Drivers' visual behavior when using handheld and hands-free cell phones.
This study investigated driver distraction and how the use of handheld (HH), portable hands-free (PHF), and integrated hands-free (IHF) cell phones affected the visual behavior of motor vehicle drivers. A naturalistic driving study recorded 204 participating drivers using video cameras and vehicle sensors for an average of 31 days. A total of 1564 cell phone calls made and 844 text messages sent while driving were sampled and underwent a video review. Baselines were established by recording epochs prior to the cell phone interactions. Total eyes-off-road time (TEORT) was examined to assess the visual demands of cell phone subtasks while driving. Percent TEORT was reported and compared against the baseline. Visual-manual subtasks performed on HH, PHF, and IHF cell phones were found to significantly increase drivers' mean percent TEORT. In contrast, conversing on an HH cell phone was found to significantly decrease drivers' mean percent TEORT, indicating that drivers looked at the forward roadway more often. No significant differences in percent TEORT were found for drivers conversing using PHF or IHF cell phones. The mean TEORT durations for visual-manual subtasks performed on an HH cell phone were significantly longer than the mean TEORT durations on either IHF or PHF cell phones. This research helps to further reinforce the distinction made between handheld and hands-free cell phone use in transportation distraction policy.


Evaluation of the effectiveness of diagnostic & management decision by teleophthalmology using indigenous equipment in comparison with in-clinic assessment of patients.
There is a concern on the quality and the usefulness of teleophthalmology images, particularly those using indigenous equipment, in making a diagnosis and treatment decisions in ophthalmology. The present study was done to compare the level of agreement and sensitivity and specificity of diagnosis and management decisions of various eye diseases by teleophthalmology using indigenous equipment, compared to the in-clinic assessment. Patients having different eye diseases were evaluated by two ophthalmologists - one ophthalmologist examined the patient in clinic setting while the other ophthalmologist made the diagnosis and management decision based on images sent by teleophthalmology. The images were taken by the ophthalmic technician using digital imaging system and fundus camera. The clinical findings and management decisions by the two ophthalmologists were masked to each others. In diagnosis of anterior segment eye diseases such as cataract and corneal diseases there was good to very good agreement (kappa values of 0.68 and 0.91 for cataract and corneal diseases respectively) between in-clinic assessment and assessment by teleophthalmology. There was moderate agreement (kappa values of 0.52 and 0.48 for glaucoma and retinal diseases respectively) between in-clinic assessment and assessment by teleophthalmology for the diagnosis of glaucoma and retinal diseases. For the management decisions of patients, there was moderate level of agreement in all groups of eye diseases. Teleophthalmology, using indigenous equipment was found to be effective in diagnosis and management decision of anterior segment eye diseases such as cataract and cornea, and with some modification and continuous training to the technicians could become an effective tool for screening and referral of glaucoma and retinal diseases.


Shallow methylmercury production in the marginal sea ice zone of the central Arctic Ocean.
Methylmercury (MeHg) is a neurotoxic compound that threatens wildlife and human health across the Arctic region. Though much is known about the source and dynamics of its inorganic mercury (Hg) precursor, the exact origin of the high MeHg concentrations in Arctic biota remains uncertain. Arctic coastal sediments, coastal marine waters and surface snow are known sites for MeHg production. Observations on marine Hg dynamics, however, have been restricted to the Canadian Archipelago and the Beaufort Sea (<79 °N). Here we present the first central Arctic Ocean (79-90 °N) profiles for total mercury (tHg) and MeHg. We find elevated tHg and MeHg concentrations in the marginal sea ice zone (81-85 °N). Similar to other open ocean basins, Arctic MeHg concentration maxima also occur in the pycnocline waters, but at much shallower depths (150-200 m). The shallow MeHg maxima just below the productive surface layer possibly result in enhanced biological uptake at the base of the Arctic marine food web and may explain the elevated MeHg concentrations in Arctic biota. We suggest that Arctic warming, through thinning sea ice, extension of the seasonal sea ice zone, intensified surface ocean stratification and shifts in plankton ecodynamics, will likely lead to higher marine MeHg production.


A series report of autoimmune hypothyroidism associated with Hashimoto's encephalopathy: an under diagnosed clinical entity with good prognosis.
Thyroid dysfunctions may be accompanied by numerous neurological and psychiatric disorders. The most well-known is cognitive impairment and depression in hypothyroid patients, as well as an increased risk of cerebrovascular accidents. A separate, although a rare entity, is Hashimoto's encephalopathy. Unlike encephalopathy associated with other conditions, management in Hashimoto's encephalopathy highly responds to steroid treatment and may be associated with normal thyroid profile at presentation. Hashimoto's encephalopathy, while rare, may have been under-recognised since its clinical presentation overlaps several more common disorders, such as depression, seizures or anxiety. We present two cases of hypothyroidism with peculiar presentation. The first case has rapidly progressive neurological dysfunction, normal thyroid function at presentation, normal MRI finding and responds to steroid treatment. The second case has a subacute progressive neurological deterioration with elevated thyroid-stimulating hormone titre at presentation. Both these cases are known hypothyroidism on regular thyroxin replacement therapy with elevated anti-thyroid peroxidase antibodies. We conclude that Hashimoto's encephalopathy can present with a wide spectrum of neurological illnesses in the setting of hypothyroidism. Thyroid status may vary from hypothyroid, normothyroid to even hyperthyroid. This condition usually has an abnormal electroencephalography (EEG) background and usually responds to high dose steroids.


Structural-functional interactions of NS1-BP protein with the splicing and mRNA export machineries for viral and host gene expression.
The influenza virulence factor NS1 protein interacts with the cellular NS1-BP protein to promote splicing and nuclear export of the viral M mRNAs. The viral M1 mRNA encodes the M1 matrix protein and is alternatively spliced into the M2 mRNA, which is translated into the M2 ion channel. These proteins have key functions in viral trafficking and budding. To uncover the NS1-BP structural and functional activities in splicing and nuclear export, we performed proteomics analysis of nuclear NS1-BP binding partners and showed its interaction with constituents of the splicing and mRNA export machineries. NS1-BP BTB domains form dimers in the crystal. Full-length NS1-BP is a dimer in solution and forms at least a dimer in cells. Mutations suggest that dimerization is important for splicing. The central BACK domain of NS1-BP interacts directly with splicing factors such as hnRNP K and PTBP1 and with the viral NS1 protein. The BACK domain is also the site for interactions with mRNA export factor Aly/REF and is required for viral M mRNA nuclear export. The crystal structure of the C-terminal Kelch domain shows that it forms a β-propeller fold, which is required for the splicing function of NS1-BP. This domain interacts with the polymerase II C-terminal domain and SART1, which are involved in recruitment of splicing factors and spliceosome assembly, respectively. NS1-BP functions are not only critical for processing a subset of viral mRNAs but also impact levels and nuclear export of a subset of cellular mRNAs encoding factors involved in metastasis and immunity.


Effects of a dietary excess of leucine on the metabolism of tryptophan in the rat: a mechanism for the pellagragenic action of leucine.
In order to investigate the mechanism of the pellagragenic action of excess dietary leucine, rats were fed on diets providing a minimally-adequate amount of tryptophan, with no preformed niacin, with and without the addition of 15 g leucine/kg diet. This amount of leucine in the diet has been demonstrated previously to lead to depletion of blood and liver nicotinamide nucleotides. The metabolism of tryptophan was assessed by measurement of the production of 14CO2 after the administration of [methylene-14C]tryptophan to estimate the activity of kynureninase (L-kynurenine hydrolase, EC 22.214.171.124) and [benzene ring U-14C]tryptophan to estimate the activity of picolinate carboxylase (aminocarboxymuconate semialdehyde decarboxylase, EC 18.104.22.168). A dietary excess of leucine led to inhibition of kynureninase and increased the activity of picolinate carboxylase. Both of these effects would result in a reduction in the rate of metabolism of acroleylaminofumarate (aminocarboxymuconate semialdehyde) to quinolinic acid and hence to nicotinamide nucleotides. These two effects provide an explanation for the pellagragenic effect of a dietary excess of leucine in animals that are wholly or partly reliant on endogenous synthesis from tryptophan to meet their requirements for nicotinamide nucleotides, and presumably also explain the pellagragenic effect of a dietary excess of leucine in man.


