Canadian results from the European Men-who-have-sex-with-men Internet survey (EMIS-2017).
In 2017, the international European Men-who-have-sex-with-men Internet Survey (EMIS-2017) collected data from 50 countries, including Canada for the first time. To provide an overview of the Canadian EMIS-2017 data to describe the sexually transmitted and other bloodborne infection (STBBI) related needs of gay, bisexual and other men who have sex with men (gbMSM). The EMIS-2017 questionnaire was an updated version of EMIS-2010. It included self-reported sociodemographic data, experience of discrimination, mental health and substance use, knowledge of preexposure prophylaxis (PrEP) for HIV, sexual practices and history of STBBI testing and diagnosis. Analysis was largely descriptive. Of the 6,059 respondents from Canada, 5,165 participants met the inclusion criteria for this analysis. The majority of participants were born in Canada (79.3%); and over half of the respondents (56.7%) were under the age of 39. In terms of discrimination related to their attraction to other men, participants reported high levels of intimidation (31.9%), verbal abuse (22.1%) and physical violence (1.5%) in the previous year. Regarding mental health, 23.9% had a moderate to severe depression/anxiety score. Almost two-thirds (64.1%) indicated substance use and one-fifth (21.5%) reported chemsex (or the use of stimulant drugs to make sex more intense or last longer). Only 8.4% of participants reported use of PrEP for HIV; however, 51.7% reported being likely to use PrEP if it was available and affordable. Sexual practices, such as condom use, varied by PrEP use with 91.3% of men using PrEP reporting condomless anal intercourse (CAI) compared with 71.5% of men not on PrEP. In terms of STBBI testing, 1.5% reported being diagnosed with hepatitis C and 9.0% reported an HIV diagnosis. Of those with an HIV diagnosis, most were on treatment (99.1%) and had an undetectable viral load (96.7%). gbMSM in Canada experienced stigma, discrimination and mental health problems; substance use was high as were high-risk sexual practices, such as CAI, among some groups of men. There was a gap between the proportion of men who were interested in PrEP and those who actually used it; and comprehensive STBBI testing was low.These findings can inform public health action and provide a baseline to examine the impact of current and new interventions.


The HhoA protease from Synechocystis sp. PCC 6803 - Novel insights into structure and activity regulation.
Proteases play a vital role in the removal of proteins, which become damaged due to temperature or oxidative stress. Important to this process in the cyanobacterium Synechocystis sp. PCC6803 is the family of Deg/HtrA proteases; HhoA (sll1679), HhoB (sll1427) and HtrA (slr1204). While previous studies have elucidated the structures of Deg/HtrA proteases from Escherichia coli and from the chloroplast of the higher plant Arabidopsis thaliana, no structural data have been available for any Deg/HtrA protease from cyanobacteria, the evolutionary ancestor of the chloroplast. To gain a deeper insight into the molecular mechanisms and regulation of these proteins we have solved the structure of the Synechocystis HhoA protease in complex with a co-purified peptide by X-ray crystallography. HhoA assembles into stable trimers, mediated by its protease domain and further into a cage-like hexamer by a novel interaction between the PDZ domains of opposing trimers. Each PDZ domain contains two loops for PDZ-PDZ formation: interaction clamp one and two (IC1, IC2). IC1 interacts with IC2 on the opposing PDZ domain and vice versa. Our structure shows a peptide bound to a conserved groove on the PDZ domain and the properties of this pocket suggest that it binds substrate proteins as well as the neo C-termini of cleaved substrates. In agreement with previous studies showing the proteolytic activity of HhoA to be activated by Ca2+ or Mg2+, binding of divalent metal ions to the central channel of the trimer by the L1 activation loop was observed.


[Availability of generic drugs in the public sector and prices in the private sector in different regions of Brazil].
A study to identify availability and prices of medicines, according to type of provider, was conducted in the five regions of Brazil. A list of medicines to treat prevalent diseases was investigated, using the medicines price methodology developed by the World Health Organization and Health Action International, adapted for Brazil. In the public sector, bioequivalent (vis-à-vis reference brand) generics are less available than multisource products. For most medicines (71.4%), the availability of bioequivalent generics was less than 10%. In the private sector, the average number of different bioequivalent generic versions in the outlets was far smaller than the number of versions on the market. There was a positive correlation between the number of generics on the market, or those found at outlets, and the price variation in bioequivalent generic products, in relation to the maximum consumer price. It is estimated that price competition is occurring among bioequivalent generic drugs and between them and multisource products for the same substance, but not with reference brands.


Programmable High-Throughput Platform for the Rapid and Scalable Synthesis of Polyester and Polycarbonate Libraries.
The critical role of composition, architecture, molecular weight, and molecular weight distribution on the functional properties of macromolecular materials underscores the need for reproducible, robust, scalable, and programmable synthetic methods to generate macromolecules that span a systematic and wide range of structure-property space. Herein, we describe the marriage of tunable and highly active organic catalysts with programmed continuous-flow reactors to rapidly generate libraries of polyester and polycarbonate homopolymers and block copolymers with exquisite efficiency and control. Under continuous-flow conditions, highly controlled polymerizations occur with residence times as low as 6 ms (TOF = 24 000 000 h-1) and can be readily scaled-up to generate polymers at a rate of tens of grams per minute. We describe an in-flow catalyst switch strategy to enable the rapid generation of block copolymer libraries (100 distinct polymers in 9 min) from monomers with drastically different reactivity profiles.


HIV Infection, Immunosuppression, and Age at Diagnosis of Non-AIDS-Defining Cancers.
It is unclear whether immunosuppression leads to younger ages at cancer diagnosis among people living with human immunodeficiency virus (PLWH). A previous study found that most cancers are not diagnosed at a younger age in people with AIDS, with the exception of anal and lung cancers. This study extends prior work to include all PLWH and examines associations between AIDS, CD4 count, and age at cancer diagnosis. We compared the median age at cancer diagnosis between PLWH in the North American AIDS Cohort Collaboration on Research and Design and the general population using data from the Surveillance, Epidemiology and End Results Program. We used statistical weights to adjust for population differences. We also compared median age at cancer diagnosis by AIDS status and CD4 count. After adjusting for population differences, younger ages at diagnosis (P < .05) were observed for PLWH compared with the general population for lung (difference in medians = 4 years), anal (difference = 4), oral cavity/pharynx (difference = 2), and kidney cancers (difference = 2) and myeloma (difference = 4). Among PLWH, having an AIDS-defining event was associated with a younger age at myeloma diagnosis (difference = 4; P = .01), and CD4 count <200 cells/µL (vs ≥500) was associated with a younger age at lung cancer diagnosis (difference = 4; P = .006). Among PLWH, most cancers are not diagnosed at younger ages. However, this study strengthens evidence that lung cancer, anal cancer, and myeloma are diagnosed at modestly younger ages, and also shows younger ages at diagnosis of oral cavity/pharynx and kidney cancers, possibly reflecting accelerated cancer progression, etiologic heterogeneity, or risk factor exposure in PLWH.


Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. clinicaltrials.gov Identifier: NCT01000727.


Adenine methylation is very scarce in the Drosophila genome and not erased by the ten-eleven translocation dioxygenase.
N6-methyladenine (6mA) DNA modification has recently been described in metazoans, including in Drosophila, for which the erasure of this epigenetic mark has been ascribed to the ten-eleven translocation (TET) enzyme. Here, we re-evaluated 6mA presence and TET impact on the Drosophila genome. Using axenic or conventional breeding conditions, we found traces of 6mA by LC-MS/MS and no significant increase in 6mA levels in the absence of TET, suggesting that this modification is present at very low levels in the Drosophila genome but not regulated by TET. Consistent with this latter hypothesis, further molecular and genetic analyses showed that TET does not demethylate 6mA but acts essentially in an enzymatic-independent manner. Our results call for further caution concerning the role and regulation of 6mA DNA modification in metazoans and underline the importance of TET non-enzymatic activity for fly development.


Speckle photography of lateral sinusoidal vibrations: error due to varying halo intensity.
The effect of varying halo intensity in speckle photography of lateral sinusoidal vibration using Young's fringes is discussed. An interesting new result is found that, for nonunity contrast or visibility, the relative fringe shift (or the error) for minima is always minimum for the lower-order fringes. Also the error in the fringe maxima position is lowest generally at intermediate fringe orders. However, as the visibility reduces the trend becomes similar to that for the case of minima. For maxima and minima both, the error is less for larger amplitude vibrations and higher visibility.


Distribution and origins of Mycobacterium tuberculosis L4 in Southeast Asia.
Molecular and genomic studies have revealed that Mycobacterium tuberculosis Lineage 4 (L4, Euro-American lineage) emerged in Europe before becoming distributed around the globe by trade routes, colonial migration and other historical connections. Although L4 accounts for tens or hundreds of thousands of tuberculosis (TB) cases in multiple Southeast Asian countries, phylogeographical studies have either focused on a single country or just included Southeast Asia as part of a global analysis. Therefore, we interrogated public genomic data to investigate the historical patterns underlying the distribution of L4 in Southeast Asia and surrounding countries. We downloaded 6037 genomes associated with 29 published studies, focusing on global analyses of L4 and Asian studies of M. tuberculosis. We identified 2256 L4 genomes including 968 from Asia. We show that 81 % of L4 in Thailand, 51 % of L4 in Vietnam and 9 % of L4 in Indonesia belong to sub-lineages of L4 that are rarely seen outside East and Southeast Asia (L4.2.2, L4.4.2 and L4.5). These sub-lineages have spread between East and Southeast Asian countries, with no recent European ancestor. Although there is considerable uncertainty about the exact direction and order of intra-Asian M. tuberculosis dispersal, due to differing sampling frames between countries, our analysis suggests that China may be the intermediate location between Europe and Southeast Asia for two of the three predominantly East and Southeast Asian L4 sub-lineages (L4.2.2 and L4.5). This new perspective on L4 in Southeast Asia raises the possibility of investigating host population-specific evolution and highlights the need for more structured sampling from Southeast Asian countries to provide more certainty of the historical and current routes of dispersal.


