Post-transcriptional regulation in the nucleus and cytoplasm: study of mean time to threshold (MTT) and narrow escape problem

Messenger RNAs (mRNAs) can be repressed and degraded by small non-coding RNA molecules. In this paper, we formulate a coarsegrained Markov-chain description of the post-transcriptional regulation of mRNAs by either small interfering RNAs (siRNAs) or microRNAs (miRNAs). We calculate the probability of an mRNA escaping from its domain before it is repressed by siRNAs/miRNAs via cal- culation of the mean time to threshold: when the number of bound siRNAs/miRNAs exceeds a certain threshold value, the mRNA is irreversibly repressed. In some cases,the analysis can be reduced to counting certain paths in a reduced Markov model. We obtain explicit expressions when the small RNA bind irreversibly to the mRNA and we also discuss the reversible binding case. We apply our models to the study of RNA interference in the nucleus, examining the probability of mRNAs escaping via small nuclear pores before being degraded by siRNAs. Using the same modelling framework, we further investigate the effect of small, decoy RNAs (decoys) on the process of post-transcriptional regulation, by studying regulation of the tumor suppressor gene, PTEN : decoys are able to block binding sites on PTEN mRNAs, thereby educing the number of sites available to siRNAs/miRNAs and helping to protect it from repression. We calculate the probability of a cytoplasmic PTEN mRNA translocating to the endoplasmic reticulum before being repressed by miRNAs. We support our results with stochastic simulations

Evaluation of a skin self examination attitude scale using an item response theory model approach

Introduction The Skin Self-Examination Attitude Scale (SSEAS) is a brief measure that allows for the assessment of attitudes in relation to skin self-examination. This study evaluated the psychometric properties of the SSEAS using Item Response Theory (IRT) methods in a large sample of men ≥ 50 years in Queensland, Australia. Methods A sample of 831 men (420 intervention and 411 control) completed a telephone assessment at the 13-month follow-up of a randomized-controlled trial of a video-based intervention to improve skin self-examination (SSE) behaviour. Descriptive statistics (mean, standard deviation, item–total correlations, and Cronbach’s alpha) were compiled and difficulty parameters were computed with Winsteps using the polytomous Rasch Rating Scale Model (RRSM). An item person (Wright) map of the SSEAS was examined for content coverage and item targeting. Results The SSEAS have good psychometric properties including good internal consistency (Cronbach’s alpha = 0.80), fit with the model and no evidence for differential item functioning (DIF) due to experimental trial grouping was detected. Conclusions The present study confirms the SSEA scale as a brief, useful and reliable tool for assessing attitudes towards skin self-examination in a population of men 50 years or older in Queensland, Australia. The 8-item scale shows unidimensionality, allowing levels of SSE attitude, and the item difficulties, to be ranked on a single continuous scale. In terms of clinical practice, it is very important to assess skin cancer self-examination attitude to identify people who may need a more extensive intervention to allow early detection of skin cancer.

Estimation of the time of a linear trend in monitoring survival time

Change point estimation is recognized as an essential tool of root cause analyses within quality control programs as it enables clinical experts to search for potential causes of change in hospital outcomes more effectively. In this paper, we consider estimation of the time when a linear trend disturbance has occurred in survival time following an in-control clinical intervention in the presence of variable patient mix. To model the process and change point, a linear trend in the survival time of patients who underwent cardiac surgery is formulated using hierarchical models in a Bayesian framework. The data are right censored since the monitoring is conducted over a limited follow-up period. We capture the effect of risk factors prior to the surgery using a Weibull accelerated failure time regression model. We use Markov Chain Monte Carlo to obtain posterior distributions of the change point parameters including the location and the slope size of the trend and also corresponding probabilistic intervals and inferences. The performance of the Bayesian estimator is investigated through simulations and the result shows that precise estimates can be obtained when they are used in conjunction with the risk-adjusted survival time cumulative sum control chart (CUSUM) control charts for different trend scenarios. In comparison with the alternatives, step change point model and built-in CUSUM estimator, more accurate and precise estimates are obtained by the proposed Bayesian estimator over linear trends. These superiorities are enhanced when probability quantification, flexibility and generalizability of the Bayesian change point detection model are also considered.

Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium

The beta-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 mu M) or PDE4-selective inhibitor rolipram (1 mu M) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through beta(1)-adrenoceptors (beta(2)-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through beta(2)-adrenoceptors (beta(1)-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from -logEC(50)s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-beta-blocker-treated patients, consistent with the previously reported beta(2)-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular beta(2)-adrenoceptors compared to beta(1)-adrenoceptors. The beta(2)-adrenoceptor-selectivity of carvedilol may provide protection against beta(2)-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control beta(1)- and beta(2)-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.

The dependence of computed tomography number to relative electron density conversion on phantom geometry and its impact on planned dose

A computed tomography number to relative electron density (CT-RED) calibration is performed when commissioning a radiotherapy CT scanner by imaging a calibration phantom with inserts of specified RED and recording the CT number displayed. In this work, CT-RED calibrations were generated using several commercially available phantoms to observe the effect of phantom geometry on conversion to electron density and, ultimately, the dose calculation in a treatment planning system. Using an anthropomorphic phantom as a gold standard, the CT number of a material was found to depend strongly on the amount and type of scattering material surrounding the volume of interest, with the largest variation observed for the highest density material tested, cortical bone. Cortical bone gave a maximum CT number difference of 1,110 when a cylindrical insert of diameter 28 mm scanned free in air was compared to that in the form of a 30 × 30 cm2 slab. The effect of using each CT-RED calibration on planned dose to a patient was quantified using a commercially available treatment planning system. When all calibrations were compared to the anthropomorphic calibration, the largest percentage dose difference was 4.2 % which occurred when the CT-RED calibration curve was acquired with heterogeneity inserts removed from the phantom and scanned free in air. The maximum dose difference observed between two dedicated CT-RED phantoms was ±2.1 %. A phantom that is to be used for CT-RED calibrations must have sufficient water equivalent scattering material surrounding the heterogeneous objects that are to be used for calibration.

The effect of β-alanine and NaHCO3 co-ingestion on buffering capacity and exercise performance with high-intensity exercise in healthy males

Introduction β-alanine (BAl) and NaHCO3 (SB) ingestion may provide performance benefits by enhancing concentrations of their respective physiochemical buffer counterparts, muscle carnosine and blood bicarbonate, counteracting acidosis during intense exercise. This study examined the effect of BAl and SB co-supplementation as an ergogenic strategy during high-intensity exercise. Methods Eight healthy males ingested either BAl (4.8 g day−1 for 4 weeks, increased to 6.4 g day−1 for 2 weeks) or placebo (Pl) (CaCO3) for 6 weeks, in a crossover design (6-week washout between supplements). After each chronic supplementation period participants performed two trials, each consisting of two intense exercise tests performed over consecutive days. Trials were separated by 1 week and consisted of a repeated sprint ability (RSA) test and cycling capacity test at 110 % Wmax (CCT110 %). Placebo (Pl) or SB (300 mg kgbw−1) was ingested prior to exercise in a crossover design to creating four supplement conditions (BAl-Pl, BAl-SB, Pl–Pl, Pl-SB). Results Carnosine increased in the gastrocnemius (n = 5) (p = 0.03) and soleus (n = 5) (p = 0.02) following BAl supplementation, and Pl-SB and BAl-SB ingestion elevated blood HCO3 − concentrations (p < 0.01). Although buffering capacity was elevated following both BAl and SB ingestion, performance improvement was only observed with BAl-Pl and BAl-SB increasing time to exhaustion of the CCT110 % test 14 and 16 %, respectively, compared to Pl–Pl (p < 0.01). Conclusion Supplementation of BAl and SB elevated buffering potential by increasing muscle carnosine and blood bicarbonate levels, respectively. BAl ingestion improved performance during the CCT110 %, with no aggregating effect of SB supplementation (p > 0.05). Performance was not different between treatments during the RSA test.

Business process management as the 'killer app' for Petri nets

Since their inception in 1962, Petri nets have been used in a wide variety of application domains. Although Petri nets are graphical and easy to understand, they have formal semantics and allow for analysis techniques ranging from model checking and structural analysis to process mining and performance analysis. Over time Petri nets emerged as a solid foundation for Business Process Management (BPM) research. The BPM discipline develops methods, techniques, and tools to support the design, enactment, management, and analysis of operational business processes. Mainstream business process modeling notations and workflow management systems are using token-based semantics borrowed from Petri nets. Moreover, state-of-the-art BPM analysis techniques are using Petri nets as an internal representation. Users of BPM methods and tools are often not aware of this. This paper aims to unveil the seminal role of Petri nets in BPM.

