Assessment of 120 maxillofacial aneurysmal bone cysts: a nationwide quest to understand this enigma.
Compared with other maxillofacial lesions, oral and maxillofacial (OM) aneurysmal bone cysts (ABCs) are rare, and most studies have been case reports. Because the features or radiographic findings of 1 case could not be representative of the whole, conclusions cannot be drawn and data analyses will not be feasible. Our aim was to assess and describe the clinical and histopathologic characteristics of a large sample of subjects with ABCs. To our knowledge, the present case series of OM ABCs is the largest ever reported. To address our research purpose, we designed and implemented a retrospective case series. A multicenter retrospective cohort study of patient charts dated from 1967 to 2013 (46 years) at 10 major universities in 8 cities was undertaken to assess OM ABCs nationwide. Subjects were included if they had documented chart data and definitive histopathologic slides confirming the diagnosis and treatment of ABC. They were excluded if their histopathologic slides did not confirm the diagnosis of an ABC. Data were collected, and special forms were completed. Variables such as age, gender, site (ie, maxilla, mandible, anterior, posterior), histologic type (ie, solid, mixed, vascular), signs, symptoms, radiographic features (ie, radiolucency, unicystic or multilocular), and outcomes (ie, treatment modal, recurrence, complications) of the lesion were evaluated and documented by OM surgeons and confirmed by OM pathologists for assurance. Data analyses were performed using Statistical Package for Social Sciences, version 20, software (SPSS, Chicago, IL) (P < .05). We assessed the medical records and histopathologic slides of 120 patients diagnosed and treated for OM ABCs nationwide. Of these patients, 69 were male (57.5%) and 51 were female (42.5%), with no predilection found. The key findings were as follows. The mean age of occurrence was 20.7 ± 2.5 years (range 4 to 78), and occurrence was significantly greater in the first 2 decades of life (P < .001). The incidence was 2.6 cases/year. ABCs were significantly more common in the mandible (P < .05) and posterior areas (P < .05). The most common histopathologic type was the mixed type (P < .05). Firm swelling was the most common clinical presentation (P < .05); all cases were radiolucent and commonly unilateral (P < .05). Most were treated by excision and curettage. Recurrence was reported in 11 patients (9.2%) during the follow-up period (1 to 45 years). The present retrospective cohort found ABCs with a variable presentation, disease course, and histopathologic type, with no gender predilection. ABCs were significantly more common in childhood and adolescence and in the mandible and posterior areas of the jaws. Of the cases reviewed, 90% were treated by excision and curettage. ABCs had a relatively low recurrence rate (<10%), precluding the need to perform aggressive surgery primarily.


Lumbar vertebral body bone microstructural scaling in small to medium-sized strepsirhines.
Bone mass, architecture, and tissue mineral density contribute to bone strength. As body mass (BM) increases any one or combination of these properties could change to maintain structural integrity. To better understand the structural origins of vertebral fragility and gain insight into the mechanisms that govern bone adaptation, we conducted an integrative analysis of bone mass and microarchitecture in the last lumbar vertebral body from nine strepsirhine species, ranging in size from 42 g (Microcebus rufus) to 2,440 g (Eulemur macaco). Bone mass and architecture were assessed via µCT for the whole body and spherical volumes of interest (VOI). Allometric equations were estimated and compared with predictions for geometric scaling, assuming axial compression as the dominant loading regime. Bone mass, microarchitectural, and vertebral body geometric variables predominantly scaled isometrically. Among structural variables, the degree of anisotropy (Tb.DA) was the only parameter independent of BM and other trabecular architectural variables. Tb.DA was related to positional behavior. Orthograde primates had higher average Tb.DA (1.60) and more craniocaudally oriented trabeculae while lorisines had the lowest Tb.DA (1.25), as well as variably oriented trabeculae. Finally, lorisines had the highest ratio of trabecular bone volume to cortical shell volume (∼3x) and while there appears to be flexibility in this ratio, the total bone volume (trabecular + cortical) scales isometrically (BM(1.23) , r(2) = 0.93) and appears tightly constrained. The common pattern of isometry in our measurements leaves open the question of how vertebral bodies in strepsirhine species compensate for increased BM.


Mode of growth hormone action in osteoblasts.
Growth hormone (GH) affects bone size and mass in part through stimulating insulin-like growth factor type 1 (IGF-1) production in liver and bone. Whether GH acts independent of IGF-1 in bone remains unclear. To define the mode of GH action in bone, we have used a Cre/loxP system in which the type 1 IGF-1 receptor (Igf1r) has been disrupted specifically in osteoblasts in vitro and in vivo. Calvarial osteoblasts from mice homozygous for the floxed IGF-1R allele (IGF-1R(flox/flox)) were infected with adenoviral vectors expressing Cre. Disruption of IGF-1R mRNA (>90%) was accompanied by near elimination of IGF-1R protein but retention of GHR protein. GH-induced STAT5 activation was consistently greater in osteoblasts with an intact IGF-1R. Osteoblasts lacking IGF-1R retained GH-induced ERK and Akt phosphorylation and GH-stimulated IGF-1 and IGFBP-3 mRNA expression. GH-induced osteoblast proliferation was abolished by Cre-mediated disruption of the IGF-1R or co-incubation of cells with an IGF-1-neutralizing antibody. By contrast, GH inhibited apoptosis in osteoblasts lacking the IGF-1R. To examine the effects of GH on osteoblasts in vivo, mice wild type for the IGF-1R treated with GH subcutaneously for 7 days showed a doubling in the number of osteoblasts lining trabecular bone, whereas osteoblast numbers in similarly treated mice lacking the IGF-1R in osteoblasts were not significantly affected. These results indicate that although direct IGF-1R-independent actions of GH on osteoblast apoptosis can be demonstrated in vitro, IGF-1R is required for anabolic effects of GH in osteoblasts in vivo.


Approximate average head models for EEG source imaging.
We examine the performance of approximate models (AM) of the head in solving the EEG inverse problem. The AM are needed when the individual's MRI is not available. We simulate the electric potential distribution generated by cortical sources for a large sample of 305 subjects, and solve the inverse problem with AM. Statistical comparisons are carried out with the distribution of the localization errors. We propose several new AM. These are the average of many individual realistic MRI-based models, such as surface-based models or lead fields. We demonstrate that the lead fields of the AM should be calculated considering source moments not constrained to be normal to the cortex. We also show that the imperfect anatomical correspondence between all cortices is the most important cause of localization errors. Our average models perform better than a random individual model or the usual average model in the MNI space. We also show that a classification based on race and gender or head size before averaging does not significantly improve the results. Our average models are slightly better than an existing AM with shape guided by measured individual electrode positions, and have the advantage of not requiring such measurements. Among the studied models, the Average Lead Field seems the most convenient tool in large and systematical clinical and research studies demanding EEG source localization, when MRI are unavailable. This AM does not need a strict alignment between head models, and can therefore be easily achieved for any type of head modeling approach.


Ultrastructural visualization of cytoskeletal mRNAs and their associated proteins using double-label in situ hybridization.
We have been able to visualize cytoskeletal messenger RNA molecules at high resolution using nonisotopic in situ hybridization followed by whole-mount electron microscopy. Biotinated cDNA probes for actin, tubulin, or vimentin mRNAs were hybridized to Triton-extracted chicken embryo fibroblasts and myoblasts. The cells were then exposed to antibodies against biotin followed by colloidal gold-conjugated antibodies and then critical-point dried. Identification of mRNA was possible using a probe fragmented to small sizes such that hybridization of several probe fragments along the mRNA was detected as a string of colloidal gold particles qualitatively and quantitatively distinguishable from nonspecific background. Extensive analysis showed that when eight gold particles were seen in this iterated array, the signal to noise ratio was greater than 30:1. Furthermore, these gold particles were colinear, often spiral, or circular suggesting detection of a single nucleic acid molecule. Antibodies against actin, vimentin, or tubulin proteins were used after in situ hybridization, allowing simultaneous detection of the protein and its cognate message on the same sample. This revealed that cytoskeletal mRNAs are likely to be extremely close to actin protein (5 nm or less) and unlikely to be within 20 nm of vimentin or tubulin filaments. Actin mRNA was found to be more predominant in lamellipodia of motile cells, confirming previous results. These results indicate that this high resolution in situ hybridization approach is a powerful tool by which to investigate the association of mRNA with the cytoskeleton.


Modelling Spatial and Temporal Forest Cover Change Patterns (1973-2020): A Case Study from South Western Ghats (India).
This study used time series remote sensing data from 1973, 1990 and 2004 to assess spatial forest cover change patterns in the Kalakad-Mundanthurai Tiger Reserve (KMTR), South Western Ghats (India). Analysis of forest cover changes and its causes are the most challenging areas of landscape ecology, especially due to the absence of temporal ground data and comparable space platform based data. Comparing remotely sensed data from three different sources with sensors having different spatial and spectral resolution presented a technical challenge. Quantitative change analysis over a long period provided a valuable insight into forest cover dynamics in this area. Time-series maps were combined within a geographical information system (GIS) with biotic and abiotic factors for modelling its future change. The land-cover change has been modelled using GEOMOD and predicted for year 2020 using the current disturbance scenario. Comparison of the forest change maps over the 31-year period shows that evergreen forest being degraded (16%) primarily in the form of selective logging and clear felling to raise plantations of coffee, tea and cardamom. The natural disturbances such as forest fire, wildlife grazing, invasions after clearance and soil erosion induced by anthropogenic pressure over the decades are the reasons of forest cover change in KMTR. The study demonstrates the role of remote sensing and GIS in monitoring of large-coverage of forest area continuously for a given region over time more precisely and in cost-effective manner which will be ideal for conservation planning and prioritization.


