Evaluation of 2LHERP in preventing recurrences of genital herpes. Institut International 3IDI.
The objective of the study was to evaluate the effectiveness of a homeopathic complex in terms of intensity of attacks and duration of remission between attacks of genital herpes. Fifty three patients aged 18 or over with a minimum of four attacks annually were followed in this open multicentre study in a primary care setting. The principal parameters analysed were: frequency of attacks; intensity of symptoms, during treatment and/or after stopping treatment; treatment tolerance. Eighty-two percent of patients treated for recurrent genital herpes benefited. In 41% of cases, there was no recurrence after the first treatment with follow-up of between 8 and 50 months. In 32% of patients, one or two relapses, in 9% of patients recurrences continued but with reduced frequency and intensity.


Small bowel morphology in British Indian and Afro-Caribbean subjects: evidence of tropical enteropathy.
Distal duodenal biopsy specimens taken from 30 white, 35 Indian, and 20 Afro-Caribbean residents of West Birmingham during routine endoscopy for dyspepsia, were assessed by dissecting microscopy and morphometry. Finger-shaped villi were significantly less frequent in the Indian and Afro-Caribbean subjects than in the white subjects when assessed by dissecting microscopy (p less than 0.005), and both immigrant groups had decreased mucosal thickness (p less than 0.01), villous height (p less than 0.001), villous:crypt ratios (p less than 0.01) and enterocyte height (p less than 0.05) compared with the white group. In the Indian subjects, villous height and villous:crypt ratios correlated significantly with the time since the last visit to the Indian subcontinent (p less than 0.005). Serum alkaline phosphatase values were significantly higher in the Indian subjects compared with the whites (p less than 0.02), and serum globulins were increased in both the Afro-Caribbean and Indian subjects (p less than 0.01). There were no correlations between morphometric indices and body habitus or biochemical or haematological indices and the long term effect of the morphological changes is not clear.


Antiplasmodial quinones from the rhizomes of Kniphofia foliosa.
Extracts of the rhizomes of Kniphofia foliosa exhibited antiplasmodial activities against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 values of 3-5 microg/mL. A phenyloxanthrone, named 10-acetonylknipholone cyclooxanthrone (1) and an anthraquinone-anthrone dimer, chryslandicin 10-methyl ether (2), were isolated from the rhizomes, along with known quinones, including the rare phenylanthraquinone dimers, joziknipholones A and B. The structures of these compounds were determined based on spectroscopic data. This is the second report on the occurrence of the dimeric phenylanthraquinones in nature. In an in vitro antiplasmodial assay of the isolated compounds, activity was observed for phenylanthraquinones, anthraquinone-anthrone dimers and dimeric phenylanthraquinones, with joziknipholone A being the most active. The new compound, 10-acetonylknipholone cyclooxanthrone, also showed anti-plasmodial activity. In an in vivo assay, knipholone anthrone displayed marginal antimalarial activity.


Docosahexaenoic acid utilization during rod photoreceptor cell renewal.
The supply of docosahexaenoic acid (22:6) to the frog retina, and its subsequent use by retinal cells, was studied by autoradiography and biochemical methods. Different delivery routes of 3H-22:6 were evaluated. Predominant uptake by the neural retina, mainly in ganglion cell axons, outer synaptic layer, and Müller cells, was observed when the radiolabeled fatty acid was given intravitreally or by short-term incubations of eyecups. In short-term eyecup incubations, Müller cells preferentially labeled, suggesting their involvement as a transient storage site. After intravenous or dorsal lymph sac injections of 3H-22:6, most of the retinal label was seen in rod photoreceptor cells. Two different labeling patterns were found in rod outer segments (ROS) as a function of postinjection time: an overall diffuse labeling pattern, as well as a dense-label region at the ROS base. This dense-label region expanded until it reached the apex of the ROS after about 30 d. HPLC analysis of fatty acid methyl esters from retinal lipid extracts showed that 3H-22:6 comprised essentially all of the label until after day 46, indicating lack of metabolic recycling of this molecule. Lipid-extracted retinal residue was devoid of radioactivity, demonstrating that protein did not contain significant covalently bound label. 3H-22:6 acylated to phospholipids in photoreceptor membranes moved apically, as evidenced by the expanding labeled region from the base of the ROS. Oil droplets in both the pigment epithelium and the cone photoreceptors labeled heavily, suggesting that 22:6 may be transiently stored. ROS tips that were phagocytosed by the pigment epithelium contained label similar in density to that of the outer segments, demonstrating that 22:6-phospholipids, at least in part, cycle through the pigment epithelial cells during visual cell renewal. In parallel experiments in frogs injected with 3H-leucine and maintained under the same experimental conditions, well-define, narrow protein bands were observed. Since the leading edge of the 3H-leucine-labeled band (rhodopsin), and that of the dense-label region of 3H-22:6 migrated at the same rate, reaching the rod tips at the same time, we suggest that the 3H-22:6-labeled phospholipids giving this profile are a unique molecular species noncovalently associated with rhodopsin.


The impact of cryopreservation on human peripheral blood leucocyte bioenergetics.
Circulating immune cells are considered a source for biomarkers in health and disease, since they are exposed to nutritional, metabolic and immunological stimuli in the vasculature. Cryopreservation of leucocytes is routinely used for long-term storage and determination of phenotypic/functional changes at a later date. Exploring the role of bioenergetics and mitochondrial (dys)function in leucocytes is often examined by using freshly isolated cells. The aim of the pilot study described herein was to assess leucocyte bioenergetics in cryopreserved cells. Leucocytes were isolated from whole blood, counted and frozen in liquid nitrogen (LN2) for a period of 3 months. Cells were thawed at regular intervals and bioenergetic analysis performed using the Seahorse XFe96 flux analyser. Cryogenic storage reduced cell viability by 20%, but cell bioenergetic responses were largely intact for up to 1 month storage in LN2. However, after 1 month storage, mitochondrial function was impaired as reflected by decreasing basal respiration, ATP production, maximum (MAX) respiration, reserve capacity and coupling efficiency. Conversely, glycolytic activity was increased after 1 month, most notably the enhanced glycolytic response to 25 mM glucose without any change in glycolytic capacity. Finally, calculation of bioenergetic health index (BHI) demonstrated that this potential diagnostic parameter was sensitive to cryopreservation. The present study has demonstrated for the first time that cryopreservation of primary immune cells modified their metabolism in a time-dependent fashion, indicated by attenuated aerobic respiration and enhanced glycolytic activity. Taken together, we recommend caution in the interpretation of bioenergetic responses or BHI in cryopreserved samples.


Is the statistic value all we should care about in neuroimaging?
Here we address an important issue that has been embedded within the neuroimaging community for a long time: the absence of effect estimates in results reporting in the literature. The statistic value itself, as a dimensionless measure, does not provide information on the biophysical interpretation of a study, and it certainly does not represent the whole picture of a study. Unfortunately, in contrast to standard practice in most scientific fields, effect (or amplitude) estimates are usually not provided in most results reporting in the current neuroimaging publications and presentations. Possible reasons underlying this general trend include (1) lack of general awareness, (2) software limitations, (3) inaccurate estimation of the BOLD response, and (4) poor modeling due to our relatively limited understanding of FMRI signal components. However, as we discuss here, such reporting damages the reliability and interpretability of the scientific findings themselves, and there is in fact no overwhelming reason for such a practice to persist. In order to promote meaningful interpretation, cross validation, reproducibility, meta and power analyses in neuroimaging, we strongly suggest that, as part of good scientific practice, effect estimates should be reported together with their corresponding statistic values. We provide several easily adaptable recommendations for facilitating this process.


On the Efficiency of Image Metrics for Evaluating the Visual Quality of 3D Models.
3D meshes are deployed in a wide range of application processes (e.g., transmission, compression, simplification, watermarking and so on) which inevitably introduce geometric distortions that may alter the visual quality of the rendered data. Hence, efficient model-based perceptual metrics, operating on the geometry of the meshes being compared, have been recently introduced to control and predict these visual artifacts. However, since the 3D models are ultimately visualized on 2D screens, it seems legitimate to use images of the models (i.e., snapshots from different viewpoints) to evaluate their visual fidelity. In this work we investigate the use of image metrics to assess the visual quality of 3D models. For this goal, we conduct a wide-ranging study involving several 2D metrics, rendering algorithms, lighting conditions and pooling algorithms, as well as several mean opinion score databases. The collected data allow (1) to determine the best set of parameters to use for this image-based quality assessment approach and (2) to compare this approach to the best performing model-based metrics and determine for which use-case they are respectively adapted. We conclude by exploring several applications that illustrate the benefits of image-based quality assessment.


Resource partitioning in ecological communities.
To understand resource partitioning, essentially a community phenomenon, we require a holistic theory that draws upon models at the individual and population level. Yet some investigators are still content mainly to document differences between species, a procedure of only limited interest. Therefore, it may be useful to conclude with a list of questions appropriate for studies of resource partitioning, questions this article has related to the theory in a preliminary way. 1) What is the mechanism of competition? What is the relative importance of predation? Are differences likely to be caused by pressures toward reproductive isolation? 2) Are niches (utilizations) regularly spaced along a single dimension? 3) How many dimensions are important, and is there a tendency for more dimensions to be added as species number increases? 4) Is dimensional separation complementary? 5) Which dimensions are utilized, how do they rank in importance, and why? How do particular dimensions change in rank as species nuimber increases? 6) What is the relation of dimensional separation to difference in phenotypic indicators? To what extent does the functional relation of phenotype to resource characteristics constrain partitioning? 7) What is the distance between mean position of niches, what is the niche standard deviation, and what is the ratio of the two? What is the niche shape?


