Rapid GTP binding and hydrolysis by G(q) promoted by receptor and GTPase-activating proteins.
Receptor-promoted GTP binding and GTPase-activating protein (GAP)-promoted GTP hydrolysis determine the onset and termination of G protein signaling; they coordinately control signal amplitude. The mechanisms whereby cells independently regulate signal kinetics and signal amplitude are therefore central to understanding G protein function. We have used quench-flow kinetic methods to measure the rates of the individual reactions of the agonist-stimulated GTPase cycle for G(q) during steady-state signaling. G(q) and m1 muscarinic cholinergic receptor were co-reconstituted into proteoliposomes with one of two GAPs: phospholipase C (PLC)-beta1, the major G(q)-regulated effector protein, and RGS4, a GAP commonly thought to be an inhibitor of G(q) signaling. In this system, the rate constant for GAP-stimulated hydrolysis of Galpha(q)-bound GTP at 30 degrees C was 9-12 s(-1) for PLC-beta1 and 22-27 s(-1) for RGS4. These rates are 1,000- to 2,000-fold faster than in the absence of a GAP and far faster than measured previously. G(q) can thus hydrolyze bound GTP with deactivation half-times of 25-75 ms at 30 degrees C, commensurate with physiological rates of signal termination. GDP/GTP exchange, which reactivates G(q), was the principal rate-limiting step for the GTPase cycle and was also faster than previously thought. At physiological concentrations of GTP, exchange was limited by the rate of dissociation of GDP from the receptor-G(q) complex, with a maximal rate of 1.8 s(-1) at 30 degrees C. Comparison of activation and deactivation rates help explain how GDP/GTP exchange balance rapid GTP hydrolysis to maintain steady-state signal amplitude.


Capsular Repair May Improve Outcomes in Patients Undergoing Hip Arthroscopy for Femoroacetabular Impingement: A Systematic Review of Comparative Outcome Studies.
To review the existing literature in order to determine the effect of hip capsule repair on outcomes after hip arthroscopy for femoroacetabular impingement syndrome. This study used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to find articles by using PubMed and Embase. Included studies were Level I through III studies that focused on patient outcomes as a function of hip capsular treatments: capsulotomy repair, partial repair, plication, and unrepaired capsulotomies. The Methodological Index for Non-randomized Studies was used for quality assessment of clinical outcome studies. After applying inclusion and exclusion criteria, a total of 16 comparative outcome studies evaluating 2,996 hips were included; they evaluated the following capsular management techniques: complete repair (n = 1,112, 37.1%), partial repair (n = 32, 1.1%), plication (n = 223, 7.4%), and unrepaired capsulotomy (n = 1629, 54.4%). Of the 16 studies, 13 included patient-reported outcome scores (PROs), 3 included imaging outcomes data, and 2 reported on reoperation. Of the studies, 10 directly compared patient-reported outcomes between a capsular repair group and an unrepaired group. Of the 10 studies that directly compared PROs between a group with unrepaired capsulotomy and a group with capsular repair, 8 studies demonstrated statistically significantly better PROs in the repaired group compared to the unrepaired group, and 2 studies found no difference between the groups. Reoperation rates demonstrated mixed results between groups, and no difference was found in regard to imaging outcomes. Midterm outcome studies suggest that capsular repair is safe and effective in patients without arthritis who are undergoing hip arthroscopy, and it may result in superior PROs compared with those found after unrepaired capsulotomy. Studies consistently demonstrate similar or superior outcomes in cohorts after capsular repair compared to unrepaired capsulotomy, and no studies reported superior results in unrepaired capsulotomy patients. Level IV, systematic review of Level I through Level III studies.


Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation.
The increase in thickness of bronchial walls by such structural changes as subepithelial fibrosis contributes to the severity and chronicity of asthma by amplifying airway narrowing. However, the pathogenesis of this structural alteration is not known. Transforming growth factor beta 1 (TGF beta 1) is known to have biologic activities relevant to the cellular and molecular events in subepithelial fibrosis, such as the deposition of collagen I and III and the increase of myofibroblasts beneath the epithelial basement membrane. Therefore, we examined TGF beta 1 gene expression in bronchial biopsy tissues from five severe asthmatics, five mild asthmatics, and five normal subjects using in situ hybridization combined with histochemical staining. Cells expressing TGF beta 1 mRNA were detected in tissues from four normal subjects, one mild asthmatic, and five severe asthmatics. The density of positive cells in severe asthmatic tissues (52.1 +/- 22.7, mean +/- SD/mm2) was significantly greater than that in mild asthmatic tissues (1.0 +/- 1.9/mm2, P < 0.01) or normal tissues (10.5 +/- 10.6/mm2, P < 0.02). The density in mild asthmatic tissues was not significantly different from that in normal tissues. The vast majority of positive cells in severe (99.1 +/- 1.7%) and mild (100%) asthmatic tissues were identified as eosinophils. In contrast, eosinophils constituted a small portion of positive cells (20.8 +/- 21.6%) in normal tissues. These results indicated that TGF beta 1 mRNA was overexpressed in severe asthmatics and that the main source of the mRNA was eosinophils, suggesting that eosinophils play an important role in the pathogenesis not only of inflammation but also of structural changes, such as subepithelial fibrosis, in asthmatic airways.


Autobiographical memory retrieval and appraisal in social anxiety disorder.
Individuals with social anxiety disorder (SADs; n = 41) and healthy controls (HCs; n = 40) were administered the Waterloo Images and Memories Interview, in which they described mental images that they tend to experience in both anxiety-provoking and non-anxiety-provoking social situations. Participants then recalled, in as much detail as possible, specific autobiographical memories of salient aversive and non-aversive social experiences that they believed led to the formation of these images. Audio-recorded memory narratives were transcribed and coded based on the procedure of the Autobiographical Interview, which provides a precise measure of the degree of episodic detail contained within each memory. Participants also rated the subjective properties of their recalled memories. Results revealed that participants across the two groups retrieved equivalent rates of both aversive and non-aversive social memories. However, SAD participants' memories of aversive events contained significantly more episodic detail than those of HCs, suggesting that they may be more highly accessible. Moreover, participants with SAD appraised their memories of aversive experiences as more distressing and intrusive than HCs, and perceived them as having a significantly greater influence on their self-perception. In contrast, no group differences were observed for memories of non-aversive events. Findings have the potential to shed new light on autobiographical memory in SAD, with implications for psychotherapeutic intervention.


The influence of sarcoplasmic reticulum Ca2+ concentration on Ca2+ sparks and spontaneous transient outward currents in single smooth muscle cells.
Localized, transient elevations in cytosolic Ca2+, known as Ca2+ sparks, caused by Ca2+ release from sarcoplasmic reticulum, are thought to trigger the opening of large conductance Ca2+-activated potassium channels in the plasma membrane resulting in spontaneous transient outward currents (STOCs) in smooth muscle cells. But the precise relationships between Ca2+ concentration within the sarcoplasmic reticulum and a Ca2+ spark and that between a Ca2+ spark and a STOC are not well defined or fully understood. To address these problems, we have employed two approaches using single patch-clamped smooth muscle cells freshly dissociated from toad stomach: a high speed, wide-field imaging system to simultaneously record Ca2+ sparks and STOCs, and a method to simultaneously measure free global Ca2+ concentration in the sarcoplasmic reticulum ([Ca2+]SR) and in the cytosol ([Ca2+]CYTO) along with STOCs. At a holding potential of 0 mV, cells displayed Ca2+ sparks and STOCs. Ca2+ sparks were associated with STOCs; the onset of the sparks coincided with the upstroke of STOCs, and both had approximately the same decay time. The mean increase in [Ca2+]CYTO at the time and location of the spark peak was approximately 100 nM above a resting concentration of approximately 100 nM. The frequency and amplitude of spontaneous Ca2+ sparks recorded at -80 mV were unchanged for a period of 10 min after removal of extracellular Ca2+ (nominally Ca2+-free solution with 50 microM EGTA), indicating that Ca2+ influx is not necessary for Ca2+sparks. A brief pulse of caffeine (20 mM) elicited a rapid decrease in [Ca2+]SR in association with a surge in [Ca2+]CYTO and a fusion of STOCs, followed by a fast restoration of [Ca2+]CYTO and a gradual recovery of [Ca2+]SR and STOCs. The return of global [Ca2+]CYTO to rest was an order of magnitude faster than the refilling of the sarcoplasmic reticulum with Ca2+. After the global [Ca2+]CYTO was fully restored, recovery of STOC frequency and amplitude were correlated with the level of [Ca2+]SR, even though the time for refilling varied greatly. STOC frequency did not recover substantially until the [Ca2+]SR was restored to 60% or more of resting levels. At [Ca2+]SR levels above 80% of rest, there was a steep relationship between [Ca2+]SR and STOC frequency. In contrast, the relationship between [Ca2+]SR and STOC amplitude was linear. The relationship between [Ca2+]SR and the frequency and amplitude was the same for Ca2+ sparks as it was for STOCs. The results of this study suggest that the regulation of [Ca2+]SR might provide one mechanism whereby agents could govern Ca2+ sparks and STOCs. The relationship between Ca2+ sparks and STOCs also implies a close association between a sarcoplasmic reticulum Ca2+ release site and the Ca2+-activated potassium channels responsible for a STOC.


