Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study.
A new betacoronavirus-Middle East respiratory syndrome coronavirus (MERS-CoV)-has been identified in patients with severe acute respiratory infection. Although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock. We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus. 50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies. MERS-CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection. European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft.


Dual functions of the homeoprotein DLX4 in modulating responsiveness of tumor cells to topoisomerase II-targeting drugs.
Topoisomerase II (TOP2)-targeting poisons such as anthracyclines and etoposide are commonly used for cancer chemotherapy and kill tumor cells by causing accumulation of DNA double-strand breaks (DSB). Several lines of evidence indicate that overexpression of TOP2A, the gene encoding topoisomerase IIα, increases sensitivity of tumor cells to TOP2 poisons, but it is not clear why some TOP2A-overexpressing (TOP2A-High) tumors respond poorly to these drugs. In this study, we identified that TOP2A expression is induced by DLX4, a homeoprotein that is overexpressed in breast and ovarian cancers. Analysis of breast cancer datasets revealed that TOP2A-high cases that also highly expressed DLX4 responded more poorly to anthracycline-based chemotherapy than TOP2A-high cases that expressed DLX4 at low levels. Overexpression of TOP2A alone in tumor cells increased the level of DSBs induced by TOP2 poisons. In contrast, DLX4 reduced the level of TOP2 poison-induced DSBs irrespective of its induction of TOP2A. DLX4 did not stimulate homologous recombination-mediated repair of DSBs. However, DLX4 interacted with Ku proteins, stimulated DNA-dependent protein kinase activity, and increased erroneous end-joining repair of DSBs. Whereas DLX4 did not reduce levels of TOP2 poison-induced DSBs in Ku-deficient cells, DLX4 stimulated DSB repair and reduced the level of TOP2 poison-induced DSBs when Ku was reconstituted in these cells. Our findings indicate that DLX4 induces TOP2A expression but reduces sensitivity of tumor cells to TOP2 poisons by stimulating Ku-dependent repair of DSBs. These opposing activities of DLX4 could explain why some TOP2A-overexpressing tumors are not highly sensitive to TOP2 poisons.


Squeezing of the mirror motion via periodic modulations in a dissipative optomechanical system.
We investigate the generation of squeezed state of the mirror motion in a dissipative optomechanical system driven with a strong laser field accompanied with two periodically-modulated lights. Using the density operator approach we calculate the variances of quantum fluctuations around the classical orbits. Both the numerical and analytical results predict that the squeezed state of the mirror motion around its ground state is achievable. Moreover, the obtained squeezed state is robust against the thermal noise because of the strong cooling effect outside the resolved-sideband regime, which arises from the destructive interference of quantum noise.


Testosterone action in the rat ventral prostate. The effects of diethylstilboestrol and cyproterone acetate on the metabolism of ( 3 H)testosterone and the retention of labelled metabolites by rat ventral prostate in vivo and in vitro.
Recent reports have indicated that the prior metabolism of testosterone by the secondary sexual tissues may be necessary for its androgenic effect. The effects of two anti-androgens, diethylstilboestrol and cyproterone acetate (17alpha-acetoxy-6-chloro-1,2alpha-methylenepregna-4,6-diene-3,20-dione) used in the chemotherapy of human prostatic carcinoma, have been examined on both the metabolism of testosterone and the retention of its metabolites by the rat ventral prostate gland. Cyproterone acetate was found to inhibit the retention of labelled metabolites of [(3)H]-testosterone by prostatic nuclei, both in vivo and in vitro. This inhibition appeared to be competitive. In contrast with its effect on nuclear retention of metabolites of testosterone, cyproterone acetate had no significant effect on the metabolism of [(3)H]testosterone by rat ventral prostate tissue. Diethylstilboestrol similarly had little effect on the metabolism of [(3)H]testosterone by prostatic tissue, although it did appear partially to inhibit its initial metabolism in all the incubation systems used. Diethylstilboestrol inhibited the nuclear retention of dihydrotestosterone when both [(3)H]testosterone and diethylstilboestrol were injected intraperitoneally in vivo, but had no effect on dihydrotestosterone retention when both testosterone and diethylstilboestrol were supplied directly to the prostate either in vivo or in vitro. It was concluded that if diethylstilboestrol has an anti-androgenic effect at the level of the target organ as distinct from its effect on androgen production by the testes, then it is probably due to a mechanism differing from that of cyproterone acetate.


Kinesthetic illusions attenuate experimental muscle pain, as do muscle and cutaneous stimulation.
In the present study, muscle pain was induced experimentally in healthy subjects by administrating hypertonic saline injections into the tibialis anterior (TA) muscle. We first aimed at comparing the analgesic effects of mechanical vibration applied to either cutaneous or muscle receptors of the TA or to both types simultaneously. Secondly, pain alleviation was compared in subjects in whom muscle tendon vibration evoked kinesthetic illusions of the ankle joint. Muscle tendon vibration, which primarily activated muscle receptors, reduced pain intensity by 30% (p<0.01). In addition, tangential skin vibration reduced pain intensity by 33% (p<0.01), primarily by activating cutaneous receptors. Concurrently stimulating both sensory channels induced stronger analgesic effects (-51%, p<0.01), as shown by the lower levels of electrodermal activity. The strongest analgesic effects of the vibration-induced muscle inputs occurred when illusory movements were perceived (-38%, p=0.01). The results suggest that both cutaneous and muscle sensory feedback reduce muscle pain, most likely via segmental and supraspinal processes. Further clinical trials are needed to investigate these new methods of muscle pain relief.


Numerical Comparison of Prediction Models for Aerosol Filtration Efficiency Applied on a Hollow-Fiber Membrane Pore Structure.
Hollow-fiber membranes (HFMs) have been widely applied to many liquid treatment applications such as wastewater treatment, membrane contactors/bioreactors and membrane distillation. Despite the fact that HFMs are widely used for gas separation from gas mixtures, their use for mechanical filtration of aerosols is very scarce. In this work, we compared mathematical models developed for the prediction of air filtration efficiency by applying them on the structural parameters of polypropylene HFMs. These membranes are characteristic of pore diameters of about 90 nm and have high solidity, thus providing high potential for nanoparticle removal from air. A single fiber/collector and capillary pore approach was chosen to compare between models developed for fibrous filters and capillary-pore membranes (Nuclepore filters) based on three main mechanisms occurring in aerosol filtration (inertial impaction, interception and diffusion). The collection efficiency due to individual mechanisms differs significantly. The differences are caused by the parameters for which the individual models were developed, i.e., given values of governing dimensionless numbers (Reynolds, Stokes and Peclet number) and also given values of filter porosity and filter fiber diameter. Some models can be used to predict the efficiency of HFMs based on assumptions depending on the conditions and exact membrane parameters.


Index Admission Emergency Laparoscopic Cholecystectomy and Common Bile Duct Exploration: Results From a Specialist Center in the United Kingdom.
The incidence of common bile duct (CBD) stones is between 10% to 18% in people undergoing cholecystectomy for gallstones. Laparoscopic exploration of the CBD is now becoming routine practice in the elective setting, however its safety and efficacy in emergencies is poorly understood. We analyzed our results for index emergency admission laparoscopic cholecystectomy within a specialist center in the United Kingdom. Data from all emergency cholecystectomies in our unit, between 2011 to 2016 were collected and analyzed retrospectively. In total, 494 patients underwent emergency laparoscopic cholecystectomy; 53 (10.7%) patients underwent common bile duct exploration (CBDE), with 1 conversion and 1 bile leak. Indications for CBDE were based on preoperative imaging (41 cases, 81%) or intra-operative cholangiogram (44 cases, 83%) findings. Index admission laparoscopic cholecystectomy and concomitant CBDE is safe and should be the gold standard treatment for patients presenting with acute biliary complications, reducing readmissions and the need for a 2-stage procedure.


Computer-assisted video evaluation of surgical skills.
Compact video cameras have allowed the review of operations in self-directed learning sessions. Controlling the video viewing process by computer allows the selection of specific videotape segments containing the desired psychomotor skills to be evaluated--in this study, the steps involving laparoscopic tubal banding. Six faculty members were able to evaluate 23 videotapes efficiently without knowledge of the resident operator's identity. Because the computer allowed selection of only those frames of the videotape containing the skills to be evaluated, the duration of videotape seen was reduced by an average of 34% from the actual surgical time, with an increase in time saved as experience with the system was gained. Faculty members evaluated these events using a self-made checklist. It was possible to calculate the performance scores of each resident for the individual psychomotor skill components of the reviewed procedure. Computer-assisted video evaluation of surgical skills is technically feasible, allowing time-efficient review by multiple evaluators. With the development of psychometrically valid checklists for use with this technology, computer-assisted video evaluation of surgical skills may provide a new, innovative means of assessing surgical skills and training.


Incidence and correlates of receiving cigarettes as gifts and selecting preferred brand because it was gifted: findings from the ITC China Survey.
Giving cigarettes as gifts is a common practice in China, but there have been few systematic studies of this practice. The present study was designed to estimate the incidence of receiving cigarettes as gifts, correlates of this practice, and its impact on brand selection in a representative sample of urban adult smokers in China. Data were analyzed from Wave 2 of the International Tobacco Control (ITC) China Survey, where 4843 adult urban smokers were interviewed in six major Chinese cities between October 2007 and January 2008. The incidence of most recent cigarette acquisition due to gifting and the prevalence of preferred brand selection due to having received it as a gift were estimated. Bivariate and adjusted logistic regression models were estimated to identify factors associated with these two outcomes. The incidence of receiving cigarettes as a gift at most recent cigarette acquisition was 3.5%. Smokers who received these gifted cigarettes were more likely to be female, older, have higher educational attainment, live in Beijing, and smoke fewer cigarettes per day. The prevalence of choosing one's preferred brand due to having received it as a gift was 7.0%, and this was more likely among smokers who lived in Beijing and Guangzhou, had lower educational attainment, smoked less frequently, and had smoked their preferred brand for less than one year. The 3.5% incidence of one's most recent cigarette acquisition due to gifting is consistent with prevalence estimates based on longer reference periods and translates into the average smoker receiving a gift of cigarettes approximately five times a year. Gifting also appears to have a significant influence on brand preference. Tobacco control interventions in China may need to denormalize the practice of giving cigarettes as gifts in order to decrease the social acceptability of smoking.


