Expression analysis suggests a potential cytoprotective role of Birc5 in the inner ear.
Hearing impairment is a worldwide health problem. Employing semi-quantitative immunological detection methods, we found that the apoptosis inhibitor protein Birc5 is expressed in cell types critical for hearing perception. In the guinea pig model, moderate noise exposure causing only a temporary mean hearing impairment of 33dB significantly enhanced Birc5 expression in the spiral ligament, nerve fibers and the organ of Corti. In contrast, intratympanic gentamicin injection inducing permanent cell damage and mean hearing loss of 24dB correlated with a significant Birc5 downregulation in the ligament, nerve fibers and the organ of Corti. The cytoprotective activity of the guinea pig and human Birc5 protein was confirmed by cloning of the gene and by subsequent ectopic expression and challenging studies against the ototoxin gentamicin in epithelial and auditory cell models. As the mammalian cochlea is unable to regenerate upon damage, these data suggest that modulation of Birc5 expression may represent a novel physiological mechanism to protect the inner ear against stress-induced cell damage. Hence, the targeted modulation of Birc5 levels may lead to novel otoprotective therapeutic strategies.


Pinus massoniana bark extract inhibits migration of the lung cancer A549 cell line.
The bark of Pinus massoniana is a traditional Chinese medicine for the treatment of various health disorders. Previous studies have demonstrated that P. massoniana bark extract (PMBE) may induce the apoptosis of hepatoma and cervical cancer cells. However, whether PMBE is able to inhibit the migration of lung cancer cells requires further investigation. In the current study, the effects of PMBE on the viability of human lung cancer A549 cells were detected using an MTT assay. The migration of lung cancer cells following exposure to PMBE were quantified using wound healing and Transwell assays, respectively. The expression levels of matrix metalloproteinase (MMP)-9 were determined using western blotting. The results revealed that PMBE significantly inhibited the growth of the lung cancer cells. In addition, the wound closure rate and the migration of the lung cancer cells were suppressed by PMBE. Furthermore, the expression levels of MMP-9 were reduced. These findings indicated that PMBE is able to restrict the migration and invasion of lung cancer cells, and that PMBE may serve as a novel therapeutic agent for patients with metastatic lung cancer in the future.


Identifying Differences Between a Straight Face and a Posed Smile Using the Homologous Modeling Technique and the Principal Component Analysis.
Recently, a homologous modeling method was developed to simulate 3D human body forms, which can visualize principal component analysis (PCA) results and facilitate its detailed comparison with results of previous method. Herein, we aimed to construct a homologous model of the face to identify differences between a straight face and a posed smile. Thirty-eight volunteers (19 males and 19 females, 38 straight faces and 38 posed smiles) with no medical history associated with a posed smile were enrolled. Three-dimensional images were constructed using the Homologous Body Modeling software and the HBM-Rugle; 9 landmarks were identified on the 3D-model surfaces. The template model automatically fitted into an individually scanned point cloud of the face by minimizing external and internal energy functions. Faces were analyzed using PCA; differences between straight faces and posed smiles were analyzed using paired t tests. Contribution of the most important principal component was 23.8%; 8 principal components explained >75% of the total variance. A significant difference between a straight face and a posed smile was observed in the second and the fourth principal components. The second principal component images revealed differences between a straight face and a posed smile and changes around the chin area with regard to length, shape, and anteroposterior position. Such changes were inclusive of individual differences. However, the fourth principal component image only revealed differences between a straight face and a posed smile; observed differences included simultaneous shortening of upper and lower eyelid length, evaluation of the nasal ala ase, swelling of the cheek area, and elevation of the mouth angle. Although these results were clinically apparent, we believe that this article is the first to statistically verify the same.Consequently, the homologous model technique and PCA are useful for evaluation of the facial soft-tissue changes.


Entrapment of fluorescence signaling DNA enzymes in sol-gel-derived materials for metal ion sensing.
Three fluorescence signaling DNA enzymes (deoxyribozymes or DNAzymes) were successfully immobilized within a series of sol-gel-derived matrixes and used for sensing of various metal ions. The DNAzymes are designed such that binding of appropriate metal ions induces the formation of a catalytic site that cleaves a ribonucleotide linkage within a DNA substrate. A fluorophore (fluorescein) and a quencher (DABCYL, [4-(4-dimethylaminophenylazo)benzoic acid]) were placed on the two deoxythymidines flanking the ribonucleotide to allow the generation of fluorescence upon the catalytic cleavage at the RNA linkage. In general, all DNAzymes retained at least partial catalytic function when entrapped in either hydrophilic or hydrophobic silica-based materials, but displayed slower response times and lower overall signal changes relative to solution. Interestingly, it was determined that maximum sensitivity toward metal ions was obtained when DNAzymes were entrapped into composite materials containing approximately 40% of methyltrimethoxysilane (MTMS) and approximately 60% tetramethoxysilane (TMOS). Highly polar materials derived from sodium silicate, diglycerylsilane, or TMOS had relatively low signal enhancements, while materials with very high levels of MTMS showed significant leaching and low signal enhancements. Entrapment into the hybrid silica material also reduced signal interferences that were related to metal-induced quenching; such interferences were a significant problem for solution-based assays and for polar materials. Extension of the solid-phase DNAzyme assay toward a multiplexed assay format for metal detection is demonstrated, and shows that sol-gel technology can provide new opportunities for the development of DNAzyme-based biosensors.


Changes in body mass during elementary and middle school in a national cohort of kindergarteners.
To analyze changes in BMI, according to gender and race/ethnicity, in a nationally representative cohort of children in the United States during their elementary and middle school years to identify critical periods of excess BMI gains. The Early Childhood Longitudinal Study-Kindergarten Class monitored a nationally representative cohort of kindergarten students over 9 years (1998-2007). Height and weight measurements were available for 4240 white, 640 black, and 1070 Hispanic children in kindergarten and 1st, 3rd, 5th, and 8th grades. In each wave, we estimated the proportions of children with BMI values in each quartile of the Centers for Disease Control and Prevention reference-population distribution according to gender and race/ethnicity. We conducted nonparametric tests of differences in BMI distributions over time within racial/ethnic groups and across racial/ethnic groups in each wave. Piecewise linear growth models were estimated to test for specific time periods during which the largest gains in BMI percentiles occurred. Overall, nearly 40% of children started kindergarten with a BMI in the top quartile of the growth charts (BMI > 75th percentile). This proportion increased significantly during the elementary school years, and the largest gains were between 1st and 3rd grades (5.8 percentage points), but there was no further increase during middle school. Increases in BMI percentiles over time were most notable among Hispanic children and black girls. The early school years might be a critical time for excess BMI gains, even among children with normal BMI values at kindergarten entry.


The effectiveness of scoliosis screening programs: methods for systematic review and expert panel recommendations formulation.
Literature on scoliosis screening is vast, however because of the observational nature of available data and methodological flaws, data interpretation is often complex, leading to incomplete and sometimes, somewhat misleading conclusions. The need to propose a set of methods for critical appraisal of the literature about scoliosis screening, a comprehensive summary and rating of the available evidence appeared essential. To address these gaps, the study aims were: i) To propose a framework for the assessment of published studies on scoliosis screening effectiveness; ii) To suggest specific questions to be answered on screening effectiveness instead of trying to reach a global position for or against the programs; iii) To contextualize the knowledge through expert panel consultation and meaningful recommendations. The general methodological approach proceeds through the following steps: Elaboration of the conceptual framework; Formulation of the review questions; Identification of the criteria for the review; Selection of the studies; Critical assessment of the studies; Results synthesis; Formulation and grading of recommendations in response to the questions. This plan follows at best GRADE Group (Grades of Recommendation, Assessment, Development and Evaluation) requirements for systematic reviews, assessing quality of evidence and grading the strength of recommendations. In this article, the methods developed in support of this work are presented since they may be of some interest for similar reviews in scoliosis and orthopaedic fields.


Informal teacher communities enhancing the professional development of medical teachers: a qualitative study.
Informal peer learning is a particularly powerful form of learning for medical teachers, although it does not always occur automatically in the departments of medical schools. In this article, the authors explore the role of teacher communities in enhancing informal peer learning among undergraduate medical teachers. Teacher communities are groups of teachers who voluntarily gather on a regular basis to develop and share knowledge. Outside of medical education, these informal teacher communities have proved to be an effective means of enhancing peer learning of academic teachers. The processes underlying this outcome are, however, not known. This study therefore aims to explore the processes that make informal teacher communities effective in supporting peer learning of teachers. A qualitative study was performed at a Dutch medical school, where a student-centred undergraduate curriculum had recently been introduced. As part of this curriculum, tutors are segregated into separate specialty areas and thus have only limited opportunities for informal learning with other tutors. The authors followed two informal teacher communities aimed at supporting these tutors. They observed the interactions within the teacher communities and held semi-structured interviews with ten of the participants. The observation notes and interview data were analysed using thematic analysis. The informal teacher communities allowed the tutors to engage in a dialogue with colleagues and share questions, solutions, and interpretations. The teacher communities also provided opportunities to explicate tacit expertise, which helped the tutors to develop an idea of their role and form a frame of reference for their own experiences. Furthermore, the communities enhanced the tutors' sense of belonging. The tutors felt more secure in their role and they felt valued by the organisation due to the teacher communities. This study shows that informal teacher communities not only support the professional development of tutors, but also validate and strengthen their identity as teachers. They seem to provide a dialogical space where informal intercollegiate learning is stimulated, stories are shared, tacit knowledge is made explicit, concerns are shared, and teacher identity is nurtured.


