Craniometric Analysis of the Hindbrain and Craniocervical Junction of Chihuahua, Affenpinscher and Cavalier King Charles Spaniel Dogs With and Without Syringomyelia Secondary to Chiari-Like Malformation

Objectives To characterize and compare the phenotypic variables of the hindbrain and craniocervical junction associated with syringomyelia (SM) in the Chihuahua, Affenpinscher and Cavalier King Charles Spaniel (CKCS). Method Analysis of 273 T1-weighted mid-sagittal DICOM sequences of the hindbrain and craniocer-vical junction from 99 Chihuahuas, 42 Affenpinschers and 132 CKCSs. The study compared 22 morphometric features (11 lines, eight angles and three ratios) of dogs with and without SM using refined techniques based on previous studies of the Griffon Bruxellois (GB) using Discriminant Function Analysis and ANOVA with post-hoc corrections. Results The analysis identified 14/22 significant traits for SM in the three dog breeds, five of which were identical to those reported for the GB and suggest inclusion of a common aetiology. One ratio, caudal fossa height to the length of the skull base extended to an imaginary point of alignment between the atlas and supraoccipital bones, was common to all three breeds (p values 0.029 to <0.001). Associated with SM were a reduced occipital crest and two acute changes in angulation i) 'sphenoid flexure' at the spheno-occipital synchondrosis ii) 'cervical flexure' at the foramen magnum allied with medulla oblongata elevation. Comparing dogs with and without SM, each breed had a unique trait: Chihuahua had a smaller angle between the dens, atlas and basioccipital bone (p value <0.001); Affenpinschers had a smaller dis-tance from atlas to dens (p value 0.009); CKCS had a shorter distance between the spheno-occipital synchondrosis and atlas (p value 0.007). Conclusion The selected morphometries successfully characterised conformational changes in the brain and craniocervical junction that might form the basis of a diagnostic tool for all breeds. The severity of SM involved a spectrum of abnormalities, incurred by changes in both angulation and size that could alter neural parenchyma compliance and/or impede cerebrospinal fluid channels.Peer reviewe

Pharmacokinetics, Safety, and Antiviral Effects of Multiple Doses of the Respiratory Syncytial Virus (RSV) Fusion Protein Inhibitor, JNJ-53718678, in Infants Hospitalized With RSV Infection: A Randomized Phase 1b Study

BACKGROUND: This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to /=6 to /=3 to 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction. RESULTS: Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng x hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL. CONCLUSIONS: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed. CLINICAL TRIALS REGISTRATION: NCT02593851

The effectiveness and satisfaction of web-based physiotherapy in people with spinal cord injury: a pilot randomised controlled trial

Study Design: Pilot randomised controlled trial. Objectives: The aims of this study were to evaluate the effectiveness and participant satisfaction of web-based physiotherapy for people with Spinal Cord Injury (SCI). Setting: Community patients of a national spinal injury unit in a university teaching hospital, Scotland, UK. Methods: Twenty-four participants were recruited and randomised to receive eight weeks of web-based physiotherapy (intervention), twice per week, or usual care (control). Individual exercise programmes were prescribed based upon participant’s abilities. The intervention was delivered via a website (www.webbasedphysio.com) and monitored and progressed remotely by the physiotherapist. Results: Participants logged on to the website an average of 1.4±0.8 times per week. Between-group differences, although not significant were more pronounced for the 6 minute walk test. Participants were positive about using web-based physiotherapy and stated they would be happy to use it again and would recommend it to others. Overall it was rated as either good or excellent. Conclusions: Web-based physiotherapy was feasible and acceptable for people with SCI. Participants achieved good compliance with the intervention, rated the programme highly and beneficial for health and well-being at various states post injury. The results of this study warrant further work with a more homogenous sample

Cytochrome P450 CYP1B1 activity in renal cell carcinoma

Renal cell carcinoma (RCC) is the most common malignancy of the kidney and has a poor prognosis due to its late presentation and resistance to current anticancer drugs. One mechanism of drug resistance, which is potentially amenable to therapeutic intervention, is based on studies in our laboratory. CYP1B1 is a cytochrome P450 enzyme overexpressed in a variety of malignant tumours. Our studies are now elucidating a functional role for CYP1B1 in drug resistance. Cytochrome P450 reductase (P450R) is required for optimal metabolic activity of CYP1B1. Both CYP1B1 and P450R can catalyse the biotransformation of anticancer drugs at the site of the tumour. In this investigation, we determined the expression of CYP1B1 and P450R in samples of normal kidney and RCC (11 paired normal and tumour and a further 15 tumour samples). The O-deethylation of ethoxyresorufin to resorufin was used to measure CYP1B1 activity in RCC. Cytochrome P450 reductase activity was determined by following the reduction of cytochrome c at 550 nm. The key finding of this study was the presence of active CYP1B1 in 70% of RCC. Coincubation with the CYP1B1 inhibitor alpha-naphthoflavone (10nM) inhibited this activity. No corresponding CYP1B1 activity was detected in any of the normal tissue examined (n = 11). Measurable levels of active P450R were determined in all normal (n = 11) and tumour samples (n = 26). The presence of detectable CYP1B1, which is capable of metabolising anticancer drugs in tumour cells, highlights a novel target for therapeutic intervention

