bak deletion stimulates gastric epithelial proliferation and enhances Helicobacter felis-induced gastric atrophy and dysplasia in mice

Helicobacter infection causes a chronic superficial gastritis that in some cases progresses via atrophic gastritis to adenocarcinoma. Proapoptotic bak has been shown to regulate radiation-induced apoptosis in the stomach and colon and also susceptibility to colorectal carcinogenesis in vivo. Therefore we investigated the gastric mucosal pathology following H. felis infection in bak-null mice at 6 or 48 wk postinfection. Primary gastric gland culture from bak-null mice was also used to assess the effects of bak deletion on IFN-γ-, TNF-α-, or IL-1β-induced apoptosis. bak-null gastric corpus glands were longer, had increased epithelial Ki-67 expression, and contained fewer parietal and enteroendocrine cells compared with the wild type (wt). In wt mice, bak was expressed at the luminal surface of gastric corpus glands, and this increased 2 wk post-H. felis infection. Apoptotic cell numbers were decreased in bak-null corpus 6 and 48 wk following infection and in primary gland cultures following cytokine administration. Increased gastric epithelial Ki-67 labeling index was observed in C57BL/6 mice after H. felis infection, whereas no such increase was detected in bak-null mice. More severe gastric atrophy was observed in bak-null compared with C57BL/6 mice 6 and 48 wk postinfection, and 76% of bak-null compared with 25% of C57BL/6 mice showed evidence of gastric dysplasia following long-term infection. Collectively, bak therefore regulates gastric epithelial cell apoptosis, proliferation, differentiation, mucosal thickness, and susceptibility to gastric atrophy and dysplasia following H. felis infection

Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration

Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-κB subunits. Groups of five female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and Nfkb1-/- mice were exposed to 12 Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than in WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. Six hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice. NF-κB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage

Relational agency: Relational sociology, agency and interaction

yesThis article explores how the concept of agency in social theory changes when it is conceptualised as a relational rather than an individual phenomenon. I begin with a critique of the structure/agency debate, particularly of how this emerges in the critical realist approach to agency typified by Margaret Archer. It is argued that this approach, and the critical realist version of relational sociology that has grown from it, reifies social relations as a third entity to which agents have a cognitive, reflexive relation, playing down the importance of interaction. This upholds the Western moral and political view of agents as autonomous, independent, and reflexive individuals. Instead of this I consider agency from a different theoretical tradition in relational sociology in which agents are always located in manifold social relations. From this I create an understanding of agents as interactants, ones who are interdependent, vulnerable, intermittently reflexive, possessors of capacities that can only be practiced in joint actions, and capable of sensitive responses to others and to the situations of interaction. Instead of agency resting on the reflexive monitoring of action or the reflexive deliberation on structurally defined choices, agency emerges from our emotional relatedness to others as social relations unfold across time and space

Oral iron exacerbates colitis and influences the intestinal microbiome

Inflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS-induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44-fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS-induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS

Physical activity counseling in overweight and obese primary care patients: Outcomes of the VA-STRIDE randomized controlled trial.

The purpose of this 2-arm randomized clinical trial was to evaluate the effectiveness of a 12-month, expert system-based, print-delivered physical activity intervention in a primary care Veteran population in Pittsburgh, Pennsylvania. Participants were not excluded for many health conditions that typically are exclusionary criteria in physical activity trials. The primary outcome measures were physical activity reported using the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire and an accelerometer-based activity assessment at baseline, 6, and 12 months. Of the 232 Veterans enrolled in the study, 208 (89.7%) were retained at the 6-month follow-up and 203 (87.5%) were retained at 12 months. Compared to the attention control, intervention participants had significantly increased odds of meeting the U.S. recommended guideline of ≥ 150 min/week of at least moderate-intensity physical activity at 12 months for the modified CHAMPS (odds ratio [OR] = 2.86; 95% CI: 1.03-7.96; p = 0.04) but not at 6 months (OR = 1.54; 95% CI: 0.56-4.23; p = 0.40). Based on accelerometer data, intervention participants had significantly increased odds of meeting ≥ 150 min/week of moderate-equivalent physical activity at 6 months (OR = 6.26; 95% CI: 1.26-31.22; p = 0.03) and borderline significantly increased odds at 12 months (OR = 4.73; 95% CI: 0.98-22.76; p = 0.053). An expert system physical activity counseling intervention can increase or sustain the proportion of Veterans in primary care meeting current recommendations for moderate-intensity physical activity. Trial Registration Clinical trials.gov identifier: NCT00731094 URL: http://www.clinicaltrials.gov/ct2/show/NCT00731094

Effector mass and trajectory optimization in the online regulation of goal-directed movement

Goal-directed aiming movements are planned and executed so that they optimize speed, accuracy and energy expenditure. In particular, the primary submovements involved in manual aiming attempts typically undershoot targets in order to avoid costly time and energy overshoot errors. Furthermore, in aiming movements performed over a series of trials, the movement planning process considers the sensory information associated with the most recent aiming attempt. The goal of the current study was to gain further insight into how the sensory consequences associated with the recent and forthcoming aiming attempts impact performance. We first examined whether performers are more conservative in their aiming movements with a heavy, as opposed to a light, stylus by determining whether primary submovements undershot the target to a greater extent in the former due to an anticipated increase in spatial variability. Our results show that movements with the heavy stylus demonstrated greater undershoot biases in the primary submovements, as well as greater trial-to-trial spatial variability at specific trajectory kinematic landmarks. In addition, we also sought to determine whether the sensory information experienced on a previous aiming movement affected movement planning and/or online control on the subsequent aiming attempt. To vary the type sensory consequences experienced on a trial-to-trial basis, participants performed aiming movements with light and heavy styli in either blocked or random orderings of trials. In the random-order conditions, some participants were provided advance information about stylus mass for the upcoming trial, while others were not. The blocked and random trial orders had minimal impacts on end point aiming performance. Furthermore, similarities in the times to key kinematic landmarks in the trajectories of the random-order groups suggest that recent trial experience had a greater effect on the upcoming aiming movement compared with advance task knowledge