Cerebral potentials evoked by oesophageal distension in patients with non-cardiac chest pain.
Cerebral evoked potential recording was used to study the oesophagus-brain axis in 10 controls and 10 patients with non-cardiac chest pain with a manometric diagnosis of either nutcracker oesophagus or diffuse spasm and a positive edrophonium test. A series of 50 inflations (10/minute; inflation rate of 170 ml/second) of an intraoesophageal balloon (5 cm proximal to the lower oesophageal sphincter) was performed in each subject. Three different inflation volumes were used and were individually determined to cause no sensation, slight sensation, and definite sensation, respectively (volume ranges: 2-8 ml, 5-18 ml, and 8-22 ml). All signals were coded and their quality was scored on a scale from 0 (no recognisable pattern) to 5 (well defined potential of good quality) by four 'blinded' observers. The evoked potential quality scores and amplitude of the major peaks increased significantly (p less than 0.01) with increasing sensation, both in patients and in controls. In the patients, quality score and amplitude of all four peaks of the evoked potentials were lower (p less than 0.05) and latencies of two of the four peaks were longer (p less than 0.02) than in the controls. The volumes of air required to produce the various sensations were lower in the patients (p less than 0.01). When divided by the balloon volume, amplitude and quality of the evoked potential were no longer significantly different between the groups. These results suggest that the increased perception of oesophageal distension in patients with non-cardiac chest pain is caused by altered central processing rather than (functionally) abnormal receptors in the oesophageal wall.


Assessing the impact of care farms on quality of life and offending: a pilot study among probation service users in England.
To assess the feasibility of conducting a cost-effectiveness study of using care farms (CFs) to improve quality of life and reduce reoffending among offenders undertaking community orders (COs). To pilot questionnaires to assess quality of life, connection to nature, lifestyle behaviours, health and social-care use. To assess recruitment and retention at 6 months and feasibility of data linkage to Police National Computer (PNC) reconvictions data and data held by probation services. Pilot study using questionnaires to assess quality of life, individually linked to police and probation data. The pilot study was conducted in three probation service regions in England. Each site included a CF and at least one comparator CO project. CFs are working farms used with a range of clients, including offenders, for therapeutic purposes. The three CFs included one aquaponics and horticulture social enterprise, a religious charity focusing on horticulture and a family-run cattle farm. Comparator projects included sorting secondhand clothes and activities to address alcohol misuse and anger management. We recruited 134 adults (over 18) serving COs in England, 29% female. 52% of participants completed follow-up questionnaires. Privatisation of UK probation trusts in 2014 negatively impacted on recruitment and retention. Linkage to PNC data was a more successful means of follow-up, with 90% consenting to access their probation and PNC data. Collection of health and social-care costs and quality-adjusted life year derivation were feasible. Propensity score adjustment provided a viable comparison method despite differences between comparators. We found worse health and higher reoffending risk among CF participants due to allocation of challenging offenders to CFs, making risk of reoffending a confounder. Recruitment would be feasible in a more stable probation environment. Follow-up was challenging; however, assessing reconvictions from PNC data is feasible and a potential primary outcome for future studies.


Awareness of risk factors for coronary heart disease following interventional cardiology procedures: a key concern for nursing practice.
Cardiovascular risk factor modification to prevent progression of coronary heart disease is important for patients following percutaneous coronary intervention. The aims of this study were to assess patient's awareness of modifiable cardiac risk factors and examine if patients with modifiable risk factors were more likely to identify these risk as amenable to change. Awareness of risk factors was measured using the Indiana Cardiac Rehabilitation Knowledge Questionnaire in a cohort of prospective, consecutive participants post percutaneous coronary intervention. Completed questionnaires were received from 75% of the participants. The majority were able to identify high cholesterol (87%), smoking (83%) and hypertension (82%) as modifiable risk factors. Less than half (46%) of the respondents identified diabetes as a modifiable risk factor. Only a third of participants recognized all six modifiable risk factors. A large proportion of patients who were smokers, or who had high cholesterol or hypertension, identified these as risk factors. A third of people with documented diabetes did not recognize this condition as a risk factor for heart disease. The findings have important implications for nursing practice in terms of directing educational efforts for the modification of risk factors for coronary heart disease.


Low-cost (<€5), open-source, potential alternative to commercial spectrophotometers.
Spectrophotometry is a fundamental technique in many areas of science, with many applications and uses. The cost of spectrophotometers has acted as a barrier on the teaching and use of the technique. Here, we provide open-source plans to a 3D-printed cuvette holder with an interchangeable narrow-spectral bandwidth light-emitting diode (LED) block that can be used in conjunction with a smartphone's ambient light sensor (ALS) to perform spectrophotometry. A Lego version with an interchangeable LED block is also presented. Results from the smartphone spectrophotometer in comparison with commercially available spectrophotometers demonstrated functionality, and the model may have many applications, especially in indirect spectrophotometry, such as in the protein assay shown here. The plans for the 3D-printed model are freely available on GitHub, as are editable files to allow customisation by users. We would encourage users to share adaptations with the scientific community.


Patient-specific mathematical neuro-oncology: using a simple proliferation and invasion tumor model to inform clinical practice.
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor associated with a poor median survival of 15-18 months, yet there is wide heterogeneity across and within patients. This heterogeneity has been the source of significant clinical challenges facing patients with GBM and has hampered the drive toward more precision or personalized medicine approaches to treating these challenging tumors. Over the last two decades, the field of Mathematical Neuro-oncology has grown out of desire to use (often patient-specific) mathematical modeling to better treat GBMs. Here, we will focus on a series of clinically relevant results using patient-specific mathematical modeling. The core model at the center of these results incorporates two hallmark features of GBM, proliferation [Formula: see text] and invasion (D), as key parameters. Based on routinely obtained magnetic resonance images, each patient's tumor can be characterized using these two parameters. The Proliferation-Invasion (PI) model uses [Formula: see text] and D to create patient-specific growth predictions. The PI model, its predictions, and parameters have been used in a number of ways to derive biological insight. Beyond predicting growth, the PI model has been utilized to identify patients who benefit from different surgery strategies, to prognosticate response to radiation therapy, to develop a treatment response metric, and to connect clinical imaging features and genetic information. Demonstration of the PI model's clinical relevance supports the growing role for it and other mathematical models in routine clinical practice.


Impact of obesity and diabetes on the incidence of kidney and bladder cancers: a nationwide cohort study.
Obesity and type 2 diabetes are becoming increasingly prevalent worldwide and are both associated with the increased incidence of kidney and bladder cancers. However, previous reports have provided conflicting results. We investigated the impact of body mass index (BMI) and diabetes on the incidence of both cancers in the general population. Using nationally representative data from the Korean National Health Insurance System, 9,777,133 subjects without any malignancy who underwent health examinations in 2009 were followed to the end of 2017. After a median follow-up period of 8.32 years, 12,544 incidents of kidney cancer and 15,137 incidents of bladder cancer were identified. The hazard ratio (HR) for kidney cancer was the lowest in people with a BMI <18.5 kg/m2 (HR: 0.82, 95% confidence interval (CI): 0.72-0.94) and the highest in those with a BMI ≥30 kg/m2 (HR: 1.71, 95% CI: 1.57-1.87) compared to a reference BMI group (18.5-23 kg/m2). In subjects with diabetes, obesity was associated with increased risk of kidney cancer, although the HRs were lower than observed in those without diabetes. Otherwise, there was a reduction in risk of bladder cancer with obesity in men and the HR for bladder cancer was not affected by BMI increase in women. There was a strongly positive association between diabetes and bladder cancer in the total study population. Obesity was a strong risk factors for kidney cancer, whereas the association between obesity and bladder cancer differed by gender. The subjects with diabetes had a higher risk for both cancers than those without diabetes.


Percutaneous vertebroplasty for painful compression fractures in a small cohort of patients with a decreased expectation-related placebo effect due to dementia.
Although abundant literature has reported success with vertebroplasty for the treatment of painful compression fractures, none has accounted for a potential expectation-related placebo effect. We report the results of vertebroplasty for painful vertebral body compression fractures in a small cohort of patients with dementia with the assumption that this patient subgroup is subjected to a decreased placebo effect. All patients with objective evidence of dementia (N = 10) who had undergone vertebroplasty at our institution were identified from a comprehensive prospectively constructed vertebroplasty data base. The patients' pain at rest and activity, mobility, and pain-medication use were analyzed at 2 hours postprocedure, 1 week, 1 month, 6 months, and 1 year. Pain with activity decreased or resolved in 80%-100% of patients at each time point, whereas pain at rest decreased or resolved in 78%-100% of all patients at each time point. Improved mobility was reported in 80%-100% of patients at all time points. Pain medication was decreased or stopped in 67% of patients at 1 week and in 100% of patients at 6 months and 1 year. Treatment of painful compression fractures in patients with dementia demonstrates a high rate of success regarding pain relief and mobility. This study offers additional evidence that vertebroplasty has true benefit.


A Low Critical Event Rate Despite a High Abnormal Event Rate in Patients with Cardiac Implantable Electric Devices Followed Up by Remote Monitoring.
Objective Remote monitoring (RM) of cardiac implantable electric devices (CIEDs) has been advocated as a healthcare standard. However, expert consensus statements suggest that all patients require annual face-to-face follow-up consultations at outpatient clinics even if RM reveals no episodes. The objective of this study was to determine the critical event rate after CIED implantation through RM. Methods This multicenter, retrospective, cohort study evaluated patients with pacemakers (PMs), implantable cardioverter defibrillators (ICDs), or cardiac resynchronization therapy defibrillator (CRT-Ds) and analyzed whether or not the data drawn from RM included abnormal or critical events. Patients A total of 1,849 CIED patients in 12 hospitals who were followed up by the RM center in Okayama University Hospital were included in this study. Results During the mean follow-up period of 774.9 days, 16,560 transmissions were analyzed, of which 11,040 (66.7%) were abnormal events and only 676 (4.1%) were critical events. The critical event rate in the PM group was significantly lower than that in the ICD or CRT-D groups (0.9% vs. 5.0% or 5.9%, p<0.001). A multivariate analysis revealed that ICD, CRT-D, and a low ejection fraction were independently associated with critical events. In patients with ICD, the independent risk factors for a critical event were old age, low ejection fraction, Brugada syndrome, dilated phase hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Conclusion Although abnormal events were observed in two-thirds of the transmitted RM data, the critical event rate was <1% in patients with a PM, which was lower in comparison to the rates in patients with ICDs or CRT-Ds. A low ejection fraction was an independent predictor of critical events.


