Patient perspectives on test result communication in primary care: a qualitative study.
Although the number of blood tests ordered in primary care continues to increase, efficient systems for the communication of blood test results to patients are lacking. This is a concern in terms of both patient safety and patient satisfaction. To gain an understanding of patient perspectives on organisational and technological aspects of current and prospective systems for communicating laboratory test results in primary care, and the influences that impact patients' preferred methods for receiving results. Qualitative study using patient focus groups in four primary care practices in Birmingham, UK. The primary care practices were purposively selected to ensure they varied in size, socioeconomic environment, and the default pathways they used to communicate test results. A total of 26 patients from the four practices who had had a recent blood test were recruited. Over a 6 month period in 2011, six, 1-hour focus groups were conducted at the four practices involved in the study. Patients expressed a preference for receiving results from the ordering GP or a clinically qualified member of staff. Suggestions for refining current systems included improved access to phlebotomy appointments, better management of patient telephone calls, and a clear, accessible protocol for the communication of results. Despite the testing and result communication process being a core activity in primary care, it was found that practices could improve their service in a number of areas. Patients described frequent delays and inconsistency in both the level of information and the method of communication, as well as dissatisfaction with non-clinical staff relaying results. Patient preferences for result communication based on their experience of current systems have produced practical suggestions to improve processes.


Phase I/II trial of 2-weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer (JCOG0807).
We carried out a phase I/II trial of adding 2-weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2-weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2-weekly docetaxel (30 mg/m(2) [dose level (DL)1] or 40 mg/m(2) [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed-dose CF (80 mg/m(2) cisplatin, day 1; 800 mg/m(2) fluorouracil, days 1-5) repeated every 4 weeks. The primary endpoint was dose-limiting toxicity (DLT) in phase I and central peer review-based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty-two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48-75%); median overall survival and progression-free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment-related death in one patient. The 2-weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737.


Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy.
The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8(+) T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.


Chest radiographs are valuable in demonstrating clinically significant pacemaker complications that require reoperation.
To evaluate the utility of chest radiography in demonstrating clinically significant pacemaker complications that required reoperation. In this retrospective case-controlled series, we identified 14 consecutive adults who required pacemaker reoperation and who had chest radiographs available for review (6 men, 8 women; mean age, 71 years [range, 43-95 years]). Ten patients had pacemakers implanted at our institution, and 4 were referred for reoperation. Forty-two controls, 3 for each patient, had postoperative chest radiographs and normal device function (25 men, 17 women; mean age 76 years [range, 37-96 years]). All postoperative chest radiographs, including 1-year follow-ups, were blindly reviewed by at least 2 of 4 radiologists for lead perforation and position of right atrial and right ventricular leads. Follow-up radiographs were assessed for lead perforation, lead displacement, and lead fracture. Data were analysed by using the Fisher exact test. Of the patients, 1.7% (10/581) required reoperation for pacemaker dysfunction (noncapture, oversensing, abnormal atrial and ventricular thresholds, failing impedance), extracardiac stimulation, and lead perforation and/or displacement. There were no lead fractures. Chest radiographs demonstrated pacemaker complications in 57% of patients (8/14) at a median of 2 days (<1-32 days) after implantation and in 5% of the controls (2/42) (P < .0001). None of the abnormalities were noted on the official reports. Among subgroups, chest radiographs were abnormal for the following indications: pacemaker dysfunction in 4 of 7 patients versus 0 of 21 controls (P = .0017), extracardiac stimulation in 1 of 3 patients vs 0 of 9 controls (P = .25), and lead perforation and/or displacement in 3 of 4 patients vs 2 of 12 controls (P = .06). Chest radiographs are useful after pacemaker placement and demonstrate the majority of complications that require reoperation. Familiarity with the expected normal position of the leads, appearances of pacemaker complications, and comparison with prior radiographs is crucial in rendering a correct diagnosis that guides patient management.


Return-to-work self-efficacy: development and validation of a scale in claimants with musculoskeletal disorders.
INTRODUCTION We report on the development and validation of a 10-item scale assessing self-efficacy within the return-to-work context, the Return-to-Work Self-Efficacy (RTWSE) scale. METHODS Lost-time claimants completed a telephone survey 1 month (n = 632) and 6 months (n = 446) after a work-related musculoskeletal injury. Exploratory (Varimax and Promax rotation) and confirmatory factor analyses of self-efficacy items were conducted with two separate subsamples at both time points. Construct validity was examined by comparing scale measurements and theoretically derived constructs, and the phase specificity of RTWSE was studied by examining changes in strength of relationships between the RTWSE Subscales and the other constructs at both time measures. RESULTS Factor analyses supported three underlying factors: (1) Obtaining help from supervisor, (2) Coping with pain (3) Obtaining help from co-workers. Internal consistency (alpha) for the three subscales ranged from 0.66 to 0.93. The total variance explained was 68% at 1-month follow-up and 76% at 6-month follow-up. Confirmatory factor analyses had satisfactory fit indices to confirm the initial model. With regard to construct validity: relationships of RTWSE with depressive symptoms, fear-avoidance, pain, and general health, were generally in the hypothesized direction. However, the hypothesis that less advanced stages of change on the Readiness for RTW scale would be associated with lower RTWSE could not be completely confirmed: on all RTWSE subscales, RTWSE decreased significantly for a subset of participants who started working again. Moreover, only Pain RTWSE was significantly associated with RTW status and duration of work disability. With regard to the phase specificity, the strength of association between RTWSE and other constructs was stronger at 6 months post-injury compared to 1 month post-injury. CONCLUSIONS A final 10-item version of the RTWSE has adequate internal consistency and validity to assess the confidence of injured workers to obtain help from supervisor and co-workers and to cope with pain. With regard to phase specificity, stronger associations between RTWSE and other constructs at 6-month follow-up suggest that the association between these psychological constructs consolidates over time after the disruptive event of the injury.


Single Nucleotide Polymorphisms (SNPs) Reveal Sibship Among Founders of a Bangladeshi Rohu (Labeo rohita) Breeding Population.
Rohu (Labeo rohita) is a significant freshwater aquaculture species with approximately 1.8 Mt produced annually. Fin clips obtained from the founders of a newly established Bangladesh-based breeding population (∼140 fish from each of the Halda, Jamuna, and Padma rivers) were used to identify 9157 SNPs and 14 411 silicoDArT markers using the Diversity Arrays Technology (DArT) genotyping-by-sequencing platform known as DArTseq. After quality control, 1985 SNPs were retained and used to examine population structure within and among river systems. Examination of genomic relationships revealed evidence of full- and half-sibling relationships among founders. Accordingly, sibship and dummy parents were assigned within each river population using a maximum likelihood approach with COLONY software. Founders that had no dummy parents in common were then identified for population genetic analyses. Only 40 unique dummy parents and 17 founders with no common dummy parents were identified from the Halda river, compared with 206 (96) from the Jamuna and 184 (83) from the Padma. Overall pairwise FST estimates among rivers were low (<0.005) and the optimum number of clusters using unsupervised K-means clustering was one, indicating little genetic divergence among the river populations in our SNPs. These results suggest that observed sibship among founders should be accounted for in future pedigree-based analyses and it cannot be assumed that fertilized spawn collections are representative samples of river populations.


Semiconducting nanowires from hairpin-shaped self-assembling sexithiophenes.
Conjugated organic molecules can be designed to self-assemble from solution into nanostructures for functions such as charge transport, light emission, or light harvesting. We report here the design and synthesis of a novel hairpin-shaped self-assembling molecule containing electronically active sexithiophene moieties. In several nonpolar organic solvents, such as toluene or chlorocyclohexane, this compound was found to form organogels composed of nanofibers with uniform diameters of 3.0 (±0.3) nm. NMR analysis and spectroscopic measurements revealed that the self-assembly is driven by π-π interactions of the sexithiophene moieties and hydrogen bonding among the amide groups at the head of the hairpin. Field effect transistors built with this molecule revealed p-type semiconducting behavior and higher hole mobilities when films were cast from solvents that promote self-assembly. We propose that hydrogen bonding and π-π stacking act synergistically to create ordered stacking of sexithiophene moieties, thus providing an efficient pathway for charge carriers within the nanowires. The nanostructures formed exhibit unusually broad absorbance in their UV-vis spectrum, which we attribute to the coexistence of both H and J aggregates from face-to-face π-π stacking of sexithiophene moieties and hierarchical bundling of the nanowires. The large absorption range associated with self-assembly of the hairpin molecules makes them potentially useful in light harvesting for energy applications.


Novel neuropeptides related to frog growth hormone-releasing peptide: isolation, sequence, and functional analysis.
We previously identified in the bullfrog a novel hypothalamic RFamide peptide (SLKPAANLPLRF-NH(2)) that stimulated GH release in vitro and in vivo and therefore was designated frog GH-releasing peptide (fGRP). Molecular cloning of cDNA encoding the deduced fGRP precursor polypeptide further revealed that it encodes fGRP and its related peptides (fGRP-RP-1, -RP-2, and -RP-3). In this study immunoaffinity purification using the antibody against fGRP was therefore conducted to determine whether these three putative fGRP-RPs exist as mature endogenous ligands in the frog brain. The mass peaks of the isolated immunoreactive substances were detected at 535.78, 1034.14, and 1079.71 m/z ([M+2H](2+)), and their sequences, SIPNLPQRF-NH(2), YLSGKTKVQSMANLPQRF-NH(2), and AQYTNHFVHSLDTLPLRF-NH(2), were revealed by the fragmentation, showing mature forms encoded in the cDNA sequences of fGRP-RP-1, -RP-2, and -RP-3, respectively. All of these fGRP-RPs contained a C-terminal -LPXRF-NH(2) (X = L or Q) sequence, such as fGRP. This study further analyzed hypophysiotropic activities of the identified endogenous fGRP-RPs. Only fGRP-RP-2 stimulated, in a dose-related way, the release of PRL from cultured frog pituitary cells; its threshold concentration ranged from less than 10(-7) M. A similar stimulatory action of fGRP-RP-2 on GH release was evident. It was ascertained that fGRP-RP-2 was also effective in elevating the circulating GH and PRL levels when administered systemically. In contrast, fGRP-RPs did not have any appreciable effect on the release of gonadotropins. Thus, fGRP-RP-2 may act as a novel hypothalamic factor on the frog pituitary to stimulate the release of GH and PRL.