Environmental tobacco use and indicators of metabolic syndrome in Chinese adults.
Exposure to environmental tobacco smoke (ETS) is a widespread source of nicotine exposure, and an estimated 540 million Chinese are exposed to ETS in mainland China. We aimed to investigate associations of ETS exposure and metabolic syndrome (MetS) as well as its individual components independent of active smoking status in Chinese adults. A cross-sectional data of 304 randomly selected Chinese households with fourth (elementary school) and seventh (middle school) graders in Qingdao city was used. Assessments of fat mass, metabolic biomarkers, personal history of illness, and health behaviors were conducted. Proportions of current smokers were 3% in women and 60.5% in men, and more men reported exposure to ETS 5-7 days per week than women (60.8% vs. 48.1%). Exposure to ETS was significantly associated with enhanced risks of MetS (odds ratio [OR] = 2.8, p = .01), hypertriglyceridemia (OR = 2.1, p = .02), and central obesity (OR = 2.7, p < .001) and reduced levels of high-density lipoprotein cholesterol (OR = 1.9, p = .02) and elevated mean levels of fasting insulin (p < .01). These observed associations were independent of active smoking status and were successfully replicated in female never-smokers. Results of our study support the hypothesis that ETS exposure is independently associated with MetS and its individual components. Further large-scale studies with longitudinal design and objective assessment of ETS exposure are needed to elucidate the underlying mechanisms and the causal effects of passive smoking on MetS. Findings of this work emphasize the importance of developing community intervention to reduce smoking, ETS, and promote healthy lifestyle.


Genetic Counseling, Reproductive Behavior and Future Reproductive Intentions of People with Neurofibromatosis Type 1 (NF1).
Neurofibromatosis type 1(NF1) is a complex and variable inherited disorder. The complexity and variability present particular difficulty for genetic counseling. Thirty-three people with NF1 of reproductive age were interviewed about their experience of genetic counseling, their past reproductive behavior and future intentions. One third reported having had no genetic counseling or not having it until after their first child. In part, this may be due to delay in diagnosis but also indicates poor access to genetic services. Only three people had ever been offered prenatal genetic testing and only one had accepted. Although testing is still technically difficult, the greatest deterrent to uptake of prenatal testing for NF1 is the variability of the disorder. However, six of the 17 people planning future pregnancies would want a test with a view to termination if necessary. Others would welcome testing in order to be prepared but not to terminate. We discuss some of the factors which influence reproductive decision making for people with NF1 and some of the difficulties in genetic counseling in such a variable and complex disorder.


Stereotactic Body Radiation Therapy (SBRT) Combined With Chemotherapy for Unresected Pancreatic Adenocarcinoma.
The role of radiation therapy in the management of unresectable pancreatic cancer is controversial. One concern about concurrent chemoradiation relates to the timing of chemotherapy. In contrast to conventional radiation therapy, stereotactic body radiation therapy (SBRT) delivers high doses in a shorter duration resulting in minimal disruption in chemotherapy. Here, we report our results of patients treated with SBRT and chemotherapy for inoperable pancreatic cancer. Thirty-eight patients treated with SBRT and chemotherapy for locally advanced, borderline resectable, and medically inoperable pancreatic cancer at our institution from January 2008 to December 2012 were included in this retrospective analysis. Treatment was delivered in 5 fractions of 5 or 6 Gy per fraction over 5 days. Toxicities were scored using the Common Terminology Criteria for Adverse Events version 3. Survival was calculated using the Kaplan-Meier method. The median age was 70 years (range, 45 to 90 y). Eastern Cooperative Oncology Group performance status ranged from 0 to 3. Thirty-four patients received concurrent chemotherapy. Four patients received sequential chemotherapy. Median overall survival was 14.3 months and median progression-free survival was 9.2 months from diagnosis. From radiation, overall survival and progression-free survival were 12.3 and 6.8 months, respectively. The overall local control rate was 79%. Acute toxicity was minimal. Severe late SBRT-related toxicities included 1 grade 3 gastric outlet obstruction, 1 grade 4 biliary stricture, and 1 grade 5 gastric hemorrhage. SBRT combined with chemotherapy for unresectable pancreatic cancer is convenient, feasible, and generally well tolerated. Outcomes of SBRT combined with chemotherapy compare favorably to results obtained with chemotherapy and conventional radiation therapy.


Viral antigens elicit augmented immune responses in primary Sjögren's syndrome.
Infections have been suggested in the pathogenesis of primary SS (pSS). Systematic studies of immune responses to microbial antigens in vivo may be performed during vaccination. In the present study, we therefore longitudinally followed patients with pSS and controls during split-virion influenza vaccination to identify pSS-specific cellular, transcriptomic and serological responses. Patients without treatment (pSSUntr, n = 17), on hydroxychloroquine-treatment (pSSHCQ, n = 8), and healthy controls (n = 16) were included. Antibody titres were determined by ELISA. Plasma proteins were measured by proximity extension assay. Monocyte gene expression was assessed by Nanostring. Routine laboratory tests were performed and clinical disease symptoms were registered by questionnaires. pSSUntr developed higher vaccine-specific IgG titres compared with controls. Notably, anti-Ro52 autoantibody titres increased in pSSUntr but remained unchanged in pSSHCQ. No changes in disease symptoms including EULAR Sjögren's Syndrome Patient Reported Index score were registered. Twenty-four hours after vaccination, the leucocyte count in pSSUntr decreased, with a concomitant increase of CCL7 in plasma. Transcriptomic analysis in monocytes revealed differential vaccination-related expression of the NEMO/IKBKG gene, and its higher induced expression in pSSUntr associated with higher serological vaccine responses. Moreover, titres of vaccine-specific antibodies were associated with higher vaccination-induced NF-κB signalling and higher steady-state IFN signatures in monocytes, and with the levels of several plasma proteins with soluble PD-1 displaying the strongest association. We observed augmented innate and adaptive immune responses in pSS following viral antigen exposure suggesting an underlying hyper-responsiveness to immune challenges, supporting a role for infections driving the immunopathology and acting as environmental risk factor for pSS.


Cationic currents induced by Clostridium perfringens type A enterotoxin in human intestinal CaCO-2 cells.
Clostridium perfringens type A produces an enterotoxin that induces diarrhoea experimentally in man and animals. The enterotoxin causes increased membrane permeability in susceptible cells which is thought to be due to pore formation in the host cell membrane. The effect of purified C. perfringens enterotoxin on intact intestinal CaCO-2 monolayers was examined in Ussing chambers and on single cells by whole-cell patch clamp. Mucosal application of C. perfringens enterotoxin resulted in prompt increases in short-circuit current coupled with a reduction in transepithelial resistance consistent with movement of sodium and other cations smaller than diethanolamine from mucosa to serosa. These changes were independent of extracellular calcium. Increases in short-circuit current were also observed in the apical membranes of CaCO-2 monolayers permeabilised across the basolateral membrane with nystatin. Currents were blocked by subsequent exposure to mucosal barium and zinc. Zinc also prevented the development of the current increases in apical membranes. Cationic currents were also observed following exposure of single CaCO-2 cells in whole-cell patch clamp recordings. These data indicate that C. perfringens enterotoxin is able to form cation permeant pores in the apical membrane of human intestinal CaCO-2 epithelia and the increases in short-circuit current can be prevented by pre-exposure to zinc ions.


Outcome after reduced chemotherapy for intermediate-risk neuroblastoma.
The survival rate among patients with intermediate-risk neuroblastoma who receive dose-intensive chemotherapy is excellent, but the survival rate among patients who receive reduced doses of chemotherapy for shorter periods of time is not known. We conducted a prospective, phase 3, nonrandomized trial to determine whether a 3-year estimated overall survival of more than 90% could be maintained with reductions in the duration of therapy and drug doses, using a tumor biology-based therapy assignment. Eligible patients had newly diagnosed, intermediate-risk neuroblastoma without MYCN amplification; these patients included infants (<365 days of age) who had stage 3 or 4 disease, children (≥365 days of age) who had stage 3 tumors with favorable histopathological features, and infants who had stage 4S disease with a diploid DNA index or unfavorable histopathological features. Patients who had disease with favorable histopathological features and hyperdiploidy were assigned to four cycles of chemotherapy, and those with an incomplete response or either unfavorable feature were assigned to eight cycles. Between 1997 and 2005, a total of 479 eligible patients were enrolled in this trial (270 patients with stage 3 disease, 178 with stage 4 disease, and 31 with stage 4S disease). A total of 323 patients had tumors with favorable biologic features, and 141 had tumors with unfavorable biologic features. Ploidy, but not histopathological features, was significantly predictive of the outcome. Severe adverse events without disease progression occurred in 10 patients (2.1%), including secondary leukemia (in 3 patients), death from infection (in 3 patients), and death at surgery (in 4 patients). The 3-year estimate (±SE) of overall survival for the entire group was 96±1%, with an overall survival rate of 98±1% among patients who had tumors with favorable biologic features and 93±2% among patients who had tumors with unfavorable biologic features. A very high rate of survival among patients with intermediate-risk neuroblastoma was achieved with a biologically based treatment assignment involving a substantially reduced duration of chemotherapy and reduced doses of chemotherapeutic agents as compared with the regimens used in earlier trials. These data provide support for further reduction in chemotherapy with more refined risk stratification. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003093.)


NMR structural inference of symmetric homo-oligomers.
Symmetric homo-oligomers represent a majority of proteins, and determining their structures helps elucidate important biological processes, including ion transport, signal transduction, and transcriptional regulation. In order to account for the noise and sparsity in the distance restraints used in Nuclear Magnetic Resonance (NMR) structure determination of cyclic (C(n)) symmetric homo-oligomers, and the resulting uncertainty in the determined structures, we develop a Bayesian structural inference approach. In contrast to traditional NMR structure determination methods, which identify a small set of low-energy conformations, the inferential approach characterizes the entire posterior distribution of conformations. Unfortunately, traditional stochastic techniques for inference may under-sample the rugged landscape of the posterior, missing important contributions from high-quality individual conformations and not accounting for the possible aggregate effects on inferred quantities from numerous unsampled conformations. However, by exploiting the geometry of symmetric homo-oligomers, we develop an algorithm that provides provable guarantees for the posterior distribution and the inferred mean atomic coordinates. Using experimental restraints for three proteins, we demonstrate that our approach is able to objectively characterize the structural diversity supported by the data. By simulating spurious and missing restraints, we further demonstrate that our approach is robust, degrading smoothly with noise and sparsity.


