Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes.

In specific cell types like keratinocytes, Notch signaling plays an important pro-differentiation and tumor suppressing function, with down-modulation of the Notch1 gene being associated with cancer development. Besides being controlled by p53, little else is known on regulation of Notch1 gene expression in this context. We report here that transcription of this gene is driven by a TATA-less "sharp peak" promoter and that the minimal functional region of this promoter, which extends from the -342 bp position to the initiation codon, is differentially active in normal versus cancer cells. This GC rich region lacks p53 binding sites, but binds Klf4 and Sp3. This finding is likely to be of biological significance, as Klf4 and, to a lesser extent, Sp3 are up-regulated in a number of cancer cells where Notch1 expression is down-modulated, and Klf4 over-expression in normal cells is sufficient to down-modulate Notch1 gene transcription. The combined knock-down of Klf4 and Sp3 was necessary for the reverse effect of increasing Notch1 transcription, consistent with the two factors exerting an overlapping repressor function through their binding to the Notch1 promoter.

Impact of perinatal factors on continuous early monitoring of brain electrocortical activity in very preterm newborns by amplitude-integrated EEG.

Background:Amplitude-integrated electroencephalogram (aEEG) is increasingly used for neuromonitoring in preterms. We aimed to quantify the effects of gestational age (GA), postnatal age (PNA), and other perinatal factors on the development of aEEG early after birth in very preterm newborns with normal cerebral ultrasounds.Methods:Continuous aEEG was prospectively performed in 96 newborns (mean GA: 29.5 (range: 24.4-31.9) wk, birth weight 1,260 (580-2,120) g) during the first 96 h of life. aEEG tracings were qualitatively (maturity scores) and quantitatively (amplitudes) evaluated using preestablished criteria.Results:A significant increase in all aEEG measures was observed between day 1 and day 4 and for increasing GA (P < 0.001). The effect of PNA on aEEG development was 6.4- to 11.3-fold higher than that of GA. In multivariate regression, GA and PNA were associated with increased qualitative and quantitative aEEG measures, whereas small-for-GA status was independently associated with increased maximum aEEG amplitude (P = 0.003). Morphine administration negatively affected all aEEG measures (P < .05), and caffeine administration negatively affected qualitative aEEG measures (P = 0.02).Conclusion:During the first few days after birth, aEEG activity in very preterm infants significantly develops and is strongly subjected to the effect of PNA. Perinatal factors may alter the early aEEG tracing and interfere with its interpretation.

Division of labour and worker size polymorphism in ant colonies: the impact of social and genetic factors

Division of labour among workers is central to the organisation and ecological success of insect societies. If there is a genetic component to worker size, morphology or task preference, an increase in colony genetic diversity arising from the presence of multiple breeders per colony might improve division of labour. We studied the genetic basis of worker size and task preference in Formica selysi, an ant species that shows natural variation in the number of mates per queen and the number of queens per colony. Worker size had a heritable component in colonies headed by a doubly mated queen (h(2)=0.26) and differed significantly among matrilines in multiple-queen colonies. However, higher levels of genetic diversity did not result in more polymorphic workers across single- or multiple-queen colonies. In addition, workers from multiple-queen colonies were consistently smaller and less polymorphic than workers from single-queen colonies. The relationship between task, body size and genetic lineage appeared to be complex. Foragers were significantly larger than brood-tenders, which may provide energetic or ergonomic advantages to the colony. Task specialisation was also often associated with genetic lineage. However, genetic lineage and body size were often correlated with task independently of each other, suggesting that the allocation of workers to tasks is modulated by multiple factors. Overall, these results indicate that an increase in colony genetic diversity does not increase worker size polymorphism but might improve colony homeostasis.

Effects of short-term high-fructose diets in humans: modulation by environmental factors

It is currently suspected that sugar overconsumption, and more specifically fructose, may promote the development of obesity and of several cardio-metabolic disorders. However, environmental factors, such as fish oil and dietary proteins, may prevent some deleterious effects of fructose. The aim of this thesis was to identify potential environmental factors that may modulate the metabolic effects of fructose. The first study was designed to evaluate the impact of endurance exercise in healthy young men fed a high-fructose, isocaloric diet. Fructose-induced effects on lipid profile were totally prevented by endurance exercise and may be explained by an enhanced clearance of TRL-TG and the inhibition of de novo lipogenesis. As energy intake was adjusted to energy requirement, we can conclude that exercise acts on fructose metabolism independently of energy imbalance. The second study aimed at determining whether coffee and more specifically chlorogenic acid consumption may prevent fructose-induced intrahepatic lipids accumulation, hypertriglyceridemia and hepatic insulin resistance, through a stimulation of lipid oxidation. Coffee did not prevent the fructose-induced increase in IHCL or plasma TG. Interestingly, the three coffees tested prevented the decrease in hepatic insulin sensitivity, independently of their content in caffeine or chlorogenic acid. Finally, in the third study, we evaluated the effect of essential amino acid supplementation on the increase of hepatic lipids induced by a high-fructose diet. This intervention slightly decreased IHCL concentration. The exact mechanisms remain unidentified but may involve an increased secretion of VLDL-TG. In conclusion, the environmental factors evaluated allow to prevent some of the deleterious effects of fructose and suggest that recommendations on fructose consumption should also take into account environmental factors.

