences for teacher-reported classroom problems in acting out (-1.0; 95% CI, -2.5 to 0.5), shyness/anxiousness (0.1; 95% CI, -1.5 to 1.7), and learning (-1.1, 95% CI, -2.9 to 0.8). At 6 months, after both groups had received the intervention, the differences between the 2 groups were not significantly different for symptoms of PTSD and depression; showed similar ratings for psychosocial function; and teachers did not report significant differences in classroom behaviors. CONCLUSION A standardized 10-session cognitive-behavioral group intervention can significantly decrease symptoms of PTSD and depression in students who are exposed to violence and can be effectively delivered on school campuses by trained school-based mental health clinicians.

Title: Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans. Content: Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and has been proposed as having antiatherosclerotic property. Vascular endothelial cells also produce endothelin-1 (ET-1), which is a potent vasoconstrictor peptide and has potent proliferating activity on vascular smooth muscle cells. Therefore, ET-1 has been implicated in the progression of atheromatous vascular disease. Because exercise training has been reported to produce an alteration in the function of vascular endothelial cells in animals, we hypothesized that exercise training influences the production of NO and ET-1 in humans. The purpose of the present study was to examine whether chronic exercise could influence the plasma levels of NO (measured as the stable end product of NO, i.e., nitrite/nitrate [NOx]) and ET-1 in humans. Eight healthy young subjects (20.3 +/- 0.5 yr old) participated in the study and exercised by cycling on a leg ergometer (70% VO2max for 1 hour, 3-4 days/week) for 8 weeks. Venous plasma concentrations of NOx and ET-1 were measured before and after (immediately before the end of 8-week exercise training) the exercise training, and also after the 4th and 8th week after the cessation of training. The VO2max significantly increased after exercise training. After the exercise training, the plasma concentration of NOx significantly increased (30.69 +/- 3.20 vs. 48.64 +/- 8.16 micromol/L, p < 0.05), and the plasma concentration of ET-1 significantly decreased (1.65 +/- 0.14 vs. 1.23 +/- 0.12 pg/mL, p < 0.05). The increase in NOx level and the decrease in ET-1 level lasted to the 4th week after the cessation of exercise training and these levels (levels of NOx and ET-1) returned to the basal levels (the levels before the exercise training) in the 8th week after the cessation of exercise training. There was a significant negative correlation between plasma NOx concentration and plasma ET-1 concentration. The present study suggests that chronic exercise causes an increase in production of NO and a decrease in production of ET-1 in humans, which may produce beneficial effects (i.e., vasodilative and antiatherosclerotic) on the cardiovascular system.

Title: Skeletal muscle interleukin‐6 regulates metabolic factors in iWAT during HFD and exercise training Content: OBJECTIVE To investigate the role of skeletal muscle (SkM) interleukin (IL)-6 in the regulation of adipose tissue metabolism. METHODS Muscle-specific IL-6 knockout (IL-6 MKO) and IL-6(loxP/loxP) (Floxed) mice were subjected to standard rodent diet (Chow), high-fat diet (HFD), or HFD in combination with exercise training (HFD ExTr) for 16 weeks. RESULTS Total fat mass increased (P < 0.05) in both genotypes with HFD. However, HFD IL-6 MKO mice had lower (P < 0.05) inguinal adipose tissue (iWAT) mass than HFD Floxed mice. Accordingly, iWAT glucose transporter 4 (GLUT4) protein content, 5'AMP activated protein kinase (AMPK)(Thr172) phosphorylation, and fatty acid synthase (FAS) mRNA content were lower (P < 0.05) in IL-6 MKO than Floxed mice on Chow. In addition, iWAT AMPK(Thr172) and hormone-sensitive lipase (HSL)(Ser565) phosphorylation as well as perilipin protein content was higher (P < 0.05) in HFD IL-6 MKO than HFD Floxed mice, and pyruvate dehydrogenase E1α (PDH-E1α) protein content was higher (P < 0.05) in HFD ExTr IL-6 MKO than HFD ExTr Floxed mice. CONCLUSIONS These findings indicate that SkM IL-6 affects iWAT mass through regulation of glucose uptake capacity as well as lipogenic and lipolytic factors.

Title: Acute exercise activates nuclear factor (NF)-kappaB signaling pathway in rat skeletal muscle. Content: Two studies were performed to investigate the effects of an acute bout of physical exercise on the nuclear protein kappaB (NF-kappaB) signaling pathway in rat skeletal muscle. In Study 1, a group of rats (n=6) was run on the treadmill at 25 m/min, 5% grade, for 1 h or until exhaustion (Ex), and compared with a second group (n=6) injected with two doses of pyrrolidine dithiocarbamate (PDTC, 100 mg/kg, i.p.) 24 and 1 h prior to the acute exercise bout. Three additional groups of rats (n=6) were injected with either 8 mg/kg (i.p.) of lipopolysaccharide (LPS), 1 mmol/kg (i.p.) t-butylhydroperoxide (tBHP), or saline (C) and killed at resting condition. Ex rats showed higher levels of NF-kappaB binding and P50 protein content in muscle nuclear extracts compared with C rats. Cytosolic IkappaBalpha and IkappaB kinase (IKK) contents were decreased, whereas phospho-IkappaBalpha and phospho-IKK contents were increased, comparing Ex vs. C. The exercise-induced activation of NF-kappaB signaling cascade was partially abolished by PDTC treatment. LPS, but not tBHP, treatment mimicked and exaggerated the effects observed in Ex rats. In Study 2, the time course of exercise-induced NF-kappaB activation was examined. Highest levels of NF-kappaB binding were observed at 2 h postexercise. Decreased cytosolic IkappaBalpha and increased phosphor-IkappaBalpha content were found 0-1 h postexercise whereas P65 reached peak levels at 2-4 h. These data suggest that the NF-kappaB signaling pathway can be activated in a redox-sensitive manner during muscular contraction, presumably due to increased oxidant production. The cascade of intracellular events may be the overture to elevated gene expression of manganese superoxide dismutase reported earlier (Pfluegers Arch. 442, 426-434, 2001).

