Quantification of Pulse-Dependent Trabecular Meshwork Motion in Normal Humans Using Phase-Sensitive OCT.
The purpose of this study was to characterize the pulsatile motion of trabecular meshwork (TM) in normal subjects and demonstrate its changes in accommodation with phase-sensitive optical coherence tomography (PhS-OCT). A new PhS-OCT laboratory prototype was designed to measure pulsatile TM motion in 13 healthy humans. Two sets of images were captured in 10 subjects, first with best corrective refraction and the other with an additional 3.0 diopters of accommodation. In each image, both maximum velocity (MV) and cumulative displacement (CD) in two selected regions of TM, the internal (IMV and ICD) and external (EMV and ECD) region, were measured. For all parameters the intraclass correlation coefficient was >0.75. Neither MV nor CD was significantly different between eyes in individual subjects (PIMV = 0.967, PEMV = 0.391, PICD = 0.603, PECD = 0.482). In 26 eyes, with best corrective refraction, the EMV was higher than the IMV (23.9 ± 9.8 vs. 18.9 ± 8.08 μm/s; P = 0.0001), as was the ECD compared with the ICD (0.340 ±0.125 vs. 0.264 ± 0.111 μm; P = 0.000004). With accommodation, MV and CD significantly increased (PIMV = 0.0003, PEMV = 0.0003, PICD = 0.019, and PECD = 0.007), whereas MV and CD in the external region were still larger than those in the internal area (PEMV vs. IMV = 0.009, PECD vs. ICD = 0.023). This study demonstrates the differences in TM motion between the internal and external regions of TM and displays its change with accommodation. The findings and good reproducibility suggest PhS-OCT helps to understand TM function in regulation of IOP, and, with further refinements, it may be useful in clinical management of glaucoma.


An oral health literacy intervention for Indigenous adults in a rural setting in Australia.
Indigenous Australians suffer substantially poorer oral health than their non-Indigenous counterparts and new approaches are needed to address these disparities. Previous work in Port Augusta, South Australia, a regional town with a large Indigenous community, revealed associations between low oral health literacy scores and self-reported oral health outcomes. This study aims to determine if implementation of a functional, context-specific oral health literacy intervention improves oral health literacy-related outcomes measured by use of dental services, and assessment of oral health knowledge, oral health self-care and oral health- related self-efficacy. This is a randomised controlled trial (RCT) that utilises a delayed intervention design. Participants are Indigenous adults, aged 18 years and older, who plan to reside in Port Augusta or a nearby community for the next two years. The intervention group will receive the intervention from the outset of the study while the control group will be offered the intervention 12 months following their enrollment in the study. The intervention consists of a series of five culturally sensitive, oral health education workshops delivered over a 12 month period by Indigenous project officers. Workshops consist of presentations, hands-on activities, interactive displays, group discussions and role plays. The themes addressed in the workshops are underpinned by oral health literacy concepts, and incorporate oral health-related self-efficacy, oral health-related fatalism, oral health knowledge, access to dental care and rights and entitlements as a patient. Data will be collected through a self-report questionnaire at baseline, at 12 months and at 24 months. The primary outcome measure is oral health literacy. Secondary outcome measures include oral health knowledge, oral health self-care, use of dental services, oral health-related self-efficacy and oral health-related fatalism. This study uses a functional, context-specific oral health literacy intervention to improve oral health literacy-related outcomes amongst rural-dwelling Indigenous adults. Outcomes of this study will have implications for policy and planning by providing evidence for the effectiveness of such interventions as well as provide a model for working with Indigenous communities.


CyclinG1 Amplification Enhances Aurora Kinase Inhibitor-Induced Polyploid Resistance and Inhibition of Bcl-2 Pathway Reverses the Resistance.
CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.


Effect of pigment epithelium-derived factor on glutamate uptake in retinal Muller cells under high-glucose conditions.
A predominant function of Müller cells is to regulate glutamate levels, but it is compromised in diabetic retinopathy (DR). The present study was performed to determine the role of pigment epithelium-derived factor (PEDF) in glutamate uptake in retinal Müller cells in high-glucose conditions. The levels of Kir4.1, PEDF, and GLAST in retinal Müller cells in high-glucose conditions were analyzed by Western blot analysis and real-time RT-PCR, and a glutamate uptake assay was undertaken to investigate the activity of GLAST. Intracellular reactive oxygen species (ROS) generation was measured, and a glutathione peroxidase (GPx) activity assay was performed to determine oxidative stress in the presence of high glucose. After being treated with PEDF in high-glucose conditions, these proteins (Kir4.1 and GLAST) and their mRNAs, glutamate uptake activity, and oxidative stress in Müller cells were investigated. A PEDF siRNA method was used to confirm the effect of PEDF on glutamate uptake activity in Müller cells. In high-glucose conditions, glutamate uptake and Kir4.1, PEDF, and GLAST expression in Müller cells decreased significantly. Simultaneously, ROS generation increased, and GPx activity decreased. PEDF treatment inhibited the high-glucose-induced decreases in glutamate uptake and in Kir4.1 and GLAST expression and ameliorated oxidative stress. Moreover, downregulation of PEDF expression by siRNA in Müller cells resulted in decreases in glutamate uptake, Kir4.1 and GLAST expression, and induced oxidative stress. These findings suggest that PEDF acts as an antioxidative agent against the decrease in Kir4.1 and GLAST expression and compromise of glutamate uptake activity in retinal Müller cells in diabetic conditions.


Anemia and growth status in pediatric patients receiving maintenance dialysis after a failed renal transplant course: an NAPRTCS report.
We conducted a retrospective review of the North American Renal Transplant Cooperative Study (NAPRTCS) Registry transplant and dialysis arms to assess anemia and growth patterns in children who returned to dialysis after a failed renal transplant from January 1, 1992 to February 3, 2004. Of the 1807 potential study subjects, 1451 had transplant removal data (TxIn vs. TxOut) available for analysis. Four hundred and twenty-one of 1451 patients (29%) had a transplant nephrectomy at the time of entry into the NAPRTCS Registry Dialysis arm. Anemia rates steadily decreased from 72.2% at 30 days after dialysis initiation to 59.5% at 12 months after dialysis initiation. Factors associated with anemia at 30 days after dialysis initiation included hemodialysis, lack of Epo use, and patients who comprised earlier study era cohorts. At one yr after return to dialysis, earlier study cohort era was the only factor associated with anemia status. Patients did not demonstrate significant improvement in height SDS over the course of the study (-2.17 at day 30 to -2.32 at 24 months). The high anemia, poor growth, and low recombinant human growth hormone utilization rates in a group of patients followed longitudinally as they transition from renal transplant to dialysis should cause the pediatric nephrology community to reassess the processes in place to provide optimal care to pediatric end-stage renal disease patients.


The Burkholderia cenocepacia K56-2 pleiotropic regulator Pbr, is required for stress resistance and virulence.
Burkholderia cenocepacia is one of the most virulent species of the Burkholderia cepacia complex, a group of bacteria that emerged as important pathogens, especially to cystic fibrosis (CF) patients. In this study, we report the identification and characterization of a mutant strain derived form the CF isolate Burkholderia cenocepacia K56-2, carrying a plasposon insertion in a gene, located in a 3516 bp chromosomal region with an atypical G+C content, encoding a 80 amino acid putative regulatory protein named Pbr. Besides its inability to produce phenazines, the B. cenocepacia K56-2 pbr mutant exhibited a pleiotropic phenotype, including impaired survival to oxidative and osmotic stress, aromatic amino acid and prolonged nutrient starvation periods. In addition, the pbr mutant exhibited decreased virulence the nematode Caenorhabditis elegans. Altogether, our results demonstrate the involvement of Pbr on the regulation of phenazine biosynthesis, and an important role for this regulatory protein on several cellular processes related to stress resistance and virulence.


White syndrome in Acropora muricata: nonspecific bacterial infection and ciliate histophagy.
Selective antibiotic treatment of white syndrome (WS)-affected corals (Acropora muricata) from Fiji was used to identify 3 potential bacterial pathogens of the disease. Interestingly, the suite of bacterial associates of the disease was different to that recently identified using identical primer sets for WS on the GBR and in the Solomon Islands. In addition to the three bacterial pathogenic candidates and as previously shown for WS and more recently for white band disease (WBD) in the Caribbean, all samples of the disease were specifically associated with the histophagous ciliate Philaster lucinda. From the pattern of disease progression and histopathology in relation to the selective elimination of microbial groups, we conclude that these 'white' diseases are a result of a nonspecific bacterial infection and a 'secondary' infection by the P. lucinda ciliate. Although we have not observed the initiation of infection, a nonspecific, multispecies bacterial infection appears to be a corequirement for WS lesion progression and we hypothesize that the bacterial infection occurs initially, weakening the defences of the host to predation by the ciliates. Such ciliate histophagy gives rise to the characteristic white band of denuded coral skeleton that gives these diseases their names. The characteristics of the microbial communities of WBD and WS appear identical, and since the bacterial associates of WS vary geographically (and/or temporally), there appears to be no logical distinction between WS in the Indo-Pacific and WBD in the Caribbean.