Molecularly imprinted polymers immobilized on 3D printed scaffolds as novel solid phase extraction sorbent for metergoline.
In the present work, a novel solid phase extraction (SPE) sorbent was developed based on molecularly imprinted polymers (MIPs) immobilized on 3D-printed scaffolds using polymer networks as MIP-immobilizing layer. MIPs were produced by precipitation polymerization in acetonitrile (ACN) using methacrylic acid (MAA) as functional monomer, trimethylolpropane trimethacrylate (TRIM) as crosslinker and metergoline as model template which allows final recognition of ergot alkaloid mycotoxins. Scanning electron microscopy (SEM) and dynamic light scattering (DLS) analyses showed an average MIP particle size of 457 ± 145 nm. Functional MIP analysis revealed dissociation constants (KD) of 0.29 and 38.90 μM for high and low affinity binding sites respectively. Subsequently, crosslinking of polymer network building blocks was applied as MIP immobilization method on poly-ε-caprolactone (PCL) which was selected as polymer model. Methodology optimization and subsequent evaluation were first realized on 2D PCL surfaces. Based on analyses such as optical evaluation of MIP availability after immobilization through SEM and depth profilometry, an optimal polymer network building block concentration of 7.5 w/w% was selected. In a final part, transfer of MIP immobilization to 3D PCL scaffolds was successfully realized. Functional analysis showed that the newly developed SPE sorbents were able to rebind 44.87 ± 8.30% of a 1 μM metergoline solution. In conclusion, a new type of SPE sorbent was developed for the detection of metergoline by the use of MIP-functionalized polymer scaffolds. The applied technology opens up future possibilities for the extraction of a broad range of components such as other mycotoxins.


Absorbing and transferring risk: assessing the impact of a statewide high-risk-pregnancy telemedical program on VLBW maternal transports.
Prior research has shown that resources have an impact on birth outcomes. In this paper we ask how combinations of telemedical and hospital-level resources impact transports of mothers expecting very low birth weight (VLBW) babies in Arkansas. Using de-identified birth certificate data from the Arkansas Department of Health, data were gathered on transports of women carrying VLBW babies for two six-month periods: a period just before the start of ANGELS (12/02-05/03), a telemedical outreach program for high-risk pregnancies, and a period after the program had been running for six months (12/03-05/04). For each maternal transport, the following information was recorded: maternal race-ethnicity, maternal age, and the birth weight of the infant. Logistic regression was used to assess the relationship between the predictors (telemedicine, hospital level, maternal characteristics) and the probability of a transport. Having a telemedical site available increases the probability of a mother carrying a VLBW baby being transported to a level III facility either before or during birth. Having at least a level II nursery also increases the chance of a maternal transport. Where both level II nurseries and telemedical access are available, the odds of VLBW maternal transports are only modestly increased in comparison to the case where neither is present. At the individual level, Hispanic mothers were less likely to be transported than other mothers, and teenaged mothers were more likely to be transported than those 18 and over. A mother's being Black or being over 35 did not have an impact on the odds of being transported to a level III facility. Combinations of resources have an impact on physician decisions regarding VLBW transports and are interpretable in terms of the capacity to diagnose and absorb risk. We suggest a collegial review of transport patterns and birth outcomes from areas with different levels of resources as a vehicle for moving the entire system of care forward over time. With such an evidence-based review in place, the collegial relations among level III specialists and obstetricians from around the state can, over time, develop workable protocols for when and how level III facilities should be involved.


Toward the storage metabolome: profiling the barley vacuole.
While recent years have witnessed dramatic advances in our capacity to identify and quantify an ever-increasing number of plant metabolites, our understanding of how metabolism is spatially regulated is still far from complete. In an attempt to partially address this question, we studied the storage metabolome of the barley (Hordeum vulgare) vacuole. For this purpose, we used highly purified vacuoles isolated by silicon oil centrifugation and compared their metabolome with that found in the mesophyll protoplast from which they were derived. Using a combination of gas chromatography-mass spectrometry and Fourier transform-mass spectrometry, we were able to detect 59 (primary) metabolites for which we know the exact chemical structure and a further 200 (secondary) metabolites for which we have strong predicted chemical formulae. Taken together, these metabolites comprise amino acids, organic acids, sugars, sugar alcohols, shikimate pathway intermediates, vitamins, phenylpropanoids, and flavonoids. Of the 259 putative metabolites, some 12 were found exclusively in the vacuole and 34 were found exclusively in the protoplast, while 213 were common in both samples. When analyzed on a quantitative basis, however, there is even more variance, with more than 60 of these compounds being present above the detection limit of our protocols. The combined data were also analyzed with respect to the tonoplast proteome in an attempt to infer specificities of the transporter proteins embedded in this membrane. Following comparison with recent observations made using nonaqueous fractionation of Arabidopsis (Arabidopsis thaliana), we discuss these data in the context of current models of metabolic compartmentation in plants.


Two faces of patient safety and care quality: a Franco-American comparison.
Patient safety, and more broadly the quality of care, is typically discussed with reference to the reduction of preventable adverse events within hospitals and adherence to practice guidelines on care processes. We call it the 'care-centered approach' and recognize that the United States is a leader in the field. Another face of patient safety and care quality may be defined as the 'system-centered approach'. It focuses on access to a timely and effective continuum of health-care services--clinical prevention, primary care and appropriate referral to and receipt of specialty care. Although France's efforts to pursue a care-centered approach to patient safety are limited, its system-centered approach yields some benefits. Based on the evidence we have reviewed for access to primary care (hospital discharges for avoidable hospital conditions), mortality amenable to medical intervention and consumer satisfaction, in the United States and France, there appear to be good grounds for bolstering the system-centered approach in the United States.


Effect of thyroid hormone on slow calcium channel function in cultured chick ventricular cells.
The hyperthyroid state is associated with increased myocardial contractility. To clarify responsible mechanisms, we examined the effects of thyroid hormone on slow Ca channels, beta-adrenergic receptors, transsarcolemmal 45Ca flux and cytosolic free calcium in cultured chick ventricular cells. Compared with cells grown without triiodothyronine (T3), cells grown in 10 nM T3 possessed 67% (P less than 0.05) more dihydropyridine 3H-PN200-110 binding sites, 24% (P less than 0.05) more beta-adrenergic antagonist 3H-CGP12177 binding sites, a 57% (P less than 0.05) greater nifedipine-sensitive initial 45Ca uptake rate, and a 31% (P less than 0.05) greater nifedipine-sensitive 45Ca uptake rate in response to BAY k 8644. Time-averaged mean intracellular free Ca concentration ([Ca]i) measured with fura-2, total protein content, and dissociation constant values for 3H-PN200-110 or 3H-CGP12177 binding was not significantly different in the two groups of cells. BAY k 8644 (1 microM) increased mean [Ca]i 2.85- or 2.16-fold in cells grown with or without 10 nM T3, respectively. l-Isoproterenol (1 microM) increased [Ca]i 1.53- or 1.28-fold in cells grown with or without 10 nM T3, respectively. We conclude that thyroid hormone augments transsarcolemmal Ca influx, at least in part via slow Ca channels associated with increased numbers of these channels. T3-treated cells appear to be more responsive to the effects of BAY k 8644 or isoproterenol on [Ca]i.


Developmental plasticity and disparity in early dipnoan (lungfish) dentitions.
Although the lungfish (Dipnoi) belong within the Osteichthyes, their dentitions are radically different from other osteichthyans. Lungfish dentitions also show a uniquely high structural disparity during the early evolution of the group, partly owing to the independent variation of odontogenic and odontoclastic processes that are tightly and stereotypically coordinated in other osteichthyans. We present a phylogenetic analysis of early lungfishes incorporating a novel approach to coding these process characters in preference to the resultant adult dental morphology. The results only partially resolve the interrelationships of Devonian dipnoans, but show that the widely discussed hypothesis of separate tooth-plated, dentine-plated, and denticulated lineages is unlikely to be true. The dipnoan status of Diabolepis is corroborated. Lungfish dentitions seem to have undergone extensive and nonparsimonious evolution during the early history of the group, but much of the resulting disparity can be explained by a modest number of evolutionary steps in the underlying developmental processes, those for dental formation (odontogenic) and those for the remodeling of dentine tissue (odontoclastic). Later in lungfish evolution, this disparity was lost as the group settled to a pattern of dental development that is just as stereotypic as, but completely different from, that of other osteichthyans.


Timing of preoperative antibiotics for knee arthroplasties: Improving the routines in Sweden.
A slight increase in revisions for infected joint arthroplasties has been observed in the Nordic countries since 2000 for which the reasons are unclear. However, in 2007 a Swedish study of the timing for prophylactic antibiotics in a random sample of knee arthroplasties found that only 57% of the patients had received the antibiotic during the optimal time interval 45-15 minutes before surgery. The purpose of the report was to evaluate the effect of measures taken to improve the timing of prophylactic antibiotics. Reporting this finding to surgeons at national meetings during 2008 the Swedish Knee Arthroplasty Register (SKAR) introduced a new report form from January 2009 including the time for administration of preoperative antibiotics. Furthermore, the WHO's surgical checklist was introduced during 2009 and a national project was started to reduce infections in arthroplasty surgery (PRISS). The effect of these measures was found to be positive showing that in 2009, 69% of the 12,707 primary knee arthroplasties were reported to have received the prophylaxis within the 45-15 min time interval and 79% of the first 7,000 knee arthroplasties in 2010. A survey concerning the use of the WHO checklist at Swedish hospitals showed that 73 of 75 clinics had introduced a surgical checklist. By registration and bringing back information to surgeons on the state of infection prophylaxis in combination with the introduction of the WHO checklist and the preventive work done by the PRISS project, the timing of preoperative prophylactic antibiotics in knee arthroplasty surgery was clearly improved.


