Sunitinib mediates mitochondrial ROS production in adult rat cardiac fibroblasts via CaMKII oxidation

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a central mediator of Ca2+-induced signalling in the heart and regulates both normal cardiac physiology and pathology. Sunitinib malate is an oral Type I tyrosine kinase inhibitor (TKI) known to inhibit more than 50 kinases, with anti-angiogenic and anti-proliferative effects affiliated with off-target cardiotoxicity. Previous work has shown that chronic sunitinib treatment significantly increases CaMKII expression and activity and this correlates with significant cardiac dysfunction in vivo.1 Mitochondrial dysfunction, mediated by increased mitochondrial Ca2+ and resultant mitochondrial ROS production, has been proposed as an underlying mechanism for TKI-induced cardiotoxicity in cardiomyocytes.2 However, little is known of how TKIs may affect the non-contractile cells of the heart. Here, we have investigated whether sunitinib treatment increases mitochondrial ROS production in cardiac fibroblasts (CF) and whether CaMKII may play a role in this potential cardiotoxic mechanis

Diffuse infiltrative lymphocytosis syndrome presenting as renal failure in South African HIV-positive individuals: a single-centre case series

Diffuse infiltrative lymphocytosis syndrome (DILS) in human immunodeficiency virus (HIV) infection presented most commonly with parotidomegaly and sicca symptoms in the pre-antiretroviral era. However, numerous clinical manifestations are possible due to the multi-organ nature of the CD8+ lymphocytic infiltration. Renal involvement is infrequently described, but common characteristics of a renal syndrome associated with DILS have been identified. This case series describes four South African HIV-positive patients with DILS, in whom renal failure was the sole clinical manifestation. As DILS responds well to antiretroviral and corticosteroid therapy, this series highlights the importance of considering this syndrome as a cause of renal failure in an HIV-positive patient

Interventional suite and equipment management: cradle to grave

The acquisition process for interventional equipment and the care that this equipment receives constitute a comprehensive quality improvement program. This program strives to (a) achieve the production of good image quality that meets clinical needs, (b) reduce radiation doses to the patient and personnel to their lowest possible levels, and (c) provide overall good patient care at reduced cost. Interventional imaging equipment is only as effective and efficient as its supporting facility. The acquisition process of interventional equipment and the development of its environment demand a clinical project leader who can effectively coordinate the efforts of the many professionals who must communicate and work effectively on this type of project. The clinical project leader needs to understand (a) clinical needs of the end users, (b) how to justify the cost of the project, (c) the technical needs of the imaging and all associated equipment, (d) building and construction limitations, (e) how to effectively read construction drawings, and (f) how to negotiate and contract the imaging equipment from the appropriate vendor. After the initial commissioning of the equipment, it must not be forgotten. The capabilities designed into the imaging device can be properly utilized only by well-trained operators and staff who were initially properly trained and receive ongoing training concerning the latest clinical techniques throughout the equipment’s lifetime. A comprehensive, ongoing maintenance and repair program is paramount to reducing costly downtime of the imaging device. A planned periodic maintenance program can identify and eliminate problems with the imaging device before these problems negatively impact patient care

Distinct Genetic Architectures for Male and Female Inflorescence Traits of Maize

We compared the genetic architecture of thirteen maize morphological traits in a large population of recombinant inbred lines. Four traits from the male inflorescence (tassel) and three traits from the female inflorescence (ear) were measured and studied using linkage and genome-wide association analyses and compared to three flowering and three leaf traits previously studied in the same population. Inflorescence loci have larger effects than flowering and leaf loci, and ear effects are larger than tassel effects. Ear trait models also have lower predictive ability than tassel, flowering, or leaf trait models. Pleiotropic loci were identified that control elongation of ear and tassel, consistent with their common developmental origin. For these pleiotropic loci, the ear effects are larger than tassel effects even though the same causal polymorphisms are likely involved. This implies that the observed differences in genetic architecture are not due to distinct features of the underlying polymorphisms. Our results support the hypothesis that genetic architecture is a function of trait stability over evolutionary time, since the traits that changed most during the relatively recent domestication of maize have the largest effects

The Canadian Bandaging Trial: Evidence-informed leg ulcer care and the effectiveness of two compression technologies

Background: Objective: To determine the relative effectiveness of evidence-informed practice using two high compression systems: four-layer (4LB) and short-stretch bandaging (SSB) in community care of venous leg ulcers. Design and Setting: Pragmatic, multi-centre, parallel-group, open-label, randomized controlled trial conducted in 10 centres. Cognitively intact adults (≥18 years) referred for community care (home or clinic) with a venous ulceration measuring ≥0.7cm and present for ≥1 week, with an ankle brachial pressure index (ABPI) ≥0.8, without medication-controlled Diabetes Mellitus or a previous failure to improve with either system, were eligible to participate.Methods: Consenting individuals were randomly allocated (computer-generated blocked randomization schedule) to receive either 4LB or SSB following an evidence-informed protocol. Primary endpoint: time-to- healing of the reference ulcer. Secondary outcomes: recurrence rates, health-related quality of life (HRQL), pain, and expenditures.Results: 424 individuals were randomized (4LB n = 215; SSB n = 209) and followed until their reference ulcer was healed (or maximum 30 months). An intent-to-treat analysis was conducted on all participants. Median time to ulcer healing in the 4LB group was 62 days [95% confidence interval (CI) 51 to 73], compared with 77 days (95% CI 63 to 91) in the SSB group. The unadjusted Kaplan-Meier curves revealed the difference in the distribution of cumulative healing times was not significantly different between group (log rank χ2 = 0.001, P = 0.98) nor ulcers recurrence (4LB, 10.1%; SSB, 13.3%; p = 0.345). Multivariable Cox Proportional Hazard Modeling also showed no significant between-bandage differences in healing time after controlling for significant covariates (p = 0.77). At 3-months post-baseline there were no differences in pain (no pain: 4LB, 22.7%; SSB, 26.7%; p = 0.335), or HRQL (SF-12 Mental Component Score: 4LB, 55.1; SSB, 55.8; p = 0.615; SF-12 Physical Component Score: 4LB, 39.0; SSB, 39.6; p = 0.675). The most common adverse events experienced by both groups included infection, skin breakdown and ulcer deterioration.Conclusions: The Canadian Bandaging Trial revealed that in the practice context of trained RNs using an evidence-informed protocol, the choice of bandage system (4LB and SSB) does not materially affect healing times, recurrence rates, HRQL, or pain. From a community practice perspective, this is positive news for patient-centred care allowing individual/family and practitioner choice in selecting compression technologies based on circumstances and context.Trial registration: clinicaltrials.gov Identifier: NCT00202267

