An analysis of free-choice electives in an undergraduate medical degree.
The University College Dublin Elective Programme was introduced in 2005 with the intention of broadening the learning of its undergraduate students. Undergraduate medical students undertake seven free-choice electives during their six-year degree programme. They are permitted to choose electives from any school in the University. Students also have the option of selecting 'In-Programme' electives, which are aligned to medical themes. The purpose of this study is to analyse the electives taken by medical students with a view to better understanding the factors that influence their choices. In this mixed methodology study, the quantitative phase consisted of a retrospective analysis of 3318 elective choices associated with 474 medical students between 2006 and 2013. Elective choices were analysed in terms of popularity, difficulty level and subject matter. The prospective qualitative phase consisted of a series of semi-structured focus groups held with current medical students. Discussions from the focus groups underwent thematic analysis with a few to exploring and clarifying the quantitative findings. The most frequently chosen electives were In-Programme (38.6%) and Applied Language (21.6%) electives, with patterns not significantly varying from year to year. Male and female students tended to take the same type of electives. Focus group discussions revealed that the primary factor motivating choice was workload, with students preferring less demanding electives. Participants indicated that elective grading and assessment criteria had a significant impact on their choices. Participants described ways in which the elective selection process could be improved, including a desire for more structured electives and a revision of the elective selection process. The retrospective data analysis revealed a high level of consistency in medical students' elective choices from stage to stage and between different year cohorts. Qualitative investigation revealed that medical students tend to focus on grading, assessment strategies and skills development when choosing their electives. The implication that students may be reluctant to take more challenging electives despite having an interest in the subject is one that warrants consideration when designing or adapting programmes for the future. Although these findings are associated with a free-choice elective programme, similar strategies are likely to be employed for the more traditional option-based programmes that are associated with the majority of medical degrees internationally.


Outbreak of Salmonella Newport infections linked to cucumbers--United States, 2014.
In August 2014, PulseNet, the national molecular subtyping network for foodborne disease surveillance, detected a multistate cluster of Salmonella enterica serotype Newport infections with an indistinguishable pulse-field gel electrophoresis (PFGE) pattern (XbaI PFGE pattern JJPX01.0061). Outbreaks of illnesses associated with this PFGE pattern have previously been linked to consumption of tomatoes harvested from Virginia's Eastern Shore in the Delmarva region and have not been linked to cucumbers or other produce items. To identify the contaminated food and find the source of the contamination, CDC, state and local health and agriculture departments and laboratories, and the Food and Drug Administration (FDA) conducted epidemiologic, traceback, and laboratory investigations. A total of 275 patients in 29 states and the District of Columbia were identified, with illness onsets occurring during May 20-September 30, 2014. Whole genome sequencing (WGS), a highly discriminating subtyping method, was used to further characterize PFGE pattern JJPX01.0061 isolates. Epidemiologic, microbiologic, and product traceback evidence suggests that cucumbers were a source of Salmonella Newport infections in this outbreak. The epidemiologic link to a novel outbreak vehicle suggests an environmental reservoir for Salmonella in the Delmarva region that should be identified and mitigated to prevent future outbreaks.


Metabolic profiling of zebrafish embryo development from blastula period to early larval stages.
The zebrafish embryo is a popular model for drug screening, disease modelling and molecular genetics. In this study, samples were obtained from zebrafish at different developmental stages. The stages that were chosen were 3/4, 4/5, 24, 48, 72 and 96 hours post fertilization (hpf). Each sample included fifty embryos. The samples were analysed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Principle component analysis (PCA) was applied to get an overview of the data and orthogonal projection to latent structure discriminant analysis (OPLS-DA) was utilised to discriminate between the developmental stages. In this way, changes in metabolite profiles during vertebrate development could be identified. Using a GC-TOF-MS metabolomics approach it was found that nucleotides and metabolic fuel (glucose) were elevated at early stages of embryogenesis, whereas at later stages amino acids and intermediates in the Krebs cycle were abundant. This agrees with zebrafish developmental biology, as organs such as the liver and pancreas develop at later stages. Thus, metabolomics of zebrafish embryos offers a unique opportunity to investigate large scale changes in metabolic processes during important developmental stages in vertebrate development. In terms of stability of the metabolic profile and viability of the embryos, it was concluded at 72 hpf was a suitable time point for the use of zebrafish as a model system in numerous scientific applications.


The effect of Me2SO overexposure during cryopreservation on HOS TE85 and hMSC viability, growth and quality.
With the cell therapy industry continuing to grow, the ability to preserve clinical grade cells, including mesenchymal stem cells (MSCs), whilst retaining cell viability and function remains critical for the generation of off-the-shelf therapies. Cryopreservation of MSCs, using slow freezing, is an established process at lab scale. However, the cytotoxicity of cryoprotectants, like Me2SO, raises questions about the impact of prolonged cell exposure to cryoprotectant at temperatures >0 °C during processing of large cell batches for allogenic therapies prior to rapid cooling in a controlled rate freezer or in the clinic prior to administration. Here we show that exposure of human bone marrow derived MSCs to Me2SO for ≥1 h before freezing, or after thawing, degrades membrane integrity, short-term cell attachment efficiency and alters cell immunophenotype. After 2 h's exposure to Me2SO at 37 °C post-thaw, membrane integrity dropped to ∼70% and only ∼50% of cells retained the ability to adhere to tissue culture plastic. Furthermore, only 70% of the recovered MSCs retained an immunophenotype consistent with the ISCT minimal criteria after exposure. We also saw a similar loss of membrane integrity and attachment efficiency after exposing osteoblast (HOS TE85) cells to Me2SO before, and after, cryopreservation. Overall, these results show that freezing medium exposure is a critical determinant of product quality as process scale increases. Defining and reporting cell sensitivity to freezing medium exposure, both before and after cryopreservation, enables a fair judgement of how scalable a particular cryopreservation process can be, and consequently whether the therapy has commercial feasibility.


Analysis of behavioral change techniques in community-led total sanitation programs.
The lack of sanitation facilitates the spread of diarrheal diseases-a leading cause of child deaths worldwide. As of 2012, an estimated 1 billion people still practiced open defecation (OD). To address this issue, one behavioral change approach used is community-led total sanitation (CLTS). It is now applied in an estimated 66 countries worldwide, and many countries have adopted this approach as their main strategy for scaling up rural sanitation coverage. While it appears that many of the activities used in CLTS-that target community-level changes in sanitation behaviors instead of household-level changes-have evolved out of existing behavior change frameworks and techniques, it is less clear how these activities are adapted by different organizations and applied in different country contexts. The aims of this study are to (i) show which behavior change frameworks and techniques are the most common in CLTS interventions; (ii) describe how activities are implemented in CLTS interventions by region and context; and (3) determine which activities program implementers considered the most valuable in achieving open defecation free (ODF) status and sustaining it. The results indicate that a wide range of activities are conducted across the different programs and often go beyond standard CLTS activities. CLTS practitioners ranked follow-up and monitoring activities as the most important activities for achieving an ODF community, yet only 1 of 10 organizations conducted monitoring and follow-up throughout their project. Empirical studies are needed to determine which specific behavioral change activities are most effective at ending OD and sustaining it.


CD40 and IgE: synergism between anti-CD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells.
A novel pathway of IgE-B cell differentiation has been identified. Engagement of the B cell antigen CD40 by F(ab')2 fragments of monoclonal antibody (mAb) 626.1 in the presence of recombinant interleukin 4 (rIL-4) induced intense IgE synthesis, but modest IgG synthesis, by highly purified human B cells. Surface IgE- B cells isolated by cell sorting were induced to produce IgE by mAb 626.1 and IL-4. Thus, IgE synthesis is unlikely to result from expansion of a B cell population precommitted to IgE in vivo. A neutralizing anti-IL-6 antibody strongly, but not completely, inhibited the IgE response. This indicates that autocrine production of IL-6 plays an important amplification role in IgE synthesis triggered by anti-CD40 mAb and IL-4. Although the exact role played by CD40 in IgE responses in vivo remains to be established, this T cell-independent system represents a useful model to characterize the biochemical and molecular events leading to IgE synthesis in human B cells.


Sanchi for acute ischaemic stroke.
Currently very few drugs are supported for routine use for acute ischaemic stroke. Sanchi is one of the most widely used herbal medicines for ischaemic stroke in China. To assess the effectiveness and safety of sanchi in the treatment of acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched January 2008), the Chinese Stroke Trials Register (searched February 2007), the Cochrane Complementary Medicine Field trials register (searched February 2007), the Chinese Cochrane Centre Controlled Trials Register (last searched February 2007). We also searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2007), MEDLINE (1966 to February 2007), EMBASE (1980 to February 2007), CINAHL (1982 to February 2007), AMED (1985 to February 2007), CNKI (1979 to February 2007), CBM-disc (1979 to February 2007), Chinese scientific periodical database of VIP INFORMATION (1989 to February 2007), Wanfang Data (1982 to February 2007), CISCOM (1980 to February 2007), and TCMLARS (1984 to February 2007). Randomised controlled trials comparing sanchi with placebo or no treatment for acute ischaemic stroke within 30 days of onset. Two review authors extracted data and assessed trial quality. Eight trials involving 660 participants were included. Seven of the eight studies were of poor quality. Follow-up time was less than one month in six trials. Only two trials provided data for the number of participants who were dead or dependent at the end of 28 days of treatment, indicating a significantly lower rate of death and dependency in the sanchi group than in the control group (relative risk (RR) 0.63, 95% confidence interval (Cl) 0.45 to 0.88). One trial reported higher Barthel index scores in the sanchi group. Pooled analysis of seven trials indicated that sanchi might improve neurological deficit more than control with a significant difference (RR 0.29, 95%Cl 0.18 to 0.47). The total case fatality rate was lower than 1% indicating that participants probably had mild strokes. Few adverse events were reported. Data were limited in respect of stroke recurrence and quality of life. Sanchi appears to be beneficial and safe for acute ischaemic stroke in this review, but the small sample and inferior quality of studies prevented a definite conclusion. More well-designed randomised controlled trials are required.


