Copper Chaperone for Cu/Zn Superoxide Dismutase is a sensitive biomarker of mild copper deficiency induced by moderately high intakes of zinc

BACKGROUND: Small increases in zinc (Zn) consumption above recommended amounts have been shown to reduce copper (Cu) status in experimental animals and humans. Recently, we have reported that copper chaperone for Cu/Zn superoxide dismutase (CCS) protein level is increased in tissues of overtly Cu-deficient rats and proposed CCS as a novel biomarker of Cu status. METHODS: Weanling male Wistar rats were fed one of four diets normal in Cu and containing normal (30 mg Zn/kg diet) or moderately high (60, 120 or 240 mg Zn/kg diet) amounts of Zn for 5 weeks. To begin to examine the clinical relevance of CCS, we compared the sensitivity of CCS to mild Cu deficiency, induced by moderately high intakes of Zn, with conventional indices of Cu status. RESULTS: Liver and erythrocyte CCS expression was significantly (P < 0.05) increased in rats fed the Zn-60 and/or Zn-120 diet compared to rats fed normal levels of Zn (Zn-30). Erythrocyte CCS expression was the most sensitive measure of reduced Cu status and was able to detect a decrease in Cu nutriture in rats fed only twice the recommended amount of Zn. Liver, erythrocyte and white blood cell CCS expression showed a significant (P < 0.05) inverse correlation with plasma and liver Cu concentrations and caeruloplasmin activity. Unexpectedly, rats fed the highest level of Zn (Zn-240) showed overall better Cu status than rats fed a lower level of elevated Zn (Zn-120). Improved Cu status in these rats correlated with increased duodenal mRNA expression of several Zn-trafficking proteins (i.e. MT-1, ZnT-1, ZnT-2 and ZnT-4). CONCLUSION: Collectively, these data show that CCS is a sensitive measure of Zn-induced mild Cu deficiency and demonstrate a dose-dependent biphasic response for reduced Cu status by moderately high intakes of Zn

Immunohistochemical assessment of protein phosphorylation state: the dream and the reality

The development of phosphorylation state-specific antibodies (PSSAs) in the 1980s, and their subsequent proliferation promised to enable in situ analysis of the activation states of complex intracellular signaling networks. The extent to which this promise has been fulfilled is the topic of this review. I review some applications of PSSAs primarily in the assessment of solid tumor signaling pathway activation status. PSSAs have received considerable attention for their potential to reveal cell type-specific activation status, provide added prognostic information, aid in the prediction of response to therapy, and most recently, demonstrate the efficacy of kinase-targeted chemotherapies. However, despite some successes, many studies have failed to demonstrate added value of PSSAs over general antibody immunohistochemistry. Moreover, there is still a large degree of uncertainty about the interpretation of complex and heterogeneous staining patterns in tissue samples and their relationship to the actual phosphorylation states in vivo. The next phase of translational research in applications of PSSAs will entail the hard work of antibody validation, gathering of detailed information about epitope-specific lability, and implementation of methods for standardization

Conditioning Individual Mosquitoes to an Odor: Sex, Source, and Time

Olfactory conditioning of mosquitoes may have important implications for vector-pathogen-host dynamics. If mosquitoes learn about specific host attributes associated with pathogen infection, it may help to explain the heterogeneity of biting and disease patterns observed in the field. Sugar-feeding is a requirement for survival in both male and female mosquitoes. It provides a starting point for learning research in mosquitoes that avoids the confounding factors associated with the observer being a potential blood-host and has the capability to address certain areas of close-range mosquito learning behavior that have not previously been described. This study was designed to investigate the ability of the southern house mosquito, Culex quinquefasciatus Say to associate odor with a sugar-meal with emphasis on important experimental considerations of mosquito age (1.2 d old and 3–5 d old), sex (male and female), source (laboratory and wild), and the time between conditioning and testing (<5 min, 1 hr, 2.5 hr, 5 hr, 10 hr, and 24 hr). Mosquitoes were individually conditioned to an odor across these different experimental conditions. Details of the conditioning protocol are presented as well as the use of binary logistic regression to analyze the complex dataset generated from this experimental design. The results suggest that each of the experimental factors may be important in different ways. Both the source of the mosquitoes and sex of the mosquitoes had significant effects on conditioned responses. The largest effect on conditioning was observed in the lack of positive response following conditioning for females aged 3–5 d derived from a long established colony. Overall, this study provides a method for conditioning experiments involving individual mosquitoes at close range and provides for future discussion of the relevance and broader questions that can be asked of olfactory conditioning in mosquitoes

Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug

\ua9 2018 The Authors We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to &lt;7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes

A call for transparent reporting to optimize the predictive value of preclinical research

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress

Pain patterns and descriptions in patients with radicular pain: Does the pain necessarily follow a specific dermatome?

