Time-dependent localization of high- and low-sulfated keratan sulfates in the song nuclei of developing zebra finches.
Keratan sulfate proteoglycans (KSPGs) and chondroitin sulfate proteoglycans (CSPGs) consist of a protein core with covalently attached glycosaminoglycan side chain. Although CSPGs are known to regulate the end of the critical period, the role of KSPGs in brain development remains unclear. Young male zebra finches memorise song templates during development. The brain regions that are responsible for song learning, known as song nuclei, are recognized as a suitable model for the study of brain development. To understand the potential role of KSPGs, here we examined the localization of KSs with different degrees of sulfation in the brain of developing male zebra finches. Exclusively in the song nuclei, an increase in expression of 5-D-4-positive (5-D-4(+)) high-sulfated KS started after hatching, and reached a plateau at the end of the sensory period, during which the young bird listens to and memorises the song of an adult tutor. By contrast, weak and ubiquitous expression of BCD-4(+) low-sulfated KS remained unchanged until the end of the sensory period, and first increased in the song nuclei at the end of the sensorimotor period, during which the young bird produces plastic songs. Immunoblot analysis showed that phosphacan was a common core protein of 5-D-4(+) KS and BCD-4(+) KS. Finally, we confirmed that the sulfotransferase responsible for the synthesis of high-sulfated KS was exclusively localised in the song nuclei. Our observations suggest that time-dependent localization of KSPGs with different sulfation patterns in the song nuclei may underlie song learning in developing male zebra finches.


Predictors of safety-related enquiries about psychotropic medication in young people and families accessing a medicines information service.
Many consumers express concerns about the safety of psychotropic medication for young people. Despite the increased use of psychotropic medication in children and adolescents, few studies have examined information needs of this group and predictors of safety-related concerns. This study was conducted within a national, consumer-based medicines information service. Between September, 2002, and December, 2005, all calls relating to use of psychotropic medications in children and adolescents were identified and reviewed. Information extracted included call characteristics, reason for calling, prior information, and medication details. Calls related to safety were compared to calls about non-safety-related issues. A total of 286 calls related to psychotropic medication in young people were reviewed. The majority of callers were adults calling on behalf of either a child (73.4%) or client (12.9%). Stimulants were the most common medication enquired about (44.0% of calls), followed by antidepressants (40.2%), and antipsychotics (18.9%). More than half of all calls were for medicines not registered for pediatric use. Almost two thirds of calls related to safety issues (61.9%; 177/286). Safety-related calls were not related to specific medication groups (e.g., stimulants or antidepressants). Significant and independent predictors of safety-related concerns were medication not registered for pediatric use (p < 0.05), receipt of lay information (p < 0.05), concomitant enquiry about nonpsychotropic medication (p < 0.01), and a potential medication problem (p < 0.05). Safety is one of the key areas of concern in young people and families accessing a medicines information service with questions about psychotropic medication. Off-label use of medication was common and may contribute to safety concerns. Provision of information that is tailored for young people has the potential to improve outcomes in this group.


Socio-cultural disparities in GDM burden differ by maternal age at first delivery.
Several socio-cultural and biomedical risk factors for gestational diabetes mellitus (GDM) are modifiable. However, few studies globally have examined socio-cultural associations. To eliminate confounding of increased risk of diabetes in subsequent pregnancies, elucidating socio-cultural associations requires examination only of first pregnancies. Data for all women who delivered their first child in Victoria, Australia between 1999 and 2008 were extracted from the Victorian Perinatal Data Collection. Crude and adjusted GDM rates were calculated. Multivariate logistic regression was used to examine odds of GDM within and between socio-cultural groups. From 1999 to 2008, 269,682 women delivered their first child in Victoria. GDM complicated 11,763 (4.4%) pregnancies and burden increased with maternal age, from 2.1% among women aged below 25 years at delivery to 7.0% among those aged 35 years or more. Among younger women, GDM rates were relatively stable across socioeconomic levels. Amongst older women GDM rates were highest in those living in most deprived areas, with a strong social gradient. Asian-born mothers had highest GDM rates. All migrant groups except women born in North-West Europe had higher odds of GDM than Australian-born non-Indigenous women. In all ethnic groups, these differences were not pronounced among younger mothers, but became increasingly apparent amongst older women. Socio-cultural disparities in GDM burden differ by maternal age at first delivery. Socio-cultural gradients were not evident among younger women. Health and social programs should seek to reduce the risk amongst all older women to that of the least deprived older mothers.


Basic factorization for multilayers.
We present a factorization scheme that is particularly suited to multilayer optics, and we exploit it to develop a consistent description of the action of a multilayer in terms of three basic matrices. Connections with equivalent behaviors in geometrical optics are discussed.


Clinical rating of dyskinesias in Parkinson's disease: use and reliability of a new rating scale.
Drug-induced dyskinesias (DID) manifested as hyperkinetic and/or dystonic movements or postures are common problems in Parkinson's disease (PD). Novel therapeutic interventions may offer possibilities to counteract these common adverse effects of an otherwise necessary treatment. To be able to evaluate the effects of such interventions on DID, reliable and relevant clinical assessment tools are needed. We tested the inter- and intrarater reliability of a new clinical dyskinesia rating scale consisting of separate ratings of different body parts, including lateralization and separate ratings of dystonia and hyperkinesias. Interrater reliability was tested both with and without a defined scoring code and clarification of the dystonia section. The nondefined version was also tested for intrarater reliability. Thirteen raters independently reviewed 23 videotape sequences showing PD patients performing standardized motor tests. Inter- and intrarater agreement was significant in all evaluations, and no differences were detected when comparing ratings performed with the defined and nondefined version of the scale. The rationale for, and the role and use of, the present scale are addressed.


Hospital admissions as a function of temperature, other weather phenomena and pollution levels in an urban setting in China.
To explore the relationship between weather phenomena and pollution levels and daily hospital admissions (as an approximation to morbidity patterns) in Hong Kong Special Administrative Region (SAR), China, in 1998-2009. Generalized additive models and lag models were constructed with data from official sources on hospital admissions and on mean daily temperature, mean daily wind speed, mean relative humidity, daily total global solar radiation, total daily rainfall and daily pollution levels. During the hot season, admissions increased by 4.5% for every increase of 1 °C above 29 °C; during the cold season, admissions increased by 1.4% for every decrease of 1 °C within the 8.2-26.9 °C range. In subgroup analyses, admissions for respiratory and infectious diseases increased during extreme heat and cold, but cardiovascular disease admissions increased only during cold temperatures. For every increase of 1 °C above 29 °C, admissions for unintentional injuries increased by 1.9%. During the cold season, for every decrease of 1 °C within the 8.2-26.9 °C range, admissions for cardiovascular diseases and intentional injuries rose by 2.1% and 2.4%, respectively. Admission patterns were not sensitive to sex. Admissions for respiratory diseases rose during hot and cold temperatures among children but only during cold temperatures among the elderly. In people aged 75 years or older, admissions for infectious diseases rose during both temperature extremes. In Hong Kong SAR, hospitalizations rise during extreme temperatures. Public health interventions should be developed to protect children, the elderly and other vulnerable groups from excessive heat and cold.


The social psychology of amateur ethicists: blood product recall notification and the value of reflexivity.
The purpose of this article is to highlight ways in which institutional policymakers tend to insufficiently conceptualise their role as ethics practitioners. We use the case of blood product recall notification as a means of raising questions about the way in which, as we have observed it, discourse for those who make institutional ethics policies is constrained by routine balancing of simplified principles to the exclusion of reflexive practices-those that turn ethics reasoning back on itself. The latter allows ethics practitioners with comparatively little formal training to take ownership of traditional parameters, which define their discussions and ultimately ought to make them more insightful when doing ethics. Thus, in the midst of calls for more training to increase the competency of ethics committees, we suggest that an additional problem of how these lay ethicists conceive of their roles also needs to be addressed.


Bacterial Genomics Reveal the Complex Epidemiology of an Emerging Pathogen in Arctic and Boreal Ungulates.
Northern ecosystems are currently experiencing unprecedented ecological change, largely driven by a rapidly changing climate. Pathogen range expansion, and emergence and altered patterns of infectious disease, are increasingly reported in wildlife at high latitudes. Understanding the causes and consequences of shifting pathogen diversity and host-pathogen interactions in these ecosystems is important for wildlife conservation, and for indigenous populations that depend on wildlife. Among the key questions are whether disease events are associated with endemic or recently introduced pathogens, and whether emerging strains are spreading throughout the region. In this study, we used a phylogenomic approach to address these questions of pathogen endemicity and spread for Erysipelothrix rhusiopathiae, an opportunistic multi-host bacterial pathogen associated with recent mortalities in arctic and boreal ungulate populations in North America. We isolated E. rhusiopathiae from carcasses associated with large-scale die-offs of muskoxen in the Canadian Arctic Archipelago, and from contemporaneous mortality events and/or population declines among muskoxen in northwestern Alaska and caribou and moose in western Canada. Bacterial genomic diversity differed markedly among these locations; minimal divergence was present among isolates from muskoxen in the Canadian Arctic, while in caribou and moose populations, strains from highly divergent clades were isolated from the same location, or even from within a single carcass. These results indicate that mortalities among northern ungulates are not associated with a single emerging strain of E. rhusiopathiae, and that alternate hypotheses need to be explored. Our study illustrates the value and limitations of bacterial genomic data for discriminating between ecological hypotheses of disease emergence, and highlights the importance of studying emerging pathogens within the broader context of environmental and host factors.