Mapping the Paediatric Quality of Life Inventory (PedsQL™) Generic Core Scales onto the Child Health Utility Index-9 Dimension (CHU-9D) Score for Economic Evaluation in Children.
The Paediatric Quality of Life Inventory (PedsQL™) questionnaire is a widely used, generic instrument designed for measuring health-related quality of life (HRQoL); however, it is not preference-based and therefore not suitable for cost-utility analysis. The Child Health Utility Index-9 Dimension (CHU-9D), however, is a preference-based instrument that has been primarily developed to support cost-utility analysis. This paper presents a method for estimating CHU-9D index scores from responses to the PedsQL™ using data from a randomised controlled trial of prednisolone therapy for treatment of childhood corticosteroid-sensitive nephrotic syndrome. HRQoL data were collected from children at randomisation, week 16, and months 12, 18, 24, 36 and 48. Observations on children aged 5 years and older were pooled across all data collection timepoints and were then randomised into an estimation (n = 279) and validation (n = 284) sample. A number of models were developed using the estimation data before internal validation. The best model was chosen using multi-stage selection criteria. Most of the models developed accurately predicted the CHU-9D mean index score. The best performing model was a generalised linear model (mean absolute error = 0.0408; mean square error = 0.0035). The proportion of index scores deviating from the observed scores by < 0.03 was 53%. The mapping algorithm provides an empirical tool for estimating CHU-9D index scores and for conducting cost-utility analyses within clinical studies that have only collected PedsQL™ data. It is valid for children aged 5 years or older. Caution should be exercised when using this with children younger than 5 years, older adolescents (> 13 years) or patient groups with particularly poor quality of life. 16645249.


Child defecation behaviour, stool disposal practices, and childhood diarrhoea in Burkina Faso: results from a case-control study.
To investigate the association between where young children defecate, where stools are disposed of, and the presence of human stools on the ground in the compound and the rate of hospital admission with diarrhoea. This was a case-control study with two control groups. The study took place in Bobo-Dioulasso, the second city of Burkina Faso in West Africa. Three groups of children aged 36 months and under, and living in Bobo-Dioulasso were studied. Cases were 757 children admitted to hospital with symptoms of diarrhoea or dysentery. The first control group comprised 757 neighbourhood control children approximately matched on age and date of recruitment, and the second, 631 children admitted to the same hospital without symptoms of diarrhoea or dysentery. There was no evidence of any association between where the child was reported to defecate and hospital admission with diarrhoea or dysentery (odds ratio = 1.10; 95% confidence interval (CI) 0.78, 1.57, cases v neighbourhood controls; odds ratio = 0.84; 95% CI 0.60, 1.18, cases v hospital controls). There was evidence of an association between where the mother reported disposing of the child's stools and hospital admission with diarrhoea or dysentery (odds ratio = 1.50; 95% CI 1.09, 2.06, cases v neighbourhood controls; odds ratio = 1.31; 95% CI 0.96, 1.79, cases v hospital controls). Human stools were more frequently observed in the yards of cases than controls (odds ratio = 1.38; 95% CI 0.98, 1.95, cases compared with neighbourhood controls; odds ratio = 1.33; 95% CI 0.96, 1.84, cases compared with hospital controls). The findings suggest that it is not where the child defecates that matters but how the mother then deals with the child's stools.


Importance of anemia and transferrin levels in the regulation of intestinal iron absorption in hypotransferrinemic mice.
The hypotransferrinemic mouse (trf (hpx)) is a mutant strain exhibiting transferrin deficiency, marked anemia, hyperabsorption of iron, and elevated hepatic iron stores. We set out to investigate the relative roles of anemia and of transferrin in the malregulation of intestinal iron absorption in these animals. Transfusion of erythrocytes obtained from littermate controls increased hemoglobin levels and reduced reticulocyte counts in recipient animals. Although mucosal to carcass (59)Fe transfer was reduced, total duodenal iron uptake was not significantly affected. Iron absorption in homozygotes, in contrast to littermate controls, was not reduced by hyperoxia. Mouse transferrin injections, in the short term, increased delivery of iron to the marrow and raised hemoglobin levels. Although mucosal transfer and total iron uptake were reduced at the higher transferrin doses, total uptake was still higher than in controls. Daily injections of mouse/human transferrin for 3 weeks from weaning, normalized hemoglobin values, and markedly reduced liver iron and intestinal iron absorption values in trf (hpx) animals. When such daily-injected mice were left for a week to allow transferrin clearance, iron absorption values were significantly enhanced; hemoglobin or hepatic iron levels were, however, not significantly altered. These data indicate that hyperabsorption of iron in trf (hpx) mice is not solely because of the anemia; transferrin levels per se do affect iron absorption, possibly via a direct effect on the intestinal mucosa.


Location-based health information services: a new paradigm in personalised information delivery.
Brute health information delivery to various devices can be easily achieved these days, making health information instantly available whenever it is needed and nearly anywhere. However, brute health information delivery risks overloading users with unnecessary information that does not answer their actual needs, and might even act as noise, masking any other useful and relevant information delivered with it. Users' profiles and needs are definitely affected by where they are, and this should be taken into consideration when personalising and delivering information to users in different locations. The main goal of location-based health information services is to allow better presentation of the distribution of health and healthcare needs and Internet resources answering them across a geographical area, with the aim to provide users with better support for informed decision-making. Personalised information delivery requires the acquisition of high quality metadata about not only information resources, but also information service users, their geographical location and their devices. Throughout this review, experience from a related online health information service, HealthCyberMap http://healthcybermap.semanticweb.org/, is referred to as a model that can be easily adapted to other similar services. HealthCyberMap is a Web-based directory service of medical/health Internet resources exploring new means to organise and present these resources based on consumer and provider locations, as well as the geographical coverage or scope of indexed resources. The paper also provides a concise review of location-based services, technologies for detecting user location (including IP geolocation), and their potential applications in health and healthcare.


Living with a double burden: Meanings of pain for women with fibromyalgia.
Living with fibromyalgia (FM) means living with a chronic pain condition that greatly influences daily life. The majority of people with FM are middle-aged women. The aim of this study was to elucidate meanings of pain for women with FM. Fifteen women with FM were interviewed about their pain experiences and a phenomenological hermeneutic interpretation was used to analyse the interview texts. The findings show that meanings of pain for women with FM can be understood as living with a double burden; living with an aggressive, unpredictable pain and being doubted by others in relation to the invisible pain. The ever-present pain was described as unbearable, overwhelming, and dominated the women's whole existence. Nevertheless, all the women tried to normalize life by doing daily chores in an attempt to alleviate the pain. In order to support the women's needs and help them to feel well despite their pain, it is important that nurses and health care personnel acknowledge and understand women with FM and their pain experiences.


Decompression of Chiari malformation with and without duraplasty: morbidity versus recurrence.
The optimal surgical management of Chiari malformation (CM) is evolving. Evidence continues to accrue that supports decompression without duraplasty as an effective treatment to achieve symptomatic relief and anatomical decompression. The risks and benefits of this less invasive operation need to be weighed against decompression with duraplasty. The authors performed a retrospective review of all CM decompressions from 2003 to 2007. All operations were performed by a single surgeon at a single institution. Data were analyzed for outcome, postoperative morbidity, and recurrence. Of 121 unique patients, 56 underwent posterior fossa decompressions without duraplasty (PFD) and 64 patients underwent posterior fossa decompressions with duraplasty (PFDD). Of the 56 PFD patients, 7 (12.5%) needed a subsequent PFDD for symptomatic recurrence. Of the 64 patients who underwent a PFDD, 2 (3.1%) needed a repeated PFDD for symptomatic recurrence. Patients treated with PFDD had an average operative time of 201 minutes in contrast to 127 minutes for those who underwent PFD (p = 0.0001). Patients treated with PFDD had average hospital stays of 4.0 days, whereas that for patients treated with PFD was 2.7 days (p = 0.0001). While in the hospital, patients treated with PFDD used low-grade narcotics, intravenous narcotics, muscle relaxants, and antiemetic medications at statistically significant differing rates. While PFD was associated with a higher rate of recurrent symptoms requiring repeated decompression, this may be justified by the significantly lower morbidity rate. Clearer delineation of the trade-off between morbidity and recurrence may be used to help patients and their families make decisions regarding care.


Numerical modeling of light propagation in a hexagonal array of dielectric cylinders.
To model the light-guiding properties of a hexagonal array of dielectric cylinders, we have numerically solved Maxwell's equations with the finite-difference time-domain technique. The sizes and refractive indices of the cylinders are representative of those of the outer segments of the cone photoreceptors in the human central retina. In the array, light propagates predominantly as a "slow" mode, with a noticeable contribution of a "fast" mode, with the optical field localized in the intra- and inter-cylinder spaces, respectively. Interference between these modes leads to substantial (up to approximately 60%) axial oscillations in optical power within the cylinders. Our numerical model offered approximate dependence of the optical intensity distribution within the cylinders on their radii and separations.


Recombinant deoxyribonucleoside kinase from Drosophila melanogaster can improve gemcitabine based combined gene/chemotherapy for targeting cancer cells.
A recombinant deoxyribonucleoside kinase from Drosophila melanogaster with a deletion of the last 20 amino acid residues (named DmdNKΔC20) was hypothesized as a potential therapeutic tool for gene therapy due to its broad substrate specificity and better catalytic efficiency towards nucleosides and nucleoside analogs. This study was designed to evaluate the effect of DmdNKΔC20 for sensitizing human cancer cell lines to gemcitabine and to further investigate its role in reversal of acquired drug resistance in gemcitabine-resistant cancer cell line. The DmdNKΔC20 gene was delivered to three different cancer cell lines, including breast, colon and liver cancer cells, using lipid-mediated transfection reagent. After transfection, gene expression of DmdNKΔC20 was confirmed by quantitative reverse transcription PCR (qRT-PCR) and the combined effect of DmdNKΔC20 and gemcitabine based cytotoxicity was observed by cell viability assay. We further evolved a gemcitabine-resistant breast cancer cell line (named MCF7-R) through directed evolution in the laboratory, which showed 375-fold more resistance compared with parental MCF7 cells. Upon transfection with DmdNKΔC20 gene, MCF7-R cells showed 83-fold higher sensitivity to gemcitabine compared with the control group of MCF7-R cells. Moreover, we observed 79% higher expression of p21 protein in transfected MCF7-R cells, which may indicate induction of apoptosis. Our findings highlight the importance and therapeutic potential of DmdNKΔC20 in combined gene/chemotherapy approach to target a wide range of cancers, particularly gemcitabine-resistant cancers.


