External beam radiotherapy ± chemotherapy in the treatment of anal canal cancer: a single-institute long-term experience on 100 patients.

One-hundred patients treated with curative radiotherapy (RT) ± chemotherapy (CT) for an anal canal carcinoma (T1-4N0-3M0) were retrospectively analyzed. Five- and 10-year local control (LC) rates were 73% and 67%, respectively. Acute and late G3-G4 toxicity rates were 32% and 12%, respectively. Two patients underwent a colostomy for a G4 anal toxicity. This study confirms the outcomes of RT ± CT in the treatment of anal canal cancer. Concomitant CT and LC statistically influenced Overall Survival and Colostomy-Free Survival. CT also statistically reduced the risk of nodal relapse. High rates of acute skin toxicity impose tailored volumes and techniques of irradiation.

A Confluence of Risks: Control and Compliance in the World of Unstructured Data, Big Data and the Cloud

The emergence of powerful new technologies, the existence of large quantities of data, and increasing demands for the extraction of added value from these technologies and data have created a number of significant challenges for those charged with both corporate and information technology management. The possibilities are great, the expectations high, and the risks significant. Organisations seeking to employ cloud technologies and exploit the value of the data to which they have access, be this in the form of "Big Data" available from different external sources or data held within the organisation, in structured or unstructured formats, need to understand the risks involved in such activities. Data owners have responsibilities towards the subjects of the data and must also, frequently, demonstrate that they are in compliance with current standards, laws and regulations. This thesis sets out to explore the nature of the technologies that organisations might utilise, identify the most pertinent constraints and risks, and propose a framework for the management of data from discovery to external hosting that will allow the most significant risks to be managed through the definition, implementation, and performance of appropriate internal control activities.

Somewhere between illusion of control and powerlessness : trying to situate the pathological gambler's locus of control

It has been suggested that pathological gamblers develop illusory perceptions of control regarding the outcome of the games and should express higher Internal and Chance locus of control. A sample of 48 outpatients diagnosed with pathological gambling disorder who participated in this ex post facto study, completed the Internality, Powerful Others, and Chance scale, the South Oaks Gambling Screen questionnaire, and the Beck Depression Inventory. Results for the locus of control measure were compared with a reference group. Pathological gamblers scored higher than the reference group on the Chance locus of control, which increased with the severity of cases. Moreover, Internal locus of control did show a curvilinear relationship with the severity of cases. Pathological gamblers have specific locus of control scores that vary in function of the severity, in a linear fashion or a non-linear fashion according to the scale. This effect might be caused by competition between "illusion of control" and the tendency to attribute adverse consequence of gambling to external causes.

Procedure for human saphenous veins ex vivo perfusion and external reinforcement.

The mainstay of contemporary therapies for extensive occlusive arterial disease is venous bypass graft. However, its durability is threatened by intimal hyperplasia (IH) that eventually leads to vessel occlusion and graft failure. Mechanical forces, particularly low shear stress and high wall tension, are thought to initiate and to sustain these cellular and molecular changes, but their exact contribution remains to be unraveled. To selectively evaluate the role of pressure and shear stress on the biology of IH, an ex vivo perfusion system (EVPS) was created to perfuse segments of human saphenous veins under arterial regimen (high shear stress and high pressure). Further technical innovations allowed the simultaneous perfusion of two segments from the same vein, one reinforced with an external mesh. Veins were harvested using a no-touch technique and immediately transferred to the laboratory for assembly in the EVPS. One segment of the freshly isolated vein was not perfused (control, day 0). The two others segments were perfused for up to 7 days, one being completely sheltered with a 4 mm (diameter) external mesh. The pressure, flow velocity, and pulse rate were continuously monitored and adjusted to mimic the hemodynamic conditions prevailing in the femoral artery. Upon completion of the perfusion, veins were dismounted and used for histological and molecular analysis. Under ex vivo conditions, high pressure perfusion (arterial, mean = 100 mm Hg) is sufficient to generate IH and remodeling of human veins. These alterations are reduced in the presence of an external polyester mesh.

External Fluctuations in Front Propagation

We study the effects of external noise in a one-dimensional model of front propagation. Noise is introduced through the fluctuations of a control parameter leading to a multiplicative stochastic partial differential equation. Analytical and numerical results for the front shape and velocity are presented. The linear-marginal-stability theory is found to increase its range of validity in the presence of external noise. As a consequence noise can stabilize fronts not allowed by the deterministic equation.