Female drinking, environment and biological markers.
The rate of women involved in alcohol abuse is rapidly increasing and the age of first use tends dramatically to decrease. The health and social costs are high both for the adverse effects on physical and psychological woman health, and for the teratogenic effect of alcohol on fetal development. The review takes in account physiological aspects of alcohol effects according to age and gender differences. Interaction between alcohol habit and environment are discussed together with the risk of co-exposure to alcohol and pollutants. The role of biomarkers may be invaluable for clinical utility, prevention and early intervention above all to avoid prenatal, not reversible damages. The update of alcohol studies shows the greater severity of alcohol damage in female and the need of gender-targeted intervention.


Attenuation of a dengue virus replicon by codon deoptimization of nonstructural genes.
The overwhelming increase of dengue virus (DENV) infections in recent years shows that current strategies to combat dengue do not work. The lack of a highly effective dengue vaccine and the limited effectivity of vector controls exacerbate this situation. To point the way to a novel method of creating DENV vaccine candidates, here we disrupted the codon usage in a DENV-2 reporter replicon to generate variants with different replication characteristics. Six different mutated constructs containing stretches of altered codon usage in the non-structural genes were generated. The mutated sequences were deoptimized to the least favorable codons for human cells. We studied the replication efficiency of these constructs by measuring luciferase reporter activity, relative RNA fold change, and NS1 secretion. Our findings showed that the level of virus attenuation is closely associated with the amount of codon deoptimization. Indeed, replication was completely abolished in extensively-deoptimized constructs D2Rep-6 and D2Rep-5, intermediate with constructs D2Rep-4 (771 bp silent mutations) and D2Rep-3 (756 bp silent mutations) and restored almost to wildtype levels with constructs D2Rep-2 (394 silent mutations) and D2Rep-1 (48 silent mutations). We also determined that the position of codon deoptimization within the genome is crucial to the degree of attenuation observed. Based on our analysis, we propose that the design for an ideal DENV vaccine candidate could include 700-1500 silent mutations within the NS2A and NS3 genes. Our results suggest that codon deoptimization is an ideal strategy that can readily be used to develop a DENV vaccine candidate with "fine-tuned" attenuation.


Functional Movement Screen Composite Scores in Firefighters: Effects of Corrective Exercise Training.
Firefighters require a high level of functional fitness to operate safely, effectively, and efficiently. The authors studied the distribution of functional movement screen (FMS) scores in firefighters and examined whether an 8-week corrective exercise program based on National Academy of Sport Medicine guidelines could improve them. All 524 active firefighters of a city completed the baseline FMS testing. Those who obtained a score of 14 or less, a sign of movement dysfunction, and volunteered to continue their participation were randomly assigned to either an experimental (n = 51) or a control (n = 45) group. Both groups participated in an 8-week training program. The control group used their own usual training routine, but the experimental group used the specific protocol designed for the study. The FMS scores of 43% of the population were less than 14. Repeated-measures analysis of variance revealed a significant interaction between FMS scores of the groups (F1,94 =165, P < .001). The experimental group showed a 69% improvement from pretest (10.6) to posttest (17.8), whereas the control group showed only a 3% improvement from pretest (11.8) to posttest (12.1). Preceding studies have shown that FMS scores less than 14 increase the injury risk. The findings showed that using our proposed training protocol, low FMS scores could be improved to 14 and higher. Considering the high injury rate of firefighters, the authors suggest administering FMS periodically and to use a training protocol such as ours, to increase functional fitness and reduce injury risk.


Low vitamin D status is associated with more depressive symptoms in Dutch older adults.
The existence of vitamin D receptors in the brain points to a possible role of vitamin D in brain function. We examined the association of vitamin D status and vitamin D-related genetic make-up with depressive symptoms amongst 2839 Dutch older adults aged ≥65 years. 25-Hydroxyvitamin D (25(OH)D) was measured, and five 'vitamin D-related genes' were selected. Depressive symptoms were measured with the 15-point Geriatric Depression Scale. Results were expressed as the relative risk of the score of depressive symptoms by quartiles of 25(OH)D concentration or number of affected alleles, using the lowest quartile or minor allele group as reference. A clear cross-sectional and prospective association between serum 25(OH)D and depressive symptom score was observed. Fully adjusted models indicated a 22 % (RR 0.78, 95 % CI 0.68-0.89), 21 % (RR 0.79, 95 % CI 0.68-0.90), and 18 % (RR 0.82, 95 % CI 0.71-0.95) lower score of depressive symptoms in people in the second, third, and fourth 25(OH)D quartiles, when compared to people in the first quartile (P for trend <0.0001). After 2 years of daily 15 µg vitamin D supplementation, similar associations were observed. 25(OH)D concentrations did not significantly interact with the selected genes. Low serum 25(OH)D was associated with higher depressive symptom scores. No interactions between 25(OH)D concentrations and vitamin D genetic make-up were observed. In view of the probability of reverse causation, we propose that the association should be further examined in prospective studies as well as in randomized controlled trials.


Intermittent stick-slip dynamics during the peeling of an adhesive tape from a roller.
We study experimentally the fracture dynamics during the peeling at a constant velocity of a roller adhesive tape mounted on a freely rotating pulley. Thanks to a high speed camera, we measure, in an intermediate range of peeling velocities, high frequency oscillations between phases of slow and rapid propagation of the peeling fracture. This so-called stick-slip regime is well known as the consequence of a decreasing fracture energy of the adhesive in a certain range of peeling velocity coupled to the elasticity of the peeled tape. Simultaneously with stick slip, we observe low frequency oscillations of the adhesive roller angular velocity which are the consequence of a pendular instability of the roller submitted to the peeling force. The stick-slip dynamics is shown to become intermittent due to these slow pendular oscillations which produce a quasistatic oscillation of the peeling angle while keeping constant the peeling fracture velocity (averaged over each stick-slip cycle). The observed correlation between the mean peeling angle and the stick-slip amplitude questions the validity of the usually admitted independence with the peeling angle of the fracture energy of adhesives.


Subpressor angiotensin II infusions do not stimulate sympathetic activity in humans.
Angiotensin II (ANG II) exerts significant direct and indirect pressor and chronotropic effects in experimental animals. The indirect effects have been shown to be due to interactions with the sympathetic nervous system at several levels. To test the hypothesis that ANG II in subpressor doses enhances the activity of the sympathetic nervous system in humans either at rest or in response to a stimulus from baroreceptor unloading, we measured mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine (NE), and plasma NE kinetics during infusions of ANG II at 2 ng.kg-1. min-1 [or 5% dextrose in water (D5/W) control in six healthy volunteers in the supine position and during 60 degrees head-up tilt. No changes in any measured variable occurred during either infusion in the supine position. During upright tilt with D5/W, HR increased (58 +/- 8.4 to 68 +/- 7.7 beats/min, P less than 0.005), MAP rose slightly (90 +/- 3.9 to 94 +/- 4.0 mmHg, P less than 0.005), and plasma NE increased (213 +/- 3.8 to 366 +/- 83 pg/ml, P less than 0.005). The responses of the variables to tilt during ANG II were not different from those with D5/W.(ABSTRACT TRUNCATED AT 250 WORDS)


Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.
Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.


Aquaporin CHIP: the archetypal molecular water channel.
Despite longstanding interest by nephrologists and physiologists, the molecular identities of membrane water channels remained elusive until recognition of CHIP, a 28-kDa channel-forming integral membrane protein from human red blood cells originally referred to as "CHIP28." CHIP functions as an osmotically driven, water-selective pore; 1) expression of CHIP conferred Xenopus oocytes with markedly increased osmotic water permeability but did not allow transmembrane passage of ions or other small molecules; 2) reconstitution of highly purified CHIP into proteoliposomes permitted determination of the unit water permeability, i.e., 3.9 x 10(9) water molecules.channel subunit-1 x s-1. Although CHIP exists as a homotetramer in the native red blood cell membrane, site-directed mutagenesis studies suggested that each subunit contains an individually functional pore that may be reversibly occluded by mercurial inhibitors reacting with cysteine-189. CHIP is a major component of both apical and basolateral membranes of water-permeable segments of the nephron, where it facilitates transcellular water flow during reabsorption of glomerular filtrate. CHIP is also abundant in certain other absorptive or secretory epithelia, including choroid plexus, ciliary body of the eye, hepatobiliary ductules, gall bladder, and capillary endothelia. Distinct patterns of CHIP expression occur at these sites during fetal development and maturity. Similar proteins from other mammalian tissues and plants were later shown to transport water, and the group is now referred to as the "aquaporins." Recognition of CHIP has provided molecular insight into the biological phenomenon of osmotic water movement, and it is hoped that pharmacological modulation of CHIP function may provide novel treatments of renal failure and other clinical problems.


