Ethanol inhibits dopamine uptake via organic cation transporter 3: Implications for ethanol and cocaine co-abuse.

Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.

The TGM2 inhibitor cysteamine hydrochloride does not impact corneal epithelial and stromal wound healing in vitro and in vivo.

Corneal wound healing is integral for resolution of corneal disease or for post-operative healing. However, corneal scarring that may occur secondary to this process can significantly impair vision. Tissue transglutaminase 2 (TGM2) inhibition has shown promising antifibrotic effects and thus holds promise to prevent or treat corneal scarring. The commercially available ocular solution for treatment of ocular manifestations of Cystinosis, Cystaran®, contains the TGM2 inhibitor cysteamine hydrochloride (CH). The purpose of this study is to assess the safety of CH on corneal epithelial and stromal wounds, its effects on corneal wound healing, and its efficacy against corneal scarring following wounding. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) were first used to quantify and localize TGM2 expression in the cornea. Subsequently, (i) the in vitro effects of CH at 0.163, 1.63, and 16.3 mM on corneal epithelial cell migration was assessed with an epithelial cell migration assay, and (ii) the in vivo effects of application of 1.63 mM CH on epithelial and stromal wounds was assessed in a rabbit model with ophthalmic examinations, inflammation scoring, color and fluorescein imaging, optical coherence tomography (OCT), and confocal biomicroscopy. Post-mortem assessment of corneal tissue post-stromal wounding included biomechanical characterization (atomic force microscopy (AFM)), histology (H&E staining), and determining incidence of myofibroblasts (immunostaining against α-SMA) in wounded corneal tissue. TGM2 expression was highest in corneal epithelial cells. Application of the TGM2 inhibitor CH did not affect in vitro epithelial cell migration at the two lower concentrations tested. At 16.3 mM, decreased cell migration was observed. In vivo application of CH at 57 mM was well tolerated and did not adversely affect wound healing. No difference in corneal scarring was found between CH treated and vehicle control eyes. This study shows that the TGM2 inhibitor CH, at the FDA-approved dose, is well tolerated in a rabbit model of corneal wound healing and does not adversely affect epithelial or stromal wound healing. This supports the safe use of this medication in Cystinosis patients with open corneal wounds. CH did not have an effect on corneal scarring in this study, suggesting that Cystaran® administration to patients with corneal wounds is unlikely to decrease corneal fibrosis.

Development, Validation, and Utility of Species-Specific Diagnostic Markers for Detection of Peronospora belbahrii.

Peronospora belbahrii is an oomycete and the cause of basil downy mildew, one of the most destructive diseases affecting basil production worldwide. Disease management is challenging due to wind-dispersed sporangia and contaminated seed; therefore, identifying P. belbahrii in seed lots before sale or planting or in the field before symptoms develop could allow for timely deployment of disease management strategies. In this study, a draft genome assembly and next-generation sequencing reads for P. belbahrii, as well as publicly available DNA-seq and RNA-seq reads of several other downy mildew pathogens, were incorporated into a bioinformatics pipeline to predict P. belbahrii-specific diagnostic markers. The specificity of each candidate marker was validated against a diverse DNA collection of P. belbahrii, host tissue, and related oomycetes using PCR. Two species-specific markers were identified and used as templates to develop a highly sensitive probe-based real-time quantitative PCR (qPCR) assay that could detect P. belbahrii in leaf tissue and seed samples. Both markers were capable of reliably detecting as low as 500 fg/µl of P. belbahrii genomic DNA and as few as 10 sporangia. The qPCR assay was then validated with seed samples collected from a basil cultivar experiment. In total, 48 seed samples were collected and tested; P. belbahrii was detected in samples of all cultivars at estimated concentrations of 600 fg/µl up to 250 pg/µl and at as few as 10 sporangia up to >1,000 sporangia. The markers and assays are valuable for diagnostics and identifying P. belbahrii-contaminated seed lots to mitigate the effects of future basil downy mildew epidemics.

Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

DendroScan: an open source tool to conduct comparative statistical tests and dendrogrammatic analyses on particle morphometry.