Connecting Cancer Pathways to Tumor Engines: A Stratification Tool for Colorectal Cancer Combining Human In Vitro Tissue Models with Boolean In Silico Models.
To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is-in contrast to melanoma-not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.


Use of antibiotics at a University Clinic Hospital: effect of protocolized antibiotic treatment in the evolution of hospital patients with infections.
To analyse factors associated to "failure" in patients under antibiotic (AB) treatment at a third level hospital. All patients receiving an AB treatment along April 2012 were prospectively observed and factors associated to failure were analyzed. Failure was defined as clinical or microbiological failure, relapse or death. Statistically significance was established as p<0.05. 602 of 1,265 admitted patients during the study month included an AB in their medical prescriptions, being 178 considered as prophylactic AB prescriptions, 342 empirical treatments and 82 directed treatments as empiric treatments. Ceftriaxone and levofloxacin were the most used AB; choice of empirical and directed treatments were in line with protocols in 71% (242 of 342 cases) and 67% (55 of 82), respectively. Of all the patients receiving antibiotics for therapy (n=424), 402 had infection criteria (in 22 cases antibiotic treatment was deemed unnecessary since the patient showed no infectious process). Of these, 292 (72%) showed a good evolution, while the others were considered as failed therapies, either because of microbiological persistence in 49 (12.8%), relapse in 31 (7.71%) and death in en 30 (7.46%). Factors associated to "failure" were Charlson score ≥3 (OR 3.35; 95%CI 1.602-7.009); empirical and/or directed treatment not in keeping with the protocol (OR 5.68; 95%CI 2.898-11.217); and infection by ESBL and/or ciprofloxacin resistant E. coli (OR 4.43; 95%CI 1.492-13.184). A high rate of AB prescriptions in admitted patients correspond to empirical infection treatment, being ceftriaxone and levofloxacin the most used AB. Inadequate empirical and/or directed treatment is associated to clinical or microbiological failure and death.


Influential Factors for and Outcomes of Hospitalized Patients with Suicide-Related Behaviors: A National Record Study in Taiwan from 1997-2010.
Investigating the factors related to suicide is crucial for suicide prevention. Psychiatric disorders, gender, socioeconomic status, and catastrophic illnesses are associated with increased risk of suicide. Most studies have typically focused on the separate influences of physiological or psychological factors on suicide-related behaviors, and have rarely used national data records to examine and compare the effects of major physical illnesses, psychiatric disorders, and socioeconomic status on the risk of suicide-related behaviors. To identify the characteristics of people who exhibited suicide-related behaviors and the multiple factors associated with repeated suicide-related behaviors and deaths by suicide by examining national data records. This is a cohort study of Taiwan's national data records of hospitalized patients with suicide-related behaviors from January 1, 1997, to December 31, 2010. The study population included all people in Taiwan who were hospitalized with a code indicating suicide or self-inflicted injury (E950-E959) according to the International Classification of Disease, Ninth Revision, Clinical Modification. Self-poisoning was the most common method of self-inflicted injury among hospitalized patients with suicide-related behaviors who used a single method. Those who were female, had been hospitalized for suicide-related behaviors at a younger age, had a low income, had a psychiatric disorder (i.e., personality disorder, major depressive disorder, bipolar disorder, schizophrenia, alcohol-related disorder, or adjustment disorder), had a catastrophic illness, or had been hospitalized for suicide-related behaviors that involved two methods of self-inflicted injury had a higher risk of hospitalization for repeated suicide-related behaviors. Those who were male, had been hospitalized for suicide-related behaviors at an older age, had low income, had schizophrenia, showed repeated suicide-related behaviors, had a catastrophic illness, or had adopted a single lethal method had an increased risk of death by suicide. High-risk factors should be considered when devising suicide-prevention strategies.


Endometrial cancer: Molecular markers and management of advanced stage disease.
Endometrial cancer is the most prevalent gynecologic cancer in the United States. Over the last 10 years, death rates from endometrial cancer have been rising about 1.4% per year. Traditionally endometrial cancer treatment has been driven by stage and histology. Recent studies have, however, shown that cancers of the same stage and histology have very distinct molecular and genomic profiles. Translational research is progressing rapidly and endometrial cancer-specific precision medicine is evolving. The first tissue agnostic therapy based on the molecular profile of the tumor was approved by the FDA this year. The approval of immune checkpoint inhibitor, pembrolizumab (anti-PD-1), for all solid tumors with defective DNA mismatch repair, could benefit 20-30% of patients with advanced endometrial cancer. Other genomic changes and molecular markers in endometrial cancer, such as hormone receptor status, could lead to more tailored therapy in the future. Pre-clinical and clinical investigations of targeted therapies suggest efficacy for some agents. Single agent targeted therapies, however, have modest activity. Identifying biomarkers that effectively determine response to targeted therapy remains a challenge. The next generation of clinical trials will focus on novel combinations and how to best utilize the advances that have been made in sequencing technology and bioinformatics. Although there is currently an immense body of data and many options for obtaining genomic characteristics of endometrial cancer, how to interpret and utilize this data is still being explored. This review will summarize the important trials that have led to the treatment options we have for advanced and/or recurrent endometrial cancer and discuss the important studies that have led to a better understanding of the distinctive molecular and genomic profiles within endometrial cancer. We will review the current status of biomarker-driven targeted therapy in endometrial cancer and the rationale behind ongoing clinical trials that are utilizing novel targeted agents.


A research synthesis of therapeutic interventions for whiplash-associated disorder (WAD): part 2 - interventions for acute WAD.
Whiplash-associated disorder (WAD) represents a significant public health problem, resulting in substantial social and economic costs throughout the industrialized world. While many treatments have been advocated for patients with WAD, scientific evidence supporting their effectiveness is often lacking. A systematic review was conducted to evaluate the strength of evidence associated with various WAD therapies. Multiple databases (including Web of Science, EMBASE and PubMed) were searched to identify all studies published from January 1980 through March 2009 that evaluated the effectiveness of any clearly defined treatment for acute (less than two weeks), subacute (two to 12 weeks) or chronic (more than 12 weeks) WAD. The present article, the second in a five-part series, evaluates the evidence for interventions initiated during the acute phase of WAD. Twenty-three studies that met the inclusion criteria were identified, 16 of which were randomized controlled trials with 'fair' overall methodological quality (median Physiotherapy Evidence Database score of 5.5). For the treatment of acute WAD, there was strong evidence to suggest that not only is immobilization with a soft collar ineffective, but it may actually impede recovery. Conversely, although exercise programs, active mobilization and advice to act as usual all appeared to improve recovery, it is not clear which of these interventions was the most effective. While there was also evidence supporting the use of pulsed electromagnetic field therapy and methylprednisolone infusion, the evidence was insufficient to establish the effectiveness of either of these treatments. Based on current evidence, activation-based therapy is recommended for the treatment of acute WAD; however, additional research is required to determine the relative effectiveness of various exercise⁄mobilization programs.


The connectome of a decision-making neural network.
In order to understand the nervous system, it is necessary to know the synaptic connections between the neurons, yet to date, only the wiring diagram of the adult hermaphrodite of the nematode Caenorhabditis elegans has been determined. Here, we present the wiring diagram of the posterior nervous system of the C. elegans adult male, reconstructed from serial electron micrograph sections. This region of the male nervous system contains the sexually dimorphic circuits for mating. The synaptic connections, both chemical and gap junctional, form a neural network with four striking features: multiple, parallel, short synaptic pathways directly connecting sensory neurons to end organs; recurrent and reciprocal connectivity among sensory neurons; modular substructure; and interneurons acting in feedforward loops. These features help to explain how the network robustly and rapidly selects and executes the steps of a behavioral program on the basis of the inputs from multiple sensory neurons.