Customised osteotomy guides and endoprosthetic reconstruction for periacetabular tumours

Purpose We sought to analyse clinical and oncological outcomes of patients after guided resection of periacetabular tumours and endoprosthetic reconstruction of the remaining defect. Methods From 1988 to 2008, we treated 56 consecutive patients (mean age 52.5 years, 41.1 % women). Patients were followed up either until death or February 2011 (mean follow up 5.5 years, range 0.1–22.5, standard deviation ± 5.3). Kaplan–Meier analysis was used to estimate survival rates. Results Disease-specific survival was 59.9 % at five years and 49.7 % at ten and 20 years, respectively. Wide resection margins were achieved in 38 patients, whereas 11 patients underwent marginal and seven intralesional resection. Survival was significantly better in patients with wide or marginal resection than in patients with intralesional resection (p = 0.022). Survival for patients with secondary tumours was significantly worse than for patients with primary tumours (p = 0.003). In 29 patients (51.8 %), at least one reoperation was necessary, resulting in a revision-free survival of 50.5 % at five years, 41.1 % at ten years and 30.6 % at 20 years. Implant survival was 77.0 % at five years, 68.6 % at ten years and 51.8 % at 20 years. A total of 35 patients (62.5 %) experienced one or more complications after surgery. Ten of 56 patients (17.9 %) experienced local recurrence after a mean of 8.9 months. The mean postoperative Musculoskeletal Tumor Society (MSTS) score was 18.1 (60.1 %). Conclusion The surgical approach assessed in this study simplifies the process of tumour resection and prosthesis implantation and leads to acceptable clinical and oncological outcomes.

Effects of a multiple health behavior change intervention for colorectal cancer survivors on psychosocial outcomes and quality of life: A randomized controlled trial

Background Multiple health behavior change can ameliorate adverse effects of cancer. Purpose The purpose of this study was to determine the effects of a multiple health behavior change intervention (CanChange) for colorectal cancer survivors on psychosocial outcomes and quality of life. Methods A total of 410 colorectal cancer survivors were randomized to a 6-month telephone-based health coaching intervention (11 sessions using acceptance and commitment therapy strategies focusing on physical activity, weight management, diet, alcohol, and smoking) or usual care. Posttraumatic growth, spirituality, acceptance, mindfulness, distress, and quality of life were assessed at baseline, 6 and 12 months. Results Significant intervention effects were observed for posttraumatic growth at 6 (7.5, p < 0.001) and 12 months (4.1, p = 0.033), spirituality at 6 months (1.8, p = 0.011), acceptance at 6 months (0.2, p = 0.005), and quality of life at 6 (0.8, p = 0.049) and 12 months (0.9, p = 0.037). Conclusions The intervention improved psychosocial outcomes and quality of life (physical well-being) at 6 months with most effects still present at 12 months. (Trial Registration Number: ACTRN12608000399392).

Vitamin D deficiency in patients with malignancy in Brisbane

PURPOSE: This study aims to investigate the prevalence and factors predictive of vitamin D deficiency in patients with malignancy in Brisbane, Australia (latitude 27° S). METHODS: This is a prospective cross-sectional study measuring serum levels of 25-hydroxyvitamin D (25-OHD) in 100 subjects with non-haematological cancer at least 18 years of age not taking vitamin D supplements attending a day oncology unit and oncology/palliative care inpatient ward in Brisbane, Australia. RESULTS: Thirty-seven per cent of outpatient and 49 % of inpatient subjects respectively were vitamin D deficient. Functional status was predictive of low vitamin D levels. CONCLUSION: There was a high prevalence of vitamin D deficiency in patients with cancer in Brisbane, Australia.