ABC Transporter DerAB of Lactobacillus casei Mediates Resistance against Insect-Derived Defensins.
Bce-like systems mediate resistance against antimicrobial peptides in Firmicutes bacteria. Lactobacillus casei BL23 encodes an "orphan" ABC transporter that, based on homology to BceAB-like systems, was proposed to contribute to antimicrobial peptide resistance. A mutant lacking the permease subunit was tested for sensitivity against a collection of peptides derived from bacteria, fungi, insects, and humans. Our results show that the transporter specifically conferred resistance against insect-derived cysteine-stabilized αβ defensins, and it was therefore renamed DerAB for defensin resistance ABC transporter. Surprisingly, cells lacking DerAB showed a marked increase in resistance against the lantibiotic nisin. This could be explained by significantly increased expression of the antimicrobial peptide resistance determinants regulated by the Bce-like systems PsdRSAB (formerly module 09) and ApsRSAB (formerly module 12). Bacterial two-hybrid studies in Escherichia coli showed that DerB could interact with proteins of the sensory complex in the Psd resistance system. We therefore propose that interaction of DerAB with this complex in the cell creates signaling interference and reduces the cell's potential to mount an effective nisin resistance response. In the absence of DerB, this negative interference is relieved, leading to the observed hyperactivation of the Psd module and thus increased resistance to nisin. Our results unravel the function of a previously uncharacterized Bce-like orphan resistance transporter with pleiotropic biological effects on the cell.IMPORTANCE Antimicrobial peptides (AMPs) play an important role in suppressing the growth of microorganisms. They can be produced by bacteria themselves-to inhibit competitors-but are also widely distributed in higher eukaryotes, including insects and mammals, where they form an important component of innate immunity. In low-GC-content Gram-positive bacteria, BceAB-like transporters play a crucial role in AMP resistance but have so far been primarily associated with interbacterial competition. Here, we show that the orphan transporter DerAB from the lactic acid bacterium Lactobacillus casei is crucial for high-level resistance against insect-derived AMPs. It therefore represents an important mechanism for interkingdom defense. Furthermore, our results support a signaling interference from DerAB on the PsdRSAB module that might prevent the activation of a full nisin response. The Bce modules from L. casei BL23 illustrate a biological paradox in which the intrinsic nisin detoxification potential only arises in the absence of a defensin-specific ABC transporter.


Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy.
To evaluate longitudinal retinal ganglion cell inner plexiform layer (GC-IPL) and macular retinal nerve fibre layer (mRNFL) thickness changes in acute Leber's hereditary optic neuropathy (LHON). Six eyes of four patients with LHON underwent SD-OCT (optical coherence tomography) at month 1, 3, 6 and 12 after visual loss. In two eyes, the examination was carried out in the presymptomatic stage. The relationship and curves for area under the receiver operator characteristic (AUROC) were generated to assess the ability of each parameter to detect ganglion cell loss. Significant longitudinal thinning of GC-IPL and mRNFL was detected in LHON. GC-IPL thinning was detectable in the deviation map during the presymptomatic stage in the inner ring of the nasal sector and then it progressively extended following a centrifugal and spiral pattern. Similarly, mRNFL thinning began in the inferonasal sector and it progressively extended. No further statistically significant changes were detected after month 3. The highest level of AUROC values at 1 month were detected in the nasal sectors and inferonasal mRNFL thickness reached AUROC value=1. All the parameters were equally able to detect ganglion cell loss from month 2 to 12. The natural history of GC-IPL thinning follows a specific pattern of reduction, reflecting the anatomical course of papillomacular fibres. Month 6 represents the end of GC-IPL loss. GC-IPL and mRNFL thinning is detectable before onset of visual loss. These observations can help future therapeutic approaches for both LHON carriers at high risk of conversion and patients with acute early LHON.


Hybrid-denovo: a de novo OTU-picking pipeline integrating single-end and paired-end 16S sequence tags.
Illumina paired-end sequencing has been increasingly popular for 16S rRNA gene-based microbiota profiling. It provides higher phylogenetic resolution than single-end reads due to a longer read length. However, the reverse read (R2) often has significant low base quality, and a large proportion of R2s will be discarded after quality control, resulting in a mixture of paired-end and single-end reads. A typical 16S analysis pipeline usually processes either paired-end or single-end reads but not a mixture. Thus, the quantification accuracy and statistical power will be reduced due to the loss of a large amount of reads. As a result, rare taxa may not be detectable with the paired-end approach, or low taxonomic resolution will result in a single-end approach. To have both the higher phylogenetic resolution provided by paired-end reads and the higher sequence coverage by single-end reads, we propose a novel OTU-picking pipeline, hybrid-denovo, that can process a hybrid of single-end and paired-end reads. Using high-quality paired-end reads as a gold standard, we show that hybrid-denovo achieved the highest correlation with the gold standard and performed better than the approaches based on paired-end or single-end reads in terms of quantifying the microbial diversity and taxonomic abundances. By applying our method to a rheumatoid arthritis (RA) data set, we demonstrated that hybrid-denovo captured more microbial diversity and identified more RA-associated taxa than a paired-end or single-end approach. Hybrid-denovo utilizes both paired-end and single-end 16S sequencing reads and is recommended for 16S rRNA gene targeted paired-end sequencing data.


Understanding the experience of noninclusive occupational therapy clinics: lesbians' perspectives.
This article presents understandings about how noninclusive occupational therapy environments are developed and maintained. The data are drawn from a study that, in part, explored the experiences of lesbian or bisexual occupational therapists working in a health care system. Ten participants each engaged in two to five in-depth audiotaped interviews. The narrative data were analyzed with a modified form of grounded theory. The data provide insight into how heterosexist occupational therapy work climates are created and maintained through four processes: heterosexual discourse, homophobic comments, assumed heterosexuality, and perceived stereotypes. The way in which heterosexist occupational therapy work climates may impede the professional growth of therapists also is presented. The knowledge gained from this study can help practitioners, professors, and students in their attempts to sustain an inclusive environment with respect to persons who are lesbian, gay, and bisexual.


A global call from five countries to collaborate in antibiotic stewardship: united we succeed, divided we might fail.
In February, 2016, WHO released a report for the development of national action plans to address the threat of antibiotic resistance, the catastrophic consequences of inaction, and the need for antibiotic stewardship. Antibiotic stewardship combined with infection prevention comprises a collaborative, multidisciplinary approach to optimise use of antibiotics. Efforts to mitigate overuse will be unsustainable without learning and coordinating activities globally. In this Personal View, we provide examples of international collaborations to address optimal prescribing, focusing on five countries that have developed different approaches to antibiotic stewardship-the USA, South Africa, Colombia, Australia, and the UK. Although each country's approach differed, when nurtured, individual efforts can positively affect local and national antimicrobial stewardship programmes. Government advocacy, national guidelines, collaborative research, online training programmes, mentoring programmes, and social media in stewardship all played a role. Personal relationships and willingness to learn from each other's successes and failures continues to foster collaboration. We recommend that antibiotic stewardship models need to evolve from infection specialist-based teams to develop and use cadres of health-care professionals, including pharmacists, nurses, and community health workers, to meet the needs of the global population. We also recommend that all health-care providers who prescribe antibiotics take ownership and understand the societal burden of suboptimal antibiotic use, providing examples of how countries can learn, act globally, and share best antibiotic stewardship practices.


Is the use of transdermal fentanyl inappropriate according to the WHO guidelines and the EAPC recommendations? A study of cancer patients in Italy.
World Health Organization (WHO) guidelines, Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines, and EAPC recommendations indicate oral route of opioid administration as the preferred route. Transdermal administration of opioids is considered an alternative when patients cannot take medications orally. Moreover, WHO and EAPC indicate orally administered morphine as the first-choice drug for the treatment of moderate to severe cancer-related pain. However, we can see that in Italy there is an increasing use of transdermal fentanyl (TF) as first-choice strong opioid (and route) even when oral administration of opioids is possible. The aims of this study are to describe the modality in the use of TF administration in two settings of care, taking into consideration (1) the drugs previously taken by the patients, (2) the reasons for switching from any drug to TF, (3) the conversion ratio used, and (4) the frequency of "inappropriate use of transdermal fentanyl according to the WHO guidelines and the EAPC recommendations", i.e., switching to fentanyl patch from any drug, even if there were no contraindications in using oral morphine. The settings of care considered were the out-patient palliative care unit (OP-PCU) and the oncological wards (OWs) of the National Cancer Institute (NCI) of Milan. The clinical charts of 98 patients prescribed with and given fentanyl patch for the first time at the NCI of Milan in 2002 were reviewed and the data gathered were grouped according to the administration of fentanyl at the OP-PCU (63 out-patients) or at the OWs (35 in-patients). Summary descriptive statistics and bar and box plots have been used. Fisher two-tailed exact text was applied to test the differences between in- and out-patients. Before switching to TF, (1) in-patients were more frequently treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids (mostly tramadol) in respect to the out-patients (44.1 vs 25.8%) who were mostly treated with oral morphine (48.4 vs 20.6%) (p=0.045), and (2) 88.7% of the out-patients were treated with oral opioids and only 1.6% with parenteral opioids in respect to OWs where 69.7% were on oral opioids and 18.2% on parenteral opioids (p=0.006). In 29% of out-patients and in 53% of in-patients, changing to fentanyl patch was considered as "inappropriate" (p=0.028) according to the WHO guidelines and the EAPC recommendations. No statistically significant differences between the two settings were observed regarding the reasons for switching and the conversion ratio used. There is a trend to use fentanyl patch as first-choice strong opioid in cancer patients in situations such as titration phase, in the presence of instable pain, and in the absence of dysphagia or gastrointestinal symptoms where the use of oral morphine is, however, not contraindicated.


Diplopia as the primary presentation of foodborne botulism.
Foodborne botulism is a serious condition caused by Clostridium botulinum neurotoxin. Clinically, botulism presents as bilateral cranial nerve neuropathy and descending paralysis. We report a unique presentation of botulism to remind clinicians of this potentially fatal condition. In this observational case report initial evaluation showed only esodeviation. This progressed to unilateral cranial nerve six (CN VI) paresis along with systemic signs. Clinical diagnosis was made based on in-depth history and concurrent symptoms in three other patients. Foodborne botulism presenting as diplopia and unilateral motility deficits is rare and can represent a diagnostic and therapeutic challenge to the ophthalmologist.