Accuracy of developing tooth length as an estimate of age in human skeletal remains: the permanent dentition.
In this study, the accuracy of regression equations of developing permanent tooth length for age estimation (Liversidge and Molleson. J Forensic Sci. 1999;44:917) is tested on a sample of 88 Portuguese juvenile skeletons of known age at death. Results reveal an overall high accuracy for the method, showing an average difference between estimated and chronological age between 0.56 and 0.05 years, when using single teeth and 0.16 years, when using all available teeth. Accuracy tests indicate that age estimates can be obtained within +/-0.17 years with a 95% confidence interval when several teeth are used. Overall between-tooth agreement in age estimates decreases with increasing age but there is less variability of estimates with more teeth contributing to overall mean age. However, there is a tendency for overestimation of age of younger individuals (<6 years) and of age obtained from half of the dentition. Although the advantages of this technique probably make it the preferred method of age estimation of human immature skeletal remains, when microstructural methods are not an option, a possible positive secular trend effect and differences in socioeconomic conditions detected between populations may warrant caution in its applicability to modern forensic cases.


Pathology and regulation for research in the UK: an overview.
The input of pathologists is essential for the conduct of many forms of research, including clinical trials. As the custodians of patient samples, pathology departments have a duty to ensure compliance with the relevant regulations, standards and guidelines to ensure the ethical and effective use for their intended investigational analysis. This includes where patients are participating in a research study. The results of research studies have impacts beyond the research study itself as they may inform changes in policy and practice or support the licensing of medicines and devices. Compliance with regulations and standards provides public assurance that the rights, safety and wellbeing of research participants are protected, that the data have been collected and processed to ensure their integrity and that the research will achieve its purpose. The requirements of the regulatory environment should not be seen as a barrier to research and should not significantly impact on the work of the laboratory once established and integrated into practice. This paper highlights important regulations, policy, standards and available guidance documents that apply to research involving NHS pathology departments and academic laboratories that are contributing to research involving human subjects.


Environment shapes sleep patterns in a wild nocturnal primate.
Among primates, the suborder Haplorhini is considered to have evolved a consolidated monophasic sleep pattern, with diurnal species requiring a shorter sleep duration than nocturnal species. Only a few primate species have been systematically studied in their natural habitat where environmental variables, including temperature and light, have a major influence on sleep and activity patterns. Here we report the first sleep study on a nocturnal primate performed in the wild. We fitted seven wild Javan slow lorises (Nycticebus javanicus) in West Java, Indonesia with accelerometers that collected activity data, and installed climate loggers in each individual's home range to collect ambient temperature readings (over 321 days in total). All individuals showed a strictly nocturnal pattern of activity and displayed a striking synchronisation of onset and cessation of activity in relation to sunset and sunrise. The longest consolidated rest episodes were typically clustered near the beginning and towards the end of the light period, and this pattern was inversely related to daily fluctuations of the ambient temperature. The striking relationship between daily activity patterns, light levels and temperature suggests a major role of the environment in shaping the daily architecture of waking and sleep. We concluded that well-known phenotypic variability in daily sleep amount and architecture across species may represent an adaptation to changes in the environment. Our data suggest that the consolidated monophasic sleep patterns shaped by environmental pressures observed in slow lorises represent phylogenetic inertia in the evolution of sleep patterns in humans.


City Forensics: Using Visual Elements to Predict Non-Visual City Attributes.
We present a method for automatically identifying and validating predictive relationships between the visual appearance of a city and its non-visual attributes (e.g. crime statistics, housing prices, population density etc.). Given a set of street-level images and (location, city-attribute-value) pairs of measurements, we first identify visual elements in the images that are discriminative of the attribute. We then train a predictor by learning a set of weights over these elements using non-linear Support Vector Regression. To perform these operations efficiently, we implement a scalable distributed processing framework that speeds up the main computational bottleneck (extracting visual elements) by an order of magnitude. This speedup allows us to investigate a variety of city attributes across 6 different American cities. We find that indeed there is a predictive relationship between visual elements and a number of city attributes including violent crime rates, theft rates, housing prices, population density, tree presence, graffiti presence, and the perception of danger. We also test human performance for predicting theft based on street-level images and show that our predictor outperforms this baseline with 33% higher accuracy on average. Finally, we present three prototype applications that use our system to (1) define the visual boundary of city neighborhoods, (2) generate walking directions that avoid or seek out exposure to city attributes, and (3) validate user-specified visual elements for prediction.


A System for Information Management in BioMedical Studies--SIMBioMS.
SIMBioMS is a web-based open source software system for managing data and information in biomedical studies. It provides a solution for the collection, storage, management and retrieval of information about research subjects and biomedical samples, as well as experimental data obtained using a range of high-throughput technologies, including gene expression, genotyping, proteomics and metabonomics. The system can easily be customized and has proven to be successful in several large-scale multi-site collaborative projects. It is compatible with emerging functional genomics data standards and provides data import and export in accepted standard formats. Protocols for transferring data to durable archives at the European Bioinformatics Institute have been implemented. The source code, documentation and initialization scripts are available at http://simbioms.org.


A proposal for a quality control protocol in breast CT with synchrotron radiation.
Background The SYRMA-3D collaboration is setting up the first clinical trial of phase-contrast breast CT with synchrotron radiation at the Elettra synchrotron facility in Trieste, Italy. In this communication, a quality control protocol for breast CT is proposed, and a first test of image quality measurements is performed by means of a custom-made radiographic phantom. Materials and methods A set of projections is acquired and used to perform a CT reconstruction of two selected portions of the phantom. Such portions contain a uniform layer of water and a set of radiographic inserts, respectively. Together, they allow to perform several image quality measurements, namely CT number linearity, reconstruction accuracy, uniformity, noise, and low contrast resolution. All measurements are repeated at different beam energies in the range of interest, and at two different dose values. Results Measurements show a good linearity in the soft tissue range, paired to a high accuracy of the CT number reconstruction. Uniformity and noise measurements show that reconstruction inhomogeneities are bound to a few percent of the average pixel values. However, low contrast detectability is limited to the higher portion of the explored energy range. Conclusions The results of the measurements are satisfactory in terms of their quality, feasibility and reproducibility. With minimal modifications, the phantom is promising to allow a set of image quality measurements to be used in the upcoming clinical trial.


Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11,575 patients.
This study sought to establish the risk ratio for mortality associated with calcium antagonists in a large population of patients with chronic coronary artery disease. Recent reports have suggested that the use of short-acting nifedipine may cause an increase in overall mortality in patients with coronary artery disease and that a similar effect may be produced by other calcium antagonists, in particular those of the dihydropyridine type. Mortality data were obtained for 11,575 patients screened for the Bezafibrate Infarction Prevention study (5,843 with and 5,732 without calcium antagonists) after a mean follow-up period of 3.2 years. There were 495 deaths (8.5%) in the calcium antagonist group compared with 410 in the control group (7.2%). The age-adjusted risk ratio for mortality was 1.08 (95% confidence interval [CI] 0.95 to 1.24). After adjustment for the differences between the groups in age and gender and the prevalence of previous myocardial infarction, angina pectoris, hypertension, New York Heart Association functional class, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes and current smoking, the adjusted risk ratio declined to 0.97 (95% CI 0.84 to 1.11). After further adjustment for concomitant medication, the risk ratio was estimated at 0.94 (95% CI 0.82 to 1.08). The current analysis does not support the claim that calcium antagonist therapy in patients with chronic coronary artery disease, whether myocardial infarction survivors or others harbors an increased risk of mortality.


Unrelated facultative endosymbionts protect aphids against a fungal pathogen.
The importance of microbial facultative endosymbionts to insects is increasingly being recognized, but our understanding of how the fitness effects of infection are distributed across symbiont taxa is limited. In the pea aphid, some of the seven known species of facultative symbionts influence their host's resistance to natural enemies, including parasitoid wasps and a pathogenic fungus. Here we show that protection against this entomopathogen, Pandora neoaphidis, can be conferred by strains of four distantly related symbionts (in the genera Regiella, Rickettsia, Rickettsiella and Spiroplasma). They reduce mortality and also decrease fungal sporulation on dead aphids which may help protect nearby genetically identical insects. Pea aphids thus obtain protection from natural enemies through association with a wider range of microbial associates than has previously been thought. Providing resistance against natural enemies appears to be a particularly common way for facultative endosymbionts to increase in frequency within host populations.


