Insecticide synergists biochemically inhibit insect metabolic enzyme activity and are used both to increase the effectiveness of insecticides and as a diagnostic tool for resistance mechanisms. Considerable attention has been focused on identifying new synergists from phytochemicals with recognized biological activities, specifically enzyme inhibition. Jack pine (Pinus banksiana Lamb.), black spruce (Picea mariana (Mill.) BSP.), balsam fir (Abies balsamea (L.) Mill.), and tamarack larch (Larix laricina (Du Roi) Koch) have been used by native Canadians as traditional medicine, specifically for the anti-inflammatory and antioxidant properties based on enzyme inhibitory activity. To identify the potential allelochemicals with synergistic activity, ethanol crude extracts and methanol/water fractions were separated by Sephadex LH-20 chromatographic column and tested for in vitro glutathione S-transferase (GST) inhibition activity using insecticide-resistant Colorado potato beetle, Leptinotarsa decemlineata (Say) midgut and fat-body homogenate. The fractions showing similar activity were combined and analyzed by ultra pressure liquid chromatography-mass spectrometry. A lignan, (+)-lariciresinol 9'-p-coumarate, was identified from P. mariana cone extracts, and L. laricina and A. balsamea bark extracts. A flavonoid, taxifolin, was identified from P. mariana and P. banksiana cone extracts and L. laricina bark extracts. Both compounds inhibit GST activity with taxifolin showing greater activity compared to (+)-lariciresinol 9'-p-coumarate and the standard GST inhibitor, diethyl maleate. The results suggested that these compounds can be considered as potential new insecticide synergists.
Counting the number of tender and swollen joints is an important aspect of assessing patients with an inflammatory arthritis. We provide a comprehensive overview of joint counts in inflammatory arthritis. This spans how they are undertaken, their use in clinical and research settings, their limitations and standardisation and who can perform them.
Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in 'The Cancer Genome Atlas' (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 (p=0.031) and low PTEN (p=0.042) remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas.
Early intensive treatment is now the cornerstone for the management of rheumatoid arthritis (RA). In the era of personalized medicine, when treatment is becoming more individualized, it is unclear from the current literature whether all patients with RA benefit equally from such intensive therapies. We investigated the benefit of different treatment regimens on remission rates when stratified to clinical and serological factors.
Objective To implement and evaluate strategies for improving access to emergency department (ED) care in a tertiary hospital. Methods A retrospective pre-post intervention study using routinely collected data involving all patients presenting acutely to the ED of a major tertiary hospital over a 2-year period. Main outcome measures were changes in: the percentage of patients exiting the ED (all patients, patients discharged directly from the ED, patients admitted to inpatient wards); mean patient transit times in the ED; inpatient mortality rates; rates of ED 'did not wait' and re-presentations within 48h of ED discharge; and selected safety indicators. Qualitative data on staff perceptions of interventions were also gathered. Results Working groups focused on ED internal processes, ED-inpatient unit interface, hospital-wide discharge processes and performance monitoring and feedback. Twenty-five different reforms were enacted over a 9-month period from April to December 2012. Comparing the baseline period (January-March 2012) with the post-reform period (January-March 2013), the percentage of patients exiting the ED within 4h rose for all patients presenting to the ED (from 32% to 62%), for patients discharged directly from the ED (from 41% to 75%) and for admitted patients (from 12% to 32%; P<0.001 for all comparisons). The mean (±s.d.) time all patients spent in the ED was reduced from 7.2±5.8 to 4.4±3.5h (P<0.001) and, for admitted patients, was associated with reduced in-hospital mortality (from 2.3% to 1.7%; P=0.045). The 'did not wait' rates in ED fell from 6.9% to 1.9% (P<0.001), whereas ED re-presentations within 48h among patients discharged from the ED rose slightly (from 3.1% to 3.8%; P=0.023). Improvements in outcome measures were maintained over the subsequent 12 months. Conclusions Multiple reforms targeting processes both within the ED and its interface with inpatient units greatly improved access to ED care over 12 months and were associated with decreased in-hospital mortality. What is known about this topic? Prolonged stays in the ED result in overcrowding, delayed ambulance access to ED care and increased adverse outcomes for admitted patients. The introduction in Australia of National Emergency Access Targets (NEAT), which stipulate at least 70% of patients in the ED must exit the department within 4h, have spurred hospitals into implementing a wide range of reforms with varying levels of success in achieving such targets. What does this paper add? This study demonstrates how multiple reforms implemented in a poor performing tertiary hospital caused the proportion of patients exiting the ED within 4h to double within 9 months to reach levels comparable with best performing peer hospitals. This was associated with a 26% reduction in in-hospital mortality for admitted patients and no clinically significant adverse effects. It demonstrates the importance of robust governance structures, executive sponsorship, cross-disciplinary collaboration, regular feedback of NEAT performance data and major redesign of existing clinical processes, work practices and bed management operations. What are the implications for clinicians and managers? Improving access to emergency care should be regarded as a problem located and resolved both within and without the ED. It requires a whole-of-hospital solution involving interdisciplinary collaboration and significant change in culture and practice relating to inpatient units and their interface with the ED.
The aim of this study was to estimate the cost-effectiveness of combination DMARDs with short-term glucocorticoids in early active RA using data from the 2-year Combination of Anti-Rheumatic Drugs in Early RA (CARDERA) trial.
Agricultural crop residues can be converted through thermochemical pyrolysis to bio-oil, a sustainable source of biofuel and biochemicals. The pyrolysis bio-oil is known to contain many chemicals, some of which have insecticidal activity and can be a potential source of value-added pest control products. Brassicacae crops, cabbage, broccoli, and mustards, contain glucosinolates and isocyanates, compounds with recognized anti-herbivore activity. In Canada, canola Brassica napus straw is available from over 6?000?000 ha and mustard Brassica carinata and Brassica juncea straw is available from 200?000 ha. The straw can be converted by microbial lignocellulosic enzymes as a substrate for bioethanol production but can also be converted to bio-oil by thermochemical means. Straw from all three species was pyrolyzed, and the insecticidal components in the bio-oil were isolated by bioassay-guided solvent fractionation. Of particular interest were the mustard straw bio-oil aqueous fractions with insecticidal and feeding repellent activity to Colorado potato beetle larvae. Aqueous fractions further analyzed for active compounds were found not to contain many of the undesirable phenol compounds, which were previously found in other bio-oils seen in the dichloromethane (DCM) and ethyl acetate (EA) solvent phases of the present study. Identified within the most polar fractions were hexadecanoic and octadecanoic fatty acids, indicating that separation of these compounds during bio-oil production may provide a source of effective insecticidal compounds.