Quantitative shape analysis of juvenile pyroclasts is applied in volcanology to reconstruct the dynamics and styles of eruptions, and to explore the details of tephra transport, dispersal, and emplacement. Morphometric analyses often include comparison of multiple data sets with a set of dimensionless shape parameters. Here we present "DendroScan", an open source Matlab program that provides the user with all the multivariate statistical methods needed to produce such morphometric comparisons. Serving as a statistical "toolbox", DendroScan conducts Levene-, t-, and equivalence tests, presenting the results in ad hoc interpretable graphs. Furthermore, it is designed to conduct dendrogrammatic analyses of particle morphometry, a recently developed approach for the inter-comparison of multiple morphometric data sets. DendroScan produces tree diagrams, in which the analysed samples are sorted according to their morphometric dissimilarity, allowing the user to identify, e.g., samples that are statistically equivalent. To demonstrate DendroScan's potential, ten experimental samples are compared with volcanic ash samples generated by the Havre 2012 deep-sea eruption in the Kermadec arc (New Zealand). We show how, using DendroScan-based results, information on the eruptive mechanism can be inferred, and how the cooling history of the experimental melt is reflected in the dissimilarity of thermally granulated fragments.

A high-spin ground-state donor-acceptor conjugated polymer.

Interest in high-spin organic materials is driven by opportunities to enable far-reaching fundamental science and develop technologies that integrate light element spin, magnetic, and quantum functionalities. Although extensively studied, the intrinsic instability of these materials complicates synthesis and precludes an understanding of how fundamental properties associated with the nature of the chemical bond and electron pairing in organic materials systems manifest in practical applications. Here, we demonstrate a conjugated polymer semiconductor, based on alternating cyclopentadithiophene and thiadiazoloquinoxaline units, that is a ground-state triplet in its neutral form. Electron paramagnetic resonance and magnetic susceptibility measurements are consistent with a high-to-low spin energy gap of 9.30 × 10-3 kcal mol-1. The strongly correlated electronic structure, very narrow bandgap, intramolecular ferromagnetic coupling, high electrical conductivity, solution processability, and robust stability open access to a broad variety of technologically relevant applications once thought of as beyond the current scope of organic semiconductors.

Genome Sequencing and Transcriptome Analysis of the Hop Downy Mildew Pathogen Pseudoperonospora humuli Reveal Species-Specific Genes for Molecular Detection.

Pseudoperonospora humuli is an obligate oomycete pathogen of hop (Humulus lupulus) that causes downy mildew, an important disease in most production regions in the Northern Hemisphere. The pathogen can cause a systemic infection in hop, overwinter in the root system, and infect propagation material. Substantial yield loss may occur owing to P. humuli infection of strobiles (seed cones), shoots, and cone-bearing branches. Fungicide application and cultural practices are the primary methods to manage hop downy mildew. However, effective, sustainable, and cost-effective management of downy mildew can be improved by developing early detection systems to inform on disease risk and timely fungicide application. However, no species-specific diagnostic assays or genomic resources are available for P. humuli. The genome of the P. humuli OR502AA isolate was partially sequenced using Illumina technology and assembled with ABySS. The assembly had a minimum scaffold length of 500 bp and an N50 (median scaffold length of the assembled genome) of 19.2 kbp. A total number of 18,656 genes were identified using MAKER standard gene predictions. Additionally, transcriptome assemblies were generated using RNA-seq and Trinity for seven additional P. humuli isolates. Bioinformatics analyses of next generation sequencing reads of P. humuli and P. cubensis (a closely related sister species) identified 242 candidate species-specific P. humuli genes that could be used as diagnostic molecular markers. These candidate genes were validated using polymerase chain reaction against a diverse collection of isolates from P. humuli, P. cubensis, and other oomycetes. Overall, four diagnostic markers were found to be uniquely present in P. humuli. These candidate markers identified through comparative genomics can be used for pathogen diagnostics in propagation material, such as rhizomes and vegetative cuttings, or adapted for biosurveillance of airborne sporangia, an important source of inoculum in hop downy mildew epidemics.

Cumulative live birth rates following a 'freeze-all' strategy: a population-based study.