From tides to mixing along the Hawaiian ridge.
The cascade from tides to turbulence has been hypothesized to serve as a major energy pathway for ocean mixing. We investigated this cascade along the Hawaiian Ridge using observations and numerical models. A divergence of internal tidal energy flux observed at the ridge agrees with the predictions of internal tide models. Large internal tidal waves with peak-to-peak amplitudes of up to 300 meters occur on the ridge. Internal-wave energy is enhanced, and turbulent dissipation in the region near the ridge is 10 times larger than open-ocean values. Given these major elements in the tides-to-turbulence cascade, an energy budget approaches closure.


Multidrug-resistant human sarcoma cells with a mutant P-glycoprotein, altered phenotype, and resistance to cyclosporins.
A variant of the multidrug-resistant human sarcoma cell line Dx5 was derived by co-selection with doxorubicin and the cyclosporin D analogue PSC 833, a potent inhibitor of the multidrug transporter P-glycoprotein. The variant DxP cells manifest an altered phenotype compared with Dx5, with decreased cross-resistance to Vinca alkaloids and no resistance to dactinomycin. Resistance to doxorubicin and paclitaxel is retained. The multidrug resistance phenotype of DxP cells is not modulated by 2 microM PSC 833 or cyclosporine. DxP cells manifest a decreased ability to transport [3H]cyclosporine. DNA heteroduplex analysis and sequencing reveal a mutant mdr1 gene (deletion of a phenylalanine at amino acid residue 335) in the DxP cell line. The mutant P-glycoprotein has a decreased affinity for PSC 833 and vinblastine and a decreased ability to transport rhodamine 123. Transfection of the mutant mdr1 gene into drug-sensitive MES-SA sarcoma cells confers resistance to both doxorubicin and PSC 833. Our study demonstrates that survival of cells exposed to doxorubicin and PSC 833 in a multistep selection occurred as a result of a P-glycoprotein mutation in transmembrane region 6. These data suggest that Phe335 is an important binding site on P-glycoprotein for substrates such as dactinomycin and vinblastine and for inhibitors such as cyclosporine and PSC 833.


Profiles of infant communicative behavior.
Prior studies of mother-infant interaction have generally used a variable-centered approach to associate face-to-face communication with psychosocial outcomes. Herein, we use a person-centered approach to identify clusters of infants who exhibit similar behavioral profiles during face-to-face communication with their mothers. Four infant communication channels were examined-gaze, facial affect, vocal affect, and head orientation-coded from videotape at a 1-s temporal resolution. We used k-means clustering to classify community infants (N = 132) into 10 groups, based on variation in the intercept and the autocorrelation function at the first time lag, representing respectively the overall level of behavior and the predictability of the infant's moment-by-moment behavioral stream, in each of the 4 communication channels. In this exploratory study, 10 clusters were identified, some with unusual levels or predictability of behavior in varying channels, and clusters associated differentially with risk outcomes (infant 4-month temperament and 12-month attachment). Distinct forms of affective dysregulation were identified: sustained negative vocal affect associated with degree of disorganization; random vocal affect associated with attachment resistance; random facial affect and vocal affect, irrespective of positive/negative valence, associated with infant difficult temperament. Clustering multiple channels of infant communication generated unique behavioral profiles and predicted 4- and 12-month outcomes, suggesting that these clusters may indeed represent natural types of infant communicative behavior, not easily observed with the naked eye, that may be useful behavioral markers of clinical risk. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Blind Forensics of Successive Geometric Transformations in Digital Images Using Spectral Method: Theory and Applications.
Geometric transformations, such as resizing and rotation, are almost always needed when two or more images are spliced together to create convincing image forgeries. In recent years, researchers have developed many digital forensic techniques to identify these operations. Most previous works in this area focus on the analysis of images that have undergone single geometric transformations, e.g., resizing or rotation. In several recent works, researchers have addressed yet another practical and realistic situation: successive geometric transformations, e.g., repeated resizing, resizing-rotation, rotation-resizing, and repeated rotation. We will also concentrate on this topic in this paper. Specifically, we present an in-depth analysis in the frequency domain of the second-order statistics of the geometrically transformed images. We give an exact formulation of how the parameters of the first and second geometric transformations influence the appearance of periodic artifacts. The expected positions of characteristic resampling peaks are analytically derived. The theory developed here helps to address the gap left by previous works on this topic and is useful for image security and authentication, in particular, the forensics of geometric transformations in digital images. As an application of the developed theory, we present an effective method that allows one to distinguish between the aforementioned four different processing chains. The proposed method can further estimate all the geometric transformation parameters. This may provide useful clues for image forgery detection.


α-Lipoic acid inhibits sevoflurane-induced neuronal apoptosis through PI3K/Akt signalling pathway.
Sevoflurane is a widely used anaesthetic agent, including in anaesthesia of children and infants. Recent studies indicated that the general anaesthesia might cause the cell apoptosis in the brain. This issue raises the concerns about the neuronal toxicity induced by the application of anaesthetic agents, especially in the infants and young children. In this study, we used Morris water maze, western blotting and immunohistochemistry to elucidate the role of α-lipoic acid in the inhibition of neuronal apoptosis. We found that sevoflurane led to the long-term cognitive impairment in the young rats. This adverse effect may be caused by the neuronal death in the hippocampal region, mediated through PI3K/Akt signalling pathway. We also showed that α-lipoic acid offset the effect of sevoflurane on the neuronal apoptosis and cognitive dysfunction. This study elucidated the potential clinical role of α-lipoic acid, providing a promising way in the prevention and treatment of long-term cognitive impairment induced by sevoflurane general anesthesia.


Wideband antireflection coatings by combining interference multilayers with structured top layers.
The residual reflectance obtained for a broad wavelength range depends mainly on the refractive index of the last layer. Using interference layer stacks composed of naturally available low- and high-index materials, the residual reflection for a broad range cannot be adjusted below a certain limit. However, nanostructured (gradient) and porous layers are effective media with a refractive index lower than that of natural materials. Results demonstrate that an interference layer stack combined with a structured layer as the last layer yields better antireflection properties owing to the low effective index of the structure.


Characterizing pharmaceutical, personal care product, and hormone contamination in a karst aquifer of southwestern Illinois, USA, using water quality and stream flow parameters.
Karst aquifers are drinking water sources for 25% of the global population. However, the unique geology of karst areas facilitates rapid transfer of surficial chemicals to groundwater, potentially contaminating drinking water. Contamination of karst aquifers by nitrate, chloride, and bacteria have been previously observed, but little knowledge is available on the presence of contaminants of emerging concern (CECs), such as pharmaceuticals. Over a 17-month period, 58 water samples were collected from 13 sites in the Salem Plateau, a karst region in southwestern Illinois, United States. Water was analyzed for 12 pharmaceutical and personal care products (PPCPs), 7 natural and synthetic hormones, and 49 typical water quality parameters (e.g., nutrients and bacteria). Hormones were detected in only 23% of samples, with concentrations of 2.2-9.1ng/L. In contrast, PPCPs were quantified in 89% of groundwater samples. The two most commonly detected PPCPs were the antimicrobial triclocarban, in 81% of samples, and the cardiovascular drug gemfibrozil, in 57%. Analytical results were combined with data of local stream flow, weather, and land use to 1) characterize the extent of aquifer contamination by CECs, 2) cluster sites with similar PPCP contamination profiles, and 3) develop models to describe PPCP contamination. Median detection in karst groundwater was 3 PPCPs at a summed concentration of 4.6ng/L. Sites clustered into 3 subsets with unique contamination models. PPCP contamination in Cluster I sites was related to stream height, manganese, boron, and heterotrophic bacteria. Cluster II sites were characterized by groundwater temperature, specific conductivity, sodium, and calcium. Cluster III sites were characterized by dissolved oxygen and barium. Across all sites, no single or small set of water quality factors was significantly predictive of PPCP contamination, although gemfibrozil concentrations were strongly related to the sum of PPCPs in karst groundwater.


Current Trends and Challenges in Biointerfaces Science and Engineering.
The cellular microenvironment is extremely complex, and a plethora of materials and methods have been employed to mimic its properties in vitro. In particular, scientists and engineers have taken an interdisciplinary approach in their creation of synthetic biointerfaces that replicate chemical and physical aspects of the cellular microenvironment. Here the focus is on the use of synthetic materials or a combination of synthetic and biological ligands to recapitulate the defined surface chemistries, microstructure, and function of the cellular microenvironment for a myriad of biomedical applications. Specifically, strategies for altering the surface of these environments using self-assembled monolayers, polymer coatings, and their combination with patterned biological ligands are explored. Furthermore, methods for augmenting an important physical property of the cellular microenvironment, topography, are highlighted, and the advantages and disadvantages of these approaches are discussed. Finally, the progress of materials for prolonged stem cell culture, a key component in the translation of stem cell therapeutics for clinical use, is featured.


Reserves, resilience and dynamic landscapes.
In a world increasingly modified by human activities, the conservation of biodiversity is essential as insurance to maintain resilient ecosystems and ensure a sustainable flow of ecosystem goods and services to society. However, existing reserves and national parks are unlikely to incorporate the long-term and large-scale dynamics of ecosystems. Hence, conservation strategies have to actively incorporate the large areas of land that are managed for human use. For ecosystems to reorganize after large-scale natural and human-induced disturbances, spatial resilience in the form of ecological memory is a prerequisite. The ecological memory is composed of the species, interactions and structures that make ecosystem reorganization possible, and its components may be found within disturbed patches as well in the surrounding landscape. Present static reserves should be complemented with dynamic reserves, such as ecological fallows and dynamic successional reserves, that are part of ecosystem management mimicking natural disturbance regimes at the landscape level.