Diagnostic accuracy of contrast echocardiography during adenosine stress for detection of abnormal myocardial perfusion: a prospective comparison with technetium-99 m sestamibi single-photon emission computed tomography.
Myocardial contrast echocardiography (MCE) utilizes compressible microbubbles behaving similarly to red blood cells. Destruction of microbubbles and observation of the gradual refill into the myocardium are key to evaluating perfusion using real-time MCE. We aimed to assess the feasibility and diagnostic accuracy of qualitative MCE utilizing a 17-segment model for localization of myocardial perfusion abnormalities compared with simultaneous technetium-99 m sestamibi single-photon emission computed tomography (SPECT). From July 2005 through August 2007, 97 patients with known or suspected coronary artery disease underwent simultaneous SPECT and realtime MCE during adenosine stress. Qualitative MCE and tracer uptake were analyzed visually using a 17-segment model in a blinded manner. Diagnostic accuracy and 95% confidence interval (CI) were determined. Myocardial contrast echocardiography was completed in 91 patients (age, mean [SD], 69.3 [10.9] years; body mass index, 30.0 [6.3]; 59 males [65%]). Myocardial contrast echocardiography analysis was feasible in 88 (97%) patients (261 of 264 [99%] territories; 1299 of 1497 [87%] segments). At patient level, MCE sensitivity was 88% (95% CI, 79%-94%); specificity was 85% (77%-90%). For disease detection in individual coronary territories, sensitivity and specificity were 84% (71%-92%) and 79% (72%-84%) for the left anterior descending artery; 62% (38%-80%) and 88% (83%-91%) for the left circumflex artery; and 73% (57%-82%) and 94% (89%-97%) for the right coronary artery. For MCE combined with wall-motion analysis, concordance with SPECT improved from 80% to 86%. Myocardial contrast echocardiography interobserver concordance was 81% (kappa [SE], 0.611 [0.78]). Myocardial contrast echocardiography accuracy was comparable in patients classified in accordance with presence of diabetes mellitus, myocardial infarction, hypertension, or percutaneous coronary intervention. Improved MCE specificity in detecting perfusion defects was seen in patients with no history of coronary bypass graft surgery (P = 0.005). Real-time MCE with a 17-segment model for analysis has good feasibility and accuracy in evaluation of myocardial perfusion during adenosine stress.


Anesthesia Care Transitions and Risk of Postoperative Complications.
A patient undergoing surgery may receive anesthesia care from several anesthesia providers. The safety of anesthesia care transitions has not been evaluated. Using unconditional and conditional multivariable logistic regression models, we tested whether the number of attending anesthesiologists involved in an operation was associated with postoperative complications. In a cohort of patients undergoing elective colorectal surgical in an academic tertiary care center with a stable anesthesia care team model participating in the American College of Surgeons National Surgical Quality Improvement Program, using unconditional and conditional multivariable logistic regression models, we tested adjusted associations between numbers of attending anesthesiologists and occurrence of death or a major complication (acute renal failure, bleeding that required a transfusion of 4 units or more of red blood cells within 72 hours after surgery, cardiac arrest requiring cardiopulmonary resuscitation, coma of 24 hours or longer, myocardial infarction, unplanned intubation, ventilator use for 48 hours or more, pneumonia, stroke, wound disruption, deep or organ-space surgical-site infection, superficial surgical-site infection, sepsis, septic shock, systemic inflammatory response syndrome). We identified 927 patients who underwent elective colectomy of comparable surgical intensity. In all, 71 (7.7%) patients had major nonfatal complications or death. One anesthesiologist provided care for 530 (57%) patients, 2 anesthesiologists for 287 (31%), and 3 or more for 110 (12%). The number of attending anesthesiologists was associated with increased odds of postoperative complication (unadjusted odds ratio [OR] = 1.52, 95% confidence interval [CI] 1.18-1.96, P = 0.0013; adjusted OR = 1.44, 95% CI 1.09-1.91, P = 0.0106). In sensitivity analyses, occurrence of a complication was significantly associated with the number of in-room providers, defined as anesthesia residents and nurse anesthetists (adjusted OR = 1.39, 95% CI 1.01-1.92, P = 0.0446) and for all anesthesia providers (adjusted OR = 1.58, 95%CI 1.20-2.08, P = 0.0012). Findings persisted across multiple, alternative adjustments, sensitivity analyses, and conditional logistic regression with matching on operative duration. In our study, care by additional attending anesthesiologists and in-room providers was independently associated with an increased odds of postoperative complications. These findings challenge the assumption that anesthesia transitions are care neutral and not contributory to surgical outcomes.


Placental findings in singleton stillbirths.
To compare placental lesions for stillbirth cases and live birth controls in a population-based study. Pathologic examinations were performed on placentas from singleton pregnancies using a standard protocol. Data were analyzed overall and within gestational age groups at delivery. Placentas from 518 stillbirths and 1,200 live births were studied. Single umbilical artery was present in 7.7% of stillbirths and 1.7% of live births, velamentous cord insertion was present in 5% of stillbirths and 1.1% of live births, diffuse terminal villous immaturity was present in 10.3% of stillbirths and 2.3% of live births, inflammation (eg, acute chorioamnionitis of placental membranes) was present in 30.4% of stillbirths and 12% of live births, vascular degenerative changes in chorionic plate were present in 55.7% of stillbirths and 0.5% of live births, retroplacental hematoma was present in 23.8% of stillbirths and 4.2% of live births, intraparenchymal thrombi was present in 19.7% of stillbirths and 13.3% of live births, parenchymal infarction was present in 10.9% of stillbirths and 4.4% of live births, fibrin deposition was present in 9.2% of stillbirths and 1.5% of live births, fetal vascular thrombi was present in 23% of stillbirths and 7% of live births, avascular villi was present in 7.6% of stillbirths and 2.0% of live births, and hydrops was present in 6.4% of stillbirths and 1.0% of live births. Among stillbirths, inflammation and retroplacental hematoma were more common in placentas from early deliveries, whereas thrombotic lesions were more common in later gestation. Inflammatory lesions were especially common in early live births. Placental lesions were highly associated with stillbirth compared with live births. All lesions associated with stillbirth were found in live births but often with variations by gestational age at delivery. Knowledge of lesion prevalence within gestational age groups in both stillbirths and live birth controls contributes to an understanding of the association between placental abnormality and stillbirth. II.


A Common CDH13 Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD.
The cell-cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.


Who Is Exposed to Harmful Online Content? The Role of Risk and Protective Factors Among Czech, Finnish, and Spanish Adolescents.
Although adolescents' exposure to harmful online content has been linked to decreased subjective well-being and offline risky behaviors, there is limited research on the factors that underlie such problematic online behavior. Using the conceptual framework of Problem Behavior Theory, this study examined the role of risk (i.e., emotional problems, sensation seeking) and protective (i.e., the quality of family environment, social support from friends) factors in exposure to harmful online content among 4473 12- to 16-year-olds (M = 13.9, SD = 1.3, 49% girls) in the Czech Republic, Finland, and Spain. Individual country samples included 1848 adolescents from the Czech Republic (age: M = 14, SD = 1.4; 51% girls), 788 from Finland (age: M = 13.9, SD = 1.3; 52% girls), and 1837 from Spain (age: M = 13.5, SD = 1.2; 47% girls). In all of the sampled countries, emotional problems and sensation seeking served as risk factors, whereas good family relationships were protective. In some countries, the effects of emotional problems and sensation seeking were moderated by the quality of the family environment and social support from friends. These moderating effects suggest that individual risk factors for exposure to harmful online content may be buffered by a positive family environment and friends' support. The findings revealed similarities in the risk and protective factors underlying online problem behavior across three different countries. They demonstrate that the mechanisms proposed by Problem Behavior Theory can help to understand the etiology of adolescent problem behavior across different countries as well as offline and online contexts.


A phase II randomized double-blind placebo-controlled study of 6-gingerol as an anti-emetic in solid tumor patients receiving moderately to highly emetogenic chemotherapy.
6-Gingerol is a natural compound extracted from ginger. Preclinical studies demonstrated that 6-gingerol has an anti-emetic activity by inhibiting neurokinin-1, serotonin, and dopamine receptors. Several clinical trials examined crude ginger powder for preventing chemotherapy-induced nausea and vomiting (CINV), but none of them was conducted with a standardized bioactive compound. Patients who received moderately to highly emetogenic adjuvant chemotherapy were randomized to receive 6-gingerol 10 mg or placebo orally twice daily for 12 weeks. Ondansetron, metoclopramide, and dexamethasone were given to all patients. The primary endpoint was complete response (CR) rate defined as no emesis or rescue treatment at any time. Eighty-eight patients were randomized to receive 6-gingerol (N = 42) or placebo (N = 46). Most patients received highly emetogenic chemotherapy (93%). Overall CR rate was significantly higher in 6-gingerol group as compared with that of the placebo (77 vs. 32%; P < 0.001). The difference in means of appetite score was significant (P = 0.001) and more noticeable over time. Mean FACT-G score indicating quality of life was significantly higher (86.21) in 6-gingerol group at 64 days as compared with that of placebo group (72.36) (P < 0.001). No toxicity related to 6-gingerol was observed. Patients treated with 6-gingerol reported significantly less grade 3 fatigue (2 vs. 20%; P = 0.020). 6-Gingerol significantly improved overall CR rate in CINV, appetite and quality of life in cancer patients receiving adjuvant chemotherapy. A phase III randomized study of 6-gingerol is warranted to confirm these results.