Validation of de-identified record linkage to ascertain hospital admissions in a cohort study.
Cohort studies can provide valuable evidence of cause and effect relationships but are subject to loss of participants over time, limiting the validity of findings. Computerised record linkage offers a passive and ongoing method of obtaining health outcomes from existing routinely collected data sources. However, the quality of record linkage is reliant upon the availability and accuracy of common identifying variables. We sought to develop and validate a method for linking a cohort study to a state-wide hospital admissions dataset with limited availability of unique identifying variables. A sample of 2000 participants from a cohort study (n = 41 514) was linked to a state-wide hospitalisations dataset in Victoria, Australia using the national health insurance (Medicare) number and demographic data as identifying variables. Availability of the health insurance number was limited in both datasets; therefore linkage was undertaken both with and without use of this number and agreement tested between both algorithms. Sensitivity was calculated for a sub-sample of 101 participants with a hospital admission confirmed by medical record review. Of the 2000 study participants, 85% were found to have a record in the hospitalisations dataset when the national health insurance number and sex were used as linkage variables and 92% when demographic details only were used. When agreement between the two methods was tested the disagreement fraction was 9%, mainly due to "false positive" links when demographic details only were used. A final algorithm that used multiple combinations of identifying variables resulted in a match proportion of 87%. Sensitivity of this final linkage was 95%. High quality record linkage of cohort data with a hospitalisations dataset that has limited identifiers can be achieved using combinations of a national health insurance number and demographic data as identifying variables.


Immunoglobulin response to Plasmodium falciparum RESA proteins in uncomplicated and severe malaria.
The three members of the ring-infected erythrocyte surface antigen (RESA) proteins family share high sequence homologies, which impair the detection and assignment to one or another protein of some pathogenic processes inherent to Plasmodium falciparum malaria. The present study was intended to determine if the antibody and inflammatory responses of children living in a malaria-endemic area varied depending on the RESA-1, RESA-2 or RESA-3 proteins and the severity of the disease, two groups of severe and uncomplicated malaria cases being considered. Two synthetic peptides representing predicted B cell epitopes were designed per RESA protein, all located outside of the 3' and 5' repetition blocks, in order to allow an antibody detection specific of each member of the family. Recombinant rRESA-1B and rRESA-3B proteins were also engineered. Two groups of Beninese children admitted to hospital in 2009 for either uncomplicated or severe malaria were compared for their plasma levels of IgG specifically recognizing each recombinant RESA protein or synthetic peptide, and for their plasma inflammatory cytokine levels (IFN-γ, TNF-α and IL-10), taking into account host and parasite genetic factors. The absence of IgG cross-reactivity between rRESA proteins and their protein carrier as well as between each RESA peptide and a non-epitopic RESA control peptide validated the use of the engineered recombinant proteins and peptides for the measurement of plasma IgG. Taking into account age, fever duration and parasitaemia, a multiple logistic regression performed on children clustered according to their antibody responses' profiles concluded to an increased risk of severe malaria for P2 (representative of RESA-1) responders (P = 0.007). Increased IL-10 plasma levels were found in children harbouring multiclonal P. falciparum infections on the basis of the T1526G resa2 gene polymorphism (P = 0.004). This study provided novel tools to dissect the seroreactivity against the three members of the RESA protein family and to describe its relation to protection against malaria. It suggested the measurement of plasma antibodies raised against specific peptides to serve as predictive immunologic markers for disease severity. Lastly, it reinforced previous observations linking the T1526G resa2 gene mutation to severe malaria.


Application of a strain-specific rRNA oligonucleotide probe targeting Pseudomonas fluorescens Ag1 in a mesocosm study of bacterial release into the environment.
Sequence analysis of domains 3 and 4 of 23S rRNA from Pseudomonas fluorescens Ag1 was carried out to allow the design of a strain-specific rRNA oligonucleotide probe targeting this strain. The specificity of the probe, Ps-Ag1, was assessed by dot blot analysis and whole-cell hybridization, and it was found to be specific for P. fluorescens Ag1. The correlation between the ribosomal content of P. fluorescens Ag1 and growth rate was determined during balanced growth conditions with generation times ranging from 1.2 to 31.8 h. Hybridization of the rRNA-targeting probes combined with charged coupled device-enhanced microscopy was used to determine the rRNA content. The total RNA content per cell was determined by staining with acridine orange and charged coupled device-enhanced microscopy. After 2 h under carbon starvation conditions, the rRNA content per cell decreased to 45% of the content of an exponentially growing cell. After 1 day of carbon starvation, the rRNA content had decreased to 20%. When cells were grown at different temperatures, it was found that the rRNA content per cell was only dependent on the substrate in the temperature range from 5 to 30 degrees C. P. fluorescens Ag1 was used in a mesocosm release experiment. The strain could be detected by use of the oligonucleotide probe targeting rRNA for 8 days in the water column and for 10 days on solid surfaces. The standard curve correlating growth rate with rRNA content was used to estimate the physiological activity of P. fluorescens Ag1 in the mesocosm experiment.


Epidermal growth factor improves survival and prevents intestinal injury in a murine model of pseudomonas aeruginosa pneumonia.
Mortality from pneumonia is mediated, in part, through extrapulmonary causes. Epidermal growth factor (EGF) has broad cytoprotective effects, including potent restorative properties in the injured intestine. The purpose of this study was to determine the efficacy of EGF treatment following Pseudomonas aeruginosa pneumonia. FVB/N mice underwent intratracheal injection of either P. aeruginosa or saline and were then randomized to receive either systemic EGF or vehicle beginning immediately or 24 h after the onset of pneumonia. Systemic EGF decreased 7-day mortality from 65% to 10% when initiated immediately after the onset of pneumonia and to 27% when initiated 24 h after the onset of pneumonia. Even though injury in pneumonia is initiated in the lungs, the survival advantage conferred by EGF was not associated with improvements in pulmonary pathology. In contrast, EGF prevented intestinal injury by reversing pneumonia-induced increases in intestinal epithelial apoptosis and decreases in intestinal proliferation and villus length. Systemic cytokines and kidney and liver function were unaffected by EGF therapy, although EGF decreased pneumonia-induced splenocyte apoptosis. To determine whether the intestine was sufficient to account for extrapulmonary effects induced by EGF, a separate set of experiments was done using transgenic mice with enterocyte-specific overexpression of EGF (IFABP-EGF [intestinal fatty acid-binding protein linked to mouse EGF] mice), which were compared with wild-type mice subjected to pneumonia. IFABP-EGF mice had improved survival compared with wild-type mice following pneumonia (50% vs. 28%, respectively, P < 0.05) and were protected from pneumonia-induced intestinal injury. Thus, EGF may be a potential adjunctive therapy for pneumonia, mediated in part by its effects on the intestine.


Guanidination of notexin alters its membrane-damaging activity in response to sphingomyelin and cholesterol.
To elucidate the contribution of phospholipase A 2 (PLA2) activity of notexin to its ability to perturb membranes, comparative studies on the interaction of notexin and guanidinated notexin (Gu-notexin) with egg yolk phosphatidylcholine (EYPC), EYPC/egg yolk sphingomyelin (EYSM) and EYPC/EYSM/cholesterol vesicles were conducted. EYSM notably reduced the membrane-damaging activity of notexin against EYPC vesicles, but had an insignificant influence on that of Gu-notexin. Unlike the effects noted with notexin, inactivation of PLA 2 activity by EDTA led to a reduction in the ability of Gu-notexin to induce EYPC/EYSM vesicle leakage and to increase Gu-notexin-induced membrane permeability of EYPC/EYSM/cholesterol vesicles. The geometrical arrangement of notexin and Gu-notexin in contact with either EYPC/EYSM vesicles or EYPC/EYSM/cholesterol vesicles differed. Moreover, global conformation of notexin and Gu-notexin differed in either Ca2+-bound or metal-free states. These results indicate that notexin and Gu-notexin could induce membrane permeability without the involvement of PLA 2 activity, and suggest that guanidination alters the membrane-bound mode of notexin on damaging phospholipid vesicles containing sphingomyelin and cholesterol.


