Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC

Estimating the returns to UK publicly funded cancer-related research in terms of the net value of improved health outcomes

© 2014 Glover et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background - Building on an approach developed to assess the economic returns to cardiovascular research, we estimated the economic returns from UK public and charitable funded cancer-related research that arise from the net value of the improved health outcomes. Methods - To assess these economic returns from cancer-related research in the UK we estimated: 1) public and charitable expenditure on cancer-related research in the UK from 1970 to 2009; 2) net monetary benefit (NMB), that is, the health benefit measured in quality adjusted life years (QALYs) valued in monetary terms (using a base-case value of a QALY of GB£25,000) minus the cost of delivering that benefit, for a prioritised list of interventions from 1991 to 2010; 3) the proportion of NMB attributable to UK research; 4) the elapsed time between research funding and health gain; and 5) the internal rate of return (IRR) from cancer-related research investments on health benefits. We analysed the uncertainties in the IRR estimate using sensitivity analyses to illustrate the effect of some key parameters. Results - In 2011/12 prices, total expenditure on cancer-related research from 1970 to 2009 was £15 billion. The NMB of the 5.9 million QALYs gained from the prioritised interventions from 1991 to 2010 was £124 billion. Calculation of the IRR incorporated an estimated elapsed time of 15 years. We related 17% of the annual NMB estimated to be attributable to UK research (for each of the 20 years 1991 to 2010) to 20 years of research investment 15 years earlier (that is, for 1976 to 1995). This produced a best-estimate IRR of 10%, compared with 9% previously estimated for cardiovascular disease research. The sensitivity analysis demonstrated the importance of smoking reduction as a major source of improved cancer-related health outcomes. Conclusions - We have demonstrated a substantive IRR from net health gain to public and charitable funding of cancer-related research in the UK, and further validated the approach that we originally used in assessing the returns from cardiovascular research. In doing so, we have highlighted a number of weaknesses and key assumptions that need strengthening in further investigations. Nevertheless, these cautious estimates demonstrate that the returns from past cancer research have been substantial, and justify the investments made during the period 1976 to 1995.Wellcome Trust, Cancer Research UK, the National Institute of Health Research, and the Academy of Medical Sciences

A Comparison of Stress Levels, Coping Styles and Psychological Morbidity Between Graduate-entry and Traditional Undergraduate Medical Students During the First 2 Years at a UK Medical School.

Background: Stress levels and psychological morbidity are high among undergraduate medical students (UGs), but there is a lack of research into the psychological health of UK graduate-entry medical students (GEs). GEs are likely to experience different (perhaps more severe) stressors and to cope with stress differently. We compared stress levels, psychological morbidity and coping styles in GE versus UG medical students studying at the same UK medical school in the same academic year. Method: A cross-sectional self-rated questionnaire study of all first- and second-year GE and UG medical students. Perceived stress, psychological morbidity, recent adverse life events, stress-related personality traits and coping styles were assessed using standard questionnaires. Results: 75% GEs and 46% UGs responded to the questionnaire. Both groups reported equally high levels, and similar profiles of, perceived stress and psychological morbidity. Levels of recent adverse life events and stress-related personality traits were similar in both groups. Compared to UGs, GEs were more likely to use active coping (p = 0.02) and positive reframing (p = 0.03), but were also more likely to use substances (alcohol and other drugs; p < 0.001) to help them cope. Unlike UGs, second-year GEs showed less perceived stress (p = 0.007) and psychological morbidity (p = 0.006) than first-year GEs although levels of both were still high. Conclusion: Our results show that both GE students and their younger UG counterparts on a traditional medical course have similar profiles of stress symptoms. They do, however, cope with stress differently. GEs are more likely to use active problem-focused coping strategies, and they are also more likely to cope by using substances (alcohol or other drugs). GE students need interventions to prevent maladaptive coping styles and encourage adaptive coping that are tailored to their needs. Such interventions should be targeted at first-year students. It is vital that these students develop positive coping skills to benefit them during training and in a future career that is inherently stressful

Scientific Opinion on the evaluation of the safety in use of Yohimbe (Pausinystalia yohimbe (K. Schum.) Pierre ex Beille)

The Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion evaluating the safety in use of yohimbe bark and its preparations originating from Yohimbe (Pausinystalia yohimbe (K. Schum.) Pierre ex Beille when used in food, e.g. in food supplements. The bark of the plant contains a number of indole alkaloids of biological relevance and preparations of yohimbe bark have been traditionally used as general tonic, performance enhancer and as an aphrodisiac. Food supplements containing yohimbe bark preparations are available nowadays, especially via internet retail. Yohimbine, the major alkaloid of yohimbe bark and raubasine, another alkaloid occurring in lower concentrations in the bark, are used as active ingredients in a number of medicinal products for which adverse effects are described. The Panel reviewed the available scientific data on a possible association between the intake of yohimbe bark and its preparations and potential harmful effects on health. When those data were not available, priority was given to yohimbine, as the only alkaloid for which occurrence had been shown and quantified in food supplements containing yohimbe bark. The Panel concluded that the chemical and toxicological characterisation of yohimbe bark and its preparations for use in food are not adequate to conclude on their safety as ingredients of food, e.g. in food supplements. Thus the Panel could not provide advice on a daily intake of yohimbe bark and its preparations that do not give rise to concerns about harmful effects to health. An estimation of exposure to yohimbine from food supplements was performed showing that theoretical maximum daily intake may exceed the maximum approved daily dose of yohimbine from use as a medicinal product