Association between obesity indices and cardiovascular risk factors in late adolescence in the Seychelles.

ABSTRACT: BACKGROUND: The ability of different obesity indices to predict cardiovascular risk is still debated in youth and few data are available in sub Saharan Africa. We compared the associations between several indices of obesity and cardiovascular risk factors (CVRFs) in late adolescence in the Seychelles. METHODS: We measured body mass index (BMI), waist circumference, waist/hip ratio (WHiR), waist/height ratio (WHtR) and percent fat mass (by bioimpedance) and 6 CVRFs (blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, fasting blood glucose and uric acid) in 423 youths aged 19-20 years from the general population. RESULTS: The prevalence of overweight/obesity and several CVRFs was high, with substantial sex differences. Except for glucose in males and LDL-cholesterol in females, all obesity indices were associated with CVRFs. BMI consistently predicted CVRFs at least as well as the other indices. Linear regression on BMI had standardized regression coefficients of 0.25-0.36 for most CVRFs (p<0.01) and ROC analysis had an AUC between 60%-75% for most CVRFs. BMI also predicted well various combinations of CVRFs: 36% of male and 16% of female lean subjects (BMI P90). CONCLUSION: There was an elevated prevalence of obesity and of several CVRFs in youths in Seychelles. BMI predicted single or combined CVRFs at least as well as other simple obesity indices.

Confounding factors and genetic polymorphism in the evaluation of individual steroid profiling

In the fight against doping, steroid profiling is a powerful tool to detect drug misuse with endogenous anabolic androgenic steroids. To establish sensitive and reliable models, the factors influencing profiling should be recognised. We performed an extensive literature review of the multiple factors that could influence the quantitative levels and ratios of endogenous steroids in urine matrix. For a comprehensive and scientific evaluation of the urinary steroid profile, it is necessary to define the target analytes as well as testosterone metabolism. The two main confounding factors, that is, endogenous and exogenous factors, are detailed to show the complex process of quantifying the steroid profile within WADA-accredited laboratories. Technical aspects are also discussed as they could have a significant impact on the steroid profile, and thus the steroid module of the athlete biological passport (ABP). The different factors impacting the major components of the steroid profile must be understood to ensure scientifically sound interpretation through the Bayesian model of the ABP. Not only should the statistical data be considered but also the experts in the field must be consulted for successful implementation of the steroidal module.

Comportament dinàmic de biomarcadors com a factors pronòstics de supervivència en la sèpsia greu i xoc sèptic.

La sèpsia greu i el xoc sèptic constitueixen una de les principals causes de mort en les unitats de cures intensives. Els biomarcadors són elements importants per al diagnòstic i seguiment, i intenten ser marcadors pronòstics de la gravetat i mortalitat. En aquest treball s’analitza en una cohort de pacients la dinàmica de paràmetres i biomarcadors com la febre, leucòcits, proteïna C reactiva, saturació venosa central d’oxigen, lactat i procalcitonina d’una forma seqüencial i sistemàtica durant les primeres hores de la sèpsia amb l’objectiu d’avaluar el seu poder discriminatiu en quant a pronòstic de supervivència.

Health at work and risk factors related to ergonomics: some results from the Swiss sample of the 4th European working conditions survey

Introduction The European Foundation for the improvement of living and working conditions conducts a survey every 5 years since 1990. The foundation also offers the possibility to non-EU countries to be included in the survey: in 2005, Switzerland took part for the first time in the fourth edition of this survey. The Institute for Work and Health (IST) has been associated to the Swiss project conducted under the leadership of the SECO and the Fachhochschule Nordwestschweiz. The survey covers different aspects of work like job characteristics and employment conditions, health and safety, work organization, learning and development opportunities, and the balance between working and non-working life (Parent-Thirion, Fernandez Macias, Hurley, & Vermeylen, 2007). More particularly, one question assesses the worker's self-perception of the effects of work on health. We identified (for the Swiss sample) several factors affecting the risk to report health problems caused by work. The Swiss sample includes 1040 respondents. Selection of participants was based on a random multi-stage sampling and was carried out by M.I.S Trend S.A. (Lausanne). Participation rate was 59%. The database was weighted by household size, gender, age, region of domicile, occupational group, and economic sector. Specially trained interviewers carried out the interviews at the respondents home. The survey was carriedout between the 19th of September 2005 and the 30th of November 2005. As detailed in (Graf et al., 2007), 31% of the Swiss respondents identify work as the cause of health problems they experience. Most frequently reported health problems include back pain (18%), stress (17%), muscle pain (13%), and overall fatigue (11%). Ergonomic aspects associated with higher risk of reporting health problems caused by work include frequent awkward postures (odds ratio [OR] 4.7, 95% confidence interval [CI] 3.1 to 5.4), tasks involving lifting heavy loads (OR 2.7, 95% CI 2.0 to 3.6) or lifting people (OR 2.2, 95% CI 1.4 to 3.5), standing or walking (OR 1.4, 95% CI 1.1 to 1.9), as well as repetitive movements (OR 1.7, 95% CI 1.3 to 2.3). These results highlight the need to continue and intensify the prevention of work related health problems in occupations characterized by risk factors related to ergonomics.

