Accelerated longitudinal cortical atrophy in OEF/OIF/OND veterans with severe PTSD and the impact of comorbid TBI.

Veterans who deployed in support of Operation Enduring Freedom (OEF), Iraqi Freedom (OIF), and New Dawn (OND) commonly experience severe psychological trauma, often accompanied by physical brain trauma resulting in mild traumatic brain injury (mTBI). Prior studies of individuals with posttraumatic stress disorder (PTSD) have revealed alterations in brain structure, accelerated cellular aging, and impacts on cognition following exposure to severe psychological trauma and potential interactive effects of military-related mTBI. To date, however, little is known how such deployment-related trauma changes with time and age of injury of the affected veteran. In this study, we explored changes in cortical thickness, volume, and surface area after an average interval of approximately 2 years in a cohort of 254 OEF/OIF/OND Veterans ranging in age from 19 to 67 years. Whole-brain vertex-wise analyses revealed that veterans who met criteria for severe PTSD (Clinician-Administered PTSD Scale ≥60) at baseline showed greater negative longitudinal changes in cortical thickness, volume, and area over time. Analyses also revealed a significant severe-PTSD by age interaction on cortical measures with severe-PTSD individuals exhibiting accelerated cortical degeneration with increasing age. Interaction effects of comorbid military-related mTBI within the severe-PTSD group were also observed in several cortical regions. These results suggest that those exhibiting severe PTSD symptomatology have accelerated atrophy that is exacerbated with increasing age and history of mTBI.

Neural Correlates of Traumatic Brain Injury in Women Survivors of Intimate Partner Violence: A Structural and Functional Connectivity Neuroimaging Study.

OBJECTIVE: More than one-third of women in the United States experience intimate partner violence (IPV) in their lifetime, increasing their risk for traumatic brain injury (TBI). Despite the prevalence of TBI among IPV survivors, research is sparse in comparison with parallel populations (eg, military, accidents, sports). This pilot study aimed to provide a preliminary investigation of the effect of TBI on brain morphometry and resting-state functional connectivity in women who experience IPV. PARTICIPANTS: A total of 45 community-dwelling women survivors of IPV who screened positive for posttraumatic stress disorder (PTSD). DESIGN: Participants completed comprehensive assessments of trauma exposure, PTSD, TBI history, and brain neurological health. Twenty-three participants (51.1%) met diagnostic criteria for lifetime TBI. Of these, 15 participants experienced 1 or more TBIs resulting from IPV. The remaining participants experienced TBI from non-IPV exposures (eg, sports/motor vehicle accident). Surface-based neuroimaging analyses were performed to examine group differences in cortical thickness and in functional connectivity of amygdala and isthmus cingulate seeds to examine emotion regulation and the default mode network, respectively. MAIN MEASURES: Boston Assessment of Traumatic Brain Injury-Lifetime for Intimate Partner Violence (BAT-L/IPV); Clinician Administered PTSD Scale (CAPS); structural and functional neuroimaging. RESULTS: History of lifetime TBI in women IPV survivors was associated with differences in cortical thickness as well as functional connectivity between the isthmus cingulate seed and a variety of regions, including superior parietal and frontal cortices. Individuals with IPV-related TBI showed lower cortical thickness in the right paracentral gyrus than individuals with TBI from other non-IPV etiologies. CONCLUSION: Significant differences in brain structure and connectivity were observed in individuals with IPV and TBI. A lower mean cortical thickness of the paracentral gyrus was associated with TBI due to IPV than TBI from other etiologies. Although preliminary, findings from this pilot study present a step toward identifying potential mechanisms by which IPV and TBI secondary to IPV impact brain health in women.

Test-retest reliability of FreeSurfer automated hippocampal subfield segmentation within and across scanners.