Expression, purification, and crystallization of glutamyl-tRNA(Gln) specific amidotransferase from Bacillus stearothermophilus.
Although the genes that encode the glutamyl-tRNA(Gln) (Glu-tRNA(Gln)) specific amidotransferase (Glu-AdTase) from various bacteria and eukaryotic organelles are known, the precise mechanism of the enzyme is still unclear. One of the reasons is that there is no information on the three-dimensional structure of the complex, the Glu-AdTase:Glu-tRNA(Gln):ATP:amino group donor. To obtain the crystals of Glu-AdTase, the Glu-AdTase of Bacillus stearothermophilus was overexpressed and purified after cloning of the gene that encodes the enzyme. The cloned DNA contained the full-length gene cluster that represented the Glu-AdTase of B. stearothermophilus, and was organized as an operon that consisted of three open-reading frames (ORFs). The order of the genes was gatCAB, as shown in Bacillus subtilis. The ORFs showed a high amino-acid homology to those of B. subtilis (A subunit, 73.2%; B subunit, 81.6%; C subunit, 69.5%) and Staphylococcus aureus (A subunit, 61.9%; B subunit, 71.8%; C subunit, 45.9%). The ORFs were re-cloned on the overexpression vector, pTrc99a, and a recombinant pTrcgatCABBST was obtained. The Glu-AdTase that was overexpressed with pTrcgatCABBST in Escherichia coli retained transamidation activity on the mischarged glutamic acid on the tRNA(Gln). It also produced correctly-charged Gln-tRNA(Gln) at 37, 42, and 50 degrees C. Although Glu-AdTases from both B. subtilis and B. stearothermophilus were subjected to crystallization, the micro-crystals were only obtained from the B. stearothermophilus enzyme.


Complex population structure of Lyme borreliosis group spirochete Borrelia garinii in subarctic Eurasia.
Borrelia garinii, a causative agent of Lyme borreliosis in Europe and Asia, is naturally maintained in marine and terrestrial enzootic cycles, which primarily involve birds, including seabirds and migratory passerines. These bird groups associate with, correspondingly, Ixodes uriae and Ixodes ricinus ticks, of which the latter species may bite and transmit the infection to humans. Studies of the overlap between these two natural cycles of B. garinii have been limited, in part due to the absence of representative collections of this spirochete's samples, as well as of the lack of reliable measure of the genetic heterogeneity of its strains. As a prerequisite for understanding the epidemiological correlates of the complex maintenance of B. garinii, the present study sought to assess the diversity and phylogenetic relationships of this species' strains from its natural hosts and patients with Lyme borreliosis from subarctic Eurasia. We used sequence typing of the partial rrs-rrl intergenic spacer (IGS) of archived and prospective samples of B. garinii from I. uriae ticks collected predominantly on Commander Islands in North Pacific, as well as on the islands in northern Sweden and arctic Norway. We also typed B. garinii samples from patients with Lyme borreliosis and I. ricinus ticks infesting migratory birds in southern Sweden, or found questing in selected sites on the islands in the Baltic Sea and Lithuania. Fifty-two (68%) of 77 B. garinii samples representing wide geographical range and associated with I. ricinus and infection of humans contributed 12 (60%) of total 20 identified IGS variants. In contrast, the remaining 25 (32%) samples recovered from I. uriae ticks from a few islands accounted for as many as 10 (50%) IGS types, suggesting greater local diversity of B. garinii maintained by seabirds and their ticks. Two IGS variants of the spirochete in common for both tick species were found in I. ricinus larvae from migratory birds, an indication that B. garinii strains are exchanged between different ecological niches. Notably, B. garinii variants associated with I. uriae ticks were found in each of the six clusters, representing two phylogenetic lineages of this species identified among the studied samples. Our findings suggest that B. garinii in subarctic Eurasia comprises two partially overlapping populations with different levels of genetic heterogeneity, presumably, due to distinctive selective pressures on the spirochete in its marine and terrestrial enzootic cycles.


Guidelines for Validation of Next-Generation Sequencing-Based Oncology Panels: A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists.
Next-generation sequencing (NGS) methods for cancer testing have been rapidly adopted by clinical laboratories. To establish analytical validation best practice guidelines for NGS gene panel testing of somatic variants, a working group was convened by the Association of Molecular Pathology with liaison representation from the College of American Pathologists. These joint consensus recommendations address NGS test development, optimization, and validation, including recommendations on panel content selection and rationale for optimization and familiarization phase conducted before test validation; utilization of reference cell lines and reference materials for evaluation of assay performance; determining of positive percentage agreement and positive predictive value for each variant type; and requirements for minimal depth of coverage and minimum number of samples that should be used to establish test performance characteristics. The recommendations emphasize the role of laboratory director in using an error-based approach that identifies potential sources of errors that may occur throughout the analytical process and addressing these potential errors through test design, method validation, or quality controls so that no harm comes to the patient. The recommendations contained herein are intended to assist clinical laboratories with the validation and ongoing monitoring of NGS testing for detection of somatic variants and to ensure high quality of sequencing results.


High rate of awarding compensation for claims of injuries related to clinical trials by pharmaceutical companies in Japan: a questionnaire survey.
International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported. Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan. With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation. Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country's compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.


A Prospective Analysis of Plasma Adiponectin and Risk of Incident Cancer: The Dallas Heart Study.
Adiponectin dysregulation is postulated to affect cancer risk via modulation of insulin resistance and inflammation. Epidemiologic studies evaluating this relationship have conflicting results and data from non-white cohorts are lacking. We examined the association between adiponectin and risk of cancer incidence in the multiethnic Dallas Heart Study (DHS). Participants enrolled in the DHS and known adiponectin values were included. Incident cancer cases were identified through a systematic linkage of the DHS and the Texas Cancer Registry. Univariate/multivariate analysis were performed to test the association between adiponectin and incident cancer after adjusting for age, diabetes status, gender, ethnicity, C-reactive protein level, smoking status, and body mass index. Adiponectin level was evaluated both as a continuous variable and in race/ethnicity specific quartiles. Of 3444 individuals, there were 152 incident cancers. The study population was comprised of 44.4% men, and 51.05% were black. Baseline median adiponectin levels were 6.43 mcg/mL (interquartile range [IQR], 4.37-9.45 mcg/mL) in the incident cancer group versus 6.33 mcg/mL (IQR, 4.57-9.97 mcg/mL) in those without cancer. In multivariable analysis, adiponectin level was not associated with cancer incidence after adjusting for covariates. In analyses stratified by race/ethnic group, no association was observed in white, Hispanic, or African American subgroups. In this study of a predominant ethnic minority population, no association between adiponectin and cancer incidence was demonstrated. Despite preclinical rationale and confirmatory findings in other studies, this association may not replicate across all ethnic populations. Additional studies with strong minority representation are warranted to further examine this association.


A comparison of the antimicrobial activity of garlic, ginger, carrot, and turmeric pastes against Escherichia coli O157:H7 in laboratory buffer and ground beef.
The antimicrobial effects of garlic, ginger, carrot and turmeric pastes against Escherichia coli O157:H7 in laboratory buffer and model food system were investigated. Turmeric paste, fresh carrot, ginger and garlic pastes from roots, and commercial ginger and garlic paste were heated alone or with buffered peptone water (BPW) or ground beef at 70 degrees C for 7 min. All samples were inoculated with a three strain cocktail of overnight cultures of E. coli O157: H7 and stored at 4 degrees C and 8 degrees C for 2 weeks. Each paste exhibited different antimicrobial effects alone and in ground beef or BPW at 4 degrees C and 8 degrees C for 2 weeks. Commercial ginger paste and fresh garlic paste showed the strongest antimicrobial activity with complete inactivation of E. coli O157:H7 in the paste at 3 days at 4 degrees C and 8 degrees C. Carrot and turmeric pastes did not show any antimicrobial activity both at 4 degrees C and 8 degrees C. Commercial garlic showed antimicrobial activity at both 4 degrees C and 8 degrees C (about 1 log CFU/g reduction) in the paste. However, fresh ginger paste showed antimicrobial activity only at 8 degrees C. Only commercial ginger paste had antimicrobial activity in BPW at 4 degrees C for 2 weeks. However, commercial ginger paste showed antimicrobial activity in ground beef at 3 days and after (about 1-2 log CFU/g) compared to control samples at 8 degrees C for 2 weeks. Fresh garlic paste showed antimicrobial activity only in BPW (1.3 log CFU/g) at 8 degrees C. These results indicate that the antimicrobial activity of these pastes is decreased in ground beef and laboratory buffer.


HIV self-care practices during pregnancy and maternal health outcomes among HIV-positive postnatal mothers aged 18-35 years at Mbuya Nehanda maternity hospital.
HIV-related conditions are one of the indirect causes of maternal deaths in Zimbabwe and the prevalence rate was estimated to be 13.63% in 2009. The study utilised a descriptive correlational design on 80 pregnant women who were HIV positive at Mbuya Nehanda maternity hospital in Harare, Zimbabwe. Participants comprised a random sample of 80 postnatal mothers. Permission to carry out the study was obtained from the respective review boards. Participants signed an informed consent. Data were collected using a structured questionnaire and record review from 1 to 20 March 2012. Interviews were done in a private room and code numbers were used to identify the participants. Completed questionnaires were kept in a lockable cupboard and the researcher had sole access to them. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 12. Descriptive statistics were used to analyse data on demographics, maternal health outcomes and self-care practices. Inferential statistics (Pearson's correlation and regression analysis) were used to analyse the relationship between self-care practices and maternal health outcomes. Self-care practices were good with a mean score of 8 out of 16. Majority (71.3%) fell within the good category. Maternal outcomes were poor with a mean score of 28 out of 62 and 67.5% falling in the poor category. Pearson's correlation indicated a weak significant positive relationship (r = .317, p = <.01). Regression analysis (R2) was .10 implying that self-care practices explained 10% of the variance observed in maternal health outcomes. More research needs to be carried out to identify other variables affecting maternal outcomes in HIV-positive pregnant women.