Exercise is good for your blood pressure: effects of endurance training and resistance training.
1. Although several epidemiological studies have not observed significant independent relationships between physical activity or fitness and blood pressure, others have concluded that blood pressure is lower in individuals who are more fit or active. However, longitudinal intervention studies are more appropriate for assessing the effects of physical activity on blood pressure. 2. Previously, we have performed meta-analyses of randomized controlled trials involving dynamic aerobic endurance training or resistance training. Inclusion criteria were: random allocation to intervention and control; physical training as the sole intervention; inclusion of healthy sedentary normotensive and/or hypertensive adults; intervention duration of at least 4 weeks; availability of systolic and/or diastolic blood pressure; and publication in a peer-reviewed journal up to December 2003. 3. The meta-analysis on endurance training involved 72 trials and 105 study groups. After weighting for the number of trained participants, training induced significant net reductions of resting and day time ambulatory blood pressure of 3.0/2.4 mmHg (P < 0.001) and 3.3/3.5 mmHg (P < 0.01), respectively. The reduction of resting blood pressure was more pronounced in the 30 hypertensive study groups (-6.9/-4.9) than in the others (-1.9/-1.6; P < 0.001 for all). Systemic vascular resistance decreased by 7.1% (P < 0.05), plasma noradrenaline by 29% (P < 0.001) and plasma renin activity by 20% (P < 0.05). Bodyweight decreased by 1.2 kg (P < 0.001), waist circumference by 2.8 cm (P < 0.001), percentage body fat by 1.4% (P < 0.001) and the Homeostatic Model Assessment (HOMA) index of insulin resistance by 0.31 units (P < 0.01). High-density lipoprotein-cholesterol increased by 0.032 mmol/L (P < 0.05). 4. Resistance training has been less well studied. A meta-analysis of nine randomized controlled trials (12 study groups) on mostly dynamic resistance training revealed a weighted net reduction of diastolic blood pressure of 3.5 mmHg (P < 0.01) associated with exercise and a non-significant reduction of systolic blood pressure of 3.2 mmHg (P = 0.10). 5. In conclusion, dynamic aerobic endurance training decreases blood pressure through a reduction of systemic vascular resistance, in which the sympathetic nervous system and the renin-angiotensin system appear to be involved, and favourably affects concomitant cardiovascular risk factors. In addition, the few available data suggest that resistance training is able to reduce blood pressure.


Laser projection using generalized phase contrast.
We demonstrate experimental laser projection of a gray-level photographic image with 74% light efficiency using the generalized phase contrast (GPC) method. In contrast with a previously proposed technique [Alonzo, New J. Phys. 9, 132 (2007)], a new approach to image construction via GPC is introduced. An arbitrary phase shift filter eliminates the need for high-frequency modulation and conjugate phase encoding. This lowers device performance requirements and allows practical implementation with currently available dynamic spatial light modulators.


Ventilatory response to an inhaled constant CO2 load and added dead space in healthy men, awake and asleep.
Experiments were conducted in ten adult men to determine if rapid-eye-movement sleep (REMS) reduced the ventilatory response to two 'steady-state' respiratory loads compared to slow wave sleep (SWS). A constant addition of 150 (or 200) ml/min pure CO2 to the inspirate (7 subjects) and 230 ml of added dead space (5 subjects) were the two respiratory loads. Inspiratory ventilation was measured by pneumotachygraph for at least five continuous minutes in wakefulness, SWS and REMS. The increase in ventilation to both stimuli was equal in SWS and REMS with no suggestion of an impaired response during the latter: increases in ventilation during CO2 loading being 49 and 51%, SWS and REMS, respectively, and during additional dead space they were 53 and 59%, SWS and REMS, respectively. Following the addition of extra dead space, end tidal PCO2 levels did not rise significantly more during REMS compared to SWS (P greater than 0.5). These findings show that when ventilatory responses to CO2 are considered across the whole of REMS (including periods with and without actual eye-movements) then they do not appear to be blunted compared to SWS.


Influence of the rate of ventricular enlargement on the ultrastructural morphology of the white matter in experimental hydrocephalus.
The influence of the rate of ventricular enlargement on the morphology of hydrocephalic white matter was studied and correlated with previous studies of water content. Different rates of ventricular enlargement were obtained in two groups of cats by opening either the calvaria or the calvaria and the dura mater before injecting kaolin into the cisterna magna. Animals from each group underwent in vivo fixation of brain 2, 3, and 6 weeks after hydrocephalus was induced. Specimens of white matter were taken 1, 2, and 3 mm lateral to the ependymal surface of the lateral ventricles, imbedded, and examined using transmission electron microscopy. The ultrastructural changes associated with ventricular enlargement varied with the model used and the duration of hydrocephalus. Marked expansion of the extracellular space extending 2 mm lateral from the ependyma was found in the craniectomy-durectomy preparations examined 2 to 3 weeks after kaolin injection. Time-matched craniectomy preparations had less enlargement of the extracellular space that was confined to the white matter immediately adjacent to the ventricle. Marked glial reaction was observed in these areas in the early craniectomy preparations. When studied 6 weeks after hydrocephalus induction, both models had less expansion of the extracellular spaces compared to early observations. Glial reaction was found in both models, but was greater in the craniectomy model. The correlation of these morphological findings with the rate of ventricular enlargement and earlier studies of water content are discussed.


CT colonography versus double-contrast barium enema for screening of colorectal cancer: comparison of radiation burden.
Our aim is to compare the radiation dose associated with a low-dose CT colonography (CTC) protocol for colorectal cancer screening with that delivered by double-contrast barium enema (DCBE). CTC of twenty asymptomatic individuals (M:F = 10:10) participating to a colorectal cancer screening program and DCBE of fifteen patients (M:F = 6:9) were evaluated. For CTC, absorbed dose was determined by calculating the dose-length product for each CTC examination from measurements on a CT dose phantom equipped with a CT ion chamber. For DCBE, the free-in-air Kerma at the patient's X-ray entry surface and the Kerma-area product during fluoroscopy and fluorography were measured with a Barracuda system, with fluoroscopy times being recorded blinded to the performing operator. Effective dose at CTC was 2.17 ± 0.12 mSv, with good and excellent image quality in 14/20 (70%) and 6/20 cases (30%), respectively. With DCBE, effective patient dose was 4.12 ± 0.17 mSv, 1.9 times greater than CTC (P < 0.0001). Our results show that effective dose from screening CTC is substantially lower than that from DCBE, suggesting that CTC is the radiological imaging technique of the large bowel with the lowest risk of stochastic radiation effects.


Who pays attention in stated-choice surveys?
Responses of inattentive or inconsistent subjects in stated-choice (SC) surveys can lead to imprecise or biased estimates. Several SC studies have investigated inconsistency and most of these studies dropped subjects who were inconsistent. However, none of these studies reported who is more likely to fail consistency tests. We investigated the effect of the personal characteristics and task complexity on preference inconsistency in eight different SC surveys. We found that white, higher-income and better-educated female subjects were less likely to fail consistency tests. Understanding the characteristics of subjects who are inattentive to the choice task may help in designing and pre-testing instruments that work effectively for a wider range of subjects.


Proteins as diverse, efficient, and evolvable scaffolds for artificial metalloenzymes.
By combining synthetic catalysts and biochemical tools, numerous artificial metalloenzymes have been designed to exhibit high catalytic activity and selectivity in diverse chemical transformations. Out of the nearly infinite number of discovered or characterised proteins, however, only a handful of proteins have been employed as scaffolds for artificial metalloenzymes, implying that specific proteins are preferred owing to their native structural, functional, or biochemical properties. In the present review, we extract and group the biochemical and structural properties of proteins that are advantageous in the design of artificial metalloenzymes; protein stability, pre-existing metal centre, native binding affinity for small molecules, confined and empty space, well-defined secondary structure, and native cellular location. The desirable properties highlight proteins as the key players in the design of metal-dependent biocatalysts. We also propose rarely considered, yet promising, proteins that could be versatile and unique scaffolds for novel metalloenzymes.


Visible Korean human. improved serially sectioned images of the entire body.
The data from the Visible Human Project (VHP) and the Chinese Visible Human (CVH), which are the serially sectioned images of the entire cadaver, are being used to produce three-dimensional (3D) images and software. The purpose of our research, the Visible Korean Human (VKH), is to produce an enhanced version of the serially sectioned images of an entire cadaver that can be used to upgrade the 3D images and software. These improvements are achieved without drastically changing the methods developed for the VHP and CVH; thus, a complementary solution was found. A Korean male cadaver was chosen without anything perfused into the cadaver; the entire body was Magnetic Resonance (MR) and Computed Tomography (CT) scanned at 1.0 mm intervals to produce MR and CT images. After scanning, entire body of the cadaver was embedded and serially sectioned at 0.2 mm intervals; each sectioned surface was inputted into a personal computer to produce anatomical images (pixel size: 0.2 mm) without any missing images. Eleven anatomical organs in the anatomical images were segmented to produce segmented images. The anatomical and segmented images were stacked and reconstructed to produce 3D images. The VKH is an ongoing research; we will produce a female version of the VKH and provide more detailed segmented images. The data from the VHP, CVH, and VKH will provide valuable resources to the medical image library of 3D images and software in the field of medical education and clinical trials.


Phase-retrieval analysis of pre- and post-repair Hubble Space Telescope images.
Phase-retrieval measurements of point-spread functions from the pre- and post-repair Hubble Space Telescope are presented. The primary goal was to determine the aberrations present in the second wide-field and planetary camera (WFPC2) to align and validate its corrective optics. With both parametric model-fitting techniques and iterative (Gerchberg-Saxton) methods, accurate measurements have been obtained of the WFPC2 and Hubble Space Telescope optics, including improved maps of the zonal errors in the mirrors. Additional phase-retrieval results were obtained for the aberrated, prerepair cameras and the corrected faint-object camera. The information has been used to improve models produced by point-spread-function simulation programs. On the basis of the measurements a conic constant for the primary mirror of κ = -1.0144 has been derived.


Update on transcobalamin deficiency: clinical presentation, treatment and outcome.
Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.