Effects of fibrillin-1 degradation on microfibril ultrastructure.
Current models of the elastic properties and structural organization of fibrillin-containing microfibrils are based primarily on microscopic analyses of microfibrils liberated from connective tissues after digestion with crude collagenase. Results presented here demonstrate that this digestion resulted in the cleavage of fibrillin-1 and loss of specific immunoreactive epitopes. The proline-rich region and regions near the second 8-cysteine domain in fibrillin-1 were easily cleaved by crude collagenase. Other sites that may also be cleaved during microfibril digestion and extraction were identified. In contrast to collagenase-digested microfibrils, guanidine-extracted microfibrils contained all fibrillin-1 epitopes recognized by available antibodies. The ultrastructure of guanidine-extracted microfibrils differed markedly from that of collagenase-digested microfibrils. Fibrillin-1 filaments splayed out, extending beyond the width of the periodic globular beads. Both guanidine-extracted and collagenase-digested microfibrils were subjected to extensive digestion by crude collagenase. Collagenase digestion of guanidine-extracted microfibrils removed the outer filaments, revealing a core structure. In contrast to microfibrils extracted from tissues, cell culture microfibrils could be digested into short units containing just a few beads. These data suggest that additional cross-links stabilize the long beaded microfibrils in tissues. Based on the microfibril morphologies observed after these experiments, on the crude collagenase cleavage sites identified in fibrillin-1, and on known antibody binding sites in fibrillin-1, a model is proposed in which fibrillin-1 molecules are staggered in microfibrils. This model further suggests that the N-terminal half of fibrillin-1 is asymmetrically exposed in the outer filaments, whereas the C-terminal half of fibrillin-1 is present in the interior of the microfibril.


Functional divergence of gene duplicates - a domain-centric view.
Gene duplicates have been shown to evolve at different rates. Here we further investigate the mechanism and functional underpinning of this phenomenon by assessing asymmetric evolution specifically within functional domains of gene duplicates. Based on duplicate genes in five teleost fishes resulting from a whole genome duplication event, we first show that a Fisher Exact test based approach to detect asymmetry is more sensitive than the previously used Likelihood Ratio test. Using our Fisher Exact test, we found that the evolutionary rate asymmetry in the overall protein is largely explained by the asymmetric evolution within specific protein domains. Moreover, among cases of asymmetrically evolving domains, for the gene copy containing a fast evolving domain, the non-synonymous substitutions often cluster within the fast evolving domain. We found that rare substitutions were preferred within asymmetrically evolving domains suggestive of functional divergence. While overall ~32 % of the domains tested were found to be evolving asymmetrically, certain protein domains such as the Tyrosine and Ser/Thr Kinase domains had a much greater prevalence of asymmetric evolution. Finally, based on the spatial expression of Zebra fish duplicate proteins during development, we found that protein pairs containing asymmetrically evolving domains had a greater divergence in gene expression as compared to the duplicate proteins that did not exhibit asymmetric evolution. Taken together, our results suggest that the previously observed asymmetry in the overall duplicate protein evolution is largely due to divergence of specific domains of the protein, and coincides with divergence in spatial expression domains.


Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia.
Nuclear factor I-C (NFIC) belongs to a family of NFI transcription factors that binds to DNA through CAATT-boxes and are involved in cellular differentiation and stem cell maintenance. Here we show NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients. Examination of the functional consequences of NFIC overexpression in HSPCs showed that this protein promoted monocytic differentiation. Single-cell RNA sequencing analysis further demonstrated that NFIC overexpressing monocytes had increased expression of growth and survival genes. In contrast, depletion of NFIC through shRNA decreased cell growth, increased cell cycle arrest and apoptosis in AML cell lines and AML patient blasts. Further, in AML cell lines (THP-1), bulk RNA sequencing of NFIC knockdown led to downregulation of genes involved in cell survival and oncogenic signaling pathways including mixed lineage leukemia-1 (MLL-1). Lastly, we show that NFIC knockdown in an ex vivo mouse MLL::AF9 pre-leukemic stem cell model, decreased their growth and colony formation and increased expression of myeloid differentiation markers Gr1 and Mac1. Collectively, our results suggest that NFIC is an important transcription factor in myeloid differentiation as well as AML cell survival and is a potential therapeutic target in AML.


n-Channel semiconductor materials design for organic complementary circuits.
Organic semiconductors have unique properties compared to traditional inorganic materials such as amorphous or crystalline silicon. Some important advantages include their adaptability to low-temperature processing on flexible substrates, low cost, amenability to high-speed fabrication, and tunable electronic properties. These features are essential for a variety of next-generation electronic products, including low-power flexible displays, inexpensive radio frequency identification (RFID) tags, and printable sensors, among many other applications. Accordingly, the preparation of new materials based on π-conjugated organic molecules or polymers has been a central scientific and technological research focus over the past decade. Currently, p-channel (hole-transporting) materials are the leading class of organic semiconductors. In contrast, high-performance n-channel (electron-transporting) semiconductors are relatively rare, but they are of great significance for the development of plastic electronic devices such as organic field-effect transistors (OFETs). In this Account, we highlight the advances our team has made toward realizing moderately and highly electron-deficient n-channel oligomers and polymers based on oligothiophene, arylenediimide, and (bis)indenofluorene skeletons. We have synthesized and characterized a "library" of structurally related semiconductors, and we have investigated detailed structure-property relationships through optical, electrochemical, thermal, microstructural (both single-crystal and thin-film), and electrical measurements. Our results reveal highly informative correlations between structural parameters at various length scales and charge transport properties. We first discuss oligothiophenes functionalized with perfluoroalkyl and perfluoroarene substituents, which represent the initial examples of high-performance n-channel semiconductors developed in this project. The OFET characteristics of these compounds are presented with an emphasis on structure-property relationships. We then examine the synthesis and properties of carbonyl-functionalized oligomers, which constitute second-generation n-channel oligothiophenes, in both vacuum- and solution-processed FETs. These materials have high carrier mobilities and good air stability. In parallel, exceptionally electron-deficient cyano-functionalized arylenediimide derivatives are discussed as early examples of thermodynamically air-stable, high-performance n-channel semiconductors; they exhibit record electron mobilities of up to 0.64 cm(2)/V·s. Furthermore, we provide an overview of highly soluble ladder-type macromolecular semiconductors as OFET components, which combine ambient stability with solution processibility. A high electron mobility of 0.16 cm(2)/V·s is obtained under ambient conditions for solution-processed films. Finally, examples of polymeric n-channel semiconductors with electron mobilities as high as 0.85 cm(2)/V·s are discussed; these constitute an important advance toward fully printed polymeric electronic circuitry. Density functional theory (DFT) computations reveal important trends in molecular physicochemical and semiconducting properties, which, when combined with experimental data, shed new light on molecular charge transport characteristics. Our data provide the basis for a fundamental understanding of charge transport in high-performance n-channel organic semiconductors. Moreover, our results provide a road map for developing functional, complementary organic circuitry, which requires combining p- and n-channel transistors.


A missense single nucleotide polymorphism in the ALDH2 gene, rs671, is associated with hip fracture.
Hip fracture is the most severe bone fragility fracture among osteoporotic injuries. Family history is a known risk factor for fracture and now included among criteria for osteoporosis diagnosis and treatment; however, genetic factors underlying family history favoring fracture remain to be elucidated. Here we demonstrate that a missense SNP in the ALDH2 gene, rs671 (ALDH2*2), is significantly associated with hip fracture (odds ratio = 2.48, 95% confidence interval: 1.20-5.10, p = 0.021). The rs671 SNP was also significantly associated with osteoporosis development (odds ratio = 2.04, 95% confidence interval: 1.07-3.88, p = 0.040). For analysis we enrolled 92 hip fracture patients plus 48 control subjects without bone fragility fractures with higher than -2.5 SD bone mineral density. We also recruited 156 osteoporosis patients diagnosed as below -2.5 SD in terms of bone mineral density but without hip fracture. Association of rs671 with hip fracture and osteoporosis was significant even after adjustment for age and body mass index. Our results provide new insight into the pathogenesis of hip fracture.


Long-term clinical outcomes and risk factors for the occurrence of post-operative complications after cardiovascular surgery in patients with Behçet's disease.
Cardiovascular surgery in patients with Behçet's disease (BD) frequently leads to postoperative complications such as anastomotic leakage, occlusion or pseudoaneurysm. We evaluated the clinical outcomes and related risk factors of postoperative complications in BD patients undergoing cardiovascular surgeries, as well as the long-term efficiency of postoperative immunosuppressive treatment. Forty-one patients with BD who had undergone cardiovascular surgery between 1990 and 2009 were studied. We evaluated the patients' clinical data, postoperative complications, and survival rate. Risk factors related to the occurrence of postoperative complications were identified by univariate analysis using the Kaplan-Meier method with the log-rank test and multivariate analysis using the Cox proportional hazards regression model. Fifty-nine operations were performed in 41 patients. During the mean follow-up period of 65.3±48.1 months, complications such as paravalvular leakage, dehiscence, fistula, graft occlusion, or pseudoaneurysm occurred in 29 operations (49.2%). The cumulative occurrence rate of postoperative complication was 10.2% at three months, 32.8% at 12 months, and 43.8% at 24 months. Upon univariate analysis, young age, high Creactive protein levels, lack of postoperative immunosuppression, and short disease duration were identified as significant factors responsible for the occurrence of postoperative complications. In multivariate analysis, postoperative immunosuppression was found to independently lower the risk of complications. The 5-year survival rate was significantly higher in patients with postoperative immunosup immunosuppression than in those without (84.5% vs. 45.0%, p=0.011). The present study suggests that postoperative immunosuppressive therapy after cardiovascular surgeries in BD patients is important for reducing the development of serious postoperative complications.