Late-life obesity is associated with smaller global and regional gray matter volumes: a voxel-based morphometric study.
Obesity adversely affects frontal lobe brain structure and function. Here we sought to show that people who are obese versus those who are of normal weight over a 5-year period have differential global and regional brain volumes. Using voxel-based morphometry, contrasts were done between those who were recorded as being either obese or of normal weight over two time points in the 5 years prior to the brain scan. In a post-hoc preliminary analysis, we compared scores for obese and normal weight people who completed the trail-making task. A total of 292 subjects were examined following exclusions (for example, owing to dementia, stroke and cortical infarcts) from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort with a body mass index of normal weight (<25 kg m(-2)) or obese (30 kg m(-2)). People who were obese had significantly smaller total brain volumes and specifically, significantly reduced total gray matter (GM) volume (GMV) (with no difference in white matter or cerebrospinal fluid). Initial exploratory whole brain uncorrected analysis revealed that people who were obese had significantly smaller GMV in the bilateral supplementary motor area, bilateral dorsolateral prefrontal cortex (DLPFC), left inferior frontal gyrus and left postcentral gyrus. Secondary more stringent corrected analyses revealed a surviving cluster of GMV difference in the left DLPFC. Finally, post-hoc contrasts of scores on the trail-making task, which is linked to DLPFC function, revealed that obese people were significantly slower than those of normal weight. These findings suggest that in comparison with normal weight, people who are obese have smaller GMV, particularly in the left DLPFC. Our results may provide evidence for a potential working memory mechanism for the cognitive suppression of appetite that may lower the risk of developing obesity in later life.


Emerging organic contaminant removal depending on primary treatment and operational strategy in horizontal subsurface flow constructed wetlands: influence of redox.
This study aimed at assessing the influence of primary treatment (hydrolytic upflow sludge blanket (HUSB) reactor vs. conventional settling) and operational strategy (alternation of saturated/unsaturated phases vs. permanently saturated) on the removal of various emerging organic contaminants (i.e. ibuprofen, diclofenac, acetaminophen, tonalide, oxybenzone, bisphenol A) in horizontal subsurface flow constructed wetlands. For that purpose, a continuous injection experiment was carried out in an experimental treatment plant for 26 days. The plant had 3 treatment lines: a control line (settler-wetland permanently saturated), a batch line (settler-wetland operated with saturate/unsaturated phases) and an anaerobic line (HUSB reactor-wetland permanently saturated). In each line, wetlands had a surface area of 2.95 m(2), a water depth of 25 cm and a granular medium D(60) = 7.3 mm, and were planted with common reed. During the study period the wetlands were operated at a hydraulic and organic load of 25 mm/d and about 4.7 g BOD/m(2)d, respectively. The injection experiment delivered very robust results that show how the occurrence of higher redox potentials within the wetland bed promotes the elimination of conventional quality parameters as well as emerging microcontaminants. Overall, removal efficiencies were always greater for the batch line than for the control and anaerobic lines, and to this respect statistically significantly differences were found for ibuprofen, diclofenac, oxybenzone and bisphenol A. As an example, ibuprofen, whose major removal mechanism has been reported to be biodegradation under aerobic conditions, showed a higher removal in the batch line (85%) than in the control (63%) and anaerobic (52%) lines. Bisphenol A showed also a great dependence on the redox status of the wetlands, finding an 89% removal rate for the batch line, as opposed to the control and anaerobic lines (79 and 65%, respectively). Furthermore, diclofenac showed a greater removal under a higher redox status (70, 48 and 32% in the batch, control and anaerobic lines). Average removal efficiencies of acetaminophen, oxybenzone and tonalide were almost >90% for the 3 treatment lines. The results of this study indicate that the efficiency of horizontal flow constructed wetland systems can be improved by using a batch operation strategy. Furthermore, we tentatively identified 4-hydroxy-diclofenac and carboxy-bisphenol A as intermediate degradation products. The higher abundance of the latter under the batch operation strategy reinforced biodegradation as a relevant bisphenol A removal pathway under higher redox conditions.


Effect of sulfur doping on structural reversibility and cycling stability of a Li2MnSiO4 cathode material.
Based on the existing calculation reports, sulfur doping is an effective approach to alleviate the structure collapse of Li2MnSiO4 during cycling. Herein, we investigate the feasibility and limitations of S doping in Li2MnSiO4 by experiment. In our work, the solid solubility of S is confirmed and exceeding the threshold results in MnS impurity. The existence state and site of the S element in a Li2MnSiO4 crystal structure is also confirmed. It is found that S doping significantly improves the structural reversibility and cycling stability. Compared with a pristine sample, a 1mol% S doped sample exhibits a much higher initial coulombic efficiency (88.3%), excellent capacity retention (98% at 10th cycles for instance) and enhanced rate performance. Moreover, the 1mol% S doped sample can retain a discharge capacity of 137 mA h g-1 after 30 cycles while the pristine sample only has 61.6 mA h g-1. This study confirms the effectivity of S doping in suppressing the structural distortion in Li2MnSiO4.


The influence of surface functionalization on thermal transport and thermoelectric properties of MXene monolayers.
The newest members of a two-dimensional material family, involving transition metal carbides and nitrides (called MXenes), have garnered increasing attention due to their tunable electronic and thermal properties depending on the chemical composition and functionalization. This flexibility can be exploited to fabricate efficient electrochemical energy storage (batteries) and energy conversion (thermoelectric) devices. In this study, we calculated the Seebeck coefficients and lattice thermal conductivity values of oxygen terminated M2CO2 (where M = Ti, Zr, Hf, Sc) monolayer MXene crystals in two different functionalization configurations (model-II (MD-II) and model-III (MD-III)), using density functional theory and Boltzmann transport theory. We estimated the thermoelectric figure-of-merit, zT, of these materials by two different approaches, as well. First of all, we found that the structural model (i.e. adsorption site of oxygen atom on the surface of MXene) has a paramount impact on the electronic and thermoelectric properties of MXene crystals, which can be exploited to engineer the thermoelectric properties of these materials. The lattice thermal conductivity κl, Seebeck coefficient and zT values may vary by 40% depending on the structural model. The MD-III configuration always has the larger band gap, Seebeck coefficient and zT, and smaller κl as compared to the MD-II structure due to a larger band gap, highly flat valence band and reduced crystal symmetry in the former. The MD-III configuration of Ti2CO2 and Zr2CO2 has the lowest κl as compared to the same configuration of Hf2CO2 and Sc2CO2. Among all the considered structures, the MD-II configuration of Hf2CO2 has the highest κl, and Ti2CO2 and Zr2CO2 in the MD-III configuration have the lowest κl. For instance, while the band gap of the MD-II configuration of Ti2CO2 is 0.26 eV, it becomes 0.69 eV in MD-III. The zTmax value may reach up to 1.1 depending on the structural model of MXene.


Genomic and genealogical investigation of the French Canadian founder population structure.
Characterizing the genetic structure of worldwide populations is important for understanding human history and is essential to the design and analysis of genetic epidemiological studies. In this study, we examined genetic structure and distant relatedness and their effect on the extent of linkage disequilibrium (LD) and homozygosity in the founder population of Quebec (Canada). In the French Canadian founder population, such analysis can be performed using both genomic and genealogical data. We investigated genetic differences, extent of LD, and homozygosity in 140 individuals from seven sub-populations of Quebec characterized by different demographic histories reflecting complex founder events. Genetic findings from genome-wide single nucleotide polymorphism data were correlated with genealogical information on each of these sub-populations. Our genomic data showed significant population structure and relatedness present in the contemporary Quebec population, also reflected in LD and homozygosity levels. Our extended genealogical data corroborated these findings and indicated that this structure is consistent with the settlement patterns involving several founder events. This provides an independent and complementary validation of genomic-based studies of population structure. Combined genomic and genealogical data in the Quebec founder population provide insights into the effects of the interplay of two important sources of bias in genetic epidemiological studies, unrecognized genetic structure and cryptic relatedness.


Family-Driven Goals to Improve Care for Children With Autism Spectrum Disorder.
Constipation and insomnia are not consistently identified and treated in children with autism spectrum disorder (ASD) despite their high prevalence and deleterious impact in this population. To standardize care, a constipation practice pathway and an insomnia practice pathway were previously developed by Autism Treatment Network clinicians. Our objective was to implement and refine these practice pathways in clinical settings. Eleven Autism Treatment Network sites participated in a Learning Collaborative (ie, multidisciplinary quality improvement team) and chose to implement either the constipation or insomnia practice pathway in the clinical setting. Families set intervention goals (eg, increase stool frequency, decrease nighttime awakenings) before treatment. Each site began implementation with 1 patient and then increased implementation by factors of 5. Before each increase, the Learning Collaborative evaluated progress and refined the practice pathways. Process improvement was measured primarily by duration until goal attainment and by percentage of families who meet their goals. Across sites, 82 children with ASD and constipation and 101 children with ASD and insomnia were managed. Difficulties with intervention adherence and communication between providers and families were reported and were subsequently improved with parallel refinements to both practice pathways. The most notable modification was incorporating a goal-setting session in which families generated their own intervention goals (ie, family-driven goals). In this quality improvement initiative, 75% of families met at least 1 constipation or insomnia goal, with the median time to improvement being 6 weeks. By integrating a family-centered approach into the standardization of care, constipation and insomnia practice pathways may improve engagement, adherence, and management of medical conditions in children with ASD.