Title: Vasodilator responses of coronary resistance arteries of exercise-trained pigs. Content: BACKGROUND The purpose of this study was to test the hypothesis that vasodilator responses of porcine coronary resistance arteries are increased by exercise training. METHODS AND RESULTS Yucatan miniature swine were randomly divided into groups of exercise-trained (ET) and sedentary (SED) control pigs. ET pigs were placed on a progressive treadmill training program lasting 16 to 20 weeks, and SED pigs remained inactive during the same time period. Coronary resistance arteries 64 to 157 microns in diameter were isolated for in vitro evaluation of relaxation responses to the endothelium-independent dilators sodium nitroprusside (1 x 10(-10) to 1 x 10(-4) mol/L) and adenosine (1 x 10(-10) to 1 x 10(-5) mol/L) and to bradykinin (1 x 10(-13) to 3 x 10(-7) mol/L), an endothelium-dependent agent. Relaxation responses to adenosine and sodium nitroprusside were not altered by exercise training. Endothelium-dependent relaxation to bradykinin was enhanced in coronary resistance arteries from ET pigs (IC50: ET, 0.07 +/- 0.02 nmol/L; SED, 1.59 +/- 0.09 nmol/L). To determine whether prostanoids and/or the nitric oxide synthase pathway were involved in the ET-induced changes in bradykinin-induced vasodilation, responses to bradykinin were examined in coronary resistance arteries from both ET and SED pigs in the presence of indomethacin and in the presence of nitro-monomethyl L-arginine (L-NMMA). Both indomethacin and L-NMMA produced significant inhibition of the bradykinin-induced relaxation in vessels from both groups. Despite decreased bradykinin-induced relaxation after indomethacin, bradykinin-induced vasodilation was still enhanced in vessels from the ET group. L-NMMA caused greater inhibition of the bradykinin-induced relaxation in coronary resistance arteries from ET pigs relative to arteries from SED pigs and eliminated the training-induced enhancement of the bradykinin responses. CONCLUSIONS These results suggest that exercise training enhances bradykinin-induced vasodilation through increased endothelium-derived relaxing factor/nitric oxide production by the L-arginine/nitric oxide synthase pathway.

Title: Effects of exercise intensity on cardiovascular fitness, total body composition, and visceral adiposity of obese adolescents. Content: BACKGROUND Little is known about how the intensity of exercise influences cardiovascular fitness and body composition, especially in obese adolescents. OBJECTIVE Our goal was to determine the effects of physical training intensity on the cardiovascular fitness, percentage of body fat (%BF), and visceral adipose tissue (VAT) of obese adolescents. DESIGN Obese 13-16-y-olds (n = 80) were assigned to 1) biweekly lifestyle education (LSE), 2) LSE + moderate-intensity physical training, or 3) LSE + high-intensity physical training. The intervention lasted 8 mo. Physical training was offered 5 d/wk, and the target energy expenditure for all subjects in physical training groups was 1047 kJ (250 kcal)/session. Cardiovascular fitness was measured with a multistage treadmill test, %BF with dual-energy X-ray absorptiometry, and VAT with magnetic resonance imaging. RESULTS The increase in cardiovascular fitness in the high-intensity physical training group, but not in the moderate-intensity group, was significantly greater than that in the LSE alone group (P = 0.009); no other comparisons of the 3 groups were significant. Compared with the LSE alone group, a group composed of subjects in both physical training groups combined who attended training sessions >or=2 d/wk showed favorable changes in cardiovascular fitness (P < 0.001), %BF (P = 0.001), and VAT (P = 0.029). We found no evidence that the high-intensity physical training was more effective than the moderate-intensity physical training in enhancing body composition. CONCLUSIONS The cardiovascular fitness of obese adolescents was significantly improved by physical training, especially high-intensity physical training. The physical training also reduced both visceral and total-body adiposity, but there was no clear effect of the intensity of physical training.

Title: Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial. Content: RATIONALE The outcome of fully intermittent thrice-weekly antituberculosis treatment of various durations in HIV-associated tuberculosis is unclear. OBJECTIVES To compare the efficacy of an intermittent 6-month regimen (Reg6M: 2EHRZ(3)/4HR(3) [ethambutol, 1,200 mg; isoniazid, 600 mg; rifampicin, 450 or 600 mg depending on body weight <60 or > or =60 kg; and pyrazinamide, 1,500 mg for 2 mo; followed by 4 mo of isoniazid and rifampicin at the same doses]) versus a 9-month regimen (Reg9M: 2EHRZ(3)/7HR(3)) in HIV/tuberculosis (TB). METHODS HIV-infected patients with newly diagnosed pulmonary or extrapulmonary TB were randomly assigned to Reg6M (n = 167) or Reg9M (n = 160) and monitored by determination of clinical, immunological, and bacteriological parameters for 36 months. Primary outcomes included favorable responses at the end of treatment and recurrences during follow-up, whereas the secondary outcome was death. Intent-to-treat and on-treatment analyses were performed. All patients were antiretroviral treatment-naive during treatment. MEASUREMENTS AND MAIN RESULTS Of the patients, 70% had culture-positive pulmonary TB; the median viral load was 155,000 copies/ml and the CD4(+) cell count was 160 cells/mm(3). Favorable response to antituberculosis treatment was similar by intent to treat (Reg6M, 83% and Reg9M, 76%; P = not significant). Bacteriological recurrences occurred significantly more often in Reg6M than in Reg9M (15 vs. 7%; P < 0.05) although overall recurrences were not significantly different (Reg6M, 19% vs. Reg9M, 13%). By 36 months, 36% of patients undergoing Reg6M and 35% undergoing Reg9M had died, with no significant difference between regimens. All 19 patients who failed treatment developed acquired rifamycin resistance (ARR), the main risk factor being baseline isoniazid resistance. CONCLUSIONS Among antiretroviral treatment-naive HIV-infected patients with TB, a 9-month regimen resulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment. Clinical Trials Registry Information: ID# NCT00376012 registered at www.clinicaltrials.gov.