STUDY QUESTION: What is the cumulative live birth rate following a 'freeze-all' strategy compared with a 'fresh-transfer' strategy? SUMMARY ANSWER: The 'freeze-all' strategy resulted in a similar cumulative live birth rate as the 'fresh-transfer' strategy among high responders (>15 oocytes retrieved) but did not benefit normal (10-15 oocytes) and suboptimal responders (<10 oocytes). WHAT IS KNOWN ALREADY: Frozen-thawed embryo transfer is associated with a decreased risk of adverse obstetric and perinatal outcomes compared with fresh embryo transfer. It is unclear whether the 'freeze-all' strategy should be offered to all women undergoing ART treatment. STUDY DESIGN SIZE DURATION: A population-based retrospective cohort study using data collected by the Victorian Assisted Reproductive Treatment Authority. This study included 14 331 women undergoing their first stimulated ART cycle with at least one oocyte fertilised between 1 July 2009 and 30 June 2014 in Victoria, Australia. Demographic characteristics, type of ART procedures and resulting pregnancy and birth outcomes were recorded for the stimulated cycle and associated thaw cycles until 30 June 2016, or until a live birth was achieved, or until all embryos from the stimulated cycle had been used. PARTICIPANTS/MATERIALS SETTING METHODS: Women were grouped by whether they had undergone the 'freeze-all' strategy (n = 1028) where all embryos were cryopreserved for future transfer, or the 'fresh-transfer' strategy (n = 13 303) where selected embryo(s) were transferred in the stimulated cycle, and remaining embryo(s) were cryopreserved for future use. A discrete-time survival model was used to evaluate the cumulative live birth rate following 'freeze-all' and 'fresh-transfer' strategy. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1028 women undergoing 'freeze-all' strategy and 13 303 women undergoing 'fresh-transfer' strategy had 1788 and 22 334 embryo transfer cycles resulting in 452 and 5126 live births, respectively. Most women (61.3%) in the 'freeze-all' group had more than 15 oocytes retrieved in the stimulated cycle compared with 18.1% of women in the 'fresh-transfer' group (P < 0.001). For high responders (>15 oocytes), the cumulative live birth rate in the 'freeze-all' group was similar to the 'fresh-transfer' group (56.8% vs. 56.2%, adjusted hazard ratio (AHR) 0.90, 95% CI 0.77-1.04). However, the likelihood of a live birth was lower in the 'freeze-all' group compared with the 'fresh-transfer' group among normal responders (10-15 oocytes) (33.2% vs. 46.3%, AHR 0.62, 95% CI 0.46-0.83) and suboptimal responders (<10 oocytes) (14.6% vs. 28.0%, AHR 0.67, 95% CI 0.14-1.01). During the minimum follow-up time of 2 years, 34.1%, 24.4% and 8.4% of suboptimal, normal and high responders, respectively, in the 'freeze-all' group did not return for any embryo transfer after the stimulated cycle, whereas all women in the 'fresh-transfer' group had at least one embryo transferred in the stimulated cycle. LIMITATIONS REASONS FOR CAUTION: A limitation of this population-based study is the lack of information available on clinic-specific protocols for the 'freeze-all' strategy and the potential impact of these on outcomes. Data were not available on whether the 'freeze-all' strategy was used to prevent ovarian hyperstimulation syndrome (OHSS). WIDER IMPLICATIONS OF THE FINDINGS: This study presents population-based evidence on clinical efficacy associated with a 'freeze-all' and 'fresh-transfer' strategy. The 'freeze-all' strategy may benefit some subgroups of patients, including women who are high responders and those who are at risk of OHSS, but should not be offered universally. Clinicians should consider the potential impact of electively deferring embryo transfer on treatment discontinuation in choosing the optimal embryo transfer strategy for couples undergoing ART treatment. STUDY FUNDING/COMPETING INTERESTS: No specific funding was received to undertake this study. There is no conflict of interest, except that M.B. is a shareholder in Genea Ltd.

ICSI does not increase the cumulative live birth rate in non-male factor infertility.