Levobupivacaine-induced contraction of isolated rat aorta is calcium dependent.
Levobupivacaine is a long-acting local anesthetic that intrinsically produces vasoconstriction in isolated vessels. The goals of this study were to investigate the calcium-dependent mechanism underlying levobupivacaine-induced contraction of isolated rat aorta in vitro and to elucidate the pathway responsible for the endothelium-dependent attenuation of levobupivacaine-induced contraction. Isolated rat aortic rings were suspended to record isometric tension. Cumulative levobupivacaine concentration-response curves were generated in either the presence or absence of the antagonists verapamil, nifedipine, SKF-96365, 2-aminoethoxydiphenylborate, Gd(3+), N(W)-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and methylene blue, either alone or in combination. Verapamil, nifedipine, SKF-96365, 2-aminoethoxydiphenylborate, low calcium concentrations, and calcium-free Krebs solution attenuated levobupivacaine-induced contraction. Gd(3+) had no effect on levobupivacaine-induced contraction. Levobupivacaine increased intracellular calcium levels in vascular smooth muscle cells. L-NAME, ODQ, and methylene blue increased levobupivacaine-induced contraction in endothelium-intact aorta. SKF-96365 attenuated calcium-induced contraction in a previously calcium-free isotonic depolarizing solution containing 100 mmol/L KCl. Levobupivacaine-induced contraction of rat aortic smooth muscle is mediated primarily by calcium influx from the extracellular space mainly via voltage-operated calcium channels and, in part, by inositol 1,4,5-trisphosphate receptor-mediated release of calcium from the sarcoplasmic reticulum. The nitric oxide - cyclic guanosine monophosphate pathway is involved in the endothelium-dependent attenuation of levobupivacaine-induced contraction.


Lens-design issues affecting parallel readout of optical disks.
Lens designs are developed for parallel readout of data stored on optical disks. Optimizations of a single aspheric objective with standard wavelengths and numerical apertures are performed. These designs are evaluated for degree of parallelism achieved, improvement in aggregate data rate, source power requirements, and effect on head mass. We find that more than 225 channels and data rates of ~4 Gbits/s can be supported with low-cost readout optics.


Accelerated adhesion of grafted skin by laser-induced stress wave-based gene transfer of hepatocyte growth factor.
Gene therapy using wound healing-associated growth factor gene has received much attention as a new strategy for improving the outcome of tissue transplantation. We delivered plasmid DNA coding for human hepatocyte growth factor (hHGF) to rat free skin grafts by the use of laser-induced stress waves (LISWs); autografting was performed with the grafts. Systematic analysis was conducted to evaluate the adhesion properties of the grafted tissue; angiogenesis, cell proliferation, and reepithelialization were assessed by immunohistochemistry, and reperfusion was measured by laser Doppler imaging as a function of time after grafting. Both the level of angiogenesis on day 3 after grafting and the increased ratio of blood flow on day 4 to that on day 3 were significantly higher than those in five control groups: grafting with hHGF gene injection alone, grafting with control plasmid vector injection alone, grafting with LISW application alone, grafting with LISW application after control plasmid vector injection, and normal grafting. Reepithelialization was almost completed on day 7 even at the center of the graft with LISW application after hHGF gene injection, while it was not for the grafts of the five control groups. These findings demonstrate the validity of our LISW-based HGF gene transfection to accelerate the adhesion of grafted skins.


Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.
Comprehensive identification of all functional elements encoded in the human genome is a fundamental need in biomedical research. Here, we present a comparative analysis of the human, mouse, rat and dog genomes to create a systematic catalogue of common regulatory motifs in promoters and 3' untranslated regions (3' UTRs). The promoter analysis yields 174 candidate motifs, including most previously known transcription-factor binding sites and 105 new motifs. The 3'-UTR analysis yields 106 motifs likely to be involved in post-transcriptional regulation. Nearly one-half are associated with microRNAs (miRNAs), leading to the discovery of many new miRNA genes and their likely target genes. Our results suggest that previous estimates of the number of human miRNA genes were low, and that miRNAs regulate at least 20% of human genes. The overall results provide a systematic view of gene regulation in the human, which will be refined as additional mammalian genomes become available.


Status of research and development of pediatric vaccines for Streptococcus pneumoniae.
Pneumococcal disease is a major cause of morbidity and mortality in young children, particularly in the developing world. Vaccines are a critical strategy for protecting children from pneumococcal disease and licensed pneumococcal conjugate vaccines (PCVs) are having a significant impact on invasive pneumococcal disease and pneumococcal pneumonia throughout the world. Currently available PCVs do not, however, cover all pneumococcal serotypes and are complicated and relatively expensive to manufacture. While new PCV development is focused on either higher valency or more inherent affordability for developing countries, new vaccines are needed that offer serotype-independent protection. Vaccines containing proteins that are common to all pneumococcal serotypes could provide broad protection to children worldwide. Protein subunit and whole cell vaccines have advanced into Phase 1 and 2 clinical trials but face considerable challenges before they can become licensed and widely distributed.


Conformations of Prolyl-Peptide Bonds in the Bradykinin 1-5 Fragment in Solution and in the Gas Phase.
The dynamic nature of intrinsically disordered peptides makes them a challenge to characterize by solution-phase techniques. In order to gain insight into the relation between the disordered state and the environment, we explore the conformational space of the N-terminal 1-5 fragment of bradykinin (BK[1-5](2+)) in the gas phase by combining drift tube ion mobility, cold-ion spectroscopy, and first-principles simulations. The ion-mobility distribution of BK[1-5](2+) consists of two well-separated peaks. We demonstrate that the conformations within the peak with larger cross-section are kinetically trapped, while the more compact peak contains low-energy structures. This is a result of cis-trans isomerization of the two prolyl-peptide bonds in BK[1-5](2+). Density-functional theory calculations reveal that the compact structures have two very different geometries with cis-trans and trans-cis backbone conformations. Using the experimental CCSs to guide the conformational search, we find that the kinetically trapped species have a trans-trans configuration. This is consistent with NMR measurements performed in a solution, which show that 82% of the molecules adopt a trans-trans configuration and behave as a random coil.


Effect of intonation on cantonese lexical tones.
In tonal languages, there are potential conflicts between the FO-based changes due to the coexistence of intonation and lexical tones. In the present study, the interaction of tone and intonation in Cantonese was examined using acoustic and perceptual analyses. The acoustic patterns of tones at the initial, medial, and final positions of questions and statements were measured. Results showed that intonation affects both the FO level and contour, while the duration of the six tones varied as a function of positions within intonation contexts. All six tones at the final position of questions showed rising FO contour, regardless of their canonical form. Listeners were overall more accurate in the identification of tones presented within the original carrier than of the same tones in isolation. However, a large proportion of tones 33, 21, 23, and 22 at the final position of questions were misperceived as tone 25 both within the original carrier and as isolated words. These results suggest that although the intonation context provided cues for correct tone identification, the intonation-induced changes in FO contour cannot always be perceptually compensated for, resulting in some erroneous perception of the identity of Cantonese tone.


Elevated levels of versican but not decorin predict disease progression in early-stage prostate cancer.
Patients with clinically localized prostate cancer who might be cured by aggressive management are not easily identified using current clinical information. Additional, more accurate, biomarkers of tumor behavior need to be identified to improve clinical outcome. Our previous studies indicated that the concentration of the glycosaminoglycan chondroitin sulfate in prostatic stroma might be a useful biomarker of disease progression in early-stage prostate cancer. In this study, two chondroitin sulfate proteoglycans, versican and decorin, were investigated. Versican and decorin were immunolocalized to the periacinar and peritumoral fibromuscular stroma in sections of nonmalignant and malignant human prostate tissues. Video image measurements indicated that the concentrations of both proteoglycans were increased in the prostatic tissue of men with early-stage prostate cancer compared with tissue from men without cancer (P = 0.0006). Cox's univariate analysis indicated that increases in versican concentration but not in that of decorin were associated with increased risk of prostate-specific antigen (PSA) progression. Versican concentration was compared with other clinical or biological features of prognosis in two-variable regression analyses. Versican and serum PSA concentrations were independent predictors of PSA progression. Versican was a stronger prognostic factor than tumor grade, and it could predict outcome for patients with moderately differentiated tumors. Patients with low versican concentration had significantly better progression-free survival than patients with high levels of versican (Kaplan-Meier plot, 89% versus 27% PSA progression-free at 5 years, respectively; P = 0.0001). We conclude that the measurement of prostatic concentrations of versican, a molecule with reported anticellular adhesive properties, may be a useful marker of disease progression in patients with early-stage prostate cancer and that further study of versican in other patient cohorts is warranted.


