Glycemic and Insulinemic Responses of Healthy Humans to a Nutrition Bar with or without Added Fibersym® RW, a Cross-Linked Phosphorylated RS4-Type Resistant Wheat Starch.

The current study compared postprandial glycemic and insulinemic responses to four nutrition bars containing two different doses of resistant starch type-4. Normoglycemic adults (n = 17) completed six treatments, consuming either 50 g or 30 g digestible carbohydrate as: dextrose beverages (DEX), control puffed wheat bars (PWB), or RS4 test bars (RS4). Glucose (mg/dL) and insulin (µIU/mL) were measured at baseline and 10, 20, 30, 60, 90, and 120 min. There was a main effect of dose and treatment on glucose incremental area under the curve (iAUC, ps < 0.001), such that RS4 (50 g: 941, 95% confidence interval (CI): 501, 1519; 30 g: 481, 95% CI: 186, 914) was lower than PWB (50 g: 1746, 95% CI: 1109, 2528; 30 g: 693, 95% CI: 331, 1188) and DEX (50 g: 1940, 95% CI: 1249, 2783; 30 g:1432, 95% CI: 883, 2114). There was a main effect of dose and treatment on insulin iAUC (ps < 0.001), such that RS4 (50 g: 1993, 95% CI: 1347, 2764; 30 g: 943, 95% CI: 519, 1493) was lower than PWB (50 g: 3501, 95% CI: 2625, 4502; 30 g: 1789, 95% CI: 1193, 256) and DEX (50 g: 3143, 95% CI: 2317, 4095; 30 g: 2184, 95% CI: 1519, 2970). Results demonstrate significantly lower glycemic and insulinemic responses following consumption of nutrition bars containing RS4, regardless of dose, when compared with puffed wheat bars and dextrose.

Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system.

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 µg/cm2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 µg/cm2 (based on 331 sensitisers) and an HPC DST of 1.0 µg/cm2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner.

Effects of short-term sugary beverage consumption on glucose control and cardiovascular disease risk factors: A randomized controlled parallel-arm trial.

OBJECTIVE: To determine differences in glucose control and cardiovascular disease risk factors following three weeks of added soda, 100% fruit juice, or water in apparently healthy, college-aged adults. PARTICIPANTS: Thirty-six adults (18 males; 18 females) between the ages of 18 and 30 years of age. METHODS: A 3-arm randomized controlled parallel-arm trial; at baseline and after three weeks consuming the assigned beverage, participants completed glucose control and cardiovascular disease risk factor assessments. RESULTS: There were no significant differences between beverage conditions for glucose control or cardiovascular disease risk factors (ps > 0.05). There were no significant changes in caloric intake or differences in caloric intake between conditions, p = 0.17. CONCLUSIONS: In healthy, young adults, under free-living conditions, short-term consumption of two commercially packaged servings of SBs did not lead to significant glucose control or cardiovascular disease risk factor changes, indicating potential compensation and/or resilience to negative short-term effects.

Arterial stiffness is associated with cardiovascular and cancer mortality in cancer patients: Insight from NHANESIII.

BACKGROUND: Cancer survivors are at greater risk for cardiovascular disease (CVD) than second malignancy, resulting in a decreased quality of life and increased cost of care. Additional knowledge of CVD prevention by identifying possible risk factors has clinical relevance. Our main objective was to determine the relevance of a clinical index of arterial stiffness, pulse pressure, in predicting CVD mortality in cancer patients, with a second objective to examine its relationship with cancer mortality. METHODS: We retrospectively analyzed 781 cancer patients from Third National Health and Nutrition Examination Survey and Linked Mortality File, including demographic, anthropometric, blood pressure, and cause of death. Kaplan-Meier survival curve and Cox hazard regression analyses were performed to assess the relationship between pulse pressure and cardiovascular, cancer, and all-cause mortality. RESULTS: During a mean follow-up time of 8.1 years, 603 deaths, 257 cancer and 151 CVD, occurred. In unadjusted models, the risk of CVD, cancer, and all-cause mortality were 3.8-fold, 5.3-fold, and 1.6-fold higher, respectively, for pulse pressure ≥70 â€‹mmHg compared to <50 â€‹mmHg. Adjusted analyses revealed a higher CVD mortality in cancer patients <65 years with a pulse pressure 60-70 â€‹mmHg (adjusted hazard ratio, 5.26; 95%CI, 1.12-24.78) when compared to pulse pressure of <50 â€‹mmHg. Pulse pressure was not associated with risk of all-cause, CVD, or cancer in those ≥65 years. CONCLUSION: Pulse pressure, an index of arterial stiffness, is predictive of CVD mortality in cancer patients. Our findings support non-invasive office-setting measurements of arterial stiffness to identify high risk patients.