Longterm blood pressure variability in patients with rheumatoid arthritis and its effect on cardiovascular events and all-cause mortality in RA: a population-based comparative cohort study.
To examine longterm visit-to-visit blood pressure (BP) variability in patients with rheumatoid arthritis (RA) versus non-RA subjects and to assess its effect on cardiovascular (CV) events and mortality in RA. Clinic BP measures were collected in a population-based incident cohort of patients with RA (1987 American College of Rheumatology criteria met between January 1, 1995, and January 1, 2008) and non-RA subjects. BP variability was defined as within-subject SD in systolic and diastolic BP. The study included 442 patients with RA (mean age 55.5 yrs, 70% females) and 424 non-RA subjects (mean age 55.7 yrs, 69% females). Patients with RA had higher visit-to-visit variability in systolic BP (13.8 ± 4.7 mm Hg) than did non-RA subjects (13.0 ± 5.2 mm Hg, p = 0.004). Systolic BP variability declined after the index date in RA (p < 0.001) but not in the non-RA cohort (p = 0.73), adjusting for age, sex, and calendar year of RA. During the mean followup of 7.1 years, 33 CV events and 57 deaths occurred in the RA cohort. Visit-to-visit systolic BP variability was associated with increased risk of CV events (HR per 1 mm Hg increase in BP variability 1.12, 95% CI 1.01-1.25). Diastolic BP variability was associated with all-cause mortality in RA (HR 1.14, 95% CI 1.03-1.27), adjusting for systolic and diastolic BP, body mass index, smoking, diabetes, dyslipidemia, and use of antihypertensives. Patients with RA had higher visit-to-visit systolic BP variability than did non-RA subjects. There was a significant decline in systolic BP variability after RA incidence. Higher visit-to-visit BP variability was associated with adverse CV outcomes and all-cause mortality in RA.


Acquired neuromyotonia in thymoma-associated myasthenia gravis: a clinical and serological study.
Acquired neuromyotonia can occur in patients with thymoma, alone or in association with myasthenia gravis (MG), but the clinical prognostic significance of such comorbidity is largely unknown. The clinico-pathological features were investigated along with the occurrence of neuromyotonia as predictors of tumour recurrence in patients with thymoma-associated myasthenia. A total number of 268 patients with thymomatous MG were studied retrospectively. Patients with symptoms of spontaneous muscle overactivity were selected for autoantibody testing using immunohistology for neuronal cell-surface proteins and cell-based assays for contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated 1 (LGI1), glycine receptor and Netrin-1 receptor antibodies. Neuromyotonia was diagnosed according to the presence of typical electromyography abnormalities and/or autoantibodies against LGI1/CASPR2. Overall, 33/268 (12%) MG patients had a thymoma recurrence. Five/268 (2%) had neuromyotonia, four with typical autoantibodies, including LGI1 (n = 1), CASPR2 (n = 1) or both (n = 2). Three patients had Netrin-1 receptor antibodies, two with neuromyotonia and concomitant CASPR2+LGI1 antibodies and one with spontaneous muscle overactivity without electromyography evidence of neuromyotonia. Thymoma recurrence was more frequent in those with (4/5, 80%) than in those without (28/263, 10%, P < 0.001) neuromyotonia. Neuromyotonia preceded the recurrence in 4/5 patients. In univariate analysis, predictors of thymoma recurrence were age at thymectomy [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.93-0.97], Masaoka stage ≥IIb (OR 10.73, 95% CI 2.38-48.36) and neuromyotonia (OR 41.78, 95% CI 4.71-370.58). De novo occurrence of neuromyotonia in MG patients with previous thymomas is a rare event and may herald tumour recurrence. Neuronal autoantibodies can be helpful to assess the diagnosis. These observations provide pragmatic risk stratification for tumour vigilance in patients with thymomatous MG.


Nanofountain Probe Electroporation Enables Versatile Single-Cell Intracellular Delivery and Investigation of Postpulse Electropore Dynamics.
Introducing exogenous molecules into cells with high efficiency and dosage control is a crucial step in basic research as well as clinical applications. Here, the capability of the nanofountain probe electroporation (NFP-E) system to deliver proteins and plasmids in a variety of continuous and primary cell types with appropriate dosage control is reported. It is shown that the NFP-E can achieve fine control over the relative expression of two cotransfected plasmids. Finally, the dynamics of electropore closure after the pulsing ends with the NFP-E is investigated. Localized electroporation has recently been utilized to demonstrate the converse process of delivery (sampling), in which a small volume of the cytosol is retrieved during electroporation without causing cell lysis. Single-cell temporal sampling confers the benefit of monitoring the same cell over time and can provide valuable insights into the mechanisms underlying processes such as stem cell differentiation and disease progression. NFP-E parameters that maximize the membrane resealing time, which is essential for increasing the sampled volume and in meeting the challenge of monitoring low copy number biomarkers, are identified. Its application in CRISPR/Cas9 gene editing, stem cell reprogramming, and single-cell sampling studies is envisioned.


African Burkitt lymphoma: age-specific risk and correlations with malaria biomarkers.
African Burkitt lymphoma is an aggressive B-cell, non-Hodgkin lymphoma linked to Plasmodium falciparum malaria. Malaria biomarkers related to onset of African Burkitt lymphoma are unknown. We correlated age-specific patterns of 2,602 cases of African Burkitt lymphoma (60% male, mean ± SD age = 7.1 ± 2.9 years) from Uganda, Ghana, and Tanzania with malaria biomarkers published from these countries. Age-specific patterns of this disease and mean multiplicity of P. falciparum malaria parasites, defined as the average number of distinct genotypes per positive blood sample based on the merozoite surface protein-2 assessed by polymerase chain reaction, were correlated and both peaked between 5 and 9 years. This pattern, which was strong and consistent across regions, contrasted parasite prevalence, which peaked at 2 years and decreased slightly, and geometric mean parasite density, which peaked between 2 and 3 years and decreased sharply. Our findings suggest that concurrent infection with multiple malaria genotypes may be related to onset of African Burkitt lymphoma.


The intake of flavonoids and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study.
The role of flavonoids in CVD is still unclear. In this cross-sectional study we assessed the relation between the intakes of twenty-six flavonoids from five subclasses: flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins, and the mean common carotid artery intima-media thickness (CCA-IMT). The study population consisted of 1380 middle-aged eastern Finnish men for whom the mean CCA-IMT examinations were carried out as a part of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD). The mean intake of flavonoids was 128.5 (sd 206.7) mg/d and the mean CCA-IMT was 0.78 (sd 0.17) mm. In the lowest quartile of total flavonoid intake the non-adjusted mean CCA-IMT was 0.79 (sd 0.19) mm, while the mean CCA-IMT was 0.76 (sd 0.15) in the highest quartile (P < 0.001). After adjustment for age, variables related to CCA-IMT measurement, history of atherosclerosis, smoking, BMI, diabetes, systolic blood pressure, serum HDL- and LDL-cholesterol, VO2 max, and intakes of alcohol, SFA, folate, vitamins C and E, the total flavonoid intake was inversely associated with the mean CCA-IMT (P = 0.018). Out of different flavonoid subclasses, flavan-3-ols were inversely associated with CCA-IMT (P = 0.025) after statistical adjustment. There was a trend for an inverse association between intake of flavonols and mean CCA-IMT (P = 0.055). We conclude that high intake of flavonoids is associated with decreased carotid atherosclerosis in middle-aged Finnish men.


UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Tract (GIT) 2.0 Reflux Scale Correlates With Impaired Esophageal Scintigraphy Findings in Systemic Sclerosis.
The University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (GIT 2.0) instrument is a self-report tool measuring gastrointestinal (GI) quality of life in patients with systemic sclerosis (SSc). Scarce data are available on the correlation between patient-reported GI symptoms and motility dysfunction as assessed by esophageal transit scintigraphy (ETS). We evaluated the GIT 2.0 reflux scale in patients with SSc admitted to our clinic and undergoing ETS, and correlated their findings. Thirty-one patients with SSc undergoing ETS were included. Twenty-seven were female, and 9 had diffuse cutaneous SSc. Twenty-six of 31 (84%) patients had a delayed transit and an abnormal esophageal emptying activity (EA); they also had a higher GIT 2.0 reflux score (P = 0.04). Mean EA percentage was higher in patients with none to mild GIT 2.0 reflux score (81.1 [SD 11.5]) than in those with moderate (55.7 [SD 17.8], P = 0.003) and severe to very severe scores (55.8 [SD 19.7], P = 0.002). The percentage of esophageal EA negatively correlated with the GIT 2.0 reflux score (r = -0.68, P < 0.0001), but it did not correlate with the other GIT 2.0 scales and the total GIT 2.0 score. SSc patients with impaired ETS findings have a higher GIT 2.0 reflux score. The GIT 2.0 is a complementary tool for objective measurement of esophageal involvement that can be easily administered in day-to-day clinical assessment.