Anti-vascular endothelial growth factor for choroidal neovascularisation in people with pathological myopia.
Choroidal neovascularisation (CNV) is a common complication of pathological myopia. Once developed, most eyes with myopic CNV (mCNV) experience a progression to macular atrophy, which leads to irreversible vision loss. Anti-vascular endothelial growth factor (anti-VEGF) therapy is used to treat diseases characterised by neovascularisation and is increasingly used to treat mCNV. To assess the effects of anti-vascular endothelial growth factor (anti-VEGF) therapy for choroidal neovascularisation (CNV), compared with other treatments, sham treatment or no treatment, in people with pathological myopia. We searched a number of electronic databases including CENTRAL and Ovid MEDLINE, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP). We did not use any date or language restrictions in the electronic searches for trials. Electronic databases were last searched on 16 June 2016. We included randomised controlled trials (RCTs) and quasi-RCTs comparing anti-VEGF therapy with another treatment (e.g. photodynamic therapy (PDT) with verteporfin, laser photocoagulation, macular surgery, another anti-VEGF), sham treatment or no treatment in participants with mCNV. We used standard methodological procedures expected by Cochrane. Two authors independently screened records, extracted data, and assessed risk of bias. We contacted trial authors for additional data. We analysed outcomes as risk ratios (RRs) or mean differences (MDs). We graded the certainty of the evidence using GRADE. The present review included six studies which provided data on the comparison between anti-VEGF with PDT, laser, sham treatment and another anti-VEGF treatment, with 594 participants with mCNV. Three trials compared bevacizumab or ranibizumab with PDT, one trial compared bevacizumab with laser, one trial compared aflibercept with sham treatment, and two trials compared bevacizumab with ranibizumab. Pharmaceutical companies conducted two trials. The trials were conducted at multiple clinical centres across three continents (Europe, Asia and North America). In all these six trials, one eye for each participant was included in the study.When compared with PDT, people treated with anti-VEGF agents (ranibizumab (one RCT), bevacizumab (two RCTs)), were more likely to regain vision. At one year of follow-up, the mean visual acuity (VA) in participants treated with anti-VEGFs was -0.14 logMAR better, equivalent of seven Early Treatment Diabetic Retinopathy Study (ETDRS) letters, compared with people treated with PDT (95% confidence interval (CI) -0.20 to -0.08, 3 RCTs, 263 people, low-certainty evidence). The RR for proportion of participants gaining 3+ lines of VA was 1.86 (95% CI 1.27 to 2.73, 2 RCTs, 226 people, moderate-certainty evidence). At two years, the mean VA in people treated with anti-VEGFs was -0.26 logMAR better, equivalent of 13 ETDRS letters, compared with people treated with PDT (95% CI -0.38 to -0.14, 2 RCTs, 92 people, low-certainty evidence). The RR for proportion of people gaining 3+ lines of VA at two years was 3.43 (95% CI 1.37 to 8.56, 2 RCTs, 92 people, low-certainty evidence). People treated with anti-VEGFs showed no obvious reduction (improvement) in central retinal thickness at one year compared with people treated with PDT (MD -17.84 μm, 95% CI -41.98 to 6.30, 2 RCTs, 226 people, moderate-certainty evidence). There was low-certainty evidence that people treated with anti-VEGF were more likely to have CNV angiographic closure at 1 year (RR 1.24, 95% CI 0.99 to 1.54, 2 RCTs, 208 people). One study allowed ranibizumab treatment as of month 3 in participants randomised to PDT, which may have led to an underestimate of the benefits of anti-VEGF treatment.When compared with laser photocoagulation, there was more improvement in VA among bevacizumab-treated people than among laser-treated people after one year (MD -0.22 logMAR, equivalent of 11 ETDRS letters, 95% CI -0.43 to -0.01, 1 RCT, 36 people, low-certainty evidence) and after two years (MD -0.29 logMAR, equivalent of 14 ETDRS letters, 95% CI -0.50 to -0.08, 1 RCT, 36 people, low-certainty evidence).When compared with sham treatment, people treated with aflibercept had better vision at one year (MD -0.19 logMAR, equivalent of 9 ETDRS letters, 95% CI -0.27 to -0.12, 1 RCT, 121 people, moderate-certainty evidence). The fact that this study allowed for aflibercept treatment at 6 months in the control group might cause an underestimation of the benefit with anti-VEGF.People treated with ranibizumab had similar improvement in VA recovery compared with people treated with bevacizumab after one year (MD -0.02 logMAR, equivalent of 1 ETDRS letter, 95% CI -0.11 to 0.06, 2 RCTs, 80 people, moderate-certainty evidence).Of the included six studies, two studies reported no adverse events in either group and two industry-sponsored studies reported both systemic and ocular adverse events. In the control group, there were no systemic or ocular adverse events reported in 149 participants. Fifteen people reported systemic serious adverse events among 359 people treated with anti-VEGF agents (15/359, 4.2%). Five people reported ocular adverse events among 359 people treated with anti-VEGF agents (5/359, 1.4%). The number of adverse events was low, and the estimate of RR was uncertain regarding systemic serious adverse events (4 RCTs, 15 events in 508 people, RR 4.50, 95% CI 0.60 to 33.99, very low-certainty evidence) and serious ocular adverse events (4 RCTs, 5 events in 508 people, RR 1.82, 95% CI 0.23 to 14.71, very low-certainty evidence). There were no reports of mortality or cases of endophthalmitis or retinal detachment.There was sparse reporting of data for vision-related quality of life (in favour of anti-VEGF) in only one trial at one year of follow-up. The studies did not report data for other outcomes, such as percentage of participants with newly developed chorioretinal atrophy. There is low to moderate-certainty evidence from RCTs for the efficacy of anti-VEGF agents to treat mCNV at one year and two years. Moderate-certainty evidence suggests ranibizumab and bevacizumab are equivalent in terms of efficacy. Adverse effects occurred rarely and the trials included here were underpowered to assess these. Future research should be focused on the efficacy and safety of different drugs and treatment regimens, the efficacy on different location of mCNV, as well as the effects on practice in the real world.


When is it cost-effective to change the behavior of health professionals?
Because of the workings of health care systems, new, important, and cost-effective treatments sometimes do not become routine care while well-marketed products of equivocal value achieve widespread adoption. Should policymakers attempt to influence clinical behavior and correct for these inefficiencies? Implementation methods achieve a certain level of behavioral change but cost money to enact. These factors can be combined with the cost-effectiveness of treatments to estimate an overall policy cost-effectiveness. In general, policy cost-effectiveness is always less attractive than treatment cost-effectiveness. Consequently trying to improve the uptake of underused cost-effective care or reduce the overuse of new and expensive treatments may not always make economic sense. In this article, we present a method for calculating policy cost-effectiveness and illustrate it with examples from a recent trial, conducted during 1997 and 1998, of educational outreach by community pharmacists to influence physician prescribing in England.


Plasma Concentrations of Trimethylamine-N-oxide Are Directly Associated with Dairy Food Consumption and Low-Grade Inflammation in a German Adult Population.
Trimethylamine-N-oxide (TMAO) is a metabolite of carnitine, choline, and phosphatidylcholine, which is inversely associated with survival of cardiovascular disease (CVD) patients. We examined the associations of diet with plasma concentrations of TMAO, choline, and betaine and the associations of TMAO with plasma concentrations of various cytokines. Plasma TMAO, choline, and betaine concentrations were measured using LC-high resolution mass spectrometry in 271 participants, ≥18 y old, of the Second Bavarian Food Consumption Survey, conducted in 2002 and 2003. Food consumption was assessed using at least two 24-h dietary recalls. Cytokines were measured in plasma with enzyme-linked immunosorbent assays. Geometric mean concentrations of TMAO, choline, and betaine by categories of meat, dairy food, egg, and fish consumption were computed, adjusted for sex, age, and BMI. Multivariable-adjusted geometric mean concentrations of cytokines [tumor necrosis factor-α (TNF-α), soluble TNF receptors (sTNF-R) p55, sTNF-R p75, interleukin-6 (IL-6), and C-reactive protein (CRP)] were computed by quartiles of TMAO concentration using general linear models. Meat, egg, or fish consumption was not associated with TMAO, choline, or betaine concentrations (all P-trend ≥ 0.05). With increases in milk and other dairy food consumption, the plasma TMAO concentration increased [geometric mean bottom quartile of milk consumption: 2.08 μM (95% CI: 1.69, 2.57 μM); compared with top quartile: 3.13 μM (95% CI: 2.56, 3.84 μM); P-trend = 0.008]. Participants in the top TMAO quartile had higher plasma concentrations of TNF-α, sTNF-R p55, and sTNF-R p75 than participants in the bottom quartile (percentage difference ranging between 14.4% and 17.3%; all P-trend < 0.05), but there were no differences in plasma concentrations of CRP and IL-6 (all P-trend ≥ 0.05). Results of this study conducted among healthy adults from the general population do not indicate a strong effect of diet on plasma concentrations of TMAO, choline, or betaine, with the exception of a positive association between dairy food consumption and plasma TMAO concentrations. Also, plasma TMAO concentrations were positively associated with inflammation. Whether habitual diet is strongly linked to the plasma TMAO concentration, a potential marker of CVD risk, needs to be determined in further studies.


Diversification times among Brassica (Brassicaceae) crops suggest hybrid formation after 20 million years of divergence.
Cruciferous vegetables, many of which are in the genus Brassica (Brassicaceae), are prized for their nutritive value and have been cultivated for thousands of years. There are numerous wild northwestern Mediterranean species in the tribe Brassiceae, and it is therefore assumed this center of diversity is also the region of origin. Within the tribe, the Nigra and Oleracea clades contain the three diploid Brassica crops, B. oleracea, B. rapa, and B. nigra. These three species hybridized in the past to form the tetraploid crop species B. juncea, B. carinata, and B. napus. Collectively, these crop Brassicas have been thought to be closely related because they can still hybridize. Using a combination of molecular phylogenetics, diversification analysis, and historical biogeography, we evaluated the relationships and origins of four nested clades: the tribe Brassiceae, the Nigra-Oleracea clade, the core Oleracea (includes B. oleracea + B. rapa and their respective wild relatives), and Brassica oleracea and relatives. We found evidence that the tribe originated around the intersection forming between the Arabian Peninsula and Saharan Africa approximately 24 million years ago (Mya). Our data also suggest that the maternal genomes of the three diploid crop Brassicas are not closely related and that the Nigra-Oleracea clade diverged 20 Mya. Finally, our analyses indicate that the core Oleracea lineage giving rise to B. oleracea + B. rapa originated ≈3 Mya in the northeastern Mediterranean, from where ancestors of B. oleracea spread through Europe and B. rapa to Asia. These results challenge previous hypotheses about the biogeographic origins of the tribe Brassiceae and the crop Brassica species and appear to be correlated with major geological and climatic events in the Mediterranean basin.


A technology evaluation of Annovera: a segesterone acetate and ethinyl estradiol vaginal ring used to prevent pregnancy for up to one year.
The segesterone acetate and ethinyl estradiol contraceptive vaginal ring (SA/EE CVR) was FDA-approved in August 2018 and is now available in the U.S. The CVR is placed vaginally for 21 days followed by a 7-day ring-free interval, when withdrawal bleeding typically occurs. One ring can be used for up to a year (13 cycles). This review summarizes this novel method of contraception, including the delivery system and the hormonal components. We describe the potential market, how it is used, the pharmacokinetic properties of the device, and results of clinical trials including efficacy, bleeding profile, acceptability, and safety. The SA/EE CVR represents the first long-lasting user-controlled hormonal contraceptive device. The bleeding pattern is highly favorable and consistent over the entire year and is associated with very low discontinuation. Efficacy and safety are similar to other methods of combined hormonal contraceptives. Unscheduled ring removals increase the risk of failure. Further studies are needed to evaluate continuous use of the ring for greater than 21 days, and potential non-contraceptive benefits of the ring such as reduced menstrual bleeding.