Assessment on latitudinal tree species richness using environmental factors in the southeastern United States.
The southeastern region of the United States exhibits an unusual trend of decreasing tree species richness (TSR) from higher to lower latitudes over the Florida peninsula. This trend contradicts the widely marked latitudinal diversity gradient where species richness is highest in tropical zones and decreases towards extratropical regions. This study aims to assess the environmental factors that prompt this atypical inverse latitudinal gradient seen in TSR using the USDA Forest Service's Forest Inventory and Analysis (FIA) database. Fifteen variables under four categories of forested area, groundwater, soil properties, and climate groups were examined to model TSR in the region. Generalized linear models (GLMs) with Poisson distributions first assessed individual variables to test explanatory power then the LASSO regularization method was utilized to extract two subsets of the most influential variables to predict TSR. Forest area and four climate variables (mean annual temperature, precipitation seasonality, mean temperature of coldest quarter, and mean precipitation of driest quarter) were the top five variables during the initial GLM assessment implying their potential individual influence in regulating TSR. Two subsets of LASSO models contained seven and three predictor variables, respectively. Frist subset includes seven predictors, presented in highest to low standardized coefficient, mean temperature of coldest quarter, forested area, precipitation seasonality, mean precipitation of driest quarter, water table depth, spodosol, and available water storage. The other subset further excluded four lowest influential variables from the first set, leaving the top three variables from the first subset. The first subset of the LASSO model predicted TSR with 63.4% explained deviance while the second subset reproduced 60.2% of deviance explained. With only three variables used, the second model outperformed the first model evaluated by the AIC value. We conclude that forest patch area, mean temperature of coldest quarter, and precipitation seasonality are the highly influential variables of TSR among environmental factors in the southeastern region of U.S., but evolutionary or historic cause should be further incorporated to fully understand tree species diversity pattern in this region.


Predictors of mortality in trauma patients.
The purpose of this study was to ascertain risk factors for death from trauma. The large cohort allows for simultaneous evaluation of known mortality risk factors along with controlling for factors to assess the influence of each independently. Individually, base deficit, temperature, hypotension, age, and injury severity have been shown to be associated with an increased risk of death. However, in the English literature, there is no data on the independent predictive power and interaction of these risk factors. A review of trauma registry parameters from 1995 to 2000 was used. Demographics, injury severity, physiological and hematological parameters, and time data were evaluated in a univariate analysis. Variables significantly associated with mortality were entered into a stepwise backward multiple logistic regression. There were 1276 deaths (8.9%) with 25 per cent of the deaths within 3 hours. The top four predictors of mortality in this group were partial thromboplastin time (OR 3.37, 95% CI: 2.51-4.52), positive head computed tomography result (OR, 2.47; 95% CI, 1.95-3.04), initial hemoglobin (OR, 1.69; 95% CI, 1.23-2.31), base deficit (OR, 1.62; 95% CI, 1.29-2.04), and trauma resuscitation bay systolic blood pressure (OR, 1.45; 95% CI, 1.11-1.88). We conclude that prognostic indicators of all-cause mortality after trauma, which remain independent in the presence of all other factors and are potentially treatable, included low hemoglobin, elevated prothrombin and partial thromboplastin time, low scene and trauma bay systolic pressure, and elevated base deficit. The independent indicators of mortality, which are untreatable, included head injury, increasing age, and Injury Severity Score.


Embolization of epistaxis and juvenile nasopharyngeal angiofibromas.
This article reviews arterial embolization of epistaxis and juvenile nasopharyngeal angiofibromas. A protocol for the complete and rapid exploration of epistaxis is suggested that is based upon which arteries providing blood to the nasal fossa may be responsible for the bleeding and the most optimal way for their demonstration and evaluation. The relevant anatomy of the major arteries, their branches, and important anastomoses are described. The goals of embolization are to control severe or recurrent epistaxis, prevent recurrence if possible, and avoid occlusion of any vessels not responsible for the hemorrhage. The most appropriate embolic material is chosen, realizing that recurrence can be caused by the use of resorbable embolic material or by a very proximal or too complete embolization. Embolization may be used for specific causes of epistaxis including idiopathic, hereditary hemorraghic telangiectasia, hemorrhagic tumors, vascular malformations, trauma, disorders of hemostasis, and postsurgical problems. Juvenile nasopharyngeal angiofibromas are discussed with respect to their clinical presentation, classification, computed tomographic, MR imaging, and angiographic evaluation, treatment, future trends in treatment, and precautions and complications.


Macromolecular design, nucleic acid junctions, and crystal formation.
The simplest form of macromolecular design involves the ligation of nucleic acids. Recent results on the concatenation of nucleic acid junctions show that these molecules can act as fairly rigid macromolecular valence clusters on the nanometer scale. These clusters can be joined to form closed stick figures in which each edge is double helical DNA or RNA and each vertex is a nucleic acid junction. The geometrical criteria for forming discrete-closed and periodic structures from these components are established. The helicity of each edge limits the possible structures that can be formed. The formation of a periodic array from nucleic acid junction building blocks is compared with the crystallization of molecular systems. This comparison leads to a new interpretation of the nature of order in the solid state for molecular crystals. The suggestion is made that the structure of a solid molecular system described by the fewest unique orthogonal (Fourier) components is the one which will be entropically favored, since it contains the least information. This is the crystalline state, with a small number of molecules per asymmetric unit. The free energy from the proposed entropic driving force responsible for this behavior is available, in principle, to correct small deviations from ideality in forming covalent crystals from nucleic acid junction components, as well as in non-bonded molecular systems. Nucleic acid junction periodic arrays provide an appropriate vehicle with which to test this interpretation.


The maximum a posteriori probability rule for atom column detection from HAADF STEM images.
Recently, the maximum a posteriori (MAP) probability rule has been proposed as an objective and quantitative method to detect atom columns and even single atoms from high-resolution high-angle annular dark-field (HAADF) scanning transmission electron microscopy (STEM) images. The method combines statistical parameter estimation and model-order selection using a Bayesian framework and has been shown to be especially useful for the analysis of the structure of beam-sensitive nanomaterials. In order to avoid beam damage, images of such materials are usually acquired using a limited incoming electron dose resulting in a low contrast-to-noise ratio (CNR) which makes visual inspection unreliable. This creates a need for an objective and quantitative approach. The present paper describes the methodology of the MAP probability rule, gives its step-by-step derivation and discusses its algorithmic implementation for atom column detection. In addition, simulation results are presented showing that the performance of the MAP probability rule to detect the correct number of atomic columns from HAADF STEM images is superior to that of other model-order selection criteria, including the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC). Moreover, the MAP probability rule is used as a tool to evaluate the relation between STEM image quality measures and atom detectability resulting in the introduction of the so-called integrated CNR (ICNR) as a new image quality measure that better correlates with atom detectability than conventional measures such as signal-to-noise ratio (SNR) and CNR.


New calculation of surface wave contributions associated with mie backscattering.
Diffracted field contributions to backscattering of an electromagnetic plane wave by a spherical particle are calculated. The diffracted fields give rise to surface waves in the shadow region and can be evaluated by finding surface wave poles and computing their residues. In order to compute the residues the valid range of the Schobe and Debye asymptotic expansion formulas for the Hankel function is examined. With these asymptotic formulas numerical values of the surface wave complex poles are tabulated. Curves for backscattering cross section due to the first six surface waves are presented as a function of the size parameter kappaa between 5 and 60 for absorbing spheres of refractive index m = 1.61-i0.0025 as well as nonabsorbing spheres with m = 1.60.


Infectious cDNA clone of the epidemic west nile virus from New York City.
We report the first full-length infectious clone of the current epidemic, lineage I, strain of West Nile virus (WNV). The full-length cDNA was constructed from reverse transcription-PCR products of viral RNA from an isolate collected during the year 2000 outbreak in New York City. It was cloned into plasmid pBR322 under the control of a T7 promoter and stably amplified in Escherichia coli HB101. RNA transcribed from the full-length cDNA clone was highly infectious upon transfection into BHK-21 cells, resulting in progeny virus with titers of 1 x 10(9) to 5 x 10(9) PFU/ml. The cDNA clone was engineered to contain three silent nucleotide changes to create a StyI site (C to A and A to G at nucleotides [nt] 8859 and 8862, respectively) and to knock out an EcoRI site (A to G at nt 8880). These genetic markers were retained in the recovered progeny virus. Deletion of the 3'-terminal 199 nt of the cDNA transcript abolished the infectivity of the RNA. The plaque morphology, in vitro growth characteristics in mammalian and insect cells, and virulence in adult mice were indistinguishable for the parental and recombinant viruses. The stable infectious cDNA clone of the epidemic lineage I strain will provide a valuable experimental system to study the pathogenesis and replication of WNV.


Intelligence in offspring born to women exposed to intimate partner violence: a population-based cohort study.
Background: Intimate partner violence (IPV) is a risk factor for developmental problems in offspring. Despite a high prevalence of IPV in the UK and elsewhere, the longer-term outcomes of offspring born to exposed mothers remain under-researched. Methods: Population-based cohort study. We assessed IPV prevalence by type and timing for 3,153 mother-child pairs with complete data within our study population and examined associations between IPV and offspring IQ. We used multiple-imputation to evaluate bias due to our exclusion of observations with missing covariate data. Results: Nearly one in five mothers reported IPV during the study period, with 17.6% reporting emotional violence and 6.8% reporting physical violence. Taking into account potential confounders, the IQ scores of children born to mothers exposed to physical violence remained lower than those of maternally unexposed children (full-scale IQ = -2.8 points [95%CI -4.9 to -0.7], verbal IQ = -2.2 [95%CI -4.4 to -0.1], performance IQ = -2.7 [95%CI -5.0 to -0.5]) and odds of below-average intelligence (IQ<90) remained increased for full-scale (OR 1.48 [95%CI 1.03 to 2.14] and performance IQ (OR 1.48 [95%CI 1.08 to 2.04]) but not verbal IQ (OR 1.06 [95%CI 0.69 to 1.64]). Most physical violence occurred postnatally, and relative odds were most substantial when mothers were exposed to violence across pre-/perinatal and postnatal study periods (OR performance IQ<90 = 2.97 [95%CI 1.30 to 6.82]). Conclusions: Maternal exposure to physical IPV is associated with lower offspring IQ at age 8. Associations persisted after adjusting for potential confounders and were driven by violence occurring postnatally.