Large-Scale Transdisciplinary Collaboration for Adaptation Research: Challenges and Insights.
An increasing number of research programs seek to support adaptation to climate change through the engagement of large-scale transdisciplinary networks that span countries and continents. While transdisciplinary research processes have been a topic of reflection, practice, and refinement for some time, these trends now mean that the global change research community needs to reflect and learn how to pursue collaborative research on a large scale. This paper shares insights from a seven-year climate change adaptation research program that supports collaboration between more than 450 researchers and practitioners across four consortia and 17 countries. The experience confirms the importance of attention to careful design for transdisciplinary collaboration, but also highlights that this alone is not enough. The success of well-designed transdisciplinary research processes is also strongly influenced by relational and systemic features of collaborative relationships. Relational features include interpersonal trust, mutual respect, and leadership styles, while systemic features include legal partnership agreements, power asymmetries between partners, and institutional values and cultures. In the new arena of large-scale collaborative science efforts, enablers of transdisciplinary collaboration include dedicated project coordinators, leaders at multiple levels, and the availability of small amounts of flexible funds to enable nimble responses to opportunities and unexpected collaborations.


Imiquimod as an antiaging agent.
Topical imiquimod therapy has proven to be effective for a variety of infectious, neoplastic, and inflammatory dermatologic diseases. Several published reports have validated the benefit of imiquimod therapy for actinic keratoses and superficial melanoma and nonmelanoma skin cancers. There is, however, limited evidence demonstrating the use of topical imiquimod application as an antiaging treatment. We examined the effectiveness of imiquimod 5% cream in the treatment of photoaging by evaluating pretreatment and posttreatment biopsy specimens and documenting the histologic changes. This study represents an extension of an earlier project in our department in which patients with biopsy-proven lesions of lentigo maligna (LM) were recruited from a university dermatology service, a hospital, and referrals from private practitioners for an open-labeled efficacy trial with daily topical application of 5% imiquimod for 3 months. Biopsy of clinically affected skin was carried out on all patients before and after treatment. Using a semiquantitative method, biopsy specimens were analyzed for changes in the dermal collagen table (solar elastosis vs papillary dermal fibroplasia). Additional parameters analyzed included epidermal changes (atrophy vs acanthosis, melanin content, and hypergranulosis) and inflammatory effects (epidermal and dermal cell populations along with presence of pigment incontinence). Variables were compared using paired Wilcoxan rank sums. Of 26 evaluable patients who completed 3 months of daily application, 24 (>92.3%) showed a significant increase in papillary dermal fibroplasia (P < .0001) with associated reduction in solar elastosis (P = .0036). Other noteworthy findings were restoration of normal epidermal thickness (P = .0073) and melanization (P < .0001). This study only evaluates the effect of imiquimod in the lesional skin of LM. It is not known whether the results are applicable to nonlesional, photoaged skin. Topical imiquimod appears to induce reparative changes to the epidermis and the dermal collagen table in chronically sun-damaged skin associated with LM, indicating its potential use as an antiaging treatment. These findings need to be confirmed in photodamaged skin not associated with LM.


Lysine acetylation targets protein complexes and co-regulates major cellular functions.
Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technological limitations have so far prevented a global analysis of lysine acetylation's cellular roles. We used high-resolution mass spectrometry to identify 3600 lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other major posttranslational modifications.


DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells.
DNA methylation is a heritable epigenetic mark, enabling stable but reversible gene repression. In mammalian cells, DNA methyltransferases (DNMTs) are responsible for modifying cytosine to 5-methylcytosine (5mC), which can be further oxidized by the TET dioxygenases to ultimately cause DNA demethylation. However, the genome-wide cooperation and functions of these two families of proteins, especially at large under-methylated regions, called canyons, remain largely unknown. Here we demonstrate that DNMT3A and TET1 function in a complementary and competitive manner in mouse embryonic stem cells to mediate proper epigenetic landscapes and gene expression. The longer isoform of DNMT3A, DNMT3A1, exhibits significant enrichment at distal promoters and canyon edges, but is excluded from proximal promoters and canyons where TET1 shows prominent binding. Deletion of Tet1 increases DNMT3A1 binding capacity at and around genes with wild-type TET1 binding. However, deletion of Dnmt3a has a minor effect on TET1 binding on chromatin, indicating that TET1 may limit DNA methylation partially by protecting its targets from DNMT3A and establishing boundaries for DNA methylation. Local CpG density may determine their complementary binding patterns and therefore that the methylation landscape is encoded in the DNA sequence. Furthermore, DNMT3A and TET1 impact histone modifications which in turn regulate gene expression. In particular, they regulate Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 enrichment to constrain gene expression from bivalent promoters. We conclude that DNMT3A and TET1 regulate the epigenome and gene expression at specific targets via their functional interplay.


Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication.
Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee. We investigated a potential molecular mechanism underlying a CAPE-mediated protective effect against ischemia/reperfusion (I/R) injury and analyzed the structure contributing to the CAPE effect. CAPE induced hypoxia-inducible factor-1 (HIF-1) alpha protein, concomitantly transactivating the HIF-1 target genes vascular endothelial growth factor and heme oxygenase-1, which play a protective role in I/R injury. CAPE delayed the degradation of HIF-1alpha protein in cells, which occurred by inhibition of HIF prolyl hydroxylase (HPH), the key enzyme for von Hippel-Lindau-dependent HIF-1alpha degradation. CAPE inhibition of HPH and induction of HIF-1alpha protein were neutralized by an elevated dose of iron. The catechol moiety, a chelating group, is essential for HPH inhibition, while hydrogenation of the double bond (-C=C-) in the Michael reaction acceptor markedly reduced potency. Removal of the phenethyl moiety of CAPE (substitution with the methyl moiety) severely deteriorated its inhibitory activity for HPH. Our data suggest that a beneficial effect of CAPE on I/R injury may be ascribed to the activation of HIF-1 pathway via inhibition of HPH and reveal that the chelating moiety of CAPE acted as a pharmacophore while the double bond and phenethyl moiety assisted in inhibiting HPH.


Validation of the European Health Literacy Survey Questionnaire in Women With Breast Cancer.
Health literacy enables effective communication, participation, and cooperation with clinicians of patients with breast cancer in healthcare processes. The European Health Literacy Survey Questionnaire (HLS-EU-Q) comprehensively assesses multiple conceptual domains of health literacy in a diverse range of health contexts. However, the HLS-EU-Q has not been validated in women with breast cancer. We examined the psychometric properties, particularly the factorial validity, of the HLS-EU-Q in women with breast cancer. We performed a first-order confirmatory factor analysis (CFA) to verify the 12-subdomain model of the 47-item HLS-EU-Q. A second-order CFA was conducted to investigate whether the 12 subdomains reflected the 3 domains of healthcare, disease prevention, and health promotion correspondingly. A total of 475 women with breast cancer participated in this study. The first-order CFA fitted with the HLS-EU-Q containing 47 items. However, item 29, with a low factor loading (-0.05), was deleted. The modified first-order CFA adequately fitted the data of the HLS-EU-Q with 46 items. The second-order CFA model acceptably fitted with the data, but the 3 domains with high correlations (0.92-1.00) were merged into a single domain, health literacy. Our results supported the factorial validity of the 12-subdomain HLS-EU-Q with 46 items in women with breast cancer. It is recommended that the 12 subdomain scores be summed up to represent overall health literacy. The HLS-EU-Q with 46 items is recommended for use in capturing the diverse health literacy competencies of women with breast cancer in different health contexts.


Mediating roles of preterm birth and restricted fetal growth in the relationship between maternal education and infant mortality: A Danish population-based cohort study.
Socioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality. We developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981-2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0-27 days) and postneonatal (28-364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48-1.80, P < 0.001) and 1.19 (95% CI 1.08-1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRRPE = 1.27, 95% CI 1.15-1.40, P < 0.001) for low and 60% (MRRPE = 1.11, 95% CI 1.01-1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%-81%) than with postneonatal mortality (proportion eliminated: 21%-23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare. PTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors.


Cannabidiol inhibits priming-induced reinstatement of methamphetamine in REM sleep deprived rats.
Methamphetamine (METH) is a widely abused and a severely addictive psychostimulant. Relapse is the main cause of concern when treating addiction. It could manifest after a long period of abstinence. Previous studies showed that there is a strong connection between sleep impairment and relapse. Also, it has been reported that cannabidiol might be a potential treatment for drug craving and relapse. In this study, we used conditioned place preference (CPP) to investigate whether Cannabidiol (CBD), a phytocannabinoid, can prevent METH-induced reinstatement in Rapid Eye Movement Sleep Deprived (RSD) rats. In order to induce CPP, the animals were given METH (1mg/kg; sc) for five days. The effective priming dose of METH (0.5mg/kg, sc) reinstated the extinguished METH-induced CPP. In order to investigate the effect of RSD on METH-induced reinstatement, we used the inverted flowerpot technique to deprive the rats of REM sleep. We found that 24h-RSD could facilitate priming-induced reinstatement of METH. In addition to this, the ICV administration of CBD 10μg/5μl could suppress the METH-induced reinstatement even in RSD rats. In conclusion, the administration of CBD 10μg/5μl effectively prevents METH-induced CPP, even in a condition of stress. CBD can be considered an agent that reduces the risk of the relapse; however, this requires more investigation.


Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets.
The European Union multi-disciplinary Personalised RNA interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway inhibitor. Through the analysis of tumor tissue derived from pre-operative renal cell carcinoma (RCC) clinical trials, the PREDICT consortium will use established and novel methods to integrate comprehensive tumor-derived genomic data with personalized tumor-derived small hairpin RNA and high-throughput small interfering RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients. PREDICT's approach to predictive biomarker discovery differs from conventional associative learning approaches, which can be susceptible to the detection of chance associations that lead to overestimation of true clinical accuracy. These methods will identify molecular pathways important for survival and growth of RCC cells and particular targets suitable for therapeutic development. Importantly, our results may enable individualized treatment of RCC, reducing ineffective therapy in drug-resistant disease, leading to improved quality of life and higher cost efficiency, which in turn should broaden patient access to beneficial therapeutics, thereby enhancing clinical outcome and cancer survival. The consortium will also establish and consolidate a European network providing the technological and clinical platform for large-scale functional genomic biomarker discovery. Here we review our current understanding of molecular mechanisms driving resistance to anti-angiogenesis agents, the current limitations of laboratory and clinical trial strategies and how the PREDICT consortium will endeavor to identify a new generation of predictive biomarkers.


Stopping and changing in adults with ADHD.
A lack of inhibitory control has been suggested to be the core deficit in children with attention deficit hyperactivity disorder (ADHD). This means that a primary deficit in behavioral inhibition mediates a cascade of secondary deficits in other executive functions, such as arousal regulation. Clinical observations have revealed that with increasing age symptoms of hyperactivity and impulsivity decline at a higher rate than those of inattention. This might imply that a deficit in attention rather than a lack of inhibitory control is the major feature in adult ADHD. To study whether an attentional or inhibitory deficit predominates, the stop-signal task and the stop-change task were presented to 24 adults with ADHD combined subtype and 24 controls. Relative to controls, the stop-signal reaction time (SSRT) was significantly more prolonged than the go-stimulus reaction time (RT) in patients with ADHD. This disproportionate elongation of the SSRT was comparable across tasks, even though the stop-change task exerted more complex (or at least different) demands on the inhibitory system than the stop-signal task. ADHD patients had a higher proportion of choice errors, possibly reflecting more premature responses. Specifically in the stop-change task, patients had more variable choice responses and made more inappropriate change responses, which may also reflect enhanced impulsivity. The results support a core deficit in behavioral inhibition in adults with ADHD. We further suggest that there is more evidence for a critical role of deficient inhibitory control in adults than in children with ADHD.


A framework for understanding sources of bias in medication adherence research.
The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty-three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research.


The Good, the Bad, and the Future of Drones in Tactical/Operational Medicine.
Unmanned aerial vehicles (UAVs) have seen expansion with their applications in many fields, including the opportunity these tools offer to improve medical care. Drones have significant potential for use in the tactical setting. New, unique possibilities for these drones are emerging constantly, but there is no standardized inclusion specifically with tactical medicine operations. This article is a review of the future possibilities of drones, the associated risks that drones present, and the current application of drone technology in the field of civilian operational/tactical medicine.


Selection of functional single domain antibody fragments for interfering with protein-protein interactions inside cells: a "one plasmid" mammalian two-hybrid system.
As a complement to the intracellular antibody capture method to isolate intracellular single domain antibody fragments (iDabs) from high diverse libraries, we describe here a simple mammalian two-hybrid (M2H) protocol using a "bait-prey hybrid single plasmid" to assess those interfering iDabs that will block protein-protein interactions of a target with its natural partner proteins. This rapid method identifies interfering iDabs in one step and improves the reproducibility of the results between experiments and samples (e.g., different single domain antibody clones) compared to traditional M2H. This method yields functional, interfering iDabs and can be applied to any interfering molecule for use as a research tool or template for clinical inhibitor production.


GRACE principles: recognizing high-quality observational studies of comparative effectiveness.
Nonrandomized comparative effectiveness studies contribute to clinical and biologic understanding of treatments by themselves, via subsequent confirmation in a more targeted randomized clinical trial, or through advances in basic science. Although methodological challenges and a lack of accepted principles to assess the quality of nonrandomized studies of comparative effectiveness have limited the practical use of these investigations, even imperfect studies can contribute useful information if they are thoughtfully designed, well conducted, carefully analyzed, and reported in a manner that addresses concerns from skeptical readers and reviewers. The GRACE (Good Research for Comparative Effectiveness) principles have been developed to help healthcare providers, researchers, journal readers, and editors evaluate the quality inherent in observational research studies of comparative effectiveness. The GRACE principles were developed by experienced academic and private sector researchers and were vetted over several years through presentation, critique, and consensus building among outcomes researchers, pharmacoepidemiologists, and other medical scientists and via formal review by the International Society of Pharmacoepidemiology. In contrast to other documents that guide systematic review and reporting, the GRACE principles are high-level concepts about good practice for nonrandomized comparative effectiveness research. The GRACE principles comprise a series of questions to guide evaluation. No scoring system is provided or encouraged, as interpretation of these observational studies requires weighing of all available evidence, tempered by judgment regarding the applicability of the studies to routine care.


Effects of Inhalation of Essential Oil of Citrus aurantium L. var. amara on Menopausal Symptoms, Stress, and Estrogen in Postmenopausal Women: A Randomized Controlled Trial.
This study aimed to investigate the effects of inhalation of the essential oil of Citrus aurantium L. var. amara (neroli oil) on menopausal symptoms, stress, and estrogen in postmenopausal women. Sixty-three healthy postmenopausal women were randomized to inhale 0.1% or 0.5% neroli oil or almond oil (control) for 5 minutes twice daily for 5 days. Menopause-related symptoms, as determined by the Menopause-Specific Quality of Life Questionnaire (MENQOL); sexual desire visual analog scale (VAS); serum cortisol and estrogen concentrations, blood pressure, pulse, and stress VAS, were measured before and after inhalation. Compared with the control group, the two neroli oil groups showed significant improvements in the physical domain score of the MENQOL and in sexual desire. Systolic blood pressure was significantly lower in the group inhaling 0.5% neroli oil than in the control group. Compared with the control group, the two neroli oil groups showed significantly lower diastolic blood pressure and tended to improve pulse rate and serum cortisol and estrogen concentrations. These findings indicate that inhalation of neroli oil helps relieve menopausal symptoms, increase sexual desire, and reduce blood pressure in postmenopausal women. Neroli oil may have potential as an effective intervention to reduce stress and improve the endocrine system.


Interpersonal violence in a deprived Scottish urban area with aggregations of physical health risks and psychiatric morbidity: an ecological study.
Glasgow, Scotland, has previously shown exceptional levels of violence among young men, shows aggregations of health conditions, with shortened life expectancy. Health conditions can be both causes and consequences of violence, of shared community-level socio-economic risk factors, and can result from large-scale social forces beyond the control of populations with high levels of violence. The aim of the study was to provide an in depth understanding of the Public Health problem of violence among young adult men in Glasgow East. Ecological investigation of violence and its associations with health conditions in areas of contrasting socioeconomic deprivation. National survey of 1916 British men aged 18-34 years, augmented by a sub-sample of 765 men in Glasgow East (GE). Participants completed questionnaires covering current physical and sexual health, psychiatric symptoms, substance misuse, lifestyle, and crime and violence. The 5-year prevalence of violence was similar in both surveys but fights involving weapons (AOR 3.32, 95% CI 2.29-4.79), gang fights (AOR 2.30, 95% CI 1.77-2.98), and instrumental violence supporting criminal lifestyles were more common in GE, where 1 in 9 men had been in prison. Violent men in both samples reported poorer physical and sexual health and all types of psychiatric morbidity except depression, with multiple high-risk behaviours for both future poor health and violence. Associations between drug and alcohol dependence and violence in GE could not be entirely explained by deprivation. Violence in deprived urban areas is one among many high-risk behaviours and lifestyle factors leading to, as well as resulting from, aggregations of both psychiatric and physical health conditions. Poverty partly explained raised levels of violence in GE. Other factors such as drug and alcohol misuse and macho attitudes to violence, highly prevalent among men in this socially excluded community, also contributed. Multi-component preventive interventions may be needed in deprived areas and require future investigations into how multiple co-existing risk factors produce multimorbidity, including psychiatric disorders, substance misuse, poor physical health and violence.