The human hippocampus is vulnerable to a range of degenerative conditions and as such, accurate in vivo measurement of the hippocampus and hippocampal substructures via neuroimaging is of great interest for understanding mechanisms of disease as well as for use as a biomarker in clinical trials of novel therapeutics. Although total hippocampal volume can be measured relatively reliably, it is critical to understand how this reliability is affected by acquisition on different scanners, as multiple scanning platforms would likely be utilized in large-scale clinical trials. This is particularly true for hippocampal subregional measurements, which have only relatively recently been measurable through common image processing platforms such as FreeSurfer. Accurate segmentation of these subregions is challenging due to their small size, magnetic resonance imaging (MRI) signal loss in medial temporal regions of the brain, and lack of contrast for delineation from standard neuroimaging procedures. Here, we assess the test-retest reliability of the FreeSurfer automated hippocampal subfield segmentation procedure using two Siemens model scanners (a Siemens Trio and Prismafit Trio upgrade). T1-weighted images were acquired for 11 generally healthy younger participants (two scans on the Trio and one scan on the Prismafit). Each scan was processed through the standard cross-sectional stream and the recently released longitudinal pipeline in FreeSurfer v6.0 for hippocampal segmentation. Test-retest reliability of the volumetric measures was examined for individual subfields as well as percent volume difference and Dice overlap among scans and intra-class correlation coefficients (ICC). Reliability was high in the molecular layer, dentate gyrus, and whole hippocampus with the inclusion of three time points with mean volume differences among scans less than 3%, overlap greater than 80%, and ICC >0.95. The parasubiculum and hippocampal fissure showed the least improvement in reliability with mean volume difference greater than 5%, overlap less than 70%, and ICC scores ranging from 0.78 to 0.89. Other subregions, including the CA regions, were stable in their mean volume difference and overlap (<5% difference and >75% respectively) and showed improvement in reliability with the inclusion of three scans (ICC â€‹> â€‹0.9). Reliability was generally higher within scanner (Trio-Trio), however, Trio-Prismafit reliability was also high and did not exhibit an obvious bias. These results suggest that the FreeSurfer automated segmentation procedure is a reliable method to measure total as well as hippocampal subregional volumes and may be useful in clinical applications including as an endpoint for future clinical trials of conditions affecting the hippocampus.

Self-Incentives Uniquely Boost Cessation in Community-Based Stop Smoking Programs: Randomized Controlled Trial.

BACKGROUND: Self-incentives offer a plausible alternative to paying smokers to quit but have not yet been tested in a randomized controlled trial. PURPOSE: The present study tested whether, compared with a control group, prompting smokers explicitly to self-incentivize if they abstain from smoking for a week or a month encouraged sustained abstinence. METHOD: One hundred and fifty-nine smokers were recruited from stop smoking clinics and randomized to an active control condition (asked to form a plan to quit, n = 65) or one of two intervention conditions in which they were asked to form implementation intentions designed to ensure that they incentivized themselves if they had not smoked at all by the end of (a) the week (n = 44) or (b) the month (n = 50). The main outcome measure was self-reported abstinence at 3- and 6-month follow-ups, which was biochemically verified at baseline and in a subsample at 3-month follow-up. RESULTS: At 3-month follow-up, 34% (15/44; p < .05, d = 0.45) and 36% (18/50; p < .05, d = 0.49) of smokers abstained in the weekly and monthly self-incentivizing conditions respectively, compared with 15% (10/65) in the control. The same pattern of findings was observed at 6-month follow-up: 30% (13/44; p < .05, d = 0.35), 34% (17/50; p < .05, d = 0.45) and 15% (10/65) of smokers remained abstinent in the two intervention groups and control group, respectively. CONCLUSIONS: Ensuring that smokers self-incentivized boosted significantly the effectiveness of the stop smoking program. Self-incentivizing implementation intentions could be implemented at low cost with high public health "reach" to change many health behaviors beyond smoking. TRIAL REGISTRATION: ISRCTN11610200.

Nontargeted LC-MSn Profiling of Compounds in Ileal Fluids That Decrease after Raspberry Intake Identifies Consistent Alterations in Bile Acid Composition.