Title: Transtheoretical model-based multiple behavior intervention for weight management: effectiveness on a population basis. Content: BACKGROUND The increasing prevalence of overweight and obesity underscores the need for evidence-based, easily disseminable interventions for weight management that can be delivered on a population basis. The Transtheoretical Model (TTM) offers a promising theoretical framework for multiple behavior weight management interventions. METHODS Overweight or obese adults (BMI 25-39.9; n=1277) were randomized to no-treatment control or home-based, stage-matched multiple behavior interventions for up to three behaviors related to weight management at 0, 3, 6, and 9 months. All participants were re-assessed at 6, 12, and 24 months. RESULTS Significant treatment effects were found for healthy eating (47.5% versus 34.3%), exercise (44.90% versus 38.10%), managing emotional distress (49.7% versus 30.30%), and untreated fruit and vegetable intake (48.5% versus 39.0%) progressing to Action/Maintenance at 24 months. The groups differed on weight lost at 24 months. Co-variation of behavior change occurred and was much more pronounced in the treatment group, where individuals progressing to Action/Maintenance for a single behavior were 2.5-5 times more likely to make progress on another behavior. The impact of the multiple behavior intervention was more than three times that of single behavior interventions. CONCLUSIONS This study demonstrates the ability of TTM-based tailored feedback to improve healthy eating, exercise, managing emotional distress, and weight on a population basis. The treatment produced a high level of population impact that future multiple behavior interventions can seek to surpass.

Title: Functional outcomes of multi-condition collaborative care and successful ageing: results of randomised trial Content: OBJECTIVE To evaluate the effectiveness of integrated care for chronic physical diseases and depression in reducing disability and improving quality of life. DESIGN A randomised controlled trial of multi-condition collaborative care for depression and poorly controlled diabetes and/or risk factors for coronary heart disease compared with usual care among middle aged and elderly people SETTING Fourteen primary care clinics in Seattle, Washington. PARTICIPANTS Patients with diabetes or coronary heart disease, or both, and blood pressure above 140/90 mm Hg, low density lipoprotein concentration >3.37 mmol/L, or glycated haemoglobin 8.5% or higher, and PHQ-9 depression scores of ≥ 10. INTERVENTION A 12 month intervention to improve depression, glycaemic control, blood pressure, and lipid control by integrating a "treat to target" programme for diabetes and risk factors for coronary heart disease with collaborative care for depression. The intervention combined self management support, monitoring of disease control, and pharmacotherapy to control depression, hyperglycaemia, hypertension, and hyperlipidaemia. MAIN OUTCOME MEASURES Social role disability (Sheehan disability scale), global quality of life rating, and World Health Organization disability assessment schedule (WHODAS-2) scales to measure disabilities in activities of daily living (mobility, self care, household maintenance). RESULTS Of 214 patients enrolled (106 intervention and 108 usual care), disability and quality of life measures were obtained for 97 intervention patients at six months (92%) and 92 at 12 months (87%), and for 96 usual care patients at six months (89%) and 92 at 12 months (85%). Improvements from baseline on the Sheehan disability scale (-0.9, 95% confidence interval -1.5 to -0.2; P = 0.006) and global quality of life rating (0.7, 0.2 to 1.2; P = 0.005) were significantly greater at six and 12 months in patients in the intervention group. There was a trend toward greater improvement in disabilities in activities of daily living (-1.5, -3.3 to 0.4; P = 0.10). CONCLUSIONS Integrated care that covers chronic physical disease and comorbid depression can reduce social role disability and enhance global quality of life. Trial registration Clinical Trials NCT00468676.

Title: Relationship between activity levels, aerobic fitness, and body fat in 8- to 10-yr-old children. Content: The relationships between children's activity, aerobic fitness, and fatness are unclear. Indirect estimates of activity, e.g., heart rate (HR) and recall, may mask any associations. The purpose of this study was to assess these relationships by using the Tritrac-R3D, a pedometer, and heart rate. Thirty-four children, ages 8-10 yr, participated in the study. The Tritrac and pedometer were worn for up to 6 days. HR was measured for 1 day. Activity measured by Tritrac or pedometer correlated positively to fitness in the whole group (Tritrac, r = 0.66; pedometer, r = 0.59; P < 0.01) and in boys and girls separately (P < 0.05) and correlated negatively to fatness in the whole group (r = -0.42, P < 0.05). In contrast, HR did not correlate significantly to fitness, and HR of >139 beats/min correlated positively to fatness in girls (r = 0.64, P < 0.05). This suggests that HR is misleading as a measure of activity. This study supports a positive relationship between activity and fitness and suggests a negative relationship between fatness and activity.

Title: Mindfulness meditation and improvement in sleep quality and daytime impairment among older adults with sleep disturbances: a randomized clinical trial. Content: IMPORTANCE Sleep disturbances are most prevalent among older adults and often go untreated. Treatment options for sleep disturbances remain limited, and there is a need for community-accessible programs that can improve sleep. OBJECTIVE To determine the efficacy of a mind-body medicine intervention, called mindfulness meditation, to promote sleep quality in older adults with moderate sleep disturbances. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial with 2 parallel groups conducted from January 1 to December 31, 2012, at a medical research center among an older adult sample (mean [SD] age, 66.3 [7.4] years) with moderate sleep disturbances (Pittsburgh Sleep Quality Index [PSQI] >5). INTERVENTIONS A standardized mindful awareness practices (MAPs) intervention (n = 24) or a sleep hygiene education (SHE) intervention (n = 25) was randomized to participants, who received a 6-week intervention (2 hours per week) with assigned homework. MAIN OUTCOMES AND MEASURES The study was powered to detect between-group differences in moderate sleep disturbance measured via the PSQI at postintervention. Secondary outcomes pertained to sleep-related daytime impairment and included validated measures of insomnia symptoms, depression, anxiety, stress, and fatigue, as well as inflammatory signaling via nuclear factor (NF)-κB. RESULTS Using an intent-to-treat analysis, participants in the MAPs group showed significant improvement relative to those in the SHE group on the PSQI. With the MAPs intervention, the mean (SD) PSQIs were 10.2 (1.7) at baseline and 7.4 (1.9) at postintervention. With the SHE intervention, the mean (SD) PSQIs were 10.2 (1.8) at baseline and 9.1 (2.0) at postintervention. The between-group mean difference was 1.8 (95% CI, 0.6-2.9), with an effect size of 0.89. The MAPs group showed significant improvement relative to the SHE group on secondary health outcomes of insomnia symptoms, depression symptoms, fatigue interference, and fatigue severity (P < .05 for all). Between-group differences were not observed for anxiety, stress, or NF-κB, although NF-κB concentrations significantly declined over time in both groups (P < .05). CONCLUSIONS AND RELEVANCE The use of a community-accessible MAPs intervention resulted in improvements in sleep quality at immediate postintervention, which was superior to a highly structured SHE intervention. Formalized mindfulness-based interventions have clinical importance by possibly serving to remediate sleep problems among older adults in the short term, and this effect appears to carry over into reducing sleep-related daytime impairment that has implications for quality of life. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01534338.

