Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures.
Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m(3)), for which clear exposure-response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose-response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation of particulate chromium in the bifurcations of the lung resulting in exceedance of clearance mechanisms and cellular absorption of Cr(VI). Once inside the cell, reduction of Cr(VI) results in oxidative stress and the formation of Cr ligands. Subsequent protein and DNA damage lead to tissue irritation, inflammation, and cytotoxicity. These effects, concomitant with increased cell proliferation, result in changes to DNA sequences and/or methylation status that can lead to tumorigenesis. This MOA supports the use of non-linear approaches when extrapolating lung cancer risk occurring at high concentration occupational exposures to environmentally-relevant exposures.


Dynamic patterns of subcellular protein localization during spore coat morphogenesis in Bacillus subtilis.
Endospores of Bacillus subtilis are encased in a thick, proteinaceous shell known as the coat, which is composed of a large number of different proteins. Here we report the identification of three previously uncharacterized coat-associated proteins, YabP, YheD, and YutH, and their patterns of subcellular localization during the process of sporulation, obtained by using fusions of the proteins to the green fluorescent protein (GFP). YabP-GFP was found to form both a shell and a ring around the center of the forespore across the short axis of the sporangium. YheD-GFP, in contrast, formed two rings around the forespore that were offset from its midpoint, before it eventually redistributed to form a shell around the developing spore. Finally, YutH-GFP initially localized to a focus at one end of the forespore, which then underwent transformation into a ring that was located adjacent to the forespore. Next, the ring became a cap at the mother cell pole of the forespore that eventually spread around the entire developing spore. Thus, each protein exhibited its own distinct pattern of subcellular localization during the course of coat morphogenesis. We concluded that spore coat assembly is a dynamic process involving diverse patterns of protein assembly and localization.


Sexual abuse: a sociological perspective.
How have contemporary social changes affected the problem of child sexual abuse? The rapid rise of this problem to public attention in the United States is in part due to the mobilization around the problem by the women's movement and the child welfare movement there. But factors shown by research to be associated with the problem--social isolation and patriarchal authority--are so widespread as to suggest that this is a problem of international proportions, as well. The rising divorce rate in the U.S. and worldwide, would appear to put more children at risk at the same time that it has also made it easier for children and their mothers to escape from the most oppressive and intolerable family situations. The sexual revolution and the erosion of external controls on sexual behavior have also in all likelihood aggravated the problem, too. Sexual abuse needs to be seen as a problem distinct from physical child abuse--characterized by the preponderance of offenders who are males. This suggests searching for the sources of the problem in male sexual socialization rather than in problems of inadequate and disaffected parenting.


Value of Information Analytical Methods: Report 2 of the ISPOR Value of Information Analysis Emerging Good Practices Task Force.
The allocation of healthcare resources among competing priorities requires an assessment of the expected costs and health effects of investing resources in the activities and of the opportunity cost of the expenditure. To date, much effort has been devoted to assessing the expected costs and health effects, but there remains an important need to also reflect the consequences of uncertainty in resource allocation decisions and the value of further research to reduce uncertainty. Decision making with uncertainty may turn out to be suboptimal, resulting in health loss. Consequently, there may be value in reducing uncertainty, through the collection of new evidence, to better inform resource decisions. This value can be quantified using value of information (VOI) analysis. This report from the ISPOR VOI Task Force describes methods for computing 4 VOI measures: the expected value of perfect information, expected value of partial perfect information (EVPPI), expected value of sample information (EVSI), and expected net benefit of sampling (ENBS). Several methods exist for computing EVPPI and EVSI, and this report provides guidance on selecting the most appropriate method based on the features of the decision problem. The report provides a number of recommendations for good practice when planning, undertaking, or reviewing VOI analyses. The software needed to compute VOI is discussed, and areas for future research are highlighted.