To articulate the concept of high-value care (i.e. clinically relevant, patient-important benefit at lowest possible cost) and suggest strategies by which clinicians can promote such care in rendering the Australian healthcare system more affordable and sustainable.
Codling moth is a major pest of pome fruit worldwide. Insecticide resistance has become a widespread pest management issue. However, the current status of insecticide resistance in Ontario and Quebec codling moth populations is unknown.
The assessment of health-related quality-of-life (HRQoL) in rheumatoid arthritis (RA) is becoming increasingly common in both research and clinical practice. One of the most widely used tools for measuring HRQoL is the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). We conducted a systematic review examining the impact of RA on HRQoL, measured through the SF-36.
The development of small-molecule inhibitors of inflammatory cascade signaling kinases offers a potential approach to treating rheumatoid arthritis (RA). Spleen tyrosine kinase is one such tyrosine kinase. Recent research efforts have focussed on the development and testing of a spleen tyrosine kinase inhibitor, fostamatinib. We reviewed the results of the clinical trials of fostamatinib in RA with the aim of outlining its clinical efficacy and the nature and frequency of its main adverse events. To date, this drug has been evaluated in over 3,200 RA patients enrolled in three phase II, one phase IIb and three phase III trials. These studies showed fostamatinib was effective. In four trials in which patients received 100 mg twice daily, fostamatinib reduced inflammatory synovitis; the relative risks of achieving American College of Rheumatology Responder rates compared with placebo in the combined studies ranged from 1.6 for 20 % of responders to 3.7 for 70 % of responders. There was a similar relative risk of achieving a clinically meaningful reduction in disability of 1.6 for the chance of patients achieving a reduction in health assessment questionnaire scores of 0.22 or more. Three of the trials examined the impact of fostamatinib on erosive radiographic damage using changes in the modified total Sharp score. None of them provided any evidence for a significant effect of fostamatinib on erosive damage over 6 months. All the trials included descriptions of adverse events. Hypertension was common, involving over 40 % of patients treated. Other common adverse events included diarrhoea, neutropenia and increases in hepatic enzyme levels. Some patients developed infections. On the conclusion of the phase III trials, one of the main pharmaceutical sponsors decided not to further develop fostamatinib for RA.
The correct segmentation of myofibres in histological muscle biopsy images is a critical step in the automatic analysis process. Errors occurring as a result of incorrect segmentations have a compounding effect on latter morphometric analysis and as such it is vital that the fibres are correctly segmented. This paper presents a new automatic approach to myofibre segmentation in H&E stained adult skeletal muscle images that is based on Coherence-Enhancing Diffusion filtering.
Hypnosedatives are commonly prescribed for anxiety and sleep problems. Changes in pharmacokinetics and pharmacodynamics of benzodiazepines (BZDs) during ageing may increase their potential to cause adverse outcomes.
Inappropriate polypharmacy in older patients imposes a significant burden of decreased physical functioning, increased risk of falls, delirium and other geriatric syndromes, hospital admissions and death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed medications. Deprescribing is the process of tapering or stopping drugs, with the goal of minimising polypharmacy and improving outcomes. Barriers to deprescribing include underappreciation of the scale of polypharmacy-related harm by both patients and prescribers; multiple incentives to overprescribe; a narrow focus on lists of potentially inappropriate medications; reluctance of prescribers and patients to discontinue medication for fear of unfavourable sequelae; and uncertainty about effectiveness of strategies to reduce polypharmacy. Ways of countering such barriers comprise reframing the issue to one of highest quality patient-centred care; openly discussing benefit-harm trade-offs with patients and assessing their willingness to consider deprescribing; targeting patients according to highest risk of adverse drug events; targeting drugs more likely to be non-beneficial; accessing field-tested discontinuation regimens for specific drugs; fostering shared education and training in deprescribing among all members of the health care team; and undertaking deprescribing over an extended time frame under the supervision of a single generalist clinician.
the use of water immersion for labour and birth has been shown to be beneficial for women in normal labour (Cluett et al, 2009). It was decided to use problem solving coordinator workshops to change in the way waterbirth practice was promoted and organised on labour ward. Findings from the first Action Research phase (Russell, 2011) led to the development of a waterbirth questionnaire to measure midwives' personal knowledge of waterbirth practice, waterbirth self-efficacy, social support and frequency of hydrotherapy and waterbirth practice. The aim of this paper is to share the questionnaire findings from an on-going action research study.
A survey of insecticide resistance in over 150 Canadian populations of Colorado potato beetle was completed between 2008 and 2011. Three neonicotinoid and two anthranilic diamide insecticides were tested at a discriminating concentration (DC) with second-instar larvae in a leaf-disc bioassay.
Carbohydrate deficient transferrin (CDT) is the most specific serum biomarker of heavy alcohol consumption, defined as ??350-420 g alcohol/week. Despite introduction of a standardized reference measurement technique, widespread use of CDT remains limited due to low sensitivity. The aim of this study was to determine the factors that affect diagnostic sensitivity in patients with sustained heavy alcohol intake.
UK guidelines recommend that all early active rheumatoid arthritis (RA) patients are offered combination disease-modifying antirheumatic drugs (DMARDs) and short-term corticosteroids. Anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA may differ in their treatment responses. We used data from a randomized controlled trial - the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial - to examine whether responses to intensive combination treatments in early RA differ by ACPA status.
In chilling conditions (5°C), salicylic acid (SA)-deficient mutants (sid2, eds5 and NahG) of Arabidopsis thaliana produced more biomass than wild type (Col-0), whereas the SA overproducer cpr1 was extremely stunted. The hypothesis that these phenotypes were reflected in metabolism was explored using 600?MHz (1) H nuclear magnetic resonance (NMR) analysis of unfractionated polar shoot extracts. Biomass-related metabolic phenotypes were identified as multivariate data models of these NMR 'fingerprints'. These included principal components that correlated with biomass. Also, partial least squares-regression models were found to predict the relative size of plants in previously unseen experiments in different light intensities, or relative size of one genotype from the others. The dominant signal in these models was fumarate, which was high in SA-deficient mutants, intermediate in Col-0 and low in cpr1 at 5°C. Among signals negatively correlated with biomass, malate was prominent. Abundance of transcripts of the FUM2 cytosolic fumarase (At5g50950) showed strong positive correlation with fumarate levels and with biomass, whereas no significant differences were found for the FUM1 mitochondrial fumarase (At2g47510). It was confirmed that the morphological effects of SA under chilling find expression in the metabolome, with a role of fumarate highlighted.