Evaluation of Eruption Pattern and Caries Occurrence among Children Affected with Fluorosis.
The aim of this study was to evaluate eruption pattern and occurrence of caries in children affected with fluorosis. One hundred and fifty subjects (75 each with/without fluorosis) with age group of 7-8 years were selected. Dental fluorosis assessed on the buccal surfaces of the permanent incisors and molars and scored using the Thylstrup and Fejerskov index. The tooth were scored as emerged when at least one cusp of the tooth was visible in the mouth. Caries attack rate in primary and permanent teeth were estimated using DMFS and defs index in fluorosis patient. The findings were subjected to statistical analysis. The data were analyzed using Student "t" test and ANOVA "F" test. There was statistically highly significant difference found in the incidence of occlusal, mesioproximal, and distoproximal caries between fluorotic and nonfluorotic patients (p < 0.001). The result of present study showed a nonsignificant association between fluoride exposure parameter and median emergence ages of permanent incisors and molar teeth. On the other hand, caries occurrence shows a significant association with fluorosis. In this study, a significant positive correlation exists in the prevalence of caries and fluorosis. It is concluded that occlusal and proximal caries are less pronounced in fluorosis patients. Dental caries is a public health problem. In this study, we study the fluoride effect since the predominant cariostatic effect of fluoride is beneficial in extensive caries reduction without a concomitant risk of dental fluorosis. How to cite this article: Trivedi S, Trivedi A, Banda NR, et al. Evaluation of Eruption Pattern and Caries Occurrence among Children Affected with Fluorosis. J Contemp Dent Pract 2019;20(10):1217-1222.


Patterns and determinants of cardiovascular drug utilization in coronary care unit patients of a tertiary care hospital.
A wide variation exists in the patterns of pharmacotherapy among patients admitted with cardiovascular diseases. Very few studies have evaluated the potential determinants of drug utilization. Our objective was to evaluate the clinical characteristics and patterns of cardiovascular drug utilization among patients in coronary care unit (CCU) and assess the determinants of cardiovascular drug use among patients with coronary artery disease (CAD). In this retrospective cohort study, the medical records of CCU patients were reviewed independently by two trained physicians over one year. Patients were analyzed as two groups - those with CAD and without CAD. Multivariate logistic regression was done to identify the determinants of cardiovascular drug utilization in the CAD group. Of 574 patients, 65% were males, 57% were <60 years. The five commonly prescribed drug classes were platelet inhibitors (88.7%), statins (76.3%), ACE-inhibitors/Angiotensin receptor blockers (72%), beta-blockers (58%) and heparin (57%). Poly-pharmacy (>5 drugs) was noticed in 71% of patients. A majority of patients had diagnosis of CAD (72.6%). CAD patients received significantly higher median number of drugs and had longer duration of CCU stay (p < 0.0001). Renal dysfunction for ACE-inhibitors [0.18 (0.09-0.36)], ST-elevation myocardial infarction for calcium channel blockers [0.29 (0.09-0.93)] and brady-arrhythmias for beta-blockers [0.3 (0.2-0.7)] were identified as determinants of decreased drug use in CAD group. Predominance of male gender, age <60 and poly-pharmacy was observed in CCU. Antithrombotics, statins, ACE-inhibitors/Angiotensin receptor blockers and beta-blockers were the most frequently prescribed drugs. Clinical co-morbidities (renal dysfunction, arrhythmias) decreased the utilization of ACE-inhibitors, beta-blockers among CAD patients.


Optimized cutoff value and indication for washout thyroglobulin level according to ultrasound findings in patients with well-differentiated thyroid cancer.
Washout thyroglobulin provides evidence for metastatic or recurrent lesions, However, the cutoff value is still controversial. We investigated an optimized cutoff value and indication for the use of washout thyroglobulin from fine-needle aspiration in neck lymph nodes from preoperative or postoperative patients with well-differentiated thyroid cancers. A total of 177 lymph nodes from 161 patients underwent sonographically guided fine-needle aspiration cytology and washout thyroglobulin measurement and then underwent surgery and clinical follow-up. We assessed an optimized cutoff value of washout thyroglobulin for diagnosing metastasis and compared its diagnostic performance with that of washout thyroglobulin > 10 ng/mL, the currently accepted cutoff value. We also analyzed diagnostic performances of fine-needle aspiration cytology alone and of the combination of fine-needle aspiration cytology and washout thyroglobulin on the basis of the presence or absence of suspicious ultrasonographic findings. Of the 177 lymph nodes, 77 were metastases and 100 were benign. An optimized cutoff value for washout thyroglobulin was 1.8 ng/mL. The sensitivity and negative predictive value in diagnosing metastasis improved significantly with a cutoff value of 1.8 ng/mL compared with a cutoff value of 10 ng/mL (P = .0412 for sensitivity, P = .0188 for negative predictive value). In patients with suspicious ultrasonographic findings, applying washout thyroglobulin along with fine-needle aspiration cytology significantly enhanced the sensitivity and negative predictive value of fine-needle aspiration cytology performances to 100% and 100%, respectively (P = .0051, and P = .0088). There was no difference in diagnostic performance between fine-needle aspiration cytology and the combination of the 2 methods in patients without suspicious ultrasonographic findings. Applying the optimized cutoff value of washout thyroglobulin of 1.8 ng/mL in patients with suspicious ultrasonographic features facilitates the diagnostic evaluation of neck lymph nodes in both preoperative and postoperative patients with well-differentiated thyroid cancer.


Unfolded protein response, activated by OASIS family transcription factors, promotes astrocyte differentiation.
OASIS is a member of the CREB/ATF family of transcription factors and modulates cell- or tissue-specific unfolded protein response signalling. Here we show that this modulation has a critical role in the differentiation of neural precursor cells into astrocytes. Cerebral cortices of mice specifically deficient in OASIS (Oasis(-/-)) contain fewer astrocytes and more neural precursor cells than those of wild-type mice during embryonic development. Furthermore, astrocyte differentiation is delayed in primary cultured Oasis(-/-) neural precursor cells. The transcription factor Gcm1, which is necessary for astrocyte differentiation in Drosophila, is revealed to be a target of OASIS. Introduction of Gcm1 into Oasis(-/-) neural precursor cells improves the delayed differentiation of neural precursor cells into astrocytes by accelerating demethylation of the Gfap promoter. Gcm1 expression is temporally controlled by the unfolded protein response through interactions between OASIS family members during astrocyte differentiation. Taken together, our findings demonstrate a novel mechanism by which OASIS and its associated family members are modulated by the unfolded protein response to finely control astrocyte differentiation.


Relationships and the social brain: integrating psychological and evolutionary perspectives.
Psychological studies of relationships tend to focus on specific types of close personal relationships (romantic, parent-offspring, friendship) and examine characteristics of both the individuals and the dyad. This paper looks more broadly at the wider range of relationships that constitute an individual's personal social world. Recent work on the composition of personal social networks suggests that they consist of a series of layers that differ in the quality and quantity of relationships involved. Each layer increases relationship numbers by an approximate multiple of 3 (5-15-50-150) but decreasing levels of intimacy (strong, medium, and weak ties) and frequency of interaction. To account for these regularities, we draw on both social and evolutionary psychology to argue that relationships at different layers serve different functions and have different cost-benefit profiles. At each layer, the benefits are asymptotic but the costs of maintaining a relationship at that level (most obviously, the time that has to be invested in servicing it) are roughly linear with the number of relationships. The trade-off between costs and benefits at a given level, and across the different types of demands and resources typical of different levels, gives rise to a distribution of social effort that generates and maintains a hierarchy of layered sets of relationships within social networks. We suggest that, psychologically, these trade-offs are related to the level of trust in a relationship, and that this is itself a function of the time invested in the relationship.


Mercury in eggs and feathers of great egrets (Ardea albus) from the Florida Everglades.
Great egret (Ardea albus) eggs and nestling feathers were collected for total mercury (THg) and methylmercury (MeHg) analysis from two colonies in the Florida Everglades in 1999 and 2000. THg was present in all eggs at a mean concentration of 0.39 +/- 0.19 microg/g fresh weight (n = 33, range = 0.08-0.86 microg/g). Egg-THg levels did not differ significantly between colonies or years. MeHg concentration in eggs was 0.35 +/- 0.18 microg/g fresh weight (n = 20, range = 0.05-0.82 microg/g,), and on average represented 85% of the THg found in the egg. Concentration of THg in feathers from egret nestlings, age 11-31 days, ranged from 1.4 to 8.6 microg/g dry weight. Feather-THg levels also did not differ significantly between colonies or years. THg concentrations in feathers, normalized based on bill length, were positively correlated to THg concentrations in eggs from the same clutch. Levels of THg in both eggs and feathers were lower in 1999 and 2000 than values reported for similar samples collected in 1993-95, indicating that MeHg exposure has decreased in the southern Everglades since the mid-1990s. THg levels in eggs and nestling feathers for the period of this study were below levels associated with toxic reproductive effects. Clutch size, fledging success, and brood size observed in this study were consistent for this species in the Everglades. Collectively, these results suggest that MeHg was not adversely affecting the reproductive performance of this population during the study.