Competitive integration of visual and goal-related signals on neuronal accumulation rate: a correlate of oculomotor capture in the superior colliculus.
The mechanisms that underlie the integration of visual and goal-related signals for the production of saccades remain poorly understood. Here, we examined how spatial proximity of competing stimuli shapes goal-directed responses in the superior colliculus (SC), a midbrain structure closely associated with the control of visual attention and eye movements. Monkeys were trained to perform an oculomotor-capture task [Theeuwes, J., Kramer, A. F., Hahn, S., Irwin, D. E., & Zelinsky, G. J. Influence of attentional capture on oculomotor control. Journal of Experimental Psychology. Human Perception and Performance, 25, 1595-1608, 1999], in which a target singleton was revealed via an isoluminant color change in all but one item. On a portion of the trials, an additional salient item abruptly appeared near or far from the target. We quantified how spatial proximity between the abrupt-onset and the target shaped the goal-directed response. We found that the appearance of an abrupt-onset near the target induced a transient decrease in goal-directed discharge of SC visuomotor neurons. Although this was indicative of spatial competition, it was immediately followed by a rebound in presaccadic activation, which facilitated the saccadic response (i.e., it induced shorter saccadic RT). A similar suppression also occurred at most nontarget locations even in the absence of the abrupt-onset. This is indicative of a mechanism that enabled monkeys to quickly discount stimuli that shared the common nontarget feature. These results reveal a pattern of excitation/inhibition across the SC visuomotor map that acted to facilitate optimal behavior-the short duration suppression minimized the probability of capture by salient distractors, whereas a subsequent boost in accumulation rate ensured a fast goal-directed response. Such nonlinear dynamics should be incorporated into future biologically plausible models of saccade behavior.


Comparative ability of dobutamine and exercise stress in inducing myocardial ischaemia in active patients.
To compare the ability of dobutamine and exercise stress to induce myocardial ischaemia and perfusion heterogeneity under routine clinical circumstances. 86 active patients without previous myocardial infarction were studied by dobutamine and exercise stress protocols and coronary angiography. During both tests patients underwent electrocardiography, digitised echocardiography, and perfusion scintigraphy using Tc-99m methoxybutylisonitrile (MIBI) single photon emission computed tomography. Coronary disease defined as an ST segment depression of > or = 0.1 mV, a resting or stress induced perfusion defect, or a resting or stress induced wall motion abnormality on exercise and dobutamine stress testing. Dobutamine stress was submaximal in 51 patients because of ingestion of beta adrenoceptor blocking agents on the day of the test (n = 25) or failure to attain the peak dose owing to side effects (n = 28). Exercise was limited in 23 patients by non-cardiac symptoms. The peak heart rate with dobutamine was less than that attained with exercise (105 (25) v 132 (24) beats/min, P < 0.0001); the response to maximal dobutamine stress significantly exceeded that to submaximal stress. Peak blood pressure was greatest with exercise (206 (27) v 173 (25) mm Hg, P < 0.001), values at maximal and submaximal dobutamine stress being comparable. Electrocardiographic evidence of ischaemia was induced less frequently by dobutamine than exercise (32% v 77% of the 56 patients with significant coronary disease, P < 0.01), as was abnormal wall motion (54% v 88%, P < 0.001). Ischaemia was induced more readily with maximal stress of either type; thus the sensitivities of dobutamine and exercise echocardiography were comparable only in patients undergoing a maximal dobutamine testing (73% v 77%, NS). Perfusion heterogeneity was induced in 58% of patients with coronary disease at submaximal dobutamine stress, 73% at maximal dobutamine stress, and 73% at exercise stress (NS). Among 30 patients without coronary stenoses, normal function was obtained in 83% of echocardiography studies with dobutamine and in 80% with exercise (NS). Normal perfusion was identified in 70% of these patients at exercise MIBI, and 68% at dobutamine stress (NS). In a group of patients studied under normal clinical circumstances antianginal treatment and inability to complete the stress protocol are frequent and compromise the capacity of dobutamine stress to induce ischaemia. In contrast, the induction of perfusion heterogeneity is less susceptible to submaximal stress.


Diffusion Processes and Drug Release: Capsaicinoids - Loaded Poly (ε-caprolactone) Microparticles.
We present a generalmodel based on fractional diffusion equation coupled with a kinetic equation through the boundary condition. It covers several scenarios that may be characterized by usual or anomalous diffusion or present relaxation processes on the surface with non-Debye characteristics. A particular case of this model is used to investigate the experimental data obtained from the drug release of the capsaicinoids-loaded Poly (ε-caprolactone) microparticles. These considerations lead us to a good agreement with experimental data and to the conjecture that the burst effect, i.e., an initial large bolus of drug is released before the release rate reaches a stable profile, may be related to an anomalous diffusion manifested by the system.


Bone spicule pigment formation in retinitis pigmentosa: insights from a mouse model.
Bone spicule pigments (BSP) are a hallmark of retinitis pigmentosa (RP). In this study, we examined the process of BSP formation in the rhodopsin knockout (rho (-/-)) mouse, a murine model for human RP. In rho (-/-) mice from 2 to 16 months of age, representing the range from early to late stages of degeneration, retinal sections and whole mounts were examined morphologically by light and electron microscopy. The results were compared to scanning laser ophthalmoscopy of BSP degeneration in human RP. After the loss of all photoreceptor cells in rho-/- mice, the outer retina successively degenerated, leading to approximation and finally a direct contact of inner retinal vessels and the retinal pigment epithelium (RPE). We could show that it was the event of proximity of retinal vessel and RPE that triggered migration of RPE cells along the contacting vessels towards the inner retina. Ultrastructurally, these mislocalized RPE cells partially sealed the vessels by tight junction linkage and deposited extracellular matrix perivascularly. Also, the vascular endothelium developed fenestrations similar to the RPE-choroid interface. In whole mounts, the pigmented cell clusters outlining retinal capillaries correlated well with BSPs in human RP. The structure of the inner retina remained well preserved, even in late stages. The Rho (-/-) mouse is the first animal model that depicts all major pathological changes, even in the late stages of RP. Using the rho (-/-) mouse model we were able to analyze the complete dynamic process of BSP formation. Therefore we conclude that: (1) In rho (-/-) retinas, BSPs only form in areas devoid of photoreceptors; (2) Direct contact between inner retinal vessels and RPE appears to be a major trigger for migration of RPE cells; (3) The distribution of the RPE cells in BSPs reflects the vascular network at the time of formation. The similarity of the disease process between mouse and human and the possibility to study all consecutive steps of the course of the disease makes the rho (-/-) mouse valuable for further insights in the dynamics of BSP formation in human RP.


Colorectal cancer liver metastases - a population-based study on incidence, management and survival.
Colorectal cancer (CRC) is a leading cause of cancer-associated deaths with liver metastases developing in 25-30% of those affected. Previous data suggest a survival difference between right- and left-sided liver metastatic CRC, even though left-sided cancer has a higher incidence of liver metastases. The aim of the study was to describe the liver metastatic patterns and survival as a function of the characteristics of the primary tumour and different combinations of metastatic disease. A retrospective population-based study was performed on a cohort of patients diagnosed with CRC in the region of Stockholm, Sweden during 2008. Patients were identified through the Swedish National Quality Registry for Colorectal Cancer Treatment (SCRCR) and additional information on intra- and extra-hepatic metastatic pattern and treatment were retrieved from electronic patient records. Patients were followed for 5 years or until death. Factors influencing overall survival (OS) were investigated by means of Cox regression. OS was compared using Kaplan-Meier estimations and the log-rank test. Liver metastases were diagnosed in 272/1026 (26.5%) patients within five years of diagnosis of the primary. Liver and lung metastases were more often diagnosed in left-sided colon cancer compared to right-sided cancer (28.4% versus 22.1%, p = 0.029 and 19.7% versus 13.2%, p = 0.010, respectively) but the extent of liver metastases were more extensive for right-sided cancer as compared to left-sided (p = 0.001). Liver metastatic left-sided cancer, including rectal cancer, was associated with a 44% decreased mortality risk compared to right-sided cancer (HR = 0.56, 95% CI: 0.39-0.79) with a 5-year OS of 16.6% versus 4.3% (p < 0.001). In liver metastatic CRC, the presence of lung metastases did not significantly influence OS as assessed by multivariate analysis (HR = 1.11, 95% CI: 0.80-1.53). The worse survival in liver metastatic right-sided colon cancer could possibly be explained by the higher number of metastases, as well as more extensive segmental involvement compared with left-sided colon and rectal cancer, even though the latter had a higher incidence of liver metastases. Detailed population-based data on the metastatic pattern of CRC and survival could assist in more structured and individualized guidelines for follow-up of patients with CRC.


Urine concentrating mechanism in the inner medulla of the mammalian kidney: role of three-dimensional architecture.
The urine concentrating mechanism in the mammalian renal inner medulla (IM) is not understood, although it is generally considered to involve countercurrent flows in tubules and blood vessels. A possible role for the three-dimensional relationships of these tubules and vessels in the concentrating process is suggested by recent reconstructions from serial sections labelled with antibodies to tubular and vascular proteins and mathematical models based on these studies. The reconstructions revealed that the lower 60% of each descending thin limb (DTL) of Henle's loops lacks water channels (aquaporin-1) and osmotic water permeability and ascending thin limbs (ATLs) begin with a prebend segment of constant length. In the outer zone of the IM (i) clusters of coalescing collecting ducts (CDs) form organizing motif for loops of Henle and vasa recta; (ii) DTLs and descending vasa recta (DVR) are arrayed outside CD clusters, whereas ATLs and ascending vasa recta (AVR) are uniformly distributed inside and outside clusters; (iii) within CD clusters, interstitial nodal spaces are formed by a CD on one side, AVR on two sides, and an ATL on the fourth side. These spaces may function as mixing chambers for urea from CDs and NaCl from ATLs. In the inner zone of the IM, cluster organization disappears and half of Henle's loops have broad lateral bends wrapped around terminal CDs. Mathematical models based on these findings and involving solute mixing in the interstitial spaces can produce urine slightly more concentrated than that of a moderately antidiuretic rat but no higher.