Mass-gathering health research foundational theory: part 2 - event modeling for mass gatherings.
Current knowledge about mass-gathering health (MGH) fails to adequately inform the understanding of mass gatherings (MGs) because of a relative lack of theory development and adequate conceptual analysis. This report describes the development of a series of event lenses that serve as a beginning "MG event model," complimenting the "MG population model" reported elsewhere. Existing descriptions of "MGs" were considered. Analyzing gaps in current knowledge, the authors sought to delineate the population of events being reported. Employing a consensus approach, the authors strove to capture the diversity, range, and scope of MG events, identifying common variables that might assist researchers in determining when events are similar and might be compared. Through face-to-face group meetings, structured breakout sessions, asynchronous collaboration, and virtual international meetings, a conceptual approach to classifying and describing events evolved in an iterative fashion. Findings Embedded within existing literature are a variety of approaches to event classification and description. Arising from these approaches, the authors discuss the interplay between event demographics, event dynamics, and event design. Specifically, the report details current understandings about event types, geography, scale, temporality, crowd dynamics, medical support, protective factors, and special hazards. A series of tables are presented to model the different analytic lenses that might be employed in understanding the context of MG events. Interpretation The development of an event model addresses a gap in the current body of knowledge vis a vis understanding and reporting the full scope of the health effects related to MGs. Consistent use of a consensus-based event model will support more rigorous data collection. This in turn will support meta-analysis, create a foundation for risk assessment, allow for the pooling of data for illness and injury prediction, and support methodology for evaluating health promotion, harm reduction, and clinical response interventions at MGs.


Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project.
Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.


Effects of inpatient geriatric interventions in a German geriatric hospital: Impact on ADL, mobility and cognitive status.
Given the demographic changes, the need for effective geriatric intervention is obvious. Geriatric care aims to maintain the highest possible level of independence and quality of life and to reduce the risk of need for care. This study investigated the benefits of geriatric care on functional performance, mobility and cognition. This study involved a retrospective analysis of clinical data from 646 patients. At hospital admission and discharge functional status was assessed using the Barthel index. Mobility was evaluated by means of the Tinetti test and cognition by the mini-mental state examination (MMSE). A follow-up was conducted on 112 patients 2-5 months after hospital discharge. Statistical analysis included t-tests including Cohen's d for effect size and multivariate regression analysis. The mean age of the study population was 81.1 ± 7.1 years including 439 women (68%) and 207 men (32%). There were significant average improvements for activities of daily living (ADL), mobility and cognition comparing discharge and admission scores. For functional and mobility status, effect sizes were medium to high. Regression analyses showed that ADL improvement was predicted by functional, mobile and cognitive status at admission. Follow-up analyses revealed a high percentage of former patients still living at home and an overall maintenance of ADL levels. Geriatric patients seem to experience long-term improvements during geriatric treatment, which appears to fulfill its aim of recovering independence. For a better understanding of relevant factors for the recreation of geriatric patients, further research is needed, e.g. with respect to the impact of the nutritional status.


Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control.
Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.


An exploration of nursing research perceptions of registered nurses engaging in research activities at a metropolitan hospital in Western Australia.
To explore perceptions about nursing research of registered nurses (RNs) who were engaged in research activities at a metropolitan hospital in Western Australia. In order to improve RNs' research engagement and promote evidence-based practice, Nurse Research Consultants (NRCs) were appointed jointly by the study hospital and a local university. This joint appointment commenced in 2004 in the hospital's emergency department. Early findings indicated that the NRC role was effective in assisting registered nurses with research activities and hence the NRC role was expanded to all areas of the hospital. However, no formal investigation had been carried out to explore the effect of the NRC role on RNs' engagement with nursing research across the hospital. A qualitative interview process. Ten RN participants from the adult and paediatric wards were interviewed. Audio-recorded data were transcribed verbatim and thematic analysis was undertaken. Four main themes were identified, namely: perceptions of nursing research, perceived enablers, perceived barriers and improving research engagement. There was some overlap with some sub-themes being linked with more than one theme. This appeared to be due to differing levels of research education and research engagement. 6pc some of the RNs that participated in this study were experienced in the conduct of research, finding adequate support from NRCs in the workplace, whilst others experienced barriers limiting their involvement in nursing research activities. These barriers could be reduced with additional education, support, improved communication, time and opportunities to undertake research activities.


Factors in Patient Empowerment: A Survey of an Online Patient Research Network.
Providers and healthcare organizations have begun recognizing the importance of patient empowerment as a driver of patient-centered care. Unfortunately, most studies have investigated empowerment with single diseases. Identifying factors of empowerment across conditions and populations would enable a greater understanding of this construct. The purpose of this study was to understand empowerment in relation to health information-seeking, interactions with providers and peers, and healthcare access in chronic disease patients. This study also sought to identify key empowerment factors and their association with patient characteristics. Participants were recruited through PatientsLikeMe, an online research platform where patients share their personal and medical history data. Patients completed an online survey that assessed self-reported health behavior (e.g. knowledge-seeking, experiences with healthcare providers, and peer interactions) and healthcare access. An exploratory factor analysis identified key empowerment domains. Domain level sum scores and sum of all domains (total score) were compared across patient characteristics and diseases. Overall, 3988 participants were included in the study, with the majority actively involved in their healthcare, but many cited difficulties with matching their treatment goals with those of their physician (34 %) and spending sufficient time with the physician (36 %). Factor analysis identified two domains-Positive Patient-Provider Interaction, and Knowledge and Personal Control-that explained >60 % of the overall variance in the observed variables. Mean total empowerment scores for patients with a primary complaint of Parkinson's disease (61.8) and multiple sclerosis (60.3) were significantly greater than fibromyalgia (55.3) and chronic fatigue syndrome (54.8). Patients who were older, male, more educated, and insured also reported significantly greater levels of empowerment. The two domains of empowerment identified in this study are consistent with previous studies, but the differences in empowerment levels across diseases suggest a need for further studies on disease-related attributes of empowerment. Future research should examine the pathways for empowerment, as well as the relationship between empowerment domains and clinical outcomes.


Classification of sleep stages using multi-wavelet time frequency entropy and LDA.
The process of automatic sleep stage scoring consists of two major parts: feature extraction and classification. Features are normally extracted from the polysomnographic recordings, mainly electroencephalograph (EEG) signals. The EEG is considered a non-stationary signal which increases the complexity of the detection of different waves in it. This work presents a new technique for automatic sleep stage scoring based on employing continuous wavelet transform (CWT) and linear discriminant analysis (LDA) using different mother wavelets to detect different waves embedded in the EEG signal. The use of different mother wavelets increases the ability to detect waves in the EEG signal. The extracted features were formed based on CWT time frequency entropy using three mother wavelets, and the classification was performed using the linear discriminant analysis. Thirty-two data sets from the MIT-BIH database were used to evaluate the performance of the proposed method. Features of a single EEG signal were extracted successfully based on the time frequency entropy using the continuous wavelet transform with three mother wavelets. The proposed method has shown to outperform the classification based on a CWT using a single mother wavelet. The accuracy was found to be 0.84, while the kappa coefficient was 0.78. This work has shown that wavelet time frequency entropy provides a powerful tool for feature extraction for the non-stationary EEG signal; the accuracy of the classification procedure improved when using multiple wavelets compared to the use of single wavelet time frequency entropy.


Coli surface antigens 1 and 3 of colonization factor antigen II-positive enterotoxigenic Escherichia coli: morphology, purification, and immune responses in humans.
Enterotoxigenic Escherichia coli (ETEC) of serotype O6:H16, biotype A, bearing colonization factor antigen II (CFA/II) possesses two distinct coli surface antigens, CS1 and CS3, whereas CFA/II-positive ETEC of serotype O8:H9 manifests only CS3. CS1 has been shown to be fimbrial in nature, but heretofore the morphology of CS3 has not been described. Accordingly, by immune electron microscopy we investigated the morphological characteristics of CS3 on bacterial cells and after purification. CS3 was found to consist of thin (2-nm), flexible, wiry, "fibrillar" fimbriae, visible both on bacteria (O6:H16, biotype A, and O8:H9 strains) and in the pure state. In contrast, CS1 exists as wider (6-nm), rigid fimbriae on the surface of O6:H16, biotype A, strains. By the use of antisera to CS1 and CS3 in immune electron microscopy, immunodiffusion in gel, and immunoblotting techniques, CS1 and CS3 were found to be immunologically as well as morphologically distinct. Six of nine volunteers who developed diarrhea after challenge with an O139:H28 ETEC strain bearing CS1 and CS3 had significant serological rises to purified CS1 and CS3 antigens, suggesting that both antigens are elaborated in vivo, play a role in pathogenesis, and stimulate an immune response.


Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments.
Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83-248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence.


Clinical Characteristics of Patients with Cochlear Fistulas Caused by Chronic Otitis Media with Cholesteatoma.
To analyze the clinical characteristics of cochlear fistulas (CFs) and propose a new fistula classification system with regard to the cochlea. A retrospective chart review was conducted between January 2008 and December 2015 to identify patients who had undergone surgery for cholesteatoma with an associated CF. The following data were collected: preoperative symptoms, findings of temporal bone computed tomography (TBCT), fistula stage, cholesteatoma classification, surgical technique, and pre- and postoperative pure-tone audiometry. We analyzed a total of 159 patients, out of which 9 (5.7%) were diagnosed with a CF. The average duration of the chronic otitis media was 19.8 years. Cholesteatomas that induced CF rarely existed in the nonaggressive state; recurrent otorrhea was observed in all but one of our subjects. All the patients with CF had a distinct origin of cholesteatoma that developed from the retraction of posterior pars tensa; further, 88.9% cholesteatomas extended to and filled the sinus tympani. Preoperative audiometry revealed total hearing loss in 4 (44.4%) patients. Further, five patients with residual hearing before surgery had stage I fistulas, and the bone conduction thresholds remained stable after surgery. Cochlear fistulas were often detected in patients with (1) a history of chronic otitis media (exceeding 10 years), (2) frequently recurring otorrhea, and (3) pars tensa cholesteatomas that extended to the posterior mesotympanum and filled the sinus tympani. Such patients can suffer from potentially severe and irreparable sensorineural hearing loss.