The relationship between dietary fat intake, impulsive choice, and metabolic health.

Unhealthful foods are convenient, ubiquitous, and inexpensive. Overconsumption of unhealthful foods can result in disease states such as obesity and Type 2 diabetes. In addition to the physiological consequences of unhealthful foods, research in rats has shown that diets high in processed fat and sugar induce impulsive choice behavior. Research in humans has demonstrated a link between metabolic health and impulsive choice, but most investigations have not included diet. We investigated how dietary fat intake interacts with body fat percentage, fasting glucose, insulin response, and systemic inflammation levels to predict impulsive choices in humans. Participants were split into either Control (<35% calories from fat) or High-Fat (≥40% calories from fat) groups based on self-reported dietary intake, completed an impulsive choice task, and underwent testing to determine their body fat, glucose, insulin response, and inflammation levels. High-fat diets were not predictive of impulsive choices, but added sugar was predictive. Body fat percentage was associated with impulsive choices only in the group who reported consuming high-fat diets. In addition, fasting glucose was associated with impulsive choices in the control group. Therefore, metabolic health and dietary fat intake interacted to predict impulsive choices. These findings indicate that knowledge of dietary patterns coupled with metabolic health markers may help us better understand impulsive choices, thereby improving our ability to target individuals who could benefit from interventions to reduce impulsive choice behavior, with the goal of promoting more self-controlled food choices.

Health behaviors and patient-practitioner communication in cancer patients and the general population: an analysis of the National Health and Nutrition Examination Survey (NHANES) 2005-2014.

PURPOSE: The purpose of the study was to investigate the prevalence of poor health behaviors (low dietary quality, low physical activity (PA), and high body mass index (BMI)) in cancer patients and the general population and its relationship with receipt of patient-physician recommendations. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2005-2014 to compare 1846 patients with a history of cancer to 16,641 with no cancer history. BMI was measured during physical exam. Dietary quality and PA were obtained from a questionnaire, along with receipt of physician recommendations for each behavior. RESULTS: Cancer patients had dietary quality that "needs improvement," were not meeting PA recommendations, and were overweight. Compared to the general population, dietary quality (54 vs. 54, p = .80), prevalence of physical inactivity (34% vs. 31%, p = .01), and BMI (28 vs. 28, p < .01) were similar. Among cancer patients, prevalence of physician recommendations to improve dietary quality (33.5%), increase PA or exercise (47.7%), and lose or control weight (32.1%) were low. Physicians recommended health behavior change to cancer patients more frequently than the general population (p < .01). Overweight and physically inactive cancer patients were more likely to receive physician recommendations (ps < .01). Physician recommendations were not associated with dietary quality (p = .65). CONCLUSIONS: Prevalence of poor diet, physical inactivity, and obesity is high in both populations with less than 50% of patients receiving physician health behavior recommendations. These findings underscore the need for increased frequency and efficacy of patient-physician health behavior recommendations, especially in cancer patients, to improve patient outcomes.

Anticancer Therapy-Related Increases in Arterial Stiffness: A Systematic Review and Meta-Analysis.

Background Cardio-oncology is a clinical discipline focused primarily on the early detection of anticancer therapy-related cardiomyopathy. However, there is growing evidence that the direct adverse consequences extend beyond the myocardium to affect the vasculature, but this evidence remains limited. In addition, there remains a paucity of clinically based strategies for monitoring vascular toxicity in these patients. Importantly, arterial stiffness is increasingly recognized as a surrogate end point for cardiovascular disease and may be an important vascular outcome to consider. Therefore, the aim of this systematic review and meta-analysis was to summarize evidence of increased arterial stiffening with anticancer therapy and evaluate the effect of treatment modifiers. Methods and Results A total of 19 longitudinal and cross-sectional studies that evaluated arterial stiffness both during and following anticancer therapy were identified using multiple databases. Two separate analyses were performed: baseline to follow-up (12 studies) and control versus patient groups (10 studies). Subgroup analysis evaluated whether stiffness differed as a function of treatment type and follow-up time. Standard mean differences and mean differences were calculated using random effect models. Significant increases in arterial stiffness were identified from baseline to follow-up (standard mean difference, 0.890; 95% CI, 0.448-1.332; P<0.0001; mean difference, 1.505; 95% CI, 0.789-2.221; P≤0.0001) and in patient versus control groups (standard mean difference, 0.860; 95% CI, 0.402-1.318; P=0.0002; mean difference, 1.437; 95% CI, 0.426-2.448; P=0.0052). Subgroup analysis indicated differences in arterial stiffness between anthracycline-based and non-anthracycline-based therapies (standard mean difference, 0.20; 95% CI, 0.001-0.41; P=0.048), but not follow-up time. Conclusions Significant arterial stiffening occurs following anticancer therapy. Our findings support the use of arterial stiffness as part of a targeted vascular imaging strategy for the identification of early cardiovascular injury during treatment and for the detection of long-term cardiovascular injury into survivorship.