First Report of Brown Ring Patch Caused by Waitea circinata var. circinata on Agrostis stolonifera and Poa pratensis in China.
Brown ring patch, caused by Waitea circinata var. circinata, is a recently described disease of turf grass (1,2). The disease was first reported in Japan in 2005 (2) and then in the United States (1). In late May to early September 2011, large yellow rings (20 to 30 cm in diameter) were observed on creeping bentgrass (Agrostis stolonifera) and Kentucky bluegrass (Poa pratensis) growing at the Qinghe Bay golf course, Beijing, China. Leaf blades turned from yellow to brown as the disease developed, and eventually died. The disease incidence was estimated at 20 to 30%. The rings became continuous on creeping bentgrass and Kentucky bluegrass in several putting greens. The same symptom was observed on the lawn of China Agricultural University. Symptomatic leaves were collected and incubated in high humidity at 25°C until mycelia developed. The leaves were then disinfested in 1% NaClO for 1 min, rinsed with sterile water three times, and placed on potato dextrose agar (PDA). Four isolates were obtained, including one isolate from the lawn of China Agricultural University (cau-1), and three from Qinghe Bay golf course (qhw-1, qhw-2, and qhw-3). The colonies that formed on PDA changed from white to orange over time, and minute orange to brown sclerotia (approx. 2 to 3 mm in diameter) formed after 2 weeks at 25°C. These characteristics were similar to W. circinata var. circinata (1,2). DNA was extracted from each isolate using a CTAB extraction method (3) and the internal transcribed spacer (ITS) regions were amplified with the ITS1/ITS4 universal primers. The ITS sequences of the isolated fungi (Accession Nos. JQ964235 and JQ964236) had 99 to 100% homology with the sequences of W. circinata in GenBank (Accession Nos. EU591763 and HQ207169). Pathogen inocula were prepared by inoculating autoclaved oat grains with strains qhw-1 and cau-1 respectively, followed by 4 days of incubation at 25°C. Each inoculum was placed in five spots in a uniform arrangement (5 g grain inoculum per spot) on soil in a 40 × 60 cm tray, followed by sowing bluegrass seed. In another experiment, 4-week-old bentgrass was transplanted into soil infested with 5 g grain inoculum in the middle of a 20-cm diameter pot (non-colonized grain was used as a control). There were five replicates for each isolate. Plants were then incubated in a growth chamber at 26°C and high relative humidity (>90%). After 5 to 6 days, the grass in the inoculated pots and trays began to turn yellow, and then became chlorotic and necrotic as the disease developed. Orange sclerotia were observed on the bluegrass leaves by the eighth day, and all the bentgrass turned chlorotic by the tenth day. After 2 weeks, brown ring patches formed in the trays with inoculated bluegrass. Waitea circinata var. circinata was reisolated from all inoculated plants and confirmed by morphological observation and the ITS sequences analysis as described above, while no symptoms were observed on the control plants and no isolate was obtained from them. To our knowledge, this is the first report of W. circinata var. circinata infecting turf grass in China. References: (1) K. A. De La Cerda et al. Plant Dis. 91:791, 2007. (2) T. Toda et al. Plant Dis. 89:536, 2005. (3) J. A. H. Van Burik et al. Med. Mycol. 36:299, 1998.


Comparative performance of lung cancer risk models to define lung screening eligibility in the United Kingdom.
The National Health Service England (NHS) classifies individuals as eligible for lung cancer screening using two risk prediction models, PLCOm2012 and Liverpool Lung Project-v2 (LLPv2). However, no study has compared the performance of lung cancer risk models in the UK. We analysed current and former smokers aged 40-80 years in the UK Biobank (N = 217,199), EPIC-UK (N = 30,813), and Generations Study (N = 25,777). We quantified model calibration (ratio of expected to observed cases, E/O) and discrimination (AUC). Risk discrimination in UK Biobank was best for the Lung Cancer Death Risk Assessment Tool (LCDRAT, AUC = 0.82, 95% CI = 0.81-0.84), followed by the LCRAT (AUC = 0.81, 95% CI = 0.79-0.82) and the Bach model (AUC = 0.80, 95% CI = 0.79-0.81). Results were similar in EPIC-UK and the Generations Study. All models overestimated risk in all cohorts, with E/O in UK Biobank ranging from 1.20 for LLPv3 (95% CI = 1.14-1.27) to 2.16 for LLPv2 (95% CI = 2.05-2.28). Overestimation increased with area-level socioeconomic status. In the combined cohorts, USPSTF 2013 criteria classified 50.7% of future cases as screening eligible. The LCDRAT and LCRAT identified 60.9%, followed by PLCOm2012 (58.3%), Bach (58.0%), LLPv3 (56.6%), and LLPv2 (53.7%). In UK cohorts, the ability of risk prediction models to classify future lung cancer cases as eligible for screening was best for LCDRAT/LCRAT, very good for PLCOm2012, and lowest for LLPv2. Our results highlight the importance of validating prediction tools in specific countries.


The growing importance of achieving national self-sufficiency in immunoglobulin in Italy. The emergence of a national imperative.
Since the inception of industrial plasma fractionation during the Second World War, a succession of protein therapies isolated from plasma have determined the volume of plasma requiring collection, and have also shaped the economics of the industry. These so-called plasma drivers have successively included albumin, coagulation Factor VIII (FVIII) and, for the past thirty years, intravenously (IV) and subcutaneously (SC) administered immunoglobulin (IG) solutions. The sale of IG underpins the profitability of the industry and has experienced continuous growth over the past decades, as the result of growing clinical demand. Modelling this demand using decision analysis indicates that supplying the evidence-based indications for IG therapies will generate a need for IG which exceeds the current plasma collection capacity of most countries. A notable exception to this situation is the United States (US) of America, whose population of compensated plasma donors generates two thirds of the global supply of plasma for fractionation. The US is also the leading consumer of IG, and its health care providers pay the highest price for the product globally. Shortages of IG occur whenever the demand for the product outstrips the supply. Current shortages, following other historical periods of shortage, threaten the well-being of patients dependant on these products and incur heavy costs on health systems. In Italy, the national blood system, which is based on voluntary unpaid donors, reflects a policy of national self-sufficiency in blood-derived therapies (a strategic objective of the national blood system itself), based on solidarity as an ethical principle. This system has increased the collection of plasma for fractionation by 3.8% per annum over 2008-2017, in accordance to a plan for plasma procurement targeting a collection rate of 14.1 L of plasma per thousand (103) population by 2020. Over the same period, IG usage has increased by 8.5/per annum, to 89.2 g IG/103 population. In this paper, we review the factors which, increasingly, are causing an imbalance between the global supply and demand for IG, and we assess Italy's capacity to ensure that increasing this level of independence is no longer simply an ethical, but also an economic imperative, with implications for the security of Italy's health system.


Time to rethink: an evidence-based response from pelvic surgeons to the FDA Safety Communication: "UPDATE on Serious Complications Associated with Transvaginal Placement of Surgical Mesh for Pelvic Organ Prolapse".
In July of 2011 the U.S. Food and Drug Administration (FDA) released a safety communication entitled "UPDATE on Serious Complications Associated with Transvaginal Placement of Surgical Mesh for Pelvic Organ Prolapse." The stated purpose of this communication is to inform health care providers and patients that serious complications with placement of this mesh are not rare and that it is not clear that these repairs are more effective than nonmesh repair. The comments regarding efficacy are based on a systematic review of the scientific literature from 1996-2011 conducted by the FDA. Our review of the literature during this time yields some different conclusions regarding the safety and efficacy of mesh use in prolapse repair. It may be useful to consider this information prior to making recommendations regarding mesh use in prolapse surgery according to the recent UPDATE.


Survival of Anisakis simplex in arrowtooth flounder (Atheresthes stomia) during frozen storage.
Survival of naturally occurring larvae of Anisakis simplex in fresh arrowtooth flounder (Atheresthes stomia) was determined after storage for specified periods at four freezing temperatures. All larvae were killed by 96, 60, 12, and 9 h at temperatures of -15, -20, -30, and -40 degrees C, respectively. The average percentages of live larvae per fillet at the next shortest holding time were as follows: 72 h at -15 degrees C, 0 to 3%; 48 h at -20 degrees C, 11 to 30%; 9 h at -30 degrees C, 5%; and 6 h at -40 degrees C, 0 to 3%. Larval survival was directly related to fillet thickness or weight (P < or = 0.05). Larval death was directly correlated to freezing temperatures. Holding time necessary to kill larval nematodes decreased as storage temperature decreased.


Association Between the Diabetes mellitus Duration and the Severity of Diabetic Foot Disease in Hospitalized Patients in Latin America.
The objective was to determine the association between a diabetes mellitus duration greater than 10 years and the severity of diabetic foot in hospitalized patients in Latin America.Analytical, observational, and retrospective study based in secondary databases. Patients older than 18 years with diagnosis of diabetes mellitus (DM) and hospitalized for any causes were included. The independent and dependent variables were having more than 10 years of diagnosis of DM and the severity of the diabetic foot disease (Wagner> = 2), respectively. A crude Poisson regression analysis was performed to obtain prevalence rates adjusted to confounders.Male gender was 54.8% and the median age was 62 years. In the group with more than10 years of disease (n = 903) 18% (n = 162) had severe injuries. We performed two Poisson regression analyzes, one of which included the entire sample; and in the other, only patients with some degree of ulcer were included at the time of evaluation (Wagner > = 1). In the first analysis the PR was 1.95 (p < 0.01) adjusted for the significant variables in the bivariate analysis and in the second analysis the PR was 1.18 (p < 0.01) adding to the adjustment the days of injury prior to hospitalization and the location of the ulcer.We conclude that in patients with more than 10 years of diabetes mellitus, diabetic foot injuries are more severe, regardless type of diabetes, gender, age, history of amputation and days of injury prior to hospitalization for inpatients in Latin America.