The use of telepathology for clinical applications in Canada has steadily become more attractive over the last 10 years, driven largely by its potential to provide rapid pathology consulting services throughout the country regardless of the location of a particular institution. Based on this trend, the president of the Canadian Association of Pathologists asked a working group consisting of pathologists, technologists, and healthcare administrators from across Canada to oversee the development of guidelines to provide Canadian pathologists with basic information on how to implement and use this technology. The guidelines were systematically developed, based on available medical literature and the clinical experience of early adopters of telepathology in Canada. While there are many different modalities and applications of telepathology, this document focuses specifically on whole-slide imaging as applied to intraoperative pathology consultation (frozen section), primary diagnosis, expert or second opinions and quality assurance activities. Applications such as hematopathology, microbiology, tumour boards, education, research and technical and/or standard-related issues are not covered.
The improved characterisation of risk factors for rheumatoid arthritis (RA) suggests they could be combined to identify individuals at increased disease risks in whom preventive strategies may be evaluated. We aimed to develop an RA prediction model capable of generating clinically relevant predictive data and to determine if it better predicted younger onset RA (YORA). Our novel modelling approach combined odds ratios for 15 four-digit/10 two-digit HLA-DRB1 alleles, 31 single nucleotide polymorphisms (SNPs) and ever-smoking status in males to determine risk using computer simulation and confidence interval based risk categorisation. Only males were evaluated in our models incorporating smoking as ever-smoking is a significant risk factor for RA in men but not women. We developed multiple models to evaluate each risk factors impact on prediction. Each models ability to discriminate anti-citrullinated protein antibody (ACPA)-positive RA from controls was evaluated in two cohorts: Wellcome Trust Case Control Consortium (WTCCC: 1,516 cases; 1,647 controls); UK RA Genetics Group Consortium (UKRAGG: 2,623 cases; 1,500 controls). HLA and smoking provided strongest prediction with good discrimination evidenced by an HLA-smoking model area under the curve (AUC) value of 0.813 in both WTCCC and UKRAGG. SNPs provided minimal prediction (AUC 0.660 WTCCC/0.617 UKRAGG). Whilst high individual risks were identified, with some cases having estimated lifetime risks of 86%, only a minority overall had substantially increased odds for RA. High risks from the HLA model were associated with YORA (P<0.0001); ever-smoking associated with older onset disease. This latter finding suggests smokings impact on RA risk manifests later in life. Our modelling demonstrates that combining risk factors provides clinically informative RA prediction; additionally HLA and smoking status can be used to predict the risk of younger and older onset RA, respectively.
The study aims to (i) profile clinical characteristics, risk estimates of acute coronary syndrome (ACS), use and yield of non-invasive cardiac testing, discharge diagnosis and 30-day outcomes among patients admitted with acute chest pain of possible coronary origin; and (ii) construct a risk stratification algorithm that informs management decisions.
When rheumatoid arthritis (RA) patients have achieved sustained good clinical responses can their disease-modifying anti-rheumatic drugs (DMARDs) be reduced or discontinued? This review addresses this question by summarising the clinical evidence about DMARD withdrawal. It includes an assessment of predictive factors for sustained DMARD-free remissions.
Perioperative cardiac complications are a common cause of death and major morbidity in patients undergoing non-cardiac surgery. Preoperative evaluation and medical optimisation can improve outcomes, although the evidence base is limited. Evidence of effectiveness is strongest for prophylactic use of ?-blockers in high-risk patients and aspirin in patients with coronary artery disease. Particular challenges arise among patients with heart failure or valvular heart disease or those receiving antithrombotic therapy for coronary artery stents or atrial fibrillation. Close liaison between general practitioners, surgeons, anaesthetists and cardiologists is needed for optimising preoperative management and subsequent clinical outcomes in high-risk patients.
KLF3 is a Krüppel family zinc finger transcription factor with widespread tissue expression and no previously known role in heart development. In a screen for dominant mutations affecting cardiovascular function in N-ethyl-N-nitrosourea (ENU) mutagenized mice, we identified a missense mutation in the Klf3 gene that caused aortic valvular stenosis and partially penetrant perinatal lethality in heterozygotes. All homozygotes died as embryos. In the first of three zinc fingers, a point mutation changed a highly conserved histidine at amino acid 275 to arginine (Klf3(H275R) ). This change impaired binding of the mutant protein to KLF3s canonical DNA binding sequence. Heterozygous Klf3(H275R) mutants that died as neonates had marked biventricular cardiac hypertrophy with diminished cardiac chambers. Adult survivors exhibited hypotension, cardiac hypertrophy with enlarged cardiac chambers, and aortic valvular stenosis. A dominant negative effect on protein function was inferred by the similarity in phenotype between heterozygous Klf3(H275R) mutants and homozygous Klf3 null mice. However, the existence of divergent traits suggested the involvement of additional interactions. We conclude that KLF3 plays diverse and important roles in cardiovascular development and function in mice, and that amino acid 275 is critical for normal KLF3 protein function. Future exploration of the KLF3 pathway provides a new avenue for investigating causative factors contributing to cardiovascular disorders in humans.
Chronic heart failure (CHF) is an increasingly prevalent problem within ageing populations and accounts for thousands of hospitalisations and deaths annually in Australia. Disease management programs for CHF (CHF-DMPs) aim to optimise care, with the predominant model being cardiologist led, hospital based multidisciplinary clinics with cardiac nurse outreach. However, findings from contemporary observational studies and clinical trials raise uncertainty around the effectiveness and sustainability of traditional CHF-DMPs in real-world clinical practice.
To determine the spectrum of disease among non-urgent referrals to a tertiary hospital hepatology outpatient clinic, assess the adequacy of referral information in terms of risk stratification and determine whether a specifically designed referral template altered urgency for specialist assessment.
Hand1 is a basic helix-loop-helix transcription factor that is essential for development of the placenta, yolk sac and heart during mouse development. While Hand1 is essential for trophoblast giant cell (TGC) differentiation, its potential heterodimer partners are not co-expressed in TGCs. To test the hypothesis that Hand1 functions as homodimer, we generated knock-in mice in which the Hand1 gene was altered to encode a tethered homodimer (TH). Some Hand1(TH/-) conceptuses in which the only form of Hand1 is Hand1(TH) are viable and fertile, indicating that homodimer Hand1 is sufficient for mouse survival. ~2/3 of Hand1(TH/-) and all Hand1(TH/TH) mice died in utero and displayed severe placental defects and variable cardial and cranial-facial abnormalities, indicating a dosage-dependent effect of Hand1(TH). Meanwhile, expression of the Hand1(TH) protein did not have negative effects on viability or fertility in all Hand1(TH/+) mice. These data imply that Hand1 homodimer plays a dominant role during development and its expression dosage is critical for survival, whereas Hand1 heterodimers can be either dispensable or play a regulatory role to modulate the activity of Hand1 homodimer in vivo.
