Coffee and chemoprevention – the genotype decides

In a human intervention study comprising 49 healthy participants, coffee combining natural green coffee bean constituents and dark roast products was identified as a genotype-dependent inducer of Nrf2, significantly affecting Nrf2 gene expression and downstream transcription. Specifically, with 65% of participants showing ≥1.5 fold increase in Nrf2-transcription, the presence of the -651G/A SNP in the Nrf2 gene in conjunction with heterozygosity of the 6/7 AT repeat sequence in the UGT1A1 gene significantly down-regulated coffee-mediated gene expression. Considering the role of the Nrf/ARE pathway in the regulation of antioxidative and chemopreventive phase II efficacy, individual genotype must be considered when examining the potency of bioactive food/food constituents and therapeutic potential.

Direct observation of the gas phase reaction of the cyclohexyl radical with dioxygen using a distonic radical ion approach

Alkylperoxyl radicals are intermediates in the oxidation Of hydrocarbons. The reactive nature of these intermediates, however, has made therin elusive to direct observation and isolation. We have employed ion trap mass spectrometry to synthesize and characterize 4-carboxylatocyclohexyl radical anions ((center dot)C(6)H(10)-CO(2)(-)) and observe their reactivity in the presence of dioxygen. The resulting reaction is facile (k = 1.8 x 10(-10) cm(3) molecule(-1) s(-1) or 30% of calculated collision rate) and results in (i) the addition Of O(2) to form stabilized 4-carboxylatocyclohexylperoxyl radical anions ((center dot)OO-C(6)H(10)-CO(2)(-)), providing the first direct observation of a cyclohexylperoxyl radical, and (ii) elimination of HO(2)(center dot) and HO(center dot) radicals consistent with recent laser-induced fluorescence studies of the reaction of neutral cyclohexyl radicals with O(2). Electronic structure calculations at the B3LYP/6-31+G(d) level of theory reveal viable pathways for the observed reactions showing that formation of the peroxyl radical is exothermic by 37 kcal mol(-1) with subsequent transition states its low as -6.6 kcal mol(-1) (formation of HO(2)(center dot)) and -9.1 kcal mol(-1) (formation of HO(center dot)) with respect to the entrance channel. The combined computational and experimental data Suggest that the structures of the reaction products correspond to cyclohexenes and epoxides from HO(2)(center dot) and HO(center dot) loss, respectively, while alternative pathways leading to cyclohexanone or ring-opened isomers ate not observed, Activation of the charged peroxyl radical (center dot)OO-C(6)H(10)-CO(2)(-) by collision induced disassociation also results in the loss Of HO(2)(center dot) and HO(center dot) radicals confirming that these products are directly connected to the peroxyl radical intermediate.

Effects of short-duration and long-duration exercise on lipoprotein(a)