Properties and characterization of monoclonal antibodies to Tacaribe virus.
Monoclonal antibodies prepared against Tacaribe and Junin viruses have been used to define further the serological relationships between arenaviruses of the Tacaribe complex. A close relationship was found between these two viruses and the heterologous Amapari and Machupo viruses, with Pichinde virus and Parana virus being more distantly related. Among the antibodies specific for Tacaribe virus, five were found to react with viral antigens at the surface of infected cells and to neutralize virus infectivity in vitro. These five antibodies could be differentiated by competitive immunoassay as recognizing at least two antigenically distinct epitopes. The kinetics of reaction between antibody and virus were examined for all five neutralizing antibodies. One antibody (2.25.4) effectively neutralized all infectious virus. The remaining four directed against a second epitope gave significant persistent fractions which could be reduced by addition of complement, anti-mouse immunoglobulin, or antibody 2.25.4. Variants of Tacaribe virus resistant to neutralization by antibody 2.25.4 were obtained by growth in the presence of this antibody and neutralization kinetics were reexamined using the heterologous monoclonal neutralizing antibodies. Several different neutralization profiles were obtained, suggesting that point mutations resulted in conformational changes at topographically selected distinct epitopes recognized by the remaining antibodies.


Ankyrin-G coordinates intercalated disc signaling platform to regulate cardiac excitability in vivo.
Nav1.5 (SCN5A) is the primary cardiac voltage-gated Nav channel. Nav1.5 is critical for cardiac excitability and conduction, and human SCN5A mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Nav1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Nav1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Nav1.5 membrane targeting, assembly, and regulation are still largely undefined. Define the in vivo mechanisms underlying Nav1.5 membrane regulation. Here, we define the molecular basis of an Nav channel regulatory platform in heart. Using new cardiac-selective ankyrin-G(-/-) mice (conditional knock-out mouse), we report that ankyrin-G targets Nav1.5 and its regulatory protein calcium/calmodulin-dependent kinase II to the intercalated disc. Mechanistically, βIV-spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin-dependent kinase II-δ; however, βIV-spectrin is not essential for ankyrin-G expression. Ankyrin-G conditional knock-out mouse myocytes display decreased Nav1.5 expression/membrane localization and reduced INa associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Nav channel antagonists. Moreover, we report that ankyrin-G links Nav channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to β-adrenergic stimulation. Our findings provide the first in vivo data for the molecular pathway required for intercalated disc Nav1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Nav1.5.


Solution-processible conjugated electrophosphorescent polymers.
We report the synthesis and photophysical study of a series of solution-processible phosphorescent iridium complexes. These comprise bis-cyclometalated iridium units [Ir(ppy)(2)(acac)] or [Ir(btp)(2)(acac)] where ppy is 2-phenylpyridinato, btp is 2-(2'-benzo[b]thienyl)pyridinato, and acac is acetylacetonate. The iridium units are covalently attached to and in conjugation with oligo(9,9-dioctylfluorenyl-2,7-diyl) [(FO)(n)] to form complexes [Ir(ppy-(FO)(n))(2)(acac)] or [Ir(btp-(FO)(n))(2)(acac)], where the number of fluorene units, n, is 1, 2, 3, approximately 10, approximately 20, approximately 30, or approximately 40. All the complexes exhibit emission from a mixed triplet state in both photoluminescence and electroluminescence, with efficient quenching of the fluorene singlet emission. Short-chain complexes, 11-13, [Ir(ppy-(FO)(n)-FH)(2)(acac)] where n = 0, 1, or 2, show green light emission, red-shifted through the FO attachment by about 70 meV, but for longer chains there is quenching because of the lower energy triplet state associated with polyfluorene. In contrast, polymer complexes 18-21 [Ir(btp-(FO)(n))(2)(acac)] where n is 5-40 have better triplet energy level matching and can be used to provide efficient red phosphorescent polymer light-emitting diodes, with a red shift due to the fluorene attachment of about 50 meV. We contrast this small (50-70 meV) and short-range modification of the triplet energies through extended conjugation, with the much more substantial evolution of the pi-pi* singlet transitions, which saturate at about n = 10. These covalently bound materials show improvements in efficiency over simple blends and will form the basis of future investigations into energy-transfer processes occurring in light-emitting diodes.


Surgical removal of endometrioma decreases the NF-kB1 (p50/105) and NF-kB p65 (Rel A) expression in the eutopic endometrium during the implantation window.
We aimed to investigate whether the surgical removal of endometrioma alters the nuclear factor-kappa B1 (NF-kB1; p50/105) and NF-kB p65 (Rel A) expression in the eutopic endometrium of infertile women with endometrioma before and after laparoscopic removal of the ovarian endometrioma during the mid-secretory phase. Infertile women with endometrioma (n = 15) were enrolled. Infertile patients with nonendometriotic ovarian cyst (n = 10) and healthy fertile women (n = 10) were recruited as controls. Endometrial samples were obtained before and 3 months after the laparoscopic cystectomy. The NF-kB1 (p50/105) levels were analyzed by enzyme-linked immunosorbent assay (ELISA) in the endometrium of all groups before and after laparoscopic ovarian cystectomy during implantation window. Expression of NF-kB1 (p50/105) in eutopic endometrium was significantly higher in infertile women with endometrioma compared to nonendometriotic cyst and fertile controls (P < .05). Laparoscopic cystectomy resulted in a significant decrease in NF-kB1 expression in women with endometrioma. The NF-kB p65 (Rel A) immunoreactivity of eutopic endometrium decreased significantly subsequent to the surgical removal of the endometrioma. In conclusion, increased endometrial NF-kB expression may contribute to endometriosis-associated infertility.


Leaf herbivores decrease fitness of a tropical plant.
Damage by insect herbivores to neighboring individuals of the shrub Piper arieianum in a neotropical wet forest varies greatly. This differential damage has a genetic basis and results in a 2-year decrease in growth, seed production, and seed viability, with larger plants recovering before smaller plants. The results provide evidence that leaf herbivores represent a potentially strong selective force for the evolution of plant defenses.


Kinetic and chemical mechanism of arylamine N-acetyltransferase from Mycobacterium tuberculosis.
Arylamine N-acetyltransferases (NATs) are cytosolic enzymes that catalyze the transfer of the acetyl group from acetyl coenzyme A (AcCoA) to the free amino group of arylamines and hydrazines. Previous studies have reported that overexpression of NAT from Mycobacterium smegmatis and Mycobacterium tuberculosis may be responsible for increased resistance to the front-line antitubercular drug, isoniazid, by acetylating and hence inactivating the prodrug. We report the kinetic characterization of M. tuberculosis NAT which reveals that substituted anilines are excellent substrates but that isoniazid is a very poor substrate for this enzyme. We propose that the expression of NAT from M. tuberculosis (TBNAT) is unlikely to be a significant cause of isoniazid resistance. The kinetic parameters for a variety of TBNAT substrates were examined, including 3-amino-4-hydroxybenzoic acid and AcCoA, revealing K m values of 0.32 +/- 0.03 and 0.14 +/- 0.02 mM, respectively. Steady-state kinetic analysis of TBNAT reveals that the enzyme catalyzes the reaction via a bi-bi ping-pong kinetic mechanism. The pH dependence of the kinetic parameters reveals that one enzyme group must be deprotonated for optimal catalytic activity and that two amino acid residues at the active site of the free enzyme are involved in binding and/or catalysis. Solvent kinetic isotope effects suggest that proton transfer steps are not rate-limiting in the overall reaction for substituted aniline substrates but become rate-limiting when poor hydrazide substrates are used.


The association between crowding within households and behavioural problems in children: Longitudinal data from the Southampton Women's Survey.
In England, nearly one child in ten lives in overcrowded housing. Crowding is likely to worsen with increasing population size, urbanisation, and the ongoing concerns about housing shortages. Children with behavioural difficulties are at increased risk of mental and physical health problems and poorer employment prospects. To test the association between the level of crowding in the home and behavioural problems in children, and to explore what factors might explain the relationship. Mothers of 2576 children from the Southampton Women's Survey population-based mother-offspring cohort were interviewed. Crowding was measured at age 2 years by people per room (PPR) and behavioural problems assessed at age 3 years with the Strengths and Difficulties Questionnaire (SDQ). Both were analysed as continuous measures, and multivariable linear regression models were fitted, adjusting for confounding factors: gender, age, single-parent family, maternal education, receipt of benefits, and social class. Potential mediators were assessed with formal mediation analysis. The characteristics of the sample were broadly representative of the population in England. Median (IQR) SDQ score was 9 (6-12) and PPR was 0.75 (0.6-1). In households that were more crowded, children tended to have more behavioural problems (by 0.20 SDQ points (95% CI 0.08, 0.32) per additional 0.2 PPR, adjusting for confounding factors). This relationship was partially mediated by greater maternal stress, less sleep, and strained parent-child interactions. Living in a more crowded home was associated with a greater risk of behavioural problems, independent of confounding factors. The findings suggest that improved housing might reduce childhood behavioural problems and that families living in crowded circumstances might benefit from greater support.


The right temporoparietal junction enables delay of gratification by allowing decision makers to focus on future events.
Studies of neural processes underlying delay of gratification usually focus on prefrontal networks related to curbing affective impulses. Here, we provide evidence for an alternative mechanism that facilitates delaying gratification by mental orientation towards the future. Combining continuous theta-burst stimulation (cTBS) with functional neuroimaging, we tested how the right temporoparietal junction (rTPJ) facilitates processing of future events and thereby promotes delay of gratification. Participants performed an intertemporal decision task and a mental time-travel task in the MRI scanner before and after receiving cTBS over the rTPJ or the vertex (control site). rTPJ cTBS led to both stronger temporal discounting for longer delays and reduced processing of future relative to past events in the mental time-travel task. This finding suggests that the rTPJ contributes to the ability to delay gratification by facilitating mental representation of outcomes in the future. On the neural level, rTPJ cTBS led to a reduction in the extent to which connectivity of rTPJ with striatum reflected the value of delayed rewards, indicating a role of rTPJ-striatum connectivity in constructing neural representations of future rewards. Together, our findings provide evidence that the rTPJ is an integral part of a brain network that promotes delay of gratification by facilitating mental orientation to future rewards.