STUDY QUESTION: What is the cumulative live birth rate following ICSI cycles compared with IVF cycles for couples with non-male factor infertility? SUMMARY ANSWER: ICSI resulted in a similar cumulative live birth rate compared with IVF for couples with non-male factor infertility. WHAT IS KNOWN ALREADY: The ICSI procedure was developed for couples with male factor infertility. There has been an increased use of ICSI regardless of the cause of infertility. Cycle-based statistics show that there is no difference in pregnancy rates between ICSI and IVF in couples with non-male factor infertility. However, evidence indicates that ICSI is associated with an increased risk of adverse perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A population-based cohort of 14 693 women, who had their first ever stimulated cycle with fertilization performed for at least one oocyte by either IVF or ICSI between July 2009 and June 2014 in Victoria, Australia was evaluated retrospectively. The pregnancy and birth outcomes following IVF or ICSI were recorded for the first oocyte retrieval (fresh stimulated cycle and associated thaw cycles) until 30 June 2016, or until a live birth was achieved, or until all embryos from the first oocyte retrieval had been used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Demographic, treatment characteristics and resulting outcome data were obtained from the Victorian Assisted Reproductive Treatment Authority. Data items in the VARTA dataset were collected from all fertility clinics in Victoria. Women were grouped by whether they had undergone IVF or ICSI. The primary outcome was the cumulative live birth rate, which was defined as live deliveries (at least one live birth) per woman after the first oocyte retrieval. A discrete-time survival model was used to evaluate the cumulative live birth rate following IVF and ICSI. The adjustment was made for year of treatment in which fertilization occurred, the woman's and male partner's age at first stimulated cycle, parity and the number of oocytes retrieved in the first stimulated cycle. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 4993 women undergoing IVF and 8470 women undergoing ICSI had 7980 and 13 092 embryo transfers, resulting in 1848 and 3046 live deliveries, respectively. About one-fifth of the women (19.0% of the IVF group versus 17.9% of the ICSI group) had three or more cycles during the study period. For couples who achieved a live delivery, the median time from oocyte retrieval to live delivery was 8.9 months in both IVF (range: 4.2-66.5) and ICSI group (range: 4.5-71.3) (P = 0.474). Fertilization rate per oocyte retrieval was higher in the IVF than in the ICSI group (59.8 versus 56.2%, P < 0.001). The overall cumulative live birth rate was 37.0% for IVF and 36.0% for ICSI. The overall likelihood of a live birth for women undergoing ICSI was not significantly different to that for women undergoing IVF (adjusted hazard ratio (AHR): 0.99, 95% CI: 0.92-1.06). For couples with a known cause of infertility, non-male factor infertility (female factor only or unexplained infertility) was reported for 64.0% in the IVF group and 36.8% in the ICSI group (P < 0.001). Among couples with non-male factor infertility, ICSI resulted in a similar cumulative live birth rate compared with IVF (AHR: 0.96, 95% CI: 0.85-1.10). LIMITATIONS, REASONS FOR CAUTION: Data were not available on clinic-specific protocols and processes for IVF and ICSI and the potential impact of these technique aspects on clinical outcomes. The reported causes of infertility were based on the treating clinician's classification which may vary between clinicians. WIDER IMPLICATIONS OF THE FINDINGS: This population-based study found ICSI resulted in a lower fertilization rate per oocyte retrieved and a similar cumulative live birth rate compared to conventional IVF. These data suggest that ICSI offers no advantage over conventional IVF in terms of live birth rate for couples with non-male factor infertility. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was received to undertake this study. There is no conflict of interest, except that M.B. is a shareholder in Genea Ltd. TRIAL REGISTRATION NUMBER: N/A.

Controversies in the diagnosis of Type 1 von Willebrand disease.

von Willebrand disease (VWD) is the most common bleeding disorder. Type 1 VWD represents the majority of cases and results from a partial quantitative deficiency of von Willebrand factor (VWF). The diagnosis of Type 1 VWD presents many challenges, despite there being three established diagnostic criteria: a personal history of mucocutaneous bleeding, a family history and low VWF levels. These criteria do not always coexist, and there is great overlap of clinical phenotypes and laboratory parameters between healthy individuals and those with VWD. Mild bleeding symptoms can have any number of causes and bleeding is commonly reported in the general population. VWF levels do not always correlate with bleeding symptoms and can be variable between affected family members. Additionally, VWF levels vary widely as a result of both genetic and non-genetic influences. Perhaps the greatest current controversy in the diagnosis of Type 1 VWD is that there is no consensus laboratory cut-off for the diagnosis, raising concern about both over- and under-diagnosis. Ongoing studies are addressing these issues by clarifying the underlying pathogenesis of the disease, as well as the natural history and the risk of future bleeding in those with the diagnosis.

Discrepant platelet and plasma von Willebrand factor in von Willebrand disease patients with p.Pro2808Leufs*24.