Ileostomy studies provide a unique insight into the digestion of foods, allowing identification of physiologically relevant dietary phytochemicals and their metabolites that are important to gut health. We previously reported an increase of components, including novel triterpenoids, in ileal fluids of 11 ileostomates following consumption of raspberries using nontargeted LC-MSn techniques in combination with data deconvolution software. The current study focused on components that consistently decreased postsupplementation. After data deconvolution, 32 components were identified that met exclusion parameters of m/z signals and which decreased significantly in ileal fluids from eight of 11 participants post-raspberry supplementation. Two-thirds of these components were identified putatively from their MS properties. Consistent decreases were observed in components that possibly reflected "washing out" of presupplementation intake of common foods/drinks including (poly)phenol metabolites. Metabolites associated with fat metabolism such as hydroxylated fatty acids and cholate-type bile acids were specifically reduced. However, more directed re-examination of the data revealed that although some cholates were consistently reduced, the more polar glyco- and tauro-linked bile acid derivatives increased consistently, by as much as 100-fold over presupplementation levels. The possible reasons for these substantial alterations in bile acid composition in ileal fluids in response to raspberry intake are discussed.

Do Self-Incentives and Self-Rewards Change Behavior? A Systematic Review and Meta-Analysis.

Encouraging people to self-incentivize (i.e., to reward themselves in the future if they are successful in changing their behavior) or self-reward (i.e., prompt people to reward themselves once they have successfully changed their behavior) are techniques that are frequently embedded within complex behavior change interventions. However, it is not clear whether self-incentives or self-rewards per se are effective at bringing about behavior change. Nine databases were searched alongside manual searching of systematic reviews and online research registers. One thousand four hundred papers were retrieved, spanning a range of behaviors, though the majority of included papers were in the domain of "health psychology". Ten studies matched the inclusion criteria for self-incentive but no studies were retrieved for self-reward. The present systematic review and meta-analysis is therefore the first to evaluate the unique effect of self-incentives on behavior change. Effect sizes were retrieved from 7 of the 10 studies. Analysis of the 7 studies produced a very small pooled effect size for self-incentives (k = 7, N = 1,161), which was statistically significant, d+ = 0.17, CI [0.06, 0.29]. The weak effect size and dearth of studies raises the question of why self-incentivizing is such a widely employed component of behavior change interventions. The present research opens up a new field of inquiry to establish: (a) whether or not self-incentivizing and self-rewarding are effective behavior change techniques, (b) whether self-incentives and self-rewards need to be deployed alongside other behavior change techniques, and, (c) when and for whom self-incentives and self-rewards could support effective behavior change.

Novel colon-available triterpenoids identified in raspberry fruits exhibit antigenotoxic activities in vitro.

SCOPE: Ileostomy studies provide a unique insight into digestion of food, allowing identification of physiologically relevant dietary phytochemicals and their metabolites important to gut health. We previously reported the consistent increase of components in ileal fluids of ileostomates after consumption of raspberries with use of nontargeted LC-MSn techniques and data deconvolution software highlighting two major unknown components (m/z 355 and 679). METHODS AND RESULTS: In-depth LC-MSn analyses suggested that the ileal m/z 355 components were p-coumaroyl glucarates. These compounds have not been identified previously and were confirmed in raspberry extracts after partial purification. The major ileal component with m/z 679 was a glycoside with an aglycone of m/z 517 and was present as two peaks in extracts of whole puree, unseeded puree, and isolated seeds. These components were purified using Sephadex LH20 and C18 SPE units and identified as major, novel raspberry triterpenoid glycosides. This triterpenoid-enriched fraction (100 nM) protected against H2 O2 -induced DNA damage in both colon cancer and normal cell lines and altered expression of cytoprotective genes. CONCLUSION: The presence of these novel raspberry triterpenoid components in ileal fluids indicates that they would be colon-available in vivo, so confirmation of their anticancer bioactivities is of key physiological relevance.

The composition of potentially bioactive triterpenoid glycosides in red raspberry is influenced by tissue, extraction procedure and genotype.