Defining regions and rearrangements of the Silene latifolia Y chromosome.
We combine data from published marker genotyping of three sets of S. latifolia Y chromosome deletion mutants with changed sex phenotypes and add genotypes for several new genic markers to refine the deletion map of the Y chromosome and compare it with the X chromosome genetic map. We conclude that the Y chromosome of this species has been derived through multiple rearrangements of the ancestral gene arrangement and that none of the rearrangements so far detected was involved in stopping X-Y recombination. Different Y genotypes may also differ in their gene content and possibly arrangements, suggesting that mapping the Y-linked sex-determining genes will be difficult, even if many further genic markers are obtained. Even in determining the map of Y chromosome markers to discover all the rearrangements, physical mapping by FISH or other experiments will be essential. Future deletion mapping work should ensure that markers are studied in the parents of deletion mutants and should probably include additional deletions that were not ascertained by causing mutant sex phenotypes.


Role of conserved residues within the carboxy phosphate domain of carbamoyl phosphate synthetase.
Carbamoyl phosphate synthetase (CPS) catalyzes the formation of carbamoyl phosphate from glutamine, bicarbonate, and 2 mol of MgATP. The heterodimeric protein is composed of a small amidotransferase subunit and a larger synthetase subunit. The synthetase subunit contains a large tandem repeat for each of the nucleotides used in the overall synthesis of carbamoyl phosphate. A working model for the three-dimensional fold of the carboxy phosphate domain of CPS was constructed on the basis of amino acid sequence alignments and the X-ray crystal structure coordinates for biotin carboxylase and D-alanine:D-alanine ligase. This model was used to select ten residues within the carboxy phosphate domain of CPS for modification and subsequent characterization of the kinetic constants for the mutant proteins. Residues R82, R129, R169, D207, E215, N283, and Q285 were changed to alanine residues; residues E299 and R303 to glutamine; and residue N301 to aspartate. No significant changes in the catalytic constants were observed upon mutation of either R82 or D207, and thus these residues appear to be nonessential for binding and/or catalytic activity. The Michaelis constant for ATP was most affected by modification of residues R129, R169, Q285, and N301. The binding of bicarbonate was most affected by the mutagenesis of residues E215, E299, N301, and R303. The mutation of residues E215, N283, E299, N301, and R303 resulted in proteins which were unable to synthesize carbamoyl phosphate at a significant rate. All of the mutations, with the exception of the N301D mutant, primarily affected the enzyme by altering the step for the phosphorylation of bicarbonate. However, mutation of N301 to aspartic acid also disrupted the catalytic step involved in the phosphorylation of carbamate. These results are consistent with a role for the N-terminal half of the synthetase subunit of CPS that is primarily directed at the initial phosphorylation of bicarbonate by the first ATP utilized in the overall synthesis of carbamoyl phosphate. The active site structure appears to be very similar to the ones previously determined for D-alanine:D-alanine ligase and biotin carboxylase.


Pathogenic mechanisms underlying the clinical symptoms of allergic rhinitis.
This paper reviews our previous studies on an objective evaluation of nasal symptoms, a quantitative determination of biochemical mediators, and inflammatory cells in nasal secretions of atopic patients after nasal allergen challenge (NAC) and during natural allergen exposure. The use of the microsuction technique has proved to be a useful and reliable nasal sampling method permitting quantitative analysis of important mediators in nasal secretions. This has provided accurate data on the activity of some important inflammatory cells such as mast cells, basophils, and eosinophils in allergic rhinitis. Our studies demonstrate that a significant increase in the concentrations of histamine, tryptase, and LTC4 in nasal secretions occurs within seconds or minutes after NAC, and this is accompanied by itching, sneezing, rhinorrhea, and nasal obstruction. The infiltration and activation of eosinophils are found to be the predominant condition during the late-phase reaction (LPR), which is mainly characterized by unilateral and/or bilateral nasal obstruction with little sneezing and rhinorrhea. The latter condition is found to be very much similar to the pathophysiology of patients with ongoing allergic rhinitis. In conclusion, our studies demonstrate that patients with ongoing allergic rhinitis seem to be in a continuous late phase state of eosinophilia and increased mediator release, a condition that can explain priming and nonspecific hyperreactivity of the nasal mucous membrane.


Declining trends in serum cotinine levels in US worker groups: the power of policy.
To explore trends in cotinine levels in US worker groups. Using NHANES III data, serum cotinine levels of US workers not smokers nor exposed to secondhand smoke (SHS) at home were evaluated for trends by occupational/industrial and race/ethnicity-gender sub-groups. Decreases from 1988 to 2002 ranged from 0.08 to 0.30 ng/mL (67% to 85% relative decrease), with largest absolute reductions in: blue-collar and service occupations; construction/manufacturing industrial sectors; non-Hispanic Black male workers. All worker groups had declining serum cotinine levels. Most dramatic reductions occurred in sub-groups with the highest before cotinine levels, thus disparities in SHS workforce exposure are diminishing with increased adoption of clean indoor laws. However, Black male workers, construction/manufacturing sector workers, and blue-collar and service workers have the highest cotinine levels. Further reductions in SHS exposure will require widespread adoption of workplace clean air laws without exemptions.


Density Distribution of Pharyngeal Carriage of Meningococcus in Healthy Young Adults: New Approaches to Studying the Epidemiology of Colonization and Vaccine Indirect Effects.
Improved understanding of Neisseria meningitidis (Nm) carriage biology and better methods for detection and quantification would facilitate studies of potential impact of new vaccines on colonization and transmission in adolescents. We performed plate cultures on 107 oropharyngeal swabs stored frozen in skim milk tryptone glucose glycerol (STGG) broth and previously positive for Nm. We compared quantitative polymerase chain reaction (qPCR) detection of Nm in 601 STGG-swabs with culture. Using qPCR (n = 87), a log-phase broth culture standard curve and semiquantitative plate cultures (n = 68), we measured density of carriage. We compared qPCR genogrouping of DNA extracts from STGG-swabs and from plate culture lawns (n = 110) with purified isolates (n = 80). Swab storage resulted in only 10% loss of culture sensitivity. Direct sodC qPCR Nm detection yielded more positives (87/601, 14.5%) than culture (80/601, 13.3%). Most samples (57/110) positive by culture were also positive by qPCR and vice versa, but discrepancies (single positives) were frequent among low-density samples. sodC qPCR was positive in 79/80 isolates but in only 65 by ctrA qPCR. Density both by culture and qPCR varied across 4 orders of magnitude with the majority being low (<50 bacteria-gene copies/mL) and a minority being high (>1000). Genogrouping qPCRs yielded more positive results when performed on DNA extracts from lawn cultures. We provide the first description of the distribution of Nm carriage density. This could be important for understanding transmission dynamics and population-level effectiveness of adolescent vaccine programs. Storage of swabs frozen in STGG for batched laboratory analysis facilitates carriage studies and direct sodC qPCR for Nm combined with qPCR genogrouping of lawn culture extracts provides accurate, detailed description of colonization.


Effect of CYP2C9 and VKORC1 Gene Variants on Warfarin Response in Patients with Continuous-Flow Left Ventricular Assist Devices.
Bleeding and thrombotic complications continue to plague continuous-flow left ventricular assist device (CF-LVAD) therapy in patients with end-stage heart failure. Warfarin genotyping information can be incorporated into decision making for initial dosing as recommended by the Food and Drug Administration; however, clinical utility of this data in the CF-LVAD population has not been well studied. Genotypes testing for CYP2C9 and VCORC1 polymorphisms were determined in 90 CF-LVAD patients. Outcomes studied were the association of CYP2C9 (*1, *2, or *3) and VKORC1 (-1639 G>A) gene variants with time-to-target international normalized ratio (INR), total warfarin dose, maintenance warfarin dose. Continuous-flow left ventricular assist device patients carrying a rare variant in the VKORC1 gene had a significantly lower cumulative warfarin dose until target INR achieved (18.9 vs. 35.0 mg, p = 0.002), days spent until INR target achieved (4.9 vs. 7.0 days, p = 0.021), and discharge warfarin dose (3.2 vs. 5.6 mg, p = 0.001) compared with patients with wild-type genotype. Genotype-guided warfarin dosing may lead to safer anticoagulation and potentially improve outcomes in CF-LVAD patients.


A morphological study of chronic cerebral toxoplasmosis in mice: comparison of four different strains of Toxoplasma gondii.
The pathological changes, host-parasite relationship and structure of the tissue cysts in the brains of mice chronically infected with four different strains of Toxoplasma gondii were examined by light and electron microscopy. In mice infected with the mouse-adapted ME49 strain for 4, 8, 12, 16 and 25 weeks, the pathological changes consisted of moderate to severe meningitis and cuffing of blood vessels by inflammatory cells. At 4 weeks post-infection (p.i.), lymphocytes were the major cell type, but at later time points, plasma cells predominated. Large numbers of cysts were observed at between 4 and 12 weeks p.i., with a decrease being seen at 16 weeks p.i. Microglial nodules, many containing tachyzoites or bradyzoites, were present at all time points. In contrast, the three strains isolated from patients with the acquired immune deficiency syndrome (AIDS) resulted in no meningitis in two cases (DEY, DAG) and in mild meningitis in one case (WIL), although all three showed some cuffing of blood vessels. In addition, only very low numbers of cysts and nodules were observed. Ultrastructurally, the cysts of all four strains were seen to be located within host cells. The cysts of the ME49 strain differed from those of the other strains in that a proportion contained immature and dividing bradyzoites at all time points, whereas those of the other strains contained only mature bradyzoites. From the observation of nodules with parasites and cysts with immature zoites, it would appear that the ME49 strain may result in an unstable chronic infection with a continuous turnover of cysts, a feature that should be taken into consideration when this strain is used as an experimental model of chronic toxoplasmosis.