PEP4LEP study protocol: integrated skin screening and SDR-PEP administration for leprosy prevention: comparing the effectiveness and feasibility of a community-based intervention to a health centre-based intervention in Ethiopia, Mozambique and Tanzania.
Leprosy, or Hansen's disease, remains a cause of preventable disability. Early detection, treatment and prevention are key to reducing transmission. Post-exposure prophylaxis with single-dose rifampicin (SDR-PEP) reduces the risk of developing leprosy when administered to screened contacts of patients. This has been adopted in the WHO leprosy guidelines. The PEP4LEP study aims to determine the most effective and feasible method of screening people at risk of developing leprosy and administering chemoprophylaxis to contribute to interrupting transmission. PEP4LEP is a cluster-randomised implementation trial comparing two interventions of integrated skin screening combined with SDR-PEP distribution to contacts of patients with leprosy in Ethiopia, Mozambique and Tanzania. One intervention is community-based, using skin camps to screen approximately 100 community contacts per leprosy patient, and to administer SDR-PEP when eligible. The other intervention is health centre-based, inviting household contacts of leprosy patients to be screened in a local health centre and subsequently receive SDR-PEP when eligible. The mobile health (mHealth) tool SkinApp will support health workers' capacity in integrated skin screening. The effectiveness of both interventions will be compared by assessing the rate of patients with leprosy detected and case detection delay in months, as well as feasibility in terms of cost-effectiveness and acceptability. Ethical approval was obtained from the national ethical committees of Ethiopia (MoSHE), Mozambique (CNBS) and Tanzania (NIMR/MoHCDEC). Study results will be published open access in peer-reviewed journals, providing evidence for the implementation of innovative leprosy screening methods and chemoprophylaxis to policymakers. NL7294 (NTR7503).


Theobroma cacao: Review of the Extraction, Isolation, and Bioassay of Its Potential Anti-cancer Compounds.
Plants have been a good source of therapeutic agents for thousands of years; an impressive number of modern drugs used for treating human diseases are derived from natural sources. The Theobroma cacao tree, or cocoa, has recently garnered increasing attention and become the subject of research due to its antioxidant properties, which are related to potential anti-cancer effects. In the past few years, identifying and developing active compounds or extracts from the cocoa bean that might exert anti-cancer effects have become an important area of health- and biomedicine-related research. This review provides an updated overview of T. cacao in terms of its potential anti-cancer compounds and their extraction, in vitro bioassay, purification, and identification. This article also discusses the advantages and disadvantages of the techniques described and reviews the processes for future perspectives of analytical methods from the viewpoint of anti-cancer compound discovery.


Iowa nurses' knowledge of living wills and perceptions of patient autonomy.
The principle of patient autonomy is well recognized in the nursing profession. This study extends the exploration of patient autonomy by examining nurses' knowledge about living wills. The questions addressed in this study included the following: (1) Were Iowa nurses aware of the living will statute? (2) What sources of information did nurses use to learn about this legislation? (3) What were nurses' perceptions of patients' rights? (4) What were nurses' perceptions of nurses' role involving living wills? (5) Were living wills followed? (6) If not followed, which factors contributed to the failure to honor a living will? and (7) Which communication mechanisms were used to alert nurses to a living will? A questionnaire was mailed to 10,000 actively licensed nurses in Iowa. Approximately 3,000 Iowa nurses responded to the questionnaire regarding Iowa living wills. Seventy per cent of the nurses knew that Iowa had living will legislation. No single educational source was a predominate choice for targeted information about the living will statute. Nurses were reluctant to suggest to patients that they should consider writing a living will. Nurses were also more willing to assume a passive role of suggesting that patients talk with relatives about the need for a living will but were less likely to be suggest that a patient write a living will for future health care treatment decisions. The majority of the nurses favored the patient having some control in health care treatment decisions. Three major factors were pertinent to the failure to follow a living will: family request, treating physician's refusal, and lack of information that the living will existed. The medical record was the primary means of communication regarding a living will. To enhance patient efforts at self-determination, nurses must recognize the advance directive legislation is available in their state and the potential impact that their nursing care may have on the implementation of the document.


RED BLOOD CELLS: CHANGE IN SHAPE IN CAPILLARIES.
Evidence obtained from high-speed cinephotography of the microcirculation in the mesentery of the dog shows that the shape of the red blood cell is changed during its flow through capillaries from a biconcave disk to a paraboloid with a hollow bell-like center. The degree of deformation is dependent upon the velocity of flow in the capillaries. Although the effect of change in shape on the surface area of the cell is uncertain, a larger portion of the surface is brought into closer proximity to the capillary wall than in a cell that is in the form of a biconcave disk. Thus, the change in shape may have functional significance related to the exchange of respiratory gases.


Pericardium in Reconstructive Urologic Surgeries: A Systematic Review and Meta-Analysis.
The use of pericardium has been expanded into different surgical modalities; however, there are scarce data regarding the feasibility of the pericardium in reconstructive urologic surgeries. We systematically reviewed the literature on the effectiveness of the pericardial tissue for reconstructive urologic surgeries. PubMed and Scopus were searched online for evidence on the use of the pericardium in urologic surgeries. Through the methodology recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, 38 of 4,071 studies were identified. A total of 715 patients and 139 animals underwent reconstructive urologic surgeries using the pericardium. Bladder, urethral, and renal reconstructions were successful in 100% of the human cases. The rates of dissatisfaction, glans hypoesthesia, and penile shortening were comparable between the pericardial graft surgeries and the other operations during penile straightening, but there was a trend among the patients with pericardial grafts toward having a more penile curvature at follow-up (risk ratio [RR] 2.03, 95% CI 0.90-4.61, p = 0.09; I2 = 0%). Among the animal studies, there were 4 reports of penile reconstruction, 7 studies of bladder reconstruction, and 1 study of urethroplasty. Bladder reconstruction and urethroplasty were successful in 83 and 20% of the animals, respectively. The pooled result of the stimulated intracorporeal pressure 5 V significantly favored pericardial grafts during penile reconstruction (RR 2.61, 95% CI 1.26-3.97, p = 0.0002; I2 = 0%). Our systematic review demonstrates the feasibility of the pericardium, regardless of its type, in urologic surgeries. It, however, seems that urethral substitution needs further investigation. Given the lower cost, easier handling, and less immunogenicity of the pericardium, further studies are required to examine its pros and cons.


Nerve growth factor is critical requirement for in vitro angiogenesis in gastric endothelial cells.
Angiogenesis is critical for the healing of gastric mucosal injury and is considered to be primarily regulated by vascular endothelial growth factor (VEGF), the fundamental proangiogenic factor. The role of nerve growth factor (NGF) in gastric angiogenesis is unknown. We examined the expression of NGF and its TrkA receptor in endothelial cells (ECs) isolated from gastric mucosa of rats (GMECs), the effect of NGF treatment on in vitro angiogenesis in GMECs, and, the mechanisms underlying NGF's proangiogenic actions. Isolated GMECs from Fisher rats were treated with vehicle, NGF (10-1,000 ng/ml), VEGF (20 ng/ml), or NGF+VEGF. To determine whether and to what extent NGF is critical for angiogenesis in GMECs, we silenced NGF expression using specific siRNA and examined in vitro angiogenesis with and without treatment with exogenous NGF and/or VEGF. Treatment of GMECs with NGF significantly increased in vitro angiogenesis similar to that seen in GMECs treated with VEGF. Silencing of NGF in GMECs abolished angiogenesis, and this effect was reversed only by exogenous NGF but not VEGF, which indicates a direct proangiogenic action of NGF on GMECs that is, at least in part, distinct and independent of VEGF. NGF's proangiogenic action on GMECs was mediated via PI3-K/Akt signaling. This study showed for the first time that gastric mucosal ECs express NGF and its receptor TrkA and that NGF is critical for angiogenesis in these cells.


Pharmacological basis for the medicinal use of psyllium husk (Ispaghula) in constipation and diarrhea.
The objective of this study was to determine the pharmacological basis of the medicinal use of psyllium husk (Ispaghula) in gastrointestinal motility disorders. In-vivo studies were conducted on mice, and isolated rabbit jejunum and guinea-pig ileum were used in in-vitro experiments. The crude extract of Ispaghula (Po.Cr) had a laxative effect in mice at 100 and 300 mg/kg, which was partially sensitive to atropine or SB203186 (5-HT(4) antagonist). At higher doses (500 and 1,000 mg/kg), Po.Cr had antisecretory and antidiarrheal activity. In guinea-pig ileum, Po.Cr (1-10 mg/ml) had a stimulatory effect, which was partially sensitive to atropine or SB203186. In rabbit jejunum, Po.Cr had a partially atropine-sensitive stimulatory effect followed by relaxation at 10 mg/ml. The relaxation was inhibited by the presence of L-NAME, a nitric oxide (NO) synthase inhibitor, or methylene blue, a guanylyl cyclase inhibitor. Similarly, the relaxant effect of Po.Cr on K(+) (80 mM)-induced contractions, was attenuated in the presence of L-NAME or methylene blue. Activity-directed fractionation of Po.Cr revealed that the gut stimulatory and inhibitory constituents were widely distributed in the aqueous and organic fractions. This study demonstrates that Ispaghula has a gut-stimulatory effect, mediated partially by muscarinic and 5-HT(4) receptor activation, which may complement the laxative effect of its fiber content, and a gut-inhibitory activity possibly mediated by blockade of Ca(2+) channels and activation of NO-cyclic guanosine monophosphate pathways. This may explain its medicinal use in diarrhea. It is, perhaps, also intended by nature to offset an excessive stimulant effect.


Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.
3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma. Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 every 28 days) 1 h after completing a 4-h infusion of 3-AP given at a dose of 105 mg/m(2) in patients with normal liver function (stratum A) or 80 mg/m(2) if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B. Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3-4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24 h after 3-AP therapy showed increased R2 mRNA expression by in situ RT-PCR, suggesting RR inhibition. Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract.