Many patients at the end of life receive care that is inappropriate or futile and, if given the opportunity to discuss their care preferences well ahead of death, may well have chosen to forgo such care. Advance care planning (ACP) is a process of making decisions about future health care for patients in consultation with clinicians, family members and important others, and to safeguard such decisions if patients were to lose decisional capacity. Although ACP has existed as an idea for decades, acceptance and operationalisation of ACP within routine practice has been slow, despite evidence of its benefits. The chief barriers have been social and personal taboos about discussing the dying process, avoidance by medical professionals of responsibility for initiating, coordinating and documenting discussions about ACP, absence of robust and standardised procedures for recording and retrieving ACP documents across multiple care settings, and legal and ethical concerns about the validity of such documents. For ACP to become part of mainstream patient-centred care, accountable clinicians working in primary care, hospitals and nursing homes must effectively educate colleagues and patients about the purpose and mechanics of ACP, mandate ACP for all eligible patients, document ACP in accessible formats that enable patient wishes to accurately guide clinical management, devise methods for reviewing ACP decisions when clinically appropriate, and evaluate congruence between expressed patient wishes and actual care received. Public awareness campaigns coupled with implementation of ACP programs sponsored by collaborations between hospital and health services, Medicare locals and residential care facilities will be needed in making system-wide ACP a reality.
During aging, there is a decreased ability to maintain skeletal muscle mass and function (sarcopenia). Such changes in skeletal muscle are also co-morbidities of diseases including cancer, congestive heart failure and chronic obstructive pulmonary disease. The loss of muscle mass results in decreased strength and exercise tolerance and reduced ability to perform daily activities. Pharmacological agents addressing these pathologies could have significant clinical impact, but their identification requires understanding of mechanisms driving myotube formation (myogenesis) and atrophy and provision of relevant assays. The aim of this study was to develop robust in vitro methods to study human myogenesis.
Our aim was to establish whether alcohol protects against RA development and to determine whether this effect is influenced by alcohol dose, duration and serological status through systematically reviewing the literature and undertaking a meta-analysis.
In Canada, availability of and access to mental health professionals is limited. Only 6.6% of practising physicians are psychiatrists, a situation unlikely to improve in the foreseeable future. Identifying student characteristics present at medical school entry that predict a subsequent psychiatry residency choice could allow targeted recruiting or support to students early on in their careers, in turn creating a supply of psychiatry-oriented residency applicants.
Rheumatoid arthritis (RA) is a long-term condition causing joint pain and swelling and sometimes systemic involvement. The aims of treatment are, first, to reduce the impact the disease has on a patient and, second, to halt progression of disease. The advent of intensive therapy, including biologics, has led to a major improvement in outcome. To assess treatment impact, formal outcome measures have been developed. Traditionally, these focussed on the clinical aspects such as disease activity and joint damage. More recently, there has been an increased focus on patient-related outcome measures including quality-of-life measures. These enable illness evaluation from patients perspectives, examination of care quality and comparison of the effectiveness and cost-effectiveness of treatment. This article examines advantages and disadvantages of the various outcome measures which are generally used in RA, with a focus on quality of life and patient-related measures.
Student choice is an important determinant of the specialty mix of practicing physicians in Canada. Understanding student characteristics at medical school entry that are associated with a student choosing a residency in surgery can assist surgical educators in supporting medical students interested in surgery and in serving health human resources needs.
Development of the heart requires recruitment of cardiovascular progenitor cells (CPCs) to the future heart-forming region. CPCs are the building blocks of the heart, and have the potential to form all the major cardiac lineages. However, little is known regarding what regulates CPC fate and behavior. Activity of GATA4, SMARCD3 and TBX5 - the `cardiac BAF (cBAF) complex, can promote myocardial differentiation in embryonic mouse mesoderm. Here, we exploit the advantages of the zebrafish embryo to gain mechanistic understanding of cBAF activity. Overexpression of smarcd3b and gata5 in zebrafish results in an enlarged heart, whereas combinatorial loss of cBAF components inhibits cardiac differentiation. In transplantation experiments, cBAF acts cell autonomously to promote cardiac fate. Remarkably, cells overexpressing cBAF migrate to the developing heart and differentiate as cardiomyocytes, endocardium and smooth muscle. This is observed even in host embryos that lack endoderm or cardiac mesoderm. Our results reveal an evolutionarily conserved role for cBAF activity in cardiac differentiation. Importantly, they demonstrate that Smarcd3b and Gata5 can induce a primitive, CPC-like state.
The role of postoperative radiotherapy in patients undergoing first-time resection of WHO Grade II meningioma remains unclear as reflected by varied practices in published clinical studies and national professional surveys. Much of the relevant literature is based on pre-2000 WHO grading criteria for atypical meningiomas. Authors in this study set out to explore the role of postoperative radiotherapy in patients undergoing first-time surgery for WHO Grade II meningiomas diagnosed using revised WHO 2000 criteria, against a background of otherwise limited published literature on this issue.
Australian Health Ministers have endorsed the hospital standardised mortality ratio (HSMR) as a key indicator of quality and safety, and efforts are currently underway towards its national implementation. In the United Kingdom, Canada, the Netherlands and the United States, the HSMR has been used for several years within organisations to monitor performance and response to various quality and safety programs. In the UK and Canada, the HSMR is also publicly reported and used to compare performance between hospitals. The validity and reliability of the HSMR as a screening tool for distinguishing low-quality from high-quality hospitals remain in doubt, and it has not yet been proven that HSMR reporting necessarily leads to worthwhile improvement in quality of care and patient outcomes. Institutions may respond to an unfavourable HSMR by "gaming" administrative data and risk-adjustment models or implementing inappropriate changes to care. Despite its apparent low cost and ease of measurement, the HSMR is currently not "fit for purpose" as a screening tool for detecting low-quality hospitals and should not be used in making interhospital comparisons. It may be better suited to monitoring changes in outcomes over time within individual institutions.