Essentials von Willebrand factor (VWF) is synthesized in endothelial cells and platelet precursors. Type 3 patients with Pro2808Leufs*24 have lower bleeding scores than other type 3s. The Pro2808Leufs*24 variant was examined in patient platelets and endothelial cells. Type 3s with this variant contain releaseable VWF, possibly reducing bleeding. SUMMARY: Background A novel variant, p.Pro2808Leufs*24, in the von Willebrand factor (VWF) gene was previously identified in the Canadian von Willebrand disease (VWD) patient population. Clinical observations of type 3 VWD patients with this variant indicate a milder bleeding phenotype compared with other type 3 patients. Objective To assess the effect of the Pro2808Leufs*24 variant on the molecular pathogenesis of VWD and correlate this with the phenotype observed in patients. Patients/Methods Phenotypic data from individuals in the Canadian type 3 VWD study were analyzed. VWF expression in platelets and plasma was assessed via immunoblotting. Cellular expression of VWF in platelets and blood outgrowth endothelial cells (BOEC) was examined via immunofluorescence microscopy and biochemical analysis in a type 3 index case and family member with Pro2808Leufs*24. Results Twenty-six individuals with the Pro2808Leufs*24 variant (16 type 3 VWD homozygous or compound heterozygous and 10 heterozygous family members) were studied. Bleeding scores were lower in type 3 patients with Pro2808Leufs*24 compared with type 3 patients with other variants, confirming a milder bleeding phenotype. Immunoblotting of platelet lysates detected VWF in the platelets of type 3 patients with Pro2808Leufs*24. Examination of an index case detected VWF within platelets via immunofluorescence microscopy, and in vitro experiments showed that this VWF was released upon platelet activation. Patient BOECs showed decreased VWF synthesis and secretion, although some VWF-containing granules were observed. Conclusion Type 3 VWD patients with the Pro2808Leufs*24 have bioavailable platelet-derived VWF that may produce a milder bleeding phenotype than other type 3s.

Australia-wide assessment of perfluoroalkyl substances (PFASs) in landfill leachates.

Leachate from 27 landfills was analysed for nine perfluoroalkyl substances (PFASs). Five PFASs were detected ubiquitously, with perfluorohexanoate (PFHxA) the predominant PFAS (mean 1700ng/L; range 73-25,000ng/L). Despite the complexity of landfill-specific factors, some general trends in PFAS concentrations were observed. Mean concentrations of eight PFASs were higher in operating landfills (or landfill cells) accepting primarily municipal waste, compared to closed municipal landfills. Landfills accepting primarily construction and demolition wastes produced leachate that had higher mean PFAS concentrations than municipal landfills. Younger landfills appeared to have a higher burden of waste containing PFASs (or their precursors), as significant relationships (p<0.05) were observed between selected PFAS concentrations and landfill age. Increasing pH and total organic carbon (TOC) in leachate were associated with increased concentrations of several PFASs. Eight landfills discharged leachate to wastewater treatment plants (WWTPs). Estimated masses of PFASs discharged reached a maximum of 62g annually (PFHxA), with a national estimate reaching 31kg (PFHxA) annually. The practise of treating leachate at WWTPs allows redistribution of PFASs between the solid and liquid waste streams, although the contribution of leachate to the total load of PFASs entering WWTPs is minor compared to domestic waste water sources.

The transition to self-regulated learning for first-year dental students: threshold concepts.

Research shows that when students arrive at university they are often not prepared for independent learning. New students enter a period of transition during their first year, which is often characterised by emotional destabilisation, as they move towards becoming more self-regulating in their new learning environment. In this small-scale qualitative study, data from an in-depth pair interview were triangulated with data from a questionnaire, to explore participants' experiences of self-regulated learning in the first year of a Dental Surgery course. Five threshold concepts relating to learning in transition emerged from the analysis of the data. These concepts were as follows: learning how to learn using a range of self-chosen sources instead of a single textbook, learning how to organise incoming information without guidance, distinguishing between main ideas and detail during revision, coping with a heavy workload, and knowing what to expect from examinations and coursework. Strong emotions (feeling confused, overwhelmed and scared) were associated with negotiating these threshold concepts. However, the study illustrates how the participants adopted new cognitive and metacognitive strategies to become more self-regulating over time. The findings of the study suggest that lecturers, tutors, study advisers and peers all have an important role to play in explicitly guiding first-year students as they grapple with troublesome threshold concepts relating to self-regulated learning. Furthermore, structural changes to the content-heavy, lecture-based curricula often associated with first-year Medical and Dental courses would help ease students' transition to independent learning, which may make an impact on student attainment.

Can we improve on situational judgement tests?