Single-gene greenbeard effects in the social amoeba Dictyostelium discoideum.
Selection can favor reproductive altruism if an altruism allele aids copies of itself by helping relatives. The alternative "greenbeard" mechanism, in which an allele directly recognizes and aids copies of itself in others, is generally thought to be too complex for a single gene to carry out. The csA gene in Dictyostelium discoideum acts as a single-gene greenbeard. When wild-type cells are mixed with csA-knockout cells, the wild type is more altruistic, but is also able preferentially to direct the benefits to other wild-type cells. Both properties derive directly from homophilic cell adhesion of the protein encoded by csA.


Secular changes in late-life cognition and well-being: Towards a long bright future with a short brisk ending?
How sociocultural contexts shape individual functioning is of prime interest for psychological inquiry. Secular increases favoring later-born cohorts in fluid intelligence measures are widely documented for young adults. In the current study, we quantified such trends in old age using data from highly comparable participants living in a narrowly defined geographical area and examined whether these trends would generalize to quality-of-life indicators. To do so, we compared data obtained 20 years apart in the Berlin Aging Study (in 1990-1993) and the Berlin Aging Study II (in 2013-2014), applied a case-matched control design (per cohort, n = 161, Mage = 75), quantified sample selection using a nationally representative sample as the reference, and controlled for number of physical diseases. The later cohort performed better on the fluid intelligence measure (d = .85) and reported higher morale, less negative affect, and more positive affect (ds > .39) than the earlier cohort. We concluded that secular advances have resulted in better cognitive performance and perceived quality of life among older adults and discuss when and how advantages of later cohorts reach their limits.


Chemical composition of precloacal secretions of two Liolaemus fabiani populations: are they different?
The chemical composition of secretions of precloacal pores from two populations of the lizard Liolaemus fabiani (Puilar and Punta-Brava) were compared. This is an endemic species from the Atacama Salt Flat (26 degrees 46'S 68 degrees 14'W; 2400 m) in northern Chile, restricted to the internal lakes of the salt flat. Interpopulational differences in the chemical composition of the secretions were expected considering that populations have genetic differences and are subject to different thermal conditions. By using GC-MS, a total of 44 compounds were found belonging to three categories: n-alkanes, long-chain carboxylic acids, and steroids. Six compounds were found in all the individuals studied: tetradecanoic, pentadecanoic, hexadecanoic, hexadecenoic, octadecanoic, and octadecenoic acids. The secretions of both populations had similar types and proportions of the different compounds, except for cholesterol and hexanoic acid, which were more abundant in the Puilar population. These differences can be ascribed to the different environmental conditions to which populations are subjected. The adaptive meaning of these differences is discussed.


Xenopus cell-free extracts and their contribution to the study of DNA replication and other complex biological processes.
Here we discuss the important contributions that cell-free extracts have made to the study of complex biological processes. We provide a brief history of how cell-free extracts of frog eggs were developed to avoid many of the problems that can arise from the dilution and mixing of cellular components that typically occur when cell-free extracts are prepared. We briefly describe how Xenopus egg extracts have been fundamental to the study of many important cellular processes including DNA replication, cell cycle progression, nuclear protein import, nuclear assembly and chromosome organisation. We describe how, in particular, Xenopus egg extracts have made a major contributions to the study of DNA replication, by permitting the direct manipulation of proteins in a system that is extraordinarily faithful to the way that DNA replication occurs in the living embryo. Finally we consider how results obtained using Xenopus egg extracts are being translated to produce diagnostic reagents for cancer screening and diagnosis.


Photodecomposition properties of brominated flame retardants (BFRs).
This study investigates the geometric and electronic properties of selected BFRs in their ground (S0) and first singlet excited (S1) states deploying methods of the density functional theory (DFT) and the time-dependent density functional theory (TDDFT). We estimate the effect of the S0→ S1 transition on the elongations of the C-Br bond, identify the frontier molecular orbitals involved in the excitation process and compute partial atomic charges for the most photoreactive bromine atoms. The bromine atom attached to an ortho position in HBB (with regard to C-C bond; 2,2',4,4',6,6'-hexabromobiphenyl), TBBA (with respect to the hydroxyl group; 2,2',6,6'-tetrabromobisphenol A), HBDE and BTBPE (in reference to C-O linkage; 2,2',4,4',6,6'-hexabromodiphenylether and 1,2-bis(2,4,6-tribromophenoxy)ethane, respectively) bears the highest positive atomic charge. This suggests that, these positions undergo reductive debromination reactions to produce lower brominated molecules. Debromination reactions ensue primarily in the aromatic compounds substituted with the highest number of bromine atoms owing to the largest stretching of the C-Br bond in the first excited state. The analysis of the frontier molecular orbitals indicates that, excitations of BFRs proceed via π→π*, or π→σ* or n→σ* electronic transitions. The orbital analysis reveals that, the HOMO-LUMO energy gap (EH-L) for all investigated bromine-substituted aromatic molecules falls lower (1.85-4.91 eV) than for their non-brominated analogues (3.39-8.07 eV), in both aqueous and gaseous media. The excitation energies correlate with the EH-L values. The excitation energies and EH-L values display a linear negative correlation with the number of bromine atoms attached to the molecule. Spectral analysis of the gaseous-phase systems reveals that, the highly brominated aromatics endure lower excitation energies and exhibit red shifts of their absorption bands in comparison to their lower brominated congeners. We attained a satisfactory agreement between the experimentally measured absorption peak (λmax) and the theoretically predicted oscillator strength (λmax) for the UV-Vis spectra. This study further confirms that, halogenated aromatics only absorb light in the UV spectral region and that effective photodegradation of these pollutants requires the presence of photocatalysts.


Recombinant human erythropoietin versus placebo or no treatment for the anaemia of chronic kidney disease in people not requiring dialysis.
Treatment with recombinant human erythropoietin (rHuEPO) in dialysis patients has been shown to be highly effective in terms of correcting anaemia and improving quality of life. There is debate concerning the benefits of rHuEPO use in predialysis patients which may accelerate the deterioration of kidney function. However the opposing view is that if rHuEPO is as effective in predialysis patients, improving the patient's sense of well-being may result in the onset of dialysis being delayed. This is an update of a review first published in 2001 and last updated in 2005. The objective of this review was to ascertain the effects of rHuEPO treatment in predialysis patients primarily in terms of the timing of the onset of dialysis; but also that predialysis rHuEPO: 1) corrects haemoglobin/haematocrit (markers of anaemia); 2) improves quality of life; and 3) is not associated with an increased incidence of adverse events such as hastening of the onset of dialysis, increased hypertension, clotting of arterio-venous fistulae or seizures. We searched the Cochrane Kidney and Transplant's Specialised Register (up to 29 June 2015) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Randomised controlled trials (RCTs) or quasi-RCTs comparing the use of rHuEPO with no treatment or placebo in predialysis patients. Only published data were used. Quality assessment was performed by two assessors independently. Data were abstracted by a single author onto a standard form, a sample of which was checked by another author. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). Nineteen studies (enrolling 993 participants) were included. Due to the age of the included studies (most performed prior to 2000) the risk of bias was judged to be unclear in the majority of the studies for most of the domains. There was an improvement in haemoglobin (MD 1.90 gm/L, 95% CI -2.34 to -1.47) and haematocrit (MD 9.85%, 95% CI 8.35 to 11.34) with treatment and a decrease in the number of patients requiring blood transfusions (RR 0.32, 95% CI 0.12 to 0.83). The data from studies reporting quality of life or exercise capacity demonstrated an improvement in the treatment group. Most of the measures of progression of kidney disease showed no statistically significant difference. No significant increase in adverse events was identified. Treatment with rHuEPO in predialysis patients corrects anaemia, avoids the requirement for blood transfusions and also improves quality of life and exercise capacity. We were unable to assess the effects of rHuEPO on progression of kidney disease, delay in the onset of dialysis or adverse events. Based on the current evidence, decisions on the putative benefits in terms of quality of life are worth the extra costs of predialysis rHuEPO need careful evaluation.


MYB8 controls inducible phenolamide levels by activating three novel hydroxycinnamoyl-coenzyme A:polyamine transferases in Nicotiana attenuata.
A large number of plants accumulate N-acylated polyamines (phenolamides [PAs]) in response to biotic and/or abiotic stress conditions. In the native tobacco (Nicotiana attenuata), the accumulation of two major PAs, caffeoylputrescine and dicaffeoylspermidine (DCS), after herbivore attack is known to be controlled by a key transcription factor, MYB8. Using a broadly targeted metabolomics approach, we show that a much larger spectrum of PAs composed of hydroxycinnamic acids and two polyamines, putrescine and spermidine, is regulated by this transcription factor. We cloned several novel MYB8-regulated genes, annotated as putative acyltransferases, and analyzed their function. One of the novel acyltransferases (AT1) is shown to encode a hydroxycinnamoyl-coenzyme A:putrescine acyltransferase responsible for caffeoylputrescine biosynthesis in tobacco. Another gene (acyltransferase DH29), specific for spermidine conjugation, mediates the initial acylation step in DCS formation. Although this enzyme was not able to perform the second acylation toward DCS biosynthesis, another acyltransferase gene, CV86, proposed to act on monoacylated spermidines, was isolated and partially characterized. The activation of MYB8 in response to herbivore attack and associated signals required the activity of LIPOXYGENASE3, a gene involved in jasmonic acid (JA) biosynthesis in N. attenuata. These new results allow us to reconstruct a complete branch in JA signaling that defends N. attenuata plants against herbivores: JA via MYB8's transcriptional control of AT1 and DH29 genes controls the entire branch of PA biosynthesis, which allows N. attenuata to mount a chemically diverse (and likely efficient) defense shield against herbivores.