Title: Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. Content: 1. Plasma interleukin (IL)-6 concentration is increased with exercise and it has been demonstrated that contracting muscles can produce IL-The question addressed in the present study was whether the IL-6 production by contracting skeletal muscle is of such a magnitude that it can account for the IL-6 accumulating in the blood. 2. This was studied in six healthy males, who performed one-legged dynamic knee extensor exercise for 5 h at 25 W, which represented 40% of peak power output (Wmax). Arterial-femoral venous (a-fv) differences over the exercising and the resting leg were obtained before and every hour during the exercise. Leg blood flow was measured in parallel by the ultrasound Doppler technique. IL-6 was measured by enzyme-linked immunosorbent assay (ELISA). 3. Arterial plasma concentrations for IL-6 increased 19-fold compared to rest. The a-fv difference for IL-6 over the exercising leg followed the same pattern as did the net IL-6 release. Over the resting leg, there was no significant a-fv difference or net IL-6 release. The work was produced by 2.5 kg of active muscle, which means that during the last 2 h of exercise, the median IL-6 production was 6.8 ng min-1 (kg active muscle)-1 (range, 3.96-9.69 ng min-1 kg-1). 4. The net IL-6 release from the muscle over the last 2 h of exercise was 17-fold higher than the elevation in arterial IL-6 concentration and at 5 h of exercise the net release during 1 min was half of the IL-6 content in the plasma. This indicates a very high turnover of IL-6 during muscular exercise. We suggest that IL-6 produced by skeletal contracting muscle contributes to the maintenance of glucose homeostasis during prolonged exercise.

Title: How long will long-term potentiation last? Content: The paramount feature of long-term potentiation (LTP) as a memory mechanism is its characteristic persistence over time. Although the basic phenomenology of LTP persistence was established 30 years ago, new insights have emerged recently about the extent of LTP persistence and its regulation by activity and experience. Thus, it is now evident that LTP, at least in the dentate gyrus, can either be decremental, lasting from hours to weeks, or stable, lasting months or longer. Although mechanisms engaged during the induction of LTP regulate its subsequent persistence, the maintenance of LTP is also governed by activity patterns post-induction, whether induced experimentally or generated by experience. These new findings establish dentate gyrus LTP as a useful model system for studying the mechanisms governing the induction, maintenance and interference with long-term memory, including very long-term memory lasting months or longer. The challenge is to study LTP persistence in other brain areas, and to relate, if possible, the properties and regulation of LTP maintenance to these same properties of the information that is actually stored in those regions.

Title: Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. Content: HIV-1 replication within macrophages of the CNS often results in cognitive and motor impairment, which is known as HIV-associated dementia (HAD) in its most severe form. IFN-beta suppresses viral replication within these cells during early CNS infection, but the effect is transient. HIV-1 eventually overcomes this protective innate immune response to resume replication through an unknown mechanism, initiating the progression toward HAD. In this article, we show that Suppressor of Cytokine Signaling (SOCS)3, a molecular inhibitor of IFN signaling, may allow HIV-1 to evade innate immunity within the CNS. We found that SOCS3 is elevated in an in vivo SIV/macaque model of HAD and that the pattern of expression correlates with recurrence of viral replication and onset of CNS disease. In vitro, the HIV-1 regulatory protein transactivator of transcription induces SOCS3 in human and murine macrophages in a NF-kappaB-dependent manner. SOCS3 expression attenuates the response of macrophages to IFN-beta at proximal levels of pathway activation and downstream antiviral gene expression and consequently overcomes the inhibitory effect of IFN-beta on HIV-1 replication. These studies indicate that SOCS3 expression, induced by stimuli present in the HIV-1-infected brain, such as transactivator of transcription, inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. This consequence of SOCS3 expression in vitro, supported by a correlation with increased viral load and onset of CNS disease in vivo, suggests that SOCS3 may allow HIV-1 to evade the protective innate immune response within the CNS, allowing the recurrence of viral replication and, ultimately, promoting progression toward HAD.

Title: Exercise blood flow patterns within and among rat muscles after training. Content: This study was designed to determine the influence of a long-term, moderate-intensity treadmill training program on the distribution of blood flow within and among muscles of rats during exercise. One group (T) of male Sprague-Dawley rats trained for 1 h/day for 13-17 wk at 30 m/min on a motor-driven treadmill. A second group (UT) of rats was conditioned for 10 min/day for 4 wk at the same speed. Muscle succinate dehydrogenase activities were higher in T than UT rats indicating a significant training effect. Blood flows (BFs) in 32 hindlimb muscles or muscle parts and other selected organs were measured in the two groups with radiolabeled microspheres during preexercise and while the rats ran for 30 s, 5 min, or 15 min at 30 m/min on the treadmill. The data indicate 1) there were no differences in total hindlimb muscle BF between UT and T rats at any time; however, 2) T rats had higher preexercise heart rates and higher muscle BFs in the deep red extensor muscles, suggesting a greater anticipatory response to the impending exercise; 3) T rats demonstrated more rapid elevations in BF in the red extensor muscles at the commencement of exercise; 4) T rats had higher BFs in red extensor muscles during exercise, whereas UT rats had higher BFs in white muscles; and 5) T rats maintained higher BFs in the visceral organs during exercise. These findings demonstrate that exercise training results in changes in the distribution of BF within and among muscles and among organs during exercise. Specifically, data indicate the high-oxidative motor units that are primarily recruited in the muscles during the initial stages of moderate treadmill exercise receive higher blood flows in the trained rats; this presumably contributes to increased resistance to fatigue.