Prevalence of delay in seeking tuberculosis care and the health care seeking behaviour profile of tuberculous patients in a rural district of KwaZulu Natal, South Africa.
patient delay in seeking TB (tuberculosis) care is reported as one of the major hurdles undermining the efforts of controlling TB by many TB control programmes of the world. The main aim of this study was to determine the prevalence of this phenomenon and to profile the TB patients that delayed seeking TB care in a rural area of KwaZulu Natal province of South Africa. this was a cross-sectional study, conducted among 200 TB patients attending primary health care facilities in Ugu District. Patient data were collected by a self-administered questionnaire, entered into an Excel file and imported into the EpiInfo 7 statistical software for analysis. Frequency tables were used to display the data and the p value was used for statistical significance. about 40% of the participants delayed seeking TB care in this study, and these were mostly individuals who were married, the employed and those who walked to the clinic. Delay was also prevalent among those that self-medicated, bought medication from the pharmacy and sought TB care from a private doctor. The reasons included the great distances, long queues waiting at the facilities, and not feeling ill. the 4 weeks cut-off in seeking TB care in this study far exceeds the recommended 2 weeks. This study recommends periodic active TB case finding and active engagement between the public and the private health sectors.


Long-term clinical outcomes and cost-effectiveness analysis in multivessel percutaneous coronary interventions: comparison of drug-eluting stents, bare-metal stents and a mixed approach in patients at high and low risk of repeat revascularisation.
To evaluate the long-term effectiveness and cost-efficacy of drug-eluting stents (DES) in a real world setting of multivessel percutaneous coronary intervention (PCI). We evaluated the 2-year outcome of all multivessel PCI in de novo lesions enrolled in a prospective web-based multicentre registry from July 2003 to December 2006. Among the 2,898 eligible patients, 1,315 were treated with bare-metal stent (BMS) alone, 657 with DES alone, and 926 with both. At 2-years, use of DES was associated with a lower propensity score adjusted incidence of major adverse cardiac events (MACE), death and myocardial infarction, and target vessel revascularisation (TVR) compared with BMS but only in patients at high risk of TVR. No difference was apparent between "pure" DES and the mixed approach. The matched cost-effectiveness analysis revealed DES to be more costly and more effective with a reasonable incremental cost-efficacy ratio for any MACE avoided only in patients with a high risk of TVR and only in comparison with "pure" BMS patients. In this real-world multivessel PCI registry, the use of DES and a mixed approach were associated with a 2-year reduction of adverse clinical outcomes in comparison with BMS especially in patients with a high risk of TVR. DES were cost-effective only in patients at high risk of TVR.


Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures.
To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers. Double-blind, placebo-controlled clinical trial. Academic medical centers. Subjects with mild to moderate Alzheimer disease. Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo. Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer's Disease Cooperative Study Activities of Daily Living Scale). Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau(181) levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups. Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted. clinicaltrials.gov Identifier: NCT00117403.


Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression.
Treatment of bipolar disorder often results in patients taking several drugs in an attempt to alleviate residual depressive symptoms, which can lead to an accumulation of side effects. New treatments for bipolar depression that do not increase the side effect burden are needed. One nonpharmacological treatment with few side effects, bright light therapy, has been shown to be an effective therapy for seasonal affective disorder, yet has not been extensively studied for other forms of depression. Forty-four adults with bipolar disorder, depressed phase were randomized to treatment with bright light therapy, low-density or high-density negative ion generator for 8 weeks. The primary measure of efficacy was the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS). Adverse events were assessed using the Young Mania Rating Scale (YMRS) and Systematic Assessment for Treatment Emergent effects (SAFTEE). All outcome variables were statistically analyzed using a mixed model repeated measure analysis of variance (ANOVA). The results showed no statistically significant differences between groups in any outcome measures at study end point; adverse events, including switches into hypomania, were rare. Further research is needed to determine the efficacy of bright light therapy in this population.


A Particle Model for Prediction of Cement Infiltration of Cancellous Bone in Osteoporotic Bone Augmentation.
Femoroplasty is a potential preventive treatment for osteoporotic hip fractures. It involves augmenting mechanical properties of the femur by injecting Polymethylmethacrylate (PMMA) bone cement. To reduce the risks involved and maximize the outcome, however, the procedure needs to be carefully planned and executed. An important part of the planning system is predicting infiltration of cement into the porous medium of cancellous bone. We used the method of Smoothed Particle Hydrodynamics (SPH) to model the flow of PMMA inside porous media. We modified the standard formulation of SPH to incorporate the extreme viscosities associated with bone cement. Darcy creeping flow of fluids through isotropic porous media was simulated and the results were compared with those reported in the literature. Further validation involved injecting PMMA cement inside porous foam blocks - osteoporotic cancellous bone surrogates - and simulating the injections using our proposed SPH model. Millimeter accuracy was obtained in comparing the simulated and actual cement shapes. Also, strong correlations were found between the simulated and the experimental data of spreading distance (R(2) = 0.86) and normalized pressure (R(2) = 0.90). Results suggest that the proposed model is suitable for use in an osteoporotic femoral augmentation planning framework.


Empirical evidence of senescence in adult damselflies (Odonata: Zygoptera).
1. Age-dependent increases in mortality have been documented in a variety of species of insect under laboratory conditions. However, while strong statistical evidence has been presented for senescence in vertebrate populations in the wild, we know little about the rate and shape of senescence in wild populations of insects. 2. Odonates (damselflies and dragonflies) provide excellent candidate species for evaluating demographic senescence as they are large enough to be marked individually and they are easily re-sighted without recapture. The prevailing opinion - based entirely on qualitative examination of the declines in log numbers alive with time since marking - is that odonates exhibit age-independent daily survivorship. 3. Here, we examine mark-recapture data on the Azure Damselfly Coenagrion puella over two consecutive seasons. For the first time, we evaluate and compare the fit of quantitative models that not only account for weather-dependent daily variation in daily re-sighting rates, but also age-dependent variation in daily survivorship. 4. Models with age-dependent declines in daily survivorship provide a more parsimonious explanation for the data than similar models without these age-dependent effects. In general, models in which mortality increases in an exponential (Gompertz) fashion explain the mark-recapture sequences more efficiently than a range of alternative models, including those in which mortality increases as a power function (Weibull) or reaches a plateau (logistic). These results are indicative of a general senescent decline in physiological functioning, which is particularly marked after 15 days as a mature adult. 5. Weather (temperature, sun and precipitation) and initial mite load influenced the probability of daily re-sighting. Weather and mite load also influenced daily survivorship, but their effects differed between seasons. 6. Overall, fitting models with age as an explicit covariate demonstrates that odonates do indeed senesce. This contradicts previously held assumptions that Odonata do not exhibit age-dependent survivorship in the wild.


Natural anti-bacterial activity against Salmonella typhi by human T4+ lymphocytes armed with IgA antibodies.
Peripheral blood mononuclear cells from normal volunteers possess natural anti-bacterial (NA) activity against S. typhi that can be measured in a 2-hr in vitro assay. Employing fractionation on nylon wool columns, Percoll gradients, plastic adherence, and E rosetting, the effector cell of NA activity appeared to be a lymphocyte of the T lineage rather than a macrophage, a B lymphocyte, or a large granular cell. Moreover, complement-dependent killing with monoclonal antibodies such as OKM1, OKB7, OKT8, 5.9 and the anti-natural killer cells AB8.28 did not reduce NA activity. On the contrary, this was completely inhibited when OKT3, OKT11, or OKT4 antibodies and complement were used to pretreat the effector lymphocytes. Indeed, T4+ cells sorted with a FACS displayed an extremely high NA activity against S. typhi. By pretreatment of peripheral lymphocytes with F(ab')2 fragments against human IgA, the NA activity was blocked. It is therefore suggested that NA activity by human cells might be a mechanism of defense against infections, acting as antibody-dependent cellular cytotoxicity expressed by T4+ lymphocytes coated with preexisting anti-Salmonella IgA antibodies.


The stereochemistry of trans-4-hydroxynonenal-derived exocyclic 1,N2-2'-deoxyguanosine adducts modulates formation of interstrand cross-links in the 5'-CpG-3' sequence.
The trans-4-hydroxynonenal (HNE)-derived exocyclic 1, N(2)-dG adduct with (6S,8R,11S) stereochemistry forms interstrand N(2)-dG-N(2)-dG cross-links in the 5'-CpG-3' DNA sequence context, but the corresponding adduct possessing (6R,8S,11R) stereochemistry does not. Both exist primarily as diastereomeric cyclic hemiacetals when placed into duplex DNA [Huang, H., Wang, H., Qi, N., Kozekova, A., Rizzo, C. J., and Stone, M. P. (2008) J. Am. Chem. Soc. 130, 10898-10906]. To explore the structural basis for this difference, the HNE-derived diastereomeric (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals were examined with respect to conformation when incorporated into 5'-d(GCTAGC XAGTCC)-3' x 5'-d(GGACTCGCTAGC)-3', containing the 5'-CpX-3' sequence [X = (6S,8R,11S)- or (6R,8S,11R)-HNE-dG]. At neutral pH, both adducts exhibited minimal structural perturbations to the DNA duplex that were localized to the site of the adduction at X(7) x C(18) and its neighboring base pair, A(8) x T(17). Both the (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals were located within the minor groove of the duplex. However, the respective orientations of the two cyclic hemiacetals within the minor groove were dependent upon (6S) versus (6R) stereochemistry. The (6S,8R,11S) cyclic hemiacetal was oriented in the 5'-direction, while the (6R,8S,11R) cyclic hemiacetal was oriented in the 3'-direction. These cyclic hemiacetals effectively mask the reactive aldehydes necessary for initiation of interstrand cross-link formation. From the refined structures of the two cyclic hemiacetals, the conformations of the corresponding diastereomeric aldehydes were predicted, using molecular mechanics calculations. Potential energy minimizations of the duplexes containing the two diastereomeric aldehydes predicted that the (6S,8R,11S) aldehyde was oriented in the 5'-direction while the (6R,8S,11R) aldehyde was oriented in the 3'-direction. These stereochemical differences in orientation suggest a kinetic basis that explains, in part, why the (6S,8R,11S) stereoisomer forms interchain cross-links in the 5'-CpG-3' sequence whereas the (6R,8S,11R) stereoisomer does not.