HDR brachytherapy boost and external radiotherapy for unfavorable prostate cancer patients

Purpose/Objective: To evaluate the outcome of prostate cancer patients treated with a combination of HDR Brachytherapy boost (HDR-BT) and 3D conformal external pelvic radiotherapy (EBRT) in a dose escalation study. Materials and Methods: 162 patients were followed between November 2004 and December 2010 . Two different dose escalation groups were done: group 1 (n= 92), 1 fraction HDR boost (9-10 Gy ) followed by EBRT (60 Gy in 6 weeks) - BED: 203-216 Gy and group 2 (n=70): 2 fraction HDR boost (18-19 Gy), 6 hours interval between fractions, followed by EBRT (46 Gy in 4.5 weeks) - BED: 233.3 -247 Gy; 116 pts (71.6%) received concomitant androgen deprivation. Patients were classified according to the MSKCC criteria into high (N=137) and intermediate (N=25) risk. Phoenix biochemical failure definition was used. Toxicity was scored by Radiation Morbidity Scoring Criteria (RTOG) Results: The mean follow-up was 41 (range 7-84) months. The 7- years cancer-specific and overall survival was 100% an 92%, respectively. The 7 years actuarial biochemical control rate was 89% and 100% for group 1 and 2, respectively. One patient from group 1 and two patients from group 2 never reached a low nadir. Two patients developed distant metastases 12 and 16 months after the treatment. In a multivariate Cox-regression analysis neither treatment nor risk group (intermediate vs. high risk) were associated with increased risk for biochemical failure. The RTOG grade 3 genitourinary early toxicity was 1.0% and 8.5% while gastrointestinal/genitourinary late toxicity was 7.6% and 1.4% for group 1 and 2, respectively Conclusions: HDR BT boost followed by EBRT appears to be a safe, feasible and effective treatment for patients with unfavorable localized prostate cancer. This study shows a beneficial effect on biochemical control in group 2 pts, however without statistical significance. Higher radiation doses (BED 233.3-247 Gy) do not seem to carry extra toxicity.

A treatment planning method for sequentially combining radiopharmaceutical therapy and external radiation therapy.

PURPOSE: Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate three-dimensional dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning method, using the patient-specific three-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. METHODS AND MATERIALS: The biologic effective dose (BED) was used to translate voxelized RPT absorbed dose (D(RPT)) values into a normalized total dose (or equivalent 2-Gy-fraction XRT absorbed dose), NTD(RPT) map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTD(RPT). A treatment plan from the combined Samarium-153 and external beam was designed that would deliver a tumoricidal dose while delivering no more than 50 Gy of NTD(sum) to the spinal cord of a patient with a paraspinal tumor. RESULTS: The average voxel NTD(RPT) to tumor from RPT was 22.6 Gy (range, 1-85 Gy); the maximum spinal cord voxel NTD(RPT) from RPT was 6.8 Gy. The combined therapy NTD(sum) to tumor was 71.5 Gy (range, 40-135 Gy) for a maximum voxel spinal cord NTD(sum) equal to the maximum tolerated dose of 50 Gy. CONCLUSIONS: A method that enables real-time treatment planning of combined RPT-XRT has been developed. By implementing a more generalized conversion between the dose values from the two modalities and an activity-based treatment of partial volume effects, the reliability of combination therapy treatment planning has been expanded.

Modulation of plant HMG-CoA reductase by protein phosphatase 2A: Positive and negative control at a key node of metabolism

The enzyme HMG-CoA reductase (HMGR) has a key regulatory role in the mevalonate pathway for isoprenoid biosynthesis, critical not only for normal plant development, but also for the adaptation to demanding environmental conditions. Consistent with this notion, plant HMGR is modulated by many diverse endogenous signals and external stimuli. Protein phosphatase 2A (PP2A) is involved in auxin, abscisic acid, ethylene and brassinosteroid signaling and now emerges as a positive and negative multilevel regulator of plant HMGR, both during normal growth and in response to a variety of stress conditions. The interaction with HMGR is mediated by B" regulatory subunits of PP2A, which are also calcium binding proteins. The new discoveries uncover the potential of PP2A to integrate developmental and calcium-mediated environmental signals in the control of plant HMGR.