Previous exposure to intact speech increases intelligibility of its digitally degraded counterpart as a function of stimulus complexity.
Recent studies have shown that acoustically distorted sentences can be perceived as either unintelligible or intelligible depending on whether one has previously been exposed to the undistorted, intelligible versions of the sentences. This allows studying processes specifically related to speech intelligibility since any change between the responses to the distorted stimuli before and after the presentation of their undistorted counterparts cannot be attributed to acoustic variability but, rather, to the successful mapping of sensory information onto memory representations. To estimate how the complexity of the message is reflected in speech comprehension, we applied this rapid change in perception to behavioral and magnetoencephalography (MEG) experiments using vowels, words and sentences. In the experiments, stimuli were initially presented to the subject in a distorted form, after which undistorted versions of the stimuli were presented. Finally, the original distorted stimuli were presented once more. The resulting increase in intelligibility observed for the second presentation of the distorted stimuli depended on the complexity of the stimulus: vowels remained unintelligible (behaviorally measured intelligibility 27%) whereas the intelligibility of the words increased from 19% to 45% and that of the sentences from 31% to 65%. This increase in the intelligibility of the degraded stimuli was reflected as an enhancement of activity in the auditory cortex and surrounding areas at early latencies of 130-160ms. In the same regions, increasing stimulus complexity attenuated mean currents at latencies of 130-160ms whereas at latencies of 200-270ms the mean currents increased. These modulations in cortical activity may reflect feedback from top-down mechanisms enhancing the extraction of information from speech. The behavioral results suggest that memory-driven expectancies can have a significant effect on speech comprehension, especially in acoustically adverse conditions where the bottom-up information is decreased.


Improving pulse detection in multibin photon-counting detectors.
Energy-discriminating, photon-counting (EDPC) detectors are attractive for their potential for improved detective quantum efficiency and for their spectral imaging capabilities. However, at high count rates, counts are lost, the detected spectrum is distorted, and the advantages of EDPC detectors disappear. Existing EDPC detectors identify counts by analyzing the signal with a bank of comparators. We explored alternative methods for pulse detection for multibin EDPC detectors that could improve performance at high count rates. The detector signal was simulated in a Monte Carlo fashion assuming a bipolar shape and analyzed using several methods, including the conventional bank of comparators. For example, one method recorded the peak energy of the pulse along with the width (temporal extent) of the pulse. The Cramer-Rao lower bound of the variance of basis material estimates was numerically found for each method. At high count rates, the variance in water material (bone canceled) measurements could be reduced by as much as an order of magnitude. Improvements in virtual monoenergetic images were modest. We conclude that stochastic noise in spectral imaging tasks could be reduced if alternative methods for pulse detection were utilized.


Developmental potential of CD4-8- thymocytes. Peripheral progeny include mature CD4-8- T cells bearing alpha beta T cell receptor.
We have used the intra-thymic transfer system to investigate the population dynamics of thymocyte and mature T cell subsets in the absence of continuing precursor input from the bone marrow. We have followed the development and life span of CD4+ and CD8+ thymocyte subsets and mature peripheral T cells from intra-thymically injected adult or fetal CD4-8- thymic precursors. Both precursor types proliferated, differentiated, and exported to peripheral lymphoid tissues alpha beta-TCR+CD4+8- and CD4-8+ progeny which formed a stable, long-lived component of the peripheral T cell pool. The production of phenotypically mature thymocytes and peripheral T cells occurred more rapidly from fetal CD4-8- precursors. CD4+8-:CD4-8+ ratios among peripheral progeny of intra-thymically-injected CD4-8- precursors were initially normal, but they steadily declined among progeny of the fetal precursors. Thus, there appear to be differences in the life span and/or proliferative capacity of mature T cells derived from embryonic vs adult progenitors. In addition to the predominant CD4+8- and CD4-8+ subsets of peripheral T cells, a minor (1 to 20%) population of Thy-1+CD3+4-8- T cells was identified among peripheral progeny of intra-thymically-injected CD4-8- thymocytes, as well as in lymph nodes of unmanipulated animals. A total of 20 to 34% of this subset expressed V beta 8+ TCR and the majority were CD5hi, Pgp-1+, and J11d-. The function and specificity of this newly identified population of thymically derived peripheral T cells remains to be investigated.


Microengineered Human Vein-Chip Recreates Venous Valve Architecture and Its Contribution to Thrombosis.
Deep vein thrombosis (DVT) and its consequences are lethal, but current models cannot completely dissect its determinants-endothelium, flow, and blood constituents-together called Virchow's triad. Most models for studying DVT forego assessment of venous valves that serve as the primary sites of DVT formation. Therefore, the knowledge of DVT formed at the venous cusps has remained obscure due to lack of experimental models. Here, organ-on-chip methodology is leveraged to create a Vein-Chip platform integrating fully vascularized venous valves and its hemodynamic, as seen in vivo. These Vein-Chips reveal that vascular endothelium of valve cusps adapts to the locally disturbed microenvironment by expressing a different phenotype from the regions of uniform flow. This spatial adaptation of endothelial function recreated on the in vitro Vein-Chip platform is shown to protect the vein from thrombosis from disturbed flow in valves, but interestingly, cytokine stimulation reverses the effect and switches the valve endothelium to becoming prothrombotic. The platform eventually modulates the three factors of Virchow's triad and provides a systematic approach to investigate the determinants of fibrin and platelet dynamics of DVT. Therefore, this Vein-Chip offers a new preclinical approach to study venous pathophysiology and show effects of antithrombotic drug treatment.


Laminin-coated nerve guidance conduits based on poly(l-lactide-co-glycolide) fibers and yarns for promoting Schwann cells' proliferation and migration.
To develop an effective nerve guidance conduit with cooperative effects of topological structure and biological cues for promoting Schwann cells' (SCs) proliferation and migration, a laminin-coated and yarn-encapsulated poly(l-lactide-co-glycolide) (PLGA) nerve guidance conduit (LC-YE-PLGA NGC) was fabricated in this study. The PLGA fiber yarns were fabricated through a double-nozzle electrospinning system and then the PLGA fibrous outer layer was collected using a general electrospinning method. Subsequently, laminin was coated on the yarn-encapsulated PLGA NGC through covalent binding. The results showed satisfactory tensile mechanical strength of the laminin-coated PLGA fibers/yarns and good compressive mechanical support of the LC-YE-PLGA NGC. SCs proliferation was significantly superior (p < 0.05) on the PLGA and laminin-coated PLGA yarns than the PLGA fibers. Furthermore, the LC-YE-PLGA NGC performed much better in SCs migration compared with the NGCs without yarn-encapsulation or laminin-coating, indicating the synergistic effect of the three-dimensional yarn structure (topological structure) and the laminin-coating (biological cues) for SCs proliferation and migration. Therefore, the LC-YE-PLGA NGC demonstrated promising potential in promoting SCs proliferation and inducing SCs migration in nerve tissue engineering.


The scale, scope, coverage, and capability of childbirth care.
All women should have access to high quality maternity services-but what do we know about the health care available to and used by women? With a focus on low-income and middle-income countries, we present data that policy makers and planners can use to evaluate whether maternal health services are functioning to meet needs of women nationally, and potentially subnationally. We describe configurations of intrapartum care systems, and focus in particular on where, and with whom, deliveries take place. The necessity of ascertaining actual facility capability and providers' skills is highlighted, as is the paucity of information on maternity waiting homes and transport as mechanisms to link women to care. Furthermore, we stress the importance of assessment of routine provision of care (not just emergency care), and contextualise this importance within geographic circumstances (eg, in sparsely-populated regions vs dense urban areas). Although no single model-of-care fits all contexts, we discuss implications of the models we observe, and consider changes that might improve services and accelerate response to future challenges. Areas that need attention include minimisation of overintervention while responding to the changing disease burden. Conceptualisation, systematic measurement, and effective tackling of coverage and configuration challenges to implement high quality, respectful maternal health-care services are key to ensure that every woman can give birth without risk to her life, or that of her baby.


Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin.
We investigated the chemopreventive action of dietary curcumin on 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12,0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in Swiss albino mice. Curcumin, a yellow coloring matter isolated from roots of Curcuma longa Linn, is a phenolic compound possessing antioxidant, free radical scavenger, and antiinflammatory properties. It has been shown by previously reported work that TPA-induced skin tumors were inhibited by topical application of curcumin, and curcumin has been shown to inhibit a variety of biological activities of TPA. Topical application of curcumin was reported to inhibit TPA-induced c-fos, c-jun and c-myc gene expression in mouse skin. This paper reports the effects of orally administered curcumin, which was consumed as a dietary component at concentrations of 0.2 % or 1 %, in ad libitum feeding. Animals in which tumors had been initiated with DMBA and promoted with TPA experienced significantly fewer tumors and less tumor volume if they ingested either 0.2% or 1% curcumin diets. Also, the dietary consumption of curcumin resulted in a significantly decreased expression of ras and fos proto-oncogenes in the tumorous skin, as measured by enhanced chemiluminesence Western blotting detection system (Amersham). Whereas earlier work demonstrated that topical application of curcumin to mouse skin inhibited TPA-induced expression of c-fos, c-jun and c-myc oncogenes, our results are the first to show that orally consumed curcumin significantly inhibited DMBA- and TPA-induced ras and fos gene expression in mouse skin.