Conjoint developmental trajectories of young adult substance use.
Despite the prominence of comorbidity among substances and the recent attention focused on trajectory-based approaches to characterizing developmental change, little research in the substance use field has simultaneously considered both course and comorbidity. Using nationally representative panel data from the Monitoring the Future Project (MTF; n = 32,087; 56% female; 82% Caucasian), we identified developmental courses of heavy drinking, smoking, and marijuana use using 4 waves of data spanning ages 18 to 26 in a multi-cohort young adult sample. Comorbidity was examined by cross-classifying group membership in substance use trajectories. Finally, the extent to which risk factors (sex, race, alcohol expectancies, delinquency, sensation seeking, depressive affect, religiosity, academic achievement, and parent education) accounted for combinations of comorbidity that occurred at a rate greater than chance was examined. For each substance, we identified 4 courses of substance use that were largely consistent with those found in the literature (chronic high use, late-onset use, developmentally limited use, and low-use), with a fifth moderate smoking group. Heavy drinking, smoking, and marijuana use were each highly associated, and distinct patterns of comorbidity were evident, with greatest agreement along the diagonal. All risk factors explained comorbidity to some degree, with delinquency, sensation seeking, alcohol expectancies, and religion in particular predicting combinations of comorbidity that were characterized by early onset and chronic high use. Cross-substance trajectory concordance was high, with parallel changes in substance use over emerging adulthood. This suggests similar developmental timing of use, perhaps due to the experience of developmental transitions that have a common influence on use of different substances. Prediction of combinations of comorbidity characterized by early onset and persistently high use suggests that to some extent, individuals use multiple substances because of a common vulnerability to each, rather than directional relations among substances (e.g., cross-tolerance, cueing).


Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association.
This clinical practice position statement, a product of the Fatty Liver Research Group of the Korean Diabetes Association, proposes recommendations for the diagnosis, progression and/or severity assessment, management, and follow-up of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NAFLD have an increased risk of non-alcoholic steatohepatitis (NASH) and fibrosis and a higher risk of cardiovascular diseases and diabetic complications compared to those without NAFLD. With regards to the evaluation of patients with T2DM and NAFLD, ultrasonography-based stepwise approaches using noninvasive biomarker models such as fibrosis-4 or the NAFLD fibrosis score as well as imaging studies such as vibration-controlled transient elastography with controlled attenuation parameter or magnetic resonance imaging-proton density fat fraction are recommended. After the diagnosis of NAFLD, the stage of fibrosis needs to be assessed appropriately. For management, weight reduction achieved by lifestyle modification has proven beneficial and is recommended in combination with antidiabetic agent(s). Evidence that some antidiabetic agents improve NAFLD/NASH with fibrosis in patients with T2DM is emerging. However, there are currently no definite pharmacologic treatments for NAFLD in patients with T2DM. For specific cases, bariatric surgery may be an option if indicated.


Cytotoxicity of Selenium Immunoconjugates against Triple Negative Breast Cancer Cells.
Within the subtypes of breast cancer, those identified as triple negative for expression of estrogen receptor α (ESR1), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), account for 10⁻20% of breast cancers, yet result in 30% of global breast cancer-associated deaths. Thus, it is critical to develop more targeted and efficacious therapies that also demonstrate less side effects. Selenium, an essential dietary supplement, is incorporated as selenocysteine (Sec) in vivo into human selenoproteins, some of which exist as anti-oxidant enzymes and are of importance to human health. Studies have also shown that selenium compounds hinder cancer cell growth and induce apoptosis in cancer cell culture models. The focus of this study was to investigate whether selenium-antibody conjugates could be effective against triple negative breast cancer cell lines using clinically relevant, antibody therapies targeted for high expressing breast cancers and whether selenium cytotoxicity was attenuated in normal breast epithelial cells. To that end, the humanized monoclonal IgG1 antibodies, Bevacizumab and Trastuzumab were conjugated with redox selenium to form Selenobevacizumab and Selenotrastuzumab and tested against the triple negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231 as well as a normal, immortalized, human mammary epithelial cell line, HME50-5E. VEGF and HER2 protein expression were assessed by Western. Although expression levels of HER2 were low or absent in all test cells, our results showed that Selenobevacizumab and Selenotrastuzumab produced superoxide (O2•-) anions in the presence of glutathione (GSH) and this was confirmed by a dihydroethidium (DHE) assay. Interestingly, superoxide was not elevated within HME50-5E cells assessed by DHE. The cytotoxicity of selenite and the selenium immunoconjugates towards triple negative cells compared to HME-50E cells was performed in a time and dose-dependent manner as measured by Trypan Blue exclusion, MTT assay and Annexin V assays. Selenobevacizumab and Selenotrastuzumab were shown to arrest the cancer cell growth but not the HME50-5E cells. These results suggest that selenium-induced toxicity may be effective in treating TNBC cells by exploiting different immunotherapeutic approaches potentially reducing the debilitating side effects associated with current TNBC anticancer drugs. Thus, clinically relevant, targeting antibody therapies may be repurposed for TNBC treatment by attachment of redox selenium.


Perception of epilepsy in Turkey in the light of two different cities.
The aim of this study was to investigate the perception of epilepsy in Turkey, from west to east, in Kutahya and Yuksekova, two cities of different sociocultural and ethnic status. This was a retrospective comparison study which evaluated the results of two prior studies investigating stigmatization of patients diagnosed with epilepsy and their first-degree relatives in two different cities of Turkey, Kutahya and Yuksekova. The Survey of Epileptic Patient Relatives on the Knowledge, Attitudes, and Behavior Regarding the Disorder was used and included questions on descriptive characteristics, familiarity with epilepsy, attitudes toward epilepsy, and understanding of epilepsy. Data collected by use of the SPSS 15.0 software were analyzed with chi2-test. In Yuksekova group, 88.5% of first-degree relatives of people with epilepsy felt primarily fear when they heard the diagnosis of epilepsy in their relatives; in Kutahya group, the respective rate was 19.1% (p < 0.05). The number of participants who objected their child marrying someone with epilepsy was significantly higher in Yuksekova group (p < 0.05); however, if married, the Yuksekova group significantly stated that they should have a baby, revealing the importance of children as an indicator of power and dignity in the eastern region of Turkey (p < 0.05). Although understanding of epilepsy was favorable, educating the community about epilepsy and personal contacts are the major strategies against epileptic stigmatization.


Diagnostic Mycology: Xtreme Challenges.
Developing any diagnostic assay that receives United States Food and Drug Administration (FDA) approval can be a slow and difficult process. FDA-approved assays for fungal diagnosis are generally few in number and are focused mainly on diagnosing candidiasis, which is caused by several species of Candida, in addition to a limited number of systemic mycotic agents. While all microbial diagnostic assays face challenges before they are FDA approved and reach the market, there are a number of challenges to fungal diagnostic assay development that have been difficult hurdles to overcome. These hurdles include template preparation, fungal morphology, how many fungi should be identified in a single assay (scope), taxonomy and nomenclature, discriminating colonizers from invasive infection, combining identification with antifungal susceptibility, and navigating the administrative hurdles required to integrate an assay into a clinical laboratory. Some of these challenges are easier to overcome than others, but all seem to be particularly difficult for fungal diagnostic assays.


Hepatocytes maintain greater fluorescent bile acid accumulation and greater sensitivity to drug-induced cell death in three-dimensional matrix culture.
Primary hepatocytes undergo phenotypic dedifferentiation upon isolation from liver that typically includes down regulation of uptake transporters and up regulation of efflux transporters. Culturing cells between layers of collagen in a three-dimensional (3D) "sandwich" is reported to restore hepatic phenotype. This report examines how 3D culturing affects accumulation of fluorophores, the cytotoxic response to bile acids and drugs, and whether cell to cell differences in fluorescent anion accumulation correlate with differences in cytotoxicity. Hepatocytes were found to accumulate fluorescent bile acid (FBA) at significantly higher levels than the related fluorophores, carboxyfluorescein diacetate, (4.4-fold), carboxyfluorescein succinimidyl ester (4.8-fold), and fluorescein (30-fold). In 2D culture, FBA accumulation decreased to background levels by 32 h, Hoechst nuclear accumulation strongly decreased, and nuclear diameter increased, indicative of an efflux phenotype. In 3D culture, FBA accumulation was maintained through 168 h but at 1/3 the original intensity. Cell to cell differences in accumulated FBA did not correlate with levels of liver zonal markers L-FBAP (zone 1) or glutamine synthetase (zone 3). Cytotoxic response to hydrophobic bile acids, acetaminophen, and phalloidin was maintained in 3D culture, and cells with higher FBA accumulation showed 12-18% higher toxicity than the total population toward hydrophobic bile acids (P < 0.05). Long-term imaging showed oscillations in the accumulation of FBA over periods of hours. Overall, the studies suggest that high accumulation of FBA can indicate the sensitivity of cultured hepatocytes to hydrophobic bile acids and other toxins.


Effect of dignity therapy on distress and end-of-life experience in terminally ill patients: a randomised controlled trial.
Dignity therapy is a unique, individualised, short-term psychotherapy that was developed for patients (and their families) living with life-threatening or life-limiting illness. We investigated whether dignity therapy could mitigate distress or bolster the experience in patients nearing the end of their lives. Patients (aged ≥18 years) with a terminal prognosis (life expectancy ≤6 months) who were receiving palliative care in a hospital or community setting (hospice or home) in Canada, USA, and Australia were randomly assigned to dignity therapy, client-centred care, or standard palliative care in a 1:1:1 ratio. Randomisation was by use of a computer-generated table of random numbers in blocks of 30. Allocation concealment was by use of opaque sealed envelopes. The primary outcomes--reductions in various dimensions of distress before and after completion of the study--were measured with the Functional Assessment of Chronic Illness Therapy Spiritual Well-Being Scale, Patient Dignity Inventory, Hospital Anxiety and Depression Scale, items from the Structured Interview for Symptoms and Concerns, Quality of Life Scale, and modified Edmonton Symptom Assessment Scale. Secondary outcomes of self-reported end-of-life experiences were assessed in a survey that was undertaken after the completion of the study. Outcomes were assessed by research staff with whom the participant had no previous contact to avoid any possible response bias or contamination. Analyses were done on all patients with available data at baseline and at the end of the study intervention. This study is registered with ClinicalTrials.gov, number NCT00133965. 165 of 441 patients were assigned to dignity therapy, 140 standard palliative care, and 136 client-centred care. 108, 111, and 107 patients, respectively, were analysed. No significant differences were noted in the distress levels before and after completion of the study in the three groups. For the secondary outcomes, patients reported that dignity therapy was significantly more likely than the other two interventions to have been helpful (χ(2)=35·50, df=2; p<0·0001), improve quality of life (χ(2)=14·52; p=0·001), increase sense of dignity (χ(2)=12·66; p=0·002), change how their family saw and appreciated them (χ(2)=33·81; p<0·0001), and be helpful to their family (χ(2)=33·86; p<0·0001). Dignity therapy was significantly better than client-centred care in improving spiritual wellbeing (χ(2)=10·35; p=0·006), and was significantly better than standard palliative care in terms of lessening sadness or depression (χ(2)=9·38; p=0·009); significantly more patients who had received dignity therapy reported that the study group had been satisfactory, compared with those who received standard palliative care (χ(2)=29·58; p<0·0001). Although the ability of dignity therapy to mitigate outright distress, such as depression, desire for death or suicidality, has yet to be proven, its benefits in terms of self-reported end-of-life experiences support its clinical application for patients nearing death. National Cancer Institute, National Institutes of Health.


