Chronic diseases are first associated with the degradation and artificialization of food matrices rather than with food composition: calorie quality matters more than calorie quantity.

PURPOSE: For decades, it has been customary to relate human health to the nutritional composition of foods, and from there was born food composition databases, composition labelling scores and the recommendation to eat varied foods. However, individuals can fully address their nutritional needs and become chronically ill. The nutrient balance of a food is only a small part of its overall health potential. In this paper, we discussed the proof of concept that the increased risk of chronic diseases worldwide is primarily associated with the degradation and artificialization of food matrices, rather than only their nutrient contents, based on the assumption that "food matrices govern the metabolic fate of nutrients". METHODS: An empirico-inductive proof of concept research design has been used, based on scientific data linking the degree of food processing, food matrices and human health, notably on the glycaemic index, nutrient bioavailability, satiety potential, and synergistic effects. RESULTS: We postulate that if the nutrient content is insufficient to fully characterize the diet-global health relationship, one other dimensions is necessary, i.e., the food matrix through the degree of processing. Both matrix and nutrient composition dimensions have been included under the new concept of the 3V index for Real (Vrai), Vegetal (Végétal), and Varied (Varié) foods. The Real metric, reflecting the integrity of the initial food matrix, is the most important, followed by the Vegetal (nutrient origin) and the Varied ("composition" effect) metrics. CONCLUSION: Concerning their effects on health, food matrix comes first, and then nutrient composition, and calorie quality matters more than calorie quantity.

How to protect both health and food system sustainability? A holistic 'global health'-based approach via the 3V rule proposal.

OBJECTIVE: To define a generic diet to protect human health and food system sustainability based on three dimensions: animal:plant ratio, degree of food processing and food diversity. DESIGN/SETTING: The percentages of maximum animal and ultra-processed energy content were evaluated from scientific papers (Web of Science database) and reports from international scientific institutions. Then, a weekly French standard diet, including these percentages and food diversity (≥42 different foods), was designed to calculate adequacy to nutritional needs. RESULTS: Based on traditional and scientifically based healthy diets, and on foresight scenarios for sustainable diets at horizon 2050, a median daily animal energy content intake of 15 % was found to be protective towards both human health and environment. Based on epidemiological studies associating ultra-processed energy consumption with increased overweight/obesity risk, a precautionary threshold of approximately 15 % ultra-processed energy content was observed. The French diet allows addressing all nutritional needs and other nutritional indicators such as maximum salt and simple sugar consumption, α-linolenic acid:linoleic acid ratio and essential amino acids. This diet was named the '3V rule' for Végétal (plant), Vrai (real) and Varié (varied, if possible organic, local and seasonal). This generic diet can be adapted according to regional traditions and environmental characteristics. Excluding only one dimension of it would threaten both health and food system sustainability. CONCLUSIONS: Tending towards a 3V-based diet, while respecting local constraints, should allow preserving human health, environment (greenhouse gas emissions, pollution, deforestation, etc.), small farmers, animal welfare and biodiversity, culinary traditions and socioeconomics (including an alleviation of public health cost).

Impact of anthocyanin-rich whole fruit consumption on exercise-induced oxidative stress and inflammation: a systematic review and meta-analysis.

CONTEXT: Supplementing with fruits high in anthocyanins to reduce exercise-induced oxidative stress and inflammation has produced mixed results. OBJECTIVE: This systematic review and meta-analysis aims to discuss the impact of whole fruits high in anthocyanins, including processing methods and the type and amount of fruit, on inflammation and oxidative stress. DATA SOURCES: PICOS reporting guidelines and a customized coding scheme were used to search 5 databases (SPORTDiscus, Science Direct, Web of Science [BIOSIS], Medline [Pubmed], and the Cochrane Collaboration) with additional cross-referencing selection. DATA EXTRACTION: A random-effects meta-analysis was used to measure effects of the fruit supplements with 3 statistics; the QTotal value based on a χ2 distribution, τ2 value, and I2 value were used to determine homogeneity of variances on 22 studies (out of 807). Outliers were identified using a relative residual value. RESULTS: A small significant negative summary effect across the sum of all inflammatory marker outcomes (P < 0.001) and a moderate negative effect for the sum of all oxidative stress marker outcomes (P = 0.036) were found. Moderator analyses did not reveal significant (P > 0.05) differences between subgrouping variables. CONCLUSIONS: Results indicate that consumption of whole fruit high in anthocyanins can be beneficial for reducing inflammation and oxidative stress.