<p>Abstract</p> <p>Background</p> <p>It is commonly stated that nerve root pain should be expected to follow a specific dermatome and that this information is useful to make the diagnosis of radiculopathy. There is little evidence in the literature that confirms or denies this statement. The purpose of this study is to describe and discuss the diagnostic utility of the distribution of pain in patients with cervical and lumbar radicular pain.</p> <p>Methods</p> <p>Pain drawings and descriptions were assessed in consecutive patients diagnosed with cervical or lumbar nerve root pain. These findings were compared with accepted dermatome maps to determine whether they tended to follow along the involved nerve root's dermatome.</p> <p>Results</p> <p>Two hundred twenty-six nerve roots in 169 patients were assessed. Overall, pain related to cervical nerve roots was non-dermatomal in over two-thirds (69.7%) of cases. In the lumbar spine, the pain was non-dermatomal in just under two-thirds (64.1%) of cases. The majority of nerve root levels involved non-dermatomal pain patterns except C4 (60.0% dermatomal) and S1 (64.9% dermatomal). The sensitivity (SE) and specificity (SP) for dermatomal pattern of pain are low for all nerve root levels with the exception of the C4 level (Se 0.60, Sp 0.72) and S1 level (Se 0.65, Sp 0.80), although in the case of the C4 level, the number of subjects was small (n = 5).</p> <p>Conclusion</p> <p>In most cases nerve root pain should not be expected to follow along a specific dermatome, and a dermatomal distribution of pain is not a useful historical factor in the diagnosis of radicular pain. The possible exception to this is the S1 nerve root, in which the pain does commonly follow the S1 dermatome.</p

Do Queens of Bumblebee Species Differ In Their Choice Of Flower Colour Morphs Of Corydalis Cava (Fumariaceae)?

International audienceAbstractBumblebee queens require a continuous supply of flowering food plants from early spring for the successful development of annual colonies. Early in spring, Corydalis cava provides essential nectar and pollen resources and a choice of flower colour. In this paper, we examine flower colour choice (purple or white) in C. cava and verify the hypothesis that bumblebee queens differ in their choice of flower colour. A total of 10,615 observations of flower visits were made in spring 2011 and spring 2014 near Poznań, western Poland. Our results suggest that Bombus lucorum/cryptarum used purple flowers less, while Bombus terrestris used purple flowers more and Bombus hortorum showed no preference. Therefore, the colour morphs of C. cava are probably co-evolutionary adaptations to the development of another part of the insect community which has different colour preferences

Safety profile of Coartem®: the evidence base

This article reviews the comprehensive data on the safety and tolerability from over 6,300 patients who have taken artemether/lumefantrine (Coartem®) as part of Novartis-sponsored or independently-sponsored clinical trials. The majority of the reported adverse events seen in these studies are mild or moderate in severity and tend to affect the gastrointestinal or nervous systems. These adverse events, which are common in both adults and children, are also typical of symptoms of malaria or concomitant infections present in these patients. The wealth of safety data on artemether/lumefantrine has not identified any neurological, cardiac or haematological safety concerns. In addition, repeated administration is not associated with an increased risk of adverse drug reactions including neurological adverse events. This finding is especially relevant for children from regions with high malaria transmission rates who often receive many courses of anti-malarial medications during their lifetime. Data are also available to show that there were no clinically relevant differences in pregnancy outcomes in women exposed to artemether/lumefantrine compared with sulphadoxine-pyrimethamine during pregnancy. The six-dose regimen of artemether/lumefantrine is therefore well tolerated in a wide range of patient populations. In addition, post-marketing experience, based on the delivery of 250 million treatments as of July 2009, has not identified any new safety concerns for artemether/lumefantrine apart from hypersensitivity and allergies, known class effects of artemisinin derivatives

A review of multi-component maintenance models with economic dependence

In this paper we review the literature on multi-component maintenance models with economic dependence. The emphasis is on papers that appeared after 1991, but there is an overlap with Section 2 of the most recent review paper by Cho and Parlar (1991). We distinguish between stationary models, where a long-term stable situation is assumed, and dynamic models, which can take information into account that becomes available only on the short term. Within the stationary models we choose a classification scheme that is primarily based on the various options of grouping maintenance activities: grouping either corrective or preventive maintenance, or combining preventive-maintenance actions with corrective actions. As such, this classification links up with the possibilities for grouped maintenance activities that exist in practice

Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy

The role of nitric oxide (NO) in the response to Photofrin-based photodynamic therapy (PDT) was investigated using mouse tumour models characterized by either relatively high or low endogenous NO production (RIF and SCCVII vs EMT6 and FsaR, respectively). The NO synthase inhibitors Nω-nitro- L -arginine (L-NNA) or Nω-nitro- L -arginine methyl ester (L-NAME), administered to mice immediately after PDT light treatment of subcutaneously growing tumours, markedly enhanced the cure rate of RIF and SCCVII models, but produced no obvious benefit with the EMT6 and FsaR models. Laser Doppler flowmetry measurement revealed that both L-NNA and L-NAME strongly inhibit blood flow in RIF and SCCVII tumours, but not in EMT6 and FsaR tumours. When injected intravenously immediately after PDT light treatment, L-NAME dramatically augmented the decrease in blood flow in SCCVII tumours induced by PDT. The pattern of blood flow alterations in tumours following PDT indicates that, even with curative doses, regular circulation may be restored in some vessels after episodes of partial or complete obstruction. Such conditions are conducive to the induction of ischaemia-reperfusion injury, which is instigated by the formation of superoxide radical. The administration of superoxide dismutase immediately after PDT resulted in a decrease in tumour cure rates, thus confirming the involvement of superoxide in the anti-tumour effect. The results of this study demonstrate that NO participates in the events associated with PDT-mediated tumour destruction, particularly in the vascular response that is of critical importance for the curative outcome of this therapy. The level of endogenous production of NO in tumours appears to be one of the determinants of sensitivity to PDT. © 2000 Cancer Research Campaig