Title: Determinants of adolescent physical activity and inactivity patterns. Content: OBJECTIVES Despite recognition of the important influence of environmental determinants on physical activity patterns, minimal empirical research has been done to assess the impact of environmental/contextual determinants of physical activity. This article aims to investigate environmental and sociodemographic determinants of physical activity and inactivity patterns among subpopulations of US adolescents. We define environmental determinants as modifiable factors in the physical environment that impose a direct influence on the opportunity to engage in physical activity. The present research examines environmental and sociodemographic determinants of physical activity and inactivity with the implication that these findings can point toward societal-level intervention strategies for increasing physical activity and decreasing inactivity among adolescents. STUDY DESIGN AND METHODOLOGY The study population consists of nationally representative data from the 1996 National Longitudinal Study of Adolescent Health on 17 766 US adolescents enrolled in US middle and high schools (including 3933 non-Hispanic blacks, 3148 Hispanics, and 1337 Asians). Hours/week of inactivity (TV/video viewing and video/computer games) and times/week of moderate to vigorous physical activity were collected by questionnaire. Outcome variables were moderate to vigorous physical activity and inactivity, which were broken into categories (physical activity: 0-2 times/week, 3-4 times/week, and >/=5 times/week; inactivity: 0-10 hours/week, 11-24 hours/week, and >/=25 hours/week). Sociodemographic and environmental correlates of physical activity and inactivity were used as exposure and control variables and included sex, age, urban residence, participation in school physical education program, use of community recreation center, total reported incidents of serious crime in neighborhood, socioeconomic status, ethnicity, generation of residence in the United States, presence of mother/father in household, pregnancy status, work status, in-school status, region, and month of interview. Logistic regression models of high versus low and medium physical activity and inactivity were used to investigate sex and ethnic interactions in relation to environmental and sociodemographic factors to examine evidence for the potential impact of physical education and recreation programs and sociodemographic factors on physical activity and inactivity patterns. RESULTS Moderate to vigorous physical activity was lower and inactivity higher for non-Hispanic black and Hispanic adolescents. Participation in school physical education programs was considerably low for these adolescents and decreased with age. Participation in daily school physical education (PE) program classes (adjusted odds ratio [AOR]: 2.21; confidence interval [CI]: 1.82-2.68) and use of a community recreation center (AOR: 1.75; CI: 1.56-1.96) were associated with an increased likelihood of engaging in high level moderate to vigorous physical activity. Maternal education was inversely associated with high inactivity patterns; for example, having a mother with a graduate or professional degree was associated with an AOR of.61 (CI:.48-.76) for high inactivity. High family income was associated with increased moderate to vigorous physical activity (AOR: 1.43; CI: 1.22-1.67) and decreased inactivity (AOR:.70; CI:.59-.82). High neighborhood serious crime level was associated with a decreased likelihood of falling in the highest category of moderate to vigorous physical activity (AOR:.77; CI:.66-.91). CONCLUSIONS These results show important associations between modifiable environmental factors, such as participation in school PE and community recreation programs, with activity patterns of adolescents. Despite the marked and significant impact of participation in school PE programs on physical activity patterns of US adolescents, few adolescents participated in such school PE programs; only 21.3% of all adolescents

Title: Unmet needs mediate the relationship between symptoms and quality of life in breast cancer survivors Content: This study aimed to compare the symptoms, unmet needs, and QoL reported by women at 6 months to <2 years and 2 to 5 years following surgery and adjuvant treatment for breast cancer. It also evaluated the relationships among symptoms, unmet needs, and QoL using structural equation modeling. In this study, 113 and 137 survivors following breast cancer treatment 6 months to <2 years and 2 to 5 years, respectively, completed the Memorial Symptom Assessment Scale, the Supportive Care Needs Survey-34, and the Medical Outcomes Study 12-item Short Form Health Survey version 2.0 during their medical follow-up. The mean numbers of symptoms and unmet needs were 5.43 and 3.0, respectively, for survivors at <2 years, and 5.24 and 2.42, respectively, for survivors at 2 to 5 years following treatment. The most common reported symptoms were related primarily to physical domains. No significant differences were found between the two survivor groups on the MSAS scores. Survivors at <2 years reported significantly higher scores in Psychological and Health Care System/Information needs (p < 0.01), and lower composite scores in physical and mental QoL (p < 0.05) than those at 2 to 5 years post-treatment. Significant direct and indirect effects were found of symptom burden through unmet needs on survivors’ physical and mental QoL after adjustment for survival time, and the models showed a good fit. Results suggest that breast cancer survivors continue to endure many symptoms independent of the survivorship period. The unmet needs mediate the relationship between symptom burden and survivors’ QoL.

Title: Improving Adherence to Antiretroviral Therapy With Triggered Real-time Text Message Reminders: The China Adherence Through Technology Study. Content: BACKGROUND Real-time adherence monitoring is now possible through medication storage devices equipped with cellular technology. We assessed the effect of triggered cell phone reminders and counseling using objective adherence data on antiretroviral therapy (ART) adherence among Chinese HIV-infected patients. METHODS We provided ART patients in Nanning, China, with a medication device (Wisepill) to monitor their ART adherence electronically. After 3 months, we randomized subjects within optimal (≥95%) and suboptimal (<95%) adherence strata to intervention vs. control arms. In months 4-9, intervention subjects received individualized reminders triggered by late dose taking (no device opening by 30 minutes past dose time) and counseling using device-generated data. Controls received no reminders or data-informed counseling. We compared postintervention proportions achieving optimal adherence, mean adherence, and clinical outcomes. RESULTS Of 120 subjects enrolled, 116 (96.7%) completed the trial. Preintervention optimal adherence was similar in intervention vs. control arms (63.5% vs. 58.9%, respectively; P = 0.60). In the last intervention month, 87.3% vs. 51.8% achieved optimal adherence [risk ratio (RR): 1.7, 95% confidence interval (CI): 1.3 to 2.2] and mean adherence was 96.2% vs. 89.1% (P = 0.003). Among preintervention suboptimal adherers, 78.3% vs. 33.3% (RR: 2.4, CI: 1.2 to 4.5) achieved optimal adherence and mean adherence was 93.3% vs. 84.7% (P = 0.039). Proportions were 92.5% and 62.9% among optimal adherers, respectively (RR: 1.5, CI: 1.1 to 1.9) and mean adherence was 97.8% vs. 91.7% (P = 0.028). Postintervention clinical outcomes were not significant. CONCLUSIONS Real-time reminders significantly improved ART adherence in this population. This approach seems promising for managing HIV and other chronic diseases and warrants further investigation and adaptation in other settings.