The effect of physical activity interventions on youth with autism spectrum disorder: A meta-analysis.

The purpose of this meta-analysis was to examine the effect of physical activity interventions on youth diagnosed with autism spectrum disorder. Standard meta-analytical procedures determining inclusion criteria, literature searches in electronic databases, coding procedures, and statistical methods were used to identify and synthesize articles retained for analysis. Hedge's g (1988) was utilized to interpret effect sizes and quantify research findings. Moderator and outcome variables were assessed using coding procedures. A total of 29 studies with 30 independent samples (N = 1009) were utilized in this analysis. Results from meta-analyses indicated an overall moderate effect (g = 0.62). Several outcomes indicated moderate-to-large effects (g ≥ 0.5); specifically, moderate to large positive effects were revealed for participants exposed to interventions targeting the development of manipulative skills, locomotor skills, skill-related fitness, social functioning, and muscular strength and endurance. Moderator analyses were conducted to explain variance between groups; environment was the only subgrouping variable (intervention characteristics) to produce a significant difference (QB = 5.67, P < 0.05) between moderators. While no significant differences were found between other moderators, several trends were apparent within groups in which experimental groups outperformed control groups. Autism Res 2018, 11: 818-833. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Results of the meta-analysis-a method for synthesizing research-showed physical activity interventions to have a moderate or large effect on a variety of outcomes, including for the development of manipulative skills, locomotor skills, skill-related fitness, social functioning, and muscular strength and endurance. The authors conclude that physical activity's standing as an evidence-based strategy for youth with ASD is reinforced.

Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

Primed Low Frequency Transcranial Magnetic Stimulation Effects on Smoking Cue-Induced Craving

Abstract Repetitive Transcranial Magnetic Stimulation (rTMS) has shown the potential to reduce craving to smoke and the amount of cigarettes smoked. When low frequency rTMS is preceded by a priming session the cortical inhibitory effects are enhanced provoking a lasting performance. In this study we evaluate the brain regional activations and self-reported mood effect of one session of primed low frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) in response to smoking- related cues during temporary nicotine abstinence. Ten moderate nicotine dependent subjects participated in a crossover design, comparing a single session of active versus sham stimulation. After treatment, a functional Magnetic Resonance Imaging (fMRI) study was performed in all participants while completing a block-design cue reactivity paradigm. Our measures also included self-reported craving and mood score before and after every rTMS session. The number of daily smoked cigarette in a one week around period was also recorded. The results show that self-reported cravings were lower following the active stimulation; significant activation was found in areas associated with emotion control (anterior cingulate gyrus and subgenual area) and episodic memory (precuneus and posterior cingulate gyrus) as a result of the stimulation. No significant difference was found in the number of cigarettes smoked and mood scores between the sham and active condition during the one week period records. This study confirms the previous evidence that rTMS can reduce cigarette cravings and provides evidence of the neural mechanism of action that take place in order to achieve these neuromodulation effects.

Resumen La Estimulación Magnética Transcranea repetitiva (EMTr) ha demostrado ser capaz de reducir el deseo por fumar y el consume de cigarrillos. Cuando una baja frecuencia de EMTr es precedida por una sesión de primado, los efectos inhibidores de la corteza cerebral aumentan y también su duración. En este estudio se evalúan las activaciones regionales del cerebro y el efecto en el estado de ánimo auto-reportado de una sesión de EMTr de baja frecuencia primada sobre la corteza dorsolateral prefrontal izquierda en respuesta a estímulos visuales relacionados con el tabaco durante una abstinencia temporal a la nicotina. Diez sujetos con dependencia moderada a la nicotina participaron en un experimento de diseño cruzado, comparando una sola sesión de estimulación activa contra una simulada. Después del tratamiento, se llevó a cabo un estudio de Imagen por Resonancia Magnética funcional (IRMf) en todos los participantes mientras llevaban a cabo un paradigma visual de bloques. Las mediciones incluyeron una puntuación auto-reportada del deseo por fumar y estado de ánimo antes y después de cada sesión de EMTr. Los resultados muestran que el deseo por fumar era menor luego de una sesión activa de estimulación; se encontraron activaciones significativas en áreas asociadas con el control emocional (giro del cíngulo anterior) y memoria episódica (precúneo y giro del cíngulo posterior) como resultado de la estimulación. No se encontró diferencia significativa en el número de cigarros fumados entre la sesión activa y simulado durante el periodo evaluado. Tampoco se registraron diferencias en las evaluaciones de estado de ánimo luego del tratamiento. Este estudio confirma la evidencia previa de que la EMTr puede reducir el deseo por fumar y proporciona evidencia del mecanismo de acción neural que se lleva a cabo para lograr estos efectos neuromoduladores.