Effect of Grape Seed Extract on Lipid Profile and Expression of Interleukin-6 in Polycystic Ovarian Syndrome Wistar Rat Model.
Polycystic ovary syndrome (PCOS) is a common but complex endocrine disorder and is the major cause of anovulation and consequent subfertility. In this study the effect of grape seed extract (GSE) on triglyceride (TG), total cholesterol (TC), highdensity lipoprotein-cholestrol (HDL-C), low-density lipoprotein-cholestrol (LDL-C) and interleukin-6 (IL-6) in PCOS Wistar rats were assessed. In this experimental study, 84 adult female Wistar rats were divided into 7 groups (n=12) including control (intact), Sham (estradiol valerate solvent injection), control PCOS and 4 experimental PCOS groups. To induce the syndrome, a single subcutaneous injection of 2 mg estradiol valerate was applied. In experimental groups, PCOS rats were treated with different doses of 50, 75, 100 and 200 mg/kg body weight (BW) GSE by intraperitoneal injection for 10 consecutive days. After harvesting blood serum, TG was measured by Glycerol-3-phosphate Oxidase-Peoxidase (GPOPAP), TC by Cholesterol Oxidase-Peroxidase (CHOD-PAP), and HDL-C by sedimentation method, LDL-C by Friedwald calculation and IL-6 by ELISA method. The serum values of each parameter were analyzed using one-way ANOVA at P≤0.05. In all experimental groups significant decrease of visceral fat was obvious as compared with control PCOS group. LDL-C, TC and IL-6 levels in experimental groups, particularly at dose of 50 mg/kg of GSE, were significantly decreased as compared with PCOS group. However, HDL-C levels were not significantly changed. According to the findings of this study, it can be concluded that GSE with its effects on serum TC, LDL-C and IL-6 could reduce the effects of dyslipidemia and inflammation in PCOS rats and improve systemic symptoms of PCOS.


The roots of stereotype threat: when automatic associations disrupt girls' math performance.
Although stereotype awareness is a prerequisite for stereotype threat effects (Steele & Aronson, 1995), research showed girls' deficit under stereotype threat before the emergence of math-gender stereotype awareness, and in the absence of stereotype endorsement. In a study including 240 six-year-old children, this paradox was addressed by testing whether automatic associations trigger stereotype threat in young girls. Whereas no indicators were found that children endorsed the math-gender stereotype, girls, but not boys, showed automatic associations consistent with the stereotype. Moreover, results showed that girls' automatic associations varied as a function of a manipulation regarding the stereotype content. Importantly, girls' math performance decreased in a stereotype-consistent, relative to a stereotype-inconsistent, condition and automatic associations mediated the relation between stereotype threat and performance.


Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer.
Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.


Mapping environmental injustices: pitfalls and potential of geographic information systems in assessing environmental health and equity.
Geographic Information Systems (GIS) have been used increasingly to map instances of environmental injustice, the disproportionate exposure of certain populations to environmental hazards. Some of the technical and analytic difficulties of mapping environmental injustice are outlined in this article, along with suggestions for using GIS to better assess and predict environmental health and equity. I examine 13 GIS-based environmental equity studies conducted within the past decade and use a study of noxious land use locations in the Bronx, New York, to illustrate and evaluate the differences in two common methods of determining exposure extent and the characteristics of proximate populations. Unresolved issues in mapping environmental equity and health include lack of comprehensive hazards databases; the inadequacy of current exposure indices; the need to develop realistic methodologies for determining the geographic extent of exposure and the characteristics of the affected populations; and the paucity and insufficiency of health assessment data. GIS have great potential to help us understand the spatial relationship between pollution and health. Refinements in exposure indices; the use of dispersion modeling and advanced proximity analysis; the application of neighborhood-scale analysis; and the consideration of other factors such as zoning and planning policies will enable more conclusive findings. The environmental equity studies reviewed in this article found a disproportionate environmental burden based on race and/or income. It is critical now to demonstrate correspondence between environmental burdens and adverse health impacts--to show the disproportionate effects of pollution rather than just the disproportionate distribution of pollution sources.


Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1.
TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology. Here we show that predicted nuclear export signals in TDP-43 and FUS are non-functional and that both proteins are exported independently of the export receptor CRM1/Exportin-1. Silencing of Exportin-5 or the mRNA export factor Aly/REF, as well as mutations that abrogate RNA-binding do not impair export of TDP-43 and FUS. However, artificially enlarging TDP-43 or FUS impairs their nuclear egress, suggesting that they could leave the nucleus by passive diffusion. Finally, we found that inhibition of transcription causes accelerated nuclear egress of TDP-43, suggesting that newly synthesized RNA retains TDP-43 in the nucleus, limiting its egress into the cytoplasm. Our findings implicate reduced nuclear retention as a possible factor contributing to mislocalization of TDP-43 in ALS/FTD.


Organ-specific, multimodal, wireless optoelectronics for high-throughput phenotyping of peripheral neural pathways.
The vagus nerve supports diverse autonomic functions and behaviors important for health and survival. To understand how specific components of the vagus contribute to behaviors and long-term physiological effects, it is critical to modulate their activity with anatomical specificity in awake, freely behaving conditions using reliable methods. Here, we introduce an organ-specific scalable, multimodal, wireless optoelectronic device for precise and chronic optogenetic manipulations in vivo. When combined with an advanced, coil-antenna system and a multiplexing strategy for powering 8 individual homecages using a single RF transmitter, the proposed wireless telemetry enables low cost, high-throughput, and precise functional mapping of peripheral neural circuits, including long-term behavioral and physiological measurements. Deployment of these technologies reveals an unexpected role for stomach, non-stretch vagal sensory fibers in suppressing appetite and demonstrates the durability of the miniature wireless device inside harsh gastric conditions.


Obesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database.
Study Type - Prognosis (cohort series). Level of Evidence 2a. What's known on the subject? and What does the study add? The incidence and prevalence of obesity in the USA and Europe is increasing. Higher body mass index is associated with a lower risk of overall prostate cancer diagnosis but also with an increased risk of high grade prostate cancer. Obese men undergoing primary therapy with radical prostatectomy or external beam radiation are more likely to experience a biochemical recurrence after treatment compared with normal weight men. Finally, obesity is associated with increased prostate-cancer-specific mortality. We hypothesized that obese men on androgen deprivation therapy may be at increased risk for prostate cancer progression. Previous studies have shown that obese men have lower levels of testosterone compared with normal weight men. Additionally, one previous study found that obese men have higher levels of testosterone on androgen deprivation therapy. Men with higher levels of testosterone on androgen deprivation therapy are at increased risk of prostate cancer progression. We found that men with higher body mass index were at increased risk of progression to castration-resistant prostate cancer, development of metastases and prostate-cancer-specific mortality. When we adjusted for various clinicopathological characteristics, obese men were at increased risk of progression to castration-resistant prostate cancer and development of metastases. The results of our study help generate hypotheses for further study regarding the mechanisms between obesity and aggressive prostate cancer. • To investigate whether obesity predicts poor outcomes in men starting androgen deprivation therapy (ADT) before metastasis, since previous studies found worse outcomes after surgery and radiation for obese men. • A retrospective review was carried out of 287 men in the SEARCH database treated with radical prostatectomy between 1988 and 2009. • Body mass index (BMI) was categorized to <25, 25-29.9 and ≥ 30 kg/m2. • Proportional hazards models were used to test the association between BMI and time to castration-resistant prostate cancer (PC), metastases and PC-specific mortality adjusting for demographic and clinicopathological data. • During a median 73-month follow-up after radical prostatectomy, 403 men (14%) received early ADT. • Among 287 men with complete data, median BMI was 28.3 kg/m2. • Median follow-up from the start of ADT was 52 months during which 44 men developed castration-resistant PC, 34 developed metastases and 24 died from PC. • In multivariate analysis, higher BMI was associated with a trend for greater risk of progression to castration-resistant PC (P= 0.063), a more than threefold increased risk of developing metastases (P= 0.027) and a trend toward worse PC-specific mortality (P= 0.119). • Prognostic biomarkers did not differ between BMI groups. • Among men treated with early ADT, our results suggest that obese men may have increased risk of PC progression. • These data support the general hypothesis that obesity is associated with aggressive PC, although validation of these findings and further study of the mechanisms linking obesity and poor PC outcomes are required.