Neuropsychological functioning in a national cohort of severe traumatic brain injury: demographic and acute injury-related predictors.
To determine the rates of cognitive impairment 1 year after severe traumatic brain injury (TBI) and to examine the influence of demographic, injury severity, rehabilitation, and subacute functional outcomes on cognitive outcomes 1 year after severe TBI. National multicenter cohort study over 2 years. Patients (N = 105), aged 16 years or older, with Glasgow Coma Scale score of 3 to 8 and Galveston Orientation and Amnesia Test score of more than 75. Neuropsychological tests representing cognitive domains of Executive Functions, Processing Speed, and Memory. Injury severity included Rotterdam computed tomography score, Glasgow Coma Scale score, and posttraumatic amnesia (PTA) duration, together with length of rehabilitation and Glasgow Outcome Scale-Extended score. In total, 67% of patients with severe TBI had cognitive impairment. Executive Functions, Processing Speed, and Memory were impaired in 41%, 58%, and 57% of patients, respectively. Using multiple regression analysis, Processing Speed was significantly related to PTA duration, Glasgow Outcome Scale-Extended score, and length of inpatient rehabilitation (R = 0.30); Memory was significantly related to Glasgow Outcome Scale-Extended score (R = 0.15); and Executive Functions to PTA duration (R = 0.10). Rotterdam computed tomography and Glasgow Coma Scale scores were not associated with cognitive functioning at 1 year postinjury. Findings highlight cognitive consequences of severe TBI, with nearly two-thirds of patients showing cognitive impairments in at least 1 of 3 cognitive domains. Regarding injury severity predictors, only PTA duration was related to cognitive functioning.


Efficient one-third harmonic generation in highly Germania-doped fibers enhanced by pump attenuation.
We provide a comprehensive study on one-third harmonic generation (OTHG) in highly Germania-doped fiber (HGDF) by analyzing the phase matching conditions for the step index-profile and optimizing the design parameters. For stimulated OTHG in HGDF, the process can be enhanced by fiber attenuation at the pump wavelength which dynamically compensates the accumulated phase-mismatch along the fiber. With 500 W pump and 35 W seed power, simulation results show that a 31% conversion efficiency, which is 4 times higher than the lossless OTHG process, can be achieved in 34 m of HGDF with 90 mol. % GeO2 doping in the core.


Oligomeric structure of the human EphB2 receptor SAM domain.
The sterile alpha motif (SAM) domain is a protein interaction module that is present in diverse signal-transducing proteins. SAM domains are known to form homo- and hetero-oligomers. The crystal structure of the SAM domain from an Eph receptor tyrosine kinase, EphB2, reveals two large interfaces. In one interface, adjacent monomers exchange amino-terminal peptides that insert into a hydrophobic groove on each neighbor. A second interface is composed of the carboxyl-terminal helix and a nearby loop. A possible oligomer, constructed from a combination of these binding modes, may provide a platform for the formation of larger protein complexes.


Infection Prevention in Shoulder Surgery.
The microbiome of the shoulder demonstrates distinctive differences to other orthopaedic surgical sites. Recent studies have demonstrated that the most common organisms found in deep shoulder infections are coagulase-negative staph lococcal species and Propionibacterium acnes . Many studies support diligent hand washing, decreasing operative time, routine glove changing, minimizing operating room traffic, and covering instruments as means for decreasing the risk of deep infection. On the other hand, hair clipping and the use of adhesive drapes may have little effect on decreasing the incidence of deep infection. Although generally considered the most efficacious skin preparation solution, chlorhexidine gluconate has minimal effect on eradication of P. acnes from the surgical site; however, the addition of preoperative topical applications of benzoyl peroxide to standard surgical preparation has shown promise in decreasing the rate of P . acnes culture positivity. Additionally, the use of local antibiotic formulations seems to be an effective means of preventing deep infection.


TOMATOMICS: A Web Database for Integrated Omics Information in Tomato.
Solanum lycopersicum (tomato) is an important agronomic crop and a major model fruit-producing plant. To facilitate basic and applied research, comprehensive experimental resources and omics information on tomato are available following their development. Mutant lines and cDNA clones from a dwarf cultivar, Micro-Tom, are two of these genetic resources. Large-scale sequencing data for ESTs and full-length cDNAs from Micro-Tom continue to be gathered. In conjunction with information on the reference genome sequence of another cultivar, Heinz 1706, the Micro-Tom experimental resources have facilitated comprehensive functional analyses. To enhance the efficiency of acquiring omics information for tomato biology, we have integrated the information on the Micro-Tom experimental resources and the Heinz 1706 genome sequence. We have also inferred gene structure by comparison of sequences between the genome of Heinz 1706 and the transcriptome, which are comprised of Micro-Tom full-length cDNAs and Heinz 1706 RNA-seq data stored in the KaFTom and Sequence Read Archive databases. In order to provide large-scale omics information with streamlined connectivity we have developed and maintain a web database TOMATOMICS (http://bioinf.mind.meiji.ac.jp/tomatomics/). In TOMATOMICS, access to the information on the cDNA clone resources, full-length mRNA sequences, gene structures, expression profiles and functional annotations of genes is available through search functions and the genome browser, which has an intuitive graphical interface.


The role of "watch and wait" in intestinal follicular lymphoma in rituximab era.
There is no consensus regarding the best treatment for intestinal follicular lymphoma (FL). We used "watch and wait" for patients with intestinal FL with low-tumor-burden (LTB) criteria and without mass formation causing bowel obstruction. We investigated the overall survival (OS) and time to treatment required (TTR). Thirty-three intestinal FL patients [clinical stage (CS) I:16, II1:0, II2:7, IV:10; median observation period: 45.5 months, range: 13-110 months] were diagnosed via endoscopy. Detailed clinical and pathological examinations were performed, and neoplastic process behavior was monitored. All of the 33 patients were WHO grade 1. FL lesions in the digestive tract were found frequently in the second-fourth portion of the duodenum in 91% of the patients; 87% of those patients had lesions in a broader area including the small intestine. Two patients had an enlargement of the area of the lesions and a worsening of the macroscopic findings. Three patients had CS progression; however, these remained within the indication for "watch and wait." Two patients with transformation into diffuse large B-cell lymphoma received rituximab and chemotherapy, which led to complete remission. The OS was 100%. The time to treatment required (TTR) was 49 months in one patient and 37 months in one patient. Intestinal FL in CS I-IV with broad infiltration of the digestive tract meeting the criteria for LTB had a remarkably slow course. This study suggests that "watch and wait" is appropriate for the treatment of LTB intestinal FL even in the era of rituximab.


Reversion of β-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study.
β-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk. Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes. Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies (<1%). Most (85%) reversion of single autoantibodies occurred within 2 years of seroconversion. Reversion was associated with HLA genotype, age, and decreasing titer. Children who reverted from single autoantibodies to autoantibody negative had, from birth, a risk for type 1 diabetes of 0.14 per 100 person-years; children who never developed autoantibodies, 0.06 per 100 person-years; and, children who remained single-autoantibody positive, 1.8 per 100 person-years. Type 1 diabetes risk remained high in children who had developed multiple β-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk.


Analysis of imaging for laser triangulation sensors under Scheimpflug rule.
In this work a detailed analysis of the problem of imaging of objects lying in the plane tilted with respect to the optical axis of the rotationally symmetrical optical system is performed by means of geometrical optics theory. It is shown that the fulfillment of the so called Scheimpflug condition (Scheimpflug rule) does not guarantee the sharp image of the object as it is usually declared because of the fact that due to the dependence of aberrations of real optical systems on the object distance the image becomes blurred. The f-number of a given optical system also varies with the object distance. It is shown the influence of above mentioned effects on the accuracy of the laser triangulation sensors measurements. A detailed analysis of laser triangulation sensors, based on geometrical optics theory, is performed and relations for the calculation of measurement errors and construction parameters of laser triangulation sensors are derived.


Probabilistic Template of the Lateral Parabrachial Nucleus, Medial Parabrachial Nucleus, Vestibular Nuclei Complex, and Medullary Viscero-Sensory-Motor Nuclei Complex in Living Humans From 7 Tesla MRI.
The lateral parabrachial nucleus, medial parabrachial nucleus, vestibular nuclei complex, and medullary viscero-sensory-motor (VSM) nuclei complex (the latter including among others the solitary nucleus, vagus nerve nucleus, and hypoglossal nucleus) are anatomically and functionally connected brainstem gray matter structures that convey signals across multiple modalities between the brain and the spinal cord to regulate vital bodily functions. It is remarkably difficult to precisely extrapolate the location of these nuclei from ex vivo atlases to conventional 3 Tesla in vivo images; thus, a probabilistic brainstem template in stereotaxic neuroimaging space in living humans is needed. We delineated these nuclei using single-subject high contrast 1.1 mm isotropic resolution 7 Tesla MRI images. After precise coregistration of nuclei labels to stereotaxic space, we generated a probabilistic template of their anatomical locations. Finally, we validated the nuclei labels in the template by assessing their inter-rater agreement, consistency across subjects and volumes. We also performed a preliminary comparison of their location and microstructural properties to histologic sections of a postmortem human brainstem specimen. In future, the resulting probabilistic template of these brainstem nuclei in stereotaxic space may assist researchers and clinicians in evaluating autonomic, vestibular and VSM nuclei structure, function and connectivity in living humans using conventional 3 Tesla MRI scanners.