Dietary effects on the determinants of food choice: Impulsive choice, discrimination, incentive motivation, preference, and liking in male rats.

The current study sought to understand how long-term exposure to diets high in saturated fat and refined sugar affected impulsive choice behavior, discrimination abilities, incentive motivation, food preferences, and liking of fat and sugar in male rats. The results showed that 8 weeks of dietary exposure impaired impulsive choice behavior; rats exposed to diets high in processed fat or sugar were more sensitive to changes in delay, a marker of impulsivity. For the high-fat group, these deficits in impulsive choice may stem from poor time discrimination, as their performance was impaired on a temporal discrimination task. The high-fat group also showed reduced magnitude sensitivity in the impulsive choice task, and they earned fewer rewards during lever press training indicating potentially reduced incentive motivation. The high-fat group also developed a preference for high-fat foods compared to the chow and high-sugar group who both preferred sugar. In contrast, dietary exposure did not alter the liking of fat or sugar as measured by a taste reactivity task. Together, the results suggest that the alterations in impulsive choice, time discrimination, incentive motivation, and food preferences induced by consumption of a high-fat diet could make individuals vulnerable to overeating, and thus obesity.

Experience Matters: The Effects of Hypothetical versus Experiential Delays and Magnitudes on Impulsive Choice in Delay Discounting Tasks.

Impulsive choice in humans is typically measured using hypothetical delays and rewards. In two experiments, we determined how experiencing the delay and/or the reward affected impulsive choice behavior. Participants chose between two amounts of real or hypothetical candy (M&Ms) after a real or hypothetical delay (5-30 s), where choosing the shorter delay was the impulsive choice. Experiment 1 compared choice behavior on a real-delay, real-reward (RD/RR) task where participants received M&Ms after experiencing the delays versus a real-delay, hypothetical-reward (RD/HR) task where participants accumulated hypothetical M&Ms after experiencing the delays. Experiment 2 compared the RD/HR task and a hypothetical-delay, hypothetical-reward (HD/HR) task where participants accumulated hypothetical M&Ms after hypothetical delays. The results indicated that choices did not differ between real and hypothetical M&Ms (Experiment 1), and participants were less sensitive to delay and more larger-later (LL)-preferring with hypothetical delays compared to real delays (Experiment 2). Experiencing delays to reward may be important for modeling real-world impulsive choices where delays are typically experienced. These novel experiential impulsive choice tasks may improve translational methods for comparison with animal models and may be improved procedures for predicting real-life choice behavior in humans.

Resurrecting the individual in behavioral analysis: Using mixed effects models to address nonsystematic discounting data.

Delay and probability discounting functions typically take a monotonic form, but some individuals produce functions that are nonsystematic. Johnson and Bickel (2008) developed an algorithm for classifying nonsystematic functions on the basis of two different criteria. Type 1 functions were identified as nonsystematic due to random choices and Type 2 functions were identified as nonsystematic due to relatively shallow slopes, suggesting poor sensitivity to choice parameters. Since their original publication, the algorithm has become widely used in the human discounting literature for removal of participants, with studies often removing approximately 20% of the original sample (Smith & Lawyer, 2017). Because subject removal may not always be feasible due to loss of power or other factors, the present report applied a mixed effects regression modeling technique (Wileyto, Audrain-Mcgovern, Epstein, & Lerman, 2004; Young, 2017) to account for individual differences in DD and PD functions. Assessment of the model estimates for Type 1 and 2 nonsystematic functions indicated that both types of functions deviated systematically from the rest of the sample in that nonsystematic participants were more likely to show shallower slopes and increased biases for larger amounts. The results indicate that removing these participants would fundamentally alter the properties of the final sample in undesirable ways. Because mixed effects models account for between-participant variation with random effects, we advocate for the use of these models for future analyses of a wide range of functions within the behavioral analysis field, with the benefit of avoiding the negative consequences associated with subject removal.