Oxidation of methane at the CH4/H2O-(CO2) transition zone in the external part of the Central Alps, Switzerland: Evidence from stable isotope investigations

With the aim of understanding the mechanisms that control the metamorphic transition from the CH4- to the H2O-(CO2)-dominated fluid zone in the Helvetic domain of the Central Alps of Switzerland, fluid inclusions in quartz, illite ``crystallinity'' index, vitrinite reflectance, and the stable isotope compositions of vein and whole rock minerals and fluids trapped in quartz were investigated along four cross-sections. Increasing temperature during prograde metamorphism led to the formation of dry gas by hydrocarbon cracking in the CH4-zone. Fluid immiscibility in the H2O-CH4-(CO2)-NaCl system resulted in cogenetic, CH4- and H2O-dominated fluid inclusions. In the CH4-zone, fluids were trapped at temperatures <= 270 +/- 5 degrees C. The end of the CH4-zone is markedby a sudden increase of CO2 content in the gas phase of fluid inclusions. At temperatures > 270 +/- 5 degrees C, in the H2O-zone, the total amount of volatiles within the fluid decreased below 1 mol% with no immiscibility. This resulted m total homogenization temperatures of H2O-(CO2-CH4)-NaCl inclusions below 180 degrees C. Hydrogen isotope compositions of methane in fluid inclusion have delta D values of less than -100 parts per thousand in the CH4-zone, typical for an origin through cracking of higher hydrocarbons, but where the methane has not equilibrated with the pore water. delta D values of fluid inclusion water are around -40 parts per thousand., in isotopic equilibrium with phyllosilicates of the whole rocks. Within the CH4 to H2O(CO2) transition zone, delta D(H2O) values in fluid inclusions decrease to -130 parts per thousand interpreted to reflect the contribution of deuterium depleted water from methane oxidation. In the H2O-zone, delta D(H2O) values increase again towards an average of -30 parts per thousand which is again consistent with isotopic equilibrium with host-rock phyllosilicates. delta C-13 values of methane in fluid inclusions from the CH4-zone are around -27 parts per thousand in isotopic equilibrium with calcite in veins and whole rocks. The delta C-13(CH4) values decrease to less than -35 parts per thousand at the transition to the H2O-zone and are no longer in equilibrium with the carbonates in the whole rocks. delta C-13 values of CO, are variable but too low to be in equilibrium with the wall rock fluids, compatible with a contribution of CO2 from closed system oxidation of methane. Differences in isotopic composition between host-rock and Alpine fissure carbonate are generally small, suggesting that the amount of CO2 produced by oxidation of methane was small compared to the C-budget in the rocks and local pore fluids were buffered by the wall rocks during precipitation of calcite within the fissures. (c) 2006 Elsevier B.V. All rights reserved.

Rhythmic growth explained by coincidence between internal and external cues.

Most organisms use circadian oscillators to coordinate physiological and developmental processes such as growth with predictable daily environmental changes like sunrise and sunset. The importance of such coordination is highlighted by studies showing that circadian dysfunction causes reduced fitness in bacteria and plants, as well as sleep and psychological disorders in humans. Plant cell growth requires energy and water-factors that oscillate owing to diurnal environmental changes. Indeed, two important factors controlling stem growth are the internal circadian oscillator and external light levels. However, most circadian studies have been performed in constant conditions, precluding mechanistic study of interactions between the clock and diurnal variation in the environment. Studies of stem elongation in diurnal conditions have revealed complex growth patterns, but no mechanism has been described. Here we show that the growth phase of Arabidopsis seedlings in diurnal light conditions is shifted 8-12 h relative to plants in continuous light, and we describe a mechanism underlying this environmental response. We find that the clock regulates transcript levels of two basic helix-loop-helix genes, phytochrome-interacting factor 4 (PIF4) and PIF5, whereas light regulates their protein abundance. These genes function as positive growth regulators; the coincidence of high transcript levels (by the clock) and protein accumulation (in the dark) allows them to promote plant growth at the end of the night. Thus, these two genes integrate clock and light signalling, and their coordinated regulation explains the observed diurnal growth rhythms. This interaction may serve as a paradigm for understanding how endogenous and environmental signals cooperate to control other processes.

Which factors influence glycemic control in the intensive care unit?

PURPOSE OF REVIEW: Intensive insulin therapy titrated to restore and maintain blood glucose between 80 and 110 mg/dl (4.4-6.1 mmol/l) was found to improve survival of critically ill patients in one pioneering proof-of-concept study performed in a surgical intensive care unit. The external validity of these findings was investigated. RECENT FINDINGS: Six independent prospective randomized controlled trials, involving 9877 patients in total, were unable to confirm the survival benefit reported in the pioneering trial. Several hypotheses were proposed to explain this discrepancy, including the case-mix, the features of the usual care, the quality of glucose control and the risks associated with hypoglycemia. SUMMARY: Before a better understanding and delineation of the conditions associated with and improved outcome by tight glycemic control, the choice of an intermediate glycemic target appears as a safe and effective solution.