Impact of the circadian clock on in vitro genotoxic risk assessment assays.
Our society expects safety assessment for drugs, chemicals, cosmetics, and foods, which to date cannot be achieved without the use of laboratory animals. At the same time, society aims at refining, reducing, and (ultimately) replacing animal testing. As a consequence, much effort is taken to establish alternatives, such as toxicogenomics-based risk assessment assays on cultured cells and tissues. Evidently, the properties of cells in vitro will considerably differ from the in vivo situation. This review will discuss the impact of the circadian clock, an internal time keeping system that drives 24-h rhythms in metabolism, physiology and behavior, on in vitro genotoxic risk assessment. Our recent observation that DNA damaging agents can synchronize the circadian clock of individual cells in culture (and as a consequence the cyclic expression of clock-controlled genes, comprising up to 10% of the transcriptome) implies that the circadian clock should not be neglected when developing cell or tissue-based alternatives for chronic rodent toxicity assays.


Amiloride Clinical Trial In Optic Neuritis (ACTION) protocol: a randomised, double blind, placebo controlled trial.
Neurodegeneration is a widely accepted contributor to the development of long-term disability in multiple sclerosis (MS). While current therapies in MS predominantly target inflammation and reduce relapse rate they have been less effective at preventing long-term disability. The identification and evaluation of effective neuroprotective therapies within a trial paradigm are key unmet needs. Emerging evidence supports amiloride, a licenced diuretic, as a neuroprotective agent in MS through acid sensing ion channel blockade. Optic neuritis (ON) is a common manifestation of MS with correlates of inflammation and neurodegeneration measurable within the visual pathways. Amiloride Clinical Trial In Optic Neuritis (ACTION) will utilise a multimodal approach to assess the neuroprotective efficacy of amiloride in acute ON. 46 patients will be recruited within 28 days from onset of ON visual symptoms and randomised on a 1:1 basis to placebo or amiloride 10 mg daily. Double-blinded treatment groups will be balanced for age, sex and visual loss severity by a random-deterministic minimisation algorithm. The primary objective is to demonstrate that amiloride is neuroprotective in ON as assessed by scanning laser polarimetry of the peripapillary retinal nerve fibre layer (RNFL) thickness at 6 months in the affected eye compared to the unaffected eye at baseline. RNFL in combination with further retinal measures will also be assessed by optical coherence tomography. Secondary outcome measures on brain MRI will include cortical volume, diffusion-weighted imaging, resting state functional MRI, MR spectroscopy and magnetisation transfer ratio. In addition, high and low contrast visual acuity, visual fields, colour vision and electrophysiology will be assessed alongside quality of life measures. Ethical approval was given by the south central Oxford B research ethics committee (REC reference: 13/SC/0022). The findings from ACTION will be disseminated through peer-reviewed publications and at scientific conferences. EudraCT2012-004980-39, ClinicalTrials.gov Identifier: NCT01802489.


Functional capacity in rheumatoid arthritis patients: comparison between Spanish and Brazilian sample.
The main objective of this study is to compare Spanish and Brazilian self-reported health-related functional capacity in patients with rheumatoid arthritis (RA). 197 patients diagnosed with RA were studied in Spain (n = 127) and Brazil (n = 70). Pain (Visual analog scale) and functional capacity (Health Assessment Questionnaire/HAQ) were assessed. Patients were questioned about regular exercise practice. Comparisons between groups were performed with Chi-square tests and Student t test. Pearson's correlation coefficient and linear regression models were used to analyze the associations. Brazilian patients were younger (p = 0.013), had worse levels of pain (p = 0.001) and a trend to experience worse functional capacity (p = 0.057) than Spanish ones. Spanish RA patients had higher body mass index (BMI) (p = 0.019) and longer disease duration (p = 0.001). Also, a higher percentage of subjects with RA from the Spanish cohort had been elected to take early retirement when compared with Brazilian patients (p = 0.010). Spanish RA patients had received more drugs than Brazilians (oral corticosteroids p = 0.010, Leflunomide p = 0.023, Methotrexate p = 0.072, non-steroidal anti-inflammatory drugs p = 0.064, biologic therapies p = 0.001). The functional capacity (HAQ) was correlated with age (p = 0.001), disease duration (p = 0.001), age at diagnosis (p = 0.001), pain (p = 0.001) and BMI (p = 0.001) in Spanish patients. In Brazilian, these correlations were only found with disease duration (p = 0.004) and pain (p = 0.001). In conclusion, our data suggest a better management of RA in Spanish when compared with Brazilians. Even with less pain and functional capacity, they receive more drug treatment and a higher percentage of them are retired early.


The Different Facets of Heart Rate Variability in Obstructive Sleep Apnea.
Obstructive sleep apnea (OSA), a heterogeneous and multifactorial sleep related breathing disorder with high prevalence, is a recognized risk factor for cardiovascular morbidity and mortality. Autonomic dysfunction leads to adverse cardiovascular outcomes in diverse pathways. Heart rate is a complex physiological process involving neurovisceral networks and relative regulatory mechanisms such as thermoregulation, renin-angiotensin-aldosterone mechanisms, and metabolic mechanisms. Heart rate variability (HRV) is considered as a reliable and non-invasive measure of autonomic modulation response and adaptation to endogenous and exogenous stimuli. HRV measures may add a new dimension to help understand the interplay between cardiac and nervous system involvement in OSA. The aim of this review is to introduce the various applications of HRV in different aspects of OSA to examine the impaired neuro-cardiac modulation. More specifically, the topics covered include: HRV time windows, sleep staging, arousal, sleepiness, hypoxia, mental illness, and mortality and morbidity. All of these aspects show pathways in the clinical implementation of HRV to screen, diagnose, classify, and predict patients as a reasonable and more convenient alternative to current measures.


Two-stage revision for prosthetic joint infection: predictors of outcome and the role of reimplantation microbiology.
We describe rates of success for two-stage revision of prosthetic joint infection (PJI), including data on reimplantation microbiology. We retrospectively collected data from all the cases of PJI that were managed with two-stage revision over a 4 year period. Patients were managed with an antibiotic-free period before reimplantation, in order to confirm, clinically and microbiologically, that infection was successfully treated. One hundred and fifty-two cases were identified. The overall success rate (i.e. retention of the prosthesis over 5.75 years of follow-up) was 83%, but was 89% for first revisions and 73% for re-revisions [hazard ratio = 2.9, 95% confidence interval (CI) 1.2-7.4, P = 0.023]. Reimplantation microbiology was frequently positive (14%), but did not predict outcome (hazard ratio = 1.3, 95% CI 0.4-3.7, P = 0.6). Furthermore, most unplanned debridements following the first stage were carried out before antibiotics were stopped (25 versus 2 debridements). We did not identify evidence supporting the use of an antibiotic-free period before reimplantation and routine reimplantation microbiology. Re-revision was associated with a significantly worse outcome.


Long-term vitamin D treatment decreases human uterine leiomyoma size in a xenograft animal model.
To study the effects of short- and long-term vitamin D treatment on uterine leiomyomas in vivo through cell proliferation, extracellular matrix (ECM) degradation, and apoptosis. Preclinical study of human leiomyoma treatment with vitamin D in an nonhuman animal model. Hospital and university laboratories. Human leiomyomas were collected from patients and implanted in ovariectomized NOD-SCID mice. Mice were treated with vitamin D (0.5 μg/kg/d or 1 μg/kg/d) or vehicle for 21 or 60 days. Vitamin D effect in xenograft tissue was assessed by monitoring tumor size (18F-FDG positron-emission tomography/computerized tomography and macroscopic examination), cell proliferation (immunohistochemistry and quantitative real-time polymerase chain reaction [qRT-PCR]), ECM (Western blot), transforming growth factor (TGF) β3 (qRT-PCR), and apoptosis (Westrn blot and TUNEL). Short-term treatment with vitamin D did not appear to alter leiomyoma size, based on in vivo monitoring and macroscopic examination. However, long-term high-dose treatment induced a significant reduction in leiomyoma size. Cell proliferation was not decreased in the short term, whereas 1 μg/kg/d vitamin D in the long term significantly reduced proliferation compared with control. Although collagen-I and plasminogen activator inhibitor 1 were not modified by short-term treatment, they were both significantly reduced by long-term high-dose vitamin D. Similarly, long-term high-dose vitamin D significantly reduced TGF-β3 expression. Finally, apoptosis significantly increased with both short- and long-term high-dose vitamin D treatment. Long-term vitamin D acts as an antiproliferative, antifibrotic, and proapoptotic therapy that provides a safe, nonsurgical therapeutic option for reducing uterine leiomyoma size without side-effects.


First trimester anomaly scan using virtual reality (VR FETUS study): study protocol for a randomized clinical trial.
In recent years it has become clear that fetal anomalies can already be detected at the end of the first trimester of pregnancy by two-dimensional (2D) ultrasound. This is why increasingly in developed countries the first trimester anomaly scan is being offered as part of standard care. We have developed a Virtual Reality (VR) approach to improve the diagnostic abilities of 2D ultrasound. Three-dimensional (3D) ultrasound datasets are used in VR assessment, enabling real depth perception and unique interaction. The aim of this study is to investigate whether first trimester 3D VR ultrasound is of additional value in terms of diagnostic accuracy for the detection of fetal anomalies. Health-related quality of life, cost-effectiveness and also the perspective of both patient and ultrasonographer on the 3D VR modality will be studied. Women in the first trimester of a high risk pregnancy for a fetus with a congenital anomaly are eligible for inclusion. This is a randomized controlled trial with two intervention arms. The control group receives 'care as usual': a second trimester 2D advanced ultrasound examination. The intervention group will undergo an additional first trimester 2D and 3D VR ultrasound examination. Following each examination participants will fill in validated questionnaires evaluating their quality of life and healthcare related expenses. Participants' and ultrasonographers' perspectives on the 3D VR ultrasound will be surveyed. The primary outcome will be the detection of fetal anomalies. The additional first trimester 3D VR ultrasound examination will be compared to 'care as usual'. Neonatal or histopathological examinations are considered the gold standard for the detection of congenital anomalies. To reach statistical significance and 80% power with a detection rate of 65% for second trimester ultrasound examination and 70% for the combined detection of first trimester 3D VR and second trimester ultrasound examination, a sample size of 2800 participants is needed. First trimester 3D VR detection of fetal anomalies may improve patients' quality of life through reassurance or earlier identification of malformations. Results of this study will provide policymakers and healthcare professionals with the highest level of evidence for cost-effectiveness of first trimester ultrasound using a 3D VR approach. Dutch Trial Registration number NTR6309 , date of registration 26 January 2017.