Multidimensional analysis of the frequencies and rates of cytokine secretion from single cells by quantitative microengraving.
The large diversity of cells that comprise the human immune system requires methods that can resolve the individual contributions of specific subsets to an immunological response. Microengraving is process that uses a dense, elastomeric array of microwells to generate microarrays of proteins secreted from large numbers of individual live cells (approximately 10(4)-10(5) cells/assay). In this paper, we describe an approach based on this technology to quantify the rates of secretion from single immune cells. Numerical simulations of the microengraving process indicated an operating regime between 30 min-4 h that permits quantitative analysis of the rates of secretion. Through experimental validation, we demonstrate that microengraving can provide quantitative measurements of both the frequencies and the distribution in rates of secretion for up to four cytokines simultaneously released from individual viable primary immune cells. The experimental limits of detection ranged from 0.5 to 4 molecules/s for IL-6, IL-17, IFNgamma, IL-2, and TNFalpha. These multidimensional measures resolve the number and intensities of responses by cells exposed to stimuli with greater sensitivity than single-parameter assays for cytokine release. We show that cells from different donors exhibit distinct responses based on both the frequency and magnitude of cytokine secretion when stimulated under different activating conditions. Primary T cells with specific profiles of secretion can also be recovered after microengraving for subsequent expansion in vitro. These examples demonstrate the utility of quantitative, multidimensional profiles of single cells for analyzing the diversity and dynamics of immune responses in vitro and for identifying rare cells from clinical samples.


Retinopathy of prematurity: a study of prevalence and risk factors.
Retinopathy of prematurity (ROP) is a serious complication of prematurity treatment and can lead to blindness unless recognized and treated early. The objective was to estimate the prevalence of ROP in preterm infants in the Neonatal Intensive Care Unit (NICU), to identify the risk factors which predispose to ROP, and to assess the outcome of these cases. A ROP prospective screening survey was performed enrolling all prematures admitted to the NICU from January 2009 to December 2010, with a gestational age of 32 weeks or less at birth and a birth weight of 1500 g or less. Infants whose gestational age was >32 weeks or birth weight was >1500 g were included if they were exposed to oxygen therapy for more than 7 days. A total of 172 infants (84 males and 88 females) had retinal evaluation by indirect ophthalmoscopy from the fourth postnatal week and followed up periodically. Perinatal risk factors for ROP were assessed using univariate and multivariate analysis. Infants who progressed to stage 3 ROP were given laser therapy. Out of the studied 172 infants, 33 infants (19.2%) developed ROP in one or both eyes; 18 (54.5%) cases stage 1, 9 (27.3%) cases stage 2, and 6 (18.2%) cases stage 3. None of the studied neonates presented ROP at stages 4 or 5. The six cases diagnosed as ROP stage 3 underwent laser ablative therapy. Univariate analysis showed that there was a significant relationship between the occurrence of ROP and gestational age (P = 0.000), sepsis (P = 0.004), oxygen therapy (P = 0.018), and frequency of blood transfusions (P = 0.030). However, an insignificant relationship was found between the occurrence of ROP and sex, mode of delivery, birth weight, respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, hypotension, phototherapy, duration of oxygen therapy, mechanical ventilation, and CPAP (all P > 0.05). Gestational age, sepsis, oxygen therapy, and frequency of blood transfusions remained significant variables after logistic regression analysis. The prevalence of ROP in this study was 19.2%; low gestational age, sepsis, oxygen therapy, and frequent blood transfusions were significant risk factors for ROP. Laser was effective in treatment and decreasing the progression of ROP. As this is a unit-based study, a comprehensive countrywide survey on ROP in Egypt is recommended to determine any regional differences in disease prevalence.


Folk biology and the anthropology of science: cognitive universals and cultural particulars.
This essay in the "anthropology of science" is about how cognition constrains culture in producing science. The example is folk biology, whose cultural recurrence issues from the very same domain-specific cognitive universals that provide the historical backbone of systematic biology. Humans everywhere think about plants and animals in highly structured ways. People have similar folk-biological taxonomies composed of essence-based, species-like groups and the ranking of species into lower- and higher-order groups. Such taxonomies are not as arbitrary in structure and content, nor as variable across cultures, as the assembly of entities into cosmologies, materials, or social groups. These structures are routine products of our "habits of mind," which may in part be naturally selected to grasp relevant and recurrent "habits of the world." An experiment illustrates that the same taxonomic rank is preferred for making biological inferences in two diverse populations: Lowland Maya and Midwest Americans. These findings cannot be explained by domain-general models of similarity because such models cannot account for why both cultures prefer species-like groups, although Americans have relatively little actual knowledge or experience at this level. This supports a modular view of folk biology as a core domain of human knowledge and as a special player, or "core meme," in the selection processes by which cultures evolve. Structural aspects of folk taxonomy provide people in different cultures with the built-in constraints and flexibility that allow them to understand and respond appropriately to different cultural and ecological settings. Another set of reasoning experiments shows that Maya, American folk, and scientists use similarly structured taxonomies in somewhat different ways to extend their understanding of the world in the face of uncertainty. Although folk and scientific taxonomies diverge historically, they continue to interact. The theory of evolution may ultimately dispense with the core concepts of folk biology, including species, taxonomy, and teleology; in practice, however, these may remain indispensable to doing scientific work. Moreover, theory-driven scientific knowledge cannot simply replace folk knowledge in everyday life. Folk-biological knowledge is not driven by implicit or inchoate theories of the sort science aims to make more accurate and perfect.


Early prenatal food supplementation ameliorates the negative association of maternal stress with birth size in a randomised trial.
Low birthweight increases the risk of infant mortality, morbidity and poor development. Maternal nutrition and stress influence birth size, but their combined effect is not known. We hypothesised that an early-invitation time to start a prenatal food supplementation programme could reduce the negative influence of prenatal maternal stress on birth size, and that effect would differ by infant sex. A cohort of 1041 pregnant women, who had delivered an infant, June 2003-March 2004, was sampled from among 3267 in the randomised controlled trial, Maternal Infant Nutritional Interventions Matlab, conducted in Matlab, Bangladesh. At 8 weeks gestation, women were randomly assigned an invitation to start food supplements (2.5 MJ d(-1) ; 6 days a week) either early (∼9 weeks gestation; early-invitation group) or at usual start time for the governmental programme (∼20 weeks gestation; usual-invitation group). Morning concentration of cortisol was measured from one saliva sample/woman at 28-32 weeks gestation to assess stress. Birth-size measurements for 90% of infants were collected within 4 days of birth. In a general linear model, there was an interaction between invitation time to start the food supplementation programme and cortisol with birthweight, length and head circumference of male infants, but not female infants. Among the usual-invitation group only, male infants whose mothers had higher prenatal cortisol weighed less than those whose mothers had lower prenatal cortisol. Prenatal food supplementation programmes that begin first trimester may support greater birth size of male infants despite high maternal stress where low birthweight is a public health concern.


Effect of lycopene on caspase-3 enzyme activation in liver of methanol-intoxicated rats: comparison with fomepizole.
Lycopene is one of the major carotenoids and is found almost exclusively in tomatoes and tomato products. This study was performed to evaluate the effect of lycopene on methanol-induced liver injury and to compare the results with those after fomepizole, which is used in treatment of methanol intoxication. Experiments were carried out with 30 female Wistar rats weighting 180-200 g. Rats were injected with a intraperitoneally dose of 3 g/kg methanol as a 50% solution in isotonic saline once for intoxication. Rats were pretreated with fomepizole (50 mg/kg) and/or lycopene (10 mg/kg) before methanol. After 24 hours all the drug-treated and intoxicated rats were sacrificed under anesthesia. Malondialdehyde (MDA) levels were determined in order to assess lipid peroxidation, and caspase-3 activity was determined by immunostaining of liver tissues to evaluate apoptosis. Methanol administration significantly increased the MDA level and caspase-3 activity in liver. Pretreatment with lycopene and/or fomepizole decreased the MDA levels significantly. Similarly, lycopene and fomepizole decreased methanol-induced caspase-3 activity. The findings of the present study demonstrate that methanol intoxication causes hepatic toxicity in rats and that this is likely a result of reactive oxygen species and apoptosis induction. Lycopene has protective effects against methanol-induced hepatic injury similar to fomepizole. It was demonstrated for the first time that both lycopene and fomepizole prevent methanol-induced hepatic injury by reducing the increase of lipid oxidation and caspase-3 activation.


The distribution and morphology of prefrontal cortex pyramidal neurons identified using anti-neurofilament antibodies SMI32, N200 and FNP7. Normative data and a comparison in subjects with schizophrenia, bipolar disorder or major depression.
Alterations in the density and size of pyramidal neurons in the prefrontal cortex have been described in schizophrenia and mood disorder. However, the changes are generally modest and have not always been replicated. We investigated the possibility that specific pyramidal neuron sub-populations, defined by their immunoreactivity with the anti-neurofilament antibodies SMI32, N200, and FNP7, are differentially affected in these disorders. First, we assessed the distribution and characteristics of pyramidal neurons labelled by the antibodies in the human dorsolateral prefrontal cortex (Brodmann areas 9, 32, 46), using single and double label immunocytochemistry and immunofluorescence. Three largely separate sub-populations of pyramidal neurons were identified, although with more substantial overlap between SMI32- and FNP7-positive neurons in lamina V. We then determined the density, size and shape of the three pyramidal neuron sub-populations in area 9 in patients with schizophrenia, bipolar disorder, or major depressive disorder, compared to controls (n=15 in each group). We found a lower density of lamina III N200-positive neurons in major depressive disorder than in schizophrenia or bipolar disorder. There were no other overall differences in neuronal density, or in neuronal size or shape, although a planned secondary analysis supported the previously reported decrease of neuronal size in lamina V in bipolar disorder. In summary, our study illustrates a conceptual and methodological approach which may be of value for investigating the differential neuropathological involvement of pyramidal neuron sub-populations. However, we found no clear evidence that the prefrontal neuropathology of schizophrenia or mood disorders preferentially affects SMI32-, N200- or FNP7-immunoreactive pyramidal neurons.


