The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule

IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4μ8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.

Developing an evidence-based clinical pathway for the assessment, diagnosis and management of acute Charcot Neuro-Arthropathy : a systematic review

Background: Charcot Neuro-Arthropathy (CN) is one of the more devastating complications of diabetes. To the best of the authors' knowledge, it appears that no clinical tools based on a systematic review of existing literature have been developed to manage acute CN. Thus, the aim of this paper was to systematically review existing literature and develop an evidence-based clinical pathway for the assessment, diagnosis and management of acute CN in patients with diabetes. Methods: Electronic databases (Medline, PubMed, CINAHL, Embase and Cochrane Library), reference lists, and relevant key websites were systematically searched for literature discussing the assessment, diagnosis and/or management of acute CN published between 2002-2012. At least two independent investigators then quality rated and graded the evidence of each included paper. Consistent recommendations emanating from the included papers were then fashioned in a clinical pathway. Results: The systematic search identified 267 manuscripts, of which 117 (44%) met the inclusion criteria for this study. Most manuscripts discussing the assessment, diagnosis and/or management of acute CN constituted level IV (case series) or EO (expert opinion) evidence. The included literature was used to develop an evidence-based clinical pathway for the assessment, investigations, diagnosis and management of acute CN. Conclusions: This research has assisted in developing a comprehensive, evidence-based clinical pathway to promote consistent and optimal practice in the assessment, diagnosis and management of acute CN. The pathway aims to support health professionals in making early diagnosis and providing appropriate immediate management of acute CN, ultimately reducing its associated complications such as amputations and hospitalisations.

A novel real time pricing scheme for demand response in residential distribution systems

Price based technique is one way to handle increase in peak demand and deal with voltage violations in residential distribution systems. This paper proposes an improved real time pricing scheme for residential customers with demand response option. Smart meters and in-home display units are used to broadcast the price and appropriate load adjustment signals. Customers are given an opportunity to respond to the signals and adjust the loads. This scheme helps distribution companies to deal with overloading problems and voltage issues in a more efficient way. Also, variations in wholesale electricity prices are passed on to electricity customers to take collective measure to reduce network peak demand. It is ensured that both customers and utility are benefitted by this scheme.

The acute effects of eccentrically-biased versus conventional weight training in older adults : a randomised controlled cross-over study

Background Whilst resistance training has been proven to convey considerable benefits to older people; immediately post-exercise there may be elevated transient risks for cardiac events and falls. Objectives and Measurements We assessed the acute effects of eccentrically-biased (EB) and conventional (CONV) resistance exercise on: platelet number, activation and granule exocytsosis; and mean velocity of centre of pressure displacement (Vm). Design, Setting, Participants and Intervention Ten older adults (7 males, 3 females; 69 ± 4 years) participated in this randomised controlled cross-over study in which they performed EB and CONV training sessions that were matched for total work and a control condition. Results Immediately post-exercise there was a statistically significant difference in platelet count between the control condition, in which it fell (pre 224 ± 35 109/L; post 211 ± 30 109/L: P < 0.05) and CONV in which it increased (pre 236 ± 55 109/L; post 242 ± 51 109/L: P > 0.05). There was no change in platelet activation and granule exocytsosis or Vm following EB and CONV. Conclusions Overall, while minor differences between regimens were observed, no major adverse effect on parameters of platelet function or centre of pressure displacement were observed acutely following either regimen. Eccentrically-biased and conventional resistance exercise training regimens do not appear to present an elevated acute risk in the context of changes to platelet function contributing to a cardiac event or postural stability increasing falls risk for apparently healthy older adults.

Experience of being an advanced practice nurse within Australian acute care settings : a systematic review of qualitative evidence

Background Nationally and internationally, advanced practice nurses are working under various titles and in different contexts to address gaps within healthcare systems. Analysis of advanced practice roles in different countries has been undertaken, but due to variations in cultural, geographical and professional factors, it is difficult and perhaps ineffectual to compare roles between countries. Contextual factors may also affect the actual experience of being an advanced practice nurse. A systematic review was therefore undertaken of qualitative evidence on the experience of being an advanced practice nurse in Australia, to provide deeper understanding of the role in the defined context. Methods The review followed the method for qualitative synthesis as per the Joanna Briggs Institute. An extensive search was undertaken of databases and online resources to find published and unpublished studies. Papers from 1990 to October 2011 which met specified inclusion criteria were appraised using the Joanna Briggs Institute Qualitative Assessment and Review Instrument. Results Three published studies and one unpublished dissertation were included in the review. From these studies, 216 findings were extracted and these were formed into 18 categories. Six meta-syntheses grouped under the headings of expert knowledge, confidence, education, relationships, negative experiences and patient-centred experience were created. Organisational factors impact greatly on the experience, professionally and personally. Conclusions Heterogeneity of role titles makes synthesis a difficult process, but contextualising the population provides a pragmatic approach to informing the status of the advanced practice nurse discourse. The review identifies positive and negative experiences of being an advanced practice nurse in Australian acute care settings with overlapping and intertwining findings that reinforce the complexity of the role.