Title: Humans and great apes share a large frontal cortex Content: Some of the outstanding cognitive capabilities of humans are commonly attributed to a disproportionate enlargement of the human frontal lobe during evolution. This claim is based primarily on comparisons between the brains of humans and of other primates, to the exclusion of most great apes. We compared the relative size of the frontal cortices in living specimens of several primate species, including all extant hominoids, using magnetic resonance imaging. Human frontal cortices were not disproportionately large in comparison to those of the great apes. We suggest that the special cognitive abilities attributed to a frontal advantage may be due to differences in individual cortical areas and to a richer interconnectivity, none of which required an increase in the overall relative size of the frontal lobe during hominid evolution.

Title: Training toddlers seated on mobile robots to drive indoors amidst obstacles Content: The goal of this research is to train children seated on mobile robots to purposefully and safely drive indoors. Our previous studies show that in about six weeks of training, infants can learn to drive directly to a goal using conventional joysticks. However, they are unable to acquire the advanced skill to avoid obstacles while driving. This limits mobility impaired children from exploring their home environment safely, which in turn impacts their cognitive and social developments in the important early years. In this paper, we describe results where toddlers are trained to drive a robot within an obstacle course. Using algorithms based on artificial potential fields to avoid obstacles, we create force field on the joystick that trains them to navigate while avoiding obstacles. In this ‘assist-as-needed’ approach, if the child steers the mobile robot outside a force tunnel centered around the desired direction, the driver experiences a bias force on the hand. The results suggest that force-feedback joystick results in faster learning than with a conventional joystick.

Title: Alzheimer’s disease and NGF signaling Content: Age-related degeneration of basal forebrain cholinergic neurons (BFCNs) occurs early and contributes significantly to cognitive decline in Alzheimer’s disease (AD). Proper function and morphology of BFCNs depends on the supply of nerve growth factor (NGF) from the cortex and the hippocampus. A large number of experiments have shown that decreased supply of NGF at the level of BFCN cell bodies leads to loss of neuronal markers and shrinkage, mimicking what is observed in AD. The delivery of sufficient amounts of NGF signal to BFCN cell bodies depends on the effective participation of several factors including sufficient synthesis and release of NGF, adequate synthesis and expression of NGF receptors by BFCNs, normal signaling and retrograde transport of NGF-receptor complex, and finally effective induction of gene expression by NGF. In the past few years it has become clear that decreased amounts of NGF at the level of BFCN cell bodies is largely due to failed retrograde transport rather than decreased synthesis, binding or expression of NGF receptors in the BFCN terminals. We will discuss in vivo evidence supporting decreased retrograde transport of NGF in a mouse model with BFCN degeneration, and will attempt to match these findings with our studies in postmortem human AD brain. We will speculate about the possible mechanisms of failed NGF retrograde transport and its relationship to AD pathology.

Title: Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits. Content: Methionine is converted by the transmethylation/transsulfuration pathway to homocysteine which may exert atherogenic effects by several mechanisms, including lipid peroxidation. Therefore, the excessive dietary methionine may induce the development of atherosclerosis. To test this hypothesis, plasma and aortic thiobarbituric acid reactive substances (TBARS), as well as activities of aortic and erythrocyte superoxide dismutase (SOD), catalase and selenium-dependent glutathione peroxidase (GPX) were measured in rabbits fed a diet enriched with 0.3% methionine for 6 or 9 months. Histological examinations of aortas also were performed. Feeding rabbits a methionine-enriched diet for 6 or 9 months resulted in significant increases in plasma and aortic TBARS levels and aortic antioxidant enzyme activities. However, a decrease in plasma antioxidant activity (AOA) was observed. In erythrocytes, SOD activity increased, catalase remained normal and GPX decreased in the treated animals. Histological examination of aortas showed typical atherosclerotic changes, such as intimal thickening, deposition of cholesterol, and calcification in methionine-fed rabbits. These results confirm that high-methionine diet may induce atherosclerosis in rabbits and indicate disturbances in lipid peroxidation and antioxidant processes as possible mechanisms of its atherogenic influence.

Title: Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells. Content: Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner. The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period. However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells. This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.

Title: Vegetarian diet improves insulin resistance and oxidative stress markers more than conventional diet in subjects with Type 2 diabetes Content: AIMS The aim of this study was to compare the effects of calorie-restricted vegetarian and conventional diabetic diets alone and in combination with exercise on insulin resistance, visceral fat and oxidative stress markers in subjects with Type 2 diabetes. METHODS A 24-week, randomized, open, parallel design was used. Seventy-four patients with Type 2 diabetes were randomly assigned to either the experimental group (n = 37), which received a vegetarian diet, or the control group (n = 37), which received a conventional diabetic diet. Both diets were isocaloric, calorie restricted (-500 kcal/day). All meals during the study were provided. The second 12 weeks of the diet were combined with aerobic exercise. Participants were examined at baseline, 12 weeks and 24 weeks. Primary outcomes were: insulin sensitivity measured by hyperinsulinaemic isoglycaemic clamp; volume of visceral and subcutaneous fat measured by magnetic resonance imaging; and oxidative stress measured by thiobarbituric acid reactive substances. Analyses were by intention to treat. RESULTS Forty-three per cent of participants in the experimental group and 5% of participants in the control group reduced diabetes medication (P < 0.001). Body weight decreased more in the experimental group than in the control group [-6.2 kg (95% CI -6.6 to -5.3) vs. -3.2 kg (95% CI -3.7 to -2.5); interaction group × time P = 0.001]. An increase in insulin sensitivity was significantly greater in the experimental group than in the control group [30% (95% CI 24.5-39) vs. 20% (95% CI 14-25), P = 0.04]. A reduction in both visceral and subcutaneous fat was greater in the experimental group than in the control group (P = 0.007 and P = 0.02, respectively). Plasma adiponectin increased (P = 0.02) and leptin decreased (P = 0.02) in the experimental group, with no change in the control group. Vitamin C, superoxide dismutase and reduced glutathione increased in the experimental group (P = 0.002, P < 0.001 and P = 0.02, respectively). Differences between groups were greater after the addition of exercise training. Changes in insulin sensitivity and enzymatic oxidative stress markers correlated with changes in visceral fat. CONCLUSIONS A calorie-restricted vegetarian diet had greater capacity to improve insulin sensitivity compared with a conventional diabetic diet over 24 weeks. The greater loss of visceral fat and improvements in plasma concentrations of adipokines and oxidative stress markers with this diet may be responsible for the reduction of insulin resistance. The addition of exercise training further augmented the improved outcomes with the vegetarian diet.