The beneficial effects of consumption of berry fruits on a range of chronic diseases has been attributed (at least in part) to the presence of unique phytochemicals. Recently, we identified novel ursolic acid-based triterpenoid glycosides (TTPNs) in raspberry fruit and demonstrated their survival in human ileal fluids after feeding which confirmed their colon-availability in vivo. In this paper, in vitro digestion studies demonstrated that certain TTPNs were stable under gastrointestinal conditions and confirmed that these components may have been responsible for bioactivity noted in previous studies. Sequential extractions of raspberry puree, isolated seeds and unseeded puree showed that certain TTPN components (e.g. peak T1 m/z 679, and T2 m/z 1358) had different extractabilities in water/solvent mixes and were differentially associated with the seeds. Purified seed TTPNs (mainly T1 and T2) were shown to be anti-genotoxic in HT29 and CCD841 cell based in vitro colonocyte models. Further work confirmed that the seeds contained a wider range of TTPN-like components which were also differentially extractable in water/solvent mixes. This differential extractability could influence the TTPN composition and potential bioactivity of the extracts. There was considerable variation in total content of TTPNs (∼3-fold) and TTPN composition across 13 Rubus genotypes. Thus, TTPNs are likely to be present in raspberry juices and common extracts used for bioactivity studies and substantial variation exists in both content and composition due to genetics, tissue source or extraction conditions, which may all affect observed bioactivity.

Comparison of in vivo and in vitro digestion on polyphenol composition in lingonberries: potential impact on colonic health.

The composition of polyphenols in ileal fluid samples obtained from an ileostomy subject after lingonberry intake was compared with lingonberry extracts obtained after simulated in vitro digestion (IVDL) and subsequent faecal fermentation (IVFL). HPLC-PDA-MS/MS analysis confirmed similar patterns of lingonberry (poly)phenolic metabolism after the in vivo and in vitro digestion, with reduced recovery of anthocyanins and a similar pattern of recovery for proanthocyanidins observed for both methods of digestion. On the other hand, the IVFL sample contained none of the original (poly)phenolic components but was enriched in simple aromatic components. Digested and fermented extracts exhibited significant (P < 0.05) anti-genotoxic (Comet assay), anti-mutagenic (Mutation Frequency assay), and anti-invasive (Matrigel Invasion assay) effects in human cell culture models of colorectal cancer at physiologically-relevant doses (0-50 µg/mL gallic acid equivalents). The ileal fluid induced significant anti-genotoxic activity (P < 0.05), but at a higher concentration (200 µg/mL gallic acid equivalents) than the IVDL. Despite extensive structural modification following digestion and fermentation, lingonberry extracts retained their bioactivity in vitro. This reinforces the need for studies to consider the impact of digestion when investigating bioactivity of dietary phytochemicals.

In vitro and in vivo models of colorectal cancer: antigenotoxic activity of berries.

The etiology of colorectal cancer (CRC), a common cause of cancer-related mortality globally, has strong associations with diet. There is considerable epidemiological evidence that fruits and vegetables are associated with reduced risk of CRC. This paper reviews the extensive evidence, both from in vitro studies and animal models, that components of berry fruits can modulate biomarkers of DNA damage and that these effects may be potentially chemoprotective, given the likely role that oxidative damage plays in mutation rate and cancer risk. Human intervention trials with berries are generally consistent in indicating a capacity to significantly decrease oxidative damage to DNA, but represent limited evidence for anticarcinogenicity, relying as they do on surrogate risk markers. To understand the effects of berry consumption on colorectal cancer risk, future studies will need to be well controlled, with defined berry extracts, using suitable and clinically relevant end points and considering the importance of the gut microbiota.

Virgin olive oil phenolics extract inhibit invasion of HT115 human colon cancer cells in vitro and in vivo.