Bouncing or streaming? Exploring the influence of auditory cues on the interpretation of ambiguous visual motion.
When looking at two identical objects moving toward each other on a two-dimensional visual display, two different events can be perceived: the objects can either be seen to bounce off each other, or else to stream through one another. Previous research has shown that the large bias normally seen toward the streaming percept can be modulated by the presentation of an auditory event at the moment of coincidence. However, previous behavioral research on this crossmodal effect has always relied on subjective report. In the present experiment, we used a novel experimental design to provide a more objective/implicit measure of the effect of an auditory cue on visual motion perception. In our study, two disks moved toward each other, with the point of coincidence hidden behind an occluder. When emerging from behind the occluder, the disks (one red, the other blue) could either follow the same trajectory (streaming) or else move in the opposite direction (bouncing). Participants made speeded discrimination responses regarding the side from which one of the disks emerged from behind the occluder. Participants responded more rapidly on streaming trials when no sound was presented and on bouncing trials when the sound was presented at the moment of coincidence. These results provide the first empirical demonstration of the auditory modulation of an ambiguous visual motion display using an implicit/objective behavioral measure of perception.


Sparsity as cellular objective to infer directed metabolic networks from steady-state metabolome data: a theoretical analysis.
Since metabolome data are derived from the underlying metabolic network, reverse engineering of such data to recover the network topology is of wide interest. Lyapunov equation puts a constraint to the link between data and network by coupling the covariance of data with the strength of interactions (Jacobian matrix). This equation, when expressed as a linear set of equations at steady state, constitutes a basis to infer the network structure given the covariance matrix of data. The sparse structure of metabolic networks points to reactions which are active based on minimal enzyme production, hinting at sparsity as a cellular objective. Therefore, for a given covariance matrix, we solved Lyapunov equation to calculate Jacobian matrix by a simultaneous use of minimization of Euclidean norm of residuals and maximization of sparsity (the number of zeros in Jacobian matrix) as objective functions to infer directed small-scale networks from three kingdoms of life (bacteria, fungi, mammalian). The inference performance of the approach was found to be promising, with zero False Positive Rate, and almost one True positive Rate. The effect of missing data on results was additionally analyzed, revealing superiority over similarity-based approaches which infer undirected networks. Our findings suggest that the covariance of metabolome data implies an underlying network with sparsest pattern. The theoretical analysis forms a framework for further investigation of sparsity-based inference of metabolic networks from real metabolome data.


Associations between HPA axis functioning and level of anxiety in children and adolescents with an anxiety disorder.
The hypothalamus-pituitary-adrenal (HPA) axis becomes active in response to stress. Hence, increased levels of anxiety in children and adolescents may be associated with changes in HPA-axis functioning. The aim of this study was to test if level of anxiety or specific anxiety disorders were associated with basal HPA axis activity in children and adolescents with an anxiety disorder. In 99 8- to 16-year-olds with an anxiety disorder, basal cortisol levels were assessed. It was tested if (1) cortisol levels correlated with the level of self-reported anxiety and (2) if cortisol levels were different for individuals with different anxiety disorders. In girls, low levels of anxiety were associated with a stronger rise in early morning cortisol concentrations. In both boys and girls, harm avoidance predicted low cortisol concentrations after awakening. Separation anxiety and physical anxiety symptoms predicted cortisol concentrations at noon. Differences between individuals with different anxiety disorders were not found. More research is needed regarding mechanisms that explain the associations that were found, and to investigate if treatment may influence HPA axis functioning in children and adolescents with an anxiety disorder.


Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.
The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B. A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P<0.05 for all comparisons). Reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients in group A, whereas grade 1 reductions occurred in 2.5% of the patients in group B. In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.).


Hypomorphic variants of cationic amino acid transporter 3 in males with autism spectrum disorders.
Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors.


Thioalkalimicrobium aerophilum gen. nov., sp. nov. and Thioalkalimicrobium sibericum sp. nov., and Thioalkalivibrio versutus gen. nov., sp. nov., Thioalkalivibrio nitratis sp.nov., novel and Thioalkalivibrio denitrificancs sp. nov., novel obligately alkaliphilic and obligately chemolithoautotrophic sulfur-oxidizing bacteria from soda lakes.
Forty-three strains of obligately chemolithoautotrophic sulfur-oxidizing bacteria were isolated from highly alkaline soda lakes in south-east Siberia (Russia) and in Kenya using a specific enrichment procedure at pH 10. The main difference between the novel isolates and known sulfur bacteria was their potential to grow and oxidize sulfur compounds at pH 10 and higher. The isolates fell into two groups that were substantially different from each other physiologically and genetically. Most of the Siberian isolates belonged to the group with a low DNA G+C content (48.0-51.2 mol%). They were characterized by a high growth rate, a low growth yield, a high cytochrome content, and high rates of oxidation of sulfide and thiosulfate. This group included 18 isolates with a DNA homology of more than 40%, and it is described here as a new genus, Thioalkalimicrobium, with two species Thioalkalimicrobium aerophilum (type species) and Thioalkalimicrobium sibericum. The other isolates, mainly from Kenyan soda lakes, fell into a group with a high DNA G+C content (61.0-65.6 mol%). In general, this group was characterized by a low growth rate, a high molar growth yield and low, but relatively equal, rates of oxidation of thiosulfate, sulfide, elemental sulfur and polythionates. The group included 25 isolates with a DNA homology of more than 30%. It was less compact than Thioalkalimicrobium, containing haloalkalophilic, carotenoid-producing, nitrate-reducing and facultatively anaerobic denitrifying strains. These bacteria are proposed to be assigned to a new genus, Thioalkalivibrio, with three species Thioalkalivibrio versutus (type species), Thioalkalivibrio denitrificans and Thioalkalivibrio nitratis. Phylogenetic analysis revealed that both groups belong to the gamma-Proteobacteria. The Thioalkalimicrobium species were closely affiliated with the neutrophilic chemolithoautotrophic sulfur bacteria of the genus Thiomicrospira, forming a new alkaliphilic lineage in this cluster. In contrast, Thioalkalivibrio was not related to any known chemolithoautotrophic taxa, but was distantly associated with anaerobic purple sulfur bacteria of the genus Ectothiorhodospira.


Efficacy and safety of cinnarizine in the prophylaxis of migraine in children: a double-blind placebo-controlled randomized trial.
In spite of the high occurrence of migraine headaches in school-age children, there are currently no approved and widely accepted pharmacologic agents for migraine prophylaxis in children. Our previous open-label study in children revealed the efficacy of cinnarizine, a calcium channel blocker, in migraine prophylaxis. A placebo-controlled trial was conducted to demonstrate the efficacy and safety of cinnarizine in the prophylaxis of migraine in children. A double-blind, placebo-controlled, parallel-group study conducted in a tertiary medical center in Tehran, Iran. Children (5-17 years) who experienced migraines with and without aura, as defined on the basis of 2004 International Headache Society criteria, were recruited into the study. Children were excluded if they had complicated migraine, epilepsy, or a history of use of migraine prophylactic agents. Each participant was randomly assigned to receive cinnarizine (a single 1.5 mg/kg/day dose in children weighing less than 30 kg and a single 50 mg dose in children weighing more than 30 kg, administered at bedtime) or placebo. The frequency, severity, and duration of headaches over the trial period were assessed and adverse effects were monitored. A total of 68 children (34 in each group) with migraine were enrolled and 62 participants completed the study. After 3 months of taking cinnarizine or placebo, children in both groups experienced significantly reduced frequency, severity, and duration of headaches compared with baseline measurements (P < 0.001). However, compared with 31.3% of children in the placebo group, 60% of children in the cinnarizine group reported more than 50% reduction in monthly headache frequency (P = 0.023), suggesting that cinnarizine was significantly more effective than placebo in reducing the frequency of headaches. No serious adverse effects of the medications were observed in the treated children, including no abnormal weight gain or extrapyramidal signs. Our results indicate that the use of cinnarizine at doses administered in this study is effective and safe for prophylaxis of migraine headaches in children.


Fractures of allografts used in limb preserving operations.
One hundred and thirty-seven allografts used since 1986 in limb preserving operations for malignant bone tumours were reviewed. The follow up was longer than two years. There were fourteen fractures (10.2%) in twelve patients at a mean time of 22 months from the operation. Most of them were in the metaphyseal area and were related to perforations of the allograft made for stabilisation with plates, for tendon and ligament reattachment, or any other hole in the allograft. Fractures occurred always after the allograft-host junction was united. Healing was achieved in 7 cases by internal fixation with autologous bone grafting in a mean of 5 months. In cases of multiple fractures of the allograft, the graft was exchanged. We recommend using intramedullary fixation in order to reduce the incidence of allograft fracture, and the use of internal fixation, with intramedullary whenever possible, and autologous bone grafting to achieve consolidation of the fractures.