Visits to complementary and alternative medicine providers by children and adolescents in the United States.
Determine the prevalence, patterns, costs, and predictors of visits to complementary and alternative medicine (CAM) providers and subsequent remedy use in a nationally representative pediatric sample. The 1996 Medical Expenditure Panel Survey provided data on 7371 subjects < or =21 years of age. The primary outcome variable was CAM provider visits as defined by consulting a CAM provider "for health reasons." Predictors included sociodemographics, family resources, health status, parental CAM use, and perceptions and use of conventional medical care. Bivariate analyses and logistic regression determined independent factors associated with CAM use. Overall, 2.0% used CAM. Only 12.3% disclosed this use to their usual source of care (USC). The most common providers were chiropractors and clergy or spiritualists. The most common therapies were herbal remedies and spiritual healing. Mean amount spent per person on CAM visits was 73.40 US dollars and on remedies was 13.06 US dollars. Weighted estimates to the national pediatric population of annual expenditures on CAM visits and remedies were 127 million US dollars and 22 million US dollars, respectively. Significant factors independently associated with CAM visits were female gender, older age, good and very good perceived physical health as compared with excellent health, parental CAM use, and dissatisfaction with the quality of care received from the USC. Two percent of parents reported that their children consulted a CAM provider and rarely disclosed this use to their USC. While dissatisfaction with the quality of care by the USC and less good perceived physical health predicted CAM visits, parental CAM use was the most predictive.


Long-term virologic responses to antiretroviral therapy among HIV-positive patients entering adherence clubs in Khayelitsha, Cape Town, South Africa: a longitudinal analysis.
In South Africa, an estimated 4.6 million people were accessing antiretroviral therapy (ART) in 2018. As universal Test and Treat is implemented, these numbers will continue to increase. Given the need for lifelong care for millions of individuals, differentiated service delivery models for ART services such as adherence clubs (ACs) for stable patients are required. In this study, we describe long-term virologic outcomes of patients who have ever entered ACs in Khayelitsha, Cape Town. We included adult patients enrolled in ACs in Khayelitsha between January 2011 and December 2016 with a recorded viral load (VL) before enrolment. Risk factors for an elevated VL (VL >1000 copies/mL) and confirmed virologic failure (two consecutive VLs >1000 copies/mL one year apart) were estimated using Cox proportional hazards models. VL completeness over time was assessed. Overall, 8058 patients were included in the analysis, contributing 16,047 person-years of follow-up from AC entry (median follow-up time 1.7 years, interquartile range [IQR]:0.9 to 2.9). At AC entry, 74% were female, 46% were aged between 35 and 44 years, and the median duration on ART was 4.8 years (IQR: 3.0 to 7.2). Among patients virologically suppressed at AC entry (n = 8058), 7136 (89%) had a subsequent VL test, of which 441 (6%) experienced an elevated VL (median time from AC entry 363 days, IQR: 170 to 728). Older age (adjusted hazard ratio [aHR] 0.64, 95% confidence interval [CI] 0.46 to 0.88), more recent year of AC entry (aHR 0.76, 95% CI 0.68 to 0.84) and higher CD4 count (aHR 0.67, 95% CI 0.54 to 0.84) were protective against experiencing an elevated VL. Among patients with an elevated VL, 52% (150/291) with a repeat VL test subsequently experienced confirmed virologic failure in a median time of 112 days (IQR: 56 to 168). Frequency of VL testing was constant over time (82 to 85%), with over 90% of patients remaining virologically suppressed. This study demonstrates low prevalence of elevated VLs and confirmed virologic failure among patients who entered ACs. Although ACs were expanded rapidly, most patients were well monitored and remained stable, supporting the continued rollout of this model.


Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex.
Highly accurate surface models of the cerebral cortex are becoming increasingly important as tools in the investigation of the functional organization of the human brain. The construction of such models is difficult using current neuroimaging technology due to the high degree of cortical folding. Even single voxel misclassifications can result in erroneous connections being created between adjacent banks of a sulcus, resulting in a topologically inaccurate model. These topological defects cause the cortical model to no longer be homeomorphic to a sheet, preventing the accurate inflation, flattening, or spherical morphing of the reconstructed cortex. Surface deformation techniques can guarantee the topological correctness of a model, but are time-consuming and may result in geometrically inaccurate models. In order to address this need we have developed a technique for taking a model of the cortex, detecting and fixing the topological defects while leaving that majority of the model intact, resulting in a surface that is both geometrically accurate and topologically correct.


Connective tissue metabolism in patients with unclassified polyarthritis and early rheumatoid arthritis. Relationship to disease activity, bone mineral density, and radiographic outcome.
To assess the applicability of serum concentrations of markers of synovial inflammation, cartilage, and bone metabolism in relation to conventional markers of disease activity, bone mineral density (BMD) of the hand, and radiographic outcome. Biochemical markers of collagen tissue metabolism were measured in 72 patients with symmetrically swollen and tender second and third metacarpophalangeal or proximal interphalangeal joints for at least 4 weeks and less than 2 years. At 2 years, 51 patients fulfilled the American College Rheumatology criteria for rheumatoid arthritis (RA) and 21 patients had unclassified polyarthritis. Patients with RA were divided into groups according to the mean disease activity and to magnetic resonance imaging and radiographically detected bone erosions in the hands. Patients with RA had significantly higher serum concentrations of matrix metalloproteinase-3 (MMP-3) at baseline and higher mean concentrations of serum MMP-3 and pyridinoline (Pyd) during the first 6 and 12 months than patients with unclassified polyarthritis. RA patients with persistent disease activity and erosive disease had significantly higher concentrations of serum MMP-3 and Pyd than patients with no disease activity or nonerosive disease. Significant mutual correlations between serum MMP-3 and Pyd and C-reactive protein and erythrocyte sedimentation rate were observed. The mean values of MMP-3 and Pyd correlated significantly to the alpha coefficient of the digital x-ray radiogrammetry (DXR-BMD). Serum MMP-3 and Pyd varied according to disease activity, periarticular osteoporosis measured by DXR, and radiographic outcome, and thus appear to supplement the conventional markers of disease activity for monitoring patients with RA.


Modeling the Population Health Impact of Introducing a Modified Risk Tobacco Product into the U.S. Market.
Philip Morris International (PMI) has developed the Population Health Impact Model (PHIM) to quantify, in the absence of epidemiological data, the effects of marketing a candidate modified risk tobacco product (cMRTP) on the public health of a whole population. Various simulations were performed to understand the harm reduction impact on the U.S. population over a 20-year period under various scenarios. The overall reduction in smoking attributable deaths (SAD) over the 20-year period was estimated as 934,947 if smoking completely went away and between 516,944 and 780,433 if cMRTP use completely replaces smoking. The reduction in SADs was estimated as 172,458 for the World Health Organization (WHO) 2025 Target and between 70,274 and 90,155 for the gradual cMRTP uptake. Combining the scenarios (WHO 2025 Target and cMRTP uptake), the reductions were between 256,453 and 268,796, depending on the cMRTP relative exposure. These results show how a cMRTP can reduce overall population harm additionally to existing tobacco control efforts.


Frequency of Desaturation and Association With Hemodynamic Adverse Events During Tracheal Intubations in PICUs.
Oxygen desaturation during tracheal intubation is known to be associated with adverse ICU outcomes in critically ill children. We aimed to determine the occurrence and severity of desaturation during tracheal intubations and the association with adverse hemodynamic tracheal intubation-associated events. Retrospective cohort study as a part of the National Emergency Airway Registry for Children Network's quality improvement project from January 2012 to December 2014. International PICUs. Critically ill children younger than 18 years undergoing primary tracheal intubations in the ICUs. tracheal intubation processes of care and outcomes were prospectively collected using standardized operational definitions. We defined moderate desaturation as oxygen saturation less than 80% and severe desaturation as oxygen saturation less than 70% during tracheal intubation procedures in children with initial oxygen saturation greater than 90% after preoxygenation. Adverse hemodynamic tracheal intubation-associated event was defined as cardiac arrests, hypo or hypertension requiring intervention, and dysrhythmia. A total of 5,498 primary tracheal intubations from 31 ICUs were reported. Moderate desaturation was observed in 19.3% associated with adverse hemodynamic tracheal intubation-associated events (9.8% among children with moderate desaturation vs 4.4% without desaturation; p < 0.001). Severe desaturation was observed in 12.9% of tracheal intubations, also significantly associated with hemodynamic tracheal intubation-associated events. After adjusting for patient, provider, and practice factors, the occurrence of moderate desaturation was independently associated with hemodynamic tracheal intubation-associated events: adjusted odds ratio 1.83 (95% CI, 1.34-2.51; p < 0.001). The occurrence of severe desaturation was also independently associated with hemodynamic tracheal intubation-associated events: adjusted odds ratio 2.16 (95% CI, 1.54-3.04; p < 0.001). Number of tracheal intubation attempts was also significantly associated with the frequency of moderate and severe desaturations (p < 0.001). In this large tracheal intubation quality improvement database, we found moderate and severe desaturation are reported among 19% and 13% of all tracheal intubation encounters. Moderate and severe desaturations were independently associated with the occurrence of adverse hemodynamic events. Future quality improvement interventions may focus to reduce desaturation events.