Which empowerment, which Health Promotion? Conceptual convergences and divergences in preventive health practices.
Based on the multiple meanings, 'empowerment' can be identified with either conservative or critical Health Promotion approaches. From a conservative approach, the concept is viewed as an essentially individual phenomenon, centered on the provision of information and the external transfer of power in the name of the collective good. From this approach, the relationship between 'psychological' and 'community' empowerment is not considered. From a critical approach, the concept is viewed as a relational phenomenon that manifests itself in the dialectic conflict of interests between individuals, groups, and social classes. From this approach, 'psychological' and 'community' empowerment are seen as micro and macro levels of analysis, and social transformations are the result of simultaneous changes at these levels. The use of the notion of empowerment without critical reflection or political analysis of power relations in society disseminates vague, romantic, and homogeneous views of 'community'. Therefore, to assume the relational nature of empowerment means to accept its interdependence with the notion of participation, without which there can be no social transformation. Thus, one should be vigilant about multiple meanings that empowerment can given in Health Promotion discourse.


Anxious personality predicts an increased risk of Parkinson's disease.
We studied the association of three personality traits related to neuroticism with the subsequent risk of Parkinson's disease (PD) using a historical cohort study. We included 7,216 subjects who resided within the 120-mile radius centered in Rochester, MN, at the time they completed the Minnesota Multiphasic Personality Inventory (MMPI) for research at the Mayo Clinic from 1962 to 1965. We considered three MMPI personality scales (pessimistic, anxious, and depressive traits). A total of 6,822 subjects (94.5%) were followed over four decades either actively or passively. During follow-up, 227 subjects developed parkinsonism (156 developed PD). An anxious personality was associated with an increased risk of PD [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.16-2.27]. A pessimistic personality trait was also associated with an increased risk of PD but only in men (HR = 1.92; 95% CI = 1.20-3.07). By contrast, a depressive trait was not associated with increased risk. Analyses combining scores from the three personality scales into a composite neuroticism score showed an association of neuroticism with PD (HR = 1.54; 95% CI = 1.10-2.16). The association with neuroticism remained significant even when the MMPI was administered early in life (ages 20-39 years). By contrast, none of the three personality traits was associated with the risk of non-PD types of parkinsonism grouped together. Our long-term historical cohort study suggests that an anxious personality trait may predict an increased risk of PD developing many years later.


New insights into phase distribution, phase composition and disorder in Y2(Zr,Sn)2O7 ceramics from NMR spectroscopy.
A combination of (89)Y and (119)Sn NMR spectroscopy and DFT calculations are used to investigate phase evolution, local structure and disorder in Y2Zr2-xSnxO7 ceramics, where a phase change is predicted, from pyrochlore to defect fluorite, with increasing Zr content. The ability of NMR to effectively probe materials that exhibit positional and compositional disorder provides insight into the atomic-scale structure in both ordered and disordered phases and, by exploiting the quantitative nature of the technique, we are able to determine detailed information on the composition of the phase(s) present and the average coordination number (and next-nearest neighbour environment) of the cations. In contrast to previous studies, a more complex picture of the phase variation with composition emerges, with single-phase pyrochlore found only for the Sn end member, and a single defect fluorite phase only for x = 0 to 0.6. A broad two-phase region is observed, from x = 1.8 to 0.8, but the two phases present have very different composition, with a maximum of 13% Zr incorporated into the pyrochlore phase, whereas the composition of the defect fluorite phase varies throughout. Preferential ordering of the anion vacancies in the defect fluorite phase is observed, with Sn only ever found in a six-coordinate environment, while remaining vacancies are shown to be more likely to be associated with Zr than Y. Our findings are then discussed in the light of those from previous studies, many of which utilize diffraction-based approaches, where, in most cases, a single phase of fixed composition has been assumed for the refinement procedure. The significant and surprising differences encountered demonstrate the need for complementary approaches to be considered for a detailed and accurate picture of both the long- and short-range structure of a solid to be achieved.


Self-stigma and its relationship with insight, demoralization, and clinical outcome among people with schizophrenia spectrum disorders.
Paradoxically, insight is associated with positive outcomes, such as better treatment adherence and recovery, and negative outcomes, such as depression, hopelessness, low self-esteem, and quality of life. Self-stigma as a moderating variable can be decisive whether more insight leads to better or worse outcome. On the other hand, self-stigma can act as a mediator between insight and outcomes. We therefore examined self-stigma both as a moderator and a mediator. Insight, self-stigma, demoralization, symptoms, and functioning were assessed among 145 outpatients with schizophrenia spectrum disorders using questionnaires and structured interviews. Structural equation modeling was used to analyze the cross-sectional data. Results confirmed self-stigma as a moderator: The association of insight and demoralization was stronger as self-stigma increased. Self-stigma also partially mediated the positive relationship between insight and demoralization. Moreover, demoralization fully mediated the adverse associations of self-stigma with psychotic symptoms and global functioning. Given the decisive role of self-stigma regarding the detrimental consequences of insight, interventions should address self-stigma, particularly if psychoeducational or other interventions have increased insight. Therapeutic implications for changes of dysfunctional beliefs related to illness and self and change of self-concept in the context of recovery at the level of narrative identity are discussed.


The use of meta-analysis risk estimates for candidate genes in combination to predict coronary heart disease risk.
Although the risk for coronary heart disease (CHD) associated with single SNPs is modest it has been suggested that, in combination, several common risk-associated alleles could lead to a substantially better heart disease risk prediction. We have modelled this using 10 SNPs in ten candidate genes (APOB, NOS3, APOE, ACE, SERPINE1, MTHFR, ITGA2B, PON 1, LPL, and CETP) and their predicted summary risk estimates from meta-analysis. Based on published allele frequencies, approximately 29% of the general population would be expected to carry less than three risk alleles, approximately 55% would carry 3 or 4 risk alleles, 4% would have 6 and 1% 7 or more risk alleles. Compared to the mean of those with 3 or 4 risk associated genotypes, those with 6 and 7-or-more alleles have a significantly higher risk odds ratio (OR) of CHD (mean OR (95% Confidence Intervals), 1.70 (1.14 to 2.55); and 4.51 (2.89 to 7.04) respectively), while compared to those in the lowest decile of risk, those in the highest decile have a CHD odds ratio in the range of 3.05 (2.24 to 4.14). Taking into account age and the risk alleles carried, the mean 10 year probability for developing CHD for a 55 year old man was calculated to be 15% (8.6% to 24.8%), with nearly 1 in 5 having more than 20% risk. Whether this particular group of 10 SNPs will improve the accuracy of CHD predictions over the combination of classical risk factors in clinical use requires further experimental evidence.


Binary Image Classification: A Genetic Programming Approach to the Problem of Limited Training Instances.
In the computer vision and pattern recognition fields, image classification represents an important yet difficult task. It is a challenge to build effective computer models to replicate the remarkable ability of the human visual system, which relies on only one or a few instances to learn a completely new class or an object of a class. Recently we proposed two genetic programming (GP) methods, one-shot GP and compound-GP, that aim to evolve a program for the task of binary classification in images. The two methods are designed to use only one or a few instances per class to evolve the model. In this study, we investigate these two methods in terms of performance, robustness, and complexity of the evolved programs. We use ten data sets that vary in difficulty to evaluate these two methods. We also compare them with two other GP and six non-GP methods. The results show that one-shot GP and compound-GP outperform or achieve results comparable to competitor methods. Moreover, the features extracted by these two methods improve the performance of other classifiers with handcrafted features and those extracted by a recently developed GP-based method in most cases.