The Healthy Core Metabolism: A New Paradigm for Primary Preventive Nutrition.

Research in preventive nutrition aims at elucidating mechanism by which our diet helps us to remain in good health through optimal physiological functions. However, despite decades of accumulated data in human nutrition and regular subsequent nutritional recommendations, obesity and type 2 diabetes epidemics continue to progress worldwide each year leading to a regular decrease of the Healthy Life Years, notably in Western countries. Such a paradox may be explained by the Nutrition Transition, the extreme application of the reductionist paradigm in nutrition research, the lack of nutritional education and a too strong focus on curative nutrition in at risk/ill subjects. In this position paper, we hypothesized that researchers should focus more on healthy subjects, from birth until maturity. Rather than exploring what differentiates healthy and at risk/ill subjects, we propose to thoroughly study what characterizes a healthy state and its underlying metabolism. We define it as the Healthy Core Metabolism which remains stable whatever energy inputs (diets) and outputs (exercise), genetic background and external/internal stress, e.g., temporary illnesses. As a basis for Healthy Core Metabolism investigation, we observed that main physiological and ubiquitous functions of human organism, i.e., the neuro-vasculo-sarco-osteoporotic system, tend to follow a concave curve with common phases of growth, optimum, and decline. Finally, we hypothesized that true primary preventive nutrition should focus on the growth phase to reach the maximum capital of a given physiological function so that - whatever the further decline -, Healthy Life Years may approach or coincide with theoretical Life Expectancy.

Cannabinoids suppress acute and anticipatory nausea in preclinical rat models of conditioned gaping.

The sensation of nausea is one of the most debilitating human experiences. Current antiemetic therapies are effective in reducing vomiting, but are less effective in reducing acute and delayed nausea and are completely ineffective in reducing anticipatory nausea. Recent preclinical evidence using a selective rat model of nausea (conditioned gaping reactions) has revealed that cannabinoids have great promise as treatments for nausea and that their antinausea effects may be mediated by the interoceptive insular cortex.

The search for a new paradigm to study micronutrient and phytochemical bioavailability: from reductionism to holism.

The study of micronutrient and phytochemical (MaP, i.e., non-energy nutrients) bioavailability has been mainly studied through a reductionist and pharmacological approach. This has led to associate one health effect to one MaP. However, human interventional studies have given conflicting and disappointing results about MaP supplementation. This is because the health effect is the result of the synergetic action of numerous MaPs supplied by foods and/or diets at nutritional doses. A food is not a drug. Therefore, there is a need for more holistic approach to study MaP bioavailability, then their health effect to achieve general recommendations. This paper aims to hypothesize for such a paradigm shift in this topic and to lay new foundations for research in MaP bioavailability.

Suppression of lithium chloride-induced conditioned gaping (a model of nausea-induced behaviour) in rats (using the taste reactivity test) with metoclopramide is enhanced by cannabidiolic acid.