Covert contraceptive use among women attending a reproductive health clinic in a municipality in Ghana.
Covert contraceptive use (CCU) in sub-Saharan Africa is an indication of women's inability to exercise autonomy in their reproductive choices. The aim of this study was to assess the prevalence and determinants of CCU among a sample of FP clients in a municipality of Ghana. We conducted a mixed method study among women attending a public reproductive health clinic in Sunyani, a city of over 250,000 inhabitants in Ghana. An initial survey inquired into sociodemographic characteristics, use of family planning (FP) methods and partner awareness of contraceptive use. The predictors of CCU were explored using logistic regressions. We used the findings to develop a guide which we applied in-depth interviews and focus group discussions with attendants at the same facility. Qualitative data analysis was conducted using a framework approach. We interviewed 300 women, 48 % of whom were aged between 26-33 years. The injectable was the most widely used method (56 %). The prevalence of CCU was 34 %. In multivariate analysis, single women were more likely to practice CCU than married or co-habiting women (Adjusted OR = 12.12, 95 % C.I. 4.73-31.1). Muslim and traditionalist women were similarly more likely to practice CCU than non-Muslim, non-traditionalist (Adjusted OR = 4.56, 2.29-9.06). Women who preferred to have their first or next child in 4 or more years from the time of the interview were more likely to be in CCU than women who intended to have children within 4 years of the interview (2.57; 1.37-4.83). Single women saw in covert use a statement of their social autonomy. To succeed in CCU, women wished that clinic attendance cards would not be given to them to keep at home. Though many participants saw in CCU a source of anxiety, they expected health workers to consider it and uphold confidentiality in the provision of services. Covert contraceptive use was high in this municipality and being single was the strongest predictor of the practice. Providers of FP services should reflect on how to adequately address the challenges faced by women who practice CCU.


Pilot study of congenital anomaly rates at birth in fallujah, iraq, 2010.
To examine numbers of congenital anomaly (CA) at birth overall and by class in one clinic in Fallujah General Hospital, Fallujah, Iraq. All congenital anomaly birth referrals to one pediatric clinician at Fallujah General Hospital for an eleven month period beginning November 1, 2009 were recorded. This clinic was one of three clinics to which cases would be referred. There were 291 CA cases registered at birth in the period at the study's clinic. The total number of births recorded in the hospital over the period was 6049. The CAs included 113 heart and circulatory system cases, 72 nervous system cases, 40 digestive system cases, 9 genitourinary cases, 6 ear, face and neck cases, 7 respiratory cases and 30 Down syndrome cases. Owing to difficulties establishing the exact number of births from which these cases were drawn, the exact rates cannot be precisely determined. Nevertheless, on the basis of reasonable assumptions relating to the activity of the clinic involved, these results support earlier epidemiological findings. On the basis of work reported elsewhere, the higher rates of congenital anomalies are believed to be caused by exposure to some genotoxic agent, possibly uranium.


Mapping Russian Laboratory Terms to LOINC.
The paper presents the results of semiautomatic mapping of Russian laboratory terms to LOINC. Two clinics (A and B) and a laboratory service participated in the project. We were able to map 86% (Clinic A) and 87% (Clinic B) of laboratory terms. The required effort was reasonable and the price of mapping and maintenance was considered as relatively low. We established LOINC as a canonical coding method for a laboratory data exchange. This provided semantic interoperability for the data exchange process.


Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data.
Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin < 400 µg/L and transferrin saturation (TSAT) levels < 30% receiving erythropoiesis-stimulating agents (ESA) were eligible. Enrolled patients were randomized to a proactive, high-dose IV iron arm (iron sucrose 400 mg/month unless ferritin > 700 µg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 µg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years. Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. EudraCT number: 2013-002267-25.


The sand seas of Titan: Cassini RADAR observations of longitudinal dunes.
The most recent Cassini RADAR images of Titan show widespread regions (up to 1500 kilometers by 200 kilometers) of near-parallel radar-dark linear features that appear to be seas of longitudinal dunes similar to those seen in the Namib desert on Earth. The Ku-band (2.17-centimeter wavelength) images show approximately 100-meter ridges consistent with duneforms and reveal flow interactions with underlying hills. The distribution and orientation of the dunes support a model of fluctuating surface winds of approximately 0.5 meter per second resulting from the combination of an eastward flow with a variable tidal wind. The existence of dunes also requires geological processes that create sand-sized (100- to 300-micrometer) particulates and a lack of persistent equatorial surface liquids to act as sand traps.


High-Resolution Optical Coherence Tomography as an Adjunctive Tool in the Diagnosis of Corneal and Conjunctival Pathology.
To evaluate the use of a commercially available, high-resolution, spectral-domain optical coherence tomography (HR-OCT) device in the diagnosis of corneal and conjunctival pathologies, with a focus on malignant lesions. Eighty-two eyes of 71 patients were enrolled in this prospective case series, including 10 normal eyes, 21 with ocular surface squamous neoplasia (OSSN), 24 with a pterygium or pingueculum, 3 with lymphoma, 18 with pigmented conjunctival lesions (nevus, flat melanosis, or melanoma), and 6 with Salzmann nodular degeneration. Subjects were imaged using photography and HR-OCT (RTVue, Optovue, Fremont, CA). When clinically indicated, surgery was performed and histopathologic specimens were correlated with OCT images. HR-OCT was useful in differentiating among various lesions based on optical signs. Specifically, in OSSN, HR-OCT findings included epithelial thickening and hyper-reflectivity, whereas pterygia and pinguecula showed a subepithelial mass under thinner epithelium. In lymphoma, a hypo-reflective, homogenous subepithelial mass was observed. Differentiating between pigmented lesions with HR-OCT was more difficult, but certain characteristics could be identified. Eyes with nevi and melanoma both displayed intensely hyper-reflective basal epithelial layers and discrete subepithelial lesions, but could be differentiated by the presence of cysts in nevi and intense shadowing of sublesional tissue in most melanomas. We found that a commercially available HR-OCT was a useful noninvasive adjunctive tool in the diagnosis of ocular surface lesions.


Are the resources adoptive for conducting team-based diabetes management clinics? An explorative study at primary health care centers in Muscat, Oman.
AimThe aim of this study is to explore the perceptions among primary health center staff concerning competencies, values, skills and resources related to team-based diabetes management and to describe the availability of needed resources for team-based approaches. BACKGROUND: The diabetes epidemic challenges services available at primary health care centers in the Middle East. Therefore, there is a demand for evaluation of the available resources and team-based diabetes management in relation to the National Diabetes Management Guidelines. METHOD: A cross-sectional study was conducted with 26 public primary health care centers in Muscat, the capital of Oman. Data were collected from manual and electronic resources as well as a questionnaire that was distributed to the physician-in-charge and diabetes management team members.FindingsThe study revealed significant differences between professional groups regarding how they perceived their own competencies, values and skills as well as available resources related to team-based diabetes management. The perceived competencies were high among all professions. The perceived team-related values and skills were also generally high but with overall lower recordings among the nurses. This pattern, along with the fact that very few nurses have specialized qualifications, is a barrier to providing team-based diabetes management. Participants indicated that there were sufficient laboratory resources; however, reported that pharmacological, technical and human resources were lacking. Further work should be done at public primary diabetes management clinics in order to fully implement team-based diabetes management.


Incidental lung cancers and positive computed tomography images in people living with HIV.
Lung cancer screening with low-dose computed tomography (LDCT) of high-risk groups in the general population is recommended by several authorities. This may not be feasible in people living with HIV (PLWHIV) due to higher prevalence of nodules. We therefore assessed the prevalence of positive computed tomography (CT) images and lung cancers in PLWHIV. The Copenhagen comorbidity in HIV infection (COCOMO) study is an observational, longitudinal cohort study. Single-round LDCT was performed with subsequent clinical follow-up (NCT02382822). Outcomes included histology-proven lung cancer identified by LDCT and positive CT images (noncalcified nodules) in the entire cohort and in the high-risk group (>50 years of age and >30 pack-years). We also assessed the procedures and adverse events, and clinical factors associated with a positive CT image. LDCT was performed in 901 patients, including 113 at high risk for lung cancer. A positive image was found in 28 (3.1% of the entire cohort and 9.7% of the high-risk group). Nine patients (all in the high-risk group) had invasive procedures undertaken with no serious adverse events. Lung cancer (stages IA, IIA, and IIIA) was diagnosed in three patients from the high-risk group (2.7%). CD4 cell count less than 500 cells/μl and CD4 nadir less than 200 cells/μl were each independently associated with increased odds of a positive image odds ratio 2.32 [95% confidence interval: 1.01-5.13, P = 0.04] and odds ratio 2.63 [95% confidence interval: 1.13-6.66, P = 0.03]. Randomized LDCT screening trials in PLWHIV are nonexistent, but these findings are comparable with screening rounds from the general population in terms of prevalence of lung cancer and positive CT images.


A dissection and computer tomograph study of tarsal coalitions in 100 cadaver feet.
Most of the clinical studies report the incidence of tarsal coalitions (TC) as less than 1% but they disregard the asymptomatic coalitions. TC have been associated with degenerative arthritic changes. After X-rays, computer tomography (CT) is the most commonly used diagnostic test in the detection of TC. The aims of our study were to establish the incidence of TC; the association between TC and accessory tarsal bones and between TC and tarsal arthritis; and to assess the sensitivity of CT as a diagnostic tool in TC. We performed spiral CT scans of 100 cadaver feet (mean age at death 77.7+/-10.4), which were subsequently dissected. The dissections identified nine non-osseous TC: two talocalcaneal and seven calcaneonavicular. There was no osseous coalition. Tarsal arthritis was identified in 31 cases. Both talocalcaneal coalitions were associated with arthritis while none of the calcaneonavicular coalitions were associated with tarsal arthritis. The CT diagnosed an osseous talocalcaneal coalition and was suspicious of fibrocartilaginous coalitions in eight cases. There was correlation between dissection and CT in two talocalcaneal coalitions and three calcaneonavicular coalitions thus CT identifying 55.5% of the coalitions. CT did not diagnose four non-osseous coalitions and diagnosed errouresly four possible coalitions. In conclusion our study demonstrated that the incidence of non-osseous TC is higher than previously thought (12.72%). The calcaneonavicular coalitions are the most common single type (9.09%) and they do not seem to be associated with arthritic changes in the tarsal bones. Our CT results suggest that spiral CT has a low sensitivity in the detection of non-osseous coalitions and questions if multislice CT should be used routinely when TC are suspected.