Purpose Most studies that use either a single exercise session, exercise training, or a cross-sectional design have failed to find a relationship between exercise and plasma lipoprotein(a) [Lp(a)] concentrations. However, a few studies investigating the effects of longer and/or more strenuous exercise have shown elevated Lp(a) concentrations, possibly as an acute-phase reactant to muscle damage. Based on the assumption that greater muscle damage would occur with exercise of longer duration, the purpose of the present study was to determine whether exercise of longer duration would increase Lp(a) concentration and creatine kinase. (CK) activity more than exercise of shorter duration. Methods Ten endurance-trained men (mean +/- SD: age, 27 +/- 6 yr; maximal oxygen consumption [(V)over dotO(2max)], 57 +/- 7 mL(.)kg(-1) min(-1)) completed two separate exercise sessions at 70% (V)over dotO(2max). One session required 900 kcal of energy expenditure (60 +/- 6 min), and the other required 1500 kcal (112 +/- 12 min). Fasted blood samples were taken immediately before (0-pre), immediately after (0-post), 1 d after (1-post), and 2 d after (2-post) each exercise session. Results CK activity increased after both exercise sessions (mean +/- SE; 800 kcal: 0-pre 55 +/- 11, 1-post 168 +/- 64 U(.)L(-1.)min(-1); 1500 kcal: 0-pre 51 +/- 5, 1-post 187 +/- 30, 2-post 123 +/- 19 U(.)L(-1.)min(-1); P < 0.05). However, median Lp(a) concentrations were not altered by either exercise session (800 kcal: 0-pre 5.0 mg(.)dL(-1), 0-post 3.2 mg(.)dL(-1), 1-post 4.0 mg(.)dL(-1), 2-post 3.4 mg(.)dL(-1); 1500 kcal: 0-pre 5.8 mg(.)dL(-1), 0-post 4.3 mg(.)dL(-1), 1-post 3.2 mg(.)dL(-1), 2-post 5.3 mg(.)dL(-1)). In addition, no relationship existed between exercise-induced changes in CK activity and Lp(a) concentration (800 kcal: r = -0.26; 1500 kcal: r = -0.02). Conclusion These results suggest that plasma Lp(a) concentration will not increase in response to minor exercise-induced muscle damage in endurance-trained runners.

Incidence trends of keratinocytic skin cancers and melanoma in Israel 2006-2011

BACKGROUND The incidence of skin cancer, both melanoma and keratinocyte cancers (KC) is rising throughout the world, specifically squamous cell carcinomas(SCC) and basal cell carcinoma(BCC), being the most common of all cancers. OBJECTIVE To determine trends in incidence of Melanoma, BCC and SCC among 1.7 million members of Maccabi Healthcare Services from 2006 to 2011. METHODS Data on newly diagnosed Melanoma, SCC and BCC cases was collected from the MHS Cancer Registry and based on histology reports from the centralized pathology lab. Age-specific and overall age-adjusted European standardized rates were computed. Trends were estimated by calculating Average Annual Percentage Change(AAPC). RESULTS During the six year study period, a total of 16,079 subjects were diagnosed with at least one BCC, 4,767 with SCC and 1,264 with invasive melanoma. Age-standardized incidence rates were 188, 58 and 17 per 100,000 person years for BCC, SCC and melanoma, respectively. All lesions were more common among males and primarily affected the elderly. BCC rates were stable throughout the study period(AAPC -0.7%, 95%CI -4.5% to 3.2%) while SCC incidence increased significantly(AAPC 15.5%, 95%CI: 2.6% to 30.0%). In contrast, melanoma rates continuously decreased with a significant AAPC of -3.0%, 95%CI (-4.5 to -0.1). CONCLUSIONS Previously unreported, the incidence of KC in Israel is high. The disparities in incidence trends between SCC, BCC and melanoma allude to their different etiologies. These findings underscore the importance of continuous monitoring, education and prevention programs in a growing high risk population.

Model-based analysis and optimization of bioreactor for hematopoietic stem cell cultivation

One of the problems to be solved in attaining the full potentials of hematopoietic stem cell (HSC) applications is the limited availability of the cells. Growing HSCs in a bioreactor offers an alternative solution to this problem. Besides, it also offers the advantages of eliminating labour intensive process as well as the possible contamination involved in the periodic nutrient replenishments in the traditional T-flask stem cell cultivation. In spite of this, the optimization of HSC cultivation in a bioreactor has been barely explored. This manuscript discusses the development of a mathematical model to describe the dynamics in nutrient distribution and cell concentration of an ex vivo HSC cultivation in a microchannel perfusion bioreactor. The model was further used to optimize the cultivation by proposing three alternative feeding strategies in order to prevent the occurrence of nutrient limitation in the bioreactor. The evaluation of these strategies, the periodic step change increase in the inlet oxygen concentration, the periodic step change increase in the media inflow, and the feedback control of media inflow, shows that these strategies can successfully improve the cell yield of the bioreactor. In general, the developed model is useful for the design and optimization of bioreactor operation.