Shadow boxing with an imaginary enemy : a response to "Law and Order Blues"

In our rejoinder to Don Weatherburn's paper,"Law and Order Blues", we do not take issue with his advocacy of the need to take crime seriously and to foster a more rational approach to the problems it poses. Where differences do emerge is (1) with his claim that he is willing to do so whilst we (in our different ways) are not; and (2) on the question of what this involves. Of particular concern is the way in which his argument proceeds by a combination of simple misrepresentation of the positions it seeks to disparage, and silence concerning issues of real substance where intellectual debate and exchange would be welcome and useful. Our paper challenges, in turn, the misrepresentation of Indermaur's analysis of trends in violent crime, the misrepresentation of Hogg and Brown's Rethinking Law and Order, the misrepresentation of the findings of some of the research into the effectiveness of punitive policies and the silence on sexual assault in "Law and Order Blues". We suggest that his silence on sexual assault reflects a more widespread unwillingness to acknowledge the methodological problems that arise in the measurement of crime because such problems severely limit the extent to which confident assertions can be made about prevalence and trends.

Provisional matrix deposition in hemostasis and venous insufficiency: Tissue preconditioning for nonhealing venous ulcers

Significance: Chronic wounds represent a major burden on global healthcare systems and reduce the quality of life of those affected. Significant advances have been made in our understanding of the biochemistry of wound healing progression. However, knowledge regarding the specific molecular processes influencing chronic wound formation and persistence remains limited. Recent Advances: Generally, healing of acute wounds begins with hemostasis and the deposition of a plasma-derived provisional matrix into the wound. The deposition of plasma matrix proteins is known to occur around the microvasculature of the lower limb as a result of venous insufficiency. This appears to alter limb cutaneous tissue physiology and consequently drives the tissue into a ‘preconditioned’ state that negatively influences the response to wounding. Critical Issues: Processes, such as oxygen and nutrient suppression, edema, inflammatory cell trapping/extravasation, diffuse inflammation, and tissue necrosis are thought to contribute to the advent of a chronic wound. Healing of the wound then becomes difficult in the context of an internally injured limb. Thus, interventions and therapies for promoting healing of the limb is a growing area of interest. For venous ulcers, treatment using compression bandaging encourages venous return and improves healing processes within the limb, critically however, once treatment concludes ulcers often reoccur. Future Directions: Improved understanding of the composition and role of pericapillary matrix deposits in facilitating internal limb injury and subsequent development of chronic wounds will be critical for informing and enhancing current best practice therapies and preventative action in the wound care field.

No sex difference in body fat in response to supervised and measured exercise

It is often reported that females lose less body weight than males do in response to exercise. These differences are suggested to be a result of females exhibiting a stronger defense of body fat and a greater compensatory appetite response to exercise than males do. Purpose This study aimed to compare the effect of a 12-wk supervised exercise program on body weight, body composition, appetite, and energy intake in males and females. Methods A total of 107 overweight and obese adults (males = 35, premenopausal females = 72, BMI = 31.4 ± 4.2 kg·m−2, age = 40.9 ± 9.2 yr) completed a supervised 12-wk exercise program expending approximately 10.5 MJ·wk−1 at 70% HRmax. Body composition, energy intake, appetite ratings, RMR, and cardiovascular fitness were measured at weeks 0 and 12. Results The 12-wk exercise program led to significant reductions in body mass (males [M] = −3.03 ± 3.4 kg and females [F] = −2.28 ± 3.1 kg), fat mass (M = −3.14 ± 3.7 kg and F = −3.01 ± 3.0 kg), and percent body fat (M = −2.45% ± 3.3% and F = −2.45% ± 2.2%; all P < 0.0001), but there were no sex-based differences (P > 0.05). There were no significant changes in daily energy intake in males or females after the exercise intervention compared with baseline (M = 199.2 ± 2418.1 kJ and F = −131.6 ± 1912.0 kJ, P > 0.05). Fasting hunger levels significantly increased after the intervention compared with baseline values (M = 11.0 ± 21.1 min and F = 14.0 ± 22.9 mm, P < 0.0001), but there were no differences between males and females (P > 0.05). The exercise also improved satiety responses to an individualized fixed-energy breakfast (P < 0.0001). This was comparable in males and females. Conclusions Males and premenopausal females did not differ in their response to a 12-wk exercise intervention and achieved similar reductions in body fat. When exercise interventions are supervised and energy expenditure is controlled, there are no sex-based differences in the measured compensatory response to exercise.