Stereochemical Elucidation of Natural Products from Residual Chemical Shift Anisotropies in a Liquid Crystalline Phase.
Determination of the stereochemistry of organic molecules still represents one of the major obstacles in the structure elucidation procedure in drug discovery. Although the application of residual dipolar couplings (RDCs) has revolutionized this field, residual chemical shift anisotropies (RCSAs) which contain valuable structural information for nonprotonated carbons have only been scarcely employed so far. In this study, we present a simple but highly effective solution to extract RCSAs of the analytes in a liquid crystalline phase formed by AAKLVFF oligopeptides. This method does not require any special instruments, devices, or correction during postacquisition data analysis and thus can be easily applied in any chemistry laboratory. To illustrate the potential of this method, the relative configurations of four known natural products (1-4) belonging to different structural classes were confirmed. Moreover, we unambiguously elucidated the stereochemistry of spiroepicoccin A (5), a rare thiodiketopiperazine marine natural product whose configuration could not be assigned based on conventional NMR methods.


Transient receptor potential vanilloid 4 activation constricts the human bronchus via the release of cysteinyl leukotrienes.
Prior studies have demonstrated that the ion channel transient receptor potential vanilloid 4 (TRPV4) is functionally expressed in airway smooth muscle cells and that TRPV4 single nucleotide polymorphisms are associated with airflow obstruction in patients with chronic obstructive pulmonary disease. We sought to use isometric tension measurements in ex vivo airways to determine whether short-term pharmacological activation of TRPV4 with the potent agonist GSK1016790 [N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide] would constrict human bronchial tissue. As predicted, transient receptor potential vanilloid 4 activation in the human airway produces contractions that are blocked by the nonselective transient receptor potential channel blocker ruthenium red. Moreover, the novel TRPV4-selective blocker GSK2334775 [(R)-6-(methylsulfonyl)-3-((4-(pyrrolidin-1-yl)piperindin-1-yl)methyl)-N-(2,2,2,-trifluoro-1-phenylethyl)-2-(3-(trifluoromethyl)phenyl)quinoline-4-carboxamide] inhibited these contractions over a concentration range consistent with its in vitro potency against recombinant and native TRPV4-containing channels. Surprisingly, TRPV4-dependent contractions were also blocked by a 5-lipoxygenase inhibitor and two structurally distinct cysteinyl leukotriene 1 receptor antagonists. In aggregate, our results fail to support the hypothesis that TRPV4 in airway smooth muscle cells regulates airway contractility short term. Rather, we provide pharmacological evidence that TRPV4 activation causes human airway constriction that is entirely dependent upon the production of cysteinyl leukotrienes. Together, these data identify a novel mechanism by which TRPV4 activation may contribute to pathologic remodeling and inflammation, in addition to airflow obstruction, in the diseased human respiratory tract.


Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis.
Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.


Effect of interlacing methods of stereoscopic displays on perceived image quality.
To provide two-eyed views with one device, stereoscopic 3D (S3D) displays interlace the two views either temporally or spatially: temporal interlacing (TI) alternates the two views in time with full resolution, while spatial interlacing (SI) presents the two views simultaneously but with half resolution for each eye. We investigate the effect of interlacing methods on image quality through a psychophysical experiment. We compared four experimental conditions: three S3D interlacing methods (TI, SI with raw sampling, and SI with vertical interpolation), and one nonconventional interlacing method (vertical interpolation). The stimuli were 10 natural stereo images presented at nine levels of pixel sizes (0.64, 0.78, 0.89, 1.00, 1.28, 1.55, 1.78, 2.00, and 2.56 arcmin). To test the effect of interlacing methods per se, we provided all the experimental conditions to the subjects using a single experimental setup: a mirror stereoscope. The results show that TI does not degrade the image quality for any pixel size. SI degrades the image quality when the pixel size is relatively large, but the effect of the two SI methods does not differ significantly. Comparison of SI methods against the vertical interpolation method implies that the primary cause of the degradation in image quality for SI methods is the visibility of the interlacing pattern rather than the loss of high-frequency information.


Health-e-child: an integrated biomedical platform for grid-based paediatric applications.
There is a compelling demand for the integration and exploitation of heterogeneous biomedical information for improved clinical practice, medical research, and personalised healthcare across the EU. The Health-e-Child project aims at developing an integrated healthcare platform for European Paediatrics, providing seamless integration of traditional and emerging sources of biomedical information. The long-term goal of the project is to provide uninhibited access to universal biomedical knowledge repositories for personalised and preventive healthcare, large-scale information-based biomedical research and training, and informed policy making. The project focus will be on individualized disease prevention, screening, early diagnosis, therapy and follow-up of paediatric heart diseases, inflammatory diseases, and brain tumours. The project will build a Grid-enabled European network of leading clinical centres that will share and annotate biomedical data, validate systems clinically, and diffuse clinical excellence across Europe by setting up new technologies, clinical workflows, and standards. This paper outlines the design approach being adopted in Health-e-Child to enable the delivery of an integrated biomedical information platform.


Multiple end-point analysis reveals cisplatin damage tolerance to be a chemoresistance mechanism in a NSCLC model: implications for predictive testing.
Systemic chemotherapy is extensively used in cancer therapy, however, for many treatments' response rates are limited. Furthermore, certain regimens are frequently associated with significant morbidity and occasional mortality. Consequently, when alternative options exist, it is desirable to reserve a particular chemotherapy for those patients whose tumours will respond. Therefore, attention is turning to the development of techniques that could provide predictive information regarding a tumour's particular chemosensitivity, as a means of enhancing patient selection for that specific treatment. One approach has been to focus on measures of DNA damage formation and repair as being potentially predictive of cancer cell chemosensitivity, the premise being that higher levels of induced DNA damage (resulting from the chemotherapeutic agents) and/or deficiencies in DNA damage repair are indicative of greater sensitivity. In the present study we have investigated the Comet assay response of a panel of non-small cell lung cancer cell lines towards cisplatin and found an inverse correlation between sensitivity and damage formation resulting from this agent. Moreover, an inverse correlation was found between resistance and extent of damage repair. Further analysis of multiple alternate cellular end-points (including cell cycle analysis, apoptosis and gene expression changes) revealed cisplatin damage tolerance to be a chemoresistance mechanism in this model system. This study highlights damage tolerance mechanisms as potentially confounding factors in attempts to develop predictive tests based on measures of genotoxicity. To address this we would argue that a range of multiple end-points should be analysed to ascertain the "complete predictive picture".


Health care use and costs for participants in a diabetes disease management program, United States, 2007-2008.
The Disease Management Association of America identifies diabetes as one of the chronic conditions with the greatest potential for management. TRICARE Management Activity, which administers health care benefits for US military service personnel, retirees, and their dependents, created a disease management program for beneficiaries with diabetes. The objective of this study was to determine whether participation intensity and prior indication of uncontrolled diabetes were associated with health care use and costs for participants enrolled in TRICARE's diabetes management program. This ongoing, opt-out study used a quasi-experimental approach to assess program impact for beneficiaries (n = 37,370) aged 18 to 64 living in the United States. Inclusion criteria were any diabetes-related emergency department visits or hospitalizations, more than 10 diabetes-related ambulatory visits, or more than twenty 30-day prescriptions for diabetes drugs in the previous year. Beginning in June 2007, all participants received educational mailings. Participants who agreed to receive a baseline telephone assessment and telephone counseling once per month in addition to educational mailings were considered active, and those who did not complete at least the baseline telephone assessment were considered passive. We categorized the diabetes status of each participant as "uncontrolled" or "controlled" on the basis of medical claims containing diagnosis codes for uncontrolled diabetes in the year preceding program eligibility. We compared observed outcomes to outcomes predicted in the absence of diabetes management. Prediction equations were based on regression analysis of medical claims for a historical control group (n = 23,818) that in October 2004 met the eligibility criteria for TRICARE's program implemented June 2007. We conducted regression analysis comparing historical control group patient outcomes after October 2004 with these baseline characteristics. Per-person total annual medical savings for program participants, calculated as the difference between observed and predicted outcomes, averaged $783. Active participants had larger reductions in inpatient days and emergency department visits, larger increases in ambulatory visits, and larger increases in receiving retinal examinations, hemoglobin A1c tests, and urine microalbumin tests compared with passive participants. Participants with prior indication of uncontrolled diabetes had higher per-person total annual medical savings, larger reduction in inpatient days, and larger increases in ambulatory visits than did participants with controlled diabetes. Greater intensity of participation in TRICARE's diabetes management program was associated with lower medical costs and improved receipt of recommended testing. That patients who were categorized as having uncontrolled diabetes realized greater program benefits suggests diabetes management programs should consider indication of uncontrolled diabetes in their program candidate identification criteria.


Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor h and factor h-related protein 1 to pentraxin 3.
Atypical hemolytic uremic syndrome (aHUS) is a renal disease associated with complement alternative pathway dysregulation and is characterized by endothelial injury. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule expressed by endothelial cells and upregulated under inflammatory conditions. PTX3 activates complement, but it also binds the complement inhibitor factor H. In this study, we show that native factor H, factor H-like protein 1, and factor H-related protein 1 (CFHR1) bind to PTX3 and that PTX3-bound factor H and factor H-like protein 1 maintain their complement regulatory activities. PTX3, when bound to extracellular matrix, recruited functionally active factor H. Residues within short consensus repeat 20 of factor H that are relevant for PTX3 binding were identified using a peptide array. aHUS-associated factor H mutations within this binding site caused a reduced factor H binding to PTX3. Similarly, seven of nine analyzed anti-factor H autoantibodies isolated from aHUS patients inhibited the interaction between factor H and PTX3, and five autoantibodies also inhibited PTX3 binding to CFHR1. Moreover, the aHUS-associated CFHR1*B variant showed reduced binding to PTX3 in comparison with CFHR1*A. Thus, the interactions of PTX3 with complement regulators are impaired by certain mutations and autoantibodies affecting factor H and CFHR1, which could result in an enhanced local complement-mediated inflammation, endothelial cell activation, and damage in aHUS.


Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients, the First Twelve Months of a Prospective Cohort Study.
Visceral leishmaniasis (VL) has become an important opportunistic infection in persons with HIV-infection in VL-endemic areas. The co-infection leads to profound immunosuppression and high rate of annual VL recurrence. This study assessed the effectiveness, safety and feasibility of monthly pentamidine infusions to prevent recurrence of VL in HIV co-infected patients. A single-arm, open-label trial was conducted at two leishmaniasis treatment centers in northwest Ethiopia. HIV-infected patients with a VL episode were included after parasitological cure. Monthly infusions of 4 mg/kg pentamidine-isethionate diluted in normal-saline were started for 12 months. All received antiretroviral therapy (ART). Time-to-relapse or death was the primary end point. Seventy-four patients were included. The probability of relapse-free survival at 6 months and at 12 months was 79% and 71% respectively. Renal failure, a possible drug-related serious adverse event, occurred in two patients with severe pneumonia. Forty-one patients completed the regimen taking at least 11 of the 12 doses. Main reasons to discontinue were: 15 relapsed, five died and seven became lost to follow-up. More patients failed among those with a CD4+cell count ≤ 50 cells/μl, 5/7 (71.4%) than those with counts above 200 cells/μl, 2/12 (16.7%), (p = 0.005). Pentamidine secondary prophylaxis led to a 29% failure rate within one year, much lower than reported in historical controls (50%-100%). Patients with low CD4+cell counts are at increased risk of relapse despite effective initial VL treatment, ART and secondary prophylaxis. VL should be detected and treated early enough in patients with HIV infection before profound immune deficiency installs.


Impact of Incline, Sex and Level of Performance on Kinematics During a Distance Race in Classical Cross-Country Skiing.
Here, female and male elite cross-country (XC) skiers were compared on varying terrain during an official 10-km (women) and 15-km (men) Norwegian championship race. On the basis of race performance, 82 skiers were classified as fast (FS) (20 women, 20 men) or slower (SS) (21, 21) skiers. All were video recorded on flat (0°), intermediate (3.5°), uphill (7.1°) and steep uphill (11°) terrain during the race at a distance of 0.8, 1.2, 2.1 and 7.1 km from the start, respectively. All skiers employed exclusively double-poling (DP) on the flat section and, except for the male winner, exclusively diagonal stride (DIA) on the uphill sections. On the intermediate section, more men than women utilized DP and fewer DIA (p = 0.001), with no difference in kick double-poling (DPK). More FS than SS utilized DPK and fewer DIA (p = 0.001), with similar usage of DP. Males skied with faster and longer cycles but lower cycle rate compared with females (p < 0.001), with largest absolute sex differences on flat terrain (p < 0.001) and largest relative differences for cycle velocity and length on intermediate and uphill terrain. External power output rose with increasing incline, being higher for men and FS (p < 0.001). Cycle velocity on flat terrain was the best predictor of mean race velocity for the men, while cycle velocity on steep uphill was the best predictor for the women (both p < 0.001). In conclusion, incline, sex and level of performance influenced cycle characteristics and power output. Greatest absolute sex gap was on flat terrain, whereas the relative difference was greatest on intermediate and steep uphill terrain. We recommend usage of more DP and/or DPK, and less DIA and fewer transitions between techniques on intermediate terrain. Predictors of race performance are sex specific with greatest potential for enhancing performance on flat terrain for men and on steep uphill terrain for women.


Effects on growth of single short courses of fluoroquinolones.
The aim of the study was to document the effects of short courses of fluoroquinolones given during an outbreak of multidrug resistant typhoid fever in southern Viet Nam on the growth of children over a period of two years. In a prospective cohort study, 326 Vietnamese children aged between 1 and 14 years were followed up for two years after receiving either ciprofloxacin (70 mg/kg given over 7 d) (n = 173) or ofloxacin (45-50 mg/kg given over 3-5 d) (n = 153) for suspected typhoid fever. Growth velocity and weight for height were compared with an age matched control group of children from the same locality (n = 223) who had not contracted typhoid or received any fluoroquinolones. In the ofloxacin and ciprofloxacin treated patients there was no evidence of acute joint toxicity, nor of any joint symptoms attributable to either of the fluoroquinolones. There was no difference in expected weight for height measurements between the three groups of children over the two year period. During the first year, height velocity in ciprofloxacin treated children was greater than in either ofloxacin treated children or untreated controls. Height velocity in the latter two groups was not significantly different. After two years height velocity was similar in the three groups. The results support the use of short course fluoroquinolone treatment in childhood typhoid, especially when caused by strains resistant to other antibiotics.


Field trial of an outer surface protein A (OspA) antigen-capture enzyme-linked immunosorbent assay (ELISA) to detect Borrelia burgdorferi in Ixodes scapularis.
Field-collected adult male Ixodes scapularis from Westchester County, New York were bisected and Borrelia burgdorferi infection rates were ascertained by both a direct fluorescent antibody test and an outer surface protein A (OspA) antigen-capture enzyme-linked immunosorbent assay (ELISA). Both assays gave identical antigen positivity rates with 89% concordance between the two assays. Storing dried ticks before ELISA analysis had no significant effect on the ability of the ELISA to determine the presence of OspA compared with assaying live ticks. The OspA antigen positivity rate for dried ticks was 49% compared with 53% for live ticks, with mean OspA antigen spirochete equivalents of 3,388 and 2,823 for dried and live ticks, respectively.


Persistence of single species of symbionts across multiple closely-related host species.
Some symbiont species are highly host-specific, inhabiting only one or a very few host species, and typically have limited dispersal abilities. When they do occur on multiple host species, populations of such symbionts are expected to become genetically structured across these different host species, and this may eventually lead to new symbiont species over evolutionary timescales. However, a low number of dispersal events of symbionts between host species across time might be enough to prevent population structure and species divergence. Overall, processes of evolutionary divergence and the species status of most putative multi-host symbiont systems are yet to be investigated. Here, we used DNA metabarcoding data of 6,023 feather mites (a total of 2,225 OTU representative sequences) from 147 infracommunities (i.e., the assemblage consisting of all mites of different species collected from the same bird host individual) to investigate patterns of population genetic structure and species status of three different putative multi-host feather mite species Proctophyllodes macedo Vitzthum, 1922, Proctophyllodes motacillae Gaud, 1953, and Trouessartia jedliczkai (Zimmerman, 1894), each of which inhabits a variable number of different closely related wagtail host species (genus Motacilla). We show that mite populations from different host species represent a single species. This pattern was found in all the mite species, suggesting that each of these species is a multi-host species in which dispersal of mites among host species prevents species divergence. Also, we found evidence of limited evolutionary divergence manifested by a low but significant level of population genetic structure among symbiont populations inhabiting different host species. Our study agrees with previous studies showing a higher than expected colonization opportunities in host-specific symbionts. Indeed, our results support that these dispersal events would allow the persistence of multi-host species even in symbionts with limited dispersal capabilities, though additional factors such as the geographical structure of some bird populations may also play a role.


MERS versus Standard Surgical Approaches for Porcine Vocal Fold Scarring with Adipose Stem Cell Constructs.
Cells, scaffold, and surgical approaches are important for regeneration of the lamina propria of the scarred vocal fold (VF). Microendoscopy of Reinke's space (MERS) is a surgical approach used to access the lamina propria. The present study evaluated MERS in the treatment of VF scarring as compared with standardized approaches for the treatment of VF scarring with adipose stem cell constructs. Animal study. Academic center. VF injury was performed bilaterally to induce scarring in 20 pigs. Eight weeks after injury, pigs were classified into no treatment, minithyrotomy, VF injection, VF incision/dissection, and MERS. All groups (except control) were implanted with adipose stem cell and hyaluronan. Four weeks after treatment, histology for collagen, hyaluronan, and fibronectin; mRNA expression for α-smooth muscle actin, tumor growth factor β1, collagen 1α1, collagen 3α1, matrix metalloproteinase 2, basic fibroblast growth factor, and hepatocyte growth factor; and tissue rheology were evaluated. Differences were measured among surgical approaches for protein levels of collagen, hyaluronan, and fibronectin (P = .0133, P < .0001, and P = .0025, respectively). Fibroblast growth factor, collagen 1α1, and matrix metalloproteinase 2 transcript levels were different among treatment groups (P = .003, P = .0086, and P = .014, respectively), while no differences were measured for α-smooth muscle actin, tumor growth factor β1, hepatocyte growth factor, and collagen 3α1. Rheologically, significant differences were not measured between groups. MERS is a promising surgical approach for the treatment of VF scarring, optimizing the placement of implanted biomaterials.