The effects of ambient temperature on cerebrovascular mortality: An epidemiologic study in four climatic zones in China

Background Little evidence is available about the association between temperature and cerebrovascular mortality in China. This study aims to examine the effects of ambient temperature on cerebrovascular mortality in different climatic zones in China. Method We obtained daily data on weather conditions, air pollution and cerebrovascular deaths from five cities (Beijing, Tianjin, Shanghai, Wuhan, and Guangzhou) in China during 2004-2008. We examined city-specific associations between ambient temperature and the cerebrovascular mortality, while adjusting for season, long-term trends, day of the week, relative humidity and air pollution. We examined cold effects using a 1°C decrease in temperature below a city-specific threshold, and hot effects using a 1°C increase in temperature above a city-specific threshold. We used a meta-analysis to summarize the cold and hot effects across the five cities. Results Beijing and Tianjin (with low mean temperature) had lower thresholds than Shanghai, Wuhan and Guangzhou (with high mean temperature). In Beijing, Tianjin, Wuhan and Guangzhou cold effects were delayed, while in Shanghai there was no or short induction. Hot effects were acute in all five cities. The cold effects lasted longer than hot effects. The hot effects were followed by mortality displacement. The pooled relative risk associated with a 1°C decrease in temperature below thresholds (cold effect) was 1.037 (95% confidence interval (CI): 1.020, 1.053). The pooled relative risk associated with a 1°C increase in temperature above thresholds (hot effect) was 1.014 (95% CI: 0.979, 1.050). Conclusion Cold temperatures are significantly associated with cerebrovascular mortality in China, while hot effect is not significant. People in colder climate cities were sensitive to hot temperatures, while people in warmer climate cities were vulnerable to cold temperature.

Simulating the dissipation of two herbicides using micro paddy lysimeters

A set of packed micro paddy lysimeters, placed in a greenhouse, was used to simulate the dissipation of two herbicides, simetryn and thiobencarb, in a controlled environment. Data from a field monitoring study in 2003, including the soil condition and water balances, were used in the simulation. The herbicides were applied and monitored over a period of 21 d. The water balances under two water management scenarios, intermittent irrigation management (AI) and continuous irrigation management (CI), were simulated. In the AI scenario, the pattern of herbicide dissipation in the surface water of the field were simulated, following the first-order kinetics. In the CI scenario, similarity was observed in most lysimeter and field concentrations, but there were differences in some data points. Dissipation curves of both herbicides in the surface water of the two simulated scenarios were not significantly different (P > 0.05) from the field data except for intercept of the thiobencarb curve in the CI scenario. The distribution of simetryn and thiobencarb in the soil profile after simulation were also similar to the field data. The highest concentrations of both herbicides were found on the topsoil layer at 0-2.5 cm depth. Only a small amount of herbicides moved down to the deeper soil layers. Micro paddy lysimeters are thus a good alternative for the dissipation study of pesticides in the paddy environment.

Errors in the knee joint forces and moments during gait depending on the foot and knee prosthetic components

Background Previously studies showed that inverse dynamics based on motion analysis and force-plate is inaccurate compared to direct measurements for individuals with transfemoral amputation (TFA). Indeed, direct measurements can appropriately take into account the absorption at the prosthetic foot and the resistance at the prosthetic knee. [1-3] However, these studies involved only a passive prosthetic knee. Aim The objective of the present study was to investigate if different types of prosthetic feet and knees can exhibit different levels of error in the knee joint forces and moments. Method Three trials of walking at self-selected speed were analysed for 9 TFAs (7 males and 2 females, 47±9 years old, 1.76±0.1 m 79±17 kg) with a motion analysis system (Qualisys, Goteborg, Sweden), force plates (Kitsler, Winterthur, Switzerland) and a multi-axial transducer (JR3, Woodland, USA) mounted above the prosthetic knee [1-17]. TFAs were all fitted with an osseointegrated implant system. The prostheses included different type of foot (N=5) and knee (N=3) components. The root mean square errors (RMSE) between direct measurements and the knee joint forces and moments estimated by inverse dynamics were computed for stance and swing phases of gait and expressed as a percentage of the measured amplitudes. A one-way Kruskal-Wallis ANOVA was performed (Statgraphics, Levallois-Perret, France) to analyse the effects of the prosthetic components on the RMSEs. Cross-effects and post-hoc tests were not analysed in this study. Results A significant effect (*) was found for the type of prosthetic foot on anterior-posterior force during swing (p=0.016), lateral-medial force during stance (p=0.009), adduction-abduction moment during stance (p=0.038), internal-external rotation moment during stance (p=0.014) and during swing (p=0.006), and flexion-extension moment during stance (p = 0.035). A significant effect (#) was found for the type of prosthetic knee on anterior-posterior force during swing (p=0.018) and adduction-abduction moment during stance (p=0.035). Discussion & Conclusion The RMSEs were larger during swing than during stance. It is because the errors on accelerations (as derived from motion analysis) become substantial with respect to the external loads. Thus, inverse dynamics during swing should be analysed with caution because the mean RMSEs are close to 50%. Conversely, there were fewer effects of the prosthetic components on RMSE during swing than during stance and, accordingly, fewer effects due to knees than feet. Thus, inverse dynamics during stance should be used with caution for comparison of different prosthetic components.