Human motor units in health and disease.
Recent advances in clinical neurophysiology have made it possible to non-invasively stimulate single motor axons and determine the physiological characteristics of the associated motor units. Some motor units lend themselves to longitudinal studies of their electrical and contractile characteristics. The former include the conduction velocities of their motor axons and the sizes and shapes of their motor unit action potentials and the latter such contractile characteristics of the motor unit as their contractile speeds, twitch and tetanic tensions, and resistance to fatigue. The feasibility of serially examining the same motor unit has made it possible to study the responses of single motor units to conditioning as well as changes in the responses of single motor units to diseases such as amyotrophic lateral sclerosis. The non-invasive character of these approaches offers an attractive means of studying the responses of single human cells, in these cases motor neurons, in health and disease.


Polymorphic Alu insertions and their associations with MHC class I alleles and haplotypes in the northeastern Thais.
Polymorphic Alu insertions (POALINs) are known to contribute to the strong polymorphic nature of the Major Histocompatibility Complex (MHC). Previous population studies on MHC POALINs were limited to only Australian Caucasians and Japanese. Here, we report on the individual insertion frequency of the five POALINs within the MHC class I region, their HLA-A and -B associations, and the three and four locus alpha block POALIN haplotype frequencies in the Northeastern (NE) Thai population. Of the five POALINs, the lowest frequency was 0.018 for AluyHF and the highest frequency was 0.292 for AluyHJ and AluyHG. The strongest positive associations between the POALINs and HLA class I alleles was between AluyMICB and HLA-B*57, AluyHJ and HLA-A*24 and HLA-A*01, and AluyHG and HLA-A*02, supporting previous findings in Caucasians and Japanese. Single POALIN haplotypes were found more frequently than multiple POALIN haplotypes. However, of the seven different POALIN haplotypes within the MHC alpha block, there were only two significant differences between the NE Thais, Caucasians and Japanese. This study confirms that the MHC POALINs are in linkage disequilibrium with HLA-A and -B alleles and that there are significant frequency differences for some of the POALINs when compared between NE Thai, Caucasians and Japanese.


Models for local implementation of comprehensive cancer control: meeting local cancer control needs through community collaboration.
The comprehensive cancer control approach is used by state, tribes, tribal organizations, territorial and Pacific Island Jurisdiction cancer coalitions to spur local implementation of cancer plans to reduce the burden of cancer in jurisdictions across the country. There is a rich diversity of models and approaches to the development of relationships and scope of planning for cancer control activities between coalitions and advocates in local communities. The national comprehensive cancer control philosophy provides an operational framework while support from the Centers for Disease Control and Prevention enables coalitions to act as catalysts to bring local partners together to combat cancer in communities. This manuscript describes multiple characteristics of cancer coalitions and how they are organized. Two models of how coalitions and local partners collaborate are described. A case study method was used to identify how five different state and tribal coalitions use the two models to organize their collaborations with local communities that result in local implementation of cancer plan priorities. Conclusions support the use of multiple organizing models to ensure involvement of diverse interests and sensitivity to local cancer issues that encourages implementation of cancer control activities.


Personal Visualization and Personal Visual Analytics.
Data surrounds each and every one of us in our daily lives, ranging from exercise logs, to archives of our interactions with others on social media, to online resources pertaining to our hobbies. There is enormous potential for us to use these data to understand ourselves better and make positive changes in our lives. Visualization (Vis) and visual analytics (VA) offer substantial opportunities to help individuals gain insights about themselves, their communities and their interests; however, designing tools to support data analysis in non-professional life brings a unique set of research and design challenges. We investigate the requirements and research directions required to take full advantage of Vis and VA in a personal context. We develop a taxonomy of design dimensions to provide a coherent vocabulary for discussing personal visualization and personal visual analytics. By identifying and exploring clusters in the design space, we discuss challenges and share perspectives on future research. This work brings together research that was previously scattered across disciplines. Our goal is to call research attention to this space and engage researchers to explore the enabling techniques and technology that will support people to better understand data relevant to their personal lives, interests, and needs.


Critical magnetic transition in TbNi2Mn--magnetization and Mössbauer spectroscopy.
The structural and magnetic properties of the TbNi(2)Mn(x) series (0.9 ≤ x ≤ 1.10) have been investigated using x-ray diffraction, field- and temperature-dependent AC magnetic susceptibility, DC magnetization (5-340 K; 0-5 T) and (57)Fe Mössbauer spectroscopy (5-300 K). TbNi(2)Mn(x) crystallizes in the MgCu(2)-type structure (space group Fd3m). The additional contributions to the magnetic energy terms from transition-metal-transition-metal interactions (T-T) and rare-earth-transition-metal interactions (R-T) in RNi(2)Mn compounds contribute to their increased magnetic ordering temperatures compared with RNi(2) and RMn(2). Both the lattice constant a and the Curie temperature T(C) exhibit maximal values at the x = 1 composition indicating strong magnetostructural coupling. Analyses of the AC magnetic susceptibility and DC magnetization data of TbNi(2)Mn around the Curie temperature T(C) = 147 K confirm that the magnetic transition is second order with critical exponents β = 0.77 ± 0.12, γ = 1.09 ± 0.07 and δ = 2.51 ± 0.06. These exponents establish that the magnetic interactions in TbNi(2)Mn are long range despite mixed occupancies of Tb and Mn atoms at the 8a site and vacancies. The magnetic entropy - ΔS(M) around T(C) is proportional to (μ(0)H/T(C))(2/3) in agreement with the critical magnetic analyses. The Mössbauer spectra above T(C) are fitted by two sub-spectra in agreement with refinement of the x-ray data while below T(C) three sub-spectra are required to represent the three inequivalent local magnetic environments.


Defining the cut-off point of clinically significant postoperative fatigue in three common fatigue scales.
Postoperative fatigue (POF) is an often underestimated problem after surgery. Studies on POF often report fatigue scores without relating this to the clinical relevance for the patients. The aim of this study was to define the cut-off point for clinically significant POF in three commonly applied fatigue scales; the Postoperative Fatigue Scale, Christensen's Fatigue Scale, and the Chalder Fatigue Questionnaire. The identification of cut-off points will make it possible to indicate whether statistically significant findings of increased fatigue are of clinical relevance. We combined data from day 0 (pre-operatively) and day 1, 3, 6, and 30 after surgery in two fatigue-related studies with 442 patients. In order to define clinically significant fatigue, a key question was added in each questionnaire; "Given your current description of fatigue, would you say it has been of considerable significance to you?"; "Yes/No". We analysed each scale's ability to identify clinically significant fatigue, by performing receiver-operating characteristics (ROC) analyses, and calculated the optimal cut-off point between Sensitivity and Specificity. The average weighted cut-off point for clinically significant POF when measured with the Postoperative Fatigue Scale was ≥ 50 (scale range 0-100), with Christensen's Fatigue Scale ≥ 6 (scale range 1-10) and with the Chalder Fatigue Questionnaire ≥ 16 (scale range 0-33). In three commonly used fatigue scales, we have identified cut-off points for clinically significant fatigue among patients recovering from surgery. This can be particularly valuable for diagnostic purposes and in treatment evaluation. Further, it may be possible to analyse and review data from earlier studies in light of clinical relevance.


Precision of Readout at the hunchback Gene: Analyzing Short Transcription Time Traces in Living Fly Embryos.
The simultaneous expression of the hunchback gene in the numerous nuclei of the developing fly embryo gives us a unique opportunity to study how transcription is regulated in living organisms. A recently developed MS2-MCP technique for imaging nascent messenger RNA in living Drosophila embryos allows us to quantify the dynamics of the developmental transcription process. The initial measurement of the morphogens by the hunchback promoter takes place during very short cell cycles, not only giving each nucleus little time for a precise readout, but also resulting in short time traces of transcription. Additionally, the relationship between the measured signal and the promoter state depends on the molecular design of the reporting probe. We develop an analysis approach based on tailor made autocorrelation functions that overcomes the short trace problems and quantifies the dynamics of transcription initiation. Based on live imaging data, we identify signatures of bursty transcription initiation from the hunchback promoter. We show that the precision of the expression of the hunchback gene to measure its position along the anterior-posterior axis is low both at the boundary and in the anterior even at cycle 13, suggesting additional post-transcriptional averaging mechanisms to provide the precision observed in fixed embryos.


Functions of the proteasome on chromatin.
The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for a host of cellular functions, and it has become clear in recent years that one set of critical actions of the proteasome occur on chromatin. In this review, we discuss some of the ways in which proteasomes directly regulate the structure and function of chromatin and chromatin regulatory proteins, and how this influences gene transcription. We discuss lingering controversies in the field, the relative importance of proteolytic versus non-proteolytic proteasome activities in this process, and highlight areas that require further investigation. Our intention is to show that proteasomes are involved in major steps controlling the expression of the genetic information, that proteasomes use both proteolytic mechanisms and ATP-dependent protein remodeling to accomplish this task, and that much is yet to be learned about the full spectrum of ways that proteasomes influence the genome.