A multi-scale computational model for the study of retinal prosthetic stimulation.
An implantable retinal prosthesis has been developed to restore vision to patients who have been blinded by degenerative diseases that destroy photoreceptors. By electrically stimulating the surviving retinal cells, the damaged photoreceptors may be bypassed and limited vision can be restored. While this has been shown to restore partial vision, the understanding of how cells react to this systematic electrical stimulation is largely unknown. Better predictive models and a deeper understanding of neural responses to electrical stimulation is necessary for designing a successful prosthesis. In this work, a computational model of an epi-retinal implant was built and simulated, spanning multiple spatial scales, including a large-scale model of the retina and implant electronics, as well as underlying neuronal networks.


Solar abundance ratios of the iron-peak elements in the Perseus cluster.
The metal abundance of the hot plasma that permeates galaxy clusters represents the accumulation of heavy elements produced by billions of supernovae. Therefore, X-ray spectroscopy of the intracluster medium provides an opportunity to investigate the nature of supernova explosions integrated over cosmic time. In particular, the abundance of the iron-peak elements (chromium, manganese, iron and nickel) is key to understanding how the progenitors of typical type Ia supernovae evolve and explode. Recent X-ray studies of the intracluster medium found that the abundance ratios of these elements differ substantially from those seen in the Sun, suggesting differences between the nature of type Ia supernovae in the clusters and in the Milky Way. However, because the K-shell transition lines of chromium and manganese are weak and those of iron and nickel are very close in photon energy, high-resolution spectroscopy is required for an accurate determination of the abundances of these elements. Here we report observations of the Perseus cluster, with statistically significant detections of the resonance emission from chromium, manganese and nickel. Our measurements, combined with the latest atomic models, reveal that these elements have near-solar abundance ratios with respect to iron, in contrast to previous claims. Comparison between our results and modern nucleosynthesis calculations disfavours the hypothesis that type Ia supernova progenitors are exclusively white dwarfs with masses well below the Chandrasekhar limit (about 1.4 times the mass of the Sun). The observed abundance pattern of the iron-peak elements can be explained by taking into account a combination of near- and sub-Chandrasekhar-mass type Ia supernova systems, adding to the mounting evidence that both progenitor types make a substantial contribution to cosmic chemical enrichment.


Putting trials on trial--the costs and consequences of small trials in depression: a systematic review of methodology.
To determine why, despite 122 randomised controlled trials, there is no consensus about whether the selective serotonin reuptake inhibitors or tricyclic and related antidepressants should be used as first line treatment of depression. Systematic review of all RCTs comparing selective serotonin reuptake inhibitors and tricyclic or heterocyclic antidepressants. The shortcomings identified in the 122 trials were as follows: (1) there was inadequate description of randomisation, (2) the outcomes used were mainly observer rated measurements of depression, and studies failed to use quality of life measures or perform economic evaluations, (3) doses of tricyclic antidepressants were inadequate, (4) generalisability of studies was poor (including a reliance on secondary care settings and inadequate follow up), and (5) there were statistical shortcomings such as low statistical power, failure to use intention to treat analyses, and the tendency to make multiple comparisons. Future RCTs should be designed to inform policy makers and address these methodological shortcomings.


Understanding the ways in which health visitors manage anxiety in cross-cultural work: a qualitative study.
This paper is a report of part of a study that explored the ways in which health visitors manage uncertainty and anxiety when working with clients across cultures. Internationally health care professionals are required to deliver a high standard of culturally appropriate care to increasingly diverse communities and yet problems persist. Research evidence informing cultural 'competence' is focused largely around student experience and consequently little is known about the day-to-day experiences of health professionals in diverse community settings. Anxiety and uncertainty are increasingly recognised as important emotions experienced by a variety of health care professionals when working across cultures and yet the ways in which anxiety and uncertainty is managed in practice is less well understood. Grounded theory methodology was used and 21 semi-structured interviews were conducted with participating health visitors in the North East of England between May 2008 and September 2009. All participants described themselves as white. This study identified three different positions adopted by the health visitors to manage uncertainty and anxiety in their work across cultures. Identified as, 'Fixing a culture', 'Reworking the equality agenda' and 'Asserting the professional self', these strategies identify the ways in which health visitors try to manage the uncertainty and anxiety they feel when working in diverse communities. All of these strategies attempt in different ways to negate cultural difference and to render culture as static and known. Given that health professionals report anxiety and uncertainty when working across diverse community settings, identification of the strategies used by health visitors to manage that anxiety is important for both policy and practice. New strategies need to be developed to help health professionals to manage uncertainty and anxiety in ways that promote both cultural safe care and health equity.


Serum microRNA biomarkers for detection of non-small cell lung cancer.
Non small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality world-wide and the majority of cases are diagnosed at late stages of disease. There is currently no cost-effective screening test for NSCLC, and the development of such a test is a public health imperative. Recent studies have suggested that chest computed tomography screening of patients at high risk of lung cancer can increase survival from disease, however, the cost effectiveness of such screening has not been established. In this Phase I/II biomarker study we examined the feasibility of using serum miRNA as biomarkers of NSCLC using RT-qPCR to examine the expression of 180 miRNAs in sera from 30 treatment naive NSCLC patients and 20 healthy controls. Receiver operating characteristic curves (ROC) and area under the curve were used to identify differentially expressed miRNA pairs that could distinguish NSCLC from healthy controls. Selected miRNA candidates were further validated in sera from an additional 55 NSCLC patients and 75 healthy controls. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs. A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100% in the training set. Upon further testing on additional 130 subjects (55 NSCLC and 75 healthy controls), this miRNA pair predicted NSCLC with a specificity of 84% (95% CI 0.73-0.91), sensitivity of 100% (95% CI; 0.93-1.0), NPV of 100%, and PPV of 82%. These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of NSCLC. Further testing in a Phase III biomarker study in is necessary for validation of these results.


Psychiatric morbidity among sentenced prisoners: prevalence study in Iran.
Information on psychiatric morbidity of prisoners has almost entirely been based on research in Western countries and it is uncertain whether these research findings are applicable to other settings. The primary objective was to investigate the prevalence of psychiatric disorders in Iranian prisoners. Through stratified random sampling, 351 prisoners were interviewed using the clinical version of the Structured Clinical Interview for DSM-IV Axis I Disorders and the Psychopathy Checklist: Screening Version. The majority (88%) of prisoners met DSM-IV criteria for lifetime diagnosis of at least one Axis I disorder and 57% were diagnosed with current Axis I disorders. Opioid dependence (73%) had the highest prevalence among lifetime diagnoses, whereas major depressive disorder (29%) was the most common current diagnosis. Psychopathy was recorded in 23%. Prevalence rates of psychiatric disorders were significantly different among offence categories. The results suggest that a substantial burden of psychiatric morbidity exists in the prison population of Iran, with treatment challenges that appear to be different from those observed in inmates in Western countries.


Aortic Stiffness, Pulse Pressure, and Cerebral Pulsatility Progress Despite Best Medical Management: The OXVASC Cohort.
Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P<0.0001) and aoPP (3.5%; P<0.0001) but not significantly for MCA-PI overall (0.93; P=0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P<0.0001), while aoPP and MCA-PI increased significantly above the age of 55 years (aoPP, P<0.0001; MCA-PI, P=0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP (P<0.001). Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.


Cross-Species Genome-Wide Identification of Evolutionary Conserved MicroProteins.
MicroProteins are small single-domain proteins that act by engaging their targets into different, sometimes nonproductive protein complexes. In order to identify novel microProteins in any sequenced genome of interest, we have developed miPFinder, a program that identifies and classifies potential microProteins. In the past years, several microProteins have been discovered in plants where they are mainly involved in the regulation of development by fine-tuning transcription factor activities. The miPFinder algorithm identifies all up to date known plant microProteins and extends the microProtein concept beyond transcription factors to other protein families. Here, we reveal potential microProtein candidates in several plant and animal reference genomes. A large number of these microProteins are species-specific while others evolved early and are evolutionary highly conserved. Most known microProtein genes originated from large ancestral genes by gene duplication, mutation and subsequent degradation. Gene ontology analysis shows that putative microProtein ancestors are often located in the nucleus, and involved in DNA binding and formation of protein complexes. Additionally, microProtein candidates act in plant transcriptional regulation, signal transduction and anatomical structure development. MiPFinder is freely available to find microProteins in any genome and will aid in the identification of novel microProteins in plants and animals.