The novel UDP glycosyltransferase 3A2: cloning, catalytic properties, and tissue distribution.
The human UDP glycosyltransferase (UGT) 3A family is one of three families involved in the metabolism of small lipophilic compounds. Members of these families catalyze the addition of sugar residues to chemicals, which enhances their excretion from the body. The UGT1 and UGT2 family members primarily use UDP glucuronic acid to glucuronidate numerous compounds, such as steroids, bile acids, and therapeutic drugs. We showed recently that UGT3A1, the first member of the UGT3 family to be characterized, is unusual in using UDP N-acetylglucosamine as sugar donor, rather than UDP glucuronic acid or other UDP sugar nucleotides (J Biol Chem 283:36205-36210, 2008). Here, we report the cloning, expression, and characterization of UGT3A2, the second member of the UGT3 family. Like UGT3A1, UGT3A2 is inactive with UDP glucuronic acid as sugar donor. However, in contrast to UGT3A1, UGT3A2 uses both UDP glucose and UDP xylose but not UDP N-acetylglucosamine to glycosidate a broad range of substrates including 4-methylumbelliferone, 1-hydroxypyrene, bioflavones, and estrogens. It has low activity toward bile acids and androgens. UGT3A2 transcripts are found in the thymus, testis, and kidney but are barely detectable in the liver and gastrointestinal tract. The low expression of UGT3A2 in the latter, which are the main organs of drug metabolism, suggests that UGT3A2 has a more selective role in protecting the organs in which it is expressed against toxic insult rather than a more generalized role in drug metabolism. The broad substrate and novel UDP sugar specificity of UGT3A2 would be advantageous for such a function.


Synthetic biology open language (SBOL) version 3.0.0.
Synthetic biology builds upon genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. When designing a synthetic system, synthetic biologists need to exchange information about multiple types of molecules, the intended behavior of the system, and actual experimental measurements. The Synthetic Biology Open Language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, following an open community process involving both wet bench scientists and dry scientific modelers and software developers, across academia, industry, and other institutions. This document describes SBOL 3.0.0, which condenses and simplifies previous versions of SBOL based on experiences in deployment across a variety of scientific and industrial settings. In particular, SBOL 3.0.0, (1) separates sequence features from part/sub-part relationships, (2) renames Component Definition/Component to Component/Sub-Component, (3) merges Component and Module classes, (4) ensures consistency between data model and ontology terms, (5) extends the means to define and reference Sub-Components, (6) refines requirements on object URIs, (7) enables graph-based serialization, (8) moves Systems Biology Ontology (SBO) for Component types, (9) makes all sequence associations explicit, (10) makes interfaces explicit, (11) generalizes Sequence Constraints into a general structural Constraint class, and (12) expands the set of allowed constraints.


Genome-wide association study of motor coordination problems in ADHD identifies genes for brain and muscle function.
Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD may identify a sample of reduced genetic heterogeneity. Children with ADHD from the International Multicentre ADHD Genetic (IMAGE) study were evaluated with the Parental Account of Children's Symptoms. Genetic association testing was performed in PLINK on 890 probands with genome-wide genotyping data. Bioinformatics enrichment-analysis was performed on highly ranked findings. Further characterization of the findings was conducted in 313 Dutch IMAGE children using the Developmental Coordination Disorder Questionnaire (DCD-Q). Although none of the findings reached genome-wide significance, bioinformatics analysis of the top-ranked findings revealed enrichment of genes for motor neuropathy and amyotrophic lateral sclerosis. Genes involved in neurite outgrowth and muscle function were also enriched. Among the highest ranked genes were MAP2K5, involved in restless legs syndrome, and CHD6, causing motor coordination problems in mice. Further characterization of these findings using DCD-Q subscales found nominal association for 15 SNPs. Our findings provide clues about the aetiology of motor coordination problems, but replication studies in independent samples are necessary.


Oral health in children with sleep-disordered breathing: a cross-sectional study.
Sleep-disordered breathing (SDB) is associated with a wide range of oral manifestations, including adeno-tonsillar hypertrophy, narrow dentoalveolar width, increased overjet, reduced overbite, and malocclusion. There are no studies about the relationship between SDB and poor oral health in the pediatric population. The aim of this study was to investigate oral health status and oral health-related quality of life (OHRQoL) in children at risk of SDB (SDB+), compared with a control group, not at risk for SDB (SDB). The current cross-sectional study recruited consecutive children, aged between 8 and 17 years, from a university-based dental clinic. Caregivers completed the Pediatric Sleep Questionnaire (PSQ) to stratify risk of SDB. Both children and caregivers completed the Child Oral Health Impact Profile (COHIP) to measure the OHRQoL. A dental exam was conducted to evaluate dental caries, periodontal status, oropharyngeal characteristics, and dental occlusion. DMFS (decay-missing-filled for permanent teeth), dmfs (for primary teeth), PPD (pocket probing depth), parent COHIP score, child COHIP score, and BOP (bleeding on probing) were compared between children SDB+ and SDB-. In this study, 122 children were enrolled and divided into two equal subgroups (61 each). There was a significant association between SDB and all six outcomes (all p < 0.05) with higher values in SDB+ children. SDB+ was associated with a poorer OHRQoL, and a greater COHIP score for both parents and children. In conclusion, the current study suggests that the impact of SDB on oral health and OHRQoL in children is relevant and far-reaching. Therefore, it is necessary to closely monitor the oral health of SDB+ children, and, if appropriate, to use gentle non-pharmacological treatments able to reduce nasal congestion.


Potentially modifiable factors associated with agitation and aggression in Alzheimer's disease: results of the ICTUS study.
To study potentially modifiable factors associated with the severity of agitation or aggression (A/A) symptoms among Alzheimer's disease (AD) patients. Data from the Impact of Cholinergic Treatment Use (ICTUS) study, European longitudinal prospective observational study. Community dwelling outpatients included in 29 European memory clinics. 1375 participants with probable AD (Mini-Mental State Examination score of 10-26) with an informal caregiver. At baseline and twice yearly over the two-year follow-up, patients underwent comprehensive clinical and neuropsychological assessments: sociodemographic data, cognitive status, functional impairment, and assessment of neuropsychiatric symptoms based on Neuro-Psychiatric Inventory (NPI). The ZARIT scale assessed the caregiver's burden. The variable of interest was the severity of the item of A/A of the NPI. To study factors associated to the severity of A/A symptoms six months later, a multivariate mixed regression model was used. Frequency of A/A symptom varied from 30% to 34% at each visit. Two factors were found to be independently associated with the severity of A/A: (1) the presence of affective disorder (anxiety, depression, and/or irritability) that increased the severity of the A/A by 0.89 point (coefficient:0.89; 95% Confidence Interval (CI) = [0.48,1.30], p < 0.001), and (2) a severe caregiver burden that increased the severity of the A/A by 1.08 point (coefficient:1.08; 95% CI = [0.69,1.47], p < 0.001). Research should evaluate whether the identification and treatment of an affective disorder along with the evaluation and optimal management of the caregiver would have a positive impact on the course of A/A in mild to moderate AD patients.


MicroRNA-124 inhibits the progression of adjuvant-induced arthritis in rats.
MicroRNAs (miRNAs) are small endogenous, non-coding RNAs that act as post-transcriptional regulators. We analysed the in vivo effect of miRNA-124 (miR-124, the rat analogue of human miR-124a) on adjuvant-induced arthritis (AIA) in rats. AIA was induced in Lewis rats by injecting incomplete Freund's adjuvant with heat-killed Mycobacterium tuberculosis. Precursor (pre)-miR-124 was injected into the right hind ankle on day 9. Morphological changes in the ankle joint were assessed by micro-CT and histopathology. Cytokine expression was examined by western blotting and real-time RT-PCR. The effect of miR-124 on predicted target messenger RNAs (mRNAs) was examined by luciferase reporter assays. The effect of pre-miR-124 or pre-miR-124a on the differentiation of human osteoclasts was examined by tartrate-resistant acid phosphatase staining. We found that miR-124 suppressed AIA in rats, as demonstrated by decreased synoviocyte proliferation, leucocyte infiltration and cartilage or bone destruction. Osteoclast counts and expression level of receptor activator of the nuclear factor κB ligand (RANKL), integrin β1 (ITGB1) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were reduced in AIA rats treated with pre-miR-124. Luciferase analysis showed that miR-124 directly targeted the 3'UTR of the rat NFATc1, ITGB1, specificity protein 1 and CCAAT/enhancer-binding protein α mRNAs. Pre-miR-124 also suppressed NFATc1 expression in RAW264.7 cells. Both miR-124 and miR-124a directly targeted the 3'-UTR of human NFATc1 mRNA, and both pre-miR-124 and pre-miR-124a suppressed the differentiation of human osteoclasts. We found that miR-124 ameliorated AIA by suppressing critical prerequisites for arthritis development, such as RANKL and NFATc1. Thus, miR-124a is a candidate for therapeutic use for human rheumatoid arthritis.