Surveillance for certain health behaviors among States and selected local areas - United States, 2010.
Chronic diseases (e.g., heart disease, stroke, cancer, and diabetes) are the leading causes of morbidity and mortality in the United States. Engaging in healthy behaviors (e.g., quitting smoking and tobacco use, being more physically active, and eating a nutritious diet) and accessing preventive health-care services (e.g., routine physical checkups, screening for cancer, checking blood pressure, testing blood cholesterol, and receiving recommended vaccinations) can reduce morbidity and mortality from chronic and infectious disease and lower medical costs. Monitoring and evaluating health-risk behaviors and the use of health services is essential to developing intervention programs, promotion strategies, and health policies that address public health at multiple levels, including state, territory, metropolitan and micropolitan statistical area (MMSA), and county. January-December 2010. The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing, state-based, random-digit-dialed telephone survey of noninstitutionalized adults aged ≥18 years residing in the United States. BRFSS collects data on health-risk behaviors, chronic diseases and conditions, access to health care, and use of preventive health services and practices related to the leading causes of death and disabilities in the United States. This report presents results for 2010 for all 50 states, the District of Columbia, the Commonwealth of Puerto Rico, Guam, the U.S. Virgin Islands, 192 MMSAs, and 302 counties. In 2010, the estimated prevalence of high-risk health behaviors, chronic diseases and conditions, access to health care, and use of preventive health services varied substantially by state and territory, MMSA, and county. In the following summary of results, each set of proportions refers to the range of estimated prevalence for the disease, condition, or behaviors, as reported by survey respondents. Adults reporting good or better health: 67.9%-89.3% for states and territories, 72.2%-92.1% for MMSAs, and 72.8%-95.8% for counties. Adults with health-care coverage: 69.4%-95.7% for states and territories, 45.7%-97.0% for MMSAs, and 45.7%-97.2% for counties. Adults who had a dental visit in the past year: 57.2%-81.7% for states and territories, 47.1%-83.5% for MMSAs, and 47.1%-88.2% for counties. Adults aged ≥65 years having had all their natural teeth extracted (edentulism): 7.4%-36.0% for states and territories, 4.8%-34.8% for MMSAs, and 2.4%-39.3% for counties. A routine physical checkup during the preceding 12 months: 53.8%-80.0% for states and territories, 49.5%-82.6% for MMSAs, and 49.5%-85.3% for counties. Influenza vaccination received during the preceding 12 months among adults aged ≥65 years: 26.9%-73.4% for states and territories, 51.7%-77.1% for MMSAs, and 49.3%-87.8% for counties. Pneumococcal vaccination ever received among adults aged ≥65 years: 24.7%-74.0% for states and territories, 48.6%-79.9% for MMSAs, and 47.6%-83.1% for counties. Sigmoidoscopy or colonoscopy ever received among adults aged ≥50 years: 37.8%-75.7% for states and territories, 37.3%-79.9% for MMSAs, and 37.3%-82.5% for counties. Blood stool test received during the preceding 2 years among adults aged ≥50 years: 8.5%-27.0% for states and territories, 6.7%-51.3% for MMSAs, and 6.8%-57.2% for counties. Women who reported having had a Papanicolaou test during the preceding 3 years: 67.8%-88.9% for states and territories, 63.3%-91.2% for MMSAs, and 63.2%-95.7% for counties. Women aged ≥40 years who had a mammogram during the preceding 2 years: 63.8%-83.6% for states and territories, 60.3%-86.2% for MMSAs, and 59.3%-89.7% for counties. Current cigarette smokers: 5.8%-26.8% for states and territories, 5.8%-28.5% for MMSAs, and 5.9%-29.8% for counties. Binge drinking during the preceding month: 6.6%-21.6% for states and territories, 3.6%-23.0% for MMSAs, and 3.8%-24.0% for counties. Heavy drinking during the preceding month: 2.0%-7.2% for states and territories, 1.0%-10.0% for MMSAs, and 1.0%-14.2% for counties. Adults reporting no leisure-time physical activity: 17.5%-42.3% for states and territories, 13.1%-37.6% for MMSAs, and 8.5%-39.0% for counties. Adults who were overweight: 32.6%-40.7% for states and territories, 28.5%-42.5% for MMSAs, and 27.2%-46.4% for counties. Adults aged ≥20 years who were obese: 22.1%-35.0% for states and territories, 17.1%-42.1% for MMSAs, and 13.3%-42.1% for counties. Adults with current asthma: 5.2%-11.1% for states and territories, 3.4%-14.5% for MMSAs, and 3.3%-14.6% for counties. Adults with diagnosed diabetes: 5.3%-13.2% for states and territories, 4.6%-15.4% for MMSAs, and 2.6%-18.8% for counties. Adults with limited activities because of physical, mental or emotional problems: 10.8%-28.2% for states and territories, 13.5%-38.3% for MMSAs, and 11.7%-32.0% for counties. Adults using special equipment because of any health problem: 2.8%-10.6% for states and territories, 4.5%-15.5% for MMSAs, and 1.3%-15.5% for counties. Adults aged ≥45 years who have had coronary heart disease: 5.3%-16.7% for states and territories, 6.5%-19.6% for MMSAs, and 4.9%-19.6% for counties. Adults aged ≥45 years who have had a stroke: 2.4%-7.1% for states and territories, 2.3%-8.8% for MSMAs, and 1.7%-8.8% for counties. The findings in this report indicate substantial variations in the health-risk behaviors, chronic diseases and conditions, access to health-care services, and the use of the preventive health services among U.S. adults at the state and territory, MMSA, and county levels. Healthy People 2010 (HP 2010) objectives were established to monitor health behaviors, conditions, and the use of preventive health services for the first decade of the 2000s. The findings in this report indicate that many of the HP 2010 objectives were not achieved by 2010. The findings underscore the continued need for surveillance of health-risk behaviors, chronic diseases, and conditions and of the use of preventive health-care services. Local and state health departments and federal agencies use BRFSS data to identify populations at high risk for certain health-risk behaviors, chronic diseases, and conditions and to evaluate the use of preventive health-care services. BRFSS data also are used to direct, implement, monitor, and evaluate public health programs and policies that can lead to a reduction in morbidity and mortality from chronic conditions and corresponding health-risk behaviors.


Pregnancy And Neonatal Diabetes Outcomes in Remote Australia (PANDORA) Study.
Diabetes in pregnancy carries an increased risk of adverse pregnancy outcomes for both the mother and foetus, but it also provides an excellent early opportunity for intervention in the life course for both mother and baby. In the context of the escalating epidemic of chronic diseases among Indigenous Australians, it is vital that this risk is reduced as early as possible in the life course of the individual. The aims of the PANDORA Study are to: (i) accurately assess rates of diabetes in pregnancy in the Northern Territory (NT) of Australia, where 38% of babies are born to Indigenous mothers; (ii) assess demographic, clinical, biochemical, anthropometric, socioeconomic and early life development factors that may contribute to key maternal and neonatal birth outcomes associated with diabetes in pregnancy; and (iii) monitor relevant post-partum clinical outcomes for both the mothers and their babies. Eligible participants are all NT women with diabetes in pregnancy aged 16 years and over. Information collected includes: standard antenatal clinical information, diagnosis and management of diabetes in pregnancy, socio-economic status, standard clinical birth information (delivery, gestational age, birth weight, adverse antenatal and birth outcomes). Cord blood is collected at the time of delivery and detailed neonatal anthropometric measurements performed within 72 hours of birth. Information will also be collected regarding maternal post-partum glucose tolerance and cardio-metabolic risk factor status, breastfeeding and growth of the baby up to 2 years post-partum in the first instance. This study will accurately document rates and outcomes of diabetes in pregnancy in the NT of Australia, including the high-risk Indigenous Australian population. The results of this study should contribute to policy and clinical guidelines with the goal of reducing the future risk of obesity and diabetes in both mothers and their offspring.


Factors predicting the cause and prognosis of central line-associated bloodstream infections.
The increased use of indwelling catheters has led to an increased number of deaths due to central line-associated bloodstream infection (CLABSI). Improving CLABSI outcomes requires the identification of clinical characteristics affecting drug selection and factors associated with poor prognosis. The medical records of inpatients admitted to St. Marianna University School of Medicine between April 1, 2010 and March 31, 2013 were evaluated for the results of catheter tip cultures. The clinical characteristics of these cases and the characteristics of the pathogens involved were investigated to identify prognostic factors. Of the 1629 catheter cultures investigated, 183 were CLABSIs. Among them, 105 were caused by gram-positive bacteria, 43 by gram-negative bacteria, and 35 by fungi. Gram-negative CLABSIs were more common in cases with prior colonization by gram-negative bacteria and post-surgical cases. Fungal CLASBIs were more common in the cases with prior colonization by fungi, high-calorie infusion enforcement, broad-spectrum antibiotic treatment, and post-surgical cases. Death was significantly more likely in cases with findings of inflammation at the catheter insertion site and in those with abnormal body temperature, tachycardia, or abnormal white blood cell count. Thus, when treating CLABSI in post-surgical cases and in cases with prior colonization by gram-negative bacteria, therapy should include anti-pseudomonal agents. Considering the factors predicting poor prognostic identified in this study, clinicians must check the vital signs and catheter insertion site in patients with indwelling catheters.


RNA Helicase DDX1 Converts RNA G-Quadruplex Structures into R-Loops to Promote IgH Class Switch Recombination.
Class switch recombination (CSR) at the immunoglobulin heavy-chain (IgH) locus is associated with the formation of R-loop structures over switch (S) regions. While these often occur co-transcriptionally between nascent RNA and template DNA, we now show that they also form as part of a post-transcriptional mechanism targeting AID to IgH S-regions. This depends on the RNA helicase DDX1 that is also required for CSR in vivo. DDX1 binds to G-quadruplex (G4) structures present in intronic switch transcripts and converts them into S-region R-loops. This in turn targets the cytidine deaminase enzyme AID to S-regions so promoting CSR. Notably R-loop levels over S-regions are diminished by chemical stabilization of G4 RNA or by the expression of a DDX1 ATPase-deficient mutant that acts as a dominant-negative protein to reduce CSR efficiency. In effect, we provide evidence for how S-region transcripts interconvert between G4 and R-loop structures to promote CSR in the IgH locus.


In-vivo multi-nonlinear optical imaging of a living cell using a supercontinuum light source generated from a photonic crystal fiber.
A supercontinuum light source generated with a femtosecond Ti:Sapphire oscillator has been used to obtain both vibrational and two-photon excitation fluorescence (TPEF) images of a living cell simultaneously at different wavelengths. Owing to an ultrabroadband spectral profile of the supercontinuum, multiple vibrational resonances have been detected through coherent anti-Stokes Raman scattering (CARS) process. In addition to the multiplex CARS process, multiple electronic states can be excited due to the broadband electronic two-photon excitation using the supercontinuum, giving rise to a two-photon excitation fluorescence (TPEF) signal. Using a living yeast cell whose nucleus is labeled by green fluorescent protein (GFP), we have succeeded in visualizing organelles such as mitochondria, septum, and nucleus through the CARS and the TPEF processes. The supercontinuum enables us to perform unique multi-nonlinear optical imaging through two different nonlinear optical processes.


Reproductive outcomes predicted by phase imaging with computational specificity of spermatozoon ultrastructure.
The ability to evaluate sperm at the microscopic level, at high-throughput, would be useful for assisted reproductive technologies (ARTs), as it can allow specific selection of sperm cells for in vitro fertilization (IVF). The tradeoff between intrinsic imaging and external contrast agents is particularly acute in reproductive medicine. The use of fluorescence labels has enabled new cell-sorting strategies and given new insights into developmental biology. Nevertheless, using extrinsic contrast agents is often too invasive for routine clinical operation. Raising questions about cell viability, especially for single-cell selection, clinicians prefer intrinsic contrast in the form of phase-contrast, differential-interference contrast, or Hoffman modulation contrast. While such instruments are nondestructive, the resulting image suffers from a lack of specificity. In this work, we provide a template to circumvent the tradeoff between cell viability and specificity by combining high-sensitivity phase imaging with deep learning. In order to introduce specificity to label-free images, we trained a deep-convolutional neural network to perform semantic segmentation on quantitative phase maps. This approach, a form of phase imaging with computational specificity (PICS), allowed us to efficiently analyze thousands of sperm cells and identify correlations between dry-mass content and artificial-reproduction outcomes. Specifically, we found that the dry-mass content ratios between the head, midpiece, and tail of the cells can predict the percentages of success for zygote cleavage and embryo blastocyst formation.


Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: report of a new case with literature review.
Nephrogenic fibrosing dermopathy (NFD) is a fibrosing condition of the skin that is being described increasingly in patients with renal diseases, many of whom are on dialysis therapy or have undergone renal transplantation. Its etiopathology is unknown, and no standard therapy currently exists. We describe a patient with NFD for whom histopathologic studies indicated that the fibrotic process affected subcutaneous tissue, striated muscles, diaphragm, pleura, pericardium, great vessels of the heart, left ventricle and septum, and tunica albuginea in addition to the dermis. Fibroblast-like cells positive for CD34 and CD45RO and scattered CD68-positive cells were found in affected tissues. The presentation of our case is unusual in that the disease process started in the lower abdomen and upper extremities and involved the upper extremities to a greater extent than the lower extremities. Our findings indicate that the fibrosis associated with NFD can extend beyond dermis and, as part of a systemic fibrosing disorder, can involve subcutaneous tissues, striated muscles, diaphragm, pleura, pericardium, and myocardium. We therefore suggest that "nephrogenic systemic fibrosis" would be a more appropriate term for this disease entity.


Turbo segmentation of textured images.
We consider the problem of semi-supervised segmentation of textured images. Existing model-based approaches model the intensity field of textured images as a Gauss-Markov random field to take into account the local spatial dependencies between the pixels. Classical Bayesian segmentation consists of also modeling the label field as a Markov random field to ensure that neighboring pixels correspond to the same texture class with high probability. Well-known relaxation techniques are available which find the optimal label field with respect to the maximum a posteriori or the maximum posterior mode criterion. But, these techniques are usually computationally intensive because they require a large number of iterations to converge. In this paper, we propose a new Bayesian framework by modeling two-dimensional textured images as the concatenation of two one-dimensional hidden Markov autoregressive models for the lines and the columns, respectively. A segmentation algorithm, which is similar to turbo decoding in the context of error-correcting codes, is obtained based on a factor graph approach. The proposed method estimates the unknown parameters using the Expectation-Maximization algorithm.


Surface profiling of a transparent object by use of phase-shifting Talbot interferometry.
Talbot interferometry is used to study the surface profile of a transparent object. Periodic patterns are produced by illuminating a grating with a collimated laser beam. The object is placed on the self-image plane of the grating. The deformed grating image, which interferes with another grating, results in the Talbot interferometric fringes. The fringe pattern is recorded on a CCD camera for subsequent analysis, and the phase variation is achieved by a linear translation stage. In this application two specimens are tested to demonstrate the validity of the method; one is a transparent object with a spherical shape with a height of less than 350 microm, and the other is a transparent object with an uneven surface of 50-microm average height. The experimental results are compared with the test results obtained with the mechanical stylus method.


Reduced ATR or Chk1 expression leads to chromosome instability and chemosensitization of mismatch repair-deficient colorectal cancer cells.
Genomic instability in colorectal cancer is categorized into two distinct classes: chromosome instability (CIN) and microsatellite instability (MSI). MSI is the result of mutations in the mismatch repair (MMR) machinery, whereas CIN is often thought to be associated with a disruption in the APC gene. Clinical data has recently shown the presence of heterozygous mutations in ATR and Chk1 in human cancers that exhibit MSI, suggesting that those mutations may contribute to tumorigenesis. To determine whether reduced activity in the DNA damage checkpoint pathway would cooperate with MMR deficiency to induce CIN, we used siRNA strategies to partially decrease the expression of ATR or Chk1 in MMR-deficient colorectal cancer cells. The resultant cancer cells display a typical CIN phenotype, as characterized by an increase in the number of chromosomal abnormalities. Importantly, restoration of MMR proficiency completely inhibited induction of the CIN phenotype, indicating that the combination of partial checkpoint blockage and MMR deficiency is necessary to trigger CIN. Moreover, disruption of ATR and Chk1 in MMR-deficient cells enhanced the sensitivity to treatment with the commonly used colorectal chemotherapeutic compound, 5-fluorouracil. These results provide a basis for the development of a combination therapy for those cancer patients.


Anthrax vaccine-induced antibodies provide cross-species prediction of survival to aerosol challenge.
Because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the Food and Drug Administration's "Animal Rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. U.S. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine whether an immunological bridge based on lethal toxin neutralization activity assay (TNA) can predict survival against an inhalation anthrax challenge within and across species and genera. The 21 studies were classified into 11 different settings, each of which had the same animal species, vaccine type and formulation, vaccination schedule, time of TNA measurement, and challenge time. Logistic regression models determined the contribution of vaccine dilution dose and TNA on prediction of survival. For most settings, logistic models using only TNA explained more than 75% of the survival effect of the models with dose additionally included. Cross-species survival predictions using TNA were compared to the actual survival and shown to have good agreement (Cohen's κ ranged from 0.55 to 0.78). In one study design, cynomolgus macaque data predicted 78.6% survival in rhesus macaques (actual survival, 83.0%) and 72.6% in rabbits (actual survival, 64.6%). These data add support for the use of TNA as an immunological bridge between species to extrapolate data in animals to predict anthrax vaccine effectiveness in humans.


NIMBY syndrome and public consultation policy: the implications of a discourse analysis of local responses to the establishment of a community mental health facility.
The relocation of mental health services from an institutional to community base in different parts of the UK has witnessed incidents of public opposition in relation to the establishment of community mental health projects. It has been argued that this not-in-my-backyard (NIMBY) syndrome is partly a result of the attitudes held by the public towards people with mental health problems. The present paper reports some findings from a study of community attitudes towards individuals with mental health problems in a Scottish community, and discusses their implications for the development of public consultation guidelines with respect to the establishment of community mental health facilities. Discourse analysis was used to explore people's views about individuals with mental health problems. The study examined the ways in which their views were expressed in letters to the local press, and in subsequent discussions and interviews, when arguing for or against a supported accommodation project in their neighbourhood. Participants formulated their arguments around a number of issues which they claimed were of public concern. One of these related to the way in which the project was set up. In particular, participants argued that it had been established without any prior consultation with local people and in circumstances of secrecy. The findings demonstrate that, while consultation is relatively unproblematically defined in terms of its function, the specific nature of consultation is more problematic. The implications of these findings for mental health policy and practice are considered in the light of current official guidelines on public consultation relating to the establishment of community mental health facilities. It is argued that existing guidelines fail to take account of the concerns of local people, and therefore, that any intervention based on such guidelines is likely to be ineffective. It is suggested that the findings of this study will be of interest to policy makers and practitioners seeking to devise future public consultation strategies.


Biosensing using microring resonator interferograms.
Optical low-coherence interferometry (OLCI) takes advantage of the variation in refractive index in silicon-wire microring resonator (MRR) effective lengths to perform glucose biosensing using MRR interferograms. The MRR quality factor (Q), proportional to the effective length, could be improved using the silicon-wire propagation loss and coupling ratio from the MRR coupler. Our study showed that multimode interference (MMI) performed well in broad band response, but the splitting ratio drifted to 75/25 due to the stress issue. The glucose sensing sensitivity demonstrated 0.00279 meter per refractive-index-unit (RIU) with a Q factor of ~30,000 under transverse electric polarization. The 1,310 nm DFB laser was built in the OLCI system as the optical ruler achieving 655 nm characterization accuracy. The lowest sensing limitation was therefore 2 × 10-4 RIU. Moreover, the MRR effective length from the glucose sensitivity could be utilized to experimentally demonstrate the silicon wire effective refractive index with a width of 0.45 mm and height of 0.26 mm.


Parotid Lymphoepithelial Cyst in a HIV-Negative Individual: A Case Report.
Benign lymphoepithelial cysts of the parotid are common in retropositive patients, but extremely rare in HIV-negative individuals. We present a 28-year-old man who presented with a painless, gradually increasing swelling in the left parotid region and was clinically diagnosed to have a pleomorphic adenoma of the left parotid gland. Preoperative blood investigations revealed that the patient was seronegative. He underwent a left superficial parotidectomy and the histopathology report indicated a benign lymphoepithelial cyst. The rarity of this lesion in a seronegative patient is the main reason for reporting this case.


Modeling and characterization of a few-mode EDFA supporting four mode groups for mode division multiplexing.
Numerical and experimental study of a Few-Mode (FM) Erbium Doped Fiber Amplifier (EDFA) suitable for mode division multiplexing (MDM) is reported. Based on numerical simulations, a Few-Mode Erbium Doped Fiber (FM-EDF) has been designed to amplify four mode groups and to equally amplify LP11 and LP21 mode groups with gains greater than 20 dB and with a differential modal gain of less than 1 dB. Experimental results confirmed the simulations with a good concordance. This modal gain equalization is obtained by tailoring the erbium spatial distribution in the fiber core with a ring-shaped profile.


Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension.
We have previously found that T lymphocytes are essential for development of angiotensin II-induced hypertension; however, the mechanisms responsible for T-cell activation in hypertension remain undefined. We sought to study the roles of the CNS and pressure elevation in T-cell activation and vascular inflammation caused by angiotensin II. To prevent the central actions of angiotensin II, we created anteroventral third cerebral ventricle (AV3V) lesions in mice. The elevation in blood pressure in response to angiotensin II was virtually eliminated by AV3V lesions, as was activation of circulating T cells and the vascular infiltration of leukocytes. In contrast, AV3V lesioning did not prevent the hypertension and T-cell activation caused by the peripheral acting agonist norepinephrine. To determine whether T-cell activation and vascular inflammation are attributable to central influences or are mediated by blood pressure elevation, we administered hydralazine (250 mg/L) in the drinking water. Hydralazine prevented the hypertension and abrogated the increase in circulating activated T cells and vascular infiltration of leukocytes caused by angiotensin II. We conclude that the central and pressor effects of angiotensin II are critical for T-cell activation and development of vascular inflammation. These findings also support a feed-forward mechanism in which modest degrees of blood pressure elevation lead to T-cell activation, which in turn promotes inflammation and further raises blood pressure, leading to severe hypertension.