Tamoxifen and raloxifene modulate gap junction coupling during early phases of retinoic acid-dependent neuronal differentiation of NTera2/D1 cells

Gap junctions (GJ) represent a cellular communication system known to influence neuronal differentiation and survival. To assess a putative role of this system for neural effects of tamoxifen (TAM) and raloxifene (RAL), we used the human teratocarcinoma cell line NTera2/D1, retinoic acid (RA)-dependent neuronal differentiation of which is regulated by gap junctions formed of connexin43 (Cx43). As demonstrated by Western blot analysis, concentrations above 1 µmol/l for TAM, and 0.1 µmol/l for RAL lead to a temporary time- and concentration-dependent increase in Cx43 immunoreactivity, which reached a peak for TAM after 1 day and for RAL after 2 days. Immunocytochemical stainings revealed the increase in Cx43 immunoreactivity to result from an accumulation in intracellular compartments such as the Golgi apparatus or lysosomes. In addition, TAM and RAL were able to prevent the RA-dependent decrease of Cx43 immunoreactivity in NTera2/D1 cells, normally observed during neuronal differentiation. This suggested a suppression of neuronal differentiation to result from these substances. According to this, treatment of NTera2/D1 cells with 10 µmol/l TAM or RAL during weeks 1 and 2 of a 6 weeks RA-driven differentiation schedule impaired, whereas treatment during weeks 5 and 6 did not impair, neuronal differentiation of these cells. Modulation of GJ coupling between NTera2/D1 cells by TAM and RAL seems therefore to perturb early neuronal differentiation, whereas differentiated neurons in the mature brain seem to be not affected. These effects could be of importance for actions of TAM and RAL on early embryonic steps of nervous system formation

Frequency of symptoms, determinants of severe symptoms, validity of and cut-off score for Menopause Rating Scale (MRS) as a screening tool: A cross-sectional survey among midlife Nepalese women

<p>Abstract</p> <p>Background</p> <p>Majority of Nepalese women live in remote rural areas, where health services are not easily accessible. We determined the validity of Menopause Rating Scale (MRS) as a screening tool for identification of women with severe menopausal symptoms and cut-off MRS score for referral.</p> <p>Methods</p> <p>A cross-sectional survey was carried out between February and August, 2008. Trained health workers administered MRS and a questionnaire to 729 women (40 to 65 years) attending health screening camps in Kaski district of Western Development Region of Nepal. Information about demographics, menopausal status, and use of hormone replacement therapy (HRT), chronic disease, self-perceived general health and reproductive history was also collected. Menopausal status was classified according to the Staging of Reproductive Ageing Workshop (STRAW). We calculated rates of menopausal symptoms, sensitivity, and specificity and likelihood ratios of MRS scores for referral to a gynaecologist. We also carried out multivariate analyses to identify the predictors for referral to a gynaecologist for severe symptoms.</p> <p>Results</p> <p>A total 729 women were interviewed. Mean age at menopause was 49.9 years (SD 5.6). Most frequently reported symptoms were, sleeping problems (574, 78.7%), physical and mental exhaustion (73.5%), hot flushes (508, 69.7%), joint and muscular discomfort (500, 68.6%) and dryness of vagina (449, 61.6%). Postmenopausal women (247, 33.9%) and perimenopausal (215, 29.5%) women together experienced significantly higher prevalence of all symptoms than the premenopausal (267, 36.6%) women. MRS score of ≥16 had highest ratio for (sensitivity + specificity)/2. Women who reported urogenital symptoms [OR 5.29, 95% CI 2.59, 10.78], and self perceived general health as poor [OR 1.29, 95% CI 1.11, 1.53] were more likely to be referred to a gynaecologist for severe menopausal symptoms. While women reporting somatic [OR 0.72, 95% CI 0.63, 0.82] and psychological [OR 0.86, 95% CI 0.74, 0.99] symptoms were less likely to be referred.</p> <p>Conclusion</p> <p>MRS may be used as a screening tool at a cut-off score of ≥16 with least misclassification rate. However, its utility may be limited by woman's general health status and occurrence of urogenital symptoms.</p

Sugar Overconsumption during Adolescence Selectively Alters Motivation and Reward Function in Adult Rats

International audienceBACKGROUND:There has been a dramatic escalation in sugar intake in the last few decades, most strikingly observed in the adolescent population. Sugar overconsumption has been associated with several adverse health consequences, including obesity and diabetes. Very little is known, however, about the impact of sugar overconsumption on mental health in general, and on reward-related behavioral disorders in particular. This study examined in rats the effects of unlimited access to sucrose during adolescence on the motivation for natural and pharmacological rewards in adulthood.METHODOLOGY/PRINCIPAL FINDINGS:Adolescent rats had free access to 5% sucrose or water from postnatal day 30 to 46. The control group had access to water only. In adulthood, rats were tested for self-administration of saccharin (sweet), maltodextrin (non-sweet), and cocaine (a potent drug of abuse) using fixed- and progressive-ratio schedules, and a concentration-response curve for each substance. Adult rats, exposed or not exposed to sucrose, were tested for saccharin self-administration later in life to verify the specificity of adolescence for the sugar effects. Sugar overconsumption during adolescence, but not during adulthood, reduced the subsequent motivation for saccharin and maltodextrin, but not cocaine. This selective decrease in motivation is more likely due to changes in brain reward processing than changes in gustatory perception.CONCLUSIONS/SIGNIFICANCE:Sugar overconsumption induces a developmental stage-specific chronic depression in reward processing that may contribute to an increase in the vulnerability to reward-related psychiatric disorders