Responses of spinal dorsal horn neurons to foot movements in rats with a sprained ankle.
Acute ankle injuries are common problems and often lead to persistent pain. To investigate the underlying mechanism of ankle sprain pain, the response properties of spinal dorsal horn neurons were examined after ankle sprain. Acute ankle sprain was induced manually by overextending the ankle of a rat hindlimb in a direction of plantarflexion and inversion. The weight-bearing ratio (WBR) of the affected foot was used as an indicator of pain. Single unit activities of dorsal horn neurons in response to plantarflexion and inversion of the foot or ankle compression were recorded from the medial part of the deep dorsal horn, laminae IV-VI, in normal and ankle-sprained rats. One day after ankle sprain, rats showed significantly reduced WBRs on the affected foot, and this reduction was partially restored by systemic morphine. The majority of deep dorsal horn neurons responded to a single ankle stimulus modality. After ankle sprain, the mean evoked response rates were significantly increased, and afterdischarges were developed in recorded dorsal horn neurons. The ankle sprain-induced enhanced evoked responses were significantly reduced by morphine, which was reversed by naltrexone. The data indicate that movement-specific dorsal horn neuron responses were enhanced after ankle sprain in a morphine-dependent manner, thus suggesting that hyperactivity of dorsal horn neurons is an underlying mechanism of pain after ankle sprain.


Intense isolated attosecond pulse generation in pre-excited medium.
We present a theoretical study of isolated attosecond pulse generation in pre-excited medium driven by an intense few-cycle laser pulse. We show that the generation of the macroscopic xuv supercontinuum is governed by the initial population of the excited state. Large initial population of the excited state leads to the high density of the free electrons in the media and strongly changes macroscopic properties of the driving pulse and the supercontinuum, and diminishes the isolated attosecond pulse generation. Instead, small initial population of 5% in the pre-excited media subjected to the few-cycle driving pulse can produce well phase-matched xuv supercontinuum, and a pure intense isolated attosecond pulse with the pulse duration of approximately 150 as and the pulse energy up to 0.5 nJ is directly obtained.


The impact of FDA regulatory activities on incident dispensing of LABA-containing medication: 2005-2011.
Evidence of safety issues associated with long-acting beta2-agonist (LABA) treatment has led to multiple regulatory activities by the U.S. Food and Drug Administration (FDA) on this class of medications. This study describes the impact of the regulatory activities on incident LABA-containing medication dispensing. A monthly rolling cohort of asthma patients who were eligible to initiate a LABA-containing product was created in the Mini-Sentinel Distributed Database between January 2005 and June 2011. Cohorts of individuals who initiated LABA were examined for the changes in the proportions of single-ingredient to fixed-dose inhaled corticosteroid (ICS)-LABA initiators, appropriate initiation of LABA-containing products, and use of controller medications. The impact of the 2005 and 2010 FDA regulatory activities associated with LABA-containing products was measured using interrupted time series with segmented regression. LABA-containing product initiation was declining prior to the 2005 regulatory activities and continued to decline over the study period, accompanied by increased initiation of fixed dose ICS-LABA among LABA initiators. While the 2010 regulatory activities had no immediate impact on the proportion of LABA initiation in patients with prior controller medication dispensing and/or poor asthma control, there was an increasing positive trend toward LABA initiation in the appropriate patient population after the regulatory activities. The 2005 and 2010 FDA regulatory activities likely had an impact on communicating the safety concerns of LABA products. However, the impact cannot be viewed independent of scientific publications, guidelines for asthma treatment and other regulatory activities.


Long-term effects of p-chloroamphetamine and related drugs on central serotonergic mechanisms.
Earlier studies from our laboratory have demonstrated a marked reduction in the brain level of 5-hydroxytryptamine (5-HT) and in the activity of tryptophan hydroxylase which persists for several weeks after a single dose of 10 mg/kg of p-chloroamphetamine (PCA). In the present study, equally long-lasting decreases were found after the administration of 5 mg/kg of PCA. p-Chloromethamphetamine also caused long-lasting reductions in the level of 5-HT and the activity of tryptophan hydroxylase in brain, whereas the effects of fenfluramine had disappeared 2 weeks after injection. The ability of brain synaptosomes to take up 5-HT was markedly reduced following doses of 2, 5 and 10 mg/kg of PCA. The in vitro addition of PCA to synaptosomal fractions markedly reduced the uptake of dopamine and norepinephrine; however, only a 30% reduction in the uptake of these amines was found in synaptosomes prepared from brains of rats treated with PCA. The effects on catecholamine uptake disappeared within 1 day after injection. In contrast, the time course of recovery of the synaptosomal uptake capacity for 5-HT followed a pattern similar to that found for the recovery of the level of 5-HT and the activity of tryptophan hydroxylase, with a 50% reduction still present 3 months after the injection of 10 mg/kg of PCA. The greatest reductions of 5-HT, tryptophan hydroxylase activity and synaptosomal uptake were found in the midbrain, hippocampus and striatum with less pronounced effects in the hypothalamus, medulla-pons and spinal cord. At both 1 and 14 days after injection of 5 and 7.5 mg/kg of PCA, tryptophan hydroxylase activity in whole brain was reduced by 50% or more; however, 4 days after treatment the activity of the enzyme was reduced only slightly or not at all. The results indicate that different independent mechanisms are responsible for the initial, reversible and the prolonged, irreversible effects of PCA on serotonergic neurons.


Complete Genome Sequence of Paenibacillus polymyxa Strain Sb3-1, a Soilborne Bacterium with Antagonistic Activity toward Plant Pathogens.
The genome of Paenibacillus polymyxa Sb3-1, a strain that shows antagonistic activities against pathogenic fungi and bacteria, consists of one 5.6-Mb circular chromosome and two plasmids of 223 kb and 8 kb. The genome reveals several genes that potentially contribute to its antagonistic and plant growth promotion activity.


Characterization of cell proliferation throughout the brain of the African cichlid fish Astatotilapia burtoni and its regulation by social status.
New cells are added in the brains of all adult vertebrates, but fishes have some of the greatest potential for neurogenesis and gliogenesis among all taxa, partly due to their indeterminate growth. Little is known, however, about how social interactions influence cell proliferation in the brain of these fishes that comprise the largest group of vertebrates. We used 5-bromo-2'-deoxyuridine (BrdU) to identify and localize proliferation zones in the telencephalon, diencephalon, mesencephalon, and rhombencephalon that were primarily associated with ventricular surfaces in the brain of the African cichlid fish Astatotilapia burtoni. Cell migration was evident in some regions by 1 day post injection, and many newborn cells coexpressed the neuronal marker HuC/D at 30 days, suggesting they had differentiated into neurons. To test the hypothesis that social status and perception of an opportunity to rise in rank influenced cell proliferation, we compared numbers of BrdU-labeled cells in multiple brain nuclei among fish of different social status. Socially suppressed subordinate males had the lowest numbers of proliferating cells in all brain regions examined, but males that were given an opportunity to rise in status had higher cell proliferation rates within 1 day, suggesting rapid upregulation of brain mitotic activity associated with this social transition. Furthermore, socially isolated dominant males had similar numbers of BrdU-labeled cells compared with dominant males that were housed in a socially rich environment, suggesting that isolation has little effect on proliferation and that reduced proliferation in subordinates is a result of the social subordination. These results suggest that A. burtoni will be a useful model to analyze the mechanisms of socially induced neurogenesis in vertebrates.


Physical chemistry in a single live cell: confocal microscopy.
A live cell is a complex, yet extremely important container. Understanding the dynamics in a selected intracellular component is a challenging task. We have recently made significant progress in this direction using a confocal microscope as a tool. The smallest size of the focused spot in a confocal microscope is ∼0.2 μm (200 nm). This is nearly one hundred times smaller than the size of a live cell. Thus, one can selectively study different intracellular components/organelles in a live cell. In this paper, we discuss how one can image different intracellular components/organelles, record fluorescence spectra and decay at different locations, ascertain local polarity and viscosity, and monitor the dynamics of solvation, proton transfer, red-ox and other phenomena at specified locations/organelles inside a cell. We will highlight how this knowledge enriched us in differentiating between cancer and non-cancer cells, 3D tumor spheroids and towards drug delivery.


Anatomical coupling between distinct metacognitive systems for memory and visual perception.
A recent study found that, across individuals, gray matter volume in the frontal polar region was correlated with visual metacognition capacity (i.e., how well one's confidence ratings distinguish between correct and incorrect judgments). A question arises as to whether the putative metacognitive mechanisms in this region are also used in other metacognitive tasks involving, for example, memory. A novel psychophysical measure allowed us to assess metacognitive efficiency separately in a visual and a memory task, while taking variations in basic task performance capacity into account. We found that, across individuals, metacognitive efficiencies positively correlated between the two tasks. However, voxel-based morphometry analysis revealed distinct brain structures for the two kinds of metacognition. Replicating a previous finding, variation in visual metacognitive efficiency was correlated with volume of frontal polar regions. However, variation in memory metacognitive efficiency was correlated with volume of the precuneus. There was also a weak correlation between visual metacognitive efficiency and precuneus volume, which may account for the behavioral correlation between visual and memory metacognition (i.e., the precuneus may contain common mechanisms for both types of metacognition). However, we also found that gray matter volumes of the frontal polar and precuneus regions themselves correlated across individuals, and a formal model comparison analysis suggested that this structural covariation was sufficient to account for the behavioral correlation of metacognition in the two tasks. These results highlight the importance of the precuneus in higher-order memory processing and suggest that there may be functionally distinct metacognitive systems in the human brain.