The decreased cancer risk associated with consumption of olive oil may be due to the presence of phenolics which can modulate pathways including apoptosis and invasion that are relevant to carcinogenesis. We have previously shown that a virgin olive oil phenolics extract (OVP) inhibited invasion of HT115 colon cancer cells in vitro. In the current study we assessed the in vitro effects of OVP (25 µg mL(-1)) on HT115 cell migration, spreading and integrin expression. Furthermore, the anti-metastatic activity of OVP - at a dose equivalent to 25 mg per kg per day for 2, 8 or 10 weeks - was assessed in a Severe Combined ImmunoDeficiency (SCID) Balb-c mouse model. After 24 h OVP did not inhibit cell migration but significantly reduced cell spreading on fibronectin (65% of control; p < 0.05) and expression of a range of α and ß integrins was modulated. In vivo, OVP by gavage significantly (p < 0.05) decreased not only tumour volume but also the number of metastases in SCID Balb-c mice. Collectively, the data suggest that - possibly through modulation of integrin expression - OVP decreases invasion in vitro and also inhibits metastasis in vivo.

Tracking (Poly)phenol components from raspberries in ileal fluid.

The (poly)phenols in ileal fluid after ingestion of raspberries were analyzed by targeted and nontargeted LC-MS(n) approaches. Targeted approaches identified major anthocyanin and ellagitannin components at varying recoveries and with considerable interindividual variation. Nontargeted LC-MS(n) analysis using an orbitrap mass spectrometer gave exact mass MS data which were sifted using a software program to select peaks that changed significantly after supplementation. This method confirmed the recovery of the targeted components but also identified novel raspberry-specific metabolites. Some components (including ellagitannin and previously unidentified proanthocyanidin derivatives) may have arisen from raspberry seeds that survived intact in ileal samples. Other components include potential breakdown products of anthocyanins, unidentified components, and phenolic metabolites formed either in the gut epithelia or after absorption into the circulatory system and efflux back into the gut lumen. The possible physiological roles of the ileal metabolites in the large bowel are discussed.

Mechanisms underlying the anti-proliferative effects of berry components in in vitro models of colon cancer.

Consumption of fruit and vegetables is associated with a decreased risk of several cancers, particularly colorectal cancer, possibly linked to their phytochemical content, which is of interest due to several proposed health benefits, including potential anticancer activity. Epidemiological data suggests that cancers of the digestive tract are most susceptible to dietary modification, possibly due to being in direct contact with bioactive food constituents and therefore investigating the effects of these bioactive compounds on the prevalent colorectal cancer is feasible. Berries are a common element of Western diets, with members of the Rubus, Fragria, Sorbus, Ribes and Vaccinum genus featuring in desserts, preserves, yoghurts and juices. These soft fruit are rich in bioactive phytochemicals including several classes of phenolic compounds such as flavonoids (anthocyanins, flavonols and flavanols) and phenolic acids (hydroxybenzoic and hydroxycinnamic acids). Whilst there is little data linking berry consumption to reduced risk of colorectal cancer, in vitro evidence from models representing colorectal cancer suggests that berry polyphenols may modulate cellular processes essential for cancer cell survival, such as proliferation and apoptosis. The exact mechanisms and berry constituents responsible for these potential anticancer activities remain unknown, but use of in vitro models provides a means to elucidate these matters.

Persistence of anticancer activity in berry extracts after simulated gastrointestinal digestion and colonic fermentation.

Fruit and vegetable consumption is associated at the population level with a protective effect against colorectal cancer. Phenolic compounds, especially abundant in berries, are of interest due to their putative anticancer activity. After consumption, however, phenolic compounds are subject to digestive conditions within the gastrointestinal tract that alter their structures and potentially their function. However, the majority of phenolic compounds are not efficiently absorbed in the small intestine and a substantial portion pass into the colon. We characterized berry extracts (raspberries, strawberries, blackcurrants) produced by in vitro-simulated upper intestinal tract digestion and subsequent fecal fermentation. These extracts and selected individual colonic metabolites were then evaluated for their putative anticancer activities using in vitro models of colorectal cancer, representing the key stages of initiation, promotion and invasion. Over a physiologically-relevant dose range (0-50 µg/ml gallic acid equivalents), the digested and fermented extracts demonstrated significant anti-genotoxic, anti-mutagenic and anti-invasive activity on colonocytes. This work indicates that phenolic compounds from berries undergo considerable structural modifications during their passage through the gastrointestinal tract but their breakdown products and metabolites retain biological activity and can modulate cellular processes associated with colon cancer.