Nucleus accumbens core lesions induce sub-optimal choice and reduce sensitivity to magnitude and delay in impulsive choice tasks.

The nucleus accumbens core (NAc) has long been recognized as an important contributor to the computation of reward value that is critical for impulsive choice behavior. Impulsive choice refers to choosing a smaller-sooner (SS) over a larger-later (LL) reward when the LL is more optimal in terms of the rate of reward delivery. Two experiments examined the role of the NAc in impulsive choice and its component processes of delay and magnitude processing. Experiment 1 delivered an impulsive choice task with manipulations of LL reward magnitude, followed by a reward magnitude discrimination task. Experiment 2 tested impulsive choice under manipulations of LL delay, followed by temporal bisection and progressive interval tasks. NAc lesions, in comparison to sham control lesions, produced suboptimal preferences that resulted in lower reward earning rates, and led to reduced sensitivity to magnitude and delay within the impulsive choice task. The secondary tasks revealed intact reward magnitude and delay discrimination abilities, but the lesion rats persisted in responding more as the progressive interval increased during the session. The results suggest that the NAc is most critical for demonstrating good sensitivity to magnitude and delay, and adjusting behavior accordingly. Ultimately, the NAc lesions induced suboptimal choice behavior rather than simply promoting impulsive choice, suggesting that an intact NAc is necessary for optimal decision making.

Diet-induced impulsivity: Effects of a high-fat and a high-sugar diet on impulsive choice in rats.

Impulsive choice is a common charactertistic among individuals with gambling problems, obesity, and substance abuse issues. Impulsive choice has been classified as a trans-disease process, and understanding the etiology of trait impulsivity could help to understand how diseases and disorders related to impulsive choice are manifested. The Western diet is a possible catalyst of impulsive choice as individuals who are obese and who eat diets high in fat and sugar are typically more impulsive. However, such correlational evidence is unable to discern the direction and causal nature of the relationship. The present study sought to determine how diet may directly contribute to impulsive choice. After 8 weeks of dietary exposure (high-fat, high-sugar, chow), the rats were tested on an impulsive choice task, which presented choices between a smaller-sooner reward (SS) and a larger-later reward (LL). Then, the rats were transferred to a chow diet and retested on the impulsive choice task. The high-sugar and high-fat groups made significantly more impulsive choices than the chow group. Both groups became more self-controlled when they were off the diet, but there were some residual effects of the diet on choice behavior. These results suggest that diet, specifically one high in processed fat or sugar, induces impulsive choice. This diet-induced impulsivity could be a precursor to other disorders that are characterized by impulsivity, such as diet-induced obesity, and could offer potential understanding of the trans-disease nature of impulsive choice.

It's difficult, but important, to make negative predictions.

At the confluence of predictive and regulatory toxicologies, negative predictions may be the thin green line that prevents populations from being exposed to harm. Here, two novel approaches to making confident and robust negative in silico predictions for mutagenicity (as defined by the Ames test) have been evaluated. Analyses of 12 data sets containing >13,000 compounds, showed that negative predictivity is high (∼90%) for the best approach and features that either reduce the accuracy or certainty of negative predictions are identified as misclassified or unclassified respectively. However, negative predictivity remains high (and in excess of the prevalence of non-mutagens) even in the presence of these features, indicating that they are not flags for mutagenicity.

A small molecule with differential effects on the PTS1 and PTS2 peroxisome matrix import pathways.

The use of small molecules has great power to dissect biological processes. This study presents the identification and characterisation of an inhibitor of peroxisome matrix protein import. A mini-screen was carried out to identify molecules that cause alteration in peroxisome morphology, or mislocalization of a peroxisome targeted fluorescent reporter protein. A benzimidazole lead compound (LDS-003655) was identified that resulted in reduced GFP fluorescence in peroxisomes and cytosolic GFP accumulation. The effect of the compound was specific to peroxisomes as Golgi bodies, endoplasmic reticulum and the actin cytoskeleton were unaffected even at 25 µM, whereas peroxisome import via the PTS1 pathway was compromised at 100 nM. When seedlings were grown on 25 µM LDS-003655 they displayed morphology typical of seedlings grown in the presence of auxin, and expression of the auxin reporter DR5::GFP was induced. Analysis of a focussed library of LDS-003655 derivatives in comparison with known auxins led to the conclusion that the auxin-like activity of LDS-003655 is attributable to its in situ hydrolysis giving rise to 2,5-dichlorobenzoic acid, whereas the import inhibiting activity of LDS-003655 requires the whole molecule. None of the auxins tested had any effect on peroxisome protein import. Matrix import by the PTS2 import pathway was relatively insensitive to LDS-003655 and its active analogues, with effects only seen after prolonged incubation on high concentrations. Steady-state protein levels of PEX5, the PTS1 import pathway receptor, were reduced in the presence of 100 nM LDS-003655, suggesting a possible mechanism for the import inhibition.