The adaptive metabolic response to exercise-induced weight loss influences both energy expenditure and energy intake

BACKGROUND/OBJECTIVEs A decline in resting energy expenditure (REE) beyond that predicted from changes in body composition has been noted following dietary-induced weight loss. However, it is unknown whether a compensatory downregulation in REE also accompanies exercise (EX)-induced weight loss, or whether this adaptive metabolic response influences energy intake (EI). SUBJECTS/METHODS Thirty overweight and obese women (body mass index (BMI)=30.6±3.6 kg/m2) completed 12 weeks of supervised aerobic EX. Body composition, metabolism, EI and metabolic-related hormones were measured at baseline, week 6 and post intervention. The metabolic adaptation (MA), that is, difference between predicted and measured REE was also calculated post intervention (MApost), with REE predicted using a regression equation generated in an independent sample of 66 overweight and obese women (BMI=31.0±3.9 kg/m2). RESULTS Although mean predicted and measured REE did not differ post intervention, 43% of participants experienced a greater-than-expected decline in REE (−102.9±77.5 kcal per day). MApost was associated with the change in leptin (r=0.47; P=0.04), and the change in resting fat (r=0.52; P=0.01) and carbohydrate oxidation (r=−0.44; P=0.02). Furthermore, MApost was also associated with the change in EI following EX (r=−0.44; P=0.01). CONCLUSIONS Marked variability existed in the adaptive metabolic response to EX. Importantly, those who experienced a downregulation in REE also experienced an upregulation in EI, indicating that the adaptive metabolic response to EX influences both physiological and behavioural components of energy balance.

Delirium knowledge and recognition : a randomized controlled trial of a web-based educational intervention for acute care nurses

Delirium is a significant problem for older hospitalized people and is associated with poor outcomes. It is poorly recognized and evidence suggests that a major reason is lack of education. Nurses, who are educated about delirium, can play a significant role in improving delirium recognition. This study evaluated the impact of a delirium specific educational website. A cluster randomized controlled trial, with a pretest/post-test time series design, was conducted to measure delirium knowledge (DK) and delirium recognition (DR) over three time-points. Statistically significant differences were found between the intervention and non-intervention group. The intervention groups' DK scores were higher and the change over time results were statistically significant [T3 and T1 (t=3.78 p=<0.001) and T2 and T1 baseline (t=5.83 p=<0.001)]. Statistically significant improvements were also seen for DR when comparing T2 and T1 results (t=2.56 p=0.011) between both groups but not for changes in DR scores between T3 and T1 (t=1.80 p=0.074). Participants rated the website highly on the visual, functional and content elements. This study supports the concept that web-based delirium learning is an effective and satisfying method of information delivery for registered nurses. Future research is required to investigate clinical outcomes as a result of this web-based education.

Response of a buried tunnel to surface blast using different numerical techniques

This paper presents a comparative study on the response of a buried tunnel to surface blast using the arbitrary Lagrangian-Eulerian (ALE) and smooth particle hydrodynamics (SPH) techniques. Since explosive tests with real physical models are extremely risky and expensive, the results of a centrifuge test were used to validate the numerical techniques. The numerical study shows that the ALE predictions were faster and closer to the experimental results than those from the SPH simulations which over predicted the strains. The findings of this research demonstrate the superiority of the ALE modelling techniques for the present study. They also provide a comprehensive understanding of the preferred ALE modelling techniques which can be used to investigate the surface blast response of underground tunnels.