The GSK3 hypothesis of Alzheimer's disease.
Glycogen synthase kinase 3 (GSK3) is a constitutively active, proline-directed serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. GSK3 also plays a pivotal and central role in the pathogenesis of both sporadic and familial forms of Alzheimer's disease (AD), an observation that has led us to coin the 'GSK3 hypothesis of AD'. According to this hypothesis, over-activity of GSK3 accounts for memory impairment, tau hyper-phosphorylation, increased beta-amyloid production and local plaque-associated microglial-mediated inflammatory responses; all of which are hallmark characteristics of AD. If our 'GSK3 hypothesis of AD' is substantiated and GSK3 is indeed a causal mediator of AD then inhibitors of GSK3 would provide a novel avenue for therapeutic intervention in this devastating disorder.


A network of tufted layer 5 pyramidal neurons.
Tufted layer 5 (TL5) pyramidal neurons are important projection neurons from the cerebral cortex to subcortical areas. Recent and ongoing experiments aimed at understanding the computational analysis performed by a network of synaptically connected TL5 neurons are reviewed here. The experiments employed dual and triple whole-cell patch clamp recordings from visually identified and preselected neurons in brain slices of somatosensory cortex of young (14- to 16-day-old) rats. These studies suggest that a local network of TL5 neurons within a cortical module of diameter 300 microns consists of a few hundred neurons that are extensively inter-connected with reciprocal feedback from at least first-, second- and third-order target neurons. A statistical analysis of synaptic innervation suggests that this recurrent network is not randomly arranged and hence each neuron could be functionally unique. Synaptic transmission between these neurons is characterized by use-dependent synaptic depression which confers novel properties to this recurrent network of neurons. First, a range of rates of depression for different synaptic connections enable each TL5 neuron to receive a unique mixture of information about the average firing rates and the temporally correlated action potential (AP) activity in the population of presynaptic TL5 neurons. Second, each AP generated by any neuron in the network induces a change (defined as an iteration step) in the functional coupling of the neurons in the network (defined as network configuration). It is proposed that the network configuration is iterated during a stimulus to achieve an optimally orchestrated network response. Hebbian, anti-Hebbian and neuromodulatory-induced modifications of neurotransmitter release probability change the rates of synaptic depression and thereby alter the iteration step size. These data may be important to understand the dynamics of electrical activity within the network.


Endothelial cell dysfunction and cytoskeletal changes associated with repression of p16(INK4a) during immortalization.
The immortalization process is a fundamental step in the development of most (if not all) human cancers, including the aggressive endothelial cell (EC)-derived malignancy angiosarcoma. Inactivation of the tumor suppressor p16(INK4a) and the development of multiple chromosomal abnormalities are features of angiosarcoma that are recapitulated during telomerase-mediated immortalization of human ECs in vitro. The present study used a panel of telomerase-immortalized bone marrow EC (BMEC) lines to define the consequences of inactivation of p16(INK4a) on EC function and to identify molecular changes associated with repression of p16(INK4a). In a comparison of two immortalized BMEC mass cultures and six clones, the cell lines that repressed p16(INK4a) showed a higher rate of proliferation and an impaired ability to undergo morphogenic differentiation and form vessel-like structures in vitro. Proteomic comparison of a p16(INK4a)-negative and a p16(INK4a)-positive BMEC mass culture at early- and late-passage time points following transduction with telomerase reverse transcriptase (hTERT) revealed altered expression of cytoskeletal proteins, including vimentin and α-tropomyosin (αTm), in the immortal cells. Immunoblot analyses of a panel of 11 immortal clones showed that cells that lacked p16(INK4a) expression tended to accumulate more dramatic changes in these cytoskeletal proteins than cells that retained p16(INK4a) expression. This corresponded with aberrant cytoskeletal architectures among p16(INK4a)-negative clones, which featured thicker actin stress fibers and less fluid membrane ruffles than p16(INK4a)-positive cells. A direct link between p16(INK4a) repression and defective EC function was confirmed by analysis of normal cells transfected with small interfering RNA (siRNA) targeting p16(INK4a). siRNA-mediated repression of p16(INK4a) significantly impaired random motility and vessel formation in vitro. This report is the first to demonstrate that ECs that repress the expression of p16(INK4a) are prone to defects in motility, morphogenesis and cytoskeletal organization. These defects are likely to reflect alterations that occur during the development of EC-derived malignancies.


Interprofessional Education in Dental Hygiene: Attitudes, barriers and practices of program faculty.
Purpose: Interprofessional education (IPE) experiences are an essential component in preparing dental hygiene students to participate in future interprofessional (IP) collaborations to support comprehensive patient care. The purpose of this study was to determine the attitudes, barriers and IPE practices in a national sample of dental hygiene faculty.Methods: A 25-item, researcher-designed, electronic survey was sent to 1,800 dental hygiene faculty members to determine attitudes, collaboration and practices involving interprofessional education (IPE). Descriptive statistics, Mann Whitney U and the Kruksal Wallis Test of Independent Samples were used to analyze and compare data.Results: The response rate was 22% (n=449). Results suggest faculty have positive attitudes toward IPE and most faculty (73%) incorporated IPE in their programs; however, time constraints were reported as the greatest barrier to IPE participation. A majority (85%) of respondents indicated a desire for greater emphasis on IPE in the curricula. Ethics (37%) was ranked as the most important IPE competency and teamwork the least (19%). Respondents from bachelor's degree programs were more likely to agree that learning with students in other health professions helps students become more effective members of a healthcare team than those from associate's degree programs (p = 0.025). Additionally, respondents from bachelor's degree programs were less likely to agree that clinical problem solving can only be learned when students are taught within their individual schools than those from associate degree programs (p = 0.022).Conclusion: Most of the dental hygiene faculty surveyed considered IPE important, incorporated it into student experiences, and wanted greater curricular emphasis on IPE. Time and institutional support may limit expansion of IPE activities and more collaboration amongst program faculty may be needed.


Metabolic syndrome and risk of Parkinson disease: A nationwide cohort study.
The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population. Health checkup data of 17,163,560 individuals aged ≥40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS (n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS (n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21-1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10-1.16 for abdominal obesity; 1.13, 1.10-1.15 for hypertriglyceridemia; 1.23, 1.20-1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03-1.08 for high blood pressure; 1.21, 1.18-1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p < 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components (p < 0.001). A significant interaction between age and MetS on the risk of incident PD was observed (p for interaction < 0.001), and people aged ≥65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those <65 years old without MetS (reference subgroup). Limitations of this study include the possibilities of misdiagnosis of PD and reverse causality. Our population-based large-scale cohort study suggests that MetS and its components may be risk factors of PD development.


Defining falciparum-malaria-attributable severe febrile illness in moderate-to-high transmission settings on the basis of plasma PfHRP2 concentration.
In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations. Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6-60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease. The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%-100%), with a sensitivity of 74% (95% CI, 72%-77%), whereas a concentration of <200 ng/mL denoted severe febrile illness of an alternative diagnosis in >10% (95% CI, 3%-27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles. The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.


Mammary glands of pregnant rats: development stimulated by licking.
At the end of gestation, the mamnmary glands of pregnant rats that have been prevented from licking their ventral surfaces by neck collars are about 50-percent less developed than those of control animals. Neither the burden nor the stress ejfect of the collar is an alternative explanation. A considerable proportion of mammary development during pregnancy is thus caused by the female's own licking.


Problem gambling patterns among Australian young adults: Associations with prospective risk and protective factors and adult adjustment.
There is instability in the developmental course of problem gambling [PG] over time; however, studies that examine PG at an aggregate level obscure these variations. The current study employed data from a longitudinal study of Australian young adults to investigate: 1) PG patterns (i.e., resistance, persistence, desistence, and new incidence); 2) prospective risk and protective factors for these patterns; and 3) behavioural outcomes associated with these patterns. A sample of 2261 young adults (55.73% female) from Victoria, Australia, who were part of the International Youth Development Study completed a survey in 2010 (T1, age 21) and 2012 (T2, age 23) measuring PG (two items based on established measures), risk and protective factors, and behavioural outcomes. The majority of the sample (91.69%) were resistors (no PG at T1 and T2), 3.62% were new incidence PG cases, 2.63% were desistors (PG at T1 but not T2), and 2.07% reported persistent PG at T1 and T2. Individual civic activism was protective of new incidence PG, while affiliation with antisocial peers and frequent alcohol use increased the risk of persistence. Persistent problem gamblers also experienced the greatest number of poor behavioural outcomes at T2. New incidence was associated with internalising symptoms at T2, while desistance was not associated with any behavioural outcomes. In conclusion, each PG pattern was associated with different predictors and outcomes, highlighting the need to consider variation in the course of young adult PG in order to provide efficacious prevention and intervention approaches, and to protect against relapse.