Ank3 (epithelial ankyrin), a widely distributed new member of the ankyrin gene family and the major ankyrin in kidney, is expressed in alternatively spliced forms, including forms that lack the repeat domain.
We cloned a novel ankyrin, Ank3, from mouse kidney cDNA. The full-length transcript is predicted to encode a 214-kD protein containing an 89 kD, NH2 terminal "repeat" domain; a 65 kD, central "spectrin-binding" domain; and a 56 kD, COOH-terminal "regulatory" domain. The Ank3 gene maps to mouse Chromosome 10, approximately 36 cM from the centromere, a locus distinct from Ank1 and Ank2. Ank3 is the major kidney ankyrin. Multiple transcripts of approximately 7.5, 6.9, 6.3, 5.7, 5.1, and 4.6 kb are highly expressed in kidney where Ank1 and Ank2 mRNAs are barely detectable. The smaller mRNAs (< or = 6.3 kb) lack the entire repeat domain. These transcripts have a unique 5'untranslated region and NH2-terminal sequence and encode a predicted protein of 121 kD. Two small sequences of 21 and 18 amino acids are alternatively spliced at the junction of the repeat and spectrin-binding domains in the larger (> or = 6.9 kb) RNAs. Alternative splicing of a 588 bp sequence (corresponding to a 21.5-kD acidic amino acid sequence) within the regulatory domain also occurs. Ank3 is much more widely expressed than previously described ankyrins. By Northern hybridization or immunocytochemistry, it is present in most epithelial cells, in neuronal axons, in muscle cells, and in megakaryocytes/platelets, macrophages, and the interstitial cells of Leydig (testis). On immunoblots, an antibody raised to a unique regions of the regulatory domain detects multiple Ank3 isoforms in the kidney (215, 200, 170, 120, 105 kD) and in other tissues. The 215/200 kD and 120/105-kD kidney proteins are close to the sizes predicted for the 7.5/6.9- and 6.3/5.7-kb RNAs (with/without the 588-bp acidic insert). Interestingly, it appears that Ank3 exhibits a polarized distribution only in tissues that express the approximately 7.0-kb isoforms, the only isoforms in the kidney that contain the repeat domain. In tissues where smaller transcripts (< or = 6.3 kb) are expressed. Ank3 is diffusely distributed in some or all cells and may be associated with cytoplasmic structures. We conclude that Ank3 is a broadly distributed epithelial ankyrin and is the major ankyrin in the kidney and other tissues, where it plays an important role in the polarized distribution of many integral membrane proteins.


Distinguishing endogenous D-amino acid-containing neuropeptides in individual neurons using tandem mass spectrometry.
RNA-based protein synthesis produces L-amino acid-containing proteins and peptides. D-amino acid-containing peptides (DAACPs) can be generated from L-amino acid peptides via post-translational modification. In the nervous system, the conformational change of a single L-amino acid in a peptide to its D-form results in altered bioactivity, with some DAACPs having orders-of-magnitude enhanced efficacy. However, this modification is often overlooked when characterizing endogenous peptides. Here, with the use of matrix-assisted laser desorption ionization (MALDI) time-of-flight (TOF)/TOF mass spectrometry, neuropeptides that have the second residue isomerized to the D-isoform are distinguished from their L-epimers via differences in the relative amounts of specific fragment ions during tandem MS. With the appropriate fragment ions chosen, and in some cases with the use of metal adducts, epimer discrimination is optimized. Specifically, the cardioexcitatory peptide Asn-(D)Trp-Phe-amide (NdWFa) was assayed directly from neurons isolated from the sea slug Aplysia californica; the fraction of the peptide with the second residue (W) in the D- versus L-form was 90 ± 10%. We demonstrate that this approach is well suited for confirming DAACPs directly from cells and tissue, advancing our understanding of the l to d modification and the role it plays in cell-to-cell signaling.


Present and future arboviral threats.
Arthropod-borne viruses (arboviruses) are important causes of human disease nearly worldwide. All arboviruses circulate among wild animals, and many cause disease after spillover transmission to humans and agriculturally important domestic animals that are incidental or dead-end hosts. Viruses such as dengue (DENV) and chikungunya (CHIKV) that have lost the requirement for enzootic amplification now produce extensive epidemics in tropical urban centers. Many arboviruses recently have increased in importance as human and veterinary pathogens using a variety of mechanisms. Beginning in 1999, West Nile virus (WNV) underwent a dramatic geographic expansion into the Americas. High amplification associated with avian virulence coupled with adaptation for replication at higher temperatures in mosquito vectors, has caused the largest epidemic of arboviral encephalitis ever reported in the Americas. Japanese encephalitis virus (JEV), the most frequent arboviral cause of encephalitis worldwide, has spread throughout most of Asia and as far south as Australia from its putative origin in Indonesia and Malaysia. JEV has caused major epidemics as it invaded new areas, often enabled by rice culture and amplification in domesticated swine. Rift Valley fever virus (RVFV), another arbovirus that infects humans after amplification in domesticated animals, undergoes epizootic transmission during wet years following droughts. Warming of the Indian Ocean, linked to the El Niño-Southern Oscillation in the Pacific, leads to heavy rainfall in east Africa inundating surface pools and vertically infected mosquito eggs laid during previous seasons. Like WNV, JEV and RVFV could become epizootic and epidemic in the Americas if introduced unintentionally via commerce or intentionally for nefarious purposes. Climate warming also could facilitate the expansion of the distributions of many arboviruses, as documented for bluetongue viruses (BTV), major pathogens of ruminants. BTV, especially BTV-8, invaded Europe after climate warming and enabled the major midge vector to expand is distribution northward into southern Europe, extending the transmission season and vectorial capacity of local midge species. Perhaps the greatest health risk of arboviral emergence comes from extensive tropical urbanization and the colonization of this expanding habitat by the highly anthropophilic (attracted to humans) mosquito, Aedes aegypti. These factors led to the emergence of permanent endemic cycles of urban DENV and CHIKV, as well as seasonal interhuman transmission of yellow fever virus. The recent invasion into the Americas, Europe and Africa by Aedes albopictus, an important CHIKV and secondary DENV vector, could enhance urban transmission of these viruses in tropical as well as temperate regions. The minimal requirements for sustained endemic arbovirus transmission, adequate human viremia and vector competence of Ae. aegypti and/or Ae. albopictus, may be met by two other viruses with the potential to become major human pathogens: Venezuelan equine encephalitis virus, already an important cause of neurological disease in humans and equids throughout the Americas, and Mayaro virus, a close relative of CHIKV that produces a comparably debilitating arthralgic disease in South America. Further research is needed to understand the potential of these and other arboviruses to emerge in the future, invade new geographic areas, and become important public and veterinary health problems.


Multicenter prospective study on device-associated infection rates and bacterial resistance in intensive care units of Venezuela: International Nosocomial Infection Control Consortium (INICC) findings.
Device-associated healthcare-acquired infections (DA-HAI) pose a threat to patient safety in the intensive care unit (ICU). A DA-HAI surveillance study was conducted by the International Nosocomial Infection Control Consortium (INICC) in two adult medical/surgical ICUs at two hospitals in Caracas, Venezuela, in different periods from March 2008 to April 2015, using the US Centers for Disease Control and Prevention's National Healthcare Safety Network (CDC/NHSN) definitions and criteria, and INICC methods. We followed 1041 ICU patients for 4632 bed days. Central line-associated bloodstream infection (CLABSI) rate was 5.1 per 1000 central line days, ventilator-associated pneumonia (VAP) rate was 7.2 per 1000 mechanical ventilator days, and catheter-associated urinary tract infection (CAUTI) rate was 3.9 per 1000 urinary catheter days, all similar to or lower than INICC rates (4.9 [CLABSI]; 16.5 [VAP]; 5.3 [CAUTI]), and higher than CDC/NHSN rates (0.8 [CLABSI]; 1.1 [VAP]; and 1.3 [CAUTI]). Device utilization ratios were higher than INICC and CDC/NHSN rates, except for urinary catheter, which was similar to INICC. Extra length of stay was 8 days for patients with CLABSI, 9.6 for VAP and 5.7 days for CAUTI. Additional crude mortality was 3.0% for CLABSI, 4.4% for VAP, and 16.9% for CAUTI. DA-HAI rates in our ICUs are higher than CDC/NSHN's and similar to or lower than INICC international rates.


Regeneration: sooner rather than later.
The explosive growth of information from genetics and genomics has led to an appreciation of the conservation of gene regulatory networks between organisms, and between development and regeneration. With ever increasing knowledge, it will be possible to intervene therapeutically to regulate these networks, which will lead to new therapies to induce regeneration. The question then becomes how to do this, rather then when to try. Our thesis is that the time is now, and that this feat can be achieved by combining the insights provided by developmental biologists with the technologies being developed by biomaterial engineers, to achieve the goal of engineering regeneration. We thus envision regenerative engineering as the next step toward achieving the goal of human regeneration. Among the most important discoveries about regeneration from studies of salamanders that regenerate exceptionally well, is that both pattern-following and pattern-forming cells are required. Much progress is being made toward understanding the former cells, but little is known about the cells that control positional information and pattern formation. Within the near future, it will become possible to provide the information needed for regeneration exogenously in the form of an engineered extracellular matrix that is a biomimetic of the endogenous information. Since growth factors (morphogens) can control pattern formation, an engineered grid could be based on spatially organized patterns of sulfation of glycosaminoglycans that control the behavior of cells by modulating morphogen activity. Progress in engineering the positional information grid for regeneration will necessitate learning the sulfation codes associated with successful regeneration in animals such as salamanders.


Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate.
Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10(-6)<P<10(-4)) in a test for GxETS interaction. SNPs rs3733585 and rs12508991 in SLC2A9 yielded P = 2.26×10(-7) in a test for GxETS interaction. SNPs rs6820756 and rs7699512 in WDR1 also yielded P = 1.79×10(-7) and P = 1.98×10(-7) in a 1 df test for GxE interaction. Although further replication studies are critical to confirming these findings, these results illustrate how genetic associations for nonsyndromic CP can be missed if potential GxE interaction is not taken into account, and this study suggest SLC2A9 and WDR1 should be considered as candidate genes for CP.