Title: Rapid helper T-cell recovery above 200 × 106/l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation Content: The current study evaluates the role of quantitative measurement of peripheral lymphocyte subsets, especially CD4+ helper T-cell recovery, in predicting transplant outcomes including overall survival (OS) and non-relapse mortality (NRM) after allogeneic stem cell transplantation. A total of 69 allogeneic recipients were included with following diagnoses: acute myeloid leukemia 42, acute lymphoblastic leukemia 5, chronic myeloid leukemia 15, non-Hodgkin's lymphoma 5 and high-risk myelodysplastic syndrome 2. The peripheral lymphocyte subset counts (CD3+ T cells, CD3+4+ helper T cells, CD3+8+ cytotoxic T cells, CD19+ B cells, and CD56+ natural killer cells) were measured at 3, 6 and 12 months. The CD4+ helper T-cell reconstitution at 3 months was strongly correlated with OS (P<0.0001), NRM (P=0.0007), and opportunistic infections (P=0.0108) at the cutoff value of 200 × 106/l CD4+ helper T cells. Rapid CD4+ helper T-cell recovery was also associated with a higher CD4+ helper T-cell transplant dose (P=0.006) and donor type (P<0.001). An early CD4+ helper T-cell recovery at 3 months correlated with a subsequent faster helper T-cell recovery until 12 months, yet not with B-cell recovery. In a multivariate analysis, rapid recovery of CD4+ helper T cells at 3 months was a favorable prognostic factor together with higher CD34+ cell transplant dose in terms of OS (P=0.001) and NRM (P=0.005).

Title: Vegetarian vs. conventional diabetic diet – A 1-year follow-up Content: Abstract Objective Our previous 6-month, randomized study demonstrated the beneficial effect of a vegetarian (V) compared to a conventional diet (C) with similar caloric restriction on cardiovascular risk factors for patients with type 2 diabetes (T2D), namely increased insulin sensitivity, reduced body weight, reduced volume of visceral and subcutaneous fat, decreased LDL-cholesterol and improved oxidative stress markers and chosen adipokines. We conducted post-trial monitoring to determine whether the improved outcomes persisted 1 year after the end of the study. Methods 62 subjects with T2D who completed the study were asked to come for a 1-year follow-up to measure weight, waist circumference, HbA1c and blood lipids. No attempts were made to maintain their previously assigned diets. Results 44 patients (71%) attended the post-trial monitoring. Hypoglycemic agents were increased by 14% in V and by 26% in C; insulin therapy was introduced in 5% in V and in 13% in C one year after the end of the intervention. Neither weight nor waist circumference changed significantly in either group. HbA1c increased ( p ≤ 0.05) similarly in both groups (+0.49 ± 1.04% in V vs. +0.42 ± 0.8% in C). Blood lipids did not change in either group. Conclusion One year after the end of the intervention, the positive effects of a vegetarian diet on cardiovascular risk factors compared to a conventional diet were partially maintained.

Title: Exercise and the immune system: regulation, integration, and adaptation. Content: Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress. The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems. This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, beta-endorphin, and sex steroids. The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed. Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the immune system has a role is of importance. Accordingly, drawing on the experimental, clinical, and epidemiological literature, we address the interactions between exercise and infectious diseases as well as exercise and neoplasia within the context of both aging and nutrition.

Title: JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation Content: Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.

Title: DEVELOPMENT AND VALIDATION OF A MEASURE OF EMOTIONAL INTELLIGENCE Content: This series of studies describes the development of a measure of emotional intelligence based on the model of emotional intelligence developed by Salovey and Mayer [Salovey, P. & Mayer, J. D. (1990). Emotional intelligence. Imagination, Cognition and Personality, 9, 185–211.]. A pool of 62 items represented the different dimensions of the model. A factor analysis of the responses of 346 participants suggested the creation of a 33-item scale. Additional studies showed the 33-item measure to have good internal consistency and testretest reliability. Validation studies showed that scores on the 33-item measure 1. (a) correlated with eight of nine theoretically related constructs, including alexithymia, attention to feelings, clarity of feelings, mood repair, optimism and impulse control; 2. (b) predicted first-year college grades; 3. (c) were significantly higher for therapists than for therapy clients or for prisoners; 4. (d) were significantly higher for females than males, consistent with prior findings in studies of emotional skills; 5. (e) were not related to cognitive ability and 6. (f) were associated with the openness to experience trait of the big five personality dimensions.

Title: Increased growth after long-term oral 1alpha,25-vitamin D3 in childhood renal osteodystrophy. Content: We evaluated oral 1,25-vitamin D3 for as long as 26 months in six prepubescent children with renal osteodystrophy previously treated with vitamin D2. Therapy was given at 14 to 41 ng per kilogram per day to correct hypocalcemia and reverse bone disease. Serum levels of 1,25-vitamin D3 were initially reduced at 15 +/- 5 pg per milliliter (mean +/- S.E.M.) and after treatment rose to 54 +/- 13. Serum calcium rose from 7.5 +/- 1.6 mg per deciliter (mean +/- S.D.) to 9.8 +/- 0.6 after one month (P less than 0.02). Alkaline phosphatase activity fell from 536 +/- 298 to 208 +/- 91 IU per liter after 12 months (P less than 0.05). Serum immunoreactive parathyroid levels fell from 900 +/- 562 microliter eq per milliliter 411 +/- 377. Healing of rickets and subperiosteal erosions was found. Remineralization of bone was demonstrated by the photon absorption technic. In four patients growth velocity, evaluated for 12 months before and after therapy, increased from 2.6 +/- 0.8 to 8.0 +/- 3.2 cm per year. Growth velocity per year increased from less than third percentile in each to the 10th to 97th percentile after therapy. Height increment ranged from 27 to 113 per cent of that expected for change in chronologic age and 40 to 114 per cent expected for change in bone age after therapy. This trial demonstrates that oral 1,25-vitamin D3 can reverse renal bone disease and increase growth in uremic children.