Comparative effectiveness and safety of antipsychotic drugs in patients with schizophrenia initiating or reinitiating treatment: A Real-World Observational Study.
To compare the effectiveness and safety of various second-generation antipsychotics (SGAs), newer oral and long-acting injectable (LAI) SGAs, and first-generation antipsychotics (FGAs) treatments in patients with schizophrenia or schizoaffective disorder (SCZ). This retrospective cohort study included medical administrative information for patients with a diagnosis of SCZ living in Quebec (Canada), initiating or reinitiating at least one antipsychotic (AP) drug (with a clearance baseline period of 12 months without any APs). Effectiveness was defined by a reduced risk of hospitalization for mental disorder and discontinuation, and safety by a reduced risk of all-cause death and hospitalization for non-mental disorder, 2 years after AP initiation or reinitiation. Cox proportional hazard models were used to estimate the events associated with different antipsychotics compared with oral olanzapine. The study cohort included 19,615 patients initiating or reinitiating an antipsychotic drug between January 2006 and December 2015. Results showed better effectiveness of clozapine (adjusted HR 0.36, 95% CI 0.30-0.42, p < 0.0001) and LAI SGAs (adjusted HR 0.56, 95% CI 0.51-0.61, p < 0.0001) compared with oral olanzapine when adding discontinuation to hospitalizations for mental disorder as a composite measure of effectiveness, as opposed to oral FGAs (adjusted HR 1.36, 95% CI 1.27-1.46, p < 0.0001) and LAI FGAs (adjusted HR 1.22, 95% CI 1.12-1.32, p < 0.0001). Most APs were as safe as oral olanzapine. The effectiveness of LAI SGAs and clozapine appears to justify their use and are as safe as a recognized treatment (oral olanzapine) in Quebec (Canada).


Compensatory postural adaptations during continuous, variable amplitude perturbations reveal generalized rather than sequence-specific learning.
We examined changes in the motor organization of postural control in response to continuous, variable amplitude oscillations evoked by a translating platform and explored whether these changes reflected implicit sequence learning. The platform underwent random amplitude (maximum +/- 15 cm) and constant frequency (0.5 Hz) oscillations. Each trial was composed of three 15-s segments containing seemingly random oscillations. Unbeknownst to participants, the middle segment was repeated in each of 42 trials on the first day of testing and in an additional seven trials completed approximately 24 h later. Kinematic data were used to determine spatial and temporal components of total body centre of mass (COM) and joint segment coordination. Results showed that with repeated trials, participants reduced their magnitude of COM displacement, shifted from a COM phase lag to a phase lead relative to platform motion and increased correlations between ankle/platform motion and hip/platform motion as they shifted from an ankle strategy to a multi-segment control strategy involving the ankle and hip. Maintenance of these changes across days provided evidence for learning. Similar improvements for the random and repeated segments, indicated that participants did not exploit the sequence of perturbations to improve balance control. Rather, the central nervous system may have been tuning into more general features of platform motion. These findings provide important insight into the generalizabilty of improved compensatory balance control with training.


Improved techniques reduce face mask leak during simulated neonatal resuscitation: study 2.
Techniques of positioning and holding neonatal face masks vary. Studies have shown that leak at the face mask is common and often substantial irrespective of operator experience. (1) To identify a technique for face mask placement and hold which will minimise mask leak. (2) To investigate the effect of written instruction and demonstration of the identified technique on mask leak for two round face masks. Three experienced neonatologists compared methods of placing and holding face masks to minimise the leak for Fisher & Paykel 60 mm and Laerdal size 0/1 masks. 50 clinical staff gave positive pressure ventilation to a modified manikin designed to measure leak at the face mask. They were provided with written instructions on how to position and hold each mask and then received a demonstration. Face mask leak was measured after each teaching intervention. A technique of positioning and holding the face masks was identified which minimised leak. The mean (SD) mask leaks before instruction, after instruction and after demonstration were 55% (31), 49% (30), 33% (26) for the Laerdal mask and 57% (25), 47% (28), 32% (30) for the Fisher & Paykel mask. There was no significant difference in mask leak between the two masks. Written instruction alone reduced leak by 8.8% (CI 1.4% to 16.2%) for either mask; when combined with a demonstration mask leak was reduced by 24.1% (CI 16.4% to 31.8%). Written instruction and demonstration of the identified optimal technique resulted in significantly reduced face mask leak.


The impact of diagnosis on health-related quality of life in people with coeliac disease: a UK population-based longitudinal perspective.
Before diagnosis, people with coeliac disease suffer reduced quality of life, which improves substantially after the disease has been diagnosed. Delayed diagnosis is common. The aim of this study was to assess changes over time in prevalence of coeliac disease symptoms/associated medical conditions, time to diagnosis, quality of life and its determinants before and after diagnosis in the United Kingdom. A postal questionnaire was designed in 2015 and sent to 4000 individuals with diagnosed coeliac disease, requesting information on respondents' socio-demographic and clinical characteristics, and their quality of life pre- and post-diagnosis using the EQ-5D instrument. Data were analysed and compared with results from a survey conducted in 2006 using descriptive analyses, univariate and multivariable regression methods. The survey response rate was 40%. Sixty-five percent of respondents reported at least 4 symptoms pre-diagnosis, a significant reduction by 13 percentage points (95% CI: -16.9, - 9.4; p-value: < 0.001) compared to 2006. Pre-diagnosis mean duration of symptoms was 12.8 years (SD: 15.3), a non-significant reduction of 0.6 years (95% CI: -2, 0.8; p-value: 0.426) compared to 2006. There was a significant improvement of 0.20 (95% CI: 0.18, 0.22; p-value: < 0.001) in quality of life from pre- (0.65) to post-diagnosis (0.85). Pre-diagnosis values were significantly higher by 0.09 (95% CI: 0.06, 0.12; p-value: < 0.001) than in 2006. Number of symptoms and low income were associated with decreased quality of life. Undiagnosed coeliac disease is associated with a substantial decrement in quality of life. Time to diagnosis has not significantly shortened over the decade 2006-2015, but symptoms are less severe when diagnosis occurs. Harmonising clinical guidelines for intensified active case finding will help improve quality of life of people with coeliac disease.


Synthesis of Polymer Grafted Magnetite Nanoparticle with the Highest Grafting Density via Controlled Radical Polymerization.
The surface-initiated ATRP of benzyl methacrylate, methyl methacrylate, and styrene from magnetite nanoparticle is investigated, without the use of sacrificial (free) initiator in solution. It is observed that the grafting density obtained is related to the polymerization kinetics, being higher for faster polymerizing monomer. The grafting density was found to be nearly 2 chains/nm2for the rapidly polymerizing benzyl methacrylate. In contrast, for the less rapidly polymerizing styrene, the grafting density was found to be nearly 0.7 chain/nm2. It is hypothesized that this could be due to the relative rates of surface-initiated polymerization versus conformational mobility of polymer chains anchored by one end to the surface. An amphiphilic diblock polymer based on 2-hydroxylethyl methacrylate is synthesized from the polystyrene monolayer. The homopolymer and block copolymer grafted MNs form stable dispersions in various solvents. In order to evaluate molecular weight of the polymer that was grafted on to the surface of the nanoparticles, it was degrafted suitably and subjected to gel permeation chromatography analysis. Thermogravimetric analysis, transmission electron microscopy, and Fourier transform infrared spectroscopy were used to confirm the grafting reaction.


Web-based interactive 3D visualization as a tool for improved anatomy learning.
Despite a long tradition, conventional anatomy education based on dissection is declining. This study tested a new virtual reality (VR) technique for anatomy learning based on virtual contrast injection. The aim was to assess whether students value this new three-dimensional (3D) visualization method as a learning tool and what value they gain from its use in reaching their anatomical learning objectives. Several 3D vascular VR models were created using an interactive segmentation tool based on the "virtual contrast injection" method. This method allows users, with relative ease, to convert computer tomography or magnetic resonance images into vivid 3D VR movies using the OsiriX software equipped with the CMIV CTA plug-in. Once created using the segmentation tool, the image series were exported in Quick Time Virtual Reality (QTVR) format and integrated within a web framework of the Educational Virtual Anatomy (EVA) program. A total of nine QTVR movies were produced encompassing most of the major arteries of the body. These movies were supplemented with associated information, color keys, and notes. The results indicate that, in general, students' attitudes towards the EVA-program were positive when compared with anatomy textbooks, but results were not the same with dissections. Additionally, knowledge tests suggest a potentially beneficial effect on learning.


Influx mechanisms in the embryonic and adult rat choroid plexus: a transcriptome study.
The transcriptome of embryonic and adult rat lateral ventricular choroid plexus, using a combination of RNA-Sequencing and microarray data, was analyzed by functional groups of influx transporters, particularly solute carrier (SLC) transporters. RNA-Seq was performed at embryonic day (E) 15 and adult with additional data obtained at intermediate ages from microarray analysis. The largest represented functional group in the embryo was amino acid transporters (twelve) with expression levels 2-98 times greater than in the adult. In contrast, in the adult only six amino acid transporters were up-regulated compared to the embryo and at more modest enrichment levels (<5-fold enrichment above E15). In E15 plexus five glucose transporters, in particular Glut-1, and only one monocarboxylate transporter were enriched compared to the adult, whereas only two glucose transporters but six monocarboxylate transporters in the adult plexus were expressed at higher levels than in embryos. These results are compared with earlier published physiological studies of amino acid and monocarboxylate transport in developing rodents. This comparison shows correlation of high expression of some transporters in the developing brain with higher amino acid transport activity reported previously. Data for divalent metal transporters are also considered. Immunohistochemistry of several transporters (e.g., Slc16a10, a thyroid hormone transporter) gene products was carried out to confirm translational activity and to define cellular distribution of the proteins. Overall the results show that there is substantial expression of numerous influx transporters in the embryonic choroid plexus, many at higher levels than in the adult. This, together with immunohistochemical evidence and data from published physiological transport studies suggests that the choroid plexus in embryonic brain plays a major role in supplying the developing brain with essential nutrients.


Mullerian Agenesis Associated with Turner's Syndrome.
Turner's syndrome is a chromosomal disorder with 45 X0 due to absence of a set of gene from the short arm of X chromosome. The incidence of Turner's syndrome is 1 in 2500 live births. Primary amenorrhea is well known in Turner's syndrome, the reason being streak ovaries; but mullerian agenesis as a cause of primary amenorrhea in Turner's syndrome is a very rare entity. The incidence of Turner's syndrome associated with mullerian agenesis is extremely rare as there is only a hand full of cases reported in literature. We report a rare case of adolescent female who presented with primary amenorrhea and found to have Turner's syndrome with mullerian agenesis.