Protein modifications by 4-hydroxynonenal and 4-hydroxyhexenal in light-exposed rat retina.
4-Hydroxynonenal (4-HNE) and 4-hydroxyhexenal (4-HHE) are reactive aldehydes derived from the nonenzymatic oxidation of n-6 and n-3 polyunsaturated fatty acids, respectively. Increasing evidence suggests that protein modifications by reactive aldehydes are involved in various diseases. The present study was undertaken to test whether protein modifications by 4-HNE and 4-HHE increase in retinal tissues after exposure of rats to damaging levels of light. Albino rats were exposed to 1 or 5 klux white fluorescent light for 3 hours and, at various times thereafter, the levels and localizations of aldehyde-modified proteins in retinas were assessed by densitometric analysis of semiquantitative Western dot blots and by immunohistochemistry, using 4-HNE- and 4-HHE-specific antibodies. In some rats, the protective antioxidant phenyl-N-tert-butylnitrone (PBN) was injected (50 mg/kg) before exposure to light. To assess retinal damage, outer nuclear layer (ONL) thickness was measured on hematoxylin-eosin (H&E)-stained sections, and apoptosis was semiquantitatively analyzed by TUNEL staining. By dot blot analysis, 4-HNE- and 4-HHE-modified proteins were significantly increased in retina (both by 1.7-fold) and RPE fraction (1.5- and 1.8-fold, respectively) after 5-klux exposure. In retina, increases in 4-HNE- and 4-HHE-modified proteins were more prominent at 3 hours than at 24 hours or 48 hours after exposure to light. In rod outer segments, only 4-HHE-modified proteins increased significantly (1.4-fold). Retinal thinning, TUNEL staining in ONL, 4-HNE-, and 4-HHE protein modifications were all found in the same retinal regions. PBN treatment inhibited the light-induced increase of 4-HNE and 4-HHE modified proteins in retina and RPE fractions. Exposure to intense light increases 4-HNE and 4-HHE protein modifications in the retina, suggesting that free radical initiated, nonenzymatic reactions are involved in this process. These modifications may be early events that precede photoreceptor cell apoptosis.


The K-Technique: A Novel Technique for Laparoscopic Apical Suspension Using Barbed Sutures.
Hysterectomy is among the most common gynecologic procedures performed for women, second only to cesarean sections, and the proportion of it performed laparoscopically continues to increase. Addressing apical support at the time of the hysterectomy is crucial to minimizing the risk of posthysterectomy prolapse. Barriers to addressing apical support include the lack of experience in laparoscopic suturing and knot tying that require advanced skills and dexterity. The K-technique is a novel modification of the uterosacral ligament suspension procedure using the knot-less barbed suture technology, rendering suturing easier and quicker to perform. The vaginal cuff epithelium is closed with 2 unidirectional barbed sutures that are started at the lateral fornices and ran until the midsection. The same sutures will then serially purchase the anterior and posterior vaginal endopelvic fascia and the midsegment of the uterosacral ligament. Two more passes are thrown through the same structures, yet farther laterally, back and forth. A video illustration of the procedure is attached. Eighteen patients underwent the procedure with no urinary tract injuries documented by cystoscopy and no postoperative morbidity documented during the 6-week postoperative follow-up period. Limited short- and long-term follow-up data are reassuring, but more will be needed to confirm the efficacy of barbed sutures in prolapse repair. The K-technique combines the conventional uterosacral ligament suspension concept with the ease, effectiveness, and safety of barbed sutures. The technique might aid the surgeon to add the apical vaginal support when indicated.


Fucoidan promotes mechanosensory hair cell regeneration following amino glycoside-induced cell death.
Lateral line system of the zebrafish is a useful model for study of hair cell toxicity and regeneration. We found that low molecular weight fucoidan (LMWF) stimulated the regeneration of mechanosensory hair cells after neomycin-induced cell death in zebrafish lateral line. The aims of this study were to quantify the regenerative effects of LMWF and determine their relationship to the Notch and FGF signaling pathways. Wild-type zebrafish and three different transgenic zebrafish lines (Pou4f3::GFP, scm1::GFP, and ET20::GFP) were used. At 4.5-6 days post-fertilization, lateral line hair cells of larvae were eliminated using neomycin (500 μM). Larvae were then treated with LMWF. Neuromasts were observed using confocal microscopy. Stereocilia morphology was observed using scanning electron microscopy, and the location and status of regeneration was assessed using 5-bromo-2-deoxyuridine (BrdU) incorporation. Hair cells damaged by neomycin treatment regenerated faster in wild-type and Pou4f3::GFP larvae treated with LMWF (50 μg/ml) than in untreated controls. LMWF also enhanced the regeneration of supporting cells in scm1::GFP and ET20::GFP larvae. Increased numbers of BrdU-labeled cells were found after LMWF treatment in neuromast regions corresponding to internal and peripheral supporting cells. The effect of LMWF was mimicked by the Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT), but the effects of LMWF and DAPT were not additive. LMWF enhances the regeneration of hair cells damaged by neomycin. The mechanism may involve the Notch signaling pathway. LMWF shows promise as a therapeutic agent for hearing and balance disorders.


Cytochrome p450 epoxygenase metabolism of arachidonic acid inhibits apoptosis.
The ubiquitous cytochrome P450 hemoproteins play important functional roles in the metabolism and detoxification of foreign chemicals. However, other than established roles in cholesterol catabolism and steroid hormone biosynthesis, their cellular and/or organ physiological functions remain to be fully characterized. Here we show that the cytochrome P450 epoxygenase arachidonic acid metabolite 14,15-epoxyeicosatrienoic acid (14,15-EET) inhibits apoptosis induced by serum withdrawal, H(2)O(2), etoposide, or excess free arachidonic acid (AA), as determined by DNA laddering, Hoechst staining, and fluorescein isothiocyanate-labeled annexin V binding. In the stable transfectants (BM3 cells) expressing a mutant bacterial P450 AA epoxygenase, F87V BM3, which was genetically engineered to metabolize arachidonic acid only to 14,15-EET, AA did not induce apoptosis and protected against agonist-induced apoptosis. Ceramide assays demonstrated increased AA-induced ceramide production within 1 h and elevated ceramide levels for up to 48 h, the longest time tested, in empty-vector-transfected cells (Vector cells) but not in BM3 cells. Inhibition of cytochrome P450 activity by 17-octadecynoic acid restored AA-induced ceramide production in BM3 cells. Exogenous C2-ceramide markedly increased apoptosis in quiescent Vector cells as well as BM3 cells, and apoptosis was prevented by pretreatment of Vector cells with exogenous 14,15-EET and by pretreatment of BM3 cells with AA. The ceramide synthase inhibitor fumonisin B1 did not affect AA-induced ceramide production and apoptosis; in contrast, these effects of AA were blocked by the neutral sphingomyelinase inhibitor scyphostatin. The pan-caspase inhibitor Z-VAD-fmk had no effect on AA-induced ceramide generation but abolished AA-induced apoptosis. The antiapoptotic effects of 14,15-EET were blocked by two mechanistically and structurally distinct phosphatidylinositol-3 (PI-3) kinase inhibitors, wortmannin and LY294002, but not by the specific mitogen-activated protein kinase kinase inhibitor PD98059. Immunoprecipitation followed by an in vitro kinase assay revealed activation of Akt kinase within 10 min after 14,15-EET addition, which was completely abolished by either wortmannin or LY294002 pretreatment. In summary, the present studies demonstrated that 14,15-EET inhibits apoptosis by activation of a PI-3 kinase-Akt signaling pathway. Furthermore, cytochrome P450 epoxygenase promotes cell survival both by production of 14,15-EET and by metabolism of unesterified AA, thereby preventing activation of the neutral sphingomyelinase pathway and proapoptotic ceramide formation.


Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer.
In the present study, we have taken the novel approach of using an in vitro model representative of tamoxifen-withdrawal subsequent to clinical relapse to achieve a greater understanding of the mechanisms that serve to maintain the resistant-cell phenotype, independent of any agonistic impact of tamoxifen, to identify potential novel therapeutic approaches for this disease state. Following tamoxifen withdrawal, tamoxifen-resistant MCF-7 cells conserved both drug resistance and an increased basal rate of proliferation in an oestrogen deprived environment, despite reduced epidermal growth-factor receptor expression and reduced sensitivity to gefitinib challenge. Although tamoxifen-withdrawn cells retained ER expression, a sub-set of ER-responsive genes, including pS2 and progesterone receptor (PgR), were down-regulated by promoter DNA methylation, as confirmed by clonal bisulphite sequencing experiments. Following promoter demethylation with 5-Azacytidine (5-Aza), the co-addition of oestradiol (E2) restored gene expression in these cells. In addition, 5-Aza/E2 co-treatment induced a significant anti-proliferative effect in the tamoxifen-withdrawn cells, in-contrast to either agent used alone. Microarray analysis was undertaken to identify genes specifically up regulated by this co-treatment. Several anti-proliferative gene candidates were identified and their promoters were confirmed as more heavily methylated in the tamoxifen resistant vs sensitive cells. One such gene candidate, growth differentiation factor 15 (GDF15), was carried forward for functional analysis. The addition of 5-Aza/E2 was sufficient to de-methylate and activate GDF15 expression in the tamoxifen resistant cell-lines, whilst in parallel, treatment with recombinant GDF15 protein decreased cell survival. These data provide evidence to support a novel concept that long-term tamoxifen exposure induces epigenetic silencing of a cohort of oestrogen-responsive genes whose function is associated with negative proliferation control. Furthermore, reactivation of such genes using epigenetic drugs could provide a potential therapeutic avenue for the management of tamoxifen-resistant breast cancer.