Situational judgement tests (SJTs) are multiple-choice psychological assessments that claim to measure professional attributes such as empathy, integrity, team involvement and resilience. One of their attractions is the ability to rank large numbers of candidates. Last year SJTs formed a major component (50% of the assessment marks) of the selection process for dental foundation training (DFT). However, it is not clear what SJTs are actually assessing. There is also the concern that applicants who have developed ethical reasoning skills may be disadvantaged by such tests. The DFT selection process needs to explicitly recognise the importance of ethical reasoning.

Electron spin echo envelope modulation of molecular motions of deuterium nuclei.

Electron Spin Echo Envelope Modulation (ESEEM) spectroscopy is a powerful technique for the study of hyperfine interactions between an unpaired electron and nearby nuclei in solids, and is employed in quantitative structural studies. Here, we describe the use of ESEEM to study the slow motion of deuterium nuclei using their nuclear quadrupole resonance (NQR) line shapes. Two ESEEM techniques were employed: the conventional three-pulse ESEEM experiment, π/2 - τ - π/2 - T- π/2 - τ - echo, and the four-pulse ESEEM, π/2 - τ - π/2 - T/2 - π - T/2 - π/2 - τ - echo, with the time variable T scanned in both cases. The nitroxide free radical 4-tert-butyliminomethyl-2,2,5,5-tetramethyl(d12)-3-imidazoline-1-oxyl with four deuterated methyl groups was investigated in a glassy ortho-terphenyl matrix over a wide temperature range. It was shown that four-pulse ESEEM allowed measurement of the nearly pure (2)H NQR line shape. Between 90K and 120K, the ESEEM spectra change drastically. At low temperatures, four-pulse ESEEM spectra show a Pake-like pattern, which evolves into a single line at higher temperatures, which is typical for NQR of rotating methyl CD3 groups. Comparison with literature data on NQR allows estimation of the reorientation rate, k. At ∼100K, where the spectral changes are most pronounced, k was found to be ∼10(5)s(-1). The spectral linewidths for the three-pulse ESEEM were found to decrease similarly with increasing temperature; so the three-pulse technique is also capable to detect motion of this type. The ESEEM approach, along with site-directed spin labeling, may be useful for detection of motional transitions near the spin labels in biological systems, when information on motion is required in a wide temperature range.

Effects of a silica-based feed supplement on performance, health, and litter quality of growing turkeys.

Poor litter quality is a potential challenge to footpad health as well as the primary cause of ammonia volatilization. High ambient ammonia concentration is one of the most significant factors negatively affecting poultry production today. Some minerals have been reported to reduce ammonia release from poultry litter. Silicon dioxide, a highly pure and natural mineral, shows promise in decreasing ammonia volatilization and improving litter quality. The objective of the current study was to investigate the effects of feed-borne silicon dioxide on litter quality and how this impacts bird performance, general health and footpad health throughout a 12-wk posthatching turkey study. Supplementing the diet with silicon dioxide was found to significantly improve turkey BW gain and the efficiency of feed conversion. The severity of footpad dermatitis was monitored throughout the experimental period but no significant effect of diet was seen. The feeding of silicon dioxide reduced litter pH which decreased the conversion of NH4⁺ to NH3 thereby reducing nitrogen losses from litter. It was concluded that, under our study conditions, the feeding of 0.02% silicon dioxide offers potential economic benefits to turkey producers.

Generic Pharmaceutical Association (GPhA) - 2015 Annual Meeting (February 9-11, 2015 - Miami Beach, Florida, USA).

The Generic Pharmaceutical Association (GPhA) chairman Craig Wheeler (Momenta Pharmaceuticals), welcomed attendees to the 2015 Annual Meeting by reflecting on the contributions of the generic industry over the past year and some of the challenges that lie ahead. In 2014, 86% of prescriptions dispensed in the U.S. were generic, contributing to the USD 1.4 trillion savings generated by the industry since its inception; however, there are still many challenges to face, including consolidation of customers, lag in Abbreviated New Drug Application (ANDA) approval timelines, restrictive Risk Evaluation and Mitigation Strategy (REMS) programs and labeling legislations. The continued drive into the branded business by many GPhA member companies has resulted in the association planning a structural division for companies involved in biologic and biosimilar products. During the 3-day meeting, attendees listened to expert panels discuss major business, regulatory and market trends developing in the generic industry, with insights from the U.S. Food and Drug Administration (FDA) and market analysts. The meeting also provided attendees with numerous opportunities to socialize and network with key decision makers in the industry.

Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project.

Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0-3 for adult males, 0-5 for adult females and 0-2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.