Population Analysis of the Fusarium graminearum Species Complex from Wheat in China Show a Shift to More Aggressive Isolates

A large number of Fusarium isolates was collected from blighted wheat spikes originating from 175 sampling sites, covering 15 provinces in China. Species and trichothecene chemotype determination by multilocus genotyping (MLGT) indicated that F. graminearum s. str. with the 15-acetyl deoxynivalenol (15ADON) chemotype and F. asiaticum with either the nivalenol (NIV) or the 3-acetyl deoxynivalenol (3ADON) chemotype were the dominant causal agents. Bayesian model-based clustering with allele data obtained with 12 variable number of tandem repeats (VNTR) markers, detected three genetic clusters that also show distinct chemotypes. High levels of population genetic differentiation and low levels of effective number of migrants were observed between these three clusters. Additional genotypic analyses revealed that F. graminearum s. str. and F. asiaticum are sympatric. In addition, composition analysis of these clusters indicated a biased gene flow from 3ADON to NIV producers in F. asiaticum. In phenotypic analyses, F. asiaticum that produce 3ADON revealed significant advantages over F. asiaticum that produce NIV in pathogenicity, growth rate, fecundity, conidial length, trichothecene accumulation and resistance to benzimidazole. These results suggest that natural selection drives the spread of a more vigorous, more toxigenic pathogen population which also shows higher levels of fungicide resistance

Overexpression of defense response genes in transgenic wheat enhances resistance to Fusarium head blight

Fusarium head blight (FHB) of wheat, caused by Fusarium graminearum and other Fusarium species, is a major disease problem for wheat production worldwide. To combat this problem, large-scale breeding efforts have been established. Although progress has been made through standard breeding approaches, the level of resistance attained is insufficient to withstand epidemic conditions. Genetic engineering provides an alternative approach to enhance the level of resistance. Many defense response genes are induced in wheat during F. graminearum infection and may play a role in reducing FHB. The objectives of this study were (1) to develop transgenic wheat overexpressing the defense response genes α-1-purothionin, thaumatin-like protein 1 (tlp-1), and β-1,3-glucanase; and (2) to test the resultant transgenic wheat lines against F. graminearum infection under greenhouse and field conditions. Using the wheat cultivar Bobwhite, we developed one, two, and four lines carrying the α-1-purothionin, tlp-1, and β-1,3-glucanase transgenes, respectively, that had statistically significant reductions in FHB severity in greenhouse evaluations. We tested these seven transgenic lines under field conditions for percent FHB disease severity, deoxynivalenol (DON) mycotoxin accumulation, and percent visually scabby kernels (VSK). Six of the seven lines differed from the nontransgenic parental Bobwhite line for at least one of the disease traits. A β-1,3-glucanase transgenic line had enhanced resistance, showing lower FHB severity, DON concentration, and percent VSK compared to Bobwhite. Taken together, the results showed that overexpression of defense response genes in wheat could enhance the FHB resistance in both greenhouse and field conditions

Genetic and Physiological Analysis of Iron Biofortification in Maize Kernels

BACKGROUND: Maize is a major cereal crop widely consumed in developing countries, which have a high prevalence of iron (Fe) deficiency anemia. The major cause of Fe deficiency in these countries is inadequate intake of bioavailable Fe, where poverty is a major factor. Therefore, biofortification of maize by increasing Fe concentration and or bioavailability has great potential to alleviate this deficiency. Maize is also a model system for genomic research and thus allows the opportunity for gene discovery. Here we describe an integrated genetic and physiological analysis of Fe nutrition in maize kernels, to identify loci that influence grain Fe concentration and bioavailability. METHODOLOGY: Quantitative trait locus (QTL) analysis was used to dissect grain Fe concentration (FeGC) and Fe bioavailability (FeGB) from the Intermated B73 × Mo17 (IBM) recombinant inbred (RI) population. FeGC was determined by ion coupled argon plasma emission spectroscopy (ICP). FeGB was determined by an in vitro digestion/Caco-2 cell line bioassay. CONCLUSIONS: Three modest QTL for FeGC were detected, in spite of high heritability. This suggests that FeGC is controlled by many small QTL, which may make it a challenging trait to improve by marker assisted breeding. Ten QTL for FeGB were identified and explained 54% of the variance observed in samples from a single year/location. Three of the largest FeGB QTL were isolated in sister derived lines and their effect was observed in three subsequent seasons in New York. Single season evaluations were also made at six other sites around North America, suggesting the enhancement of FeGB was not specific to our farm site. FeGB was not correlated with FeGC or phytic acid, suggesting that novel regulators of Fe nutrition are responsible for the differences observed. Our results indicate that iron biofortification of maize grain is achievable using specialized phenotyping tools and conventional plant breeding techniques