A Qualitative Study of Factors Influencing Adherence among Pregnant Women Taking Part in a Trial of E-Cigarettes for Smoking Cessation.
Use of e-cigarettes (vaping) has potential to help pregnant women stop smoking. This study explored factors influencing adherence among participants in the vaping arm of the first trial of vaping for smoking cessation in pregnancy. We conducted semi-structured telephone interviews (n = 28) with women at three-months postpartum. Interviews were analysed using thematic analysis, informed by the Theoretical-Domains Framework, Necessity-Concerns Framework and Perceptions and Practicalities Approach. Interviewees generally reported high levels of vaping. We found that: (1) intervention adherence was driven by four necessity beliefs-stopping smoking for the baby, and vaping for harm reduction, smoking cessation or as a last resort; (2) necessity beliefs outweighed vaping concerns, such as dependence and safety; (3) adherence was linked to four practicalities themes, acting as barriers and facilitators to vaping-device and e-liquid perceptions, resources and support, whether vaping became habitual, and social and environmental factors; and (4) intentional non-adherence was rare; unintentional non-adherence was due to device failures, forgetting to vape, and personal circumstances and stress. Pregnant smokers provided with e-cigarettes, and with generally high levels of vaping, had positive beliefs about the necessity of vaping for smoking cessation which outweighed concerns about vaping. Non-adherence was mainly due to unintentional factors.


Visualization of astrocytic primary cilia in the mouse brain by immunofluorescent analysis using the cilia marker Arl13b.
In vertebrates, almost all somatic cells extend a single immotile cilium, referred to as a primary cilium. Increasing evidence suggests that primary cilia serve as cellular antennae in many types of tissues by sensing chemical or mechanical stimuli in the milieu surrounding the cells. In rodents an antibody to adenylyl cyclase 3 (AC3) has been widely used to label the primary cilia of neurons in vivo by immunostaining, whereas the lack of markers for the primary cilia of astrocytes has made it difficult to observe astrocytic primary cilia in vivo. Here, we obtained a visualization of astrocytic primary cilia in the mouse brain. In the somatosensory cortex, a large portion of neurons and astrocytes at postnatal day 10 (P10), and of neurons at P56 had AC3-positive primary cilia, whereas only approx. one-half of the astrocytes in the P56 mice carried primary cilia weakly positive for AC3. In contrast, the majority of astrocytes had ADP-ribosylation factor-like protein 13B (Arl13b)-positive primary cilia in the somatosensory cortex and other brain regions of P56 mice. The lengths of astrocytic primary cilia positive for Arl13b varied among the brain regions. Our data indicate that Arl13b is a noteworthy marker of astrocytic primary cilia in the brain.


Reaction time and cognitive-linguistic performance in adults with mild traumatic brain injury.
Objective: The purpose of this study was to characterize cognitive-linguistic performance in adults with mild traumatic brain injury (mTBI) to advance assessment and treatment practices. We hypothesized that individuals with mTBI would demonstrate longer reaction times (RTs) and greater error rates when compared to an orthopedic injury (OI) group on a category-naming task. Method: Participants were age and education-matched adults with mTBI (n = 20; 12 females) and adults with OI (n = 21; 5 females) who were discharged to home after an Emergency Department visit. Our primary task was a category-naming task shown to be sensitive to language deficits after mTBI. The task was adapted and administered under speeded and unspeeded conditions. Results: There was a significant main effect of condition on RT (speeded faster than unspeeded) and accuracy (more errors in the speeded condition). There was a marginally significant effect of group on errors, with more errors in the mTBI group than the OI group. Naming RT and accuracy in both conditions were moderately correlated with injury variables and symptom burden. Conclusions: Our data showed a marginal effect of group on accuracy of performance. Correlations found between naming and neurobehavioural symptoms, including sleep quality, suggest that the latter should be considered in future research.


The genetics of diabetic nephropathy.
Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN. The identification of such variants may potentially allow for early identification of at risk patients. Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes.


Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress.
Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate (1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-thiol (1,2-NQH2-SH) and a generator of reactive oxygen species (ROS), we demonstrate that protein thiols can be modified by a reactive sulfenic acid to form disulfide adducts that undergo rapid cleavage in the presence of glutathione (GSH). As expected, 1,2-NQH2-SAc is rapidly hydrolyzed and partially oxidized to yield 1,2-NQ-SH, resulting in a redox cycling reaction that produces ROS through a chemical disproportionation reaction. The sulfenic acid forms of 1,2-NQ-SH and 1,2-NQH2-SH were detected by derivatization experiments with dimedone. 1,2-NQH2-SOH modified Keap1 at Cys171 to produce a Keap1-S-S-1,2-NQH2 adduct. Subsequent exposure of A431 cells to 1,2-NQ or 1,2-NQH2-SAc caused an extensive chemical modification of cellular proteins in both cases. Protein adduction by 1,2-NQ through a thio ether (C-S-C) bond slowly declined through a GSH-dependent S-transarylation reaction, whereas that originating from 1,2-NQH2-SAc through a disulfide (C-S-S-C) bond was rapidly restored to the free protein thiol in the cells. Under these conditions, 1,2-NQH2-SAc activated Nrf2 and upregulated its target genes, which were enhanced by pretreatment with buthionine sulfoximine (BSO), to deplete cellular GSH. Pretreatment of catalase conjugated with poly(ethylene glycol) suppressed Nrf2 activation by 1,2-NQH2-SAc. These results suggest that RSS-mediated reversible electrophilic signaling takes place through sulfenic acids formation under oxidative stress.


An electrochemical DNA microbiosensor based on succinimide-modified acrylic microspheres.
An electrochemical microbiosensor for DNA has been fabricated based on new acrylic microspheres modified with reactive N-acryloxysuccinimide (NAS) functional groups. Hydrophobic poly(n-butylacrylate-N-acryloxysuccinimide) microspheres were synthesized in an emulsion form with a simple one-step photopolymerization technique. Aminated DNA probe was attached to the succinimde functional group of the acrylic microspheres via covalent bonding. The hybridization of the immobilized DNA probe with the complementary DNA was studied by differential pulse voltametry using anthraquninone-2-sulfonic acid monohydrate sodium salt (AQMS) as the electroactive hybridization label. The influences of many factors such as duration of DNA probe immobilization and hybridization, pH, type of ions, buffer concentrations, ionic strength, operational temperature and non-complementary DNA on the biosensor performance were evaluated. Under optimized conditions, the DNA microbiosensor demonstrated a linear response range to target DNA over a wide concentration range of 1.0 × 10(-16) and 1.0 × 10(-8) M with a lower limit of detection (LOD) of 9.46 × 10(-17) M (R(2) = 0.97). This DNA microbiosensor showed good reproducibility with 2.84% RSD (relative standard deviation) (n = 3). Application of the NAS-modified acrylic microspheres in the construction of DNA microbiosensor had improved the overall analytical performance of the resultant DNA microbiosensor when compared with other reported DNA biosensors using other nano-materials for membranes and microspheres as DNA immobilization matrices.


Characterization and modelling of interspecies electron transfer mechanisms and microbial community dynamics of a syntrophic association.
Syntrophic associations are central to microbial communities and thus have a fundamental role in the global carbon cycle. Despite biochemical approaches describing the physiological activity of these communities, there has been a lack of a mechanistic understanding of the relationship between complex nutritional and energetic dependencies and their functioning. Here we apply a multi-omic modelling workflow that combines genomic, transcriptomic and physiological data with genome-scale models to investigate dynamics and electron flow mechanisms in the syntrophic association of Geobacter metallireducens and Geobacter sulfurreducens. Genome-scale modelling of direct interspecies electron transfer reveals insights into the energetics of electron transfer mechanisms. While G. sulfurreducens adapts to rapid syntrophic growth by changes at the genomic and transcriptomic level, G. metallireducens responds only at the transcriptomic level. This multi-omic approach enhances our understanding of adaptive responses and factors that shape the evolution of syntrophic communities.


Association between physical activity and sleep in adults with chronic pain: a momentary, within-person perspective.
Individuals with chronic pain consider improved sleep to be one of the most important outcomes of treatment. Physical activity has been shown to have beneficial effects on sleep in the general population. Despite these findings, the physical activity-sleep relationship has not been directly examined in a sample of people with chronic pain. This study aimed to examine the association between objective daytime physical activity and subsequent objective sleep for individuals with chronic pain while controlling for pain and psychosocial variables. An observational, prospective, within-person study design was used. A clinical sample of 50 adults with chronic pain was recruited. Participation involved completing a demographic questionnaire followed by 5 days of data collection. Over this period, participants wore a triaxial accelerometer to monitor their daytime activity and sleep. Participants also carried a handheld computer that administered a questionnaire measuring pain, mood, catastrophizing, and stress 6 times throughout the day. The results demonstrated that higher fluctuations in daytime activity significantly predicted shorter sleep duration. Furthermore, higher mean daytime activity levels and a greater number of pain sites contributed significantly to the prediction of longer periods of wakefulness at night. The small sample size used in this study limits the generalizability of the findings. Missing data may have led to overestimations or underestimations of effect sizes, and additional factors that may be associated with sleep (eg, medication usage, environmental factors) were not measured. The results of this study suggest that engagement in high-intensity activity and high fluctuations in activity are associated with poorer sleep at night; hence, activity modulation may be a key treatment strategy to address sleep complaints in individuals with chronic pain.


Continuous wave waveguide lasers of swift argon ion irradiated Nd:YVO4 waveguides.
We report on the fabrication of planar waveguide in Nd:YVO(4) crystal by using swift Ar(8+) ion irradiation. At room temperature continuous wave (cw) laser oscillation at wavelength of ~1067 nm has been realized through the optical pump at 808 nm with a low threshold of 9.3 mW. The slope efficiency of the waveguide laser system is of 8.5%. The optical-to-optical conversion efficiency is 6.6%.