Empirical relationships between tree fall and landscape-level amounts of logging and fire.
Large old trees are critically important keystone structures in forest ecosystems globally. Populations of these trees are also in rapid decline in many forest ecosystems, making it important to quantify the factors that influence their dynamics at different spatial scales. Large old trees often occur in forest landscapes also subject to fire and logging. However, the effects on the risk of collapse of large old trees of the amount of logging and fire in the surrounding landscape are not well understood. Using an 18-year study in the Mountain Ash (Eucalyptus regnans) forests of the Central Highlands of Victoria, we quantify relationships between the probability of collapse of large old hollow-bearing trees at a site and the amount of logging and the amount of fire in the surrounding landscape. We found the probability of collapse increased with an increasing amount of logged forest in the surrounding landscape. It also increased with a greater amount of burned area in the surrounding landscape, particularly for trees in highly advanced stages of decay. The most likely explanation for elevated tree fall with an increasing amount of logged or burned areas in the surrounding landscape is change in wind movement patterns associated with cutblocks or burned areas. Previous studies show that large old hollow-bearing trees are already at high risk of collapse in our study area. New analyses presented here indicate that additional logging operations in the surrounding landscape will further elevate that risk. Current logging prescriptions require the protection of large old hollow-bearing trees on cutblocks. We suggest that efforts to reduce the probability of collapse of large old hollow-bearing trees on unlogged sites will demand careful landscape planning to limit the amount of timber harvesting in the surrounding landscape.


NAADP: a new second messenger for glucose-induced Ca2+ responses in clonal pancreatic beta cells.
Important questions remain concerning how elevated blood glucose levels are coupled to insulin secretion from pancreatic beta cells and how this process is impaired in type 2 diabetes. Glucose uptake and metabolism in beta cells cause the intracellular Ca(2+) concentration ([Ca(2+)](i)) to increase to a degree necessary and sufficient for triggering insulin release. Although both Ca(2+) influx and Ca(2+) release from internal stores are critical, the roles of inositol 1,4,5-trisphosphate (IP(3)) and cyclic adenosine dinucleotide phosphate ribose (cADPR) in regulating the latter have proven equivocal. Here we show that glucose also increases [Ca(2+)](i) via the novel Ca(2+)-mobilizing agent nicotinic acid adenine dinucleotide phosphate (NAADP) in the insulin-secreting beta-cell line MIN6. NAADP binds to specific, high-affinity membrane binding sites and at low concentrations elicits robust Ca(2+) responses in intact cells. Higher concentrations of NAADP inactivate NAADP receptors and attenuate the glucose-induced Ca(2+) increases. Importantly, glucose stimulation increases endogenous NAADP levels, providing strong evidence for recruitment of this pathway. In conclusion, our results support a model in which NAADP mediates glucose-induced Ca(2+) signaling in pancreatic beta cells and are the first demonstration in mammalian cells of the presence of endogenous NAADP levels that can be regulated by a physiological stimulus.


Understanding the self-healing hydrophobic recovery of high-voltage insulators.
Amorphous siloxane polymers are designed to have high dielectric strength for use as high-voltage insulation materials. Surface hydrophobicity is essential and can be impaired by environmental, electrical, or mechanical factors, leading to leakage currents due to dielectric breakdown. Self-recovery is possible and is generally observed over a period of several hours. Using large-scale, all-atom molecular dynamics simulations, the surface wetting of water droplets on the polymer surface is simulated for various surface conditions, including oxidation and coating with small molecules, to understand the driving forces of the recovery process at the atomistic level, which is of primary importance for the developments of novel materials. In this work, we shed light onto the self-recovery mechanism and propose the use of low-molecular-weight (LMW) siloxane to accelerate the recovery of hydrophobicity.


British gynaecologists' attitudes in 2008 to the provision of legal abortion.
In 2008, we investigated the attitudes and practice of British consultant gynaecologists towards induced abortion, and made comparisons with our similar survey in 1989. A random sample of one in six (217) was selected from the register of the Royal College of Obstetricians and Gynaecologists (RCOG). The response to the postal questionnaire was 70% (152). Satisfaction with the way the 1967 Abortion Act is operating was expressed by 59% (76% in 1989) and an upper limit of 24 weeks was supported by 50% (77% in 1989). Abortion after 20 weeks was approved to protect health by 92%; after rape by 60% and for serious fetal handicap by 87%. A change in the regulations to require the signature of only one doctor (rather than two) to certify the need for abortion was supported by 65%. Only a minority (41%) provided 2nd trimester abortion in person; 61% would separate abortion provision from general gynaecology; 57% suggested there should be separate abortion units for gestations over 13 weeks and 56% felt that fertility control should become be a sub-specialty. Satisfaction with the Abortion Act 1967 has decreased during the last 20 years. Gynaecologists' attitudes to the indications for 2nd trimester abortion remain wide, with clear implications for women seeking abortion. The service to women would be improved if abortion on request was permitted in the 1st trimester and after only one medical signature in the 2nd trimester. Our view is that the decision to end a pregnancy should be made by the woman and that abortion should be decriminalised.


Social position, social roles and women's health in England: changing relationships 1984-1993.
The aim of this study is to investigate the relationships between social roles, social position and health in English women using theoretically derived measures of social position. Data are taken from the Health and Lifestyle Survey, carried out between 1984-1985, and the Health Survey for England of 1993. First the paper asks whether health inequality in women is still evident when theoretically derived measures (the Erikson-Goldthorpe schema and the Cambridge scale) are used. It goes on to explore the extent to which different combinations of family roles and employment circumstances might affect social variations in health. Finally, the paper shows that health differences between women in different combinations of social roles were not the same in 1993 as in 1984 and examines some reasons why this change may have occurred.


Detection of stiff nanoparticles within cellular structures by contact resonance atomic force microscopy subsurface nanomechanical imaging.
Detecting stiff nanoparticles buried in soft biological matrices by atomic force microscopy (AFM) based techniques represents a new frontier in the field of scanning probe microscopies, originally developed as surface characterization methods. Here we report the detection of stiff (magnetic) nanoparticles (NPs) internalized in cells by using contact resonance AFM (CR-AFM) employed as a potentially non-destructive subsurface characterization tool. Magnetite (Fe3O4) NPs were internalized in microglial cells from cerebral cortices of mouse embryos of 18 days by phagocytosis. Nanomechanical imaging of cells was performed by detecting the contact resonance frequencies (CRFs) of an AFM cantilever held in contact with the sample. Agglomerates of NPs internalized in cells were visualized on the basis of the local increase in the contact stiffness with respect to the surrounding biological matrix. A second AFM-based technique for nanomechanical imaging, i.e., HarmoniX™, as well as magnetic force microscopy and light microscopy were used to confirm the CR-AFM results. Thus, CR-AFM was demonstrated as a promising technique for subsurface imaging of nanomaterials in biological samples.


Gastrointestinal helminths of Risso's dolphin Grampus griseus from the Western Mediterranean.
The gastrointestinal helminth fauna of 17 Risso's dolphins Grampus griseus (Cuvier, 1812) from the Western Mediterranean was analysed. Five helminth species were found. Adults and juveniles of Hadwenius delamurei were collected from the duodenum of 7 animals. Adults were located significantly more anteriorly than juveniles, which is compatible with a previous hypothesis that species of Hadwenius undergo an ontogenetic migration towards the anterior duodenum. Eggs from Pholeter gastrophilus appeared in 1 small cyst in the main stomach. Adults of Tetrabothrius forsteri and Trigonocotyle globicephalae were collected from the duodenum of 1 and 4 individuals, respectively. Metacestodes, Scolex pleuronectis, were found in the liver, pancreas, pyloric stomach and intestine of 13 individuals. The most favored locations were in the mucosa of the terminal colon and in anal crypts. It is likely that worms select these locations to reach the mesenteries and blubber of the anogenital area, where S. pleuronectis might become Monorygma and/or Phyllobothrium. Two individuals of Stenurus globicephalae occurred in the intestine of 1 individual, and were probably swallowed accidentally. The intestinal helminth communities of Risso's dolphin are depauperate. The parasite species found also occur in other oceanic cetaceans from the Western Mediterranean. However, H. delamurei and T. globicephalae are only shared with pilot whales Globicephala spp., which are phylogenetically closely related to Risso's dolphins.


3-D Ultrasound Segmentation of the Placenta Using the Random Walker Algorithm: Reliability and Agreement.
Volumetric segmentation of the placenta using 3-D ultrasound is currently performed clinically to investigate correlation between organ volume and fetal outcome or pathology. Previously, interpolative or semi-automatic contour-based methodologies were used to provide volumetric results. We describe the validation of an original random walker (RW)-based algorithm against manual segmentation and an existing semi-automated method, virtual organ computer-aided analysis (VOCAL), using initialization time, inter- and intra-observer variability of volumetric measurements and quantification accuracy (with respect to manual segmentation) as metrics of success. Both semi-automatic methods require initialization. Therefore, the first experiment compared initialization times. Initialization was timed by one observer using 20 subjects. This revealed significant differences (p < 0.001) in time taken to initialize the VOCAL method compared with the RW method. In the second experiment, 10 subjects were used to analyze intra-/inter-observer variability between two observers. Bland-Altman plots were used to analyze variability combined with intra- and inter-observer variability measured by intra-class correlation coefficients, which were reported for all three methods. Intra-class correlation coefficient values for intra-observer variability were higher for the RW method than for VOCAL, and both were similar to manual segmentation. Inter-observer variability was 0.94 (0.88, 0.97), 0.91 (0.81, 0.95) and 0.80 (0.61, 0.90) for manual, RW and VOCAL, respectively. Finally, a third observer with no prior ultrasound experience was introduced and volumetric differences from manual segmentation were reported. Dice similarity coefficients for observers 1, 2 and 3 were respectively 0.84 ± 0.12, 0.94 ± 0.08 and 0.84 ± 0.11, and the mean was 0.87 ± 0.13. The RW algorithm was found to provide results concordant with those for manual segmentation and to outperform VOCAL in aspects of observer reliability. The training of an additional untrained observer was investigated, and results revealed that with the appropriate initialization protocol, results for observers with varying levels of experience were concordant. We found that with appropriate training, the RW method can be used for fast, repeatable 3-D measurement of placental volume.