Prevention and treatment of acute radiation-induced skin reactions : a systematic review and meta-analysis of randomized controlled trials

Background Radiation-induced skin reaction (RISR) is a common side effect that affects the majority of cancer patients receiving radiation treatment. RISR is often characterised by swelling,redness, pigmentation, fibrosis, and ulceration, pain, warmth, burning, and itching of the skin. The aim of this systematic review was to assess the effects of interventions which aim to prevent or manage RISR in people with cancer. Methods We searched the following databases up to November 2012: Cochrane Skin Group Specialised Register, CENTRAL (2012, Issue 11), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), CINAHL (from 1981) and LILACS (from 1982). Randomized controlled trials evaluating interventions for preventing or managing RISR in cancer patients were included. The primary outcomes were development of RISR, and levels of RISR and symptom severity. Secondary outcomes were time taken to develop erythema or dry desquamation; quality of life; time taken to heal, a number of skin reaction and symptom severity measures; cost, participant satisfaction; ease of use and adverse effects. Where appropriate, we pooled results of randomized controlled trials using mean differences (MD) or odd ratios (OR) with 95% confidence intervals (CI). Results Forty-seven studies were included in this review. These evaluated six types of interventions (oral systemic medications; skin care practices; steroidal topical therapies; non-steroidal topical therapies; dressings and other). Findings from two meta-analyses demonstrated significant benefits of oral Wobe-Mugos E for preventing RISR (OR 0.13 (95% CI 0.05 to 0.38)) and limiting the maximal level of RISR (MD −0.92 (95% CI −1.36 to −0.48)). Another meta-analysis reported that wearing deodorant does not influence the development of RISR (OR 0.80 (95% CI 0.47 to 1.37)). Conclusions Despite the high number of trials in this area, there is limited good, comparative research that provides definitive results suggesting the effectiveness of any single intervention for reducing RISR. More research is required to demonstrate the usefulness of a wide range of products that are being used for reducing RISR. Future efforts for reducing RISR severity should focus on promising interventions, such as Wobe-Mugos E and oral zinc.

Effects of scaffold architecture on mechanical characteristics and osteoblast response to static and perfusion bioreactor cultures

Tissue engineering focuses on the repair and regeneration of tissues through the use of biodegradable scaffold systems that structurally support regions of injury whilst recruiting and/or stimulating cell populations to rebuild the target tissue. Within bone tissue engineering, the effects of scaffold architecture on cellular response have not been conclusively characterized in a controlled-density environment. We present a theoretical and practical assessment of the effects of polycaprolactone (PCL) scaffold architectural modifications on mechanical and flow characteristics as well as MC3T3-E1 preosteoblast cellular response in an in vitro static plate and custom-designed perfusion bioreactor model. Four scaffold architectures were contrasted, which varied in inter-layer lay-down angle and offset between layers, whilst maintaining a structural porosity of 60 ± 5%. We established that as layer angle was decreased (90° vs. 60°) and offset was introduced (0 vs. 0.5 between layers), structural stiffness, yield stress, strength, pore size and permeability decreased, whilst computational fluid dynamics-modeled wall shear stress was increased. Most significant effects were noted with layer offset. Seeding efficiencies in static culture were also dramatically increased due to offset (~45% to ~86%), with static culture exhibiting a much higher seeding efficiency than perfusion culture. Scaffold architecture had minimal effect on cell response in static culture. However, architecture influenced osteogenic differentiation in perfusion culture, likely by modifying the microfluidic environment.

Cellular stress triggers the human topoisomerase I damage response independently of DNA damage in a p53 controlled manner

The 'human topoisomerase I (htopoI) damage response' was reported to be triggered by various kinds of DNA lesions. Also, a high and persistent level of htopoI cleavage complexes correlated with apoptosis. In the present study, we demonstrate that DNA damage-independent induction of cell death using colcemid and tumor necrosis factor is also accompanied by a strong htopoI response that correlates with the onset of apoptotic hallmarks. Consequently, these results suggest that htopoI cleavage complex formation may be caused by signaling pathways independent of the kind of cellular stress. Thus, protein interactions or signaling cascades induced by DNA damage or cellular stress might lead to the formation of stabilized cleavage complexes rather than the DNA lesion itself. Finally, we show that p53 not only plays a key role in the regulation of the htopoI response to UV-C irradiation but also to treatment with colcemid.

Demand response for residential appliances via Customer Reward Scheme

This paper proposes a reward based demand response algorithm for residential customers to shave network peaks. Customer survey information is used to calculate various criteria indices reflecting their priority and flexibility. Criteria indices and sensitivity based house ranking is used for appropriate load selection in the feeder for demand response. Customer Rewards (CR) are paid based on load shift and voltage improvement due to load adjustment. The proposed algorithm can be deployed in residential distribution networks using a two-level hierarchical control scheme. Realistic residential load model consisting of non-controllable and controllable appliances is considered in this study. The effectiveness of the proposed demand response scheme on the annual load growth of the feeder is also investigated. Simulation results show that reduced peak demand, improved network voltage performance, and customer satisfaction can be achieved.