A Tale of Two Sisters: Breast Reconstruction Options for Women With or at High Risk of Breast Cancer.
Breast reconstructive surgery has changed significantly over the past decade. The incidence of nipple-sparing procedures and prophylactic mastectomy has also increased significantly as women and their surgeons use shared decision-making strategies. The following case history of two sisters, one with breast cancer and one at elevated risk for breast cancer, highlights the current standard of care with newer gold-standard procedures for mastectomy and subsequent reconstruction. A comparison of types of mastectomies, steps in reconstruction, and reconstruction options are discussed.


The historical development of suicide mortality in Russia, 1870-2007.
Russia has one of the highest suicide mortality rates in the world. This study investigates the development of Russian suicide mortality over a longer time period in order to provide a context within which the contemporary high level might be better understood. Annual sex- and age-specific suicide-mortality data for Russia for the period 1870-2007 were studied, where available. Russian suicide mortality increased 11-fold over the period. Trends in male and female suicide developed similarly, although male suicide rates were consistently much higher. From the 1990s suicide has increased in a relative sense among the young (15-34), while the high suicide mortality among middle-aged males has reduced. Changes in Russian suicide mortality over the study period may be attributable to modernization processes.


Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
Appropriate initial antibiotic treatment and avoiding administration of unnecessary broad-spectrum antibiotics are important for the treatment of pneumonia. To achieve this, assessment of risk for drug-resistant pathogens (DRPs) at diagnosis is essential. The aim of this study was to validate a predictive rule for DRPs that we previously proposed (the community-acquired pneumonia drug-resistant pathogen [CAP-DRP] rule), comparing several other predictive methods. A prospective observational study was conducted in hospitalized patients with community-onset pneumonia at four institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP-DRPs. CAP-DRPs were identified in 73 (10.1%) of 721 patients analyzed. The CAP-DRP rule differentiated low vs high risk of CAP-DRP at the threshold of ≥3 points or 2 points plus any of methicillin-resistant Staphylococcus aureus specific factors with a sensitivity of 0.45, specificity of 0.87, positive predictive value of 0.47, negative predictive value of 0.87, and accuracy of 0.79. Its discrimination performance, area under the receiver operating characteristic curve, was 0.73 (95% confidence interval 0.66-0.79). Specificity of the CAP-DRP rule against CAP-DRPs was the highest among the six predictive rules tested. The performance of the predictive rules and criteria for CAP-DRPs was limited. However, the CAP-DRP rule yielded high specificity and could specify patients who should be treated with non-broad-spectrum antibiotics, eg, a non-pseudomonal β-lactam plus a macrolide, more precisely.


Comparison of the Effects of a Pharmaceutical Industry Decision Guide and Decision Aids on Patient Choice to Intensify Therapy in Rheumatoid Arthritis.
To compare the effects a pharmaceutical industry decision guide and International Patient Decision Aids Standard (IPDAS) compliant patient decision aids (PtDA) on patient medication beliefs and choice to intensify therapy. Rheumatoid arthritis (RA) patients, who had never taken etanercept (Enbrel), took part in a mail survey. They were presented with a hypothetical decision scenario where they were asked to consider adding etanercept to their current regimen. Each patient was randomized to review 1 of 3 forms of an etanercept-specific decision support: a long PtDA (LONG DA), a short PtDA (SHORT DA), or the manufacturer's Enbrel decision guide (Pharm Booklet). We had 402 RA patients participate in the study (response rate, 52%). Of the patients randomized to the Pharm Booklet, 30.6% elected to initiate etanercept. Only 14.6% and 14.0% of patients who reviewed the LONG DA or SHORT DA choose to take etanercept (χ2 = 15.7; P < 0.001). Patients who reviewed the LONG DA or SHORT DA had a greater increase in knowledge about etanercept than those who reviewed the Pharm Booklet. There was no difference in decisional conflict among the groups. A logistic regression model explained 44.2% (R2 = 0.442) of patient choice to intensify therapy by initiating etanercept. The strongest predictor of choice to intensify therapy were beliefs about etanercept's ability to improve symptoms (OR = 2.56, 96%CI [1.71, 3.80]), and its use by others like the respondent (OR = 2.24, 95%CI [1.49, 3.35]). Mediation analysis confirmed the presence of a partial mediating effect of decision support on patients' intent to take etanercept (OR = 0.59, 95%CI [0.39, 0.89]). Patients supported by the Pharm Booklet were twice as likely to choose to intensify therapy. The Pharm Booklet's effects are partially mediated through persuasive communication techniques that influence patients' beliefs that symptoms will improve, and increase social normative beliefs, rather than by increasing the relevant knowledge, clarifying patient values about positive or negative treatment outcomes, or increasing their self-efficacy.


Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle.
Monocarboxylate transporter (MCT) 4 is the major monocarboxylate transporter isoform present in white skeletal muscle and is responsible for the efflux of lactic acid produced by glycolysis. Here we report the characterisation of MCT4 expressed in Xenopus oocytes. The protein was correctly targeted to the plasma membrane and rates of substrate transport were determined from the rate of intracellular acidification monitored with the pH-sensitive dye 2', 7'-bis-(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). In order to validate the technique, the kinetics of monocarboxylate transport were measured in oocytes expressing MCT1. Km values determined for L-lactate, D-lactate and pyruvate of 4.4, > 60 and 2.1 mM, respectively, were similar to those determined previously in tumour cells. Comparison of the time course of [14C]lactate accumulation with the rate of intracellular acidification monitored with BCECF suggests that the latter reflects pH changes close to the plasma membrane associated with transport, whilst the former may include diffusion-limited movement of lactate into the bulk cytosol. Km values of MCT4 for these substrates were found to be 28, 519 and 153 mM, respectively, and for a range of other monocarboxylates values were at least an order of magnitude higher than for MCT1. Vmax values appeared to be similar for all substrates. K0.5 values of MCT4 (determined at 30 mM L-lactate) for inhibition by alpha-cyano-4-hydroxycinnamate (991 microM), phloretin (41 microM), 5-nitro-2-(3-phenylpropylamino)benzoate (240 microM), p-chloromercuribenzene sulphonate (21 microM) and 3-isobutyl-1-methylxanthine (970 microM, partial inhibition) were also substantially higher than for MCT1. No inhibition of MCT4 by 2 mM 4,4'-diisothiocyanostilbene-2,2'-disulphonate was observed. The properties of MCT4 are consistent with published data on giant sarcolemmal vesicles in which MCT4 is the dominant MCT isoform, and are appropriate for the proposed role of MCT4 in mediating the efflux from the cell of glycolytically derived lactic acid but not pyruvate.


Expanding access to diacetylmorphine and hydromorphone for people who use opioids in Canada.
The increasing incidence of fatal opioid overdose is a public health crisis in Canada. While buprenorphine/naloxone and methadone are the standard first-line of opioid substitution options, limitations, including difficulty achieving long-term retention for some people who use opioids, are well known. For this group, injectable diacetylmorphine or hydromorphone can achieve positive outcomes, including high retention rates, reduced use of unregulated opioids, and reduced criminal activity. In May 2019, Health Canada announced changes to increase the accessibility of diacetylmorphine and hydromorphone, and in September 2019, the CIHR-funded Canadian Research Initiative in Substance Misuse released a national clinical guideline for diacetylmorphine and hydromorphone as additional frontline substitution options. While these developments present opportunities for scale-up, significant financial, structural, and practice barriers continue to impede access. This commentary explores the current state of policy and practice for diacetylmorphine and hydromorphone as opioid substitution options in Canada, outlines the rationale for rapid expansion of access, and highlights clinical and policy changes that must be undertaken or the death toll will continue to rise.


Irradiance governs exploitation of fungi: fine-tuning of carbon gain by two partially myco-heterotrophic orchids.
While all members of the Orchidaceae are fully dependent on mycorrhizal fungi during their achlorophyllous juvenile stages, mature plants may remain fully myco-heterotrophic, become fully autotrophic or develop a nutritional mode where the carbon gain through photosynthesis is complemented by organic carbon from fungal partners. This so-called partial myco-heterotrophy is intriguingly complex. Current knowledge indicates a large range in the proportion of fungus-derived carbon between and within partially myco-heterotrophic plant species. However, the driving factors for this variation are so far mostly unknown. Here we show for two green species of the orchid genus Cephalanthera that light availability is the major determinant of the degree of myco-heterotrophy. Using leaf stable isotope natural abundance analysis together with time-integrated microscale light climate monitoring we could demonstrate that there is a sensitive reaction to varying light availability within forests. Low light levels result in strong myco-heterotrophy while higher irradiances successively drive the orchids towards autotrophy. Our results demonstrate that partial myco-heterotrophy in these species is not a static nutritional mode but a flexible mechanism driven by light availability which allows a balanced usage of carbon resources available in nature.


Tunable 2-μm optical vortex parametric oscillator.
We generated tunable 2-μm optical vortex pulses with a topological charge of 1 or 2 in the wavelength range 1.953-2.158 μm by realizing anisotropic transfer of the topological charge from the pump beam to the signal output in a vortex-pumped half-symmetric optical parametric oscillator. A maximum vortex output energy of 2.1 mJ was obtained at a pump energy of 22.8 mJ, which corresponds to a slope efficiency of 15%. The topological charges of the signal and idler output were investigated using a shearing interferometric technique employing a low-spatial-frequency transmission grating.