The Connection of the Genetic, Cultural and Geographic Landscapes of Transoxiana.
We have analyzed Y-chromosomal variation in populations from Transoxiana, a historical region covering the southwestern part of Central Asia. We studied 780 samples from 10 regional populations of Kazakhs, Uzbeks, Turkmens, Dungans, and Karakalpaks using 35 SNP and 17 STR markers. Analysis of haplogroup frequencies using multidimensional scaling and principal component plots, supported by an analysis of molecular variance, showed that the geographic landscape of Transoxiana, despite its distinctiveness and diversity (deserts, fertile river basins, foothills and plains) had no strong influence on the genetic landscape. The main factor structuring the gene pool was the mode of subsistence: settled agriculture or nomadic pastoralism. Investigation of STR-based clusters of haplotypes and their ages revealed that cultural and demic expansions of Transoxiana were not closely connected with each other. The Arab cultural expansion introduced Islam to the region but did not leave a significant mark on the pool of paternal lineages. The Mongol expansion, in contrast, had enormous demic success, but did not impact cultural elements like language and religion. The genealogy of Muslim missionaries within the settled agricultural communities of Transoxiana was based on spiritual succession passed from teacher to disciple. However, among Transoxianan nomads, spiritual and biological succession became merged.


Science and Engineering Ph.D. Students' Career Outcomes, by Gender.
We examine differences in the careers of men and women Ph.D.s from two major European universities. Having performed regression analysis, we find that women are more likely than men to be employed in public administration when the alternatives are either academia or industry. Between the latter two alternatives, women are more likely to be employed in academia. These gender differences persist after accounting for Ph.D.s' and their supervisors' characteristics. Gender gaps are smaller for Ph.D.s with large research outputs and for those who conducted applied research. Restricting the analysis to Ph.D.s who pursued postdoc training, women are less likely than men to be employed in highly ranked universities, even after controlling for their research outputs. Finally, we find gender differences in Ph.D.s' appointment to professorship, which are explained by the Ph.D.s' publication output and the quality of their postdoc training.


The APC subunit Doc1 promotes recognition of the substrate destruction box.
Accurate chromosome segregation during mitosis requires the coordinated destruction of the mitotic regulators securin and cyclins. The anaphase-promoting complex (APC) is a multisubunit ubiquitin-protein ligase that catalyzes the polyubiquitination of these and other proteins and thereby promotes their destruction. How the APC recognizes its substrates is not well understood. In mitosis, the APC activator Cdc20 binds to the APC and is thought to recruit substrates by interacting with a conserved target protein motif called the destruction box. A related protein, called Cdh1, performs a similar function during G1. Recent evidence, however, suggests that the core APC subunit Doc1 also contributes to substrate recognition. To better understand the mechanism by which Doc1 promotes substrate binding to the APC, we generated a series of point mutations in Doc1 and analyzed their effects on the processivity of substrate ubiquitination. Mutations that reduce Doc1 function fall into two classes that define spatially and functionally distinct regions of the protein. One region, which includes the carboxy terminus, anchors Doc1 to the APC but does not influence substrate recognition. The other region, located on the opposite face of Doc1, is required for Doc1 to enhance substrate binding to the APC. Importantly, stimulation of binding by Doc1 also requires that the substrate contain an intact destruction box. Cells carrying DOC1 mutations that eliminate substrate recognition delay in mitosis with high levels of APC substrates. Doc1 contributes to recognition of the substrate destruction box by the APC. This function of Doc1 is necessary for efficient substrate proteolysis in vivo.


Continuous Quality Improvement and Comprehensive Primary Health Care: A Systems Framework to Improve Service Quality and Health Outcomes.
Continuous quality improvement (CQI) processes for improving clinical care and health outcomes have been implemented by primary health-care services, with resultant health-care impacts. But only 10-20% of gain in health outcomes is contributed by health-care services; a much larger share is determined by social and cultural factors. This perspective paper argues that health care and health outcomes can be enhanced through applying CQI as a systems approach to comprehensive primary health care. Referring to the Aboriginal and Torres Strait Islander Australian context as an example, the authors provide a systems framework that includes strategies and conditions to facilitate evidence-based and local decision making by primary health-care services. The framework describes the integration of CQI vertically to improve linkages with governments and community members and horizontally with other sectors to influence the social and cultural determinants of health. Further, government and primary health-care service investment is required to support and extend integration and evaluation of CQI efforts vertically and horizontally.


Validation of a quantitative PCR diagnostic method for detection of the microsporidian Ovipleistophora ovariae in the cyprinid fish Notemigonus crysoleucas.
Microsporidian parasites are easily detected by light microscopy when infections are heavy and spores are present. However, early infections without spores, or light infections with low numbers of spores, are easily missed. This limitation has made it difficult to conduct investigations into microsporidian prevalence and transmission. In this study, we developed a quantitative TaqMan polymerase chain reaction assay to assess the presence of Ovipleistophora ovariae in the tissues of the cyprinid fish Notemigonus crysoleucas (golden shiner). The efficiency of the primer set was 100.8%, with a correlation coefficient of threshold position to copy number of 0.997 over 9 logs using a plasmid containing the cloned reaction product. No product was produced from other closely related microsporidian species (Nucleospora salmonis, Pseudoloma neurophila, Glugea stephani, Heterosporis sp., and O. mirandella). The coefficient of variation for replicate assays done on different days was 12.4%. The assay detects O. ovariae reliably at less than 10 genomic copies and 0.14 spores per reaction, but maximum sensitivity is only achieved when sonication is included as part of the DNA purification step. Using the assay, we found 4.44 x 10(1) to 7.91 x 10(6) copies microg(-1) host DNA in female golden shiners, with the spore density increasing during the spawning season. The parasite was also detected for the first time in the testes of male golden shiners at 2.60 x 10(1) to 8.62 x 102 copies microg(-1) host DNA.


Assessing the general health of diagnostic orphans using the Short Form Health Survey (SF-12v2): a latent variable modelling approach.
Research has demonstrated that diagnostic orphans (i.e. individuals who experience only one to two criteria of DSM-IV alcohol dependence) can encounter significant health problems. Using the SF-12v2, this study examined the general health functioning of alcohol users, and in particular, diagnostic orphans. Current drinkers (n = 26,913) in the National Epidemiologic Survey on Alcohol and Related Conditions were categorized into five diagnosis groups: no alcohol use disorder (no-AUD), one-criterion orphans, two-criterion orphans, alcohol abuse and alcohol dependence. Latent variable modelling was used to assess the associations between the physical and mental health factors of the SF-12v2 and the diagnosis groups and a variety of background variables. In terms of mental health, one-criterion orphans had significantly better health than two-criterion orphans and the dependence group, but poorer health than the no-AUD group. No significant differences were evident between the one-criterion orphan group and the alcohol abuse group. One-criterion orphans had significantly poorer physical health when compared to the no-AUD group. One- and two-criterion orphans did not differ in relation to physical health. Consistent with previous research, diagnostic orphans in the current study appear to have experienced clinically relevant symptoms of alcohol dependence. The current findings suggest that diagnostic orphans may form part of an alcohol use disorders spectrum severity.


Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats.
The hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Chronic Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake under extended access conditions, a model that mimics key features of compulsive cocaine taking. In addition, Hcrt silencing decreased motivation for both cocaine and a highly palatable food reward (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence for general measures of arousal and stress reactivity. At the molecular level, chronic Hcrt knockdown reduced the number of neurons expressing dynorphin (DYN), and to a smaller extent melanin-concentrating hormone (MCH), in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low-effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling.


Photochemical decoration of magnetic composites with silver nanostructures for determination of creatinine in urine by surface-enhanced Raman spectroscopy.
In this study, silver nanostructures decorated magnetic nanoparticles for surface-enhanced Raman scattering (SERS) measurements were prepared via photoreduction utilizing the catalytic activity of ZnO nanostructure. The ZnO/Fe3O4 composite was first prepared by dispersing pre-formed magnetic nanoparticles into alkaline zinc nitrate solutions. After annealing of the precipitates, the formed ZnO/Fe3O4 composites were successfully decorated with silver nanostructures by soaking the composites into silver nitrate/ethylene glycol solution following UV irradiations. To find the optimal condition when preparing Ag@ZnO/Fe3O4 composites for SERS measurements, factors such as the reaction conditions, photoreduction time, concentration of zinc nitrate and silver nitrate were studied. Results indicated that the photoreduction efficiency was significantly improved with the assistance of ZnO but the amount of ZnO in the composite is not critical. The concentration of silver nitrate and UV irradiation time affected the morphologies of the formed composites and optimal condition in preparation of the composites for SERS measurement was found using 20mM of silver nitrate with an irradiation time of 90 min. Under the optimized condition, the obtained SERS intensities were highly reproducible with a SERS enhancement factor in the order of 7. Quantitative analyses showed that a linear range up to 1 µM with a detection limit lower than 0.1 µM in the detection of creatinine in aqueous solution could be obtained. Successful applying of these prepared composites to determine creatinine in urine sample was obtained.


Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the Offspring.
Little attention has been paid to the potential impact of paternal marijuana use on offspring brain development. We administered Δ9-tetrahydrocannabinol (THC, 0, 2, or 4 mg/kg/day) to male rats for 28 days. Two days after the last THC treatment, the males were mated to drug-naïve females. We then assessed the impact on development of acetylcholine (ACh) systems in the offspring, encompassing the period from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), and including brain regions encompassing the majority of ACh terminals and cell bodies. Δ9-Tetrahydrocannabinol produced a dose-dependent deficit in hemicholinium-3 binding, an index of presynaptic ACh activity, superimposed on regionally selective increases in choline acetyltransferase activity, a biomarker for numbers of ACh terminals. The combined effects produced a persistent decrement in the hemicholinium-3/choline acetyltransferase ratio, an index of impulse activity per nerve terminal. At the low THC dose, the decreased presynaptic activity was partially compensated by upregulation of nicotinic ACh receptors, whereas at the high dose, receptors were subnormal, an effect that would exacerbate the presynaptic defect. Superimposed on these effects, either dose of THC also accelerated the age-related decline in nicotinic ACh receptors. Our studies provide evidence for adverse effects of paternal THC administration on neurodevelopment in the offspring and further demonstrate that adverse impacts of drug exposure on brain development are not limited to effects mediated by the embryonic or fetal chemical environment, but rather that vulnerability is engendered by exposures occurring prior to conception, involving the father as well as the mother.


Possibilities for intervention in adolescents' and young adults' depression from a public health perspective.
When considering measures to decrease the burden of disease that is caused by depression, depressive disorders of adolescents and young adults are of increasing interest. The prevalence of depressive disorders in adolescents and young adults is high. The probable increases in prevalence affect predominantly young people and their prognosis is particularly bad. This review discusses the potentials to influence the burden of disease through interventions such as therapy, including measures to detect persons at risk early, selective and universal prevention, and health promotion for adolescents and young adults. It considers the available evidence for the effectiveness of these interventions on the public health level. In addition, the suitability of implementation and ethical considerations are discussed. As a conclusion, health policy in its aim to reduce the burden of depressive disease should focus on increasing treatment rates and improving the efficiency of treatment in adolescents and young adults as well for depression as for other mental disease that has high co-morbidity with depression. In addition, the focus should be set on indicated prevention for children of depressed parents and--for health promotion reasons--on policies that impact on living-conditions of families.


Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria.
Acute kidney injury (AKI) is a recognized complication of pediatric severe malaria, but its long-term consequences are unknown. Ugandan children with cerebral malaria (CM, n = 260) and severe malaria anemia (SMA, n = 219) or community children (CC, n = 173) between 1.5 and 12 years of age were enrolled in a prospective cohort study. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to retrospectively define AKI and chronic kidney disease (CKD). Cognitive testing was conducted using the Mullen Scales of Early Learning in children < 5 and Kaufman Assessment Battery for Children (K-ABC) second edition in children ≥ 5 years of age. The prevalence of AKI was 35.1%, ranging from 25.1% in SMA to 43.5% in CM. In-hospital mortality was 11.9% in AKI compared to 4.2% in children without AKI (p = 0.001), and post-discharge mortality was 4.7% in AKI compared to 1.3% in children without AKI (p = 0.030) corresponding to an all-cause adjusted hazard ratio of 2.30 (95% CI 1.21, 4.35). AKI was a risk factor for short- and long-term neurocognitive impairment. At 1 week post-discharge, the frequency of neurocognitive impairment was 37.3% in AKI compared to 13.5% in children without AKI (adjusted odds ratio (aOR) 2.31 [95% CI 1.32, 4.04]); at 1-year follow-up, it was 13.3% in AKI compared to 3.4% in children without AKI (aOR 2.48 [95% CI 1.01, 6.10]), and at 2-year follow-up, it was 13.0% in AKI compared to 3.4% in children without AKI (aOR 3.03 [95% CI 1.22, 7.58]). AKI was a risk factor for CKD at 1-year follow-up: 7.6% of children with severe malaria-associated AKI had CKD at follow-up compared to 2.8% of children without AKI (p = 0.038) corresponding to an OR of 2.81 (95% CI 1.02, 7.73). The presenting etiology of AKI was consistent with prerenal azotemia, and lactate dehydrogenase as a marker of intravascular hemolysis was an independent risk factor for AKI in CM and SMA (p < 0.0001). In CM, AKI was associated with the presence and severity of retinopathy (p < 0.05) and increased cerebrospinal fluid albumin suggestive of blood-brain barrier disruption. AKI is a risk factor for long-term neurocognitive impairment and CKD in pediatric severe malaria.


Nurse-led empowerment strategies for patients with hypertension: a questionnaire survey.
Hypertension is common and may lead to cerebrovascular and cardiovascular events and mortality. District nurses frequently encounter patients requiring blood pressure monitoring, lifestyle counsel and support. Empowerment as a method enables patients to both increase their control over their health and improve it. This study aims to describe the effects of the counsel and support from district nurses to patients with hypertension. A randomized controlled intervention trial. Questionnaires were answered by patients with hypertension before and after the intervention comprising district nurses' counsel and support based upon empowerment. A specially developed card for blood pressure monitoring was also used. Blood pressure decreased in intervention and the control groups. The intervention group experienced significantly improved health, with better emotional and physical health, and reduced stress. Living habits did not change significantly in either group. Satisfaction with knowledge of hypertension increased significantly in both groups. The intervention group reported that their care was based upon their health needs. Conducting large multi-centre studies with long follow-ups is complicated and results sometimes have a tendency to decline with time. A shorter follow-up might have shown a greater difference between the groups. Nursing interventions through district nurses' counsel and support with empowerment improved patients' health. More research is needed to evaluate nursing interventions' effect on hypertension. This study highlighted that district nurses' counsel and support increased patients' health and decreased stress by focusing on empowerment.


How Do Atrial-Selective Drugs Differ From Antiarrhythmic Drugs Currently Used in the Treatment of Atrial Fibrillation?
Current pharmacologic strategies for the management of Atrial fibrillation (AF) include use of 1) sodium channel blockers, which are contraindicated in patients with coronary artery or structural heart disease because of their potent effect to slow conduction in the ventricles, 2) potassium channel blockers, which predispose to acquired long QT and Torsade de Pointes arrhythmias because of their potent effect to prolong ventricular repolarization, and 3) mixed ion channel blockers such as amiodarone, which are associated with multi-organ toxicity. Accordingly, recent studies have focused on agents that selectively affect the atria but not the ventricles. Several Atrial-selective approaches have been proposed for the management of AF, including inhibition of the Atrial-specific ultra rapid delayed rectified potassium current (IKur), acetylcholine-regulated inward rectifying potassium current (IK-ACh), or connexin-40 (Cx40). All three are largely exclusive to atria. Recent studies have proposed that an Atrial-selective depression of sodium channel-dependent parameters with agents such as ranolazine may be an alternative approach capable of effectively suppressing AF without increasing susceptibility to ventricular arrhythmias. Clinical evidence for Cx40 modulation or IK-ACh inhibition are lacking at this time. The available data suggest that Atrial-selective approaches involving a combination of INa, IKur, IKr, and, perhaps, Ito block may be more effective in the management of AF than pure IKur or INa block. The anti-AF efficacy of the Atrial-selective/predominant agents appears to be similar to that of conventionally used anti-AF agents, with the major apparent difference being that the latter are associated with ventricular arrhythmogenesis and extra cardiac toxicity.


Direct Automatic Coronary Calcium Scoring in Cardiac and Chest CT.
Cardiovascular disease (CVD) is the global leading cause of death. A strong risk factor for CVD events is the amount of coronary artery calcium (CAC). To meet the demands of the increasing interest in quantification of CAC, i.e., coronary calcium scoring, especially as an unrequested finding for screening and research, automatic methods have been proposed. The current automatic calcium scoring methods are relatively computationally expensive and only provide scores for one type of CT. To address this, we propose a computationally efficient method that employs two convolutional neural networks: the first performs registration to align the fields of view of input CTs and the second performs direct regression of the calcium score, thereby circumventing time-consuming intermediate CAC segmentation. Optional decision feedback provides insight into the regions that are contributed to the calcium score. Experiments were performed using 903 cardiac CT and 1687 chest CT scans. The method predicted calcium scores in less than 0.3 s. The intra-class correlation coefficient between predicted and manual calcium scores was 0.98 for both cardiac and chest CT. The method showed almost perfect agreement between automatic and manual CVD risk categorization in both the datasets, with a linearly weighted Cohen's kappa of 0.95 in cardiac CT and 0.93 in chest CT. Performance is similar to that of the state-of-the-art methods, but the proposed method is hundreds of times faster. By providing visual feedback, insight is given in the decision process, making it readily implementable in clinical and research settings.


Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders.
Short transverse myelitis (STM; <3 vertebral segments) is considered noncharacteristic of neuromyelitis optica (NMO) spectrum disorders (NMOSDs). Nonappreciation of the potential for STM to occur in NMOSD may lead to increased disability from delay in diagnosis and appropriate treatment. To determine the frequency of short lesions at the initial myelitis manifestation of NMOSD and to compare the demographic, clinical, and radiological characteristics of aquaporin-4-IgG (AQP4-IgG) seropositive and seronegative STM. We reviewed the records and images of patients at the Mayo Clinic who were identified as AQP4-IgG positive from 1996 to 2014. Inclusion criteria were first STM episode, magnetic resonance imaging performed 90 days or less from symptom onset, spinal cord T2-hyperintense lesion less than 3 vertebral segments, AQP4-IgG seropositivity, and a final diagnosis of NMO or NMOSD. Patients with an initial longitudinally extensive transverse myelitis were excluded (n = 151). Patients with STM who were seronegative for AQP4-IgG among an Olmsted County population-based cohort of inflammatory demyelinating disorders of the central nervous system were used as a control group. Delay to diagnosis in months, clinical and radiological characteristics, and disability measured by ambulatory status. Twenty-five patients who were AQP4-IgG seropositive with an initial STM represented 14% of initial myelitis episodes among patients with NMOSD. The STM episode was defined as the first manifestation of NMOSD in 10 patients (40%) preceded by optic neuritis in 13 patients (52%) and preceded by a nausea and vomiting episode in 2 patients (8%). In comparison with the excluded patients with NMOSD who had an initial longitudinally extensive transverse myelitis, delay to diagnosis/treatment was greater when initial lesions were short (P = .02). In AQP4-IgG-positive STM cases, subsequent myelitis episodes were longitudinally extensive in 92%. Attributes more common in patients with AQP4-IgG-positive STM than in 27 population-based patients with AQP4-IgG-negative STM included the following: nonwhite race/ethnicity; tonic spasms; coexisting autoimmunity; magnetic resonance imaging (central cord lesions, T1 hypointensity, and a brain inconsistent with multiple sclerosis); and cerebrospinal fluid (oligoclonal bands lacking). Short transverse myelitis is not uncommon in NMOSD and, when it is present, delays diagnosis and treatment. Clinical and radiological characteristics identified in this study may help select patients with STM who are at the highest risk for an NMOSD. Short transverse myelitis does not exclude consideration of AQP4-IgG testing or NMOSD diagnosis.


Regulation of the terminal event in cellular differentiation: biological mechanisms of the loss of proliferative potential.
Human plasma has been demonstrated to contain factors that induce the sequential expression of nonterminal and terminal adipocyte differentiation in 3T3 T mesenchymal stem cells. We now report the development of methods for the isolation of purified populations of nonterminally differentiated cells and terminally differentiated cells, and we show that it is possible to experimentally induce transition from the nonterminal to the terminal state of differentiation. With this model system it is therefore now possible to examine the biological and molecular processes associated with the terminal event in differentiation, i.e., the irreversible loss of proliferative potential. In this regard, we demonstrate that transition from the nonterminal to terminal state of differentiation is a complex metabolic process that consists of at least two steps and that this process can be triggered by pulse exposure to an inducer for approximately 12 h but that approximately 24-48 h is required for the process to be completed. The data also establish that induction of the terminal event in differentiation requires protein synthesis but not RNA and DNA synthesis. These and additional results suggest that loss of proliferative potential associated with the terminal event in cellular differentiation is a distinct regulatory process, and we suggest that defects in this regulatory process may be of etiological significance in the pathogenesis of specific human diseases, especially cancer.


Analysis of the functional coupling between calmodulin's calcium binding and peptide recognition properties.
The enhancement of calmodulin's (CaM) calcium binding activity by an enzyme or a recognition site peptide and its diminution by key point mutations at the protein recognition interface (e.g., E84K-CaM), which is more than 20 A away from the nearest calcium ligation structure, can be described by an expanded version of the Adair-Klotz equation for multiligand binding. The expanded equation can accurately describe the calcium binding events and their variable linkage to protein recognition events can be extended to other CaM-regulated enzymes and can potentially be applied to a diverse array of ligand binding systems with allosteric regulation of ligand binding, whether by other ligands or protein interaction. The 1.9 A resolution X-ray crystallographic structure of the complex between E84K-CaM and RS20 peptide, the CaM recognition site peptide from vertebrate smooth muscle and nonmuscle forms of myosin light chain kinase, provides insight into the structural basis of the functional communication between CaM's calcium ligation structures and protein recognition surfaces. The structure reveals that the complex adapts to the effect of the functional mutation by discrete adjustments in the helix that contains E84. This helix is on the amino-terminal side of the helix-loop-helix structural motif that is the first to be occupied in CaM's calcium binding mechanism. The results reported here are consistent with a sequential and cooperative model of CaM's calcium binding activity in which the two globular and flexible central helix domains are functionally linked, and provide insight into how CaM's calcium binding activity and peptide recognition properties are functionally coupled.


Identifying top-performing hospitals by algorithm: results from a demonstration project.
Because of the move toward performance-based reimbursement, identification of top-performing hospitals has acquired new importance. The High Performance Algorithm (HPA) for hospitals was developed on the basis of the following principles: (1) the approach must be data driven and transparent, (2) all hospitals providing the same service are held to the same standard, (3) top-performing hospitals must perform well on easily achieved and difficult quality measures, and (4) high performance demands sustained excellence over time. The HPA algorithm was applied to 16 quality measures from the national Hospital Quality Alliance (July 2003-June 2004) for acute myocardial infarction (AMI), heart failure (HF), and pneumonia. Top-performing hospitals were defined as those with the top 1% of HPA scores (n = 45). From all 3,867 hospitals, median HPA scores (interquartile range) were 17.0 (16.0-19.0) for top-performing hospitals and 3.0 (1.0-6.0) for others (p < .001). Mean performance on quality measures was higher for top hospitals on all 16 measures. For example, on administration of angiotensin-converting enzyme inhibitors to patients with HF, the mean score for top-performing hospitals was 93.3%, compared with 76.5% for others (p < .001). Although many hospitals achieved excellence on individual measures, sustained top performance across multiple conditions and time periods was uncommon, with < 1% of hospitals scoring > or = 16/36 points on the HPA scale. Using national, publicly reported data, the HPA provided good discrimination between top-performing and other hospitals. This project sets the stage for future comparisons of organizational, leadership, and policy differences between top-performing and other hospitals.


A qualitative investigation of low-income abortion clients' attitudes toward public funding for abortion.
We explored how low-income abortion clients in states where public funding was and was not available perceived the role of public funding for abortion. From October 2010 through February 2011, we conducted 71 semi-structured in-depth telephone interviews with low-income abortion clients in Arizona, Florida, New York, and Oregon. Women reported weighing numerous factors when determining which circumstances warranted public funding. Though most women generally supported coverage, they deviated from their initial support when asked about particular circumstances. Respondents felt most strongly that abortion should not be covered when a woman could not afford another child or was pregnant outside of a romantic relationship. Participants used disparaging language to describe the presumed behavior of women faced with unintended pregnancies. In seeking to discredit "other" women's abortions, women revealed the complex nature of abortion stigma. We propose that women's abortion experiences and subsequent opinions on coverage indicated three distinct manifestations of abortion stigma: women (1) resisted the prominent discourse that marks women who have had abortions as selfish and irresponsible; (2) internalized societal norms that stereotype women based on the circumstances surrounding the abortion; and (3) reproduced stigma by distancing themselves from the negative stereotypes associated with women who have had abortions.


Surveillance of Wildlife Diseases: Lessons from the West Nile Virus Outbreak.
The West Nile virus outbreak of 1999 revealed many weaknesses in this country's ability to respond to disease threats that cross species lines. There were issues of poor communication among human, domestic animal, and wildlife health agencies that delayed diagnosis; a lack of diagnostic capacity of wildlife agencies at the state level; the exclusion of captive wildlife from any surveillance efforts; an inability to visualize the geospatial relationship between the human and avian outbreaks in a timely manner; and marked disparities of funding levels across agencies. Wildlife has played an important role in recent emerging infectious diseases, and it is clear that a One Health approach will be necessary to respond to future threats. The question is, are we any better prepared to recognize and respond to a wildlife-related emerging infectious disease than we were 14 years ago? Have the lessons of WNV been learned?


Determinants of double discharges in amyotrophic lateral sclerosis and Kennedy disease.
Double discharges (DDs) of the motor unit are frequent in amyotrophic lateral sclerosis (ALS) and Kennedy's disease (KD). This likely reflects changes in the intrinsic properties of motor neurons but in ALS changes in corticomotoneuronal inputs may also contribute. We determined the corticomotoneuronal contribution to DDs. DD prevalence, intra-doublet interval (IDI) of DDs and their timing with respect to transcranial magnetic stimulation (TMS)-induced primary peaks (PPs) in the peristimulus time histogram (PSTH) were measured in 23 ALS patients (96 motor units), 11 patients with KD (45 motor units) and 13 control subjects (60 motor units). In patients with KD more motor units (82%) fired DDs than in ALS patients (51%) and control subjects (63%); (p=0.013). DDs occurred before (pre-peak), during (peak), and after (post-suppression) the peristimulus time histogram (PSTH) primary peak. The prevalence of pre-peak DD in KD was 4.06-fold higher (95% CI 0.53-2.81; p=0.0014) than in controls. In contrast the prevalence of ALS peak DDs was 4.79-fold higher (95% CI 1.09-21.10; p=0.041) than in controls. Both pre-peak and peak IDIs were significantly prolonged in ALS compared with controls (p<0.003). Motor unit action potential (MUAP) amplitude, size of the excitatory postsynaptic potential (EPSP) and interspike interval (ISI) all correlated significantly with pre-peak, but not peak DD prevalence. A high peak DD prevalence with prolonged IDIs in ALS are consistent with complex, multiple descending corticomotoneuronal volleys, indicating that the upper motor neuron contributes to the generation of DDs in ALS. Although double discharges are a manifestation of reinnervating motor neurons in ALS the corticomotoneuronal descending input is also influential and probably accounts for some of the distinguishing features of DDs in ALS.


