This paper describes an experimental study on the response of rectangular and square hollow steel members to monotonic and cyclic axial loading. Tensile monotonic tests were first performed on short ...specimens in order to relate material strength to section resistance. The observed results are compared to European and North American design provisions. The cyclic tests included assessment of bracing specimens with various member lengths and cross-section sizes. The objective of these tests was to examine performance under idealised seismic loading conditions. In general, the steel hollow brace members exhibited stable hysteresis behaviour up to the on-set of local buckling, and then showed considerable degradation in strength and ductility depending on their slenderness. The tests provide information on key response parameters, including tensile and compressive strength and post-buckling capacity, as well as ductility and energy dissipation capabilities. Particular attention is given to the influence of member slenderness. The experimental findings are compared with the recommendations of a number of international codes of practice, and areas of agreement or discrepancy are highlighted.
The results of shake table tests on three concentrically-braced sub-frames are compared with a series of correlative inelastic analyses. Both transient time-history and nonlinear static (pushover) ...analyses are considered. The lateral resistance of the test frames is provided by a pair of cold-formed tubular steel members. The brace cross-section is varied between tests to investigate the influence of brace slenderness on the stiffness, resistance and ductility displayed by the frame under strong earthquake loading. Response simulations using a two-dimensional analytical model of the test frame are compared with the experimental results. Brace strengths and elastic test frame properties established in complementary static tensile tests and low-level shake table tests, respectively, are used to determine model input data. The transient acceleration and displacement response of the frames calculated in nonlinear time-history analyses are compared with corresponding experimental measurements. The base shear–frame drift relationship is calculated using pushover analyses that consider either the resistance of both frame braces or the tension brace alone. These are compared with the experimental hysteretic response of the test frame. On the whole, the analytical results are observed to agree well with the experimental results, especially with respect to brace tension forces and frame base shear. Cases where the experimental and analytical responses deviate are identified and the implications for earthquake response assessment and design are discussed.
Objectives. Osteophytes are thought to stabilize an osteoarthritic joint, thereby preventing structural progression. Meagre longitudinal data suggest, however, that they are associated with an ...increased risk of structural progression. Our objective was to evaluate the effect of osteophyte size on radiographic progression in osteoarthritis (OA). Methods. Using data from a natural history study of persons with symptomatic knee OA, we obtained fluoroscopically positioned postero-anterior (PA) radiographs at baseline, 15 and 30 months. Using an atlas, osteophyte size was scored on a scale of 0–3 at each of four sites on the PA film and, for each knee, both compartment-specific (i.e. medial; lateral) and overall osteophyte scores were computed. Progression was defined as an increase over follow-up in medial or lateral joint space narrowing, based on a semiquantitative grading. Mechanical alignment was assessed using long limb films at the 15 month examination. Logistic regression was used to evaluate the relation of osteophyte size with progression, adjusting for age, gender and body mass index, and with and without adjustment for alignment. Results. Of 270 subjects who had 470 eligible knees with follow-up, 104 (22%) knees showed progression. Overall, osteophyte score modestly increased the risk of progression odds ratio (OR) per s.d. increase of osteophyte score = 1.4 (95% CI 1.1, 1.8, P = 0.02), but this effect weakened and became non-significant after adjustment for limb alignment (OR = 1.3). Compartment osteophyte score was strongly associated with malalignment to the side of the osteophyte (e.g. medial osteophyte and varus). Compartment-specific osteophyte score markedly increased the risk of ipsilateral progression (e.g. medial osteophytes → medial progression) OR per s.d. = 1.9 (95% CI 1.5, 2.5, P<0.001) and decreased the risk of contralateral progression OR per s.d. = 0.6 (95% CI 0.5, 0.8, P = 0.002), but these associations diminished when we adjusted for limb alignment (OR = 1.5 and 0.7 respectively). Conclusions. Large osteophytes do not affect the risk of structural progression. They are strongly associated with malalignment to the side of the osteophyte, and any relation they have with progression is partly explained by the association of malalignment with progression.
Pharmacological induction of hypoxia-inducible factor (HIF), a global transcriptional regulator of the hypoxic response, by prolyl hydroxylase inhibitors (PHDi) is protective in murine models of ...colitis, and epithelial cells are critical for the observed therapeutic efficacy. Because systemic HIF activation may lead to potentially negative off-target effects, we hypothesized that targeting epithelial HIF through oral delivery of PHDi would be sufficient to protect against colitis in a mouse model.