We aimed to determine the potential of various doses of metoclopramide (MCP, a dopamine antagonist) to reduce lithium chloride (LiCl)-induced conditioned gaping (a nausea-induced behaviour) in rats, using the taste reactivity test. We then evaluated whether an ineffective low dose of cannabidiolic acid (CBDA, 0.1 µg/kg, Rock and Parker, 2013), the potent acidic precursor of cannabidiol (CBD, a non-psychoactive component of cannabis) could enhance the anti-nausea effects of an ineffective low dose of MCP. MCP (3.0 mg/kg) reduced conditioned gaping responses. Coadministration of ineffective doses of MCP (0.3 mg/kg) and CBDA (0.1 µg/kg) enhanced the suppression of conditioned gaping, over that of either drug alone, without interfering with conditioned taste avoidance. MCP dose-dependently reduced nausea-induced conditioned gaping in rats. As well, the suppression of conditioned gaping was enhanced when ineffective doses of MCP and CBDA were coadministered. These data suggest that CBDA could be a powerful adjunct treatment to anti-emetic regimens for chemotherapy-induced nausea.

Anandamide transport inhibition by ARN272 attenuates nausea-induced behaviour in rats, and vomiting in shrews (Suncus murinus).

BACKGROUND AND PURPOSE: To understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, fatty acid amide hydrolase-1-like anandamide transporter, to provide behavioural support for anandamide cellular reuptake as a facilitated transport process. EXPERIMENTAL APPROACH: The systemic administration of the anandamide transport inhibitor ARN272 ([(4-(5-(4-hydroxy-phenyl)-3,4-diaza-bicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-2-ylamino)-phenyl)-phenylamino-methanone]) was used to evaluate the prevention of LiCl-induced nausea-induced behaviour (conditioned gaping) in rats, and LiCl-induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of cannabinoid 1 (CB1) receptors with the systemic co-administration of SR141716. KEY RESULTS: The systemic administration of ARN272 produced a dose-dependent suppression of nausea-induced conditioned gaping in rats, and produced a dose-dependent reduction of vomiting in shrews. The systemic co-administration of SR141716 with ARN272 (at 3.0 mg·kg(-1)) in rats produced a complete reversal of ARN272-suppressed gaping at 1.0 mg·kg(-1). SR141716 alone did not differ from the vehicle solution. CONCLUSIONS AND IMPLICATIONS: These results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB1 receptors and as such produces a type of indirect agonism to regulate toxin-induced nausea and vomiting. The results also provide behavioural evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.

2-arachidonoylglycerol interferes with lithium-induced vomiting in the house musk shrew, Suncus murinus.

The role of the endocannabinoid system in vomiting has been previously studied using several animal species. These investigations have clearly demonstrated an anti-emetic role for the eCB, anandamide, in these animal models; however, research concerning the role of 2-arhachidonoylglycerol (2AG) has been less clear. The aim of the present study was to assess the effects of exogenous 2AG administration in the house musk shrew, Suncus murinus. In Experiment 1, shrews were injected with vehicle or 2AG (1, 2, 5, 10 mg/kg) 15 min prior to behavioral testing in which the frequency of vomiting episodes was observed. In Experiment 2, shrews were pre-treated with 2AG (2, 5 mg/kg) prior to being administered the emetic drug, lithium chloride (LiCl). It was found that 2AG alone did not induce emesis, but interfered with vomiting in response to LiCl administration. The anti-emetic effects of 2AG in Suncus murinus do not appear to be mediated by CB1 receptors, as concomitant pretreatment with the CB1 receptor antagonist, SR141716, did not reverse the suppressive effects of 2AG. These results confirm that manipulations that increase levels of 2AG exert anti-emetic effects in the house musk shrew.

Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus.

BACKGROUND AND PURPOSE: We evaluated the anti-emetic and anti-nausea properties of the acid precursor of Δ(9) -tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), and determined its mechanism of action in these animal models. EXPERIMENTAL APPROACH: We investigated the effect of THCA on lithium chloride- (LiCl) induced conditioned gaping (nausea-induced behaviour) to a flavour, and context (a model of anticipatory nausea) in rats, and on LiCl-induced vomiting in Suncus murinus. Furthermore, we investigated THCA's ability to induce hypothermia and suppress locomotion [rodent tasks to assess cannabinoid1 (CB1 ) receptor agonist-like activity], and measured plasma and brain THCA and THC levels. We also determined whether THCA's effect could be blocked by pretreatment with SR141716 (SR, a CB1 receptor antagonist). KEY RESULTS: In rats, THCA (0.05 and/or 0.5 mg·kg(-1) ) suppressed LiCl-induced conditioned gaping to a flavour and context; the latter effect blocked by the CB1 receptor antagonist, SR, but not by the 5-hydroxytryptamine-1A receptor antagonist, WAY100635. In S. murinus, THCA (0.05 and 0.5 mg·kg(-1) ) reduced LiCl-induced vomiting, an effect that was reversed with SR. A comparatively low dose of THC (0.05 mg·kg(-1) ) did not suppress conditioned gaping to a LiCl-paired flavour or context. THCA did not induce hypothermia or reduce locomotion, indicating non-CB1 agonist-like effects. THCA, but not THC was detected in plasma samples. CONCLUSIONS AND IMPLICATIONS: THCA potently reduced conditioned gaping in rats and vomiting in S. murinus, effects that were blocked by SR. These data suggest that THCA may be a more potent alternative to THC in the treatment of nausea and vomiting.

Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats.

BACKGROUND AND PURPOSE: To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5-0.1 µg·kg⁻¹) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, ondansetron (OND). EXPERIMENTAL APPROACH: We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined. KEY RESULTS: CBDA (at doses as low as 0.5 µg·kg⁻¹) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 µg·kg⁻¹) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 µg·kg⁻¹) there was an enhancement in the suppression of LiCl-induced conditioned gaping. CONCLUSIONS AND IMPLICATIONS: CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients.

Physical activity interventions and depression in children and adolescents : a systematic review and meta-analysis.

CONTEXT: Evidence suggests chronic physical activity (PA) participation may be both protective against the onset of and beneficial for reducing depressive symptoms. OBJECTIVE: The aim of this article is to assess the impact of PA interventions on depression in children and adolescents using meta-analysis. DATA SOURCES: Published English language studies were located from manual and computerized searches of the following databases: PsycInfo, The Cochrane Database of Systematic Reviews and The Cochrane Central Register of Controlled Trials, Trials Register of Promoting Health Interventions (TRoPHI; EPPI Centre), Web of Science and MEDLINE. STUDY SELECTION: Studies meeting inclusion criteria (1) reported on interventions to promote or increase PA; (2) included children aged 5-11 years and/or adolescents aged 12-19 years; (3) reported on results using a quantitative measure of depression; (4) included a non-physical control or comparison group; and (5) were published in peer-reviewed journals written in English, up to and including May 2011 (when the search was conducted). DATA EXTRACTION: Studies were coded for methodological, participant and study characteristics. Comprehensive Meta-Analysis version-2 software was used to compute effect sizes, with subgroup analyses to identify moderating characteristics. Study quality was assessed using the Delphi technique. RESULTS: Nine studies were included (n = 581); most were school-based randomized controlled trials, randomized by individual. Studies used a variety of measurement tools to assess depressive symptoms. The summary treatment effect was small but significant (Hedges' g = -0.26, standard error = 0.09, 95% confidence intervals = -0.43, -0.08, p = 0.004). Subgroup analyses showed that methodological (e.g. studies with both education and PA intervention; those with a higher quality score; and less than 3 months in duration) and participant characteristics (e.g. single-gender studies; those targeting overweight or obese groups) contributed most to the reduction in depression. CONCLUSIONS: There was a small significant overall effect for PA on depression. More outcome-focused, high-quality trials are required to effectively inform the implementation of programmes to reduce depressive symptoms in children and adolescents.

Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation.

BACKGROUND AND PURPOSE: To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5-HT(1A) receptor activation in animal models. EXPERIMENTAL APPROACH: We investigated the effect of CBDA on (i) lithium chloride (LiCl)-induced conditioned gaping to a flavour (nausea-induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion-, LiCl- or cisplatin-induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5-HT(1A) receptor activation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and mouse whole brain CB(1) receptor activation by CP55940, using [³5S]GTPγS-binding assays. KEY RESULTS: In shrews, CBDA (0.1 and/or 0.5 mg·kg⁻¹ i.p.) reduced toxin- and motion-induced vomiting, and increased the onset latency of the first motion-induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg⁻¹ i.p.) suppressed LiCl- and context-induced conditioned gaping, effects that were blocked by the 5-HT(1A) receptor antagonist, WAY100635 (0.1 mg·kg⁻¹ i.p.), and, at 0.01 mg·kg⁻¹ i.p., enhanced saccharin palatability. CBDA-induced suppression of LiCl-induced conditioned gaping was unaffected by the CB1 receptor antagonist, SR141716A (1 mg·kg⁻¹ i.p.). In vitro, CBDA (0.1-100 nM) increased the E(max) of 8-OH-DPAT. CONCLUSIONS AND IMPLICATIONS: Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5-HT(1A) receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.