Modeling hepatitis B virus X-induced hepatocellular carcinoma in mice with the Sleeping Beauty transposon system.
The mechanisms associated with hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remain elusive, and there are currently no well-established animal models for studying this disease. Using the Sleeping Beauty transposon as a delivery system, we introduced an oncogenic component of HBV, the hepatitis B virus X (HBx) gene, into the livers of fumarylacetoacetate hydrolase (Fah) mutant mice via hydrodynamic tail vein injections. Coexpression of Fah complementary DNA from the transposon vector allowed for the selective repopulation of genetically corrected hepatocytes in Fah mutant mice. The process of hydrodynamic delivery induced liver inflammation, and the subsequent selective repopulation of hepatocytes carrying the transgene(s) could provide useful genetic information about the mechanisms of HBV-induced hyperplasia. Short hairpin RNA directed against transformation-related protein 53 (shp53) or other tumor suppressor genes and oncogenes [e.g., constitutively active neuroblastoma RAS viral (v-ras) oncogene homolog with Gly12Val substitution (NRAS(G12V) )] could also be codelivered with HBx by this system so that we could determine whether oncogenic cooperation existed. We found that the expression of HBx induced the activation of β-catenin expression in hydrodynamically injected livers, and this indicated its association with the Wnt signaling pathway in HBV-induced hyperplasia. HBx coinjected with shp53 accelerated the formation of liver hyperplasia in these mice. As expected, constitutively active NRAS(G12V) alone was sufficient to induce liver hyperplasia, and its tumorigenicity was augmented when it was coinjected with shp53. Interestingly, HBx did not seem to cooperate with constitutively active NRAS(G12V) in driving liver tumorigenesis. This system can be used as a model for studying the various genetic contributions of HBV to liver hyperplasia and finally HCC in an in vivo system.


Bioelectrical impedance self-measurement protocol development and daily variation between healthy volunteers and breast cancer survivors with lymphedema.
A significant percentage of breast cancer survivors are at risk for lymphedema for which lifelong self-care is required. Previous studies suggest that less than 50% of breast cancer survivors with lymphedema (BCS-LE) perform prescribed self-care tasks and that even wearing a compression sleeve, the most commonly reported self-care activity, is done irregularly. Reasons for poor self-care adherence include perceived lack of results from self-care (no available arm volume data) and perceived inability to manage the condition. A two-part pilot study was conducted to: 1) develop and determine the feasibility of a self-measurement protocol using a single frequency bioelectrical impedance device; and 2) examine daily variation in extracellular volume in healthy and lymphedematous limbs. Healthy and BCS-LE volunteers were recruited to refine and test a self-measurement protocol. Volunteers were trained in the use of the device and measured for 5 consecutive days in a laboratory setting. They were then given the device to use at home for an additional 5 consecutive days of self-measurement. All volunteers completed each scheduled home measurement. Daily variability in both groups was noted. Home self-measurement using bioelectrical impedance is feasible, acceptable, and captures change. This has implications for both self-care support and for the possibility of incorporating self-measurement using bioelectrical impedance in future clinical trials examining effectiveness of lymphedema treatment.


The Reemergent 1977 H1N1 Strain and the Gain-of-Function Debate.
The 1977-1978 influenza epidemic was probably not a natural event, as the genetic sequence of the virus was nearly identical to the sequences of decades-old strains. While there are several hypotheses that could explain its origin, the possibility that the 1977 epidemic resulted from a laboratory accident has recently gained popularity in discussions about the biosafety risks of gain-of-function (GOF) influenza virus research, as an argument for why this research should not be performed. There is now a moratorium in the United States on funding GOF research while the benefits and risks, including the potential for accident, are analyzed. Given the importance of this historical epidemic to ongoing policy debates, we revisit the evidence that the 1977 epidemic was not natural and examine three potential origins: a laboratory accident, a live-vaccine trial escape, or deliberate release as a biological weapon. Based on available evidence, the 1977 strain was indeed too closely matched to decades-old strains to likely be a natural occurrence. While the origin of the outbreak cannot be conclusively determined without additional evidence, there are very plausible alternatives to the laboratory accident hypothesis, diminishing the relevance of the 1977 experience to the modern GOF debate.


Tumor promotion by exposure to radiofrequency electromagnetic fields below exposure limits for humans.
The vast majority of in vitro and in vivo studies did not find cancerogenic effects of exposure to electromagnetic fields (RF-EMF), i.e. emitted by mobile phones and base stations. Previously published results from a pilot study with carcinogen-treated mice, however, suggested tumor-promoting effects of RF-EMF (Tillmann et al., 2010). We have performed a replication study using higher numbers of animals per group and including two additional exposure levels (0 (sham), 0.04, 0.4 and 2 W/kg SAR). We could confirm and extend the originally reported findings. Numbers of tumors of the lungs and livers in exposed animals were significantly higher than in sham-exposed controls. In addition, lymphomas were also found to be significantly elevated by exposure. A clear dose-response effect is absent. We hypothesize that these tumor-promoting effects may be caused by metabolic changes due to exposure. Since many of the tumor-promoting effects in our study were seen at low to moderate exposure levels (0.04 and 0.4 W/kg SAR), thus well below exposure limits for the users of mobile phones, further studies are warranted to investigate the underlying mechanisms. Our findings may help to understand the repeatedly reported increased incidences of brain tumors in heavy users of mobile phones.


Association of stellate mammographic pattern with survival in small invasive breast tumors.
We tested whether the stellate mammographic pattern of presentation of small breast tumors is a better indicator of survival than other patterns. Patients with primary invasive breast cancer diagnosed in 1993-1997 were grouped according to the size of the lesion: 0.1-0.9 cm and 1.0-1.4 cm. Each tumor was placed in one of five mammographic prognostic categories: stellate without calcifications; circular without calcifications; and calcifications with or without tumor mass in a casting, crushed-stone, or other (powdery, punctuate, or round) pattern. To assess reproducibility, a second radiologist gave an independent interpretation in the first 109 cases. Descriptive data were stratified by tumor size, and tests of association were done with an extension of Fisher's exact test. Odds ratios and confidence intervals were computed. Weighted log-rank test and Kaplan-Meier survival curves were used to compare breast cancer survival in the stellate group compared with the other groups. Two hundred one consecutive patients with a median follow-up period of 7.4 years were identified. There were nine breast cancer deaths. The stellate morphologic pattern was most common (91 [45.3%] of 201 cases), yet there was only one breast cancer death in this group (survival rate, 98.9%; 95% confidence interval [CI], 96.7-100%). In the group of stellate lesions smaller than 1.0 cm, 67.6% (25/37) of the tumors were well-differentiated without lymph node metastasis (30 [96.8%] of 31 cases), and there were no deaths. In the group of stellate lesions measuring 1.0-1.4 cm, 66.7% (36/54) of the tumors were well-differentiated with a 19.6% risk of lymph node metastasis, one death, and a survival rate of 98.1% (52/53; 95% CI, 94.4-100%). Circular tumors accounted for 29.9% (60/201) of tumors and 55.6% (5/9) of breast cancer deaths. Casting and crushed-stone microcalcifications were associated with 33.3% (3/9) of disease-specific deaths. A weighted kappa value of 0.89 (CI, 0.83-0.94) indicated very high agreement of pattern assignment. Stellate tumors had a significantly better survival prognosis than tumors with other patterns even though there were no differences in treatment. By recognizing these small malignant lesions, trained radiologists may be able to identify tumors that pose negligible risk of breast cancer death.


β-Aminobutyric acid (BABA)-induced resistance in Arabidopsis thaliana: link with iron homeostasis.
β-Aminobutyric acid (BABA) is a nonprotein amino acid inducing resistance in many different plant species against a wide range of abiotic and biotic stresses. Nevertheless, how BABA primes plant natural defense reactions remains poorly understood. Based on its structure, we hypothesized and confirmed that BABA is able to chelate iron (Fe) in vitro. In vivo, we showed that it led to a transient Fe deficiency response in Arabidopsis thaliana plants exemplified by a reduction of ferritin accumulation and disturbances in the expression of genes related to Fe homeostasis. This response was not correlated to changes in Fe concentrations, suggesting that BABA affects the availability or the distribution of Fe rather than its assimilation. The phenotype of BABA-treated plants was similar to those of plants cultivated in Fe-deficient conditions. A metabolomic analysis indicated that both BABA and Fe deficiency induced the accumulation of common metabolites, including p-coumaroylagmatine, a metabolite previously shown to be synthesized in several plant species facing pathogen attack. Finally, we showed that the protective effect induced by BABA against Botrytis cinerea was mimicked by Fe deficiency. In conclusion, the Fe deficiency response caused by BABA could bring the plant to a defense-ready state, participating in the plant resistance against the pathogens.


Heritable connective tissue disorders in childhood: Decreased health-related quality of life and mental health.
The psychosocial consequences of growing up with Heritable Connective Tissue Disorders (HCTD) are largely unknown. We aimed to assess Health-Related Quality of Life (HRQoL) and mental health of children and adolescents with HCTD. This observational multicenter study included 126 children, aged 4-18 years, with Marfan syndrome (MFS, n = 74), Loeys-Dietz syndrome (n = 8), molecular confirmed Ehlers-Danlos syndromes (n = 15), and hypermobile Ehlers-Danlos syndrome (hEDS, n = 29). HRQoL and mental health were assessed through the parent and child-reported Child Health Questionnaires (CHQ-PF50 and CHQ-CF45, respectively) and the parent-reported Strengths and Difficulties Questionnaire. Compared with a representative general population sample, parent-reported HRQoL of the HCTD-group showed significantly decreased Physical sum scores (p < 0.001, d = 0.9) and Psychosocial sum scores (p = 0.024, d = 0.2), indicating decreased HRQoL. Similar findings were obtained for child-reported HRQoL. The parent-reported mental health of the HCTD-group showed significantly increased Total difficulties sum scores (p = 0.01, d = 0.3), indicating decreased mental health. While the male and female MFS- and hEDS-subgroups both reported decreased HRQoL, only the hEDS-subgroup reported decreased mental health. In conclusion, children and adolescents with HCTD report decreased HRQoL and mental health, with most adverse outcomes reported in children with hEDS and least in those with MFS. These findings call for systematic monitoring and tailored interventions.