Neurosurgery and Manned Spaceflight.
There has been a renewed interest in manned spaceflight due to endeavors by private and government agencies. Publicized goals include manned trips to or colonization of Mars. These missions will likely be of long duration, exceeding existing records for human exposure to extra-terrestrial conditions. Participants will be exposed to microgravity, temperature extremes, and radiation, all of which may adversely affect their physiology. Moreover, pathological mechanisms may differ from those of a terrestrial nature. Known central nervous system (CNS) changes occurring in space include rises in intracranial pressure and spinal unloading. Intracranial pressure increases are thought to occur due to cephalad re-distribution of body fluids secondary to microgravity exposure. Spinal unloading in microgravity results in potential degenerative changes to the bony vertebrae, intervertebral discs, and supportive musculature. These phenomena are poorly understood. Trauma is of highest concern due to its potential to seriously incapacitate crewmembers and compromise missions. Traumatic pathology may also be exacerbated in the setting of altered CNS physiology. Though there are no documented instances of CNS pathologies arising in space, existing diagnostic and treatment capabilities will be limited relative to those on Earth. In instances where neurosurgical intervention is required in space, it is not known whether open or endoscopic approaches are feasible. It is obvious that prevention of trauma and CNS pathology should be emphasized. Further research into neurosurgical pathology, its diagnosis, and treatment in space are required should exploratory or colonization missions be attempted.


Temperature and Solvent Effects on H2 Splitting and Hydricity: Ramifications on CO2 Hydrogenation by a Rhenium Pincer Catalyst.
The catalytic hydrogenation of carbon dioxide holds immense promise for applications in sustainable fuel synthesis and hydrogen storage. Mechanistic studies that connect thermodynamic parameters with the kinetics of catalysis can provide new understanding and guide predictive design of improved catalysts. Reported here are thermochemical and kinetic analyses of a new pincer-ligated rhenium complex (tBuPOCOP)Re(CO)2 (tBuPOCOP = 2,6-bis(di-tert-butylphosphinito)phenyl) that catalyzes CO2 hydrogenation to formate with faster rates at lower temperatures. Because the catalyst follows the prototypical "outer sphere" hydrogenation mechanism, comprehensive studies of temperature and solvent effects on the H2 splitting and hydride transfer steps are expected to be relevant to many other catalysts. Strikingly large entropy associated with cleavage of H2 results in a strong temperature dependence on the concentration of [(tBuPOCOP)Re(CO)2H]- present during catalysis, which is further impacted by changing the solvent from toluene to tetrahydrofuran to acetonitrile. New methods for determining the hydricity of metal hydrides and formate at temperatures other than 298 K are developed, providing insight into how temperature can influence the favorability of hydride transfer during catalysis. These thermochemical insights guided the selection of conditions for CO2 hydrogenation to formate with high activity (up to 364 h-1 at 1 atm or 3330 h-1 at 20 atm of 1:1 H2:CO2). In cases where hydride transfer is the highest individual kinetic barrier, entropic contributions to outer sphere H2 splitting lead to a unique temperature dependence: catalytic activity increases as temperature decreases in tetrahydrofuran (200-fold increase upon cooling from 50 to 0 °C) and toluene (4-fold increase upon cooling from 100 to 50 °C). Ramifications on catalyst structure-function relationships are discussed, including comparisons between "outer sphere" mechanisms and "metal-ligand cooperation" mechanisms.


Reduction in hospital-wide mortality after implementation of a rapid response team: a long-term cohort study.
Rapid response teams (RRTs) have been shown to reduce cardiopulmonary arrests outside the intensive care unit (ICU). Yet the utility of RRTs remains in question, as most large studies have failed to demonstrate a significant reduction in hospital-wide mortality after RRT implementation. A cohort design with historical controls was used to determine the effect on hospital-wide mortality of an RRT in which clinical judgment, in addition to vital-signs criteria, was widely promoted as a key trigger for activation. All nonprisoner patients admitted to a tertiary referral public teaching hospital from 2003 through 2008 were included. In total, 77, 021 admissions before RRT implementation (2003 through 2005) and 79, 013 admissions after RRT implementation (2006 through 2008) were evaluated. The a priori primary outcome was unadjusted hospital-wide mortality. A Poisson regression model was then used to adjust for hospital-wide mortality trends over time. Secondary outcomes defined a priori were unadjusted out-of-ICU mortality and out-of-ICU cardiopulmonary-arrest codes. In total, 855 inpatient RRTs (10.8 per 1, 000 hospital-wide discharges) were activated during the 3-year postintervention period. Forty-seven percent of RRTs were activated for reasons of clinical judgment. Hospital-wide mortality decreased from 15.50 to 13.74 deaths per 1, 000 discharges after RRT implementation (relative risk, 0.887; 95% confidence interval (CI), 0.817 to 0.963; P = 0.004). After adjusting for inpatient mortality trends over time, the reduction in hospital-wide mortality remained statistically significant (relative risk, 0.825; 95% CI, 0.694 to 0.981; P = 0.029). Out-of-ICU mortality decreased from 7.08 to 4.61 deaths per 1, 000 discharges (relative risk, 0.651; 95% CI, 0.570 to 0.743; P < 0.001). Out-of-ICU cardiopulmonary-arrest codes decreased from 3.28 to 1.62 codes per 1, 000 discharges (relative risk, 0.493; 95% CI, 0.399 to 0.610; P < 0.001). Implementation of an RRT in which clinical judgment, in addition to vital-signs criteria, was widely cited as a rationale for activation, was associated with a significant reduction in hospital-wide mortality, out-of-ICU mortality, and out-of-ICU cardiopulmonary-arrest codes. The frequent use of clinical judgment as a criterion for RRT activation was associated with high RRT utilization.


ArgBP2-dependent signaling regulates pancreatic cell migration, adhesion, and tumorigenicity.
The poor prognosis of pancreatic cancer is due to rapid locoregional invasion, the early development of metastases, and the limited efficacy of current therapies. To date, none of the identified oncogenes and suppressors involved in this disease have led to efficient treatments. Here, we describe that the scaffold protein ArgBP2 is repressed during oncogenic transformation of the pancreas. We could show, using a pancreatic cancer cell line model, that this repression of ArgBP2 participates in the progression of this disease. Interestingly, in vitro analyses revealed that the antitumoral potential of ArgBP2 is linked to the control of cell adhesion and migration rather than to the regulation of cell proliferation or sensitivity to apoptosis. Moreover, we could detail part of the molecular mechanism responsible by identifying new ArgBP2-interacting proteins, and show that this function is partly achieved by the control of a WAVE/PTP-PEST/c-Abl signaling complex. These findings point to a new mechanism of pancreatic cancer progression leading to invasion and metastasis and suggest that the ArgBP2 signaling pathway could represent a new target for cancer therapy.


Dietetics students' construction of competence through assessment and placement experiences.
Competency standards are widely adopted as a framework to describe standards of performance required in the workplace. Little is known, however, about how students construct competence. This qualitative study aimed to explore how dietetics students ready to graduate construct the concept of competence and the role of assessment in developing professional competence. A qualitative description was used to gather data from a convenience sample of students ready to graduate from universities with accredited dietetics programs across Australia (10 out of 15 at the time of the study). A total of 11 focus groups were conducted to explore perspectives of competence and experiences of 'competency-based' assessment. Data were audio-recorded, transcribed and analysed using a thematic analysis approach. A total of 81 (n = 81) participants across 10 universities representing 22% of total students participated in the focus groups. Themes revealed that: (i) there is no shared understanding of competence; (ii) current work placement experiences may not reflect current standards or workforce needs; (iii) assessment approaches may not fully support the development of competence; and (iv) the competent performance of supervising dietitians/clinical educators in the workplace influences the construction of competence. There is a need to work towards a shared understanding of dietetic entry-level competence in the profession. 'Work-based' learning experiences may need to be modified to ensure students meet current competency standards. Practitioners involved in student supervision need to acknowledge the influential role they have in the development of the future workforce.


Moderation and mediation of the effect of attention training in social anxiety disorder.
While attention modification programs (AMP) have shown promise as laboratory-based treatments for social anxiety disorder, trials of internet-delivered AMP have not yielded significant differences between active and control conditions. To address these inconsistencies, we examined the moderational and mediational role of attention bias in the efficacy of attention training. We compared data reported by Carlbring et al. (2012) to an identical AMP condition, with the exception that participants were instructed to activate social anxiety fears prior to each attention training session (AMP + FACT; n = 39). We also compared all attention training groups to an internet-delivered cognitive-behavioral therapy (iCBT) condition (n = 40). Participants in the AMP + FACT group experienced greater reductions in social anxiety symptoms than both active (n = 40) and control (n = 39) groups reported by Carlbring et al., and did not differ in symptom reductions from the iCBT group. Higher attention bias predicted greater symptom reductions for participants who completed AMP, but not for the control group. Moreover, change in attention bias mediated the relationship between AMP group (active condition reported by Carlbring et al. versus AMP + FACT) and change in social anxiety symptoms. These results suggest the importance of interpreting findings related to symptom change in attention training studies in the context of bias effects. ISRCTN01715124.