The primacy of vital signs – Acute care nurses’ and midwives’ use of physical assessment skills: A cross sectional study

BACKGROUND: Registered nurses and midwives play an essential role in detecting patients at risk of deterioration through ongoing assessment and action in response to changing health status. Yet, evidence suggests that clinical deterioration frequently goes unnoticed in hospitalised patients. While much attention has been paid to early warning and rapid response systems, little research has examined factors related to physical assessment skills. OBJECTIVES: To determine a minimum data set of core skills used during nursing assessment of hospitalised patients and identify nurse and workplace predictors of the use of physical assessment to detect patient deterioration. DESIGN: The study used a single-centre, cross-sectional survey design. SETTING and PARTICIPANTS: The study included 434 registered nurses and midwives (Grades 5-7) involved in clinical care of patients on acute care wards, including medicine, surgery, oncology, mental health and maternity service areas, at a 929-bed tertiary referral teaching hospital in Southeast Queensland, Australia. METHODS: We conducted a hospital-wide survey of registered nurses and midwives using the 133-item Physical Assessment Skills Inventory and the 58-item Barriers to Registered Nurses’ Use of Physical Assessment scale. Median frequency for each physical assessment skill was calculated to determine core skills. To explore predictors of core skill utilisation, backward stepwise general linear modelling was conducted. Means and regression coefficients are reported with 95% confidence intervals. A p value < .05 was considered significant for all analyses. RESULTS: Core skills used by most nurses every time they worked included assessment of temperature, oxygen saturation, blood pressure, breathing effort, skin, wound and mental status. Reliance on others and technology (F = 35.77, p < .001), lack of confidence (F = 5.52, p = .02), work area (F = 3.79, p = .002), and clinical role (F = 44.24, p < .001) were significant predictors of the extent of physical assessment skill use. CONCLUSIONS: The increasing acuity of the acute care patient plausibly warrants more than vital signs assessment; however, our study confirms nurses’ physical assessment core skill set is mainly comprised of vital signs. The focus on these endpoints of deterioration as dictated by early warning and rapid response systems may divert attention from and devalue comprehensive nursing assessment that could detect subtle changes in health status earlier in the patient's hospitalisation.

Differences in trunk accelerometry between frail and non-frail elderly persons in functional tasks

Background Physical conditions through gait and other functional task are parameters to consider for frailty detection. The aim of the present study is to measure and describe the variability of acceleration, angular velocity and trunk displacement in the ten meter Extended Timed Get-Up-and-Go test in two groups of frail and non-frail elderly people through instrumentation with the iPhone4® smartphone. Secondly, to analyze the differences and performance of the variance between the study groups (frail and non-frail). This is a cross-sectional study of 30 subjects aged over 65 years, 14 frail subjects and 16 non-frail subjects. Results The highest difference between groups in the Sit-to-Stand and Stand-to-Sit subphases was in the y axis (vertical vector). The minimum acceleration in the Stand-to-Sit phase was -2.69 (-4.17 / -0.96) m/s2 frail elderly versus -8.49 (-12.1 / -5.23) m/s2 non-frail elderly, p < 0.001. In the Gait Go and Gait Come subphases the biggest differences found between the groups were in the vertical axis: -2.45 (-2.77 /-1.89) m/s2 frail elderly versus -5.93 (-6.87 / -4.51) m/s2 non-frail elderly, p < 0.001. Finally, with regards to the turning subphase, the statistically significant differences found between the groups were greater in the data obtained from the gyroscope than from the accelerometer (the gyroscope data for the mean maximum peak value for Yaw movement angular velocity in the frail elderly was specifically 25.60°/s, compared to 112.8°/s for the non-frail elderly, p < 0.05). Conclusions The inertial sensor fitted in the iPhone4® is capable of studying and analyzing the kinematics of the different subphases of the Extended Timed Up and Go test in frail and non-frail elderly people. For the Extended Timed Up and Go test, this device allows more sensitive differentiation between population groups than the traditionally used variable, namely time.