HYDROGEN ION CONCENTRATION IN EXUDATES OF PNEUMOCOCCUS INFECTION.
The hydrogen ion concentration in the lesions of experimental pneumococcus infection has been estimated directly by pH determinations on exudates from living animals. For indirect evidence of an increase in hydrogen ion concentration within the lesions, the difference in sugar content between exudate and blood from animals with pneumococcus infection has been measured. With sanguinous exudate from the consolidated lungs of dogs with experimental pneumococcus pneumonia, the findings were not always consistent, but usually there was either direct or indirect evidence of increased hydrogen ion concentration. The physicochemical changes in exudate from animals treated with artificial pneumothorax showed no important differences from those in other specimens. In concurrence with Lord's (1, 2) observation of increased acidity in pneumonia exudate obtained at autopsy, sugar concentrations, which are low in the blood, were markedly reduced in exudates from animals which had died of the infection. Serous exudates from dermal pneumococcus infection in rabbits uniformly showed definite acidity by both direct and indirect methods of estimation. The hydrogen ion concentrations in exudate from dermal pneumococcus infection in rabbits varied between pH 6.87 and 6.66 but were not always proportional to the difference in sugar concentrations between the exudate and blood. While these hydrogen ion concentrations are similar to those attained in the pneumonic exudate from dogs, they are of lesser magnitude than those which Takahashi (3) has described in the pus of secondary empyema due to the pneumococcus.


Detecting myocardial infarction in critical illness using screening troponin measurements and ECG recordings.
To use screening cardiac troponin (cTn) measurements and electrocardiograms (ECGs) to determine the incidence of elevated cTn and of myocardial infarction (MI) in patients admitted to the intensive care unit (ICU), and to assess whether these findings influence prognosis. This is a prospective screening study. We enrolled consecutive patients admitted to a general medical-surgical ICU over two months. All patients underwent systematic screening with cTn measurements and ECGs on ICU admission, then daily for the first week in ICU, alternate days for up to one month and weekly thereafter until ICU death or discharge, for a maximum of two months. Patients without these investigations ordered during routine clinical care underwent screening for study purposes but these results were unavailable to the ICU team. After the study, all ECGs were interpreted independently in duplicate for ischaemic changes meeting ESC/ACC criteria supporting a diagnosis of MI. Patients were classified as having MI (elevated cTn and ECG evidence supporting diagnosis of MI), elevated cTn only (no ECG evidence supporting diagnosis of MI), or no cTn elevation. One hundred and three patients were admitted to the ICU on 112 occasions. Overall, 37 patients (35.9 per cent) had an MI, 15 patients (14.6 per cent) had an elevated cTn only and 51 patients (49.5 per cent) had no cTn elevation. Patients with MI had longer duration of mechanical ventilation (p < 0.0001), longer ICU stay (p = 0.001), higher ICU mortality (p < 0.0001) and higher hospital mortality (p < 0.0001) compared with those with no cTn elevation. Patients with elevated cTn had higher hospital mortality (p = 0.001) than patients without cTn elevation. Elevated cTn was associated with increased hospital mortality (odds ratio 27.3, 95 per cent CI 1.7 - 449.4), after adjusting for APACHE II score, MI and advanced life support. The ICU team diagnosed 18 patients (17.5 per cent) as having MI on clinical grounds; four of these patients did not have MI by adjudication. Thus, screening detected an additional 23 MIs not diagnosed in practice, reflecting 62.2 per cent of MIs ultimately diagnosed. Patients with MI diagnosed by the ICU team had similar outcomes to patients with MI detected by screening alone. Systematic screening detected elevated cTn measurements and MI in more patients than were found in routine practice. Elevated cTn was an independent predictor of hospital mortality. Further research is needed to evaluate whether screening and subsequent treatment of these patients reduces mortality.


Axial birefringence in high-numerical-aperture optical systems and the light distribution close to focus.
The effects of birefringence on the light distribution in the focal region of a high-NA optical system are investigated with use of the Debye approach to vector diffraction theory. The attention is limited to uniaxially birefringent media with symmetry axis along the optical axis of the imaging system. The radially (p) and tangentially (s) polarized fields in the exit pupil produce spots in the focal region that are defocused with respect to each other. For small birefringence values the relative defocus causes a distortion and broadening of the spot; for larger values the two spots separate completely. As a corollary to the theory it is shown that there is a tangential tornadolike flow of energy in the focal region when the polarization in the entrance pupil is elliptical.


Assessing Two Dimensions of Interpersonal Trust: Other-Focused Trust and Propensity to Trust.
One's propensity to trust others and others' trustworthiness are two important aspects of interpersonal trust. Both theory and research suggest that it is possible to distinguish between an individual's propensity to trust (one's "trustingness" or the extent to which one feels able to trust others) and their other-focused trust (the extent to which one feels that others are worthy of our trust). However, there is as yet no measure that distinguishes between these two components of trust. In three studies, we examined the psychometrics of a proposed two-dimensional measure of trust that encompasses propensity to trust and other-focused trust components. To test discriminant validity, we also administered measures of personality, personal self-esteem, social capital, propensity to like people, perceived social support, as well as general and personal beliefs in a just world. Factor analyses supported the proposed two-factor model for the new trust measure. Further analyses supported the difference between these measures.


Physical random bit generation from chaotic solitary laser diode.
We demonstrate the physical generation of random bits at high bit rates (> 100 Gb/s) using optical chaos from a solitary laser diode and therefore without the complex addition of either external optical feedback or injection. This striking result is obtained despite the low dimension and relatively small bandwidth of the laser chaos, i.e. two characteristics that have been so far considered as limiting the performances of optical chaos-based applications. We unambiguously attribute the successful randomness at high speed to the physics of the laser chaotic polarization dynamics and the resulting growth rate of the dynamical entropy.


Understanding Alternative Bullying Perspectives Through Research Engagement With Young People.
Bullying research has traditionally been dominated by largescale cohort studies focusing on the personality traits of bullies and victims. These studies focus on bullying prevalence, risk and protective factors, and negative outcomes. A limitation of this approach is that it does not explain why bullying happens. Qualitative research can help shed light on these factors. This paper discusses the findings from four mainly qualitative research projects including a systematic review and three empirical studies involving young people to various degrees within the research process as respondents, co-researchers and commissioners of research. Much quantitative research suggests that young people are a homogenous group and through the use of surveys and other large scale methods, generalizations can be drawn about how bullying is understood and how it can be dealt with. Findings from the studies presented in this paper, add to our understanding that young people appear particularly concerned about the role of wider contextual and relational factors in deciding if bullying has happened. These studies underscore the relational aspects of definitions of bullying and, how the dynamics of young people's friendships can shift what is understood as bullying or not. Moreover, to appreciate the relational and social contexts underpinning bullying behaviors, adults and young people need to work together on bullying agendas and engage with multiple definitions, effects and forms of support. Qualitative methodologies, in particular participatory research opens up the complexities of young lives and enables these insights to come to the fore. Through this approach, effective supports can be designed based on what young people want and need rather than those interpreted as supportive through adult understanding.


Unemployment and substance outcomes in the United States 2002-2010.
The economic shock of 2008-2009 provided an opportunity to study the robustness of observed statistical associations between unemployment and problematic substance use. Data from 405,000 non-institutionalized adult participants in the 2002 to 2010 U.S. National Survey on Drug Use and Health were used to compare substance outcomes among unemployed and employed persons. Association of unemployment with substance outcomes was examined for the years 2002-2004, 2005-2007, 2008, and 2009-2010, corresponding to periods prior to and after the economic downturn of 2008. Multivariate logistic regression models adjusted for age, sex, race/ethnicity, education, urban/rural residence, current DSM-IV Major Depression, and local county unemployment rates. Higher rates of past month tobacco and illicit drug use, heavy alcohol use, and past-year drug or alcohol abuse/dependence were found among the unemployed. Markedly increased unemployment in 2009-2010 did not moderate the association between substance outcomes and employment. This association was not confounded by sex, age group, or race/ethnicity for tobacco and illicit drugs, although it varied for alcohol outcomes among 18-25 year-olds. Results based on retrospective data regarding marijuana use in the period prior to unemployment suggest its use was associated with future job loss. Employment status was strongly and robustly associated with problematic use of substances. Prevention and treatment interventions are warranted for a group whose employment and resulting insurance status may impair access to much needed health care.


Complementary oligonucleotides regulate induced fit ligand binding in duplexed aptamers.
Duplexed aptamers (DAs) are engineered by hybridizing an aptamer-complementary element (ACE, e.g. a DNA oligonucleotide) to an aptamer; to date, ACEs have been presumed to sequester the aptamer into a non-binding duplex state, in line with a conformational selection-based model of ligand binding. Here, we uncover that DAs can actively bind a ligand from the duplex state through an ACE-regulated induced fit mechanism. Using a widely-studied ATP DNA aptamer and a solution-based equilibrium assay, DAs were found to exhibit affinities up to 1 000 000-fold higher than predicted by conformational selection alone, with different ACEs regulating the level of induced fit binding, as well as the cooperative allostery of the DA (Hill slope of 1.8 to 0.7). To validate these unexpected findings, we developed a non-equilibrium surface-based assay that only signals induced fit binding, and corroborated the results from the solution-based assay. Our findings indicate that ACEs regulate ATP DA ligand binding dynamics, opening new avenues for the study and design of ligand-responsive nucleic acids.


Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor.
The THO complex is a key factor in co-transcriptional formation of export-competent messenger ribonucleoprotein particles, yet its structure and mechanism of chromatin recruitment remain unknown. In yeast, this complex has been described as a heterotetramer (Tho2, Hpr1, Mft1, and Thp2) that interacts with Tex1 and mRNA export factors Sub2 and Yra1 to form the TRanscription EXport (TREX) complex. In this study, we purified yeast THO and found Tex1 to be part of its core. We determined the three-dimensional structures of five-subunit THO complex by electron microscopy and located the positions of Tex1, Hpr1, and Tho2 C-terminus using various labelling techniques. In the case of Tex1, a β-propeller protein, we have generated an atomic model which docks into the corresponding part of the THO complex envelope. Furthermore, we show that THO directly interacts with nucleic acids through the unfolded C-terminal region of Tho2, whose removal reduces THO recruitment to active chromatin leading to mRNA biogenesis defects. In summary, this study describes the THO architecture, the structural basis for its chromatin targeting, and highlights the importance of unfolded regions of eukaryotic proteins.


The efficacy of cooling with phase change material for the treatment of exercise-induced muscle damage: pilot study.
Post-exercise cryotherapy treatments are typically short duration interventions. This study examined the efficacy of prolonged cooling using phase change material (PCM) on strength loss and pain after eccentric exercise. Eight adults performed 120 bilateral eccentric quadriceps contractions (90% MVC). Immediately afterwards, frozen PCM packs (15°C) were placed over the quadriceps, with room temperature PCM packs on the contralateral quadriceps. Skin temperature was recorded continually (6 h PCM application). Isometric quadriceps strength and soreness were assessed before, 24, 48, 72 and 96 h post-exercise. The protocol was repeated 5 months later, with room temperature PCM applied to both legs. There were three treatments: legs treated with 15°C PCM packs (direct cooling), legs treated with room temperature PCM packs contralateral to the 15°C PCM packs (systemic cooling), and legs tested 5 months later both treated with room temperature PCM packs (control). Skin temperature was 9°C-10°C lower with direct cooling versus systemic cooling and control (P < 0.01). Strength loss and soreness were less (P < 0.05) with direct cooling versus systemic cooling and control (strength 101%, 94%, 93%, respectively; pain 1.0, 2.3, 2.7, respectively). Six hours of PCM cooling was well tolerated and reduced strength loss and pain after damaging exercise.


Current educational status of paediatric rheumatology in Europe: the results of PReS survey.
To understand the status of education and problems in paediatric rheumatology practice in Europe, through a survey. A 26-item questionnaire was conducted during the 14th Congress of the Paediatric Rheumatology European Society in Istanbul, 2007. Physicians who were practicing or studying within the field of paediatric rheumatology for at least one year were included in the survey. One hundred and twenty eight physicians, 79 paediatric rheumatologists (including 5 paediatric immunologists and 10 paediatric nephrologists), 34 paediatric rheumatology fellows and 15 adult rheumatologists completed the survey. The physicians were from: Europe 95 (81.9%), South America 12 (10.4%), Middle East 5 (4.3%), Asia 2 (1.7%), Africa 2 (1.7%). The duration of training for paediatric rheumatology ranged between 1-5 years (mean: 3.12+/-1.11). Sixty physicians scored their education as unsatisfactory and among those, 48 physicians were from Europe. Physicians reported good skills in the following items; intraarticular injections (83.3%); soft tissue injections (47.6%); evaluation of radiographs (67.5%); whereas competence in the evaluation of computed tomography/magnetic resonance imaging (30.5%); and musculoskeletal sonography (16.7%) was much lower. A need for improved basic science and rotations among relevant fields were specifically expressed. Being a relatively new speciality in the realm of paediatrics, paediatric rheumatology education at the European level needs to be further discussed, revised and uniformed.


The effects of medical tourism: Thailand's experience.
To explore the positive and negative effects of medical tourism on the economy, health staff and medical costs in Thailand. The financial repercussions of medical tourism were estimated from commerce ministry data, with modifications and extrapolations. Survey data on 4755 foreign and Thai outpatients in two private hospitals were used to explore how medical tourism affects human resources. Trends in the relative prices of caesarean section, appendectomy, hernia repair, cholecystectomy and knee replacement in five private hospitals were examined. Focus groups and in-depth interviews with hospital managers and key informants from the public and private sectors were conducted to better understand stakeholders' motivations and practices in connection with these procedures and learn more about medical tourism. Medical tourism generates the equivalent of 0.4% of Thailand's gross domestic product but has exacerbated the shortage of medical staff by luring more workers away from the private and public sectors towards hospitals catering to foreigners. This has raised costs in private hospitals substantially and is likely to raise them in public hospitals and in the universal health-care insurance covering most Thais as well. The "brain drain" may also undermine medical training in future. Medical tourism in Thailand, despite some benefits, has negative effects that could be mitigated by lifting the restrictions on the importation of qualified foreign physicians and by taxing tourists who visit the country solely for the purpose of seeking medical treatment. The revenue thus generated could then be used to train physicians and retain medical school professors.


Template synthesis of molecular knots.
This tutorial review outlines the different template strategies that chemists have employed to synthesise knotted molecular topologies. Metal ion coordination, hydrogen bonding and aromatic donor-acceptor interactions have all been used to direct the formation of well-defined crossing points for molecular strands. Advances in the methods used to covalently capture the interwoven structures are highlighted, including the active metal template strategy in which metal ions both organise crossing points and catalyse the bond forming reactions that close the loop to form the topologically complex product. Although most non-trivial knots prepared to date from small-molecule building blocks have been trefoil knots, the first pentafoil knot was recently synthesised. Possible future directions and strategies in this rapidly evolving area of chemistry are discussed.


[CT-guided core needle biopsy of abdominal, pelvic and retroperitoneal masses].
CT-guided core needle biopsy of abdominal, pelvic and retroperitoneal masses is accurate and safe and can be performed on an outpatient basis. Between 1987 and 1995, 809 patients (age range 1-87 years) underwent 851 biopsies (minimal lesion diameter 1 cm). Cutting needles were always used, facilitating both cytological and histological diagnosis while minimizing risk of complications. A positive result (malignant, inflammatory or infectious) was obtained in 69% of the 809 and a negative result (normal tissue) in 17.4%, while in 13.6%, material for diagnosis was insufficient. Biopsy was repeated in 42 of them in whom radiological or clinical suspicion of malignancy was high. In 24 (60%) a positive result was obtained after the second biopsy. Significant complications occurred in 7 (0.8%). 1 hemo-rrhaged following liver biopsy and required blood transfusion. Pancreatitis occurred in 6 (2.6%) following pancreatic biopsy. An intraabdominal fluid collection in 1 necessitated percutaneous drainage. There was no mortality following the procedure and no documented case of needle-tract seeding of tumor. All outpatients were discharged within 3 hours of completion of the biopsy, without ill effects.


Astragaloside VI Promotes Neural Stem Cell Proliferation and Enhances Neurological Function Recovery in Transient Cerebral Ischemic Injury via Activating EGFR/MAPK Signaling Cascades.
Radix Astragali (AR) is a commonly used medicinal herb for post-stroke disability in Traditional Chinese Medicine but its active compounds for promoting neurogenic effects are largely unknown. In the present study, we tested the hypothesis that Astragaloside VI could be a promising active compound from AR for adult neurogenesis and brain repair via targeting epidermal growth factor (EGF)-mediated MAPK signaling pathway in post-stroke treatment. By using cultured neural stem cells (NSCs) and experimental stroke rat model, we investigated the effects of Astragaloside VI on inducing NSCs proliferation and self-renewal in vitro, and enhancing neurogenesis for the recovery of the neurological functions in post-ischemic brains in vivo. For animal experiments, rats were undergone 1.5 h middle cerebral artery occlusion (MCAO) plus 7 days reperfusion. Astragaloside VI (2 μg/kg) was daily administrated by intravenous injection (i.v.) for 7 days. Astragaloside VI treatment promoted neurogenesis and astrogenic formation in dentate gyrus zone, subventricular zone, and cortex of the transient ischemic rat brains in vivo. Astragaloside VI treatment enhanced NSCs self-renewal and proliferation in the cultured NSCs in vitro without affecting NSCs differentiation. Western blot analysis showed that Astragaloside VI up-regulated the expression of nestin, p-EGFR and p-MAPK, and increased neurosphere sizes, whose effects were abolished by the co-treatment of EGF receptor inhibitor gefitinib and ERK inhibitor PD98059. Behavior tests revealed that Astragaloside VI promoted the spatial learning and memory and improved the impaired motor function in transient cerebral ischemic rats. Taken together, Astragaloside VI could effectively activate EGFR/MAPK signaling cascades, promote NSCs proliferation and neurogenesis in transient cerebral ischemic brains, and improve the repair of neurological functions in post-ischemic stroke rats. Astragaloside VI could be a new therapeutic drug candidate for post-stroke treatment.


High-throughput in vivo vertebrate screening.
We demonstrate a high-throughput platform for cellular-resolution in vivo chemical and genetic screens on zebrafish larvae. The system automatically loads zebrafish from reservoirs or multiwell plates, and positions and rotates them for high-speed confocal imaging and laser manipulation of both superficial and deep organs within 19 s without damage. We performed small-scale test screening of retinal axon guidance mutants and neuronal regeneration assays in combination with femtosecond laser microsurgery.