SPINK1 and PRSS1 mutations in benign pancreatic hyperenzymemia.
The aim of this study was to determine whether mutations in SPINK1/PRSS1 genes are associated with benign pancreatic hyperenzymemia (BPH). Sixty-eight subjects with BPH (including 13 familial cases) were studied. In all, we sequenced germline DNA for all the exons and intro-exon boundaries of PRSS1 and SPINK1. Nine (13.2%) of the 68 subjects harbored PRSS1 or SPINK1 mutations. As to PRSS1, no hereditary pancreatitis-associated variant was detected, whereas previously undescribed mutations (p.Ala148Val and c.40+1G>A) were respectively found in 2 subjects (2.9%). SPINK1 mutations were detected in 7 subjects (10.3%). Five of them exhibited known mutations (3 p.Asn34Ser, 1 p.Pro55Ser, and 1 c.88-23A>T), whereas 2 had a newly found variant (p.Arg67Gly and c.*32C>T, respectively). Only 2 familial BPH, belonging to 2 different families, were found to carry a mutation (1 with p.Ala148Val for PRSS1 and 1 with p.Asn34Ser for SPINK1). No known mutations of PRSS1 have been found in BPH, whereas the frequency of known SPINK1 variants is similar to that reported in the general population. No segregation of PRSS1/SPINK1 variants occurs in BPH families. Benign pancreatic hyperenzymemia cannot be explained by mutations in genes whose variants are known to be associated with pancreatitis or by mutations in other PRSS1/SPINK1 genes.


Role of gap junction channel in the development of beat-to-beat action potential repolarization variability and arrhythmias.
The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling. Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR. Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.


Interventions for providers to promote a patient-centred approach in clinical consultations.
Communication problems in health care may arise as a result of health care providers focusing on diseases and their management, rather than people, their lives and their health problems. Patient-centred approaches to care are increasingly advocated by consumers and clinicians and incorporated into training for health care providers. The effects of interventions that aim to promote patient-centred care need to be evaluated. To assess the effects of interventions for health care providers that aim to promote patient-centred approaches in clinical consultations. We searched Medline (1966 - Dec 1999); Health Star (1975 - Dec 1999); PsycLit (1887- Dec 1999); Cinahl (1982 - Dec 1999); Embase (1985-Dec 1999) and the bibliographies of studies assessed for inclusion. Randomised controlled trials, controlled clinical trials, controlled before and after studies, and interrupted time series studies of interventions for health care providers that promote patient-centred care in clinical consultations. Patient-centred care was defined as a philosophy of care that encourages: (a) shared control of the consultation, decisions about interventions or management of the health problems with the patient, and/or (b) a focus in the consultation on the patient as a whole person who has individual preferences situated within social contexts (in contrast to a focus in the consultation on a body part or disease). The participants were health care providers, including those in training. Two reviewers independently extracted data onto a standard form and assessed study quality for each study. We extracted all outcomes other than health care providers' knowledge, attitudes and intentions. 17 studies met the inclusion criteria. These studies display considerable heterogeneity in terms of the interventions themselves, the health problems or health concerns on which the interventions focused, the comparisons made and the outcomes assessed. All included studies used training for health care providers as an element of the intervention. Ten studies evaluated training for providers only, while the remaining studies utilised multi-faceted interventions where training for providers was one of several components. The health care providers were mainly primary care physicians (general practitioners or family doctors) practising in community or hospital outpatient settings. In two studies, the providers also included nurses. There is fairly strong evidence to suggest that some interventions to promote patient-centred care in clinical consultations may lead to significant increases in the patient centredness of consultation processes. 12 of the 14 studies that assessed consultation processes showed improvements in some of these outcomes. There is also some evidence that training health care providers in patient-centred approaches may impact positively on patient satisfaction with care. Of the eleven studies that assessed patient satisfaction, six demonstrated significant differences in favour of the intervention group on one or more measures. Few studies examined health care behaviour or health status outcomes. Interventions to promote patient-centred care within clinical consultations may significantly increase the patient centredness of care. However, there is limited and mixed evidence on the effects of such interventions on patient health care behaviours or health status; or on whether these interventions might be applicable to providers other than physicians. Further research is needed in these areas.


Palm oil tocotrienol fractions restore endothelium dependent relaxation in aortic rings of streptozotocin-induced diabetic and spontaneously hypertensive rats.
Diabetes and hypertension are closely associated with impaired endothelial function. Studies have demonstrated that regular consumption of edible palm oil may reverse endothelial dysfunction. The present study investigates the effect of palm oil fractions: tocotrienol rich fraction (TRF), alpha-tocopherol and refined palm olein (vitamin E-free fraction) on the vascular relaxation responses in the aortic rings of streptozotocin-induced diabetic and spontaneously hypertensive rats (SHR). We hypothesize that the TRF and alpha-tocopherol fractions are able to improve endothelial function in both diabetic and hypertensive rat aortic tissue. A 1,1-diphenyl picryl hydrazyl assay was performed on the various palm oil fractions to evaluate their antioxidant activities. Endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) relaxations were examined on streptozotocin-induced diabetic and SHR rat aorta following preincubation with the different fractions. In 1-diphenyl picryl hydrazyl antioxidant assay, TRF and alpha-tocopherol fractions exhibited a similar degree of activity while palm olein exhibited poor activity. TRF and alpha-tocopherol significantly improved acetylcholine-induced relaxations in both diabetic (TRF, 88.5% +/- 4.5%; alpha-tocopherol, 87.4% +/- 3.4%; vehicle, 65.0 +/- 1.6%) and SHR aorta (TRF, 72.1% +/- 7.9%; alpha-tocopherol, 69.8% +/- 4.0%, vehicle, 51.1% +/- 4.7%), while palm olein exhibited no observable effect. These results suggest that TRF and alpha-tocopherol fractions possess potent antioxidant activities and provide further support to the cardiovascular protective effects of palm oil vitamin E. TRF and alpha-tocopherol may potentially improve vascular endothelial function in diabetes and hypertension by their sparing effect on endothelium derived nitric oxide bioavailability.


Mechanisms of dynamic nuclear polarization in insulating solids.
Dynamic nuclear polarization (DNP) is a technique used to enhance signal intensities in NMR experiments by transferring the high polarization of electrons to their surrounding nuclei. The past decade has witnessed a renaissance in the development of DNP, especially at high magnetic fields, and its application in several areas including biophysics, chemistry, structural biology and materials science. Recent technical and theoretical advances have expanded our understanding of established experiments: for example, the cross effect DNP in samples spinning at the magic angle. Furthermore, new experiments suggest that our understanding of the Overhauser effect and its applicability to insulating solids needs to be re-examined. In this article, we summarize important results of the past few years and provide quantum mechanical explanations underlying these results. We also discuss future directions of DNP and current limitations, including the problem of resolution in protein spectra recorded at 80-100 K.


Over-use of thyroid testing in Canadian and UK primary care in frequent attenders: A cross-sectional study.
Thyroid-stimulating hormone (TSH) is a common test used to detect and monitor clinically significant hypo- and hyperthyroidism. Population-based screening of asymptomatic adults for thyroid disorders is not recommended. The research objectives were to determine patterns of TSH testing in Canadian and English primary care practices, as well as patient and physician practice characteristics associated with testing TSH for primary care patients with no identifiable indication. In this 2-year cross-sectional observational study, Canadian and English electronic medical record databases were used to identify patients and physician practices. Cohorts of patients aged 18 years or older, without identifiable indications for TSH testing, were generated from these databases. Analyses were performed using a random-effects logistic regression to determine patient and physician practice characteristics associated with increased testing. We determined the proportion of TSH tests performed concurrently with at least one common screening blood test (lipid profile or hemoglobin A1c). Standardised proportions of TSH test per family practice were used to examine the heterogeneity in the populations. At least one TSH test was performed in 35.97% (N = 489 663) of Canadian patients and 29.36% (N = 1 030 489) of English patients. Almost all TSH tests in Canada and England (95.69% and 99.23% respectively) were within the normal range (0.40-5.00 mU/L). A greater number of patient-physician encounters was the strongest predictor of TSH testing. It was determined that 51.40% of TSH tests in Canada and 76.55% in England were performed on the same day as at least one other screening blood test. There was no association between the practice size and proportion of asymptomatic patients tested. This comparative binational study found TSH patterns suggestive of over-testing and potentially thyroid disorder screening in both countries. There may be significant opportunities to improve the appropriateness of TSH ordering in Canada and England and therefore improve the allocation of limited system resources.