Dysfunction in Brain-Derived Neurotrophic Factor Signaling Pathway and Susceptibility to Schizophrenia, Parkinson's and Alzheimer's Diseases.
Brain-Derived Neurotrophic Factor (BDNF) is a dominant neurotrophic factor in the brain which plays a crucial role in differentiation, regeneration and plasticity mechanisms. Binding of the BDNF to its high-affinity Tropomyosin-related kinase B (TrkB) receptor leads to phosphorylation of TrkB, thus activating the three important downstream intracellular signaling cascades within the neural cells including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Phospholipase C-γ (PLCγ), and mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathways. Transcription of these pathways is regulated by cAMP Response Element-Binding protein (CREB) transcription factor, which can upregulate gene expression. In this review, we attempted to explore the role of BDNF and its associated pathways in susceptibility to Schizophrenia (Scz), Alzheimer's (AD), and Parkinson's (PD) diseases. Furthermore, we discuss dysfunction in BDNF signaling pathway and the therapeutic potential of BDNF in the treatment of these disorders. The review covers various therapeutic strategies including BDNF gene therapy, transplantation of BDNFexpressing cell grafts, epigenetic manipulation, and intraparenchymal BDNF protein infusion as well. This review seeks to achieve these goals by reviewing recent studies on BDNF and examining the details of BDNF pathway in any of the above-mentioned diseases.


Fas and FasL gene polymorphisms are not associated with cervical cancer but differ among Black and Mixed-ancestry South Africans.
Cervical cancer is one of the most important cancers in African women. Polymorphisms in the Fas (FasR) and Fas ligand (FasL) genes have been reported to be associated with cervical cancer in certain populations. This study investigated whether these polymorphisms are associated with cervical cancer or human papillomavirus (HPV) infection in South African women. Participants were 447 women with invasive cervical cancer (106 black African and 341 women of mixed-ancestry) and 424 healthy women controls, matched by age, (101 black African and 323 women of mixed-ancestry) and domicile (rural or urban). Two polymorphisms in Fas gene (FasR-1377G/A, FasR-670A/G) and one in FasL gene (FasL844T/C) were genotyped by TaqMan. None of the polymorphisms, or the Fas haplotypes, showed a significant association with cervical cancer. There was also no association with HPV infection in the control group. However, on analysis of the control group, highly significant allele, genotype and haplotype differences were found between the two ethnic groups. There were generally low frequencies of FasR-1377A alleles, FasR-670A alleles and FasL-844C alleles in black women compared to the women of mixed-ancestry. This is the first study on the role of Fas and FasL polymorphisms in cervical cancer in African populations. Our results suggest that these SNPs are not associated with cervical cancer in these populations. The allele frequencies of the three SNPs differed markedly between the indigenous African black and mixed-ancestry populations.


Childhood nonspecific abdominal pain in family practice: incidence, associated factors, and management.
Nonspecific abdominal pain (NSAP) is a common complaint in childhood. In specialist care, childhood NSAP is considered to be a complex and time-consuming problem, and parents are hard to reassure. Little is known about NSAP in family practice, but the impression is that family physicians consider it to be a benign syndrome needing little more than reassurance. This discrepancy calls for a better understanding of NSAP in family practice. Data were obtained from the Second Dutch National Survey of General Practice (2001). Using registration data of 91 family practices, we identified children aged 4 to 17 years with NSAP. We calculated the incidence, and we studied factors associated with childhood NSAP, referrals, and prescriptions. The incidence of NSAP was 25.0 (95% confidence interval [CI], 23.7-26.3) per 1,000 person years. Most children (92.7%) with newly diagnosed NSAP (N = 1,480) consulted their doctor for this condition once or twice. Factors independently associated with NSAP were female sex (odds ratio [OR] = 1.4; 95% CI, 1.3-1.5), nongastrointestinal-nonspecific somatic symptoms (OR = 1.3; 95% CI, 1.1-1.5), and health care use (OR = 1.04; 95% CI, 1.03-1.05). When NSAP was diagnosed at the first visit, 3% of the patients were referred to specialist care, and 1% received additional testing. Family physicians prescribed medication in 21.3% of the visits for NSAP. Childhood NSAP is a common problem in family practice. Most patients visit their doctor once or twice for this problem. Family physicians use little additional testing and make few referrals in their management of childhood NSAP. Despite the lack of evidence for effectiveness, family physicians commonly prescribe medication for NSAP.


Incidence, predictors and outcomes of incomplete revascularization after percutaneous coronary intervention and coronary artery bypass grafting: a subgroup analysis of 3-year SYNTAX data.
To assess whether incomplete revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) has an effect on long-term outcomes. During a heart team discussion to evaluate whether patients were eligible for randomization in the SYNTAX trial, both the cardiologist and surgeon agreed on which vessels needed revascularization. This statement was compared with the actual revascularization after treatment. Incomplete revascularization was defined as when a preoperatively identified vessel with a lesion was not revascularized. Outcomes were major adverse cardiac or cerebrovascular events (MACCE), the composite safety endpoint of death/stroke/myocardial infarction (MI), and individual MACCE components death, MI and repeat revascularization at 3 years. Predictors of incomplete revascularization were explored. Incomplete revascularization was found in 43.3% (388/896) PCI and 36.8% (320/870) CABG patients. Patients with complete revascularization by PCI had lower rates of MACCE (66.5 versus 76.2%, P < 0.001), the composite safety endpoint (83.4 versus 87.9%, P = 0.05) and repeat revascularization (75.5 versus 83.9%, P < 0.001), but not death and MI. In the CABG group, no difference in outcomes was seen between incomplete and complete revascularization groups. Incomplete revascularization was identified as independent predictor of MACCE in PCI (HR = 1.55, 95% CI 1.15-2.08, P = 0.004) but not CABG patients. Independent predictors of incomplete revascularization by PCI were hyperlipidaemia (OR = 1.59, 95% CI 1.04-2.42, P = 0.031), a total occlusion (OR = 2.46, 95% CI 1.66-3.64, P < 0.001) and the number of vessels (OR = 1.58, 95% CI 1.41-1.77, P < 0.001). Independent predictors of incomplete revascularization by CABG were unstable angina (OR = 1.42, 95% CI 1.02-1.98, P = 0.038), diffuse disease or narrowed ( < 2 mm) segment distal to the lesion (OR = 1.87, 95% CI 1.31-2.69, P = 0.001) and the number of vessels (OR = 1.70, 95% CI 1.53-1.89, P < 0.001). Despite the hypothesis-generating nature of this data, this study demonstrates that incomplete revascularization is associated with adverse events during follow-up after PCI but not CABG.


The neck as a preferred recipient site for vascularized composite allotransplantation in the mouse.
The mouse is still considered the premier model in basic immunologic and transplant-related research. However, because of its much smaller size, the mouse has proven to be a technically difficult and physiologically fragile model from a surgical standpoint. That is why only a few studies currently use mouse models in vascularized composite allotransplantation. The purpose of this study therefore was to develop a reproducible and reliable surgical technique in the mouse for future vascularized composite allotransplantation studies. Forty DBA/2 (H2-D) hindlimb osteomyocutanous flaps were transplanted into the right cervical region of C57BL/6 (H2-D) mice using a nonsuture cuff technique. The donor iliac artery and femoral vein were mounted with polyimide cuffs (inner diameter, 0.404 mm; wall thickness, 0.025 mm) and subsequently anastomosed to the recipient common carotid artery and external jugular vein. Immunosuppressant drugs were used postoperatively. The overall success rate was 85.0 percent (34 of 40). The mortality rate was 12.5 percent (five of 40); all deaths resulted from perioperative bleeding. Only one arterial insufficiency was encountered after transplantation. The operative time was approximately 2 hours. Indefinite allograft survival (>120 days) could be achieved using a specific immunosuppressant regimen. This novel mouse model allows performing vascularized composite allotransplantation with very high success and survival rates. The advantages over conventional models are multifold. A high-flow common carotid artery keeps the anastomosis patent, and diastolic suction of the heart reduces the risk of venous stasis and thrombus formation. Less destruction because of the heterotopic positioning of the hindlimb graft further reduces the associated mortality and morbidity in this fragile model.


Interaction between smoking and obesity and the risk of developing breast cancer among postmenopausal women: the Women's Health Initiative Observational Study.
Obesity is a well-established risk factor for postmenopausal breast cancer. Recent studies suggest that smoking increases the risk of breast cancer. However, the effect of co-occurrence of smoking and obesity on breast cancer risk remains unclear. A total of 76,628 women aged 50-79 years enrolled in the Women's Health Initiative Observational Study were followed through August 14, 2009. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. Over an average 10.3 years of follow-up, 3,378 incident cases of invasive breast cancer were identified. The effect of smoking on the risk of developing invasive breast cancer was modified significantly by obesity status among postmenopausal women, regardless of whether the obesity status was defined by body mass index (P(interaction) = 0.01) or waist circumference (P(interaction) = 0.02). A significant association between smoking and breast cancer risk was noted in nonobese women (hazard ratio = 1.25, 95% confidence interval: 1.05, 1.47) but not in obese women (hazard ratio = 0.96, 95% confidence interval: 0.69, 1.34). In conclusion, this study suggests that the effect of smoking exposure on breast cancer risk was modified by obesity among postmenopausal women. The modification effect did not differ by general versus abdominal obesity.


Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K+ concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.