Multimodality imaging in transcatheter aortic valve implantation and post-procedural aortic regurgitation: comparison among cardiovascular magnetic resonance, cardiac computed tomography, and echocardiography.
The purpose of this study was to determine imaging predictors of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) and the agreement and reproducibility of cardiovascular magnetic resonance (CMR), cardiac computed tomography (CCT), and transthoracic echocardiography (TTE) in aortic root assessment. The optimal imaging strategy for planning TAVI is unclear with a paucity of comparative multimodality imaging data. The association between aortic root morphology and outcomes after TAVI also remains incompletely understood. A total of 202 consecutive patients assessed by CMR, CCT, and TTE for TAVI were studied. Agreement and variability among and within imaging modalities was assessed by Bland-Altman analysis. Postoperative AR was assessed by TTE. Of the 202 patients undergoing TAVI assessment with both CMR and TTE, 133 also underwent CCT. Close agreement was observed between CMR and CCT in dimensions of the aortic annulus (bias, -0.4 mm; 95% limits of agreement: -5.7 to 5.0 mm), and similarly for sinus of Valsalva, sinotubular junction, and ascending aortic measures. Agreement between TTE-derived measures and either CMR or CCT was less precise. Intraobserver and interobserver variability were lowest with CMR. The presence and severity of AR after TAVI were associated with larger aortic valve annulus measurements by both CMR (p = 0.03) and CCT (p = 0.04) but not TTE-derived measures (p = 0.10). Neither CCT nor CMR measures of annulus eccentricity, however, predicted AR after TAVI (p = 0.33 and p = 0.78, respectively). In patients undergoing imaging assessment for TAVI, the presence and severity of AR after TAVI were associated with larger aortic annulus measurements by both CMR and CCT, but not TTE. Both CMR and CCT provide highly reproducible information in the assessment of patients undergoing TAVI.


The chaperone effect in scientific publishing.
Experience plays a critical role in crafting high-impact scientific work. This is particularly evident in top multidisciplinary journals, where a scientist is unlikely to appear as senior author if he or she has not previously published within the same journal. Here, we develop a quantitative understanding of author order by quantifying this "chaperone effect," capturing how scientists transition into senior status within a particular publication venue. We illustrate that the chaperone effect has a different magnitude for journals in different branches of science, being more pronounced in medical and biological sciences and weaker in natural sciences. Finally, we show that in the case of high-impact venues, the chaperone effect has significant implications, specifically resulting in a higher average impact relative to papers authored by new principal investigators (PIs). Our findings shed light on the role played by experience in publishing within specific scientific journals, on the paths toward acquiring the necessary experience and expertise, and on the skills required to publish in prestigious venues.


Bird Communities and Environmental Correlates in Southern Oregon and Northern California, USA.
We examined avian community ecology in the Klamath Ecoregion and determined that individual bird species co-exist spatially to form 29 statistically distinguishable bird groups. We identified climate, geography, and vegetation metrics that are correlated with these 29 bird groups at three scales: Klamath Ecoregion, vegetation formation (agriculture, conifer, mixed conifer/hardwood, shrubland), and National Park Service unit. Two climate variables (breeding season mean temperature and temperature range) and one geography variable (elevation) were correlated at all scales, suggesting that for some vegetation formations and park units there is sufficient variation in climate and geography to be an important driver of bird communities, a level of variation we expected only at the broader scale. We found vegetation to be important at all scales, with coarse metrics (environmental site potential and existing vegetation formation) meaningful across all scales and structural vegetation patterns (e.g. succession, disturbance) important only at the scale of vegetation formation or park unit. Additionally, we examined how well six National Park Service units represent bird communities in the broader Klamath Ecoregion. Park units are inclusive of most bird communities with the exception of the oak woodland community; mature conifer forests are well represented, primarily associated with conifer canopy and lacking multi-layered structure. Identifying environmental factors that shape bird communities at three scales within this region is important; such insights can inform local and regional land management decisions necessary to ensure bird conservation in this globally significant region.


A high speed stellar spectrograph.
The design concept of a high speed stellar spectrograph for gratings up to a ruled length of 128 mm and for dispersions from 80 A/mm to 20 A/mm is described. It consists of a mirror collimator and two exchangeable mirror cameras. The impinging and diffracted bundle of light is corrected by means of concentric menisci which are exchanged together with the camera. Information is given about design details and the corrections obtained.


Mad acts downstream of Dpp receptors, revealing a differential requirement for dpp signaling in initiation and propagation of morphogenesis in the Drosophila eye.
Decapentaplegic (Dpp), a member of the TGF-beta family of cytokines, has been implicated in many patterning processes in Drosophila, including the initial steps of pattern formation in the developing eye. We show that the Mothers against dpp (Mad) gene is required for dpp signaling during eye development. Clonal analysis demonstrates a cell-autonomous function for Mad and genetic interactions indicate that Mad is an essential component of the signal transduction pathway downstream of the Dpp receptors in responding cells. Mad-mediated dpp signaling is absolutely required for the initiation of the morphogenetic furrow in the eye, but has only a minor role in its subsequent propagation across the eye disc. We also present evidence for the repression of wingless transcription by dpp signaling.


Assembly of the asymmetric human γ-tubulin ring complex by RUVBL1-RUVBL2 AAA ATPase.
The microtubule nucleator γ-tubulin ring complex (γTuRC) is essential for the function of microtubule organizing centers such as the centrosome. Since its discovery over two decades ago, γTuRC has evaded in vitro reconstitution and thus detailed structure-function studies. Here, we show that a complex of RuvB-like protein 1 (RUVBL1) and RUVBL2 "RUVBL" controls assembly and composition of γTuRC in human cells. Likewise, RUVBL assembles γTuRC from a minimal set of core subunits in a heterologous coexpression system. RUVBL interacts with γTuRC subcomplexes but is not part of fully assembled γTuRC. Purified, reconstituted γTuRC has nucleation activity and resembles native γTuRC as revealed by its cryo-electron microscopy (cryo-EM) structure at ~4.0-Å resolution. We further use cryo-EM to identify features that determine the intricate, higher-order γTuRC architecture. Our work finds RUVBL as an assembly factor that regulates γTuRC in cells and allows production of recombinant γTuRC for future in-depth mechanistic studies.


SSR analysis of the Medicago truncatula SARDI core collection reveals substantial diversity and unusual genotype dispersal throughout the Mediterranean basin.
The world's oldest and largest Medicago truncatula collection is housed at the South Australian Research and Development Institute (SARDI). We used six simple sequence repeat (SSR) loci to analyse the genetic diversity and relationships between randomly selected individuals from 192 accessions in the core collection. M. truncatula is composed of three subspecies (ssp.): ssp. truncatula, ssp. longeaculeata, and ssp. tricycla. Analysis at the level of six SSR loci supports the concept of ssp. tricycla, all the samples of which showed unique alleles at two loci. Contingency Chi-squared tests were significant between ssp. tricycla and ssp. truncatula at four loci, suggesting a barrier to gene flow between these subspecies. In accessions defined as ssp. longeaculeata, no unique allelic distribution or diagnostic sizes were observed, suggesting this apparent ssp. is a morphological variant of ssp. truncatula. The data also suggest M. truncatula that exhibits unusually wide genotype dispersal throughout its native Mediterranean region, possibly due to animal and trade-related movements. Our results showed the collection to be highly diverse, exhibiting an average of 25 SSR alleles per locus, with over 90% of individuals showing discrete genotypes. The rich diversity of the SARDI collection provides an invaluable resource for studying natural allelic variation of M. truncatula. To efficiently exploit the variation in the SARDI collection, we have defined a subset of accessions (n = 61) that maximises the diversity.


The spatial tuning of "motion streak" mechanisms revealed by masking and adaptation.
We previously reported that fast-moving dot arrays cause orientation-tuned masking of static gratings (D. Apthorp, J. Cass, & D. Alais, 2010), which we attribute to "motion streaks." Using similar "streaky" dot motion, we describe spatial frequency tuning of grating threshold elevations caused by masking (Experiment 1) and adaptation (Experiment 2) to motion. To compare the streaks with psychophysical tunings, we Fourier analyzed time-averaged translating dots, which were bandpass (peaking at ∼2.3 c/deg). Masking, however, was strongest at lower test frequencies (≤1 c/deg) and largely isotropic over orientation, although a small orientation-tuned effect occurred at ∼1.2 c/deg. Results were broadly similar across monoptic and dichoptic conditions. Adaptation to fast motion produced spatially bandpass threshold elevations for parallel test gratings, peaking slightly lower than the peak Fourier frequency, with little elevation below 1 c/deg (unlike the low-pass elevation resulting from masking). Slow adaptation produced little elevation for parallel gratings. For orthogonal test gratings, fast motion adaptation produced low-pass threshold elevations and slow motion produced bandpass elevations, suggesting that separable mechanisms process fast (streaky) and slow motion. The different threshold elevation patterns over spatial frequency for masking and adaptation suggest that the adaptation effects are mainly within-channel suppression, whereas the masking effects may be mainly due to between-channel suppression.


A randomised controlled trial of subcutaneous sodium salicylate therapy for osteoarthritis of the thumb.
Current treatment for osteoarthritis (OA) is limited. Many patients with OA of the hand have areas of tender subcutaneous thickening in the forearm and upper scapular region. A pilot study showed an improvement in pain from OA at the first carpometacarpal joint after injection of such areas with 0.5% sodium salicylate or saline, an inexpensive treatment that can be administered by general practitioners and nurses. The study indicated that a randomised, sham-controlled trial was justified. 40 patients with OA of the first carpometacarpal joint were randomised to receive either injections of sodium salicylate into tender, thickened areas of subcutaneous tissue on the forearm (baseline) and upper scapular region (week 1) or sham injections consisting of pressure without skin penetration. Blinded assessments were made at weeks 3, 7 and 13 after baseline. Pain and tenderness during follow-up were both significantly lower in the active treatment group compared with the sham group: 19% and 14% greater reduction in mean visual analogue scale (VAS) score, respectively (p=0.007 and 0.02, baseline mean 5.65 and 5.35 cm, average difference in change from baseline VAS 1.9 and 1.4 cm, 95% CI 0.6 to 3.2 and 0.2 to 2.5). Active and sham injections were painful, the former significantly more so; however, there was no significant correlation between the pain of active injections and response. The data show that subcutaneous sodium salicylate injections are an effective symptomatic treatment for OA of the thumb. The results provide a basis for further physiological and therapeutic research in this area.