Effect of Mitomycin - C and Triamcinolone on Preventing Urethral Strictures.
Urethral stricture is a common disease with high recurrence rate. Several manipulations were defined to prevent the recurrence but the results were disappointing. This study aimed to evaluate the efficacy of triamcinolone and mitomycin-C on urethral stricture formation and their effect on inhibition of urethral fibrosis. A total of 24 New Zealand rabbits were divided into 3 groups. Urethras of rabbits were traumatized with pediatric resectoscope. Resection area was irrigated with 10mL saline, swapped with a cotton wool soaked with 0.5mg/mL MMC and injected by 40mg triamcinolone in groups 1, 2 and 3 respectively. Retrograde urethrogram was performed at 28th day of procedure and the urethra was removed for histopathologic evaluation. There were significant differences in urethral diameters and in lumen reduction rate between the control and study groups (p<0.001). Compared to control group, all treatment groups showed mild fibrosis, less collagen bundle irregularity, and lower numbers of fibroblasts (p=0.003). The Tunnel assay showed that the number of apoptotic cells in the submucosal connective tissue was quantitatively higher in control groups (p=0.034). In the view of efficacy and safety, MMC and triamcinolone have the potential to replace the use of stents, clean intermittent catheterization, or long term catheters following internal urethrotomy. There were no statistically significant differences between two agents in terms of preventing urethral stricture formation in the present study. Mitomycin C and triamcinolone decreased the recurrence rates of urethral stricture.


CIT in context: the impact of mental health resource availability and district saturation on call dispositions.
The goals of Crisis Intervention Team (CIT) programs include improving safety during encounters between police and persons with mental illnesses, diverting persons with mental illnesses away from the criminal justice system, and increasing referral and access to mental health services. CIT is a systemic intervention, and as such, its implementation and effectiveness are influenced by existing practices and infrastructures. However, little research has considered the context in which CIT programs are implemented. In this paper, we present research on CIT in four Chicago police districts that vary in terms of two contextual factors hypothesized to influence the impact of CIT training on how calls involving persons with mental illnesses are resolved. Using data from 112 patrol officers in four Chicago police districts, we consider the impact of mental health services availability and CIT saturation (the percentage of district personnel that are CIT certified). Findings indicate that CIT training increased direction to mental health services primarily in districts with greater availability of mental health services. In districts with low service availability, higher CIT saturation increased direction to mental services. The opposite pattern emerged for contact only or informal call resolution. No effects were found for arrest as a call outcome.


Restriction endonuclease activity induced by PBCV-1 virus infection of a Chlorella-like green alga.
An enzyme was isolated from a eucaryotic, Chlorella-like green alga infected with the virus PBCV-1 which exhibits type II restriction endonuclease activity. The enzyme recognized the sequence GATC and cleaved DNA 5' to the G. Methylation of deoxyadenosine in the GATC sequence inhibited enzyme activity. In vitro the enzyme cleaved host Chlorella nuclear DNA but not viral DNA because host DNA contains GATC and PBCV-1 DNA contains GmATC sequences. PBCV-1 DNA is probably methylated in vivo by the PBCV-1-induced methyltransferase described elsewhere (Y. Xia and J. L. Van Etten, Mol. Cell. Biol. 6:1440-1445). Restriction endonuclease activity was first detected 30 to 60 min after viral infection; the appearance of enzyme activity required de novo protein synthesis, and the enzyme is probably virus encoded. Appearance of enzyme activity coincided with the onset of host DNA degradation after PBCV-1 infection. We propose that the PBCV-1-induced restriction endonuclease participates in host DNA degradation and is part of a virus-induced restriction and modification system in PBCV-1-infected Chlorella cells.


Differential effects of dietary fatty acids on the cerebral distribution of plasma-derived apo B lipoproteins with amyloid-beta.
Some dietary fats are a risk factor for Alzheimer's disease (AD) but the mechanisms for this association are presently unknown. In the present study we showed in wild-type mice that chronic ingestion of SFA results in blood-brain barrier (BBB) dysfunction and significant delivery into the brain of plasma proteins, including apo B lipoproteins that are endogenously enriched in amyloid-beta (Abeta). Conversely, the plasma concentration of S100B was used as a marker of brain-to-blood leakage and was found to be increased two-fold because of SFA feeding. Consistent with a deterioration in BBB integrity in SFA-fed mice was a diminished cerebrovascular expression of occludin, an endothelial tight junction protein. In contrast to SFA-fed mice, chronic ingestion of MUFA or PUFA had no detrimental effect on BBB integrity. Utilising highly sensitive three-dimensional immunomicroscopy, we also showed that the cerebral distribution and co-localisation of Abeta with apo B lipoproteins in SFA-fed mice are similar to those found in amyloid precursor protein/presenilin-1 (APP/PS1) amyloid transgenic mice, an established murine model of AD. Moreover, there was a strong positive association of plasma-derived apo B lipoproteins with cerebral Abeta deposits. Collectively, the findings of the present study provide a plausible explanation of how dietary fats may influence AD risk. Ingestion of SFA could enhance peripheral delivery to the brain of circulating lipoprotein-Abeta and exacerbate the amyloidogenic cascade.


H-NS regulates the Vibrio parahaemolyticus type VI secretion system 1.
The marine bacterium Vibrio parahaemolyticus, a major cause of food-borne gastroenteritis, employs a type VI secretion system 1 (T6SS1), a recently discovered protein secretion system, to combat competing bacteria. Environmental signals such as temperature, salinity, cell density and surface sensing, as well as the quorum-sensing master regulator OpaR, were previously reported to regulate T6SS1 activity and expression. In this work, we set out to identify additional transcription regulators that control the tightly regulated T6SS1 activity. To this end, we determined the effect of deletions in several known virulence regulators and in two regulators encoded within the T6SS1 gene cluster on expression and secretion of the core T6SS component Hcp1 and on T6SS1-mediated anti-bacterial activity. We report that VP1391 and VP1407, transcriptional regulators encoded within the T6SS1 gene cluster, are essential for T6SS1 activity. Moreover, we found that H-NS, a bacterial histone-like nucleoid structuring protein, which mediates transcription silencing of horizontally acquired genes, serves as a repressor of T6SS1. We also show that activation of surface sensing and high salt conditions alleviate the H-NS-mediated repression. Our results shed light on the complex network of environmental signals and transcription regulators that govern the tight regulation over T6SS1 activity.


Performance of medical residents in sterile techniques during central vein catheterization: randomized trial of efficacy of simulation-based training.
Catheter-related bloodstream infection (CRBSI) is a preventable cause of a potentially lethal ICU infection. The optimal method to teach health-care providers correct sterile techniques during central vein catheterization (CVC) remains unclear. We randomly assigned second- and third-year internal medicine residents trained by a traditional apprenticeship model to simulation-based plus video training or video training alone from December 2007 to January 2008, with a follow-up period to examine CRBSI ending in July 2009. During the follow-up period, a simulation-based training program in sterile techniques during CVC was implemented in the medical ICU (MICU). A surgical ICU (SICU) where no residents received study interventions was used for comparison. The primary outcome measures were median residents' scores in sterile techniques and rates of CRBSI per 1,000 catheter-days. Of the 47 enrolled residents, 24 were randomly assigned to the simulation-based plus video training group and 23 to the video training group. Median baseline scores in both groups were equally poor: 12.5 to 13 (52%-54%) out of maximum score of 24 (P = .95; median difference, 0; 95% CI, 0.2-2.0). After training, median score was significantly higher for the simulation-based plus video training group: 22 (92%) vs 18 (75%) for the video training group (P < .001; median difference, 4; 95% CI, 3-6). During the follow-up period, there was a significantly lower rate of CRBSI in the MICU (1.0 per 1,000 catheter-days) compared with the SICU (3.4 per 1,000 catheter-days) (P = .03). The incidence rate ratio derived from the Poisson regression (0.30; 95% CI, 0.10-0.91) indicated there was a 70% reduction in the incidence of CRBSI in the postintervention MICU compared with the preintervention MICU and the postintervention SICU. Simulation-based training in sterile techniques during CVC is superior to traditional training or video training alone and is associated with decreased rate of CRBSI. Simulation-based training in CVC should be routinely used to reduce iatrogenic risk. ClinicalTrials.gov; No.: NCT00612131; URL: clinicaltrials.gov.


Ets-mediated brain induction in embryos of the ascidian Halocynthia roretzi.
The larval ascidian brain (sensory vesicle) is located on the dorsal side of the trunk region and forms part of the anterior central nervous system. Sensory organs such as the otolith, ocellus, and hydrostatic-pressure organ reside in the brain. The brain coordinates the core roles of the larval nervous system. The brain is derived from anterior animal a-line blastomeres. The default fate of these blastomeres is epidermis, and the inductive signals from anterior vegetal blastomeres convert the fate into brain. It remains unclear, however, when these inductive interactions take place. To determine when, we examined whether partial embryos derived from brain-lineage blastomeres isolated at various stages express neural and epidermal marker genes. Partial embryos derived from brain-lineage blastomeres isolated after the 32-cell stage expressed all the neural marker genes examined. The expression of the epidermal marker gene was first reduced in partial embryos when blastomeres were isolated at the 64-cell stage. Moreover, the process for brain specification seemed to continue after the 110-cell stage. We also investigated the function of HrEts, an ascidian homolog of Ets transcription factors, to elucidate the molecular mechanism of brain induction. HrEts functions were inhibited by the use of antisense morpholino oligonucleotides. Loss of Ets functions resulted in loss of the expression of some of the neural marker genes and the ectopic expression of the epidermal marker gene in brain precursor cells. These results suggest that HrEts is an essential transcription factor that mediates ascidian brain induction.