Synthesis of small molecules with high scaffold diversity: exploitation of metathesis cascades in combination with inter- and intramolecular Diels-Alder reactions.

Our knowledge of the biological relevance of regions of chemical space is shaped, in large part, by the synthetic accessibility of small molecules. Historically, however, chemists have explored chemical space in an exceptionally uneven and unsystematic way. We have previously demonstrated that metathesis cascade chemistry may be harnessed to yield small molecule collections with high scaffold diversity. Here, we describe the extent to which inter- and intramolecular Diels-Alder reactions, when used in conjunction with metathesis cascades, can extend the range of molecular scaffolds that are accessible. A range of metathesis substrates was prepared from combinations of two or three building blocks. Metathesis cascades were exploited to "reprogram" the molecular scaffolds. In many cases, the metathesis products were 1,3-dienes, which were potential substrates for either inter- or intramolecular Diels-Alder reactions. The synthesis and functionalisation of the products was often facilitated by fluorous tagging, for example by using a "safety-catch" linker that we have developed. It was demonstrated that, in certain cases, Diels-Alder reactions could extend the range of molecular scaffolds that may be prepared by using metathesis cascade reactions.

Peroxisome biogenesis and positioning.

Plant peroxisomes are extremely dynamic, moving and undergoing changes of shape in response to metabolic and environmental signals. Matrix proteins are imported via one of two import pathways, depending on the targeting signal within the protein. Each pathway has a specific receptor but utilizes common membrane-bound translocation machinery. Current models invoke receptor recycling, which may involve cycles of ubiquitination. Some components of the import machinery may also play a role in proteolytic turnover of matrix proteins, prompting parallels with the endoplasmic-reticulum-associated degradation pathway. Peroxisome membrane proteins, some of which are imported post-translationally, others of which may traffic to peroxisomes via the endoplasmic reticulum, use distinct proteinaceous machinery. The isolation of mutants defective in peroxisome biogenesis has served to emphasize the important role of peroxisomes at all stages of the plant life cycle.

A fluorous-tagged "safety catch" linker for preparing heterocycles by ring-closing metathesis.

A fluorous-tagged "safety catch" linker is described for the synthesis of heterocycles with use of ring-closing metathesis. The linker facilitates the purification of metathesis substrates, the removal of the catalyst, the functionalization of the products, and the release of only metathesis products. The synthesis of a range of heterocycles is described.

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries.

The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed.

An efficient method for synthesising unsymmetrical silaketals: substrates for ring-closing, including macrocycle-closing, metathesis.

Diisopropylsilyl ethers were activated with N-bromosuccinimide, and reacted with a fluorous-tagged alcohol, to yield tethered substrates for ring-closing metathesis reactions.

Use of health care among adults with chronic and complex physical disabilities of childhood.

PURPOSE: The purpose of this study was to explore the patterns of health services utilization among adults with chronic and complex physical disabilities of childhood, specifically cerebral palsy, spina bifida, and acquired brain injuries.METHODS. A cohort of 345 young adults who had graduated from the Bloorview MacMillan Children's Centre was identified. Their health care records were extracted from Ontario Health Insurance Plan (OHIP) and Canadian Institute for Health Information (CIHI) databases, for a four-year period. These data were analysed to estimate the frequency of out-patient physician visits and admissions to hospital.RESULTS. The mean age of the sample was 21.9 years (range 19.0-26.9 years). The results show that 95% of the sample visited a physician at least once per year, and 24% had a primary care physician. On average, these adults visited physicians 11.5 times per year (approximately once per month) and were admitted to hospital once every 6.8 years.CONCLUSIONS. These results suggest that adults with complex physical disabling conditions from childhood have ongoing health issues that require frequent service. Their admission rate is 9.0 times that of the general population, and few have a primary care physician. A new model of service may be necessary for this high-needs group.