Clinical use of the Hamilton Depression Rating Scale: is increased efficiency possible? A post hoc comparison of Hamilton Depression Rating Scale, Maier and Bech subscales, Clinical Global Impression, and Symptom Checklist-90 scores.
The 17-item Hamilton Depression Rating Scale (HDRS) is used as a semi-gold standard in research. In treatment guidelines, the HDRS measurements serve to determine response and remission and guide clinical decision making for nonresponders. However, its use in clinical practice is limited, possibly because the HDRS is time consuming. In addition, the multidimensional HDRS is criticized for not measuring a unidimensional aspect as depression severity. The Maier and the Bech, two 6-item severity subscales extracted from the HDRS, are relatively unknown. This paper investigates whether the measurements obtained with these subscales are comparable with the original HDRS measurements. Data from 2 randomized controlled trials in 482 male and female patients, diagnosed with a major depression (with or without dysthymia) according to Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, of whom 219 participated in the trials, were reanalyzed. A standardized stepwise psychopharmacological treatment was compared with a combination of pharmacotherapy with Short Psychodynamic Supportive Psychotherapy in a psychiatric outpatient department. Outcome measures were internal consistency and concurrent validity of HDRS, Maier, Bech, Clinical Global Impression scales, and Symptom Checklist depression subscale. Effect sizes of HDRS, Maier, and Bech were used to compare measured treatment effects for the randomized subjects participating in the trials. Item Response Theory was used to obtain conversion tables for the HDRS, Maier, Bech, and Symptom Checklist depression subscale. We found moderate internal consistency (Cronbach alpha approximately 0.6-0.7) and high correlations of the Maier and Bech subscales with overall HDRS scores. Overall, there were no clinically relevant differences in effect sizes between Maier, Bech, and HDRS, although some differences were statistically significant. Receiver operating characteristic curves showed no difference between Maier and Bech to define remission but showed the Clinical Global Impression ratings to be unreliable. A cutoff < or =4 corresponded with an HDRS < or =7 criterion in both subscales. In clinical practice, both Maier and Bech scales can be used as equivalents of the HDRS, but will be more efficient.


To move or to evolve: contrasting patterns of intercontinental connectivity and climatic niche evolution in "Terebinthaceae" (Anacardiaceae and Burseraceae).
Many angiosperm families are distributed pantropically, yet for any given continent little is known about which lineages are ancient residents or recent arrivals. Here we use a comprehensive sampling of the pantropical sister pair Anacardiaceae and Burseraceae to assess the relative importance of continental vicariance, long-distance dispersal and niche-conservatism in generating its distinctive pattern of diversity over time. Each family has approximately the same number of species and identical stem age, yet Anacardiaceae display a broader range of fruit morphologies and dispersal strategies and include species that can withstand freezing temperatures, whereas Burseraceae do not. We found that nuclear and chloroplast data yielded a highly supported phylogenetic reconstruction that supports current taxonomic concepts and time-calibrated biogeographic reconstructions that are broadly congruent with the fossil record. We conclude that the most recent common ancestor of these families was widespread and likely distributed in the Northern Hemisphere during the Cretaceous and that vicariance between Eastern and Western Hemispheres coincided with the initial divergence of the families. The tempo of diversification of the families is strikingly different. Anacardiaceae steadily accumulated lineages starting in the Late Cretaceous-Paleocene while the majority of Burseraceae diversification occurred in the Miocene. Multiple dispersal- and vicariance-based intercontinental colonization events are inferred for both families throughout the past 100 million years. However, Anacardiaceae have shifted climatic niches frequently during this time, while Burseraceae have experienced very few shifts between dry and wet climates and only in the tropics. Thus, we conclude that both Anacardiaceae and Burseraceae move easily but that Anacardiaceae have adapted more often, either due to more varied selective pressures or greater intrinsic lability.


Learning from the implementation of Universal Free School Meals in Scotland using Normalisation Process Theory: Lessons for policymakers to engage multiple stakeholders.
In 2014/15, Universal Free School Meals (UFSM) were introduced in Scotland and England for children in their first three years of primary school. This study examined the implementation of UFSM in Scotland using Normalisation Process Theory (NPT), a middle-range theory of implementation, to identify areas of learning for policymakers wishing to introduce or extend similar policies. NPT is predominantly used to evaluate interventions or new technologies in healthcare settings. Qualitative data were collected across Scotland using a case study approach shortly after implementation (n = 29 school-level stakeholders) and in the following school year (n = 18 school-level stakeholders and n = 19 local authority-level stakeholders). Observations of lunchtime in each school were conducted at both timepoints. Data were analysed using a thematic framework approach using NPT constructs and sub-constructs. Results suggested education and catering stakeholders experiences of implementation diverged most around the NPT concepts of coherence, cognitive participation, and reflexive monitoring. Lack of coherence around the purpose and long-term benefits of UFSM appeared to reduce education stakeholders' willingness to engage with the policy beyond operational issues. In contrast, catering stakeholders identified a direct benefit to their everyday work and described receiving additional resources to deliver the policy. Overall, participants described an absence of monitoring data around the areas of greatest salience for education stakeholders. This study successfully used NPT to identify policy learning around school meals. Policymakers must increase the salience of such intersectoral policies for all relevant stakeholders involved before policy implementation, and plan adequate monitoring to evaluate potential long-term benefits.


Frontline diagnostic evaluation of patients suspected of angina by coronary computed tomography reduces downstream resource utilization when compared to conventional ischemia testing.
It has been proposed that the increasing use of coronary computed tomographic angiography (CTA) may introduce additional unnecessary diagnostic procedures. However, no previous study has assessed the impact on downstream test utilization of conventional diagnostic testing relative to CTA in patients suspected of angina. The purpose of this study was to investigate the consequences of frontline exercise-stress testing (Ex-test) versus CTA on downstream test utilization in clinical practice. In two collaborating departments using either Ex-test (n = 247) or CTA (n = 251) as the frontline diagnostic test in patients suspected of angina, comparable cohorts of consecutive patients were retrospectively identified (Jan. 2007-Feb. 2008). Downstream test utilization (invasive coronary angiography, ICA; myocardial perfusion scintigraphy, and CTA) during 12 months after the index diagnostic test was recorded. Mean age was 56 years (51% men), and 96% of the total study cohort were at low-intermediate pretest risk of significant coronary disease. Overall, downstream test utilization was more frequent in the Ex-test group than in the CTA group, 32% versus 21% (P = 0.003). Subsequent myocardial scintigraphy was more frequent used (9% versus 4%, P = 0.03), whereas ICA tended to be more frequent applied in the Ex-test versus CTA group (23% vs. 18%, P = 0.15). A frontline diagnostic use in symptomatic patients of Ex-test in comparison to CTA leads to more downstream diagnostic test utilization. Future prospective trials are needed in order to define the most cost-effective diagnostic use of CTA relative to conventional ischemia testing.


Effects of resistance training and chiropractic treatment in women with fibromyalgia.
The objective of this study was to evaluate resistance training (RES) and RES combined with chiropractic treatment (RES-C) on fibromyalgia (FM) impact and functionality in women with FM. The design of the study was a randomized control trial. Testing and training were completed at the university and chiropractic treatment was completed at chiropractic clinics. Participants (48 +/- 9 years; mean +/- standard deviation) were randomly assigned to RES (n = 10) or RES-C (n = 11). Both groups completed 16 weeks of RES consisting of 10 exercises performed two times per week. RES-C received RES plus chiropractic treatment two times per week. Strength was assessed using one repetition maximum for the chest press and leg extension. FM impact was measured using the FM impact questionnaire, myalgic score, and the number of active tender points. Functionality was assessed using the 10-item Continuous Scale Physical Functional Performance test. Analyses of variance with repeated measures compared groups before and after the intervention. Six (6) participants discontinued the study: 5 from RES and 1 from RES-C. Adherence to training was significantly higher in RES-C (92.0 +/- 7.5%) than in RES (82.8 +/- 7.5%). Both groups increased (p < or = 0.05) upper and lower body strength. There were similar improvements in FM impact in both groups. There were no group interactions for the functionality measures. Both groups improved in the strength domains; however, only RES-C significantly improved in the pre- to postfunctional domains of flexibility, balance and coordination, and endurance. In women with FM, resistance training improves strength, FM impact, and strength domains of functionality. The addition of chiropractic treatment improved adherence and dropout rates to the resistance training and facilitated greater improvements in the domains of functionality.


Meta-analysis of breast cancer microarray studies in conjunction with conserved cis-elements suggest patterns for coordinate regulation.
Gene expression measurements from breast cancer (BrCa) tumors are established clinical predictive tools to identify tumor subtypes, identify patients showing poor/good prognosis, and identify patients likely to have disease recurrence. However, diverse breast cancer datasets in conjunction with diagnostic clinical arrays show little overlap in the sets of genes identified. One approach to identify a set of consistently dysregulated candidate genes in these tumors is to employ meta-analysis of multiple independent microarray datasets. This allows one to compare expression data from a diverse collection of breast tumor array datasets generated on either cDNA or oligonucleotide arrays. We gathered expression data from 9 published microarray studies examining estrogen receptor positive (ER+) and estrogen receptor negative (ER-) BrCa tumor cases from the Oncomine database. We performed a meta-analysis and identified genes that were universally up or down regulated with respect to ER+ versus ER- tumor status. We surveyed both the proximal promoter and 3' untranslated regions (3'UTR) of our top-ranking genes in each expression group to test whether common sequence elements may contribute to the observed expression patterns. Utilizing a combination of known transcription factor binding sites (TFBS), evolutionarily conserved mammalian promoter and 3'UTR motifs, and microRNA (miRNA) seed sequences, we identified numerous motifs that were disproportionately represented between the two gene classes suggesting a common regulatory network for the observed gene expression patterns. Some of the genes we identified distinguish key transcripts previously seen in array studies, while others are newly defined. Many of the genes identified as overexpressed in ER- tumors were previously identified as expression markers for neoplastic transformation in multiple human cancers. Moreover, our motif analysis identified a collection of specific cis-acting target sites which may collectively play a role in the differential gene expression patterns observed in ER+ versus ER- breast cancer tumors. Importantly, the gene sets and associated DNA motifs provide a starting point with which to explore the mechanistic basis for the observed expression patterns in breast tumors.


Protein O-Fucosyltransferase 1 Undergoes Interdomain Flexibility in Solution.
Protein O-fucosyltransferase 1 (PoFUT1) is a GT-B fold enzyme that fucosylates proteins containing EGF-like repeats. GT-B glycosyltransferases have shown a remarkable grade of plasticity adopting closed and open conformations as a way of tuning their catalytic cycle, a feature that has not been observed for PoFUT1. Here, we analyzed Caenorhabditis elegans PoFUT1 (CePoFUT1) conformational behavior in solution by atomic force microscopy (AFM) and single-molecule fluorescence resonance energy transfer (SMF-FRET). Our results show that this enzyme is very flexible and adopts mainly compact conformations and to a lesser extend a highly dynamic population that oscillates between compact and highly extended conformations. Overall, our experiments illustrate the inherent complexity of CePoFUT1 dynamics, which might play a role during its catalytic cycle.