Iodine supplementation for preventing iodine deficiency disorders in children.
Iodine deficiency is the main cause of potentially preventable mental retardation in childhood, as well as causing goitre and hypothyroidism in people of all ages. It is still prevalent in large parts of the world. To assess the effects of iodine supplementation overall, and of different forms and dosages of iodine supplementation separately, in the prevention of iodine deficiency disorders in children. The Cochrane Library, MEDLINE, EMBASE and reference lists, databases of ongoing trials and the Internet were searched. Date of latest search: October 2003. We included randomised controlled trials and prospective controlled trials not using randomisation of iodine supplementation in children living in areas of iodine deficiency. Two reviewers did the initial data selection and quality assessment of trials independently. As the studies identified were not sufficiently similar and not of sufficient quality, we did not do a meta-analysis but summarised the data in a narrative format. Twenty-six prospective controlled trials were related to our question, assessing a total of 29613 children. Twenty of them were classified as being of low quality, six of moderate quality. Most studies used iodised oil as a supplement, but other supplements were also used. The intervention groups were compared to a non-supplemented control group, different doses or different forms of iodine supplementation. There was a clear tendency towards goitre reduction with iodine supplementation; this was significant in several studies. Significant differences in physical development were not seen, except in one study. Results for differences in cognitive and psychomotor measures were mixed, with only few studies showing a positive intervention effect. One study suggested that infant mortality was lowered after iodine supplementation. Most studies showed a significant increase in urinary iodine excretion and levels recommended by the WHO were reached in most cases after supplementation. Thyroid-stimulating hormone (TSH) levels were significantly reduced in one study. In 1.8% of the children investigated, adverse effects were found, most of them were minor and transient. Despite most of the included studies being of low quality, the results suggest that iodine supplementation, especially iodised oil, is an effective means of decreasing goitre rates and improving iodine status in children. Indications of positive effects on physical and mental development and mortality were seen, although results were not always significant. Adverse effects were generally minor and transient. Insufficient evidence was available on non-oil supplements. High quality controlled studies investigating relevant long term outcome measures are needed to address the question of the best form of iodine supplementation in different population groups and settings.


Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy.
Current anti-epileptic drugs (AEDs) act on a limited set of neuronal targets, are ineffective in a third of patients with epilepsy, and do not show disease-modifying properties. MicroRNAs are small noncoding RNAs that regulate levels of proteins by post-transcriptional control of mRNA stability and translation. MicroRNA-134 is involved in controlling neuronal microstructure and brain excitability and previous studies showed that intracerebroventricular injections of locked nucleic acid (LNA), cholesterol-tagged antagomirs targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in mouse models of status epilepticus. Translation of these findings would benefit from evidence of efficacy in non-status epilepticus models and validation in another species. Here, we report that electrographic seizures and convulsive behavior are strongly reduced in adult mice pre-treated with Ant-134 in the pentylenetetrazol model. Pre-treatment with Ant-134 did not affect the severity of status epilepticus induced by perforant pathway stimulation in adult rats, a toxin-free model of acquired epilepsy. Nevertheless, Ant-134 post-treatment reduced the number of rats developing spontaneous seizures by 86% in the perforant pathway stimulation model and Ant-134 delayed epileptiform activity in a rat ex vivo hippocampal slice model. The potent anticonvulsant effects of Ant-134 in multiple models may encourage pre-clinical development of this approach to epilepsy therapy.


Simple genetic selection protocol for isolation of overexpressed genes that enhance accumulation of membrane-integrated human G protein-coupled receptors in Escherichia coli.
The efficient production of membrane proteins in bacteria remains a major challenge. In this work, we sought to identify overexpressed genes that enhance the yields of recombinant membrane proteins in Escherichia coli. We developed a genetic selection system for bacterial membrane protein production, consisting of membrane protein fusions with the enzyme beta-lactamase and facile selection of high-production strains on ampicillin-containing media. This system was used to screen the ASKA library, an ordered library of plasmids encoding all the known E. coli open reading frames (ORFs), and several clones with the ability to accumulate enhanced amounts of recombinant membrane proteins were selected. Notably, coexpression of ybaB, a gene encoding a putative DNA-binding protein of unknown function, was found to enhance the accumulation of a variety of membrane-integrated human G protein-coupled receptors and other integral membrane proteins in E. coli by up to 10-fold. The results of this study highlight the power of genetic approaches for identifying factors that impact membrane protein biogenesis and for generating engineered microbial hosts for membrane protein production.


Classification and moral evaluation of uncertainties in engineering modeling.
Engineers must deal with risks and uncertainties as a part of their professional work and, in particular, uncertainties are inherent to engineering models. Models play a central role in engineering. Models often represent an abstract and idealized version of the mathematical properties of a target. Using models, engineers can investigate and acquire understanding of how an object or phenomenon will perform under specified conditions. This paper defines the different stages of the modeling process in engineering, classifies the various sources of uncertainty that arise in each stage, and discusses the categories into which these uncertainties fall. The paper then considers the way uncertainty and modeling are approached in science and the criteria for evaluating scientific hypotheses, in order to highlight the very different criteria appropriate for the development of models and the treatment of the inherent uncertainties in engineering. Finally, the paper puts forward nine guidelines for the treatment of uncertainty in engineering modeling.


Spatial band-pass filtering aids decoding musical genres from auditory cortex 7T fMRI.
Spatial filtering strategies, combined with multivariate decoding analysis of BOLD images, have been used to investigate the nature of the neural signal underlying the discriminability of brain activity patterns evoked by sensory stimulation - primarily in the visual cortex. Previous research indicates that such signals are spatially broadband in nature, and are not primarily comprised of fine-grained activation patterns. However, it is unclear whether this is a general property of the BOLD signal, or whether it is specific to the details of employed analyses and stimuli. Here we applied an analysis strategy from a previous study on decoding visual orientation from V1 to publicly available, high-resolution 7T fMRI on the response BOLD response to musical genres in primary auditory cortex. The results show that the pattern of decoding accuracies with respect to different types and levels of spatial filtering is comparable to that obtained from V1, despite considerable differences in the respective cortical circuitry.


Synthesis, structure, docking and cytotoxic studies of ferrocene-hormone conjugates for hormone-dependent breast cancer application.
Previously, ferrocene incorporation into the principal structural component of biologically active molecules resulted in enhanced cytotoxic activity against hormone-dependent MCF-7 and T-47D and hormone-independent MDA-MB-231 breast-cancer cell lines. Here we explore 4 new ferrocene estrogen conjugates at position 16 of the estrogen hormone and compared them to the previously reported ferrocene estrogen conjugate 3-ferrocenyl-estra-1,3,5(10)-triene-17β-ol. The ferrocene conjugate 16-ferrocenylidene-3-hydroxyestra-1,3,5(10)-trien-17-one was synthesized using estrone and ferrocene carboxaldehyde as starting materials in 86% yield. This ferrocene complex was used as the starting material for the synthesis of new ferrocene estrogen conjugates by a short linker group at position 16 of the estrogen hormone. The position and stereochemistry of the linker was verified by its crystal structure. The ferrocene redox behavior, in vitro studies on breast-cancer cell lines and docking studies on ERα are presented. The data suggest that the ferrocene conjugates presented, either at position 3 or 16 of the estrogen, could serve as vectors and can be recognized by ERα as a delivery mechanism into the cell. These new ferrocene hormone conjugates showed cytotoxic activity comparable to that of conventional therapeutic drugs such as tamoxifen and cisplatin.


Broadband transmission in hollow-core Bragg fibers with geometrically distributed multilayered cladding.
For the first time, the quasiperiodic Bragg fibers with geometrically distributed multilayered cladding are proposed and analyzed. We demonstrate that hollow-core Bragg fibers with quasiperiodic dielectric multilayer cladding can achieve low loss transmission over a broadband wavelength range of more than an octave (from 0.81 μm to 1.7 μm). The periods of the Bragg blocks follows a geometrical progression with a common ratio r<rc, where rc is defined as the critical ratio of the periods of two adjacent Bragg blocks. The arrangement of the quasiperiodic cladding can significantly modify the characteristics of the fiber, leading to a broadening of the guiding range compared to a hollow Bragg fiber with uniform periodic multilayer cladding structure. In general, a larger r value results in a broader guiding range. More Bragg blocks in the cladding and more unit cells in each Bragg block lead to a lower fiber modal loss.


Clinical and Pathological Benefits of Edaravone for Alzheimer's Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model.
Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis.


Mechanism-based population modelling for assessment of L-cell function based on total GLP-1 response following an oral glucose tolerance test.
GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study was to build a mechanism-based population model that describes the time course of total GLP-1 and provides indices for capability of secretion in each subject. The goal was thus to model the secretion of GLP-1, and not its effect on insulin production. Single 75 g doses of glucose were administered orally to a mixed group of subjects ranging from healthy volunteers to patients with type 2 diabetes (T2D). Glucose, insulin, and total GLP-1 concentrations were measured. Prior population data analysis on measurements of glucose and insulin were performed in order to estimate the glucose absorption rate. The individual estimates of absorption rate constants were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI. The final transit/indirect-response model obtained for GLP-1 production following an OGTT included two stimulation components (fast, slow) for the zero-order production rate. The fast stimulation was estimated to be faster than the glucose absorption rate, supporting the presence of a proximal-distal loop for fast secretion from L: -cells. The fast component (st₃) = 8.64·10⁻⁵ [mg⁻¹]) was estimated to peak around 25 min after glucose ingestion, whereas the slower component (st₄ = 26.2·10⁻⁵ [mg⁻¹]) was estimated to peak around 100 min. Elimination of total GLP-1 was characterised by a first-order loss. The individual values of the early phase GLP-1 secretion parameter (st₃) were correlated (r = 0.52) with the AUC(0-60 min.) for GLP-1. A mechanistic population model was successfully developed to describe total GLP-1 concentrations over time observed after an OGTT. The model provides indices related to different mechanisms of subject abilities to secrete GLP-1. The model provides a good basis to study influence of different demographic factors on these components, presented mainly by indices of the fast- and slow phases of GLP-1 response.


The embryonic development of the malacostracan crustacean Porcellio scaber (Isopoda, Oniscidea).
To examine the evolution of development and put it into a phylogenetic context, it is important to have, in addition to a model organism like Drosophila, more insights into the huge diversity of arthropod morphologies. In recent years, the malacostracan crustacean Porcellio scaber Latreille, 1804 has become a popular animal for studies in evolutionary and developmental biology, but a detailed and complete description of its embryonic development is still lacking. Therefore, the embryonic development of the woodlouse P. scaber is described in a series of discrete stages easily identified by examination of living animals and the widely used technique of nuclei staining on fixed specimens. It starts with the first cleavage of the zygote and ends with a hatched manca that eventually leaves the mother's brood pouch. Classical methods like normal light microscopy, scanning electron microscopy and fluorescence microscopy are used, in addition to confocal LCM and computer-aided 3D reconstruction in order to visualise important processes during ontogeny. The purpose of these studies is to offer an easy way to define the different degrees of development for future comparative analyses of embryonic development amongst crustaceans in particular, as well as between different arthropod groups. In addition, several aspects of Porcellio embryonic development, such as the mouth formation, limb differentiations and modifications or the formation of the digestive tract, make this species particularly interesting for future studies in evolutionary and developmental biology.


Resistin contributes to neointimal formation via oxidative stress after vascular injury.
Resistin may play a major potential role in vascular remodelling and may contribute to atherogenesis. However, the role of VSMC (vascular smooth muscle cell)-derived resistin in neointimal formation is not well understood. We hypothesize that endogenous resistin derived from VSMCs may contribute to neointimal formation after vascular injury. VSMCs from thoracic aorta of adult Wistar rats were cultured. The carotid artery from adult Wistar rats was injured by balloon catheter. Resistin significantly increased migration and proliferation of VSMCs. Resistin siRNA (small interfering RNA) and resistin antibody significantly inhibited migration and proliferation of VSMCs induced by conditioned medium from stretched VSMCs. Resistin protein and mRNA expression significantly increased at 14 days after carotid injury. Resistin siRNA and NAC (N-acetylcysteine) significantly reduced resistin protein and mRNA expression induced by balloon injury. Carotid artery injury increased ROS (reactive oxygen species) production. Treatment with NAC and resistin siRNA decreased ROS production. The neointimal area was significantly increased after carotid injury and was significantly reduced by resistin siRNA and NAC. In conclusion, resistin increases migration and proliferation of VSMCs, and expression of resistin in carotid artery significantly increases after injury. Resistin siRNA attenuates neointimal formation after carotid injury partly through an antioxidative mechanism. Resistin may play a pivotal role in the pathogenesis of neointimal thickening after mechanical injury.


Diagnosis and Assessment of the Asthmas.
Optimizing asthma diagnosis is an essential part of global strategies to reduce the excessive illness burden from asthma. New understanding about how to address the complexity and heterogeneity of the different forms of asthma means that asthma diagnosis now requires a compound diagnostic approach and label. Eliciting the typical symptoms and abnormal physiology of variable airflow limitation permits the recognition of asthma, and the identification of further features, such as eosinophilic or type 2 inflammation, allows a compound diagnostic label of eosinophilic asthma. This conveys key information about future exacerbation risk and likely treatment responsiveness. Treatable traits are a useful way to implement this new approach to diagnosis. Targeted assessment is used to inform a specific treatment plan in a pragmatic and iterative process.


Regulation of the glial fibrillary acidic protein, beta actin and prion protein mRNAs during brain development in mouse.
Developmental regulation in mRNAs of three brain proteins has been investigated by Northern blot evaluation in C57BL/6 mice. The mRNAs of two cytoskeletal components, glial fibrillary acidic protein (GFAP) and beta actin, varied significantly, and differently, during brain development (0-56 days postnatal). The beta actin mRNAs peaked at day 1 after a slight increase, then dropped rapidly during the first 15 days postnatal, and thereafter remained at a level which was strictly maintained throughout development and adulthood. Conversely, the GFAP mRNAs increased during the first two weeks after birth (astroglial proliferation), and then slightly declined until the adult stage (astroglial cell differentiation). The prion protein (PrP) mRNAs were detectable as soon as birth, and increased 4-fold during brain maturation. Then, during the adult life, the GFAP and PrP mRNAs did not change markedly. Nevertheless, slight but significant increases in the mRNA levels of both GFAP and PrP were observed at older stages (360 days). These results are analysed in the light of the implications of PrP and GFAP in scrapie infection models.


Validation of an Integrated Management of Childhood Illness algorithm for managing common skin conditions in Fiji.
To assess the sensitivity of an Integrated Management of Childhood Illness (IMCI) algorithm to detect common skin conditions in children in Fiji. We collected data from the assessments of children aged between 2 months and 5 years who presented to one of two health clinics. Every child was assessed by a nurse trained in the use of the IMCI algorithm and also an expert paediatrician. We used a kappa statistic to measure agreement between the nurse/algorithm assessment method and the paediatrician's diagnosis. High sensitivity for identifying skin problems (sensitivity: 98.7%; 95% confidence interval, CI: 95.5-99.9) was found for the algorithm applied by IMCI-trained nurses, who were able to identify the one child with a severe skin infection and all three children with periorbital cellulitis. Sensitivity was high for the classification of abscess/cellulitis (sensitivity: 95%; 95% CI: 75.1-99.9) and infected scabies (sensitivity: 89.1%; 95% CI: 77.8-95.9), but lower for identification of impetigo, fungal infection and, in particular, non-infected scabies. The IMCI skin algorithm is a robust tool that should be incorporated into the IMCI after some modifications relating to scabies and impetigo. Its use by primary health-care workers will reduce the burden of skin diseases in children in Fiji through improved case identification and management. The algorithm should be considered in other countries where skin diseases in children are a priority, particularly in the Pacific region.


Disc inflammation and Modic changes show an interaction effect on recovery after surgery for lumbar disc herniation.
To study the interaction between Modic changes (MC) and inflammation by macrophages in the disc, in relation to clinical symptoms before and after discectomy for lumbar disc herniation. Disc tissue was embedded in paraffin and stained with haematoxylin and CD68. Subsequently, tissue samples were categorized for degree of inflammation. Type of MC was scored on MRI at baseline. Roland Disability Questionnaire (RDQ) score and visual analogue scale for back pain and leg pain separately were considered at baseline and 1-year follow-up post-surgery. Main and interaction effects of MC and inflammation were tested against clinical outcome questionnaires. In addition, this analysis was repeated in bulging and extruded discs separately. Disc material and MRI's of 119 patients were retrieved and analysed. Forty-eight patients demonstrated mild inflammation, 45 showed moderate inflammation, and 26 showed considerable inflammation. In total, 49 out of 119 patients demonstrated MC. Grade of disc inflammation did not associate with the presence of MC. At baseline, no main or interaction effects of MC and inflammation were found on the clinical scores. However, during follow-up after discectomy, significant interaction effects were found for RDQ score: Only in patients with MC at baseline, patients remained significantly more disabled (3.2 points p = 0.006) if they showed considerable disc inflammation compared to patients with mild inflammation. The additional analysis showed similar results in extruded discs, but no significant effects in bulging discs. An interaction effect of MC and disc inflammation by macrophages is present. Only in patients with MC, those with considerable inflammation recover less satisfactory during follow-up after surgery. These slides can be retrieved under Electronic Supplementary Material.


The legislation of active voluntary euthanasia in Australia: will the slippery slope prove fatal?
At 2.00 am on the morning of May 24, 1995 the Northern Territory Legislative Assembly Australia passed the Rights of the Terminally Ill Act by the narrow margin of 15 votes to 10. The act permits a terminally ill patient of sound mind and over the age of 18 years, and who is either in pain or suffering, or distress, to request a medical practitioner to assist the patient to terminate his or her life. Thus, Australia can lay claim to being the first country in the world to legalise voluntary active euthanasia. The Northern Territory's act has prompted Australia-wide community reaction, particularly in South Australia, Tasmania and the Australian Capital Territory where proposals to legalise euthanasia have already been defeated on the floor of parliament. In New South Wales (NSW) the AIDS Council of NSW has prepared draft euthanasia legislation to be introduced into the Upper House as a Private Member's Bill some time in 1996. In this paper, we focus on a brief description of events as they occurred and on the arguments for and against the legalisation of euthanasia which have appeared in the media.


Influence of resident involvement on trauma care outcomes.
Discrepancies exist in complications and outcomes at teaching trauma centers (TTCs) vs nonteaching TCs (NTCs). Retrospective review of the National Trauma Data Bank research data sets (January 1, 2007, through December 31, 2008). Level II TCs. Patients at TTCs were compared with patients at NTCs using demographic, clinical, and outcome data. Regression modeling was used to adjust for confounding factors to determine the effect of house staff presence on failure to rescue, defined as mortality after an in-house complication. The primary outcome measures were major complications, in-hospital mortality, and failure to rescue. In total, 162 687 patients were available for analysis, 36 713 of whom (22.6%) were admitted to NTCs. Compared with patients admitted to TTCs, patients admitted to NTCs were older (52.8 vs 50.7 years), had more severe head injuries (8.3% vs 7.8%), and were more likely to undergo immediate operation (15.0% vs 13.2%) or ICU admission (28.1% vs 22.8%) (P < .01 for all). The mean Injury Severity Scores were similar between the groups (10.1 for patients admitted to NTCs vs 10.4 for patients admitted to TTCs, P < .01). Compared with patients admitted to TTCs, patients admitted to NTCs experienced fewer complications (adjusted odds ratio [aOR], 0.63; P < .01), had a lower adjusted mortality rate (aOR, 0.87; P = .01), and were less likely to experience failure to rescue (aOR, 0.81; P = .01). Admission to level II TTCs is associated with an increased risk for major complications and a higher rate of failure to rescue compared with admission to level II NTCs. Further investigation of the differences in care provided by level II TTCs vs NTCs may identify areas for improvement in residency training and processes of care.


Expression of core-binding factor α1 and osteocalcin in fluoride-treated fibroblasts and osteoblasts.
To study the effects and importance of fluoride on FBs in the development of extraperiosteal calcification and the ossification of skeletal fluorosis, the presence of the osteogenic phenotype, which is indicated by the expression of core-binding factor α1 (Cbfa1) and osteocalcin (OCN), in an FB cell line (L929) and in osteoblasts (OBs) exposed to fluoride was determined. Fibroblasts and osteoblasts were exposed to different concentrations of fluoride (0, 0.0001, 0.001, 0.1, 1.0, 10.0 and 20.0 mg/L F(-)). By using RT-PCR and ELISA, the mRNA levels of Cbfa1 and OCN were measured at 48 h, and the protein levels of Cbfa1 and OCN were measured at 2, 4, 24, 48 and 72 h. The data demonstrated the following: (1) The Cbfa1 protein level in fluoride-treated fibroblasts clearly increased at 48 h in the groups treated with 0.0001, 0.001, 0.1, 1.0 and 20.0 mg/L F(-). The Cbfa1 protein level of the group treated with 10 mg/L F(-) at 72 h was higher than that of the control group. The level of Cbfa1 mRNA in the fibroblasts was much higher at 48 h in the group treated with 10.0 mg/L F(-) than in the control group. (2) The OCN protein level in fluoride-treated fibroblasts was significantly higher than that of the control group in the 0.0001, 0.1, 1.0, 10.0 and 20.0 mg/L F(-) groups at 2 h, and in the 0.001 and 0.1 F(-) groups at 4 h. A slightly higher level of OCN mRNA in fluoride-treated fibroblasts was also found in the 1.0 and 20.0 mg/L F(-) groups compared to the control group. (3) The expressions of Cbfa1 and OCN in osteoblasts treated with the same experimental conditions as the fibroblasts were up-regulated by fluoride following the same trend as in the fibroblasts. Our results showed an increase in the expression of Cbfa1 and OCN in fibroblasts and osteoblasts exposed to fluoride and suggested that the osteogenic function of fibroblasts induced by fluoride could play an important role in the development of extraperiosteal ossification during skeletal fluorosis.


Why Henry III of Navarre's Hair Probably did not Turn White Overnight.
Although a rare event, sudden whitening of hair (canities subita) has reportedly affected a number of well-known historical figures, usually in relation to dramatic events in their lives. Although early accounts are substantiated by more recent case reports in scientific literature, we suspect that the phenomenon is not only used as a literary means in fiction, with the aim of dramatizing, but probably also in historical accounts. For this purpose, we examine the case history of Henry III of Navarre who allegedly turned white on the evening of the Saint Bartholomew's day massacre, and challenge this claim, due to inconsistencies in his biography, with the current pathophysiological understanding of canities subita.


The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies.
Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear. A retrospective analysis of two multicentre cohorts was carried out. The effect of pre-existing diabetes on the host immune response, acute organ function and mortality in patients hospitalised with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalisations in the population-based cohort study, Health ABC (n=1639) was determined. Measurements included the mortality rate within the first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumour necrosis factor, interleukin 6, interleukin 10), coagulation (Factor IX, thrombin-antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1 and D-dimer) and cell surface markers (CD120a, CD120b, human leucocyte antigen (HLA)-DR, Toll-like receptor-2 and Toll-like receptor-4). In GenIMS, diabetes increased the mortality rate within the first year after CAP (unadjusted HR 1.41, 95% CI 1.12 to 1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR 1.3, 95% CI 1.03 to 1.65, p=0.02). In Health ABC, diabetes increased the mortality rate within the first year following CAP hospitalisation, but not after hospitalisation for non-infectious illnesses (significant interaction for diabetes and reason for hospitalisation (p=0.04); HR for diabetes on mortality over the first year after CAP 1.87, 95% CI 0.76 to 4.6, p=0.16, and after non-infectious hospitalisation 1.16, 95% CI 0.8 to 1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels, in the emergency department and during the first week. Those with diabetes had a higher risk of acute kidney injury during hospitalisation (39.3% vs 31.7%, p=0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs 26.8% and 10.4% vs 4.5%, p=0.03). Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease.


Two-dimensional fluid with competing interactions exhibiting microphase separation: theory for bulk and interfacial properties.
Colloidal particles that are confined to an interface such as the air-water interface are an example of a two-dimensional fluid. Such dispersions have been observed to spontaneously form cluster and stripe morphologies in certain systems with isotropic pair potentials between the particles, due to the fact that the pair interaction between the colloids has competing attraction and repulsion over different length scales. Here we present a simple density functional theory for a model of such a two-dimensional fluid. The theory predicts a bulk phase diagram exhibiting cluster, stripe, and bubble modulated phases, in addition to homogeneous fluid phases. Comparing with simulation results for this model from the literature, we find that the theory is qualitatively reliable. The model allows for a detailed investigation of the structure of the fluid and we are able to obtain simple approximate expressions for the static structure factor and for the length scale characterizing the modulations in the microphase separated phases. We also investigate the behavior of the system under confinement between two parallel hard walls. We find that the confined fluid phase behavior can be rather complex.


Combining biometric and symbolic models for customized, automated prosthesis design.
In a previous paper [Artif. Intell. Med. 5 (1993) 431] we described RaPiD, a knowledge-based system for designing dental prostheses. The present paper discusses how RaPiD has been extended using techniques from computer vision and logic grammars. The first employs point distribution and active shape models (ASMs) to determine dentition from images of casts of patient's jaws. This enables a design to be customized to, and visualised against, an image of a patient's dentition. The second is based on the notion of a path grammar, a form of logic grammar, to generate a path linking an ordered sequence of subcomponents. The shape of an important and complex prosthesis component can be automatically seeded in this fashion. Combining these models now substantially automates the design process, beginning with a photograph of a dental cast and ending with an annotated and validated design diagram ready to guide manufacture.


Hospital emergency department visits for carbon monoxide poisoning following an October 2006 snowstorm in western New York.
Following an October 2006 snowstorm that caused widespread power outages in western New York State, hospital emergency department (ED) visits for carbon monoxide (CO) poisoning increased. Overall, 264 people representing 155 households were diagnosed with CO poisoning during the power outages. Telephone interviews were conducted with a subset of these individuals. Respondents provided information about exposure sources, CO alarms, and awareness of CO warnings. In many households, portable generators were operated in an enclosed area. Awareness of CO warnings may have contributed to knowledge about locating portable generators outside. When operated outside, however, portable generators were generally located too close to the home. Gas kitchen ranges were used for heat by numerous households. In the short term, CO education and improved clarity of CO warning information is important for increasing awareness about power outage-related CO risks. Improvements in the combustion efficiency of portable generators should be a long-term goal.


Impact of colorectal cancer diagnosis and treatment on health-related quality of life among older Americans: a population-based, case-control study.
Data on health-related quality of life (HRQoL) changes among Americans aged ≥65 following colorectal cancer (CRC) diagnosis and treatment are limited. This study compared HRQoL changes among CRC patients across stages from before to after diagnosis with matched noncancer controls. This population-based study used the Surveillance, Epidemiology, and End Results Medicare Health Outcomes Survey (MHOS) data set (1998-2007). Medicare Advantage beneficiaries diagnosed with CRC between their baseline and follow-up MHOS (n = 349) were matched to noncancer controls (n = 1745) using propensity scores. Mixed-effects analysis of covariance models estimated changes in HRQoL (measured by the Medical Outcomes Study Short Form-36/Veterans RAND 12-item Survey) and the ability to perform 6 activities of daily living (ADLs) between baseline and follow-up. Logistic regression models estimated odds ratios for ADL impairments and major depressive disorder (MDD) risk. Mean time between CRC diagnosis and follow-up MHOS was 12.3 ± 9.8 months. Compared with controls, CRC patients had significantly lower scores in all physical and mental health domains at follow-up. The greatest decrements were observed in physical health and were largely driven by declines in the 6 months postdiagnosis and in stage III and IV patients. At follow-up, CRC patients had greater overall ADL impairment and difficulty with dressing, eating, and getting in/out of chairs. CRC patients, particularly stage IV patients, had greater odds of being at risk for MDD relative to controls. This study further underscores the adverse effects of CRC on physical health and the need to support older Americans' basic self-care needs, with attention to later-stage patients' increased debility.


VHS domains of ESCRT-0 cooperate in high-avidity binding to polyubiquitinated cargo.
VHS (Vps27, Hrs, and STAM) domains occur in ESCRT-0 subunits Hrs and STAM, GGA adapters, and other trafficking proteins. The structure of the STAM VHS domain-ubiquitin complex was solved at 2.6 A resolution, revealing that determinants for ubiquitin recognition are conserved in nearly all VHS domains. VHS domains from all classes of VHS-domain containing proteins in yeast and humans, including both subunits of ESCRT-0, bound ubiquitin in vitro. ESCRTs have been implicated in the sorting of Lys63-linked polyubiquitinated cargo. Intact human ESCRT-0 binds Lys63-linked tetraubiquitin 50-fold more tightly than monoubiquitin, though only 2-fold more tightly than Lys48-linked tetraubiquitin. The gain in affinity is attributed to the cooperation of flexibly connected VHS and UIM motifs of ESCRT-0 in avid binding to the polyubiquitin chain. Mutational analysis of all the five ubiquitin-binding sites in yeast ESCRT-0 shows that cooperation between them is required for the sorting of the Lys63-linked polyubiquitinated cargo Cps1 to the vacuole.


NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference.
Plasticity of the brain's dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1(D1CreERT2) mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1(D1CreERT2) mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general.


The C-terminal region of an Apg7p/Cvt2p is required for homodimerization and is essential for its E1 activity and E1-E2 complex formation.
Apg7p/Cvt2p, a protein-activating enzyme, is essential for both the Apg12p-Apg5p conjugation system and the Apg8p membrane targeting in autophagy and cytoplasm-to-vacuole targeting in the yeast Saccharomyces cerevisiae. Similar to the ubiquitin-conjugating system, both Apg12p and Apg8p are activated by Apg7p, an E1-like enzyme. Apg12p is then transferred to Apg10p, an E2-like enzyme, and conjugated with Apg5p, whereas Apg8p is transferred to Apg3p, another E2-like enzyme, followed by conjugation with phosphatidylethanolamine. Evidence is presented here that Apg7p forms a homodimer with two active-site cysteine residues via the C-terminal region. The dimerization of Apg7p is independent of the other Apg proteins and facilitated by overexpressed Apg12p. The C-terminal 123 amino acids of Apg7p (residues 508 to 630 out of 630 amino acids) are sufficient for its dimerization, where there is neither an ATP binding domain nor an active-site cysteine essential for its E1 activity. The deletion of its carboxyl 40 amino acids (residues 591-630 out of 630 amino acids) results in several defects of not only Apg7p dimerization but also interactions with two substrates, Apg12p and Apg8p and Apg12p-Apg5p conjugation, whereas the mutant Apg7p contains both an ATP binding domain and an active-site cysteine. Furthermore, the carboxyl 40 amino acids of Apg7p are also essential for the interaction of Apg7p with Apg3p to form the E1-E2 complex for Apg8p. These results suggest that Apg7p forms a homodimer via the C-terminal region and that the C-terminal region is essential for both the activity of the E1 enzyme for Apg12p and Apg8p as well as the formation of an E1-E2 complex for Apg8p.


Thermodynamic Stability of Volatile Droplets and Thin Films Governed by Disjoining Pressure in Open and Closed Containers.
Distributed thin films of water and their coexistence with droplets are investigated using a capillary description based on a thermodynamic fundamental relation for the film Helmholtz energy, derived from disjoining pressure isotherms and an accurate equation of state. Gas-film and film-solid interfacial tensions are derived, and the latter has a dependence on film thickness. The resulting energy functionals from the capillary description are discretized, and stationary states are identified. The thermodynamic stability of configurations with thin films in systems that are closed (canonical ensemble) or connected to a particle reservoir (grand canonical ensemble) is evaluated by considering the eigenvalues of the corresponding Hessian matrices. The conventional stability criterion from the literature states that thin flat films are stable when the derivative of the disjoining pressure with respect to the film thickness is negative. This criterion is found to apply only in open systems. A closer inspection of the eigenvectors of the negative eigenvalues shows that condensation/evaporation destabilizes the film in an open system. In closed systems, thin films can be stable even though the disjoining pressure derivative is positive, and their stability is governed by mechanical instabilities of a similar kind to those responsible for spinodal dewetting in nonvolatile systems. The films are stabilized when their thickness and disjoining pressure derivative are such that the minimum unstable wavelength is larger than the container diameter. Droplets in coexistence with thin films are found to be unstable for all considered examples in open systems. In closed systems, they are found to be stable under certain conditions. The unstable droplets in both open and closed systems are saddle points in their respective energy landscapes. In the closed system, they represent the activation barrier for the transition between a stable film and a stable droplet. In the open system, the unstable droplets represent the activation barrier for the transition from a film into a bulk liquid phase. Thin films are found to be the equilibrium configuration up to a certain value of the total density in a closed system. Beyond this value, there is a morphological phase transition to stable droplet configurations.


A previously unobserved conformation for the human Pex5p receptor suggests roles for intrinsic flexibility and rigid domain motions in ligand binding.
The C-terminal tetratricopeptide (TPR) repeat domain of Pex5p recognises proteins carrying a peroxisomal targeting signal type 1 (PTS1) tripeptide in their C-terminus. Previously, structural data have been obtained from the TPR domain of Pex5p in both the liganded and unliganded states, indicating a conformational change taking place upon cargo protein binding. Such a conformational change would be expected to play a major role both during PTS1 protein recognition as well as in cargo release into the peroxisomal lumen. However, little information is available on the factors that may regulate such structural changes. We have used a range of biophysical and computational methods to further analyse the conformational flexibility and ligand binding of Pex5p. A new crystal form for the human Pex5p C-terminal domain (Pex5p(C)) was obtained in the presence of Sr2+ ions, and the structure presents a novel conformation, distinct from all previous liganded and apo crystal structures for Pex5p(C). The difference relates to a near-rigid body movement of two halves of the molecule, and this movement is different from that required to reach a ring-like conformation upon PTS1 ligand binding. The bound Sr2+ ion changes the dynamic properties of Pex5p(C) affecting its conformation, possibly by making the Sr2+-binding loop - located near the hinge region for the observed domain motions - more rigid. The current data indicate that Pex5p(C) is able to sample a range of conformational states in the absence of bound PTS1 ligand. The domain movements between various apo conformations are distinct from those involved in ligand binding, although the differences between all observed conformations so far can be characterised by the movement of the two halves of Pex5p(C) as near-rigid bodies with respect to each other.


The presence of neurological soft signs along the psychosis proneness continuum.
Neurological soft signs have been observed in patients with schizophrenia and their relatives. However, it has not been considered whether the increased rates of neurological soft signs are related to measures of psychosis proneness in the general population. We tested this hypothesis in a group of normal volunteers (n = 28) who scored highly for positive schizotypy when assessed online and a control group (n = 33) who scored below the mean. Compared with the controls, high psychosis-prone individuals showed significantly higher Total and Other Soft Signs subscale scores on the Neurological Evaluation Scale. It appears that soft signs are also associated with psychosis proneness when measured in the general population, which suggests that soft signs are distributed along a continuum of risk for schizophrenia.


Performance of third-generation confirmatory tests for detection of antibody to hepatitis C virus.
We investigated three immunoblot assays (RIBA 3.0 from Chiron, Matrix from Abbott Laboratories, and LiaTek III from Organon Teknika) for the detection of antibody to hepatitis C virus. RIBA 3.0 and Matrix require reactivity to two antigens and LiaTek III requires reactivity to one for a sample to be positive. We tested 80 samples that were positive in repeat enzyme immunoassays by supplemental tests. The results showed that 55, 46, and 28% were reactive by LiaTek III, RIBA 3.0, and Matrix, respectively; 54, 33, and 13% of the samples were indeterminate by Matrix, RIBA 3.0, and LiaTek III, respectively. There were 32, 21, and 16% nonreactive samples by LiaTek III, RIBA 3.0, and Matrix, respectively. Of the samples positive by RIBA 3.0, only 50 and 76% were reactive by Matrix and LiaTek III, respectively. A large number of samples that were indeterminate by RIBA 3.0 were positive by LiaTek III (52%). The core antigen was the most reactive antigen in all three tests (48 to 57%). The NS4 antigen in Matrix (20%) and LiaTek III (16%) was poorly reactive, although it performed better in RIBA 3.0 (45%). The NS5 and E2/NS1 antigens made minor contributions to reactivity. The combinations of the core, NS3, and NS4 antigens produced 77% of the RIBA 3.0 and 100% of the Matrix reactive samples. The results showed a poor correlation among the three tests.


COULD OZONE TREATMENT BE A PROMISING ALTERNATIVE FOR OSTEOMYELITIS? AN EXPERIMENTAL STUDY.
The aim of the present study was to investigate the biochemical and histopathological impact of ozone treatment in an experimental model of osteomyelitis in rats. A total of 24 adult male Sprague-Dawley rats (3 months old, each weighing 300 to 400 g) were randomly allocated into three groups. Group I (n=8) served as a control and received no interventions or medications. In Group II (n=8), osteomyelitis was induced in the femur and no treatment was applied. Group III (n=8) received intraperitoneal ozone treatment for 3 weeks after the formation of osteomyelitis in the femur. Serum samples were taken to assess total antioxidant capacity (TAC), protein carbonyl content (PCO), and lactate dehydrogenase (LDH). Bone specimens obtained from the femur were histopathologically evaluated for inflammation, necrosis, osteomyelitis, and abscess formation. Serum TAC levels were notably higher (p<0.001), while LDH levels were lower (p=0.002) in Group III than Group II. No significant difference was detected between groups with respect to PCO level. Similarly, Group III displayed more favorable histopathological outcomes with respect to osteomyelitis (p=0.008), inflammation (p=0.001), necrosis (p=0.022), and abscess formation (p=0.022). Ozone may be a useful adjunct treatment for osteomyelitis. Further studies in animals and humans are needed to clarify and confirm these preventive effects, understand the underlying pathophysiology, and establish guidelines. Level of Evidence II; Prospective comparative study.


Audiologic Consequences of Gunshot Wounds to the Temporal Bone Show No Relation to Concomitant Neurologic or Vascular Injuries.
To evaluate audiologic consequences of gunshot wounds (GSWs) to the temporal bone (TB), and to correlate hearing outcomes with neurologic and vascular injuries adjacent to the temporal bone. Retrospective case series. University-based level-one trauma center. Retrospective review of 35 patients surviving TB ballistic injury, 2012 to 2021. Main outcomes were audiologic results. Demographics, concomitant injuries, CT, and interventions were reviewed. Mean age was 30.7 years; 80% male. Seventeen patients (48.6%) underwent audiologic testing. Mean pure tone average (PTA) was 75 ± 35 dB, bone line average 41 ± 26 dB, and speech discrimination score (SDS) 60 ± 43%. Nineteen (54.3%) demonstrated facial nerve injury (FNI), who were more likely to show SNHL especially anacusis, though their mean PTA and SDS were not statistically different from those without (P = .30 and .47, respectively). Radiographic review of those with sensorineural loss (SNHL, 6/17) revealed otic capsule-disrupting fracture (n = 2), pneumolabyrinth (n = 2), intracranial hemorrhage (n = 3). Those with mixed loss (6/17) showed otic capsule-sparing fracture (n = 6), EAC injury (n = 5), ossicular discontinuity (n = 2), and intracranial hemorrhage (n = 4). Two with mastoid tip fractures alone had normal audiograms. Audiometric outcomes were not predicted by concomitant CSF leak, spinal injuries, vascular injuries, cranial neuropathies, or traumatic brain injury. All patterns of hearing loss-conductive, sensorineural, mixed and normal-may be seen following TB ballistic injuries. Trauma severe enough to disrupt the facial nerve is more likely to cause anacusis. However, all should be formally evaluated, since ballistic injuries complicated by neurologic or vascular damage do not necessarily correlate with worse audiologic outcomes, while patients with minimal fractures may demonstrate losses.


Imaging the effects of rTMS-induced cortical plasticity.
Repetitive Transcranial Magnetic Stimulation (rTMS) paradigms are showing increasing promise as tools for neurorehabilitation in a variety of chronic neurological and psychiatric conditions. However, the mechanisms by which they modulate cortical activation are still not completely understood. In this review we summarize what non-invasive magnetic resonance imaging techniques can tell us about the cortical effects of rTMS - from changes at a cellular level within the stimulated motor cortex, to modulating activation patterns within the wider motor network. We discuss how variation in these effects in stroke patients may inform our understanding of how rTMS could improve function in these patients.


Using a virtual patient activity to teach nurse prescribing.
The Faculty of Health and Social Care Sciences at Kingston University/St George's University of London (KU/SGUL) provides a module to train registered nurses to qualify as independent nurse prescribers. During the programme the participants engage in an online learning activity using a virtual patient (VP). The aim of this VP activity is to enable students to consolidate their learning and to practice the range of skills that the students have been developing related to prescribing. The activity was designed by the module leader and was run as a pilot on two groups of students (n = 34). An evaluative study was undertaken on the value of this blended learning activity to the student and their prescribing practice. This paper presents the development, implementation and evaluation of the VP activity. Findings showed that the VP activity was perceived as being particular useful for helping them to learn the skills of patient history/assessment, decision-making and prescription writing. The VP was also perceived as being helpful in developing their confidence.


Proposal for a Candidate Core Set of Fitness and Strength Tests for Patients with Childhood or Adult Idiopathic Inflammatory Myopathies.
Currently there are no evidence-based recommendations regarding fitness and strength tests for patients with childhood or adult idiopathic inflammatory myopathies (IIM). This hinders clinicians and researchers in choosing the appropriate fitness- or muscle strength-related outcome measures for these patients. Through a Delphi survey, we aimed to identify a candidate core set of fitness and strength tests for children and adults with IIM. Fifteen experts participated in a Delphi survey that consisted of 5 stages to achieve a consensus. Using an extensive search of published literature and through the work of experts, a candidate core set based on expert opinion and clinimetrics properties was developed. Members of the International Myositis Assessment and Clinical Studies Group were invited to review this candidate core set during the final stage, which led to a final candidate core set. A core set of fitness- and strength-related outcome measures was identified for children and adults with IIM. For both children and adults, different tests were identified and selected for maximal aerobic fitness, submaximal aerobic fitness, anaerobic fitness, muscle strength tests, and muscle function tests. The core set of fitness- and strength-related outcome measures provided by this expert consensus process will assist practitioners and researchers in deciding which tests to use in patients with IIM. This will improve the uniformity of fitness and strength tests across studies, thereby facilitating the comparison of study results and therapeutic exercise program outcomes among patients with IIM.


ACA dependent coverage provision reduced high out-of-pocket health care spending for young adults.
Since September 2010 the Affordable Care Act (ACA) has required that insurers allow children to remain as dependents on their parents' private insurance plans until age twenty-six. Studies have shown that this provision increased coverage rates among young adults. In this article we analyze whether the provision also protected young adults from large and uncertain out-of-pocket expenses. We found that the policy was associated with a statistically significant reduction in the share of young adults facing annual out-of-pocket expenditures greater than $1,500 (decreasing from 4.2 percent to 2.9 percent), compared to an increase in the proportion of their slightly older peers facing such expenditures (increasing from 4.4 percent to 5.4 percent), a net difference of -2.4 percentage points, or 57 percent. We conclude that the dependent coverage provision in the ACA provides financial protection for young adults at a time when they often face high debt burden but low wages.


Utility of the initial therapeutic alliance in evaluating psychiatric patients' risk of violence.
Evaluation of patients' potential for violence is an important component of care in psychiatric emergency and inpatient settings. Although situational variables are widely acknowledged to influence the risk of violence by psychiatric patients, most past research has been limited to patient attributes and has neglected the interpersonal context in which violence occurs. To the authors' knowledge, this is the first study to assess a new type of situational risk factor, the quality of the initial therapeutic alliance between the therapist and patient, as a predictor of the risk of violent behavior during short-term hospitalization. The admitting physician's written initial evaluation for each of 328 patients hospitalized on a locked inpatient unit was reviewed by using a standardized alliance scale. The checklist measures the patient's level of active collaboration with the treatment process. Acute symptoms were rated at admission by physicians using the Brief Psychiatric Rating Scale. Nurses rated aggressive behavior in the hospital with the Overt Aggression Scale. Patients who had a poorer therapeutic alliance at the time of admission were significantly more likely to display violent behavior during hospitalization. Logistic regression analysis showed that the quality of the initial therapeutic alliance remained a strong predictor of violence even when other clinical and demographic correlates of violence were considered concurrently. The results suggest a new class of situational, interactional variable--reflected in the quality of the therapeutic relationship--that may be useful in evaluating patients' potential for violence. Implications for risk management are discussed.


Expression of Thy-1 on human hematopoietic progenitor cells.
Expression of Thy-1 on hematopoietic cells from human fetal liver (FL), cord blood (CB), and bone marrow (BM) was studied with a novel anti-Thy-1 antibody, 5E10. Specificity of 5E10 for human Thy-1 was demonstrated by immunoprecipitation of a 25-35-kD molecule, and the sequence of a cDNA that was cloned by immunoselection of COS cells transfected with a cDNA library derived from a 5E10+ cell line. Two- and three-color immunofluorescence staining experiments revealed that the Thy-1 expression is restricted to, an average, 1-4% of FL, CB, and BM cells, and binding to these cell types is essentially restricted to a very small subset of lymphoid cells and approximately 25% of CD34+ cells. Thy-1+ CD34+ cells were further characterized as CD38lo/CD45RO+/CD45RA-/CD71lo/c-kit(lo) and rhodamine 123dull. When CD34+ cells were sorted on the basis of Thy-1 expression, the majority of clonogenic cells were recovered in the CD34+Thy-1- fraction, whereas the majority of cells capable of producing myeloid colonies after 5-8 wk of long-term culture (long-term culture initiating cells) were recovered in the Thy-1+CD34+ fraction. In addition to CD34+ cells, Thy-1 was found to be expressed on a variable, very small number (< 1%) of CD34- mononuclear cells in BM, CB, and peripheral blood that were further characterized as CD3+ CD4+ lymphocytes. The restricted expression of Thy-1 on primitive hematopoietic cells is in agreement with a previous report (Baum et al., 1992. Proc. Natl. Acad. Sci. USA. 89:2804) in which Thy-1 expression was used to enrich for primitive hematopoietic cells from fetal tissue. Compared with those previous studies, we found Thy-1 expression on a larger proportion of CD34+ cells (25% in our study vs. 5% in Baum et al.) and furthermore performed studies on Thy-1 expression on CD34+ cells from CB, FL, and BM in relation to markers that are known to be differentially expressed on hematopoietic cells. Taken together our results indicate that Thy-1-specific antibody 5E10 is an attractive tool for further studies on the biology and purification of human stem cells.


Preparation of disodium fluorescein powders in association with lauric and capric acids.
In previous studies micronized disodium fluorescein (DF) powders were coated with lauric or capric acid. This was a precursor to evaluating the effects of the fatty acids on the hygroscopic growth of the DF aerosols. Studies of the association of fatty acids with DF reflected a limited interpretation of the data obtained. The present study examines more closely the phenomena involved in coating the DF. It is concluded that lateral interactions due to the hydrophobic aliphatic tails of the fatty acids give rise to adsorption, aggregation, and flocculation, all of which cause inflections in the association isotherm rendering it nonlinear.


Lipodisqs for eukaryote lipidomics with retention of viability: Sensitivity and resistance to Leucobacter infection linked to C.elegans cuticle composition.
Lipodisq™ nanoparticles have been used to extract surface lipids from the cuticle of two strains (wild type, N2 and the bacteria-resistant strain, agmo-1) of the C. elegans nematode without loss of viability. The extracted lipids were characterized by thin layer chromatography and MALDI-TOF-MS. The lipid profiles differed between the two strains. The extracted lipids from the bacteria-resistant strain, agmo-1, contained ether-linked (O-alkyl chain) lipids, in contrast to the wild-type strain which contained exclusively ester- linked (O-acyl) lipids. This observation is consistent with the loss of a functional alkylglycerol monooxygenase (AGMO) in the bacterial resistant strain agmo-1. The presence and abundance of other lipid species also differs between the wild-type N2 and agmo-1 nematodes, suggesting that the agmo-1 mutant strain attempts to compensate for the increase in ether-linked lipids by modulating other lipid-synthesis pathways. Together these differences not only affect the fragility of the cuticle and the buoyancy of the worm in aqueous buffer, but also interactions with surface-adhering bacteria. The much greater chemical stability of O-alkyl, non-hydrolysable linked lipids compared with hydrolysable O-acyl linked lipids, may be the origin of the resistance of the agmo-1 strain to bacterial infection, providing a more resilient cuticle for the nematode. Additionally, we show that lipid extraction with a polymer of styrene and maleic acid (SMA) provides a viable route to lipidomics studies with minimal perturbation of the organism.


Peripheral vascular endothelial function in patients with hypertrophic cardiomyopathy.
Patients with hypertrophic cardiomyopathy (HC) have coronary microvascular dysfunction, which is an independent predictor of adverse left ventricular remodeling, systolic dysfunction, and mortality in these patients. Whether these defects in vasomotor function are localized to the coronary arteries or whether systemic vasomotor dysfunction is present in patients with HC has not yet been adequately examined. The aim of this study was to test the hypothesis that patients with HC have altered peripheral vascular endothelial function. Subjects without coronary artery disease (CAD) and those with CAD served as negative and positive controls, respectively. Conduit artery endothelium-dependent vasomotion was assessed with ultrasound by measuring flow-mediated dilation of the brachial artery. Flow-mediated dilation was lower in patients with HC compared with those without CAD (p <0.05) but was similar in patients with CAD (p = NS). In conclusion, vasomotor dysfunction in HC is not restricted to the coronary vasculature. Patients with HC have impaired peripheral conduit vessel endothelial function, and the magnitude of impairment is similar to that seen in older patients with advanced CAD.


Fiber-integrated frequency-doubling of a picosecond Raman laser to 560 nm.
We report the development of a fiber-integrated picosecond source at 560 nm by second harmonic generation of a Raman fiber laser. A picosecond ytterbium master oscillator power fiber amplifier is used to pulse-pump a Raman amplifier, which is seeded by a continuous wave distributed feedback laser diode operating at 1120 nm. The pulse train generated at 1120 nm is frequency-doubled in a fiber-coupled periodically-poled lithium niobate crystal module, producing 450 mW of average power at 560 nm with a pulse duration of 150 ps at a repetition rate of 47.5 MHz. The near diffraction-limited (M(2) = 1.02) collimated output beam is ideal for super-resolution microscopy applications.


Adsorption of peptides (A3, Flg, Pd2, Pd4) on gold and palladium surfaces by a coarse-grained Monte Carlo simulation.
Monte Carlo simulations are performed to study adsorption and desorption of coarse-grained peptide chains on generic gold and palladium surfaces in the presence of solvent. The atomistic structural details are ignored within the amino acid residues; however, their specificity and hydrophobicity are incorporated via an interaction matrix guided by atomistic simulation. Adsorption probabilities of the peptides A3, Flg, Pd2, Pd4, Gly10, Pro10 on gold and palladium surfaces are studied via analysis of the mobility of each residue, the interaction energy with the surface, profiles of the proximity to the surface, the radius of gyration, and comparisons to homopolymers. In contrast to the desorption of Gly10 and Pro10 (with faster global dynamics), peptides Pd2, Pd4, Flg, and A3 exhibit various degrees of adsorption on gold and palladium surfaces (with relatively slower dynamics). Adsorption on both gold and palladium occurs through aromatic anchoring residues Tyr2 and Phe12 in A3, Tyr2 in Flg, Phe2, His10 and His12 in Pd2, and His6 and His11 in Pd4. A lower (more negative) surface-interaction energy of these residues and lower mobility on palladium lead us to conclude that they are slightly more likely to be adsorbed on palladium surfaces than on gold.


Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression.
Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology. The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety. However, submaximal dosages of amitriptyline and maprotiline were used in these studies. Preliminary evidence suggests that tianeptine may also be effective in patients with endogenous depression. Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups. Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia. The overall anxiolytic properties of tianeptine in patients with coexisting depression and anxiety appear to be similar to those of amitriptyline, imipramine and fluoxetine and may be superior to those of maprotiline, although submaximal dosages of amitriptyline and maprotiline were used. Studies of tianeptine in patients with primary anxiety have not been conducted. Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. The incidence of dry mouth (38 vs 20%), constipation (19 vs 15%), dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%) and postural hypotension (8 vs 3%) are greater with amitriptyline than with tianeptine. Insomnia and nightmares occur in more tianeptine than amitriptyline recipients (20 vs 7%). The relative lack of sedative, anticholinergic and cardiovascular adverse effects with tianeptine makes it particularly suitable for use in the elderly and in patients following alcohol withdrawal; these patients are known to have increased sensitivity to the adverse effects associated with psychotropic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)


The Use of Cannabinoids in Colitis: A Systematic Review and Meta-Analysis.
Clinical trials investigating the use of cannabinoid drugs for the treatment of intestinal inflammation are anticipated secondary to preclinical literature demonstrating efficacy in reducing inflammation. We systematically reviewed publications on the benefit of drugs targeting the endo-cannabinoid system in intestinal inflammation. We collated studies examining outcomes for meta-analysis from EMBASE, MEDLINE and Pubmed until March 2017. Quality was assessed according to mSTAIR and SRYCLE score. From 2008 papers, 51 publications examining the effect of cannabinoid compounds on murine colitis and 2 clinical studies were identified. Twenty-four compounds were assessed across 71 endpoints. Cannabidiol, a phytocannabinoid, was the most investigated drug. Macroscopic colitis severity (disease activity index [DAI]) and myeloperoxidase activity (MPO) were assessed throughout publications and were meta-analyzed using random effects models. Cannabinoids reduced DAI in comparison with the vehicle (standard mean difference [SMD] -1.36; 95% CI, -1.62 to-1.09; I2 = 61%). FAAH inhibitor URB597 had the largest effect size (SMD -4.43; 95% CI, -6.32 to -2.55), followed by the synthetic drug AM1241 (SMD -3.11; 95% CI, -5.01 to -1.22) and the endocannabinoid anandamide (SMD -3.03; 95% CI, -4.89 to -1.17; I2 not assessed). Cannabinoids reduced MPO in rodents compared to the vehicle; SMD -1.26; 95% CI, -1.54 to -0.97; I2 = 48.1%. Cannabigerol had the largest effect size (SMD -6.20; 95% CI, -9.90 to -2.50), followed by the synthetic CB1 agonist ACEA (SMD -3.15; 95% CI, -4.75 to -1.55) and synthetic CB1/2 agonist WIN55,212-2 (SMD -1.74; 95% CI, -2.81 to -0.67; I2 = 57%). We found no evidence of reporting bias. No significant difference was found between the prophylactic and therapeutic use of cannabinoid drugs. There is abundant preclinical literature demonstrating the anti-inflammatory effects of cannabinoid drugs in inflammation of the gut. Larger randomised controlled-trials are warranted.


Role of surface plasmon resonant modes in anomalous terahertz transmission through double-layer metal loop arrays.
A three-layer construction was proposed to induce anomalous transmission response for a normal incidence of terahertz (THz) wave. This structure was composed of a dielectric layer of quartz and two metallic layers, which were deposited on the two surfaces of quartz and patterned the same periodic arrays of subwavelength air circular loop. Based on comparative analyses of dispersion relations of both the structure and its partial structures, propagating surface plasmon and localized surface plasmon principally dominated the lower and higher resonant peaks appearing in the calculated transmittance spectrum, respectively. A sample was fabricated by laser technology for experiment and the measured THz transmission showed a good agreement with simulation, providing reference for potential applications.