CCM3 mutations give rise to cerebral cavernous malformations (CCMs) of the vasculature through a mechanism that remains unclear. Interaction of CCM3 with the germinal center kinase III (GCKIII) subfamily of Sterile 20 protein kinases, MST4, STK24, and STK25, has been implicated in cardiovascular development in the zebrafish, raising the possibility that dysregulated GCKIII function may contribute to the etiology of CCM disease. Here, we show that the amino-terminal region of CCM3 is necessary and sufficient to bind directly to the C-terminal tail region of GCKIII proteins. This same region of CCM3 was shown previously to mediate homodimerization through the formation of an interdigitated ?-helical domain. Sequence conservation and binding studies suggest that CCM3 may preferentially heterodimerize with GCKIII proteins through a manner structurally analogous to that employed for CCM3 homodimerization.
Cerebral cavernous malformations (CCMs) are alterations in brain capillary architecture that can result in neurological deficits, seizures, or stroke. We recently demonstrated that CCM3, a protein mutated in familial CCMs, resides predominantly within the STRIPAK complex (striatin interacting phosphatase and kinase). Along with CCM3, STRIPAK contains the Ser/Thr phosphatase PP2A. The PP2A holoenzyme consists of a core catalytic subunit along with variable scaffolding and regulatory subunits. Within STRIPAK, striatin family members act as PP2A regulatory subunits. STRIPAK also contains all three members of a subfamily of Sterile 20 kinases called the GCKIII proteins (MST4, STK24, and STK25). Here, we report that striatins and CCM3 bridge the phosphatase and kinase components of STRIPAK and map the interacting regions on each protein. We show that striatins and CCM3 regulate the Golgi localization of MST4 in an opposite manner. Consistent with a previously described function for MST4 and CCM3 in Golgi positioning, depletion of CCM3 or striatins affects Golgi polarization, also in an opposite manner. We propose that STRIPAK regulates the balance between MST4 localization at the Golgi and in the cytosol to control Golgi positioning.
Australia is developing a national performance framework aimed at measuring health outcomes across the health system. Clinical registries provide a clinically credible means of monitoring health care processes and outcomes, yet only five Australian registries currently have national coverage. At a national level, clinical registry development should be prioritised to target conditions or procedures that are suspected of being associated with large variations in processes or outcomes of care and that impact significantly on health care costs and patient morbidity. Registries should also aim to capture information across care interfaces and to monitor the medium and long-term safety and effectiveness of specific devices, procedures and drugs.
A recently published critique of a set of Australian clinical practice guidelines (CPG) highlighted problematic issues in guideline development concerning conflicts of interest of guideline panellists, validity and strength of recommendations, and involvement of end users and external stakeholders. Management of financial or intellectual conflicts of interest requires: full disclosure; limitations on industry or agency financial support during guideline development; a representative panel that includes conflict-free members; and only conflict-free panellists to be involved in drafting guideline recommendations. Guideline panels should consider adopting the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system to assist in determining the validity and strength of recommendations. Guideline panels should seek formal feedback from external stakeholders and end users. Enacting such policies aims to lend greater transparency and credibility to CPG, limit protracted and unhelpful interpretive debates, and promote wider use of CPG.
INTRODUCTION In response to increasing demand for hospital beds, institution-wide clinical process redesign has been advocated for improving efficiency. METHODS This retrospective, before-after study involved five tertiary hospitals in Queensland, Australia and assessed effects of externally led redesign over 6 months within two hospitals, comprising ward-based innovations led by consultancy-led standardised processes, and internally led redesign over 25 months in one hospital which implemented medical assessment and planning unit, 23 h elective surgical ward and new bed management processes. The primary outcome measures were control chart changes in emergency department (ED) access block and overdue category 1 elective surgery waits over 3.5 years involving intervention hospitals and two control hospitals. RESULTS At one externally led redesign hospital, control charts indicated a decrease in ED access block outside control limits which coincided with the intervention, but this was not subsequently sustained. There were no special-cause variations seen in the other hospital. In contrast, at the internally led redesign hospital, there were two decreases in access block outside control limits during the intervention period, resulting in a decrease from a baseline average of 55% to a postintervention average of 22%. All hospitals showed declines in elective surgery waits with oscillations in data indicating the existence of special-cause factors other than redesign. CONCLUSION Internally led compared with externally led redesign led to superior and sustained improvements in ED access block as a result of major structural reforms that were driven by committed clinicians and managers and cut across departmental boundaries.
In patients with glioblastoma multiforme (GBM), there is no consensus on the sequential use of two existing regimens: post-operative Gliadel implantation into the surgical cavity and concomitant temozolomide with radiotherapy followed by adjuvant temozolomide (Stupp protocol). NICE in the guideline TA121 (July 2007) could not pass any judgement on the sequential use of both the regimens due to lack of evidence at the time of consultation. Since then, few prospective studies and retrospective series have been reported using these two regimens sequentially. Except in one study, results were indicative of an incremental gain of 2-3 months in median survival in comparison to the published results using Gliadel or Stupp Protocol alone. Post-surgical complications were manageable and within an acceptable range, when the sequential regimen was managed under defined guidelines and surgery was performed in a high volume centre. Moderate degree of increased myelosuppression has been reported in few series, however. In the absence of a phase III trial and the small number of patients in each series, the reported trend of toxicities and efficacy could only be substantiated by setting up a national database. Contributing to such a national database and toxicity recording could be made mandatory through peer review programme for the neurooncological services. Based on the preclinical and albeit lower level of clinical evidence, demonstrating temporal and spatial co-operation between two regimens (Gliadel and Stupp Protocol), resulting in incremental 2-3 months median survival gain, should enable NICE in its next review to issue a favourable guidance. Depending on the number of patients eligible for such a sequential regimen, which could be 15%-25% of Glioblastoma patients diagnosed in England per annum, the additional annual cost of concomitant temozolomide would be approximately £640,000 to £1 million.
We assessed the inter-relationships between the Short Form 36 (SF-36) physical and mental function in 220 patients with onset cases of mild and moderate depression and 913 adults with early and established rheumatoid arthritis (RA) through secondary analysis and compared both scores with the UK general population norms. In depression and RA the SF-36 total scores showed significant impairment across the spectrum of both domains compared with age-specific UK normative score. In RA mental health and role, mental scores were highly correlated with other SF-36 domains. In depression there was little evidence of such inter-relationships. Mental health and role mental domains were lowest in active RA (disease activity scores (DAS28) over 5.1). They had strong correlations with the vitality and social function SF-36 sub-scores and weak correlations with the physical function and role emotional sub-scores. Patients with long-term conditions require comprehensive care. At present it is unclear how best to combine treatment of RA synovitis with the management of mental health problems. Mental health symptoms are present from the earliest stages of RA and it may be appropriate to initiate multidisciplinary care as soon as practicable, although its efficacy requires a further detailed study across primary and secondary care.