Population structure, mortality and growth of Pinna nobilis Linnaeus, 1758 (Mollusca, Bivalvia) at different depths in Moraira bay (Alicante, Western Mediterranean)

An investigation to characterize the causes of Pinna nobilis population structure in Moraira bay (Western Mediterranean) was developed. Individuals of two areas of the same Posidonia meadow, located at different depths (A1, -13 and A2, -6 m), were inventoried, tagged, their positions accurately recorded and monitored from July 1997 to July 2002. On each area, different aspects of population demography were studied (i.e. spatial distribution, size structure, displacement evidences, mortality, growth and shell orientation). A comparison between both groups of individuals was carried out, finding important differences between them. In A1, the individuals were more aggregated and mean and maximum size were higher (A1, 10.3 and A2, 6 individuals/100 m(2); A1, x = 47.2 +/- 9.9; A2, x = 29.8 +/- 7.4 cm, P < 0.001, respectively). In A2, growth rate and mortality were higher, the latter concentrated on the largest individuals, in contrast to A1, where the smallest individuals had the higher mortality rate [A1, L = 56.03(1 - e(-0.17t)); A2, L = 37.59(1 - e(-0.40t)), P < 0.001; mean annual mortality A1: 32 dead individuals out of 135, 23.7% and A2: 16 dead individuals out of 36, 44.4%, and total mortality coefficients (z), z(A1(-30)) = 0.28, z(A1(31-45)) = 0.05, z(A1(46-)) = 0.08; z(A2(-30)) = 0.15, z(A2(31-45)) = 0.25]. A common shell orientation N-S, coincident with the maximum shore exposure, was observed in A2. Spatial distribution in both areas showed not enough evidence to discard a random distribution of the individuals, despite the greater aggregation on the deeper area (A1) (A1, chi(2) = 0.41, df = 3, P > 0.5, A2, chi(2)= 0.98, df = 2 and 0.3 < P < 0.5). The obtained results have demonstrated that the depth-related size segregation usually shown by P. nobilis is mainly caused by differences in mortality and growth among individuals located at different depths, rather than by the active displacement of individuals previously reported in the literature. Furthermore, dwarf individuals are observed in shallower levels and as a consequence, the relationship between size and age are not comparable even among groups of individuals inhabiting the same meadow at different depths. The final causes of the differences on mortality and growth are also discussed.

Promotion of a cancer-like phenotype, through chronic exposure to inflammatory cytokines and hypoxia in a bronchial epithelial cell line model

Globally, lung cancer accounts for approximately 20% of all cancer related deaths. Five-year survival is poor and rates have remained unchanged for the past four decades. There is an urgent need to identify markers of lung carcinogenesis and new targets for therapy. Given the recent successes of immune modulators in cancer therapy and the improved understanding of immune evasion by tumours, we sought to determine the carcinogenic impact of chronic TNF-α and IL-1β exposure in a normal bronchial epithelial cell line model. Following three months of culture in a chronic inflammatory environment under conditions of normoxia and hypoxia (0.5% oxygen), normal cells developed a number of key genotypic and phenotypic alterations. Important cellular features such as the proliferative, adhesive and invasive capacity of the normal cells were significantly amplified. In addition, gene expression profiles were altered in pathways associated with apoptosis, angiogenesis and invasion. The data generated in this study provides support that TNF-α, IL-1β and hypoxia promotes a neoplastic phenotype in normal bronchial epithelial cells. In turn these mediators may be of benefit for biomarker and/or immune-therapy target studies. This project provides an important inflammatory in vitro model for further immuno-oncology studies in the lung cancer setting.

Mutational analysis of the insulin‑like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients

The insulin‑like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non‑small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well‑documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single‑nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16‑21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease‑free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients.