Recurrent Neural Network for Computing Outer Inverse.
Two linear recurrent neural networks for generating outer inverses with prescribed range and null space are defined. Each of the proposed recurrent neural networks is based on the matrix-valued differential equation, a generalization of dynamic equations proposed earlier for the nonsingular matrix inversion, the Moore-Penrose inversion, as well as the Drazin inversion, under the condition of zero initial state. The application of the first approach is conditioned by the properties of the spectrum of a certain matrix; the second approach eliminates this drawback, though at the cost of increasing the number of matrix operations. The cases corresponding to the most common generalized inverses are defined. The conditions that ensure stability of the proposed neural network are presented. Illustrative examples present the results of numerical simulations.


CD31 signals confer immune privilege to the vascular endothelium.
Constitutive resistance to cell death induced by inflammatory stimuli activating the extrinsic pathway of apoptosis is a key feature of vascular endothelial cells (ECs). Although this property is central to the maintenance of the endothelial barrier during inflammation, the molecular mechanisms of EC protection from cell-extrinsic, proapoptotic stimuli have not been investigated. We show that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent EC death induced by TNF-α and cytotoxic T lymphocytes in vitro. Combined quantitative RT-PCR array and biochemical analysis show that, upon the engagement of the TNF receptor with TNF-α on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-α via activation of the Erk/Akt pathway. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar. Both CD31 intracellular immunoreceptor tyrosine-based inhibition motifs are required for its prosurvival function. In vivo, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31(-) pancreatic β cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.


A sibling death in the family: common and consequential.
Although a large literature analyzes the determinants of child mortality and suggests policy and medical interventions aimed at its reduction, there is little existing analysis illuminating the consequences of child mortality for other family members. In particular, there is little evidence exploring the consequences of experiencing the death of a sibling on one's own development and transition to adulthood. This article examines the prevalence and consequences of experiencing a sibling death during one's childhood using two U.S. data sets. We show that even in a rich developed country, these experiences are quite common, affecting between 5 % and 8 % of the children with one or more siblings in our two data sets. We then show that these experiences are associated with important reductions in years of schooling as well as a broad range of adult socioeconomic outcomes. Our findings also suggest that sisters are far more affected than brothers and that the cause of death is an important factor in sibling effects. Overall, our findings point to important previously unexamined consequences of child mortality, adding to the societal costs associated with childhood mortality as well as suggesting additional benefits from policy and medical innovations aimed at curbing both such deaths and subsequent effects on family members.


Improving communication with families in the intensive care unit.
Families ('family' will be used in this article to refer to anyone the patient considers significant, whether they are an actual family member or not) of patients who are critically ill have heightened communication needs. Nurses are an important source of information, particularly about day-to-day patient events and progress. Intensive care unit (ICU) nurses are valued by families because they provide clear, jargon-free information about the patient and their condition. However, they have sometimes been criticised for focusing on short-term issues while avoiding potentially difficult conversations about long-term outcomes and prognosis. A family conference or meeting is held when bad news has to be communicated to families, prognosis discussed or major decisions made, particularly about treatment withdrawal or resuscitation. These meetings should involve physicians and ICU nurses. Despite family conferences, family members' understanding of patient prognosis, diagnosis and treatment is often suboptimal. A planned and structured approach for these meetings, using quantitative statements for prognostic information, recording and communicating what has been said, and supporting meetings with written information, can improve their effectiveness. These supportive strategies increase understanding and consensus, and prevent the provision of conflicting information. It is important for nurses to be willing to follow up these meetings by supporting families to clarify their understanding and encouraging them to raise concerns and ask questions.


The RNA binding protein hnRNP Q modulates the utilization of exon 7 in the survival motor neuron 2 (SMN2) gene.
Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The human SMN2 gene has a C-to-T transition at position +6 of exon 7 and thus produces exon 7-skipping mRNAs. However, we observed an unexpectedly high level of exon 7-containing SMN2 transcripts as well as SMN protein in testis of smn(-/-) SMN2 transgenic mice. Using affinity chromatography, we identified several SMN RNA-associating proteins in mouse testis and human HeLa cells, including hnRNP Q. The major hnRNP Q isoform, Q1, directly bound SMN exon 7 in the vicinity of nucleotide +6. Overexpression of hnRNP Q1 promoted the inclusion of exon 7 in SMN2, probably by activating the use of its upstream 3' splice site. However, the minor isoforms Q2/Q3 could antagonize the activity of hnRNP Q1 and induced exon 7 exclusion. Intriguingly, enhanced exon 7 inclusion was also observed upon concomitant depletion of three hnRNP Q isoforms. Thus, differential expression of hnRNP Q isoforms may result in intricate control of SMN precursor mRNA splicing. Here, we demonstrate that hnRNP Q is a splicing modulator of SMN, further underscoring the potential of hnRNP Q as a therapeutic target for SMA.


Urine Metabolite Profiles and Nutrient Intake Based on 4-Day Weighed Food Diary in Habitual Vegans, Vegetarians, and Omnivores.
Increasing interest in diets excluding meat and other products of animal origin emphasizes the importance of objective and reliable methods to measure dietary exposure, to evaluate associations and causation between diet and health, and to quantify nutrient intakes in different diets. This study aimed to investigate if NMR analysis of urine samples can serve as an objective method to discriminate vegan, vegetarian with or without fish, and omnivore diets. A secondary aim was to assess the influence of dietary nutrient intake on the metabolomics results. Healthy individuals (43 men and 75 women, age 19-57 y) complying with habitual vegan (n = 42), vegetarian (n = 25), vegetarian + fish (n = 13), or omnivore (n = 38) diets were enrolled. Data were collected on clinical phenotype and lifestyle including a 4-d weighed food diary. Urine was analyzed for metabolites by NMR spectroscopy and data normalized using probabilistic quotient normalization and Pareto-scaled before multivariate analysis. Before orthogonal projections to latent structures with discriminant analysis, participants were assigned as meat consumers or nonmeat consumers (vegans and vegetarians), vegans or nonvegans (omnivores, vegetarian, and vegetarian + fish). The main results showed that it was possible to discriminate meat and nonmeat consumers (91% correctly classified), but discrimination between vegans and nonvegans was less rigorous (75% correctly classified). Secondary outcomes showed that reported intake of protein was higher in omnivores, and saturated fat lower and fiber higher in vegans, compared with the other groups. Discriminating metabolites were mainly related to differences in protein intake. NMR urine metabolomics appears suitable to objectively identify and predict habitual intake of meat in healthy individuals, but results should be interpreted with caution because not only food groups but also specific foods contribute to the patterns.This trial was registered at clinicaltrials.gov as NCT02039609.


One-step fabrication of supramolecular microcapsules from microfluidic droplets.
Although many techniques exist for preparing microcapsules, it is still challenging to fabricate them in an efficient and scalable process without compromising functionality and encapsulation efficiency. We demonstrated a simple one-step approach that exploits a versatile host-guest system and uses microfluidic droplets to generate porous microcapsules with easily customizable functionality. The capsules comprise a polymer-gold nanoparticle composite held together by cucurbit[8]uril ternary complexes. The dynamic yet highly stable micrometer-sized structures can be loaded in one step during capsule formation and are amenable to on-demand encapsulant release. The internal chemical environment can be probed with surface enhanced Raman spectroscopy.


Denoising scanner effects from multimodal MRI data using linked independent component analysis.
Pooling magnetic resonance imaging (MRI) data across research studies, or utilizing shared data from imaging repositories, presents exceptional opportunities to advance and enhance reproducibility of neuroscience research. However, scanner confounds hinder pooling data collected on different scanners or across software and hardware upgrades on the same scanner, even when all acquisition protocols are harmonized. These confounds reduce power and can lead to spurious findings. Unfortunately, methods to address this problem are scant. In this study, we propose a novel denoising approach that implements a data-driven linked independent component analysis (LICA) to identify scanner-related effects for removal from multimodal MRI to denoise scanner effects. We utilized multi-study data to test our proposed method that were collected on a single 3T scanner, pre- and post-software and major hardware upgrades and using different acquisition parameters. Our proposed denoising method shows a greater reduction of scanner-related variance compared with standard GLM confound regression or ICA-based single-modality denoising. Although we did not test it here, for combining data across different scanners, LICA should prove even better at identifying scanner effects as between-scanner variability is generally much larger than within-scanner variability. Our method has great promise for denoising scanner effects in multi-study and in large-scale multi-site studies that may be confounded by scanner differences.


Pathological and Molecular Characterization of Xanthomonas campestris Strains Causing Diseases of Cassava (Manihot esculenta).
Fifty-one strains representing Xanthomonas campestris pv. manihotis and cassavae and different pathovars occurring on plants of the family Euphorbiaceae were characterized by ribotyping with a 16S+23S rRNA probe of Escherichia coli and by restriction fragment length polymorphism analysis with a plasmid probe from X. campestris pv. manihotis. Pathogenicity tests were performed on cassava (Manihot esculenta). Histological comparative studies were conducted on strains of two pathovars of X. campestris (vascular and mesophyllic) that attack cassava. Our results indicated that X. campestris pv. manihotis and cassavae have different modes of action in the host and supplemented the taxonomic data on restriction fragment length polymorphism that clearly separate the two pathovars. The plasmid probe could detect multiple restriction fragment length polymorphisms among strains of the pathovar studied. Ribotyping provides a useful tool for rapid identification of X. campestris pathovars on cassava.


Epidemiology of burn-related fatalities in Australia and New Zealand, 2009-2015.
Knowledge of the epidemiology of burn-related fatalities is limited, with most previous studies based on hospital and burn centre data only. To describe the epidemiological characteristics of all burn-related fatalities in Australia and New Zealand, and to identify any trends in burn-related fatality incidence over the study period. Data from the National Coronial Information System, including data for pre-hospital and in-hospital burn-related fatality cases, was used to examine the characteristics of burn-related fatalities occurring in Australia and New Zealand from 2009 to 2015. Burn-related fatality rates per 100,000 population were estimated, and incidence trends assessed using Poisson regression analysis. Of the 310 burn-related fatalities that occurred in Australia and New Zealand, 2009-2015, 41% occurred in a pre-hospital setting. Overall, most burn-related fatality cases were fire related, occurred at home, and were of people aged 41-80 years. One quarter of all burn-related fatalities were a result of intentional self-harm. The population incidence of all burn-related fatalities combined, and for NSW, decreased over the study period. This study has identified the importance of examining all burn-related fatalities. If this is not done, vulnerable population subgroups will be missed and prevention efforts poorly targeted.


Osteocytes and Homeostasis of Remote Organs : Bone-Buried Osteocytes Talk to Remote Organs.
The study of bones has attracted researchers from many medical fields. To understand bone-organ interactions, hematologists were challenged to investigate bone marrow (BM), the core of bone where hematopoiesis takes place. Through studies of the hematopoietic stem cells niche, hematologists contributed to the discovery of unexpected functions of bone-forming osteoblasts and bone-buried osteocytes. In particular, the recent findings about osteocytes, as the regulatory system of lympho-hematopoiesis and fat metabolism, highlighted the central role of skeletal tissue in inter-organ communication. The cross-cutting consideration including hematology and many other fields will expand the bone research.


Contemporary approaches to the prevention and management of paediatric obesity: an Australian focus.
Of the 34 member countries of the Organisation for Economic Co-operation and Development, obesity prevalence is highest in the United States, with Australia ranking fifth for girls and eighth for boys. Curbing the problem is achievable and can be realised through a combination of smart governance across many sectors, community initiatives, the support of individual efforts, and clinical leadership. At 5 years of age, one in five Australian children are already affected by overweight or obesity; obesity prevention strategies must therefore start before this age. There is strong evidence that reducing screen time and promoting breastfeeding in 0-2-year-olds are effective interventions in the early years. The main behavioural risk factors for obesity are overconsumption of energy-dense, nutrient-poor foods and a lack of physical activity. Emerging evidence suggests poor sleep quality and duration and high amounts of sedentary time also play a role. Systems-based policy actions may change long term obesity prevalence in children by targeting the food environment through nutrition labelling, healthy foods in schools, restricted unhealthy food marketing to children, and fiscal policies to reduce consumption of harmful foods and sugar-sweetened beverages. Macro-environmental factors influence obesity risk. Public transport policy and the built environment (proximity to parks, bike paths, green space, schools and shops) influence play time spent outdoors, walking and cycling. Greater access to parks and playgrounds and active commuting are associated with lower body mass index. Australian interventions have largely employed individual level approaches. These are important, but of limited effectiveness unless priority is also given to policies that reduce obesity-conducive environments. Clinicians can provide anticipatory guidance to support healthy weight and weight-related behaviours, including weight monitoring, early feeding and children's diets, physical activity opportunities, and limited sedentary and screen time. Investigations in children with obesity usually include liver function tests and measuring fasting glucose, lipid and possibly insulin levels. As obesity can be associated with micronutrient deficiencies, it may be prudent to check full blood count and iron, vitamin B12 and vitamin D levels. Endocrinological assessment is usually not needed. Second line investigations may include liver ultrasound, oral glucose tolerance testing and sleep study. Traditional treatment of child and adolescent obesity has focused on family-based, multicomponent (diet, physical activity and behaviour change) interventions, although these lead to small and often short term weight reductions (mean, - 1.45 kg; 95% CI, 1.88 to - 1.02). Nevertheless, these principles remain core interventions in children and adolescents with obesity. A very low energy diet should be considered in adolescents with severe obesity or obesity-related comorbidities, and for adolescents who have not achieved weight loss following a more conventional dietary approach. Pharmacotherapy confers only small reductions in weight; for example, effect size for metformin is - 3.90 kg (95% CI, - 5.86 to - 1.94). Bariatric surgery should be considered in adolescents over 15 years of age with severe obesity (body mass index > 40 kg/m2, or > 35 kg/m2 in the presence of severe complications).


Diagnostic and management trends of giant cell arteritis: a physician survey.
Opinions regarding diagnostic and treatment issues in giant cell arteritis (GCA) vary widely, yet few controlled trials exist to address these issues. Our objective was to compare espoused clinical policies regarding diagnosis and treatment of GCA among physicians involved in GCA care. Utilizing professional society directories, US physicians were randomly selected to receive an 11-question survey. One hundred surveys were mailed to each of the following: family medicine, general internal medicine, general/vascular surgery, neurology, ophthalmology, otolaryngology, and rheumatology. Data were analyzed according to specialty and specialty group: rheumatology, medical specialties (family medicine, general internal medicine, neurology), and surgical specialties (general/vascular, ophthalmology, and otolaryngology). The percentage of surveys returned was 34.7%. Analysis was limited to the 79% participating in at least one aspect of GCA care. Greater than 90% of respondents believe that temporal arteritis biopsy (TA Bx) should be performed in all suspected cases of GCA. Eighty-five percent of rheumatology believe TA Bx is indicated even when pretest probability of GCA is high, compared to 65% of medical specialties (p = 0.03). Eighty percent of rheumatology believe steroid usage decreases the yield of TA Bx, compared to 62% of surgical specialties (p = 0.04). When initial TA Bx is negative, medical specialties (26%) and surgical specialties (31%) were more likely than rheumatology (5%) to decline contralateral biopsy, even if the contralateral side is symptomatic (p = 0.04 and 0.01, respectively). Considerable variation exists regarding key elements of diagnosis and treatment in the evaluation of suspected GCA. The morbidity of GCA and the potential toxicity of therapy highlights the need for controlled trials to address these issues.


Terminations of pregnancy in the European Union.
To study the current legislation and trends in terminations of pregnancy in the European Union (EU). Data were collected on legislation and statistics for terminations of pregnancy. Population-based statistics from the EU member states. Women in reproductive age in the 27 EU member states. Information on legislation was collected for all 27 EU member states. Statistical information until 2008 was compiled from international (n = 24) and national sources (n = 17). Statistical data were not available for Austria, Cyprus and Luxembourg. Terminations of pregnancy per 1000 women aged 15-49 years. Ireland, Malta and Poland have restrictive legislation. Luxembourg permits termination of pregnancy on physical and mental health indications; Cyprus, Finland, and the UK further include socio-economic indications. In all other EU member states termination of pregnancy can be performed in early pregnancy on a women's request. In general, the rates of termination of pregnancy have declined in recent years. In total, 10.3 terminations were reported per 1000 women aged 15-49 years in the EU in 2008. The rate was 12.3/1000 for countries requiring a legal indication for termination, and 11.0/1000 for countries allowing termination on request. Northern Europe (10.9/1000) and Central and Eastern Europe (10.8/1000) had higher rates than Southern Europe (8.9/1000). Northern Europe, however, had substantially higher rates of termination of pregnancy among teenagers. A more consistent and coherent reporting of terminations of pregnancy is needed in the EU. The large variation of termination rates between countries suggests that termination of pregnancy rates may be reduced in some countries without restricting women's access to termination. Sexual education and provision of access to reliable and affordable contraception are essential to achieve low rates of termination of pregnancy.


The Osseointegration Group of Australia Accelerated Protocol (OGAAP-1) for two-stage osseointegrated reconstruction of amputated limbs.
This study describes the Osseointegration Group of Australia's Accelerated Protocol two-stage strategy (OGAAP-1) for the osseointegrated reconstruction of amputated limbs. We report clinical outcomes in 50 unilateral trans-femoral amputees with a mean age of 49.4 years (24 to 73), with a minimum one-year follow-up. Outcome measures included the Questionnaire for persons with a Trans-Femoral Amputation, the health assessment questionnaire Short-Form-36 Health Survey, the Amputation Mobility Predictor scores presented as K-levels, 6 Minute Walk Test and timed up and go tests. Adverse events included soft-tissue problems, infection, fractures and failure of the implant. Our results demonstrated statistically significant improvements in all five outcome measures. A total of 27 patients experienced adverse events but at the conclusion of the study, all 50 were walking on osseointegrated prostheses. These results demonstrate that osseointegrated prostheses are a suitable alternative to socket-fit devices for amputees experiencing socket-related discomfort and that our strategy offers more rapid progress to walking than other similar protocols. Cite this article: Bone Joint J 2016;98-B:952-60.


Long term pharmacotherapy by methylfenidate or atomoxetine DAT 1 10/10 ADHD children in correlation with results of the imaging methods.
ADHD is one of the most significant diagnostic units in child and adolescent psychiatry. The occurrence in children is 5-6% and 50-80% continued to adult age. The presence of individual genes (polymorphism) on particular symptoms and processes in ADHD are not known. It is estimated that ADHD symptoms are up to 80% to genetic. The higher density of resultant DAT 1 protein was observed in ADHD patients in comparison with controls. The question was if DAT 1 10/10 predicted bad prognoses in long term therapy. We compared 30 ADHD DAT 1 10/10 adolescents treated for 5-6 years. Patients with 30 control adolescents. They were the same age of probands and controls. All these subjects were examined by child psychiatry scales (Conners, Achenbach…). Biological changes were tested by MRI specific CNS volumometry. We didn't confirm bad prognoses in long term therapy with methylphenidate or atomoxetine in ADHD children DAT 1 10/10 in long term therapy. In MRI specific CNS volumometry were not identify any differences in controls and ADHD probands. Gray matter thickness was significantly higher in prefrontal and occipital areas in patients compared to control in prefrontal and occipital areas with cluster-wise p-value<0.05. By this method were not identify any cerebrum damage in long term therapy by methylphenidate and atomoxetine.


Autoimmune hazards of hepatitis B vaccine.
According to Hippocratic tradition, the safety level of a preventive medicine must be very high, as it is aimed at protecting people against diseases that they may not contract. This paper points out that information on the safety of hepatitis B vaccine (HBV) is biased as compared to classical requirements of evidence-based medicine (EBM), as exemplified by a documented selectivity in the presentation or even publication of available clinical or epidemiological data. Then, a review is made of data suggesting that HBV is remarkable by the frequency, the severity and the variety of its complications, some of them probably related to a mechanism of molecular mimicry leading to demyelinating diseases, and the others reproducing the spectrum of non-hepatic manifestations of natural hepatitis B. To be explained, this unusual spectrum of toxicity requires additional investigations based upon complete release of available data.


Scoping Review: The Trajectory of Recovery of Participation Outcomes following Stroke.
Participation is a central concept in health and well-being and healthcare, yet operationalizing this concept has been difficult. Its definition, uses in healthcare, and impacts on recovery require ongoing research. Our review question goes like this: from the longitudinal evidence investigating participation among stroke survivors, what are the patterns of participation recovery in stroke survivors over time, and what interventions are used to improve participation? To fully understand these questions, we also ask, how is participation defined in the stroke literature, and what are the measures of participation used in the stroke literature? A systematic scoping review was undertaken using the search terms "stroke," "longitudinal," "participation," and "outcome" in seven databases. Articles included were published until April 2017, written in English, and had at least two longitudinal assessments of participation. Fifty-nine articles met the inclusion criteria. The International Classification of Functioning, Disability and Health was the most frequent definition of participation used (34%). There were 22 different measures of participation. Eight of ten studies demonstrated significant improvements in participation up to 12 months poststroke. Efficacy of interventions and their impact on participation varied. The various definitions, measures, and intervention efficacies of participation highlight the need for further research worldwide into achieving meaningful participation and quality of life among stroke survivors. Future practice should include participation as a main outcome measure.


Risks and benefits of triple oral anti-thrombotic therapies after acute coronary syndromes and percutaneous coronary intervention.
The key pathophysiological process underlying symptomatic coronary artery disease, including acute coronary syndromes (ACS), is usually a rupture or an erosion of an atherosclerotic plaque, followed by platelet activation and subsequent thrombus formation. Early clinical trials showed benefit with long-term aspirin treatment, and later-based on large clinical trials-dual anti-platelet therapy (DAPT), initially with clopidogrel, and more recently with prasugrel or ticagrelor, has become the established treatment in the post-ACS setting and after percutaneous coronary intervention (PCI). Treatment with DAPT is recommended for both ST-elevation myocardial infarction and non-ST-elevation ACS, as well as after PCI with stenting, in American and European clinical guidelines. Notwithstanding the benefits observed with DAPT, including third-generation P2Y12 receptor inhibitors plus aspirin, ACS patients remain at high risk for a recurrent cardiovascular event, suggesting that other treatment strategies, including the addition of a third oral anti-platelet agent or a novel oral anticoagulant (NOAC) to standard DAPT regimens, may provide additional benefit for post-ACS patients and for patients undergoing PCI. Adding a third anti-thrombotic agent to DAPT after an ACS event or a PCI procedure has been shown to have modest benefit in terms of ischemic event reduction, but has consistently been associated with increased bleeding complications. Therefore, the quest to optimize anti-thrombotic therapies post-ACS and post-PCI continues unabated but is tempered by the historical experiences to date that indicate that careful patient and dose selection will be critical features of future randomized trials.


Intraoperative immunomodulatory effects of sevoflurane versus total intravenous anesthesia with propofol in bariatric surgery (the OBESITA trial): study protocol for a randomized controlled pilot trial.
Obesity is associated with a chronic systemic inflammatory process. Volatile or intravenous anesthetic agents may modulate immune function, and may do so differentially in obesity. However, no study has evaluated whether these potential immunomodulatory effects differ according to type of anesthesia in obese patients undergoing laparoscopic bariatric surgery. The OBESITA trial is a prospective, nonblinded, single-center, randomized, controlled clinical pilot trial. The trial will include 48 patients with a body mass index ≥ 35 kg/m2, scheduled for laparoscopic bariatric surgery using sleeve or a Roux-en-Y gastric bypass technique, who will be allocated 1:1 to undergo general inhalational anesthesia with sevoflurane or total intravenous anesthesia (TIVA) with propofol. The primary endpoint is the difference in plasma interleukin (IL)-6 levels when comparing the two anesthetic agents. Blood samples will be collected prior to anesthesia induction (baseline), immediately after anesthetic induction, and before endotracheal extubation. Levels of other proinflammatory and anti-inflammatory cytokines, neutrophil chemotaxis, macrophage differentiation, phagocytosis, and occurrence of intraoperative and postoperative complications will also be evaluated. To our knowledge, this is the first randomized clinical trial designed to compare the effects of two different anesthetics on immunomodulation in obese patients undergoing laparoscopic bariatric surgery. Our hypothesis is that anesthesia with sevoflurane will result in a weaker proinflammatory response compared to anesthesia with propofol, with lower circulating levels of IL-6 and other proinflammatory mediators, and increased macrophage differentiation into the M2 phenotype in adipose tissue. Registro Brasileiro de Ensaios Clínicos, RBR-77kfj5 . Registered on 25 July 2018.


Bioequivalence of Alendronate and Vitamin D3 in a Combination Tablet Versus Corresponding-Dose Individual Tablets in Healthy Taiwanese Volunteers, Determined Using a Novel Plasma Alendronate Assay.
This study was designed to demonstrate that alendronate (ALN)/vitamin D3 combination tablets (ALN/D5600) are bioequivalent to corresponding doses of ALN and vitamin D3 as individual tablets in healthy Taiwanese volunteers. In this open-label, randomized, 2-period, crossover study, 68 volunteers were randomized to a single ALN/D5600 combination tablet or corresponding doses of 70 mg ALN + 5600 IU vitamin D3 (2 × 2800 IU), followed by a 12-day washout period and administration of the alternate formulation. Plasma ALN levels were measured using a newly developed assay. Geometric mean ratios of ALN AUC0-last, AUC0-∞, and Cmax, and unadjusted vitamin D3 AUC0-80h and Cmax were compared and considered bioequivalent if the 90% CI was within 0.8 to 1.25. The geometric mean ratios were: AUC0-last, 1.084 (90% CI, 0.937-1.253); AUC0-∞, 1.081 (90% CI, 0.935-1.249); and Cmax, 1.112 (90% CI, 0.959-1.289) for ALN, and AUC0-80h 0.953 (90% CI, 0.827-1.098) and Cmax, 0.982 (90% CI, 0.854-1.130) for vitamin D3 unadjusted for endogenous levels. The combination tablet was considered bioequivalent to coadministration based on ALN AUC0-∞ and unadjusted vitamin D3 parameters. Slight differences for ALN AUC0-last and Cmax (upper 90% CIs outside the bounds) were not considered clinically significant. The combination tablet was well tolerated. No serious adverse experiences were reported. © 2015. The Authors. Published by Elsevier Inc. All rights reserved.


Folic acid supplementation alters the DNA methylation profile and improves insulin resistance in high-fat-diet-fed mice.
Folic acid (FA) supplementation may protect from obesity and insulin resistance, the effects and mechanism of FA on chronic high-fat-diet-induced obesity-related metabolic disorders are not well elucidated. We adopted a genome-wide approach to directly examine whether FA supplementation affects the DNA methylation profile of mouse adipose tissue and identify the functional consequences of these changes. Mice were fed a high-fat diet (HFD), normal diet (ND) or an HFD supplemented with folic acid (20 μg/ml in drinking water) for 10 weeks, epididymal fat was harvested, and genome-wide DNA methylation analyses were performed using methylated DNA immunoprecipitation sequencing (MeDIP-seq). Mice exposed to the HFD expanded their adipose mass, which was accompanied by a significant increase in circulating glucose and insulin levels. FA supplementation reduced the fat mass and serum glucose levels and improved insulin resistance in HFD-fed mice. MeDIP-seq revealed distribution of differentially methylated regions (DMRs) throughout the adipocyte genome, with more hypermethylated regions in HFD mice. Methylome profiling identified DMRs associated with 3787 annotated genes from HFD mice in response to FA supplementation. Pathway analyses showed novel DNA methylation changes in adipose genes associated with insulin secretion, pancreatic secretion and type 2 diabetes. The differential DNA methylation corresponded to changes in the adipose tissue gene expression of Adcy3 and Rapgef4 in mice exposed to a diet containing FA. FA supplementation improved insulin resistance, decreased the fat mass, and induced DNA methylation and gene expression changes in genes associated with obesity and insulin secretion in obese mice fed a HFD.


H++: a server for estimating pKas and adding missing hydrogens to macromolecules.
The structure and function of macromolecules depend critically on the ionization (protonation) states of their acidic and basic groups. A number of existing practical methods predict protonation equilibrium pK constants of macromolecules based upon their atomic resolution Protein Data Bank (PDB) structures; the calculations are often performed within the framework of the continuum electrostatics model. Unfortunately, these methodologies are complex, involve multiple steps and require considerable investment of effort. Our web server http://biophysics.cs.vt.edu/H++ provides access to a tool that automates this process, allowing both experts and novices to quickly obtain estimates of pKs as well as other related characteristics of biomolecules such as isoelectric points, titration curves and energies of protonation microstates. Protons are added to the input structure according to the calculated ionization states of its titratable groups at the user-specified pH; the output is in the PQR (PDB + charges + radii) format. In addition, corresponding coordinate and topology files are generated in the format supported by the molecular modeling package AMBER. The server is intended for a broad community of biochemists, molecular modelers, structural biologists and drug designers; it can also be used as an educational tool in biochemistry courses.


Flash lamp-excited time-resolved fluorescence microscope suppresses autofluorescence in water concentrates to deliver an 11-fold increase in signal-to-noise ratio.
The ubiquity of naturally fluorescing components (autofluorophores) encountered in most biological samples hinders the detection and identification of labeled targets through fluorescence-based techniques. Time-resolved fluorescence (TRF) is a technique by which the effects of autofluorescence are reduced by using specific fluorescent labels with long fluorescence lifetimes (compared with autofluorophores) in conjunction with time-gated detection. A time-resolved fluorescence microscope (TRFM) is described that is based on a standard epifluorescence microscope modified by the addition of a pulsed excitation source and an image-intensified time-gateable CCD camera. The choice of pulsed excitation source for TRFM has a large impact on the price and performance of the instrument. A flash lamp with rapid discharge characteristics was selected for our instrument because of the high spectral energy in the UV region and short pulse length. However, the flash output decayed with an approximate lifetime of 18 micros and the TRFM required a long-lived lanthanide chelate label to ensure that probe fluorescence was visible after decay of the flash plasma. We synthesized a recently reported fluorescent chelate (BHHCT) and conjugated it to a monoclonal antibody directed against the waterborne parasite Giardia lamblia. For a 600-nm bandpass filter set and a gate delay of 60 micros, the TRFM provided an 11.3-fold improvement in the signal-to-noise ratio (S/N) of labeled Giardia over background. A smaller gain in an SNR of 9.69-fold was achieved with a 420-nm longpass filter set; however, the final contrast ratio between labeled cyst and background was higher (11.3 versus 8.5). Despite the decay characteristics of the light pulse, flash lamps have many practical advantages compared with optical chopper wheels and modulated lasers for applications in TRFM.


Community governance of the Kahnawake Schools Diabetes Prevention Project, Kahnawake Territory, Mohawk Nation, Canada.
Health promotion emphasizes the importance of community ownership in the governance of community-based programmes, yet little research has been conducted in this area. This study examined perceptions of community ownership among project partners taking responsibility for decision-making related to the Kahnawake Schools Diabetes Prevention Project (KSDPP). Project partners were surveyed cross-sectionally at 18 months (T1) and 60 months (T2) into the project. The perceived influence of each project partner was assessed at T1 and T2 for three domains: (i) KSDPP activities; (ii) KSDPP operations; and (iii) Community Advisory Board (CAB) activities. Project staff were perceived to have the greatest influence on KSDPP activities, KSDPP operations and CAB activities at both T1 and T2. High mean scores of perceived influence for CAB members and community researchers, however, suggests that project decision-making was a shared responsibility among multiple community partners. Although academic researcher influence was consistently low, they were satisfied with their level of influence. This was unlike community affiliates, who were less satisfied with their lower level of influence. In keeping with Kanien'kehaka (Mohawk) culture, the findings suggest a participatory democracy or shared decision-making as the primary mode of governance of KSDPP.


Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.
Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing. Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients. These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). MacroGenics.


Assessing the potential use of blockchain technology to improve the sharing of public health data in a western Canadian province.
This exploratory, qualitative study set out to identify the encountered and perceived barriers to public health (PH) data sharing in a Canadian province with a view to assessing blockchain technology as a potential solution. A topic guide was developed, based on previous research in the area. This was then utilised for ten in-depth, semi-structured interviews with PH professionals between 27 May and 18 June 2019. Each stage of research was congruent with the philosophical underpinning of Gadamerian hermeneutic phenomenology. The major themes that emerged from the data collected were related to the information systems in use, data quality and ownership, as well as client identity management. The recurring core theme throughout all interviews was related to ineffective leadership and management, contributing to each major theme. Overwhelmingly the results show that the majority of barriers faced in this province are human-related. It is concluded that while blockchain technology shows promise for enhancing data sharing in healthcare, it is still many years away from being implemented in this Canadian province. As the results of this study indicate, there are human related barriers that could be addressed in the meantime, which are outside the scope of a technical solution. Future work should explore the perspectives of other stakeholders, such as the provincial government to fully understand the potential for using blockchain to share PH data in this province.


Regular, sustained-release morphine for chronic breathlessness: a multicentre, double-blind, randomised, placebo-controlled trial.
Morphine may decrease the intensity of chronic breathlessness but data from a large randomised controlled trial (RCT) are lacking. This first, large, parallel-group trial aimed to test the efficacy and safety of regular, low-dose, sustained-release (SR) morphine compared with placebo for chronic breathlessness. Multisite (14 inpatient and outpatient cardiorespiratory and palliative care services in Australia), parallel-arm, double-blind RCT. Adults with chronic breathlessness (modified Medical Research Council≥2) were randomised to 20 mg daily oral SR morphine and laxative (intervention) or placebo and placebo laxative (control) for 7 days. Both groups could take ≤6 doses of 2.5 mg, 'as needed', immediate-release morphine (≤15 mg/24 hours) as required by the ethics review board. The primary endpoint was change from baseline in intensity of breathlessness now (0-100 mm visual analogue scale; two times per day diary) between groups. Secondary endpoints included: worst, best and average breathlessness; unpleasantness of breathlessness now, fatigue; quality of life; function; and harms. Analysed by intention-to-treat, 284 participants were randomised to morphine (n=145) or placebo (n=139). There was no difference between arms for the primary endpoint (mean difference -0.15 mm (95% CI -4.59 to 4.29; p=0.95)), nor secondary endpoints. The placebo group used more doses of oral morphine solution during the treatment period (mean 8.7 vs 5.8 doses; p=0.001). The morphine group had more constipation and nausea/vomiting. There were no cases of respiratory depression nor obtundation. No differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine. ACTRN12609000806268.


Part 3. Assessment of genotoxicity and oxidative damage in rats after chronic exposure to new-technology diesel exhaust in the ACES bioassay.
In 2001, the U.S. Environmental Protection Agency (EPA*) and the California Air Resources Board (CARB) adopted new standards for diesel fuel and emissions from heavy-duty diesel engines. By 2007, diesel engines were required to meet these new standards for particulate matter (PM), with other standards to follow. Through a combination of advanced compression-ignition engine technology, development of exhaust aftertreatment systems, and reformulated fuels, stringent standards were introduced. Before the 2007 standards were put in place by the EPA, human health effects linked to diesel exhaust (DE) exposure had been associated with diesel-fuel solvent and combustion components. In earlier research, diesel engine exhaust components were, in turn, linked to increased mutagenicity in cultures of Salmonella typhimurium and mammalian cells (Tokiwa and Ohnishi 1986). In addition, DE was shown to increase both the incidence of tumors and the induction of 8-hydroxy-deoxyguanosine (8-OHdG) adducts in rodents (Ichinose et al. 1997) and total DNA adducts in rats (Bond et al. 1990). Furthermore, DE is composed of a complex mixture of polycyclic aromatic hydrocarbons (PAHs) and particulates. One such PAH, 3-nitrobenzanthrone (3-NBA), is also found in urban air. 3-NBA has been observed to induce micronucleus formation in the DNA of human hepatoma cells (Lamy et al. 2004). The current study is part of the Advanced Collaborative Emissions Study (ACES), a multidisciplinary program carried out by the Health Effects Institute and the Coordinating Research Council. Its purpose was to determine whether recent improvements in the engineering of heavy-duty diesel engines reduce the toxicity associated with exposure to DE components. To this end, we evaluated potential genotoxicity and induction of oxidative stress in bioassays of serum and tissues from Wistar Han rats chronically exposed--for up to 24 months--to DE from a 2007-compliant diesel engine (new-technology diesel exhaust, or NTDE). Genotoxicity was measured as DNA strand breaks in lung tissue, using an alkaline-modified comet assay. As a correlate of possible DNA damage evaluated in the comet assay, concentrations of the free DNA adduct 8-OHdG were evaluated in serum by a competitive enzyme-linked immunosorbent assay (ELISA). The 8-OHdG fragment found in the serum is a specific biomarker for the repair of oxidative DNA damage. In addition, an assay for thiobarbituric acid reactive substances (TBARS) was used to assess oxidative stress and damage in the form of lipid peroxidation in the hippocampus region of the brains of the DE-exposed animals. These endpoints were evaluated at 1, 3, 12, and 24 months of exposure to DE or to a control atmosphere (filtered air). At the concentrations of DE evaluated, there were no significant effects of exposure in male or female rats after 1, 3, 12, or 24 months in any measure of DNA damage in the comet assay (%DNA in tail, tail length, tail moment, or olive moment). The comparison of exposure groups versus control and the comparison of groups by sex for 1 and 3 months of exposure showed no significant differences in serum 8-OHdG concentrations (P > 0.05). The concentrations of 8-OHdG in all exposure groups at 3 months were higher than those in exposure groups at any other time point (P < 0.05). Looking at the levels of 8-OHdG in serum in the 12-month and 24-month groups, we saw a significant difference from control in the 12-month group at the mid and high levels (P < 0.05), as well as some other scattered changes. Sex differences were noted in the 12-month high-level group (P < 0.05). However, these differences did not follow an exposure-dependent pattern. All other comparisons were not significant (P > 0.05). Hippocampal concentrations of TBARs, measured as malondialdehyde (MDA), showed some small and scattered changes in groups exposed to different levels of DE and at different time points, but we did not consider these to be exposure-related. We concluded that exposure to DE in these rats did not produce any significant increase in oxidative damage to lipids or damage to DNA in the form of strand breaks.


Most clinical anti-EGFR antibodies do not neutralize both wtEGFR and EGFRvIII activation in glioma.
Although epidermal growth factor receptor (EGFR) and its truncated, autoactive mutant EGFR variant (v)III are bona fide drivers of tumorigenesis in some gliomas, therapeutic antibodies developed to neutralize this axis have not improved patient survival in a limited number of trials. Previous studies using cells transduced to exogenously express EGFRvIII may have compromised mechanistic studies of anti-EGFR therapeutics. Therefore, we re-assessed the activity of clinical EGFR antibodies in patient-derived gliomaspheres that endogenously express EGFRvIII. The antitumor efficacy of antibodies was assessed using in vitro proliferation assays and intracranial orthografts. Receptor activation status, antibody engagement, oncogenic signaling, and mechanism of action after antibody treatment were analyzed by immunoprecipitation and western blotting. Tracking of antibody receptor complexes was conducted using immunofluorescence. The EGFR domain III-targeting antibodies cetuximab, necitumumab, nimotuzumab, and matuzumab did not neutralize EGFRvIII activation. Chimeric monoclonal antibody 806 (ch806) neutralized EGFRvIII, but not wild-type (wt)EGFR activation. Panitumumab was the only antibody that neutralized both EGFRvIII and wtEGFR, leading to reduction of p-S6 signaling and superior in vitro and in vivo antitumor activity. Mechanistically, panitumumab induced recycling of receptor but not degradation as previously described. Panitumumab, via its unique avidity, stably cross-linked EGFRvIII to prevent its activation, while ch806 induced a marked reduction in the active EGFRvIII disulphide-bonded dimer. We discovered a previously unknown major resistance mechanism in glioma in that most EGFR domain III-targeting antibodies do not neutralize EGFRvIII. The superior in vitro and in vivo antitumor activity of panitumumab supports further clinical testing of this antibody against EGFRvIII-stratified glioma.


Endolymphatic sac tumor in a patient with von Hippel-Lindau disease: MR imaging findings.
A 29-year-old male patient with von Hippel-Lindau disease who had an operation for cerebellar hemangioblastoma six years ago is presented. The patient had a four-year history of a slow-growing, locally invasive vascularized lesion of the temporal bone involving the cerebellopontine angle. The mass, studied by MR imaging, was almost completely cystic in appearance. Pathological examination after removal of the mass confirmed a papillary endolymphatic sac tumor.


Evidence that the lunar cycle influences human sleep.
Endogenous rhythms of circalunar periodicity (∼29.5 days) and their underlying molecular and genetic basis have been demonstrated in a number of marine species [1, 2]. In contrast, there is a great deal of folklore but no consistent association of moon cycles with human physiology and behavior [3]. Here we show that subjective and objective measures of sleep vary according to lunar phase and thus may reflect circalunar rhythmicity in humans. To exclude confounders such as increased light at night or the potential bias in perception regarding a lunar influence on sleep, we retrospectively analyzed sleep structure, electroencephalographic activity during non-rapid-eye-movement (NREM) sleep, and secretion of the hormones melatonin and cortisol found under stringently controlled laboratory conditions in a cross-sectional setting. At no point during and after the study were volunteers or investigators aware of the a posteriori analysis relative to lunar phase. We found that around full moon, electroencephalogram (EEG) delta activity during NREM sleep, an indicator of deep sleep, decreased by 30%, time to fall asleep increased by 5 min, and EEG-assessed total sleep duration was reduced by 20 min. These changes were associated with a decrease in subjective sleep quality and diminished endogenous melatonin levels. This is the first reliable evidence that a lunar rhythm can modulate sleep structure in humans when measured under the highly controlled conditions of a circadian laboratory study protocol without time cues.


Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes.
Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes). To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. Expression of CSPG4 (chondroitin sulfate proteoglycan 4) was detected in epidermal keratinocytes and the cardiac conduction system. CSPG4pos cells constituted ≈5.6±3.3% of the nonmyocyte cells in the mouse heart. Inducible postnatal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibroadipocytes, as in human arrhythmogenic cardiomyopathy. The mice exhibited palmoplantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP. Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in patients with arrhythmogenic cardiomyopathy and cardiocutaneous syndromes.


Postseismic viscoelastic rebound.
The sudden appearance of a dislocation, representing an earthquake, in an elastic layer (the lithosphere) overriding a viscoelastic half space (the asthenosphere) is followed by time-dependent surface deformation, which is very similar to in situ postseismic deformation. The spectacular postseismic deformation following the large Nankaido earthquake of 1946 yields for the asthenosphere a viscosity of 5 x 10(19) poise and a 50 percent relaxation of the shear modulus. Large thrust type earthquakes may provide, in the future, a new method for exploring the rheology of the earth's upper mantle.


High scotopic/photopic ratio white-light-emitting diodes integrated with semiconductor nanophosphors of colloidal quantum dots.
We propose and demonstrate single-chip white-light-emitting diodes (WLEDs) integrated with semiconductor nanophosphors of colloidal quantum dots for high scotopic/photopic (S/P) ratio. These color conversion WLEDs achieve S/P ratios over 3.00, which exceeds the current limit of 2.50 in common lighting technologies, while sustaining sufficient levels of color rendering index.


Double deletion of Panx1 and Panx3 affects skin and bone but not hearing.
Pannexins (Panxs), large-pore channel forming glycoproteins, are expressed in a wide variety of tissues including the skin, bone, and cochlea. To date, the use of single knock-out mouse models of both Panx1 and Panx3 have demonstrated their roles in skin development, bone formation, and auditory phenotypes. Due to sequence homology between Panx1 and Panx3, when one Panx is ablated from germline, the other may be upregulated in a compensatory mechanism to maintain tissue homeostasis and function. To evaluate the roles of Panx1 and Panx3 in the skin, bone, and cochlea, we created the first Panx1/Panx3 double knock-out mouse model (dKO). These mice had smaller litters and reduced body weight compared to wildtype controls. The dKO dorsal skin had decreased epidermal and dermal area as well as decreased hypodermal area in neonatal but not in older mice. In addition, mouse skull shape and size were altered, and long bone length was decreased in neonatal dKO mice. Finally, auditory tests revealed that dKO mice did not exhibit hearing loss and were even slightly protected against noise-induced hearing damage at mid-frequency regions. Taken together, our findings suggest that Panx1 and Panx3 are important at early stages of development in the skin and bone but may be redundant in the auditory system. KEY MESSAGES: Panx double KO mice had smaller litters and reduced body weight. dKO skin had decreased epidermal and dermal area in neonatal mice. Skull shape and size changed plus long bone length decreased in neonatal dKO mice. dKO had no hearing loss and were slightly protected against noise-induced damage.


Humans (really) are animals: picture-book reading influences 5-year-old urban children's construal of the relation between humans and non-human animals.
What is the relation between humans and non-human animals? From a biological perspective, we view humans as one species among many, but in the fables and films we create for children, we often offer an anthropocentric perspective, imbuing non-human animals with human-like characteristics. What are the consequences of these distinctly different perspectives on children's reasoning about the natural world? Some have argued that children universally begin with an anthropocentric perspective and that acquiring a biological perspective requires a basic conceptual change (cf. Carey, 1985). But recent work reveals that this anthropocentric perspective, evidenced in urban 5-year-olds, is not evident in 3-year-olds (Herrmann etal., 2010). This indicates that the anthropocentric perspective is not an obligatory first step in children's reasoning about biological phenomena. In the current paper, we introduced a priming manipulation to assess whether 5-year-olds' reasoning about a novel biological property is influenced by the perspectives they encounter in children's books. Just before participating in a reasoning task, each child read a book about bears with an experimenter. What varied was whether bears were depicted from an anthropomorphic (Berenstain Bears) or biological perspective (Animal Encyclopedia). The priming had a dramatic effect. Children reading the Berenstain Bears showed the standard anthropocentric reasoning pattern, but those reading the Animal Encyclopedia adopted a biological pattern. This offers evidence that urban 5-year-olds can adopt either a biological or a human-centered stance, depending upon the context. Thus, children's books and other media are double-edged swords. Media may (inadvertently) support human-centered reasoning in young children, but may also be instrumental in redirecting children's attention to a biological model.


Exome sequencing of bulked segregants identified a novel TaMKK3-A allele linked to the wheat ERA8 ABA-hypersensitive germination phenotype.
Using bulked segregant analysis of exome sequence, we fine-mapped the ABA-hypersensitive mutant ERA8 in a wheat backcross population to the TaMKK3-A locus of chromosome 4A. Preharvest sprouting (PHS) is the germination of mature grain on the mother plant when it rains before harvest. The ENHANCED RESPONSE TO ABA8 (ERA8) mutant increases seed dormancy and, consequently, PHS tolerance in soft white wheat 'Zak.' ERA8 was mapped to chromosome 4A in a Zak/'ZakERA8' backcross population using bulked segregant analysis of exome sequenced DNA (BSA-exome-seq). ERA8 was fine-mapped relative to mutagen-induced SNPs to a 4.6 Mb region containing 70 genes. In the backcross population, the ERA8 ABA-hypersensitive phenotype was strongly linked to a missense mutation in TaMKK3-A-G1093A (LOD 16.5), a gene associated with natural PHS tolerance in barley and wheat. The map position of ERA8 was confirmed in an 'Otis'/ZakERA8 but not in a 'Louise'/ZakERA8 mapping population. This is likely because Otis carries the same natural PHS susceptible MKK3-A-A660S allele as Zak, whereas Louise carries the PHS-tolerant MKK3-A-C660R allele. Thus, the variation for grain dormancy and PHS tolerance in the Louise/ZakERA8 population likely resulted from segregation of other loci rather than segregation for PHS tolerance at the MKK3 locus. This inadvertent complementation test suggests that the MKK3-A-G1093A mutation causes the ERA8 phenotype. Moreover, MKK3 was a known ABA signaling gene in the 70-gene 4.6 Mb ERA8 interval. None of these 70 genes showed the differential regulation in wild-type Zak versus ERA8 expected of a promoter mutation. Thus, the working model is that the ERA8 phenotype results from the MKK3-A-G1093A mutation.


Three cognitive markers of unconscious semantic activation.
A "response window" technique is described and used to reliably demonstrate unconscious activation of meaning by subliminal (visually masked) words. Visually masked prime words were shown to influence judged meaning of following target words. This priming-effect marker was used to identify two additional markers of unconscious semantic activation: (i) the activation is very short-lived (the target word must occur within about 100 milliseconds of the subliminal prime); and (ii) unlike supraliminal prime-target pairs, a subliminal pair leaves no memory trace that can be observed in response to the next prime-target pair. Thus, unconscious semantic activation is shown to be a readily reproducible phenomenon but also very limited in the duration of its effect.


Ureidosuccinate is transported by the allantoate transport system in Saccharomyces cerevisiae.
The regulatory characteristics exhibited by ureidosuccinate transport in Saccharomyces cerevisiae led us to hypothesize that this biosynthetic intermediate was transported via the degradative allantoate transport system. The hypothesis was verified by the finding that neither dal5 nor urep1 mutant strains could transport allantoate or ureidosuccinate. Mutations in the two loci were tightly linked and failed to complement one another, suggesting that they were allelic. The use of a common transport system for accumulation of both biosynthetic and degradative metabolites explains the paradoxical characteristics observed for control of ureidosuccinate and allantoate transport.


Short-Term Complications, Reoperations, and Radiographic Outcomes of a New Fixed-Bearing Total Ankle Arthroplasty.
With the increasing use of total ankle arthroplasty (TAA), new implants with varied configurations are being developed every year. This study aimed to assess the early complications, reoperations, and radiographic and clinical outcomes of the Infinity TAA. To date, clinical results of this novel implant have not been published. A retrospective analysis of 64 consecutive ankles that underwent a primary Infinity TAA from July 2014 to April 2016 was performed. Patients had an average follow-up of 24.5 (range, 18-39) months. Medical records were reviewed to determine the incidence of complications, reoperations, and revisions. Radiographic outcomes included preoperative and postoperative tibiotalar alignment, tibial implant positioning, the presence of periprosthetic radiolucency and cysts, and evidence of subsidence or loosening. Additionally, patient-reported outcomes were analyzed with the Foot and Ankle Outcome Score (FAOS). Survivorship of the implant was 95.3%. Fourteen ankles (21.8%) presented a total of 17 complications. A total of 12 reoperations were necessary in 11 ankles (17.1%). Revision surgery was indicated for 3 ankles (4.7%) as a result of subsidence of the implant. Tibiotalar coronal deformity was significantly improved after surgery ( P < .0001) and maintained during latest follow-up ( P = .81). Periprosthetic radiolucent lines were observed around the tibial component in 20 ankles (31%) and around the talar component in 2 ankles (3.1%). A tibial cyst was observed in 1 ankle (1.5%). Outcome scores were significantly improved for all FAOS components analyzed ( P < .0001), from 39.0 to 83.3 for pain, from 34.0 to 65.2 for symptoms, from 52.3 to 87.5 for activities of daily living, and from 15.7 to 64.2 for quality of life. Most complications observed in the study were minor and successfully treated with a single reoperation procedure or nonoperatively. Failures and radiographic abnormalities were most commonly related to the tibial implant. Further studies with longer follow-up are needed to evaluate the survivorship of the tibial implant in the long term. Level IV, retrospective case series.


Magnesium sulphate has beneficial effects as an adjuvant during general anaesthesia for Caesarean section.
The use of low concentrations of volatile anaesthetics with avoidance of opioids may induce intraoperative awareness and adverse haemodynamic responses during Caesarean section. Magnesium is well known to reduce anaesthetic requirements and to block noxious stimuli. We investigated whether i.v. magnesium sulphate modulates anaesthetic depth and analgesic efficacy during Caesarean section. Seventy-two patients undergoing Caesarean section were randomly assigned to receive i.v. saline (control group) or magnesium sulphate 30 mg kg(-1) bolus+10 mg kg(-1) h(-1) continuous infusion (Mg 30 group) or 45 mg kg(-1) bolus+15 mg kg(-1) h(-1) continuous infusion (Mg 45 group) after induction. Bispectral index (BIS) value, mean arterial pressure (MAP), and midazolam, fentanyl, and atracurium consumptions were recorded. BIS values [mean (sd)] at 7.5 and 10 min after surgery and before delivery in the control [64 (9), 66 (8), 67 (8), P<0.001] and the Mg 30 groups [62 (8), P<0.01; 64 (7), 63 (9), P<0.001] were higher than in the Mg 45 group [56 (8), 55 (8), 55 (7)]. MAP was greater in the control group (P<0.05) than in the Mg 30 and Mg 45 groups during the pre-delivery period. The magnesium groups required less midazolam (P<0.05), fentanyl (Mg 30, P<0.05; Mg 45, P<0.01), and atracurium (P<0.001) vs the control group. Preoperative i.v. magnesium sulphate attenuated BIS and arterial pressure increases during the pre-delivery period. Magnesium sulphate can be recommended as an adjuvant during general anaesthesia for Caesarean section to avoid perioperative awareness and pressor response resulting from inadequate anaesthesia, analgesia, or both.


Search for Violations of Lorentz Invariance and CPT Symmetry in B_{(s)}^{0} Mixing.
Violations of CPT symmetry and Lorentz invariance are searched for by studying interference effects in B^{0} mixing and in B_{s}^{0} mixing. Samples of B^{0}→J/ψK_{S}^{0} and B_{s}^{0}→J/ψK^{+}K^{-} decays are recorded by the LHCb detector in proton-proton collisions at center-of-mass energies of 7 and 8 TeV, corresponding to an integrated luminosity of 3 fb^{-1}. No periodic variations of the particle-antiparticle mass differences are found, consistent with Lorentz invariance and CPT symmetry. Results are expressed in terms of the standard model extension parameter Δa_{μ} with precisions of O(10^{-15}) and O(10^{-14}) GeV for the B^{0} and B_{s}^{0} systems, respectively. With no assumption on Lorentz (non)invariance, the CPT-violating parameter z in the B_{s}^{0} system is measured for the first time and found to be Re(z)=-0.022±0.033±0.005 and Im(z)=0.004±0.011±0.002, where the first uncertainties are statistical and the second systematic.


Bosniak category IIF designation and surgery for complex renal cysts.
We investigated whether adding the IIF categorization improved the accuracy of Bosniak renal cyst classification, as evidenced by a low rate of progression in IIF lesions and a high rate of malignancy in category III lesions. We retrospectively reviewed the records of patients with complex renal cysts categorized as a Bosniak IIF or III. Surveillance imaging and pathological outcomes of category IIF cysts were recorded to determine radiological predictors of progression. Pathological outcomes of category III cysts were recorded to determine the malignancy rate. A total of 112 patients met study inclusion criteria, of whom 81 were initially diagnosed with a category IIF cyst and 31 had a Bosniak category III cyst. At a median followup of 15 months 14.8% of Bosniak IIF lesions progressed in complexity with a median time to progression of 11 months (maximum greater than 4 years). There were no differences in tumor or patient characteristics between cysts that progressed and those that remained stable. In the 33 patients with Bosniak III lesions who underwent surgical extirpation the malignancy rate was 81.8%. Most patients had low stage, low grade disease and remained recurrence-free at a median followup of 6 months. Adding the IIF category has increased the accuracy and clinical impact of the Bosniak categorization system, as evidenced by a low rate of progression in category IIF cysts and an increased rate of malignancy in surgically treated category III lesions compared to those in historical controls.


Parenthood and host resistance to the common cold.
To determine whether parenthood predicts host resistance to the common cold among healthy volunteers experimentally exposed to a common cold virus. Participants were 795 healthy volunteers (age range = 18-55 years) enrolled in one of three viral-challenge studies conducted from 1993 to 2004. After reporting parenthood status, participants were quarantined, administered nasal drops containing one of four common cold viruses, and monitored for the development of a clinical cold (infection in the presence of objective signs of illness) on the day before and for 5 to 6 days after exposure. All analyses included controls for immunity to the experimental virus (prechallenge specific antibody titers), viral strain, season, age, sex, race/ethnicity, marital status, body mass, study, employment status, and education. Parents were less likely to develop colds than nonparents were (odds ratio [OR] = 0.48, 95% confidence interval [CI] = 0.31-0.73). This was true for both parents with one to two children (OR = 0.52, 95% CI = 0.33-0.83) and three or more children (OR = 0.39, 95% CI = 0.22-0.70). Parenthood was associated with a decreased risk of colds for both those with at least one child living at home (OR = 0.46, 95% CI = 0.24-0.87) and those whose children all lived away from home (OR = 0.27, 95% CI = 0.12-0.60). The relationship between parenthood and colds was not observed in parents aged 18 to 24 years but was pronounced among older parents. Parenthood was associated with greater host resistance to common cold viruses.


Subacute thyroiditis and dyserythropoesis after influenza vaccination suggesting immune dysregulation.
Subacute thyroiditis (SAT) is an extremely rare complication of influenza vaccination. Several infectious agents have been related with SAT. It is also well known the association between HLA-B35 and the development of SAT. We describe a case of subacute thyroiditis and dyserythropoesis occurring shortly after administration of an influenza vaccine in a 55-year-old man with history of diabetes and psoriasis, family history of autoimmunity without clinical evidence of acute viral infection prior to the onset of symptoms. We propose that, the events occurring in the patient may be explained as result of complex interactions between the individual genetic background and environmental exposure to infectious agents that generated a pro-inflammatory status, where the vaccine was the trigger for the subsequent alterations in thyroid and bone marrow. These findings highlight the importance of immunogenetic factors involved in response to vaccination that is the central theme in the growing field of 'vaccinomics'.


Is the origin of green fluorescence in unsymmetrical four-ring bent-core liquid crystals single or double proton transfer?
The origin of green fluorescence in unsymmetrical four-ring bent-core liquid crystals (BCLCs) is not understood clearly. There is no analysis of the photo-physical properties, in particular, the excited state dynamical behaviour, of these molecules. Because of the availability of two proton transfer sites in these systems, there is no clear explanation of the involvement of single or double proton transfer reactions in the origin of the large Stokes shifted green fluorescence band. Therefore, we employ the femtosecond transient absorption spectroscopy technique to recognize the formation of transient species in the excited state and its associated dynamics in the femto-picosecond time domain. In order to validate the experimental photo-physical properties, the time-dependent density functional theory (TDDFT) calculations have been performed. Our results indicate that the four-ring bent-core system is an excellent example of systems exhibiting two proton transfer reactions in a sequential process. Further, these two proton transfer sites are not electronically coupled to each other; therefore, monoketo and diketo tautomers exhibit very close absorption and emission positions. The large Stokes shifted green emission in these systems is mainly contributed by the monoketo tautomer (MK-C*). The linking ester functional group of both sites plays a significant role in controlling the rate of proton transfer reactions. A good correlation is observed between theoretical and experimental results.


Direct comparisons of the size and persistence of anisomycin-induced consolidation and reconsolidation deficits.
An issue of increasing theoretical interest in the study of learning is to compare the processes that follow an initial learning experience (such as learning an association between a context and a shock; memory consolidation processes) with those that follow retrieval of that learning experience (such as exposure to the context in the absence of shock; memory reconsolidation and extinction processes). Much of what is known about these processes comes from separate experiments examining one process or the other; there have been few attempts to compare these processes directly in a single experiment. A challenge in between-experiment comparisons of consolidation and reconsolidation deficits is that they frequently involve comparisons between groups that are not matched on factors that may influence the size and persistence of these deficits (e.g., prior learning experience, memory expression prior to deficit). The following experiments examined the size and persistence of these deficits after matching both the amount of experience with a context and the levels of performance in that context prior to delivery of the protein synthesis inhibitor anisomycin. We found that systemic or intrahippocampal administration of anisomycin caused a deficit in groups receiving context conditioning (consolidation groups) or reactivation (reconsolidation groups) immediately prior to the injections. With systemic injections, the deficit was larger and more persistent in consolidation groups; with intrahippocampal injections, the initial deficit was statistically identical, yet was more persistent in the consolidation group. These experiments showed that when experiences and performance are matched prior to anisomycin injections, consolidation deficits are generally larger and more persistent compared to reconsolidation deficits.


Black-on-black secondary occlusive IOL implantation to alleviate enigmatic light perception through a black IOL.
A 61-year-old woman presented with an 18-year history of a debilitating ghosting phenomenon and light perception in her right eye following implantation of a Morcher black intraocular lens (IOL) for intractable diplopia. On 5 occasions, she was referred to hospital ophthalmology, repeatedly requesting right optic nerve transection to alleviate the symptoms. The mechanism of light perception across the occlusive IOL remained enigmatic, preventing appropriate management. Morcher occlusive IOLs transmit high levels of near infrared (IR) light, which may cause light perception under photopic conditions by long-wavelength cone photoreceptors. Considering this, we implanted a near IR-blocking Artisan black iris-claw IOL anterior to the Morcher occlusive IOL. Postoperatively, the light perception and ghosting disappeared and the visual quality of life score (VF-14) increased from 41 to 86. We suggest consideration of this surgical approach of black-on-black IOL implantation for patients with refractory light perception despite implantation of a near IR-transmitting occlusive IOL. No author has a financial or proprietary interest in any material or method mentioned.


Increased pancreatitis in allografts flushed with histidine-tryptophan-ketoglutarate solution: a cautionary tale.
We reviewed pancreas transplantation outcomes after Histidine-Tryptophan-Ketoglutarate (HTK) and University of Wisconsin (UW) preservation solution use between 2001 and 2007 at two transplant centers. While equivalence has been claimed for kidney and liver transplant outcomes after the use of HTK or UW preservation solution, consensus has not been reached on equivalence when flushing pancreata. Others have reported comparable patient and graft survival rates, but found an association between the use of HTK and an increase in the incidence of acute rejection and pancreatitis. In reviewing our experiences, we found in pancreata flushed with HTK a higher incidence of postoperative complications including graft pancreatitis, use of octreotide and a decreased rate of insulin-independence at hospital discharge. These findings prompted us to critically review our centers' experience to determine if there is a basis for suspecting a causal relationship.


Developmental morphology of the middle ear.
The development of the murine middle ear was monitored both qualitatively and morphometrically by scanning electron microscopy from the 19th gestational day to the adult stage. At birth, the middle ear was less well developed than the inner ear. The tympanic membrane (TM) was obscured by occlusion of the external auditory canal. Ciliated cells and secretory granules were present in the middle ear epithelium already 5 days after birth (DAB). Keratin debris was discerned on the external layer of the TM 9 DAB. By 12 DAB, mesenchymal tissue had resorbed from the middle ear cavity, except around the upper part of the ossicles. The middle ear was immature at birth but developed rapidly until 12 DAB. When compared with the avian middle ear the mouse middle ear was basically similar to that of humans, although in the human the stapedial artery is vestigial whereas in the mouse it persists as an important vessel. In man, there is no orbicular apophysis and no gonial of the malleus. The hypotympanum of the human middle ear is less developed than that of the murine middle ear. The mouse external auditory canal matures postnatally until 12 DAB, while in humans its development is complete at birth.


Cell penetration properties of maurocalcine, a natural venom peptide active on the intracellular ryanodine receptor.
Maurocalcine (MCa) is a 33-amino acid residue peptide toxin initially isolated from the scorpion Scorpio maurus maurus. Its structural and functional features make it resembling many Cell Penetrating Peptides. In particular, MCa exhibits a characteristic positively charged face that may interact with membrane lipids. External application of MCa is known to produce Ca2+-release from intracellular stores within seconds. MCa binds directly to the skeletal muscle isoform of the ryanodine receptor, an intracellular channel target of the endoplasmic reticulum, and induces long-lasting channel openings in a mode of smaller conductance. The binding sites for MCa have been mapped within the cytoplasmic domain of the ryanodine receptor. In this manuscript, we further investigated how MCa proceeds to cross biological membranes in order to reach its target. A biotinylated derivative of MCa (MCab) was chemically synthesized, coupled to a fluorescent streptavidin indicator (Cy3 or Cy5) and the cell penetration of the entire complex followed by confocal microscopy and FACS analysis. The data provide evidence that MCa allows the penetration of the macro proteic complex and therefore may be used as a vector for the delivery of proteins in the cytoplasm as well as in the nucleus. Using both FACS and confocal analysis, we show that the cell penetration of the fluorescent complex is observed at concentrations as low as 10 nM, is sensitive to membrane potential and is partly inhibited by heparin. We also show that MCa interacts with the disialoganglioside GD3, the most abundant charged lipid in natural membranes. Despite its action on ryanodine receptor, MCa showed no sign of cell toxicity on HEK293 cells suggesting that it may have a wider application range. These data indicate that MCa may cross the plasma membrane directly by cell translocation and has a promising future as a carrier of various drugs and agents of therapeutic, diagnostic and technological value.


Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity.
In Heterodontus, a phylogenetically primitive shark species, the variable (VH), diversity (DH), joining (JH) segments, and constant (CH) exons are organized in individual approximately 18-20-kb "clusters." A single large VH family with > 90% nucleic acid homology and a monotypic second gene family are identified by extensive screening of a genomic DNA library. Little variation in the nucleotide sequences of DH segments from different germline gene clusters is evident, suggesting that the early role for DH was in promoting junctional diversity rather than contributing unique coding specificities. A gene-specific oligodeoxynucleotide screening method was used to relate specific transcription products (cDNAs) to individual gene clusters and showed that gene rearrangements are intra- rather than intercluster. This provides further evidence for restricted diversity in the immunoglobulin heavy chain of Heterodontus, from which it is inferred that combinatorial diversity is a more recently acquired means for generating diversity. The observed differences between cDNA sequences selected and the sequences of segmental elements derived from conventional genomic libraries as well as from VH segment-specific libraries generated by direct PCR amplification of genomic DNA indicate that the VH repertoire is diversified by both junctional diversity and somatic mutation. Taken together, these findings suggest a heretofore unrecognized contribution of somatic variation that preceded both extensive diversification of the germline repertoire and the combinatorial joining process in the evolution of humoral immunity.


Acupuncture for essential hypertension.
To systematically assess the current clinical evidence of acupuncture for hypertension. The PubMed, EMBASE, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang Data in the Cochrane Library were searched until January, 2013. All the randomized controlled trials (RCTs) based on acupuncture compared with western medicine, sham acupuncture or lifestyle intervention in patients with hypertension were included. RCTs were included as well as combined acupuncture with western medicine compared with western medicine. In addition, RCTs based on acupuncture compared with sham acupuncture combined with western medicine in patients with essential hypertension were included. No language restriction was used. Review Manager 5.1 software was used for data analysis. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. 35 randomized trials (involving 2539 patients) were included. The methodological quality of the included trials was evaluated as generally low. Two trials reported the effect of acupuncture compared with sham acupuncture in combinations of western medicine. Acupuncture significantly reduced SBP (-7.47 mmHg, 95% CI - 10.43 to -4.5, P<0.00001) and DBP (-4.22 mmHg, 95% CI - 6.26 to -2.18, P<0.0001) and no heterogeneity between studies was detected. However, other studies had substantial heterogeneity due to the quality of them was poor, and their sample sizes were not satisfactory as an equivalence study. Five trials described the adverse effects. While there are some evidences that suggest potential effectiveness of acupuncture for hypertension, the results were limited by the methodological flaws of the studies. Therefore, further thorough investigation, large-scale, proper study designed, randomized trials of acupuncture for hypertension will be required to justify the effects reported here.


miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer.
The miRNAs have great potential as biomarkers and therapeutic agents owing to their ability to control multiple genes and potential to influence cellular behavior. Here, we identified that miR-23b is a methylation-silenced tumor suppressor in prostate cancer. We showed that miR-23b expression is controlled by promoter methylation and has great promise as a diagnostic and prognostic biomarker in prostate cancer. High levels of miR-23b expression are positively correlated with higher overall and recurrence-free survival in patients with prostate cancer. Furthermore, we elucidated the tumor suppressor role of miR-23b using in vitro and in vivo models. We showed that proto-oncogene Src kinase and Akt are direct targets of miR-23b. Increased expression of miR-23b inhibited proliferation, colony formation, migration/invasion, and triggered G(0)-G(1) cell-cycle arrest and apoptosis in prostate cancer. Overexpression of miR-23b inhibited epithelial-to-mesenchymal transition (EMT) causing a decline in mesenchymal markers Vimentin and Snail and increasing the epithelial marker, E-cadherin. Depletion of Src by RNA interference conferred similar functional effects as that of miR-23b reconstitution. miR-23b expression caused a dramatic decrease in tumor growth in nude mice and attenuated Src expression in excised tumors compared with a control miR. These findings suggest that miR-23b is a methylation-silenced tumor suppressor that may be a useful biomarker in prostate cancer. Loss of miR-23b may confer proliferative advantage and promote prostate cancer migration and invasion, and reexpression of miR-23b may contribute to the epigenetic therapy for prostate cancer.


Standardized manual palpation of myofascial trigger points in relation to neck/shoulder pain; the influence of clinical experience on inter-examiner reproducibility.
A diagnosis of Myofascial Pain Syndrome (MPS) requires palpation for the identification of at least one clinically relevant trigger point (TP). However, few comparable, high quality studies currently exist from which to draw firm conclusions regarding the robustness of TP examination. An inter-observer agreement study was conducted using two experienced and two inexperienced clinicians. All performed standardized palpation of the upper Trapezius musculature, judging the clinical relevance of TP(s) using clinician global assessment (GA). A random case mix of 81 female participants was examined, 14 asymptomatic and the remainder suffering from neck/shoulder pain. Examiners received psychomotor skills training and video feedback analysis to improve protocol standardization. Kappa co-efficient calculations indicated good agreement between the experienced pairing (κ = 0.63), moderate agreement between the mixed pairings (κ = 0.35 and 0.47) and poor agreement between the inexperienced pairing (κ = 0.22). Inter-observer agreement was not stable with the experienced pairing exhibiting a sharp decline in agreement during the latter portion of the study. Identification of clinically relevant TPs of the upper Trapezius musculature is reproducible when performed by two experienced clinicians, however, a mixed observer pairing can yield acceptable agreement. A protracted period of data collection may be detrimental to inter-observer agreement; more investigation is needed in this regard.


Automated calibration and control for polarization-resolved second harmonic generation on commercial microscopes.
Polarization-resolved second harmonic generation (P-SHG) microscopy has evolved as a promising technique to reveal subresolution information about the structure and orientation of ordered biological macromolecules. To extend the adoption of the technique, it should be easily integrated onto commercial laser scanning microscopes. Furthermore, procedures for easy calibration and assessment of measurement accuracy are essential, and measurements should be fully automated to allow for analysis of large quantities of samples. In this paper we present a setup for P-SHG which is readily incorporated on commercial multiphoton microscopes. The entire system is completely automated which allows for rapid calibration through the freely available software and for automated imaging for different polarization measurements, including linear and circular polarization of the excitation beam. The results show that calibration settings are highly system dependent. We also show that the accuracy of the polarization control is easily quantified and that it varies between systems. The accuracy can be tuned by iterative alignment of optics or a more fine-grained calibration procedure. Images of real samples show that the red accuracy of the results is easily visualized with the automated setup. Through this system we believe that P-SHG could develop a wider adoption in biomedical applications.


Qualitative analysis of psychosocial impact of diagnosis of Chlamydia trachomatis: implications for screening.
To investigate the psychosocial impact for women of a diagnosis of Chlamydia trachomatis and discuss the implications for the proposed UK chlamydia screening programme. Qualitative study with semistructured interviews. Interview transcripts analysed to identify recurrent themes. Seventeen women with a current or recent diagnosis of chlamydia. A family planning clinic and a genitourinary medicine clinic in Glasgow. Three themes were identified: perceptions of stigma associated with sexually transmitted infection, uncertainty about reproductive health after diagnosis, and anxieties regarding partner's reaction to diagnosis. Most women had not previously perceived sexually transmitted infections as personally relevant; this was a function of stereotypical beliefs about who was "at risk" of sexually transmitted infection. These beliefs were pervasive and negatively affected reactions to diagnosis and produced anxiety about disclosure of the condition to others (particularly sexual partners) and future reproductive morbidity. This anxiety, given the uncertain natural history of chlamydia, may prove difficult to dispel. There are three primary areas of concern for women after a diagnosis of chlamydia which need to be examined in the proposed screening programme. Information provided should normalise and destigmatise chlamydial infection and positively promote genitourinary medicine services. Support services should be available because notification of partner can cause anxiety. Uncertainty about future reproductive morbidity may be inevitable; staff providing screening will require guidance in providing advice under such conditions.


Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder.
Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD.


The role of cognitive impairment in general functioning in major depression.
The association between cognitive performance and general functioning in depression is controversial. The present study evaluated the association between cognitive dysfunction and major depressive disorder (MDD, N=70) as compared with age- and gender-matched healthy controls (n=206) and its relationship to general functioning (physical and mental health quality of life, activities of daily living, and employment status) in participants with current MDD (n=26) and those with previous MDD only (n=44). Participants were assessed clinically using the Mini International Neuropsychiatric Interview (M.I.N.I.) for the depression groups and the Diagnostic Interview for Psychoses (DIP-DM) for the control group. Measures to evaluate cognition and quality of lifes comprised the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Short Form-36 Health Survey Questionnaire, and the Activities/Instrumental Activities of Daily Living (ADL/IADL); employment status was also assessed in MDD. The results showed that a) while individuals with current depression had worse cognitive performance in all domains than healthy controls, those individuals with previous depression had lasting cognitive impairments in the domains of immediate memory and attention as compared with healthy controls; b) individuals with current depression had lower scores in the visuospatial/constructional and attention domains and the total score than individuals with previous depression; c) individuals in the depression group as a whole who were currently unemployed had significantly lower scores in all domains (except attention) of cognitive function; d) cognitive function was not related to either physical or mental quality of life or impairments of activities of daily living (ADL, IADL); e) that unemployment in previous depression was related to poor cognitive function similar to those with current depression. The results indicate that MDD may have detrimental and lasting effects on cognitive performance partly related to poorer general functioning.