Location and Gaze-Dependent Shift of Inferior Oblique Muscle Position: Anatomic Contributors to Vertical Strabismus Following Lower Lid Blepharoplasty?
This study investigated, using high-resolution magnetic resonance imaging (MRI), inferior oblique muscle (IO) position relative to the adnexa in normal controls, subjects with and without vertical strabismus following lower lid blepharoplasty, and subjects with other hypertropia. Sagittal plane MRI was obtained in central gaze, infraduction, and supraduction in 19 controls, 11 subjects with and 2 without hypertropia following bilateral lower lid blepharoplasty, and 13 subjects with hypertropia unrelated to blepharoplasty. In the plane passing through the center of the inferior rectus muscle (IR), we analyzed IO position relative to the globe, as well as the distance from IO to the skin or orbital floor. The IO was located approximately 1 mm more anteriorly and 1.2 mm more inferiorly in hypertropic than hypotropic fellow orbits of the blepharoplasty group and controls (P < 0.05). From central gaze to infraduction, IO shift in subjects with blepharoplasty was redirected inferiorly, rather than posteriorly as in all other groups. However, from central gaze to supraduction, IO motion was similar in all groups. There was scarring between the IO-IR pulley and orbital floor in the hypertropic eye after lower lid blepharoplasty. Subjects with strabismus following lower lid blepharoplasty exhibit anterior and inferior IO pulley displacement in central gaze, as well as hindrance to normal posterior shift in infraduction. Proximity of IO to the orbital rim and lower eyelid skin is associated with strabismus following blepharoplasty, possibly because lower lid blepharoplasty may change lid forces on the IO-IR pulley system via scar tissue.


Testing the effects of a decision aid for prostate cancer screening.
There is an ever-growing trend toward more patient involvement in making health care decisions. This trend has been accompanied by the development of "informed decision-making" interventions to help patients become more engaged and comfortable with making these decisions. We describe the effects of a prostate cancer screening decision aid on knowledge, beliefs about screening, risk perception, control preferences, decisional conflict, and decisional anxiety. Data were collected from 200 males aged 50-70 years in the general population who randomly were assigned to exposure to the decision aid or no exposure as a control condition. A Solomon four-group design was used to test for possible pretest sensitization effects and to assess the effects of exposure to the decision aid. No significant pretest sensitization effects were found. Analysis of the exposure effects found that knowledge increased significantly for those exposed to the decision aid compared with those unexposed. Exposure to the decision aid also had some influence on decreasing both decisional conflict and decisional anxiety. Decision aids can play an important role in increasing patients' knowledge and decreasing anxiety when asked to make health care decisions.


Predicting Acute Pancreatitis Severity: Comparison of Prognostic Scores.
Acute pancreatitis has a broad clinical spectrum, from mild illness to multiple organ failure and death. Prognostic scores have been developed or adapted to predict disease severity. This study aimed to compare the prognostic scores according to sensitivity and specificity, receiver operating characteristic curves and area under the curve. Statistical correlation with disease severity, length of hospital stay, mortality and complication rates. Retrospective analysis of the clinical data of patients admitted to an Internal Medicine ward with the diagnosis of acute pancreatitis over a ten year period. Evaluation of prognostic scores: Ranson, Glasgow-Imrie, Balthazar, APACHE II (admission and at 48 hours) and C-reactive protein (48 hours), was carried out as well as statistical analysis using Microsoft Excel 2007® and SPSS 16®. The confidence interval used was 95%. Data from 193 clinical files was collected. However, 67 were excluded due to lack of information. According to the Atlanta criteria, 90 cases were deemed as mild and 36 severe. The mortality rate was 6% and the local complication rate was 9.3%. Ranson, Glasgow and APACHE II scores had significant correlation with mortality. Apart from C-reactive protein levels at 48 hours, all scores had significant correlation with disease severity. The scores with best area under the curve correlation were APACHE II (48 hours): 0.892, Ranson: 0.879, and APACHE II (admission): 0.861. The most accurate prognostic scores in this study were APACHE II (48 hours) and Ranson. APACHE II at admission was a good indicator, impaired only by high false positive ratio.


Osteoporosis related to WNT1 variants: a not infrequent cause of osteoporosis.
Nearly 10% of subjects with severe idiopathic osteoporosis present pathogenic WNT1 mutations. Clinical characteristics include a family history of osteoporosis, early adulthood onset, and fragility fractures which may evolve to pseudoarthrosis. WNT1 should be genetically screened in these patients as the phenotype is often variable and therapeutic approaches may differ. Recent studies have shown that homozygous WNT1 gene mutations may be related to severe osteoporosis resembling osteogenesis imperfecta (OI). Conversely, heterozygous WNT1 mutations are linked to a milder phenotype of early-onset osteoporosis. Treatment with bisphosphonates is reported to be unsatisfactory. Our aim was to analyze the presence and prevalence of WNT1 mutations and the main associated clinical characteristics in subjects with primary early-onset osteoporosis. A cohort comprising 56 subjects (aged 19-60 years) with severe, early-onset osteoporosis was screened by massive parallel sequencing with a 23-gene panel. The gene panel included 19 genes known to cause OI (including the WNT1 gene), three genes related to osteoporosis, and the gene related to hypophosphatasia (ALPL). We identified five patients (3 men) with heterozygous WNT1 variants. All presented severe osteoporosis with early fracture onset and a family history of fragility fractures. None presented a characteristic phenotype of OI or skeletal deformities. One patient was previously treated with bisphosphonates, presenting inadequate response to treatment and two developed pseudoarthrosis after upper arm fractures. All subjects were diagnosed in adulthood. Nearly 1/10 adult subjects with severe idiopathic osteoporosis may present pathogenic WNT1 mutations. Clinical characteristics commonly include a family history of osteoporosis, onset in early adulthood, marked decrease in bone mass, and prevalent fractures, particularly vertebral. WNT1 should be genetically screened in these subjects as the phenotype is often variable and the therapeutic approach may differ. The role of WNT1 mutations in the development of pseudoarthrosis should also be elucidated.


Impact of virus subtype and host IFNL4 genotype on large-scale RNA structure formation in the genome of hepatitis C virus.
Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute previously associated with formation of large-scale RNA structure in their genomic RNA. We developed novel methods to analyze and visualize genome-scale ordered RNA structure (GORS) predicted from the increasingly large data sets of complete genome sequences of HCV. Structurally conserved RNA secondary structure in coding regions of HCV localized exclusively to polyprotein ends (core, NS5B). Coding regions elsewhere were also intensely structured based on elevated minimum folding energy difference (MFED) values, but the actual stem-loop elements involved in genome folding were structurally poorly conserved, even between subtypes 1a and 1b. Dynamic remodeling was further evident from comparison of HCV strains in different host genetic backgrounds. Significantly higher MFED values, greater suppression of UpA dinucleotide frequencies, and restricted diversification were found in subjects with the TT genotype of the rs12979860 SNP in the IFNL4 gene compared to the CC (nonexpressing) allele. These structural and compositional associations with expression of interferon-λ4 were recapitulated on a larger scale by higher MFED values and greater UpA suppression of genotype 1 compared to genotype 3a, associated with previously reported HCV genotype-associated differences in hepatic interferon-stimulated gene induction. Associations between innate cellular responses with HCV structure and further evolutionary constraints represent an important new element in RNA virus evolution and the adaptive interplay between virus and host.


Phase-shifting interferometry based on the lateral displacement of the light source.
A simple and inexpensive optical setup to phase-shifting interferometry is proposed. This optical setup is based on the Twyman-Green Interferometer where the phase shift is induced by the lateral displacement of the point laser source. A theoretical explanation of the induced phase by this alternative method is given. The experimental results are consistent with the theoretical expectations. Both, the phase shift and the wrapped phase are recovered by a generalized phase-shifting algorithm from two or more interferograms with arbitrary and unknown phase shift. The experimental and theoretical results show the feasibility of this unused phase-shifting technique.


Outer membrane protein binding sites of complement component 3 during opsonization of Haemophilus influenzae.
Complement component 3 (C3) binding to Haemophilus influenzae type b (Hib) is an important step in host defense against invasive disease, but the details of this process remain poorly understood. We have shown that the P1 and P2 outer membrane proteins (OMPs) serve as binding sites for C3 on serum-opsonized Hib. Whole-cell lysates of opsonized Hib were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the resolved proteins were transferred to nitrocellulose. Immunoblot analysis with monoclonal antibodies (MAbs) to the 49-kDa P1 and 39-kDa P2 OMPs demonstrated high-molecular-weight bands that were not present when the bacteria were opsonized with heat-inactivated or methylamine-treated serum. Immunoblot analysis with MAbs to the 98- or 16-kDa (P6) OMPs did not reveal additional bands. An unencapsulated Hib mutant still lacked C3 bound to the 98-kDa or P6 OMP, indicating that the absence of C3 binding to these proteins was not the result of epitope masking by the capsule. Studies with MAbs to C3 fragments confirmed that the anti-P1- and anti-P2-reactive bands were C3 fragments bound to these OMPs. The molecular weights of proteins reactive to anti-OMP and anti-C3 antibodies indicated that multiple C3 fragments may be bound to P1 or that C3 may be bound to P2 multimers. Finally, the presence of other anti-C3-reactive proteins indicated that several other proteins serve as C3 targets during the opsonization of Hib.


Monoclonal Antibody Production Against Vimentin by Whole Cell Immunization in a Mouse Model.
Pancreatic carcinoma is the fourth-leading cause of cancer death in the United States and due to its late presentation, only few patients would be candidates for the curative treatment of pancreactomy. Monoclonal antibodies have brought hope to targeted therapy. To identify new biomarkers, a panel of monoclonal antibodies was generated against newly established cell line, Faraz-ICR from a patient with pancreatic acinar cell carcinoma. Balb/c female mice were immunized with Faraz-ICR cell line and their spleenocytes fused with SP2/0 myeloma cell line. Highly reactive hybridoma producing antibodies against Faraz-ICR was detected using ELISA, immunofluorescence staining and flow cytometry. Western blot and 2D immunoblot were utilized for further characterization of the target antibodies. Among highly reactive clones, the reactivity of 7C11 clone was assessed in comparison to other epithelial tumors. The antibody isotype was IgM that reacted with a 55 kDa protein in western blot analysis. To further characterize the target antigen, immunoproteome of the Faraz-ICR cell line was performed. By LC-MS analysis, the target of 7C11 clone was identified to be vimentin. Pancreatic cancer is a highly lethal malignancy with no reliable biomarker for early detection and diagnosis. In this study, by establishing a pancreatic acinar carcinoma cell line, a panel of monoclonal antibodies was generated to identify specific or associated cancer targets. Furthermore, 7C11 mAb was introduced that can specifically recognizes vimentin as a tumor marker. This antibody may serve as a new tool for prognostic and therapeutic strategies.