Two populations of cells, termed the first and second heart field, drive heart growth during chick and mouse development. The zebrafish has become a powerful model for vertebrate heart development, partly due to the evolutionary conservation of developmental pathways in this process. Here we provide evidence that the zebrafish possesses a conserved homolog to the murine second heart field. We developed a photoconversion assay to observe and quantify the dynamic late addition of myocardial cells to the zebrafish arterial pole. We define an extra-cardiac region immediately posterior to the arterial pole, which we term the late ventricular region. The late ventricular region has cardiogenic properties, expressing myocardial markers such as vmhc and nkx2.5, but does not express a full complement of differentiated cardiomyocyte markers, lacking myl7 expression. We show that mef2cb, a zebrafish homolog of the mouse second heart field marker Mef2c, is expressed in the late ventricular region, and is necessary for late myocardial addition to the arterial pole. FGF signaling after heart cone formation is necessary for mef2cb expression, the establishment of the late ventricular region, and late myocardial addition to the arterial pole. Our study demonstrates that zebrafish heart growth shows more similarities to murine heart growth than previously thought. Further, as congenital heart disease is often associated with defects in second heart field development, the embryological and genetic advantages of the zebrafish model can be applied to study the vertebrate second heart field.
Neisseria gonorrhoeae (Ng) has developed resistance to most antimicrobial agents and the antibiotics recommended for therapy are restricted, for the most part, to third generation cephalosporins. In order to investigate new potential sources of antimicrobial agents, the antibacterial properties of 14 Canadian plants used in traditional First Nations medicine were tested against Ng isolates having differing antimicrobial susceptibility profiles.
Both eosinophil chemotactic factor (ECF) and neutrophil chemotactic factor (NCF) activities were demonstrated in excretory/secretory (ES) products and homogenates of Haemonchus contortus and Teladorsagia circumcincta larvae and adult worms in a modified checkerboard assay using a micro-chemotaxis chamber. Neutrophil chemotaxis was seen in 28 of 35 experiments and eosinophil chemotaxis in 20 of 38 experiments. Chemokinetic activity for neutrophils and eosinophils (accounting for 40-50% of total cell migration) was also apparent in only three parasite products for each cell type. Significant NCF activity was present in six of seven adult worm ES products (three of four from T. circumcincta and in all three from H. contortus) and ECF activity in four of five adult ES products, whereas fewer L3 incubates, particularly of T. circumcincta, contained chemotactic activity. All parasite homogenates, with one exception for ECF, were chemotactic for both neutrophils and eosinophils. The sequential use of cellulose ultrafiltration membranes of decreasing pore size did not identify precisely the molecular weight of the NCF and ECF but indicated that the active chemicals were greater than 10 kDa and probably greater than 30 kDa.
CTCF nuclear factor regulates many aspects of gene expression, largely as a transcriptional repressor or via insulator function. Its roles in cellular differentiation are not clear. Here we show an unexpected role for CTCF in myogenesis. Ctcf is expressed in myogenic structures during mouse and zebrafish development. Gain- and loss-of-function approaches in C2C12 cells revealed CTCF as a modulator of myogenesis by regulating muscle-specific gene expression. We addressed the functional connection between CTCF and myogenic regulatory factors (MRFs). CTCF enhances the myogenic potential of MyoD and myogenin and establishes direct interactions with MyoD, indicating that CTCF regulates MRF-mediated muscle differentiation. Indeed, CTCF modulates functional interactions between MyoD and myogenin in co-activation of muscle-specific gene expression and facilitates MyoD recruitment to a muscle-specific promoter. Finally, ctcf loss-of-function experiments in zebrafish embryos revealed a critical role of CTCF in myogenic development and linked CTCF to broader aspects of development via regulation of Wnt signaling. We conclude that CTCF modulates MRF functional interactions in the orchestration of myogenesis.
Consistent delivery of medication to treat asthma and chronic obstructive pulmonary disease (COPD) is critical for disease control. Dose tracking may eliminate the possibility of sub-therapeutic dosing. This study evaluated the overall performance, including accuracy and ruggedness, of the mometasone furoate/formoterol (MF/F) metered-dose inhaler (MDI) with an integrated numerical dose-counting mechanism in adolescent and adult subjects (aged ? 12 y) with persistent asthma or COPD.
Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs); however, their molecular basis is not understood. Interactions between transcription factors and the Brg1/Brm-associated factor (BAF) chromatin remodelling complex suggest potential mechanisms; however, the role of BAF complexes in cardiogenesis is not known. In this study, we show that dosage of Brg1 is critical for mouse and zebrafish cardiogenesis. Disrupting the balance between Brg1 and disease-causing cardiac transcription factors, including Tbx5, Tbx20 and Nkx2-5, causes severe cardiac anomalies, revealing an essential allelic balance between Brg1 and these cardiac transcription factor genes. This suggests that the relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac gene promoters in Tbx5 haploinsufficient hearts. Our results reveal complex dosage-sensitive interdependence between transcription factors and BAF complexes, providing a potential mechanism underlying transcription factor haploinsufficiency, with implications for multigenic inheritance of CHDs.
Cerebral cavernous malformations (CCMs) are vascular anomalies of the central nervous system that arise due to mutations in genes encoding three unrelated proteins: CCM1 (KRIT1); CCM2 (Malcavernin/OSM) and CCM3 (PDCD10). Both biochemical and mutant studies suggest that CCM1 and CCM2 act as part of a physical complex to regulate vascular morphogenesis and integrity. In contrast, mouse Ccm3 mutant and in vitro cell culture data suggests an independent role for Ccm3. In this study, we sought to use the zebrafish model system to examine for the first time the role of ccm3 in cranial vessel development. We report that inhibition of zebrafish ccm3a/b causes heart and circulation defects distinct from those seen in ccm1 (santa) and ccm2 (valentine) mutants, and leads to a striking dilation and mispatterning of cranial vessels reminiscent of the human disease pathology. ccm3, but not ccm2, defects can be rescued upon overexpression of stk25b, a GCKIII kinase previously shown to interact with CCM3. Morpholino knockdown of the GCKIII gene stk25b results in heart and vasculature defects similar to those seen in ccm3 morphants. Finally, additional loss of ccm3 in ccm2 mutants leads to a synergistic increase in cranial vessel dilation. These results support a model in which CCM3 plays a role distinct from CCM1/2 in CCM pathogenesis, and acts via GCKIII activity to regulate cranial vasculature integrity and development. CCM3/GCKIII activity provides a novel therapeutic target for CCMs, as well as for the modulation of vascular permeability.
The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort.
* Increasing demand on public hospital beds has led to what many see as a hospital bed crisis requiring substantial increases in bed numbers. By 2050, if current bed use trends persist and as the numbers of frail older patients rise exponentially, a 62% increase in hospital beds will be required to meet expected demand, at a cost almost equal to the entire current Australian healthcare budget. * This article provides an overview of the effectiveness of different strategies for reducing hospital demand that may be viewed as primarily (although not exclusively) targeting the hospital sector - increasing capacity and throughput and reducing readmissions - or the non-hospital sector - facilitating early discharge or reducing presentations and admissions to hospital. Evidence of effectiveness was retrieved from a literature search of randomised trials and observational studies using broad search terms. * The principal findings were as follows: (1) within the hospital sector, throughput could be substantially improved by outsourcing public hospital clinical services to the private sector, undertaking whole-of-hospital reform of care processes and patient flow that address both access and exit block, separating acute from elective beds and services, increasing rates of day-only or short stay admissions, and curtailing ineffective or marginally effective clinical interventions; (2) in regards to the non-hospital sector, potentially the biggest gains in reducing hospital demand will come from improved access to residential care, rehabilitation services, and domiciliary support as patients awaiting such services currently account for 70% of acute hospital bed-days. More widespread use of acute care and advance care planning within residential care facilities and population-based chronic disease management programs can also assist. * This overview concludes that, in reducing hospital bed demand, clinical process redesign within hospitals and capacity enhancement of non-hospital care services and chronic disease management programs are effective strategies that should be considered before investing heavily in creating additional hospital beds devoid of any critical reappraisal of current models of care.
Metabolite fingerprinting of Arabidopsis (Arabidopsis thaliana) mutants with known or predicted metabolic lesions was performed by (1)H-nuclear magnetic resonance, Fourier transform infrared, and flow injection electrospray-mass spectrometry. Fingerprinting enabled processing of five times more plants than conventional chromatographic profiling and was competitive for discriminating mutants, other than those affected in only low-abundance metabolites. Despite their rapidity and complexity, fingerprints yielded metabolomic insights (e.g. that effects of single lesions were usually not confined to individual pathways). Among fingerprint techniques, (1)H-nuclear magnetic resonance discriminated the most mutant phenotypes from the wild type and Fourier transform infrared discriminated the fewest. To maximize information from fingerprints, data analysis was crucial. One-third of distinctive phenotypes might have been overlooked had data models been confined to principal component analysis score plots. Among several methods tested, machine learning (ML) algorithms, namely support vector machine or random forest (RF) classifiers, were unsurpassed for phenotype discrimination. Support vector machines were often the best performing classifiers, but RFs yielded some particularly informative measures. First, RFs estimated margins between mutant phenotypes, whose relations could then be visualized by Sammon mapping or hierarchical clustering. Second, RFs provided importance scores for the features within fingerprints that discriminated mutants. These scores correlated with analysis of variance F values (as did Kruskal-Wallis tests, true- and false-positive measures, mutual information, and the Relief feature selection algorithm). ML classifiers, as models trained on one data set to predict another, were ideal for focused metabolomic queries, such as the distinctiveness and consistency of mutant phenotypes. Accessible software for use of ML in plant physiology is highlighted.
The potential of analytical chemistry to predict sensory qualities of food materials is a major current theme. Standard practice is cross-validation (CV), where a set of chemical and associated sensory data is partitioned so chemometric models can be developed on training subsets, and validated on held-out subsets. CV demonstrates prediction, but is an unlikely scenario for industrial operations, where concomitant data acquisition for model development and test materials would be unwieldy. We evaluated cocoa materials of diverse provenance, and analyzed on different dates to those used in model development. Liquor extracts were analyzed by flow-injection electrospray-mass spectrometry (FIE-MS), a novel method for sensory quality prediction. FIE-MS enabled prediction of sensory qualities described by trained human panelists. Optimal models came from the Weka data-mining algorithm SimpleLinearRegression, which learns a model for the attribute giving minimal training error, which was (-)-epicatechin. This flavonoid likewise dominated partial least-squares (PLS)-regression models. Refinements of PLS (orthogonal-PLS or orthogonal signal correction) gave poorer generalization to different test sets, as did support vector machines, whose hyperparameters could not be optimized in training to avoid overfitting. In conclusion, if chemometric overfitting is avoided, chemical analysis can predict sensory qualities of food materials under operationally realistic conditions.
We systematically reviewed remission as an outcome measure in observational studies and randomized controlled trials (RCT) in early rheumatoid arthritis (RA). Our objectives were to identify its frequency using different criteria, to determine the influence of different treatment strategies on remission, and to review the effects of remission on radiological outcomes.
Policy makers, clinicians and researchers are demonstrating increasing interest in using data linked from multiple sources to support measurement of clinical performance and patient health outcomes. However, the utility of data linkage may be compromised by sub-optimal or incomplete linkage, leading to systematic bias. In this study, we synthesize the evidence identifying participant or population characteristics that can influence the validity and completeness of data linkage and may be associated with systematic bias in reported outcomes.
The care of patients 65 years or older presents a challenge for evidence-based medicine. Such patients are underrepresented in clinical trials, are more vulnerable to treatment-induced harm, and often are unable to fully participate in treatment decisions. We outline several cautionary themes in the interpretation of clinical studies of therapeutic interventions involving older persons as they apply to processes of everyday clinical decision making. In particular, we focus on issues of study design and quality of evidence, choice of outcome measures, missing outcome data, assessment of potential harm, quantifying treatment effects in individual patients (and adjusting these for effect modifiers and reduced life expectancy), eliciting patient values and preferences, prioritizing therapeutic goals and selection of treatments, and assisting patients in adhering to agreed therapeutic regimens.
The FLOTAC flotation technique has been introduced as a new diagnostic tool to detect parasitic elements from faeces. Samples from naturally infected young deer were used for counting Dictyocaulus larvae and strongylid eggs. The FLOTAC technique, using 11 different flotation solutions with specific gravities (sg) between 1.20 and 1.45, was compared with the Baermann technique and the saturated sodium chloride (sg 1.20)-based McMaster method. In addition, a comparison was made between the FLOTAC technique with magnesium sulphate (sg 1.28) and the Baermann technique for larval recovery from faeces that were examined on the day of collection or after 7 days storage at 4 degrees C. On the whole egg counts between the FLOTAC using different flotation solutions and the McMaster were unremarkable. In contrast, variations of larval counts were detected between different flotation solutions as well as with the Baermann technique. Most flotation solutions with a specific gravity of 1.20 floated significantly fewer lungworm larvae (p < 0.05) compared to flotation solutions with a higher specific gravity. Magnesium sulphate (sg 1.28) consistently produced the highest mean larval counts in all conducted experiments. Larval counts using magnesium sulphate (sg 1.28) were higher than with the Baermann technique both on the day of collection and after 7 days. Overall, the use of magnesium sulphate (sg 1.28) with FLOTAC for larval counts resulted in higher counts than the Baermann recovery technique and was the better choice of those flotation solutions examined. Furthermore, magnesium sulphate (sg 1.28) was also reliable for strongylid egg detection with the FLOTAC apparatus.
In patients with unstable angina and non-ST elevation myocardial infarction (UA/NSTEMI) two strategies are possible, either a routine invasive strategy where all patients undergo coronary angiography shortly after admission and, if indicated, coronary revascularization; or a conservative strategy where medical therapy alone is used initially, with selection of patients for angiography based on clinical symptoms or investigational evidence of persistent myocardial ischemia.
Congestive heart failure (CHF) is an increasingly common condition associated with significant hospital resource utilization. Initiating better disease management at the time of initial hospital admission has the potential to reduce readmissions.
The up-regulation of plant defense-related toxins or metabolic enzyme binding proteins often leads to a negative effect on herbivorous insects. These negative effects can manifest themselves at three points: changes in food ingestion, post-ingestive-changes, and post-digestive changes. Many studies have related the decrease in herbivore growth and/or survival with expression of chemicals that interfere with post-digestive effects such as the anti-nutritive effects of protease inhibitors. Nevertheless, it is unclear whether such compounds impact herbivores via earlier ingestive processes. We addressed this question by using a jasmonate-deficient mutant (Def-1), a jasmonate-overexpressor mutant (Prosystemin or Prosys), and wild-type tomato in three trials with 5th instar Trichoplusia ni. Decreases in relative growth rate (RGR) confirmed that T. ni fed on the Prosys plants developed poorly compared to those feeding on Def-1 plants (larvae on wild-types were intermediate). Preingestive and postingestive processes contributed to this effect. Total food ingested and the consumptive index were 25% lower on Prosys plants compared to Def-1 plants. Post-ingestive processes, measured by approximate digestibility, were 62% greater on Prosy plants. Post-digestive efficiency measured by conversion of ingested and digested food (ECI and ECD) decreased on Prosys plants two-fold compared to Def-1 plants. This post-digestive interference correlated well with the 2-fold decrease in activity of digestive enzymes, serine proteases, in Prosys-fed T. ni compared to those on Def-1 plants. No difference in detoxifying enzyme activity was detected.
To investigate what role family physicians currently play in the management of patients with nutrition-related issues and whether implementation of current nutrition counseling guidelines is feasible in primary care practices.
Unplanned readmissions of recently discharged patients impose a significant burden on hospitals with limited bed capacity. Deficiencies in discharge processes contribute to such readmissions, which have prompted experimentation with multiple types of peridischarge interventions.
The purpose of this study was to determine the diversity and prevalence of Fusarium species in a survey of cereal and grassland systems from the South Island of New Zealand by applying morphological and molecular techniques. Isolates were collected from soil, roots, and stems from 21 cereal and grassland sites. Ten Fusarium species were identified using morphological characters, including F. acuminatum, F. avenaceum, F. crookwellense, F. culmorum, F. equiseti, F. oxysporum, F. poae, F. pseudograminearum, F. sambucinum, and F. tricinctum. In general, their distribution was found to be unrelated to biogeographical location, although agricultural practice increased the overall diversity of Fusarium. Phylogenetic analyses were successfully used to identify morphologically similar isolates belonging to the F. avenaceum/F. acuminatum/F. tricinctum species complex and to resolve previously undetermined relationships amongst these species. Fifty-eight isolates classified as either F. avenaceum, F. acuminatum, or other closely related species as well as several well-characterised isolates from international culture collections were examined using DNA sequence data for ?-tubulin (?TUB), translation elongation factor 1? (EF1?), and mitochondrial small subunit ribosomal RNA (mtSSU). Analyses of DNA sequence data from both ?TUB and EF1? discriminated among isolates of F. avenaceum, F. acuminatum, and F. tricinctum and determined that these three distinct sequence groups formed a single clade. By contrast, mtSSU was unable to differentiate F. avenaceum from F. acuminatum and other closely related species believed to be F. tricinctum. Comparison of the EF1? sequences with the international FUSARIUM-ID database supported the identification of isolates in this study. As in other studies, F. avenaceum was found to be widespread in agricultural and native ecosystems. However, F. acuminatum in New Zealand was found only on non-wheat hosts. The reason for the absence of this wheat pathogen in cereal-based ecosystems in New Zealand remains unknown.
Selective breeding of dogs has culminated in a large number of modern breeds distinctive in terms of size, shape and behaviour. Inadvertently, a range of breed-specific genetic disorders have become fixed in some pure-bred populations. Several inherited conditions confer chronic metabolic defects that are influenced strongly by diet, but it is likely that many less obvious breed-specific differences in physiology exist. Using Labrador retrievers and miniature Schnauzers maintained in a simulated domestic setting on a controlled diet, an experimental design was validated in relation to husbandry, sampling and sample processing for metabolomics. Metabolite fingerprints were generated from spot urine samples using flow injection electrospray MS (FIE-MS). With class based on breed, urine chemical fingerprints were modelled using Random Forest (a supervised data classification technique), and metabolite features (m/z) explanatory of breed-specific differences were putatively annotated using the ARMeC database (http://www.armec.org). GC-MS profiling to confirm FIE-MS predictions indicated major breed-specific differences centred on the metabolism of diet-related polyphenols. Metabolism of further diet components, including potentially prebiotic oligosaccharides, animal-derived fats and glycerol, appeared significantly different between the two breeds. Analysis of the urinary metabolome of young male dogs representative of a wider range of breeds from animals maintained under domestic conditions on unknown diets provided preliminary evidence that many breeds may indeed have distinctive metabolic differences, with significant differences particularly apparent in comparisons between large and smaller breeds.
To report the proportion of Canadian medical students interested in a career in psychiatry at medical school entry and to describe the unique demographics and career influences associated with this early interest.
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