Outcome and Prognostic Factors in Adenosquamous Carcinoma of the Head and Neck - a Multicenter Rare Cancer Network Study

Background: Adenosquamous carcinoma (AC) of the head and neck is a distinct entity first described in 1968. Its natural history is more aggressive than squamous-cell carcinoma. The aim of this study was to assess the clinical profile, patterns of failure, and prognostic factors in patients with AC of the head and neck treated by radiation therapy (RT) with or without chemotherapy (CT).Materials and Methods: Data from 19 patients with stage I (n = 3), II (n = 1), III (n = 4), or IVa (n = 11) AC, treated between 1989 and 2009, were collected in a retrospective multicenter Rare Cancer Network study. Median age was 60 years (range, 48−73). Fifteen patients were male, and 4 female. Risk factors, including perineural invasion, lymphangitis, vascular invasion, positive margins were present in the majority (83%) of the patients. Tumour sites included oral cavity in 4, oropharynx in 4, hypopharynx in 2, larynx in 2, salivary glands in 2, nasal vestibule in 2, maxillary sinus in 2, and nasopharynx in 1 patient. Surgery (S) was performed in all but 5 patients. S alone was performed in only 1 patient, and definitive RT alone in 3 patients. Fifteen patients received combined modality treatment (S+RT in 11, RT+CT in 2, and all of the three modalities in 2 patients). Median RT dose to the primary and to the nodes was 66 Gy (range, 50−72) and 53 Gy (range, 44−66), respectively (1.8−2.0 Gy/fr., 5 fr./week). In 4 patients, the planning treatment volume included the primary tumour site only. Eight patients were treated with 2D RT, 7 with 3D conformal RT, and 2 with intensity-modulated RT.Results: After a median follow-up period of 39 months (range, 9−62), 9 patients developed distant metastases (lung, bone, mediastinum, and liver), 7 presented nodal recurrences, and only 4 had a local relapse at the primary site (all in-field recurrences). At last follow-up, 7 patients were alive without disease, 1 alive with disease, 9 died from progressive disease, and 2 died from intercurrent disease. The 3-year and median overall survival, disease-free survival (DFS), and locoregional control rates were 55% (95% confidence interval [CI]: 32−78%) and 39 months, 34% (95% CI: 12−56%) and 22 months, and 50% (95% CI: 22−78%) and 33 months, respectively. In multivariate analysis (Cox model), DFS was negatively influenced by the presence of extracapsular extension (p = 0.01) and advanced stage (IV versus I−III, p = 0.002).Conclusions: Overall prognosis of locoregionally advanced AC remains poor, and distant metastases and nodal relapse occur in almost half of the cases. However, local control is relatively better, and early stage AC patients had prolonged DFS when treated with combined-modality treatment.

Predisposing and precipitating factors of delirium after cardiac surgery: a prospective observational cohort study.

OBJECTIVE: To comprehensively assess pre-, intra-, and postoperative delirium risk factors as potential targets for intervention. BACKGROUND: Delirium after cardiac surgery is associated with longer intensive care unit (ICU) stay, and poorer functional and cognitive outcomes. Reports on delirium risk factors so far did not cover the full range of patients' presurgical conditions, intraoperative factors, and postoperative course. METHODS: After written informed consent, 221 consecutive patients ≥ 50 years scheduled for cardiac surgery were assessed for preoperative cognitive performance, and functional and physical status. Clinical and biochemical data were systematically recorded perioperatively. RESULTS: Of the 215 patients remaining for analysis, 31% developed delirium in the intensive care unit. Using logistic regression models, older age [73.3 (71.2-75.4) vs 68.5 (67.0-70.0); P = 0.016], higher Charlson's comorbidity index [3.0 (1.5-4.0) vs 2.0 (1.0-3.0) points; P = 0.009], lower Mini-Mental State Examination (MMSE) score (MMSE, [27 (23-29) vs 28 (27-30) points; P = 0.021], length of cardiopulmonary bypass (CPB) [CPB; 133 (112-163) vs 119 (99-143) min; P = 0.004], and systemic inflammatory response syndrome in the intensive care unit [25 (36.2%) vs 13 (8.9%); P = 0.001] were independently associated with delirium. Combining age, MMSE score, Charlson's comorbidity index, and length of CPB in a regression equation allowed for a prediction of postoperative delirium with a sensitivity of 71.19% and a specificity of 76.26% (receiver operating analysis, area under the curve: 0.791; 95% confidence interval: 0.727-0.845). CONCLUSIONS: Further research will evaluate if modification of these risk factors prevents delirium and improves outcomes.