Title: Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer's prone mice. Content: We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Title: Incidence of childhood distal forearm fractures over 30 years: a population-based study. Content: CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth. Changes in physical activity or diet may therefore influence risk of forearm fracture. OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years. DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001. MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods. RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001. Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001). The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls. CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present. Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase.

Title: Biofeedback and relaxation in the treatment of migraine headaches: comparative effectiveness and physiological correlates. Content: Twenty-seven migraine headache patients were divided into three equal groups which received thermal biofeedback, frontalis EMG biofeedback, or relaxation training. Training was given under "massed" practice conditions (nine sessions per week) and consisted of 18 training sessions and six test-generalisation sessions. While improvements in headaches were observed in all groups, the best improvements took place in the thermal biofeedback group, which had almost complete elimination of migraine attacks by the end of training, and maintained that performance as long as six months after training. Examination of the patterns of skin temperature and EMG changes in the three groups over the course of training also points to a relationship between skin temperature control and reduction in migraine headache symptomatology, and suggests that this relationship is worthy of further investigation.

Title: Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. Content: Adult neurogenesis has been shown to be regulated by a multitude of extracellular cues, including hormones, growth factors, and neurotransmitters. The cholinergic system of the basal forebrain is one of the key transmitter systems for learning and memory. Because adult neurogenesis has been implicated in cognitive performance, the present work aims at defining the role of cholinergic input for adult neurogenesis by using an immunotoxic lesion approach. The immunotoxin 192IgG-saporin was infused into the lateral ventricle of adult rats to selectively lesion cholinergic neurons of the cholinergic basal forebrain (CBF), which project to the two main regions of adult neurogenesis: the dentate gyrus and the olfactory bulb. Five weeks after lesioning, neurogenesis, defined by the number of cells colocalized for bromodeoxyuridine (BrdU) and the neuronal nuclei marker NeuN, declined significantly in the granule cell layers of the dentate gyrus and olfactory bulb. Furthermore, immunotoxic lesions to the CBF led to increased numbers of apoptotic cells specifically in the subgranular zone, the progenitor region of the dentate gyrus, and within the periglomerular layer of the olfactory bulb. We propose that the cholinergic system plays a survival-promoting role for neuronal progenitors and immature neurons within regions of adult neurogenesis, similar to effects observed previously during brain development. As a working hypothesis, neuronal loss within the CBF system leads not only to cognitive deficits but may also alter on a cellular level the functionality of the dentate gyrus, which in turn may aggravate cognitive deficits.

Title: Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease. Content: The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa). As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system. We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model. We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.

Title: The Effect of Submaximal Exercise Preceded by Single Whole-Body Cryotherapy on the Markers of Oxidative Stress and Inflammation in Blood of Volleyball Players Content: The aim of the study was to determine the effect of single whole-body cryotherapy (WBC) session applied prior to submaximal exercise on the activity of antioxidant enzymes, the concentration of lipid peroxidation products, total oxidative status, and the level of cytokines in blood of volleyball players. The study group consisted of 18 male professional volleyball players, who were subjected to extremely cold air (-130°C) prior to exercise performed on cycloergometer. Blood samples were taken five times: before WBC, after WBC procedure, after exercise preceded by cryotherapy (WBC exercise), and before and after exercise without WBC (control exercise). The activity of catalase statistically significantly increased after control exercise. Moreover, the activity of catalase and superoxide dismutase was lower after WBC exercise than after control exercise (P < 0.001). After WBC exercise, the level of IL-6 and IL-1β was also lower (P < 0.001) than after control exercise. The obtained results may suggest that cryotherapy prior to exercise may have some antioxidant and anti-inflammatory properties. The relations between the level of studied oxidative stress and inflammatory markers may testify to the contribution of reactive oxygen species in cytokines release into the blood system in response to exercise and WBC.

Title: Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats Content: The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ₁₋₄₂ and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease.

Title: Pharmacist participation on physician rounds and adverse drug events in the intensive care unit. Content: CONTEXT Pharmacist review of medication orders in the intensive care unit (ICU) has been shown to prevent errors, and pharmacist consultation has reduced drug costs. However, whether pharmacist participation in the ICU at the time of drug prescribing reduces adverse events has not been studied. OBJECTIVE To measure the effect of pharmacist participation on medical rounds in the ICU on the rate of preventable adverse drug events (ADEs) caused by ordering errors. DESIGN Before-after comparison between phase 1 (baseline) and phase 2 (after intervention implemented) and phase 2 comparison with a control unit that did not receive the intervention. SETTING A medical ICU (study unit) and a coronary care unit (control unit) in a large urban teaching hospital. PATIENTS Seventy-five patients randomly selected from each of 3 groups: all admissions to the study unit from February 1, 1993, through July 31, 1993 (baseline) and all admissions to the study unit (postintervention) and control unit from October 1, 1994, through July 7, 1995. In addition, 50 patients were selected at random from the control unit during the baseline period. INTERVENTION A senior pharmacist made rounds with the ICU team and remained in the ICU for consultation in the morning, and was available on call throughout the day. MAIN OUTCOME MEASURES Preventable ADEs due to ordering (prescribing) errors and the number, type, and acceptance of interventions made by the pharmacist. Preventable ADEs were identified by review of medical records of the randomly selected patients during both preintervention and postintervention phases. Pharmacists recorded all recommendations, which were then analyzed by type and acceptance. RESULTS The rate of preventable ordering ADEs decreased by 66% from 10.4 per 1000 patient-days (95% confidence interval [CI], 7-14) before the intervention to 3.5 (95% CI, 1-5; P<.001) after the intervention. In the control unit, the rate was essentially unchanged during the same time periods: 10.9 (95% CI, 6-16) and 12.4 (95% CI, 8-17) per 1000 patient-days. The pharmacist made 366 recommendations related to drug ordering, of which 362 (99%) were accepted by physicians. CONCLUSIONS The presence of a pharmacist on rounds as a full member of the patient care team in a medical ICU was associated with a substantially lower rate of ADEs caused by prescribing errors. Nearly all the changes were readily accepted by physicians.