Development of a health index in patients with ankylosing spondylitis (ASAS HI): final result of a global initiative based on the ICF guided by ASAS.
The burden of disease in patients with ankylosing spondylitis (AS) can be considerable. However, no agreement has been reached among expert members of Assessment of SpondyloArthritis International Society (ASAS) to define severity of AS. Based on the International Classification of Functioning, Disability and Health (ICF), a core set of items for AS has been selected to represent the entire spectrum of possible problems in functioning. Based on this, the objective of this study was to develop a tool to quantify health in AS, the ASAS Health Index. First, based on a literature search, experts' and patients' opinion, a large item pool covering the categories of the ICF core set was generated. In several steps this item pool was reduced based on reliability, Rasch analysis and consensus building after two cross-sectional surveys to come up with the best fitting items representing most categories of the ICF core set for AS. After the first survey with 1754 patients, the item pool of 251 items was reduced to 82. After selection by an expert committee, 50 items remained which were tested in a second cross-sectional survey. The results were used to reduce the number of items to a final set of 17 items. This selection showed the best reliability and fit to the Rasch model, no residual correlation, and absence of consistent differential item function and a Person Separation Index of 0.82. In this long sequential study, 17 items which cover most of the ICF core set were identified that showed the best representation of the health status of patients with AS. The ASAS Health Index is a linear composite measure which differs from other measures in the public domain.


Fluidic automation of nitrate and nitrite bioassays in whole blood by dissolvable-film based centrifugo-pneumatic actuation.
This paper demonstrates the full centrifugal microfluidic integration and automation of all liquid handling steps of a 7-step fluorescence-linked immunosorbent assay (FLISA) for quantifying nitrate and nitrite levels in whole blood within about 15 min. The assay protocol encompasses the extraction of metered plasma, the controlled release of sample and reagents (enzymes, co-factors and fluorescent labels), and incubation and detection steps. Flow control is implemented by a rotationally actuated dissolvable film (DF) valving scheme. In the valves, the burst pressure is primarily determined by the radial position, geometry and volume of the valve chamber and its inlet channel and can thus be individually tuned over an extraordinarily wide range of equivalent spin rates between 1,000 RPM and 5,500 RPM. Furthermore, the vapour barrier properties of the DF valves are investigated in this paper in order to further show the potential for commercially relevant on-board storage of liquid reagents during shelf-life of bioanalytical, ready-to-use discs.


Lung function in rescue workers at the World Trade Center after 7 years.
The terrorist attacks on the World Trade Center on September 11, 2001, exposed thousands of Fire Department of New York City (FDNY) rescue workers to dust, leading to substantial declines in lung function in the first year. We sought to determine the longer-term effects of exposure. Using linear mixed models, we analyzed the forced expiratory volume in 1 second (FEV(1)) of both active and retired FDNY rescue workers on the basis of spirometry routinely performed at intervals of 12 to 18 months from March 12, 2000, to September 11, 2008. Of the 13,954 FDNY workers who were present at the World Trade Center between September 11, 2001, and September 24, 2001, a total of 12,781 (91.6%) participated in this study, contributing 61,746 quality-screened spirometric measurements. The median follow-up was 6.1 years for firefighters and 6.4 years for emergency-medical-services (EMS) workers. In the first year, the mean FEV(1) decreased significantly for all workers, more for firefighters who had never smoked (a reduction of 439 ml; 95% confidence interval [CI], 408 to 471) than for EMS workers who had never smoked (a reduction of 267 ml; 95% CI, 263 to 271) (P<0.001 for both comparisons). There was little or no recovery in FEV(1) during the subsequent 6 years, with a mean annualized reduction in FEV(1) of 25 ml per year for firefighters and 40 ml per year for EMS workers. The proportion of workers who had never smoked and who had an FEV(1) below the lower limit of the normal range increased during the first year, from 3% to 18% for firefighters and from 12% to 22% for EMS workers, stabilizing at about 13% for firefighters and 22% for EMS workers during the subsequent 6 years. Exposure to World Trade Center dust led to large declines in FEV(1) for FDNY rescue workers during the first year. Overall, these declines were persistent, without recovery over the next 6 years, leaving a substantial proportion of workers with abnormal lung function.


Spatial distribution of lead in Sacramento, California, USA.
Chronic exposure to lead remains a health concern in many urban areas; Sacramento, California is one example, with state surveillance data showing nearly 3% of screened children reported with blood lead levels over 4.5 μg/dL in 2009. To investigate the environmental exposure, 91 soil samples were collected and analyzed by ICP-AES and ICP-MS for 14 elements. An additional 28 samples were collected from areas of focus and analyzed by hand-held X-ray fluorescence spectrometry for Pb and Zn. Analysis of the metals data revealed non-normal distributions and positive skewness, consistent with anthropogenic input. In addition, high correlation coefficients (≥0.75) of metal concentrations in Cd-Pb, Cd-Zn, Pb-Zn, and Sb-Sn pairs suggest similarities in the input mechanisms. Semivariograms generated from Pb and associated metals reveal these metals to exhibit spatial correlation. A prediction map of lead concentrations in soil was generated by ordinary kriging, showing elevated concentrations in soil located in the central, older area of Sacramento where historic traffic density and industrial activity have been historically concentrated. XRF analysis of Pb and Zn from additional samples verifies elevated concentrations in the central areas of Sacramento as predicted.


The immunological synapse.
The molecular interactions underlying regulation of the immune response take place in a nanoscale gap between T cells and antigen-presenting cells, termed the immunological synapse. If these interactions are regulated appropriately, the host is defended against a wide range of pathogens and deranged host cells. If these interactions are disregulated, the host is susceptible to pathogens or tumor escape at one extreme and autoimmunity at the other. Strategies targeting the synapse have helped to establish immunotherapy as a mainstream element in cancer treatment. This Masters' primer will cover the basics of the immunological synapse and some of the applications to tumor immunology.


Regulation of apoptosis in the atresia of dominant bovine follicles of the first follicular wave following ovulation.
During atresia of bovine follicles, granulosa cells are lost through the controlled form of cell death, apoptosis. The purpose of this study was to characterize the regulation of apoptotic death of granulosa cells in dominant bovine follicles during the first wave of follicular development. Dominant follicles were collected from Holstein heifers on days 4, 6 or 8 of the first follicular wave (n = 5/day). Regulation of apoptosis in granulosa cells was examined by annexin V and propidium iodide staining; measurement of relative levels of mRNA encoding Bcl-2, Bcl-xL and Bax; and activity of caspase-3, -8 and -9. Steady-state levels of mRNA encoding four oxidative stress-response proteins were determined. Compared with day 4, the incidence of apoptotic and nonviable granulosa cells tended to increase on day 6, and numbers of nonviable cells were higher on day 8. The ratios of relative levels of mRNA encoding Bcl-2 to Bax and Bcl-xL to Bax were higher on day 6 than days 4 and 8. Activity of caspases-3 and -9 in granulosa cells did not change among the 3 days, while caspase-8 activity decreased on day 8 compared with days 4 and 6. Amounts of GSHPx, MnSOD and Cu/ZnSOD mRNA in granulosa cells were higher on day 8 than day 6. In theca interna, amounts of Cu/ZnSOD mRNA decreased between days 4 and 6. From the decreased production of estradiol and increased numbers of apoptotic and nonviable granulosa cells, we conclude that atresia of the dominant follicle is initiated between days 4 and 6 of the first follicular wave. However, apoptosis of granulosa cells does not appear to be initiated by changes in expression of oxidative stress-response proteins.


Microencapsulated Bio-Based Rejuvenators for the Self-Healing of Bituminous Materials.
Asphalt self-healing by encapsulated rejuvenating agents is considered a revolutionary technology for the autonomic crack-healing of aged asphalt pavements. This paper aims to explore the use of Bio-Oil (BO) obtained from liquefied agricultural biomass waste as a bio-based encapsulated rejuvenating agent for self-healing of bituminous materials. Novel BO capsules were synthesized using two simple dripping methods through dropping funnel and syringe pump devices, where the BO agent was microencapsulated by external ionic gelation in a biopolymer matrix of sodium alginate. Size, surface aspect, and elemental composition of the BO capsules were characterized by optical and scanning electron microscopy and energy-dispersive X-ray spectroscopy. Thermal stability and chemical properties of BO capsules and their components were assessed through thermogravimetric analysis (TGA-DTG) and Fourier-Transform Infrared spectroscopy (FTIR-ATR). The mechanical behavior of the capsules was evaluated by compressive and low-load micro-indentation tests. The self-healing efficiency over time of BO as a rejuvenating agent in cracked bitumen samples was quantified by fluorescence microscopy. Main results showed that the BO capsules presented an adequate morphology for the asphalt self-healing application, with good thermal stability and physical-chemical properties. It was also proven that the BO can diffuse in the bitumen reducing the viscosity and consequently self-healing the open microcracks.


Vulnerability of artisanal fisheries to climate change in the Venice Lagoon.
Within the context of global warming, the western coast of the northern Adriatic Sea can be regarded as an extremely vulnerable area. Owing to the local geographic features, this area has been described as the Venetian lacuna, where Mediterranean Sea climatic conditions are replaced by Atlantic Ocean ones, supporting the presence of glacial relicts, such as sprat Sprattus sprattus, flounder Platichthys flesus and brown shrimp Crangon crangon. Nektonic assemblage therefore represents a good candidate in terms of an early proxy for thermal regime alterations. It represents a dynamic component of the lagoon ecosystem, changing in space and time, actively moving through the entire system, and dynamically exchanging with the open sea. Here, the first signals of the change have been already detected, such as the presence of alien thermophilic species. Within this context, since the beginning of the century, sampling of the nektonic assemblage has been carried out, integrating them with landings data from the fish market. Vulnerabilities to thermal regime changes have been tested by (1) categorizing species according to the mean distribution area in terms of latitudinal range (over 45°, 30°-45° and below 30°), and (2) analysing both spatial and temporal variations within fishing grounds. Results indicated a high potential vulnerability of the artisanal fishery to climate change, as the commercial catch is entirely composed of species from cold (>45° N) and temperate (between 45° and 30° N) latitudes. At present no alien thermophilic species have been recorded within the lagoon, which is possibly a sign of good resilience of the assemblage. Finally, abundance of species from cold latitudes has decreased during the past decade. All of this has been discussed in the context of the mean annual temperature trend.