The anti-nausea effects of CB1 agonists are mediated by an action at the visceral insular cortex.

BACKGROUND AND PURPOSE: Conditioned gaping reactions reflect nausea-induced behaviour in rats. Cannabinoid 1 receptor (CB(1) ) agonists interfere with the establishment of nausea-induced conditioned gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB(1) receptors. EXPERIMENTAL APPROACH: We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB(1) agonist, CB13, on the establishment of LiCl-induced gaping in rats. We further evaluated the ability of HU-210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl-induced conditioned gaping and determined if this effect was mediated by CB(1) receptors. KEY RESULTS: Central, but not peripheral, CB13 suppressed LiCl-induced conditioned gaping. Central administration of the potent CB(1) agonist, HU-210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl-induced gaping reactions, but not LiCl-induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU-210 delivered to the VIC prevented LiCl-induced nausea, but not learning per se. The suppression of LiCl-induced conditioned gaping by HU-210 was mediated by CB(1) receptors because it was prevented by co-administration of CB(1) antagonist/inverse agonist, AM-251, into the VIC. A high dose of AM-251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions. CONCLUSIONS AND IMPLICATIONS: The nausea-relieving effects of CB(1) agonists, but not the nausea-inducing effects of CB(1) inverse agonists, are mediated, at least in part, by their action at the VIC in rats.

Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus.

BACKGROUND AND PURPOSE: To evaluate the hypothesis that activation of somatodendritic 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis. EXPERIMENTAL APPROACH: The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPγS binding in rat brainstem membranes. KEY RESULTS: CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg·kg(-1) , but not 40 mg·kg(-1) )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. CONCLUSIONS AND IMPLICATIONS: These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT(1A) autoreceptors in the DRN. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Sedentary behaviour interventions in young people: a meta-analysis.

BACKGROUND: There is increasing concern about the time young people spend in sedentary behaviour ('sitting time'), especially with the development of attractive home-based electronic entertainment. This may have deleterious health effects. PURPOSE: To ascertain, through a meta-analytic review, whether interventions targeted at reducing sedentary behaviours in young people are successful. METHOD: ERIC, MedLine, PsychInfo, SportDiscus and the Cochrane Library databases were searched up to 2010. Titles and abstracts of identified papers were examined against inclusion criteria. Included papers were coded by three researchers. RESULTS: 17 papers, including 17 independent samples (N=4976), met the inclusion criteria and were analysed. There was a small but significant effect in favour of sedentary behaviour reduction for intervention groups (Hedges' g = - 0.192; SE = 0.056; 95% CI = -0.303 to -0.082; p = 0.001). Moderator analyses produced no significant between-moderator results for any of the intervention or study characteristics, although trends were evident. CONCLUSION: Behaviour change interventions targeting reductions in sedentary behaviour have been shown to be successful, although effects are small. More needs to be known about how best to optimise intervention effects.

Elucidation of relationship between tumor size and survival in non-small-cell lung cancer patients can aid early decision making in clinical drug development.

Four non-small-cell lung cancer (NSCLC) registration trials were utilized to develop models linking survival to risk factors and changes in tumor size during treatment. The purpose was to leverage existing quantitative knowledge to facilitate future development of anti-NSCLC drugs. Eleven risk factors were screened using a Cox model. A mixed exponential decay and linear growth model was utilized for modeling tumor size. Survival times were described in a parametric model. Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size were consistent prognostic factors of survival. Tumor size was well described by the mixed model. The parametric survival model includes ECOG score, baseline tumor size, and week 8 tumor size change as predictors of survival duration. The change in tumor size at week 8 allows early assessment of the activity of an experimental regimen. The survival model and the tumor model will be beneficial for early screening of candidate drugs, simulating NSCLC trials, and optimizing trial designs.