The Influence of Different Physical Activity Behaviours on the Gut Microbiota of Older Irish Adults.

OBJECTIVE: A 24-hour day is made up of time spent in a range of physical activity (PA) behaviours, including sleep, sedentary time, standing, light-intensity PA (LIPA) and moderate-to-vigorous PA (MVPA), all of which may have the potential to alter an individual's health through various different pathways and mechanisms. This study aimed to explore the relationship between PA behaviours and the gut microbiome in older adults. DESIGN: Cross-sectional study. SETTINGS AND PARTICIPANTS: Participants (n=100; age 69.0 [3.0] years; 44% female) from the Mitchelstown Cohort Rescreen (MCR) Study (2015-2017). METHODS: Participants provided measures of gut microbiome composition (profiled by sequencing 16S rRNA gene amplicons), and objective measures of PA behaviours (by a 7-day wear protocol using an activPAL3 Micro). RESULTS: Standing time was positively correlated with the abundance of butyrate-producing and anti-inflammatory bacteria, including Ruminococcaceae, Lachnospiraceae and Bifidobacterium, MVPA was positively associated with the abundance of Lachnospiraceae bacteria, while sedentary time was associated with lower abundance of Ruminococcaceae and higher abundance of Streptococcus spp. CONCLUSION: Physical activity behaviours appear to influence gut microbiota composition in older adults, with different PA behaviours having diverging effects on gut microbiota composition.

Improvements in Clinical Outcomes in Children with Cystic Fibrosis aged Six and 16 years.

Aims Our aim was to assess if outcomes for cystic fibrosis (CF) patients at six & sixteen years of age have improved in the last 17 years looking at FEV1, BMI and death. Methods A retrospective observational study using a prospectively maintained database of CF patients at Cork University Hospital. Results 84 patients were included in the 16-year-old data and 89 patients were included in the six-year-old data. The mean FEV1 and BMI (16 years) for the 2002-2007 group was 72.9±21.0% and 18.9±2.53 respectively, 2008-2013 group was 75.4±27.2% and 19.8±2.7 and for the 2014-2018 group was 95.2±16.0% and 22.9±4.1. The percentage of patients (16 years) with chronic pseudomonas status was 37.9% (11/30) in the 2002-2007 group, 51.6 % (16/31) in the 2008-2013 group and 4.2% (1/24) in the 2014-2018 group. The relationship between FEV1 and FVC with BMI remained significant in multivariate analysis (P <0.001). The mean FEV1 (six years) for the 2002-2007 group was 90.7±16.1%, 2008-2013 group was 99.3±17.9% and for the 2014-2018 group was 100.9±15.8%. Conclusions Improvements in FEV1 and BMI aged six and 16 years are notable as well as a significant decline in the number of patients with chronic pseudomonas.

Design and powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy endpoint.

BACKGROUND: Reduction in pulmonary exacerbations is an important efficacy endpoint for CF clinical studies. Powering exacerbation endpoints requires estimation of the future exacerbation incidence in CF study populations, but rates differ across the population. METHODS: We have estimated exacerbation rates for Epidemiologic Study of CF subpopulations stratified by age, FEV(1)% predicted, sex, weight-for-age percentile, respiratory signs and symptoms, and history of exacerbation and bacterial culture. Sample sizes required to attain 80% power to detect exacerbation reductions of 20% to 80% in 1:1 randomized studies of 3 to 12 month duration were determined. Exacerbation treatments with "any" antibiotic (new oral quinolone, new inhaled antibiotic, or intravenous (IV) antibiotic) and with IV antibiotics were studied. RESULTS: At all ages, decreased FEV(1), female sex, exacerbation history, and Pseudomonas aeruginosa culture history were associated with increased treatment for exacerbation. CONCLUSIONS: These data should assist investigators in the design of future CF exacerbation studies.

Design and powering of cystic fibrosis clinical trials using rate of FEV(1) decline as an efficacy endpoint.