Howard walnut trees can be brought into bearing without annual pruning

In traditionally managed Howard walnut orchards, trees are pruned annually during the orchard development phase, an expensive operation in terms of labor and prunings disposal costs. Our observations and some prior research by others had suggested that pruning may not be necessary in walnut. In a trial of pruned and unpruned hedgerow trees over 8 years, beginning a year after planting, we documented canopy growth, tree height, yield and nut quality characteristics and also the effects of fruit removal. Pruning altered canopy shape but did not lead to increases in canopy development, yield or nut quality. Although fruit removal stimulated more vegetative growth in both the pruned and unpruned treatments, fruit removal did not result in an increase in midday canopy photosynthetically active radiation interception or cumulative yield when fruit removal was stopped after year 4. After 8 years, there were no significant differences in tree height, nut quality or cumulative yield among any of the treatments, which suggests that not pruning young Howard orchards could provide a net benefit to growers

Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

A four-year, systems-wide intervention promoting interprofessional collaboration

Background: A four-year action research study was conducted across the Australian Capital Territory health system to strengthen interprofessional collaboration (IPC) through multiple intervention activities. Methods: We developed 272 substantial IPC intervention activities involving 2,407 face-to-face encounters with health system personnel. Staff attitudes toward IPC were surveyed yearly using Heinemann et al’s Attitudes toward Health Care Teams and Parsell and Bligh’s Readiness for Interprofessional Learning scales (RIPLS). At study’s end staff assessed whether project goals were achieved. Results: Of the improvement projects, 76 exhibited progress, and 57 made considerable gains in IPC. Educational workshops and feedback sessions were well received and stimulated interprofessional activities. Over time staff scores on Heinemann’s Quality of Interprofessional Care subscale did not change significantly and scores on the Doctor Centrality subscale increased, contrary to predictions. Scores on the RIPLS subscales of Teamwork & Collaboration and Professional Identity did not alter. On average for the assessment items 33% of staff agreed that goals had been achieved, 10% disagreed, and 57% checked ‘neutral’. There was most agreement that the study had resulted in increased sharing of knowledge between professions and improved quality of patient care, and least agreement that between-professional rivalries had lessened and communication and trust between professions improved. Conclusions: Our longitudinal interventional study of IPC involving multiple activities supporting increased IPC achieved many project-specific goals, but improvements in attitudes over time were not demonstrated and neutral assessments predominated, highlighting the difficulties faced by studies targeting change at the systems level and over extended periods

CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance

The cytochrome P450 CYP1B1 is consistently overexpressed in tumour cells as compared to their normal counterparts, but its precise role in drug resistance is yet to be defined. It has been reported that transfection of CYP1B1 results in increased resistance to docetaxel in V79 cells (McFadyen et al, 2001). In this study, we analysed changes in expression of CYP1B1 mRNA associated with pulse selection of MCF-7 cells with docetaxel. Docetaxel-selected MCF-7 cells (MCF-7 Txt), which showed increased resistance to this drug as compared to parental MCF-7 cells, showed a noteworthy increase in CYP1B1 mRNA expression, paralleled by increased ethoxyresorufin-O-deethylase (EROD) activity levels. This effect was not observed in cisplatin- or adriamycin-selected MCF-7 cells, or in docetaxel-selected colon, lung or pancreatic carcinoma cells. Short-term treatment with docetaxel induced CYP1B1 mRNA expression in MDA 453 and BT-20 breast carcinoma cells, but not in MCF-7 cells. Transfection of MCF-7 Txt cells with CYP1B1 siRNA did not significantly affect docetaxel-induced toxicity, but it decreased cell survival in the absence of drug. Preincubation of docetaxel with recombinant CYP1B1 did not affect drug toxicity in A549 cells. These results suggest that CYP1B1 does not directly inactivate docetaxel, but rather might promote cell survival in MCF-7 Txt cells, providing an explanation for its association with drug resistance

Synthesis, structural studies and photochemistry of cobalt(III) complexes of anthracenylcyclam macrocycles

This work reports the syntheses, structures and some photochemistry in DMF of the cobalt complexes trans-[CoIII( 2)Cl2]Cl·0.5CH3OH and trans-[CoIII( 3)Cl2]Cl·4H2O, where 2 is 6-(anthracen-9-ylmethyl)-1,4,8,11-tetraazacyclotetradecane-5,7-dione and 3 is 6-(anthracen-9-ylmethyl)-1,4,8,11-tetraazacyclotetradecane. In the preparation of the macrocyclic ligand, 3, the formation of a polycyclic bis(aminal) intermediate and its subsequent acid hydrolysis to 3 is a cleaner route than the traditional procedure in which the analogous dioxocyclam 2 is reduced with borane reagents. The crystal structure of trans-[CoIII( 3)Cl2]Cl·4H2O shows that the macrocycle adopts the trans-III conformation, in which the anthracene moiety is extended away from the cobalt ion and the anthracene to Co separation is 7.22 . For the related complex trans-[CoIII( 2)Cl2]Cl·0.5CH3OH, however, the anthracene is bent over the highly conjugated tetracycle and significant interactions between the anthracene and the complex occur. A novel new complex, trans-[Co( 12)Cl2](where 12 is 5,7-hydroxy-6-oxo-1,4,8,11-tetraazacyclotetradecane-4,7-diene) which is a degradation product of the complex trans-[CoIII( 2)Cl2]Cl is also reported