Paediatric bi-ventricular external assist device based on artificial muscles

Objective: Existing VADs are single-ventricle pumps needing anticoagulation. We developed a bi ventricular external assist device that reproduces the physiological heart muscle movement completely avoiding anticoagulants. Methods: The device has a carbon fibre skeleton fitting a 30-40 kg patient's heart, to which a Nitinol based artificial muscle is connected. The artificial muscle wraps both ventricles. The strength of the Nitinol fibres is amplified by a pivot articulation in contact with the ventricle wall. The fibres are electrically driven and a dedicated control unit has been developed. We assessed hemodynamic performances of this device using a previously described dedicated bench test. Volume ejected and pressure gradient has been measured with afterload ranging from 25 to 50mmHg. Results: With anafterload of 50mmHg the system has an ejection fraction (EF) of 10% on the right side and 8% on the left side. The system is able to generate a systolic ejection of 5,5 ml on the right side and 4,4 ml on the left side. With anafterload of 25mmHg the results are reduced of about 20%. The activation frequency is 80/minute resulting in a total volume displacement of 440 ml/minute on the right side and 352 ml/minute on the left side. Conclusions: The artificial muscle follows Starling's law as the ejected volume increases when afterload increases. These preliminary studies confirmed the possibility of improving the EF of a failing heart using artificial muscle for external cardiac compression. This device could be helpful in weaning CPB and/or for short-term cardio-circulatory support in paediatric population with cardiac failure.

Stochasticity and bistability in horizontal transfer control of a genomic island in Pseudomonas.

Genomic islands (GEI) comprise a recently recognized large family of potentially mobile DNA elements and play an important role in the rapid differentiation and adaptation of bacteria. Most importantly, GEIs have been implicated in the acquisition of virulence factors, antibiotic resistances or toxic compound metabolism. Despite detailed information on coding capacities of GEIs, little is known about the regulatory decisions in individual cells controlling GEI transfer. Here, we show how self-transfer of ICEclc, a GEI in Pseudomonas knackmussii B13 is controlled by a series of stochastic processes, the result of which is that only a few percent of cells in a population will excise ICEclc and launch transfer. Stochastic processes have been implicated before in producing bistable phenotypic transitions, such as sporulation and competence development, but never before in horizontal gene transfer (HGT). Bistability is instigated during stationary phase at the level of expression of an activator protein InrR that lays encoded on ICEclc, and then faithfully propagated to a bistable expression of the IntB13 integrase, the enzyme responsible for excision and integration of the ICEclc. Our results demonstrate how GEI of a very widespread family are likely to control their transfer rates. Furthermore, they help to explain why HGT is typically confined to few members within a population of cells. The finding that, despite apparent stochasticity, HGT rates can be modulated by external environmental conditions provides an explanation as to why selective conditions can promote DNA exchange.

Crosstalk of Notch with p53 and p63 in cancer growth control.

Understanding the complexity of cancer depends on an elucidation of the underlying regulatory networks, at the cellular and intercellular levels and in their temporal dimension. This Opinion article focuses on the multilevel crosstalk between the Notch pathway and the p53 and p63 pathways. These two coordinated signalling modules are at the interface of external damaging signals and control of stem cell potential and differentiation. Positive or negative reciprocal regulation of the two pathways can vary with cell type and cancer stage. Therefore, selective or combined targeting of the two pathways could improve the efficacy and reduce the toxicity of cancer therapies.

Effect of prestorage curing on storage life, internal and external qualities of sweet orange (Citrus sinensis)

Orange fruits from two seasons, in April and August 2006 representing late 2005 and early 2006 harvests respectively were cured in hot air at 36-37(0)C to 1%, 3%, 5% and 7% weight loss before storage at 28(0)C and 86% relative humidity (RH). The fruits were observed for incidence of decay, further weight loss, juice content, firmness or softening of the peel, total soluble solids (TSS), pH, titratable acidity, and colour during storage. Curing reduced the incidence of decay. All control fruits were rotten by day 21 in August harvest while 22.5% of the control was rotten by day 56 in the April harvest. Storage life was extended beyond 56 days in fruits cured with 1, 3, 5 and 7% in April harvest as there was no decay throughout, while decay incidence in August harvest was 88.9, 61.1, 22.2 and 31.3% in 1, 3, 5 and 7% respectively. Penicillium digitatum, Phytophthora sp., Alternaria citri and Collectotrichum gloeosporioides were among decay causing moulds detected. Control fruits lost more weight during storage than cured fruits did. Fruit rind hardening was more noticed in the control and those cured to 1% weight loss, especially from the April harvest. It was insignificant in other treatments in both trials. Titratable acidity, pH, juice content and TSS were not affected by the treatment. Colour change to yellow was however retarded by curing. Curing to 5% weight loss was best for decay control and quality retention.