BACKGROUND: Rate of lung function decline (RLFD) (as FEV(1) percent predicted/yr) is a robust measure of CF therapeutic efficacy rarely used as a study endpoint, in part due to uncertainty of sample size requirements. METHODS: Sample size requirements for 1:1 randomizations to detect RLFD treatment effects from 20% to 80% were assessed in Epidemiologic Study of CF (ESCF) patients. Effects of measuring FEV(1) 1-4 times per year in studies of 1- to 4-year durations were assessed in 399 patients age ≥ 6 years with FEV(1) ≥ 70%. Impacts of inclusion/exclusion based on risk factors in 2369 ESCF patients were assessed over 1.5 years using semi-annual FEV(1) measures. RESULTS: Increasing study duration and exclusion of lower risk patients (e.g., no P. aeruginosa infection) both substantially reduced requirements. CONCLUSIONS: CF RLFD studies of 1.5 years in duration appear feasible provided that investigators account for the beneficial effects of subject inclusion/exclusion based on risk factors in power estimates.

beta-Catenin initiates tooth neogenesis in adult rodent incisors.

beta-Catenin signaling is required for embryonic tooth morphogenesis and promotes continuous tooth development when activated in embryos. To determine whether activation of this pathway in the adult oral cavity could promote tooth development, we induced mutation of epithelial beta-catenin to a stabilized form in adult mice. This caused increased proliferation of the incisor tooth cervical loop, outpouching of incisor epithelium, abnormal morphology of the epithelial-mesenchymal junction, and enhanced expression of genes associated with embryonic tooth development. Ectopic dental-like structures were formed from the incisor region following implantation into immunodeficient mice. Thus, forced activation of beta-catenin signaling can initiate an embryonic-like program of tooth development in adult rodent incisor teeth.

Wnt/beta-catenin signaling in oral tissue development and disease.

The Wnt/beta-catenin signaling pathway is one of several key conserved intercellular signaling pathways in animals, and plays fundamental roles in the proliferation, regeneration, differentiation, and function of many cell and tissue types. This pathway is activated in a dynamic manner during the morphogenesis of oral organs, including teeth, taste papillae, and taste buds, and is essential for these processes to occur normally. Conversely, forced activation of Wnt/beta-catenin signaling promotes the formation of ectopic teeth and taste papillae. In this review, we discuss our current understanding of the roles of Wnt/beta-catenin signaling in oral tissue development and in related human diseases, and the potential of manipulating this pathway for therapeutic purposes.

Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells.

Epithelial stem cells in the bulge region within the hair follicle maintain the cyclic hair growth, but whether these stem cells also contribute to the epidermal renewal remains unclear. Here, we observed that the conditional deletion of the Rac1 gene in the mouse skin, including the potential follicular and epidermal stem cell compartments, results in alopecia owing to defective hair development. Surprisingly, mice lacking the expression of this Rho GTPase do not display major alterations in the interfollicular skin. Furthermore, Rac1 excision from primary epithelial keratinocytes results in the inability to reconstitute hair follicles and sebaceous glands when grafted onto mice, but epithelial cells lacking Rac1 can nonetheless form a healthy epidermis. Together, these findings support the emerging view that the epidermis and the hair follicles are maintained by different epithelial stem cells, and provide evidence that the requirement for Rac1 function can distinguish these distinct stem cells populations.

Over- and ectopic expression of Wnt3 causes progressive loss of ameloblasts in postnatal mouse incisor teeth.

Intercellular signaling is essential for the development of teeth during embryogenesis and in maintenance of the continuously growing incisor teeth in postnatal rodents. WNT intercellular signaling molecules have been implicated in the regulation of tooth development, and the Wnt3 gene shows specific expression in the enamel knot at the cap stage. We demonstrate here that Wnt3 also is expressed in specific epithelial cell layers in postnatal incisor teeth. To begin to delineate the functions of Wnt3 in developing and postnatal teeth, we determined the effects of over- and ectopic expression of Wnt3 in the tooth epithelium of mice carrying a keratin 14-Wnt3 transgene. Expression of the transgene caused a progressive loss of ameloblasts from postnatal lower incisor teeth. Loss of ameloblasts may be due to defective proliferation or differentiation of ameloblast precursors, progressive apoptosis of ameloblasts, or loss of ameloblast stem cells.

Cerebral hypoperfusion in immediate postoperative period following coronary artery bypass grafting, heart valve, and abdominal aortic surgery.