Perineal effects of postoperative treatment for adenocarcinoma of the rectum.
Nine (4%) first recurrences that involved the perineum were identified in a randomized study of 202 patients treated by no further therapy, chemotherapy only, radiotherapy only, combined radiotherapy and chemotherapy, following complete surgical excision of adenocarcinoma of the rectum. Six of these were in unirradiated patients and in two of the three irradiated patients the perineum was included in the treatment volume. Eight of the nine patients were male and all nine had received abdominoperineal resection (APR). Our quality assurance procedures identified 22 of 96 irradiated patients in whom the perineum was grossly outside the fields. Sixteen of these had undergone APR. As only one of these 16 relapsed in the perineum no definite effect of the surgical procedure on the likelihood of perineal recurrence could be demonstrated. Examination of the pathology reports revealed that 28 patients undergoing APR had tumors within 2 cm of the anorectal junction (pectinate line). Five (17.8%) developed perineal recurrence compared with 4 (3.6%) of 110 patients whose tumors were more than 2 cm from the anus (p less than 0.02-Fisher exact test). No survival differences could be demonstrated between those receiving perineal irradiation and those not but perineal irradiation was associated with toxicity with at least nine (12.2%) out of 74 developing severe complications directly related to the perineum. The routine inclusion of the perineum in postoperative pelvic irradiation fields for all cases of adenocarcinoma of the rectum is questioned. Our current policy following APR includes optional coverage of the perineum for those tumors more than 5 cm from the anorectal junction.


Impact of obesity and Down syndrome on peak heart rate and aerobic capacity in youth and adults.
Individuals with Down syndrome (DS) exhibit reduced aerobic capacity with reduced peak heart rate (HRpeak). This condition is often coexistent with higher level of obesity compared to individuals without DS. The purpose of this study is to investigate the effects of obesity and Down syndrome (DS) on peak heart rate (HRpeak) and peak oxygen consumption (VO2peak) in children and adults both with and without intellectual disabilities (ID)s. VO2peak and HRpeak from individualized treadmill tests on 654 individuals were analyzed. Body mass index was used to categorize individuals' weight status using standard cut-offs. DS groups had the lowest HRpeak (167bpm±14, p<0.05) compared to individuals with (183bpm±12) without ID (187bpm±12). Obesity did not affect HRpeak among adults and children with DS. VO2peak was lower among individuals with DS (25.2mL/kg/min±6.3, p<0.05) when compared individuals with (37.0mL/kg/min±10.5) and without ID (36.1mL/kg/min±10.4). Obese adults with DS had lower VO2peak (24.3mL/kg/min±6.9, p=0.001) compared to the normal weight (26.7±7.1mL/kg/min) and overweight groups (27.0mL/kg/min±6.1) with DS. Conversely, in children, obesity level did not impact VO2peak in individuals with DS. Our results suggest that DS attenuates both VO2peak and HRpeak, regardless of obesity status and age group. However, obesity was associated with lower VO2peak in all adults, but not in children with DS.


Safety of bisphosphonates.
Bisphosphonates are one of the most well studied groups of medications and they are bone specific. This tissue specificity is a rare property for a drug introduced into clinical practice as long as 40 years ago. Over the years, the therapeutic boundaries of bisphosphonates were explored and their safety profile has withstood the challenges of the harsh clinical reality and widespread use. Certainly, the esophageal or gastric irritation caused by the oral preparations is an established adverse effect, the risk of which can be reduced by the recommended routine of taking the medication. From the other reported associations with adverse events, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures have attracted most of the attention mainly because their pathophysiology remains unclear. However, overall, only a very small proportion of patients treated with bisphosphonates, especially with the oral formulations, experience adverse events and the overall benefits have consistently outweighed their potential risks. Furthermore, bisphosphonates improve the quality of life in patients with metastatic bone cancer and delay the development of adverse skeletal effects.


Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden.
Obesity is associated with low levels of sex hormone-binding globulin (SHBG). While the reason is not fully understood, we aimed to study the association between serum insulin and levels of SHBG in a random population. Between 2001 and 2005, a random sample of 2816 participants aged 30-74 years were enrolled in a cross-sectional survey in the South-west of Sweden. Fasting blood samples were collected and an oral glucose tolerance test (OGTT) was conducted in all subjects without known diabetes. Diabetes mellitus was defined according to criteria from WHO, and clinical characteristics were used to discriminate between type 1 (T1D) and type 2 diabetes (T2D). Analyses of SHBG were successful in 2782 participants (98%), who thus constituted the current study population. WE FOUND SIGNIFICANT INVERSE ASSOCIATION BETWEEN LEVELS OF SHBG AND FASTING SERUM INSULIN IN BOTH GENDERS (MEN: β=-0.090, P=0.001; women: β=-0.197, P<0.001), which was independent of differences in age and BMI. The associations remained when also differences in fasting plasma glucose were accounted for (men: β=-0.062, P=0.022; women: β=-0.176, P≤0.001). Subjects with T1D exhibited higher levels of SHBG than both T2D (men: δ=15.9 nmol/l, P<0.001; women: δ=71.1 nmol/l, P<0.001) and non-diabetic subjects (men: δ=15.1 nmol/l, P<0.001; women: δ=72.9 nmol/l, P<0.001) independent of age, BMI and fasting glucose levels. These findings are consistent with high levels of SHBG in T1D, and correspondingly low levels in T2D subjects, suggesting an inhibitory effect of insulin on the SHBG production in the liver.


Functional interaction between p75NTR and TrkA: the endocytic trafficking of p75NTR is driven by TrkA and regulates TrkA-mediated signalling.
The topology and trafficking of receptors play a key role in their signalling capability. Indeed, receptor function is related to the microenvironment inside the cell, where specific signalling molecules are compartmentalized. The response to NGF (nerve growth factor) is strongly dependent on the trafficking of its receptor, TrkA. However, information is still scarce about the role of the cellular localization of the TrkA co-receptor, p75NTR (where NTR is neurotrophin receptor), following stimulation by NGF. It has been shown that these two receptors play a key role in epithelial tissue and in epithelial-derived tumours, where the microenvironment at the plasma membrane is defined by the presence of tight junctions. Indeed, in thyroid carcinomas, rearrangements of TrkA are frequently found, which produce TrkA mutants that are localized exclusively in the cytoplasm. We used a thyroid cellular model in which it was possible to dissect the trafficking of the two NGF receptors upon neurotrophin stimulation. In FRT (Fischer rat thyroid) cells, endogenous TrkA is localized exclusively on the basolateral surface, while transfected p75NTR is selectively distributed on the apical membrane. This cellular system enabled us to selectively stimulate either p75NTR or TrkA and to analyse the role of receptor trafficking in their signalling capability. We found that, after binding to NGF, p75NTR was co-immunoprecipitated with TrkA and was transcytosed at the basolateral membrane. We showed that the TrkA-p75NTR interaction is necessary for this relocation of p75NTR to the basolateral side. Interestingly, TrkA-specific stimulation by basolateral NGF loading also induced the TrkA-p75NTR interaction and subsequent p75NTR transcytosis at the basolateral surface. Moreover, specific stimulation of p75NTR by NGF activated TrkA and the MAPK (mitogen-activated protein kinase) pathway. Our data indicate that TrkA regulates the subcellular localization of p75NTR upon stimulation with neurotrophins, thus affecting the topology of the signal transduction molecules, driving the activation of a specific signal transduction pathway.


Are systematic reviews up-to-date at the time of publication?
Systematic reviews provide a synthesis of evidence for practitioners, for clinical practice guideline developers, and for those designing and justifying primary research. Having an up-to-date and comprehensive review is therefore important. Our main objective was to determine the recency of systematic reviews at the time of their publication, as measured by the time from last search date to publication. We also wanted to study the time from search date to acceptance, and from acceptance to publication, and measure the proportion of systematic reviews with recorded information on search dates and information sources in the abstract and full text of the review. A descriptive analysis of published systematic reviews indexed in Medline in 2009, 2010 and 2011 by three reviewers, independently extracting data. Of the 300 systematic reviews included, 271 (90%) provided the date of search in the full-text article, but only 141 (47%) stated this in the abstract. The median (standard error; minimum to maximum) survival time from last search to acceptance was 5.1 (0.58; 0 to 43.8) months (95% confidence interval = 3.9 to 6.2) and from last search to first publication time was 8.0 (0.35; 0 to 46.7) months (95% confidence interval = 7.3 to 8.7), respectively. Of the 300 reviews, 295 (98%) stated which databases had been searched, but only 181 (60%) stated the databases in the abstract. Most researchers searched three (35%) or four (21%) databases. The top-three most used databases were MEDLINE (79%), Cochrane library (76%), and EMBASE (64%). Being able to identify comprehensive, up-to-date reviews is important to clinicians, guideline groups, and those designing clinical trials. This study demonstrates that some reviews have a considerable delay between search and publication, but only 47% of systematic review abstracts stated the last search date and 60% stated the databases that had been searched. Improvements in the quality of abstracts of systematic reviews and ways to shorten the review and revision processes to make review publication more rapid are needed.


Age-of-acquisition affects word naming in Italian only when stress is irregular.
In Italian, effects of age of acquisition (AoA) have been found in object naming, semantic categorization of words and lexical decision, but not in word naming (reading aloud). The lack of an AoA effect in Italian word naming is replicated in Experiment 1 which involved reading aloud two-syllable words which all have regular spelling-sound correspondences and regular stress patterns. Studies of English word naming have reported stronger effects of AoA for irregular or exception words than for words with regular, consistent spelling-sound correspondences. There are no grapheme-phoneme irregularities in Italian, but words containing three or more syllables can carry either regular stress on the penultimate syllable or irregular stress on the antepenultimate syllable. Experiment 2 found effects of AoA on reading three-syllable words for words with irregular stress. The results are interpreted in terms of the 'mapping hypothesis' of AoA, with effects arising as a result of a difficulty to generalize earlier-acquired patterns to irregular late-acquired words.