The in vivo fate of nanoparticles and nanoparticle-loaded microcapsules after oral administration in mice: Evaluation of their potential for colon-specific delivery

Anti-cancer drug loaded-nanoparticles (NPs) or encapsulation of NPs in colon-targeted delivery systems shows potential for increasing the local drug concentration in the colon leading to improved treatment of colorectal cancer. To investigate the potential of the NP-based strategies for colon-specific delivery, two formulations, free Eudragit® NPs and enteric-coated NP-loaded chitosan–hypromellose microcapsules (MCs) were fluorescently-labelled and their tissue distribution in mice after oral administration was monitored by multispectral small animal imaging. The free NPs showed a shorter transit time throughout the mouse digestive tract than the MCs, with extensive excretion of NPs in faeces at 5 h. Conversely, the MCs showed complete NP release in the lower region of the mouse small intestine at 8 h post-administration. Overall, the encapsulation of NPs in MCs resulted in a higher colonic NP intensity from 8 h to 24 h post-administration compared to the free NPs, due to a NP ‘guarding’ effect of MCs during their transit along mouse gastrointestinal tract which decreased NP excretion in faeces. These imaging data revealed that this widely-utilised colon-targeting MC formulation lacked site-precision for releasing its NP load in the colon, but the increased residence time of the NPs in the lower gastrointestinal tract suggests that it is still useful for localised release of chemotherapeutics, compared to NP administration alone. In addition, both formulations resided in the stomach of mice at considerable concentrations over 24 h. Thus, adhesion of NP- or MC-based oral delivery systems to gastric mucosa may be problematic for colon-specific delivery of the cargo to the colon and should be carefully investigated for a full evaluation of particulate delivery systems.

Environmental health risk assessment of dioxin in foods at the two most severe dioxin hot spots in Vietnam

Background Bien Hoa and Da Nang airbases were bulk storages for Agent Orange during the Vietnam War and currently are the two most severe dioxin hot spots. Objectives This study assesses the health risk of exposure to dioxin through foods for local residents living in seven wards surrounding these airbases. Methods This study follows the Australian Environmental Health Risk Assessment Framework to assess the health risk of exposure to dioxin in foods. Forty-six pooled samples of commonly consumed local foods were collected and analyzed for dioxin/furans. A food frequency and Knowledge–Attitude–Practice survey was also undertaken at 1000 local households, various stakeholders were involved and related publications were reviewed. Results Total dioxin/furan concentrations in samples of local “high-risk” foods (e.g. free range chicken meat and eggs, ducks, freshwater fish, snail and beef) ranged from 3.8 pg TEQ/g to 95 pg TEQ/g, while in “low-risk” foods (e.g. caged chicken meat and eggs, seafoods, pork, leafy vegetables, fruits, and rice) concentrations ranged from 0.03 pg TEQ/g to 6.1 pg TEQ/g. Estimated daily intake of dioxin if people who did not consume local high risk foods ranged from 3.2 pg TEQ/kg bw/day to 6.2 pg TEQ/kg bw/day (Bien Hoa) and from 1.2 pg TEQ/kg bw/day to 4.3 pg TEQ/kg bw/day (Da Nang). Consumption of local high risk foods resulted in extremely high dioxin daily intakes (60.4–102.8 pg TEQ/kg bw/day in Bien Hoa; 27.0–148.0 pg TEQ/kg bw/day in Da Nang). Conclusions Consumption of local “high-risk” foods increases dioxin daily intakes far above the WHO recommended TDI (1–4 pg TEQ/kg bw/day). Practicing appropriate preventive measures is necessary to significantly reduce exposure and health risk.