Perioperative levels of jugular bulb oxyhaemoglobin saturation (Sj(O(2))) and lactate concentration (Lj), and postoperative duration of Sj(O(2))<50% were compared between patients undergoing coronary artery bypass grafting (CABG) (n=86), heart valve (n=14) and abdominal aortic (n=16) surgery. Radial artery and jugular bulb blood samples were aspirated after induction of anaesthesia, during re-warming on cardiopulmonary bypass (CPB) (36 degrees C), on arrival in the intensive care unit (ICU) and, subsequently, at 1, 2 and 6 h after ICU admission. Most patients having heart surgery were hypocapnic at 36 degrees C on CPB. Following CABG and heart valve surgery, many patients were hypocapnic whereas after abdominal aortic surgery, most were hypercapnic. During CPB and postoperatively, Sj(O(2)) and Lj were significantly correlated to Pa(CO(2)) and the arterial concentration of lactate (La) respectively (P<0.05). After correction for arterial carbon dioxide tension (Pa(CO(2))) and La, there were no significant changes in Sj(O(2)) or Lj on CPB. Postoperatively, having corrected for Pa(CO(2)), there were significant effects on Sj(O(2)) over all groups as a result of time from surgery (P<0.001) and its interaction with operation type (P<0.001). Following correction for La, there were no postoperative effects on Lj. No significant differences (P=0.2) in duration of Sj(O(2))<50% existed between patients undergoing CABG (1054 (82) min), abdominal aortic (893 (113) min) and heart valve (1073 (91) min) surgery. The lack of significant reciprocal effects on Lj combined with the frequency of hypocapnia and strong influence of Pa(CO(2))()on Sj(O(2)), suggest that Sj(O(2))<50% during CPB and after cardiac surgery represents hypoperfusion as a consequence of hypocapnia rather than cerebral ischaemia.

Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis.

Mutations in WNT effector genes perturb hair follicle morphogenesis, suggesting key roles for WNT proteins in this process. We show that expression of Wnts 10b and 10a is upregulated in placodes at the onset of follicle morphogenesis and in postnatal hair follicles beginning a new cycle of hair growth. The expression of additional Wnt genes is observed in follicles at later stages of differentiation. Among these, we find that Wnt5a is expressed in the developing dermal condensate of wild type but not Sonic hedgehog (Shh)-null embryos, indicating that Wnt5a is a target of SHH in hair follicle morphogenesis. These results identify candidates for several key follicular signals and suggest that WNT and SHH signaling pathways interact to regulate hair follicle morphogenesis.

The effect of ionising radiation on the colour of beef, pork and lamb.

The effect of irradiation (0 and 5 kGy) of beef, pork and lamb portions in retail overwrap packs and subsequent storage at 4°C was studied in relation to colour changes. The colour of the exterior surface of beef and pork was measured on the same samples on each day of storage for up to 7 days post irradiation. On day 7 the colour of a freshly cut surface was measured. The colour of both the exterior and a freshly cut surface of lamb, in similar retail overwrap packs was measured at 2, 5 and 7 days, post irradiation, different samples being used on each day of measurement. L* values of irradiated beef increased significantly with storage and a* values for unirradiated samples decreased significantly with storage. For lamb there was a general increase in L* and h(o) values and a decrease in a*, b* and C* values with storage. Analyses of the day 7 data showed statistically significant effects for species on all CIELAB parameters. Irradiation resulted in significantly higher hue angle (h(o)) values and the a*, b* and C* values were significantly higher on the exterior than freshly cut surface. There were a number of statistically significant 2 factor and 3 factor interactions. The role of formation of a carboxyhaem pigment in the colour of irradiated meat is discussed. The problem of interpretation of pigment changes from CIELAB values is highlighted.

The effect of ionising radiation on the colour of leg and breast of poultry meat.

The effect of irradiation (0 and 5 kGy) of chicken, goose and turkey breast and leg muscles and subsequent storage at 4°C was studied in relation to colour changes. The colour of the outside surface was measured on the breast on each day of storage for up to 7 days post irradiation and for breast and leg and day 7. The colour of a freshly cut interior surface of both breast and leg was measured after 7 days storage. L* values of control and irradiated chicken, goose and turkey breast muscles changed little during storage post irradiation. The a* values for unirradiated goose breast were significantly higher than irradiated goose breast but declined to values similar to irradiated goose breast after 7 days of storage. The b* values for irradiated turkey breast were significantly higher than unirradiated turkey breast at all times post irradiation treatment. Analysis of variance was performed on the day 7 CIELAB values of breast muscle for the effects of species, surface and irradiation and their interactions. After 7 days storage a* values of poultry breast were higher on the freshly cut surface due to irradiation in all species, with decreases in hue angle due to irradiation. The a* values of leg of all species at 7 day post irradiation was significantly higher in the irradiated treatment than the controls. The results for the turkey leg indicate that this effect may be mainly due to higher a* values of the freshly cut surface. The possible role of carboxy form of the haem pigments as the irradiated pigment form is discussed.

Continuous monitoring of jugular bulb oxyhaemoglobin saturation using the Edslab dual lumen oximetry catheter during and after cardiac surgery.

Fibreoptic jugular bulb oximetry has been validated for use in the care of severely head-injured patients. We compared bench and fibreoptic methods of measuring jugular bulb oxyhaemoglobin saturation (SjO2) in 33 patients undergoing cardiac surgery both during cardiopulmonary bypass (CPB) and in the early postoperative period. After insertion of a fibreoptic reflectance oximetry catheter into the jugular bulb, it was calibrated against a bench oximeter. Comparisons were made while on CPB (n = 60) and in the postoperative period for up to 18 h (n = 215). There was negligible bias throughout. There were wide limits of agreements (mean difference +/- 2SD) between the two methods during operation (-20.29% to 18.05%), whereas after operation the limits of agreement were far narrower (-6.39% and 7.45%). Measurement of SjO2 by the fibreoptic method compared poorly with bench oximetry during CPB but there was good agreement between the two methods in the early postoperative period.

WNT signaling in the control of hair growth and structure.

Characterization of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles is central to our understanding of the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. We demonstrate that the proto-oncogene Wnt3, which encodes a secreted paracrine signaling molecule, is expressed in developing and mature hair follicles and that its overexpression in transgenic mouse skin causes a short-hair phenotype due to altered differentiation of hair shaft precursor cells, and cyclical balding resulting from hair shaft structural defects and associated with an abnormal profile of protein expression in the hair shaft. A putative effector molecule for WNT3 signaling, the cytoplasmic protein Dishevelled 2 (DVL2), is normally present at high levels in a subset of cells in the outer root sheath and in precursor cells of the hair shaft cortex and cuticle which lie immediately adjacent to Wnt3-expressing cells. Overexpression of Dvl2 in the outer root sheath mimics the short-hair phenotype produced by overexpression of Wnt3, supporting the hypothesis that Wnt3 and Dvl2 have the potential to act in the same pathway in the regulation of hair growth. These experiments demonstrate a previously unrecognized role for WNT signaling in the control of hair growth and structure, as well as presenting the first example of a mammalian phenotype resulting from overexpression of a Dvl gene and providing an accessible in vivo system for analysis of mammalian WNT signaling pathways.

Aerobic, anaerobic and combination estimates of cerebral hypoperfusion during and after cardiac surgery.

We studied 15 patients undergoing cardiac surgery involving hypothermic cardiopulmonary bypass (CPB). Cerebral arteriovenous difference in oxygen content (AVDO2) was significantly less during CPB and for up to 18 h after operation compared with pre-CPB values (P < 0.05). There were no significant changes in mean jugular bulb oxyhaemoglobin saturation (SjvO2), cerebral arteriovenous difference in lactate content or lactate-oxygen index (LOI). SjVO2 and arterial carbon dioxide tension (PaCO2) (P = 0.005) were positively correlated as were AVDO2 and haemoglobin concentration (P = 0.012). AVDO2 and PaCO2 (P = 0.007) were negatively correlated as were LOI and arterial oxyhaemoglobin saturation (P = 0.037). There were no significant correlations between mean arterial pressure and any of the variables. SjVO2 and AVDO2 may require correction for changes in PaCO2 and haemoglobin concentration before relating these variables to cerebral outcome.

Cytokines in human breast milk.

In early life humans derive all their nutrients from milk. Human milk provides the neonate with not only a food source but also a source of biologically active molecules such as hormones, growth factors and cytokines. Cytokines are multifunctional glycoproteins involved in cell communication and immune system activation. Two of these cytokines, granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6), are present in variable concentrations in human milk. We measured G-CSF and IL-6 concentrations in healthy nursing mothers. The 30 milk samples assayed contained G-CSF levels from 14 pg/mL to > 2500 pg/mL. Of the 28 milk samples assayed for IL-6, 24 contained levels from 0.81 pg/mL to 306 pg/ mL. The remainder had levels below the detection limit of the assay. These biologically active molecules may play a role in neonatal growth and development, and may also protect the infant against infection.

Controlled acceleration and inhibition of bergman cyclization by metal chlorides.

The Bergman cyclization has been the subject of renewed interest with the discovery of naturally occurring enediyne-based antitumor agents that cleave DNA by means of an aromatic diradical. These natural substrates have a means to trigger this cycloaromatization process. Control of this reaction by substrate modification would allow aromatic diradicals to be generated selectively. In the studies presented here it is disclosed that the Bergman cyclization of 1,2-bis(diphenyl phosphinoethynyl) benzene was accelerated by a factor of >30,000 by the addition of palladium(II) chloride or platinum(II) chloride and was inhibited by the addition of mercury(II) chloride.