A comparison of rice chloroplast genomes.
Using high quality sequence reads extracted from our whole genome shotgun repository, we assembled two chloroplast genome sequences from two rice (Oryza sativa) varieties, one from 93-11 (a typical indica variety) and the other from PA64S (an indica-like variety with maternal origin of japonica), which are both parental varieties of the super-hybrid rice, LYP9. Based on the patterns of high sequence coverage, we partitioned chloroplast sequence variations into two classes, intravarietal and intersubspecific polymorphisms. Intravarietal polymorphisms refer to variations within 93-11 or PA64S. Intersubspecific polymorphisms were identified by comparing the major genotypes of the two subspecies represented by 93-11 and PA64S, respectively. Some of the minor genotypes occurring as intravarietal polymorphisms in one variety existed as major genotypes in the other subspecific variety, thus giving rise to intersubspecific polymorphisms. In our study, we found that the intersubspecific variations of 93-11 (indica) and PA64S (japonica) chloroplast genomes consisted of 72 single nucleotide polymorphisms and 27 insertions or deletions. The intersubspecific polymorphism rates between 93-11 and PA64S were 0.05% for single nucleotide polymorphisms and 0.02% for insertions or deletions, nearly 8 and 10 times lower than their respective nuclear genomes. Based on the total number of nucleotide substitutions between the two chloroplast genomes, we dated the divergence of indica and japonica chloroplast genomes as occurring approximately 86,000 to 200,000 years ago.


Anatomical MRI study of borderline personality disorder patients.
Hippocampal volume reduction has been reported in patients with borderline personality disorder (BPD), and is hypothesized to be associated with traumatic childhood experiences. We extended this investigation to explore additional brain regions and other potential clinical correlates of structural brain changes in BPD. Ten unmedicated BPD subjects and 20 healthy controls were assessed for current and past Axis I and II comorbidities and histories of childhood abuse. All had magnetic resonance imaging (MRI) studies with a 1.5 T GE Signa Imaging System, performing three-dimensional-gradient echo imaging (SPGR) with the following parameters: TR=25 ms, TE=5 ms, and slice-thickness=1.5 mm. Compared with healthy controls, BPD subjects had significantly smaller right and left hippocampal volumes, most marked in subjects with childhood abuse, and significantly increased right and left putamen volumes, especially in subjects with substance use disorders. No significant differences between groups were found for caudate, amygdala, temporal lobes, dorsolateral prefrontal cortex and total brain volumes. This study replicated prior findings of diminished hippocampal volumes in subjects with BPD. Also, increased putamen volumes were found in BPD, a finding that has not been previously reported. Early traumatic experiences may play a role in hippocampal atrophy, whereas substance use disorders may contribute to putamen enlargement.


Low-field standing magnetic resonance imaging findings of the metacarpo/metatarsophalangeal joint of racing Thoroughbreds with lameness localised to the region: a retrospective study of 131 horses.
The metacarpo/metatarsophalangeal (MCP/MTP) joint is a common site of lameness in the Thoroughbred racehorse. Radiographs may fail to show pathology consistent with the degree of lameness. With a high incidence of stress fractures occurring in the distal third metacarpal/metatarsal (MC3/MT3) condyles and proximal phalanx, a definitive diagnosis as to the nature of the pathology is essential. To describe the low-field magnetic resonance imaging (MRI) findings in Thoroughbred racehorses with MCP/MTP joint pain scanned under standing sedation. The MR images and clinical records of all Thoroughbred racehorses undergoing MRI of the MCP/MTP joint between October 2006 and August 2010 were reviewed. A total of 168 joints from 131 horses were selected for inclusion. The MRI finding considered most significant in the lame (or lamest) limb was noted. Diagnostic quality images were obtainable in 97.8% of horses. The most common finding was palmar/plantar osteochondral disease in MC3/MT3 (54.9% of horses). Incomplete condylar fracture was diagnosed in 19.8% of horses, with the lateral condyle predominating. An incomplete sagittal fracure of P1 was diagnosed in 14.5% of horses and 11.4% were diagnosed with 'dorsal joint disease'. Other findings included transverse MC3 stress fractures (1.5%), soft tissue injuries (12.2%) and proximal phalangeal 'contusions' (3.8%). No significant bone/soft tissue injury was detected in 5.4% of cases. Standing MRI can detect a spectrum of disease within the MCP/MTP joints of racehorses. The procedure is well tolerated and may lead to a definitive diagnosis where radiographic imaging is inconclusive. A total of 35.8% of cases had MRI findings consistent with fracture pathology, which could not be confirmed radiographically at the time of the MRI examination. This has important therapeutic and prognostic implications and may help to prevent catastrophic injury.


Gastro-Oesophageal Reflux and Apnoea: Is There a Temporal Relationship?
Gastro-oesophageal reflux (GOR) and apnoea are common in infants; whether there is a causal relationship is controversial. To determine whether there was a temporal relationship between GOR and apnoea, in particular, the frequency of obstructive apnoeas and if the frequency of GOR episodes correlated with apnoea frequency when maturity at testing was taken into account. Polysomnography and pH/multichannel intraluminal impedance (MII) studies were performed. Apnoeas were classified as central, obstructive, or mixed. MII events were classified as acidic (pH <4) or weakly acidic (4 < pH < 7). Apnoea frequency in the 5-min period after a reflux event was compared to that in the 5-min period preceding the event and that in a 5-min reflux-free period (control period). Forty infants (median gestational age 29 [range 24-42] weeks) were assessed at a post-conceptional age of 37 (30-54) weeks. Obstructive (n = 580), central (n = 900), and mixed (n = 452) apnoeas were identified; 381 acid reflux events were detected by MII and 153 by the pH probe only. Apnoeas were not more frequent following GOR than during control periods. Both the frequency of apnoeas (p = 0.002) and GOR episodes (p = 0.01) were inversely related to post-conceptional age at testing, but were not significantly correlated with each other when controlled for post-conceptional age. These results suggest that GOR does not cause apnoea.


Labor Nurses' Views of Their Influence on Cesarean Birth.
As part of an ongoing study about nurse staffing during labor and birth sponsored by the Association of Women's Health, Obstetric, and Neonatal Nurses (AWHONN), outcomes that may be linked to aspects of labor nursing were considered. The purpose of this study was to see if labor nurses felt they influenced whether a woman has a cesarean birth. These data were used to determine if cesarean birth should be included as an outcome measure in the multistate labor nurse staffing study. Focus groups were used to explore the role of labor nurses and cesarean birth. Participants were attending the AWHONN national convention in 2015. Two open-ended questions were asked: 1) Do labor nurses influence whether a woman has a cesarean? 2) What specific things do you do as a labor nurse to help a woman avoid a cesarean? Two focus groups were held (n = 15 and n = 9). Nurses overwhelmingly agreed nursing care can influence mode of birth. They described multiple strategies routinely used to help a woman avoid a cesarean, which were categorized into three main themes: support, advocacy, and interactions with physicians. Support was emotional, informational, and physical. Advocacy involved advocating for women and helping women advocate for themselves. Nurses tried to focus on positive aspects of labor progress when communicating with physicians. Descriptions of interactions with some physicians implied less than optimal teamwork and lack of collaboration. Labor nurses are likely influential in whether some women have a cesarean. They reported consistently taking an active role to help women avoid a cesarean. Promoting vaginal birth as appropriate to the clinical situation was a high priority. Trust, partnership, and respect for roles and responsibilities of each discipline were not evident in some of the clinical situations nurses described.


Detection of fish antigens aerosolized during fish processing using newly developed immunoassays.
Aerosolization of fish proteins during seafood processing has been identified as a potential route for allergic sensitization and occupational asthma among workers involved in high-risk activities. The aim of this study was to develop immunological assays for the quantification of aerosolized fish antigens in a fish-processing factory. Polyclonal antibodies to the main fish species processed in the factory (anchovy and pilchard) were generated in rabbits and compared by ELISA inhibition assay and immunoblotting. These antisera were utilized to develop ELISA assays for the detection of fish antigens. The ELISA inhibition assays were evaluated by analyzing environmental air samples collected from three areas in a fish-processing factory: pilchard canning, fish meal production and lobster processing. By immunoblotting, the rabbit polyclonal antibodies demonstrated IgG antibody binding patterns comparable with IgE antibodies of fish-sensitized patients, particularly in regard to the major fish allergens parvalbumins. The sensitivity of the fish-specific ELISA assays developed was 0.5 microg/ml. The ELISA inhibition assays were able to differentiate between the two different fish species of interest but did not recognize a crustacean species. Notable differences in exposure levels to canned pilchard and anchovy antigens were demonstrated in the three different working areas of the factory, with assays having a detection limit as low as 105 ng/m(3). These ELISA-based assays are sensitive and specific to quantify differential exposure levels to fish antigens produced during fish processing, making it possible to investigate exposure-disease response relationships among workers in this industry.