Using a chemically induced trinitrobenzene sulfonic acid murine model of colitis, we compared the efficacy of oral and intraperitoneal (i.p.) delivery of the PHDi; AKB-4924 in preventing colitis, as measured by endoscopy, histology, barrier integrity, and immune profiling. Furthermore, we measured potential off-target effects, examining HIF and HIF target genes in the heart and kidney, as well as erythropoietin and hematocrit levels.
Oral administration of AKB-4924 exhibited mucosal protection comparable i.p. dosing. Oral delivery of PHDi led to reduced colonic epithelial HIF stabilization compared with i.p. delivery, but this was still sufficient to induce transcription of downstream HIF targets. Furthermore, oral delivery of PHDi led to reduced stabilization of HIF and activation of HIF targets in extraintestinal organs.
Oral delivery of PHDi therapies to this intestinal mucosa protects against colitis in animal models and represents a potential therapeutic strategy for inflammatory bowel disease, which also precludes unwanted extraintestinal effects.
•Functional dyspepsia patients have reduced duodenal CRHR-2 compared to controls.•The loss of CRHR-2 correlates with reduced NLRP6 expression and autophagy.•NLRP6 and autophagy are associated with ...goblet cell homeostasis.•Duodenal goblet cells and mucin exocytosis were reduced in FD patients.•In vitro assays show CRH regulates epithelial NLRP6 and mucin responses.
Functional dyspepsia (FD) affects up to 15% of the population and is characterised by recurring upper gastrointestinal (GI) symptoms occurring in the absence of clinically identifiable pathology. Psychological stress is a key factor associated with the onset of FD and locally acting hypothalamic–pituitary–adrenal (HPA) axis hormones have been implicated in GI motility and barrier dysfunction. Recent pre-clinical work has identified mechanistic pathways linking corticotropin-releasing hormone (CRH) with the innate epithelial immune protein NLRP6, an inflammasome that has been shown to regulate GI mucus secretion.
We recruited twelve FD patients and twelve healthy individuals to examine whether dysregulation of hypothalamic-pituitary adrenal (HPA) axis hormones and altered NLRP6 pathways were evident in the duodenal mucosa. Protein expression was assessed by immunoblot and immunohistochemistry in D2 duodenal biopsies. Plasma HPA axis hormones were assayed by ELISA and enteroid and colorectal cancer cell line cultures were used to verify function. FD patients exhibited reduced duodenal CRH-receptor 2, compared to non-GI disease controls, indicating a dysregulation of duodenal HPA signalling. The loss of CRH-receptor 2 correlated with reduced NLRP6 expression and autophagy function, processes critical for maintaining goblet cell homeostasis. In accordance, duodenal goblet cell numbers and mucin exocytosis was reduced in FD patients compared to controls. In vitro studies demonstrated that CRH could reduce NLRP6 in duodenal spheroids and promote mucus secretion in the HT29-MTX-E12 cell line. In conclusion, FD patients exhibit defects in the NLRP6-autophagy axis with decreased goblet cell function that may drive symptoms of disease. These features correlated with loss of CRH receptor 2 and may be driven by dysregulation of HPA signalling in the duodenum of FD patients.
A one-year monitoring study was conducted in a pilot house with extremely high radon levels to investigate the ability and efficiency of radon mitigation by soil depressurisation (SD) both active and ...passive. The study included monitoring of radon concentration, pressure field extension (PFE) under the slab and some atmospheric parameters for different testing phases. Periods in which the house remained closed to foster radon accumulation were alternated with phases of active and passive soil depressurisation under different conditions. The behaviour of the radon concentration in the pilot house was analysed along with the influence of atmospheric variables, significant correlations were found for the radon concentration with atmospheric pressure, outdoor temperature and wind. From the PFE analysis it was proven that the pressure drop with distance from the suction point of the SD system is proportional to the depressurisation generated. A behaviour law was found for the permeability characterisation of the house based on the active SD performance and also, the relationship between wind velocity and extraction airflow during passive SD operation by means of a rotating cowl was obtained. Radon reductions in excess of 85% were achieved for the different testing phases in all cases. Finally, from the results it was postulated that a fan power of 20 W is sufficient to ensure radon reductions over 85% for dwellings with similar aggregate layer and soil permeability.
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•Active and passive soil depressurisation (SD) ability was studied in a pilot house.•Radon concentration and pressure field extension (PFE) under slab were monitored.•Radon behaviour was analysed under the influence of atmospheric parameters.•Pressure drop with distance was found proportional to depressurisation under slab.•Over 85% radon reduction was achieved for active and passive SD.
Liver inflammation is a common extraintestinal manifestation in inflammatory bowel disease (IBD), yet, the mechanisms driving gut‐liver axis inflammation remain poorly understood. IBD leads to a ...breakdown in the integrity of the intestinal barrier causing an increase in portal and systemic gut‐derived antigens, which challenge the liver. Here, we examined the role of platelet activating factor receptor (PAFR) in colitis‐associated liver damage using dextran sulfate sodium (DSS) and anti‐CD40‐induced colitis models. Both DSS and anti‐CD40 models exhibited liver inflammation associated with colitis. Colitis reduced global PAFR protein expression in mouse livers causing an exclusive re‐localization of PAFR to the portal triad. The global decrease in liver PAFR was associated with increased sirtuin 1 while relocalized PAFR expression was limited to Kupffer cells (KCs) and co‐localized with toll‐like receptor 4. DSS activated the NLRP3‐inflammasome and increased interleukin (IL)‐1β in the liver. Antagonism of PAFR amplified the inflammasome response by increasing NLRP3, caspase‐1, and IL‐1β protein levels in the liver. LPS also increased NLRP3 response in human hepatocytes, however, overexpression of PAFR restored the levels of NLPR3 and caspase‐1 proteins. Interestingly, KCs depletion also increased IL‐1β protein in mouse liver after DSS challenge. These data suggest a protective role for PAFR‐expressing KCs during colitis and that regulation of PAFR is important for gut‐liver axis homeostasis.
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract (GIT). Cigarette smoke (CS) exposure and chronic obstructive pulmonary disease (COPD) are risk factors for CD, ...although the mechanisms involved are poorly understood. We employed a mouse model of CS-induced experimental COPD and clinical studies to examine these mechanisms. Concurrent with the development of pulmonary pathology and impaired gas exchange, CS-exposed mice developed CD-associated pathology in the colon and ileum, including gut mucosal tissue hypoxia, HIF-2 stabilization, inflammation, increased microvasculature, epithelial cell turnover, and decreased intestinal barrier function. Subsequent smoking cessation reduced GIT pathology, particularly in the ileum. Dimethyloxaloylglycine, a pan-prolyl hydroxylase inhibitor, ameliorated CS-induced GIT pathology independently of pulmonary pathology. Prior smoke exposure exacerbated intestinal pathology in 2,4,6-trinitrobenzenesulfonic acid-induced (TNBS-induced) colitis. Circulating vascular endothelial growth factor, a marker of systemic hypoxia, correlated with CS exposure and CD in mice and humans. Increased mucosal vascularisation was evident in ileum biopsies from CD patients who smoke compared with nonsmokers, supporting our preclinical data. We provide strong evidence that chronic CS exposure and, for the first time to our knowledge, associated impaired gas exchange cause systemic and intestinal ischemia, driving angiogenesis and GIT epithelial barrier dysfunction, resulting in increased risk and severity of CD.
Anastomotic leak rates have not improved over several decades despite improvements in surgical techniques and patient care. The gut microbiome has been implicated in the development of leaks. The ...exact mechanisms by which tissue oxygenation affects gut microbial composition and anastomotic healing physiology are unclear. Also, commonly used carbon dioxide (CO2) is a known vasodilator that improves tissue oxygen tension. We performed a systematic review to determine the influence of hyperoxia, hypoxia, and hypercapnia on the gut microbiome and anastomotic healing.
A literature search was performed in MEDLINE, EMBASE, and COCHRANE to identify studies investigating the effects of hyperoxia, hypoxia, and hypercapnia on anastomotic healing and gut microbiota published between 1998 and 2018. Two reviewers screened the articles for eligibility and quality. Fifty-three articles underwent full text review, and a narrative synthesis was undertaken.
Hyperoxia is associated with better anastomotic healing, increased gastrointestinal oxygen tension, and may reduce gut anaerobes. Hypoxia is associated with poor healing and increased gut anaerobes. However, it is unclear if hypoxia is the most important predictor of anastomotic leaks. Low pressure CO2 pneumoperitoneum and mild systemic hypercapnia are both associated with increased gastrointestinal oxygen tension and may improve anastomotic healing. We found no studies which investigated the effect of hypercapnia on gut microbiota in the context of anastomotic healing.
Tissue oxygenation influences gut anastomotic healing, but little evidence exists to demonstrate the influence on the gut microbiome in the context of healing. Further studies are needed to determine if anastomotic microbiome changes with altered tissue oxygenation and if this affects healing and leak rates. If confirmed, altering tissue oxygenation through hyperoxia or hypercapnia could be feasible means of altering the microbiome such that anastomotic leak rates reduce.
Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. ...Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40
murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.
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