Persistence of tandem arrays: implications for satellite and simple-sequence DNAs.
Recombination processes acting on tandem arrays are suggested here to have probable intrinsic biases, producing an expected net decrease in array size following each event, in contrast to previous models which assume no net change in array size. We examine the implications of this by modeling copy number dynamics in a tandem array under the joint interactions of sister-strand unequal crossing over (rate gamma per generation per copy) and intrastrand recombination resulting in deletion (rate epsilon per generation per copy). Assuming no gene amplification or selection, the expected mean persistence time of an array starting with z excess copies (i.e., array size z + 1) is z(1 + gamma/epsilon) recombinational events. Nontrivial equilibrium distributions of array sizes exist when gene amplification or certain forms of selection are considered. We characterize the equilibrium distribution for both a simple model of gene amplification and under the assumption that selection imposes a minimal array size, n. For the latter case, n + 1/alpha is an upper bound for mean array size under fairly general conditions, where alpha(= 2 epsilon/gamma) is the scaled deletion rate. Further, the distribution of excess copies over n is bounded above by a geometric distribution with parameter alpha/(1 + alpha). Tandem arrays are unlikely to be greatly expanded by unequal crossing over unless alpha much less than 1, implying that other mechanisms, such as gene amplification, are likely important in the evolution of large arrays. Thus unequal crossing over, by itself, is likely insufficient to account for satellite DNA.


Urine Spot Samples Can Be Used to Estimate 24-Hour Urinary Sodium Excretion in Children.
The gold standard to assess salt intake is 24-h urine collections. Use of a urine spot sample can be a simpler alternative, especially when the goal is to assess sodium intake at the population level. Several equations to estimate 24-h urinary sodium excretion from urine spot samples have been tested in adults, but not in children. The objective of this study was to assess the ability of several equations and urine spot samples to estimate 24-h urinary sodium excretion in children. A cross-sectional study of children between 6 and 16 y of age was conducted. Each child collected one 24-h urine sample and 3 timed urine spot samples, i.e., evening (last void before going to bed), overnight (first void in the morning), and morning (second void in the morning). Eight equations (i.e., Kawasaki, Tanaka, Remer, Mage, Brown with and without potassium, Toft, and Meng) were used to estimate 24-h urinary sodium excretion. The estimates from the different spot samples and equations were compared with the measured excretion through the use of several statistics. Among the 101 children recruited, 86 had a complete 24-h urine collection and were included in the analysis (mean age: 10.5 y). The mean measured 24-h urinary sodium excretion was 2.5 g (range: 0.8-6.4 g). The different spot samples and equations provided highly heterogeneous estimates of the 24-h urinary sodium excretion. The overnight spot samples with the Tanaka and Brown equations provided the most accurate estimates (mean bias: -0.20 to -0.12 g; correlation: 0.48-0.53; precision: 69.7-76.5%; sensitivity: 76.9-81.6%; specificity: 66.7%; and misclassification: 23.0-27.7%). The other equations, irrespective of the timing of the spot, provided less accurate estimates. Urine spot samples, with selected equations, might provide accurate estimates of the 24-h sodium excretion in children at a population level. At an individual level, they could be used to identify children with high sodium excretion. This study was registered at clinicaltrials.gov as NCT02900261.


Comparison between cold water immersion therapy (CWIT) and light emitting diode therapy (LEDT) in short-term skeletal muscle recovery after high-intensity exercise in athletes--preliminary results.
In the last years, phototherapy has becoming a promising tool to improve skeletal muscle recovery after exercise, however, it was not compared with other modalities commonly used with this aim. In the present study we compared the short-term effects of cold water immersion therapy (CWIT) and light emitting diode therapy (LEDT) with placebo LEDT on biochemical markers related to skeletal muscle recovery after high-intensity exercise. A randomized double-blind placebo-controlled crossover trial was performed with six male young futsal athletes. They were treated with CWIT (5°C of temperature [SD ±1°]), active LEDT (69 LEDs with wavelengths 660/850 nm, 10/30 mW of output power, 30 s of irradiation time per point, and 41.7 J of total energy irradiated per point, total of ten points irradiated) or an identical placebo LEDT 5 min after each of three Wingate cycle tests. Pre-exercise, post-exercise, and post-treatment measurements were taken of blood lactate levels, creatine kinase (CK) activity, and C-reactive protein (CRP) levels. There were no significant differences in the work performed during the three Wingate tests (p > 0.05). All biochemical parameters increased from baseline values (p < 0.05) after the three exercise tests, but only active LEDT decreased blood lactate levels (p = 0.0065) and CK activity (p = 0.0044) significantly after treatment. There were no significant differences in CRP values after treatments. We concluded that treating the leg muscles with LEDT 5 min after the Wingate cycle test seemed to inhibit the expected post-exercise increase in blood lactate levels and CK activity. This suggests that LEDT has better potential than 5 min of CWIT for improving short-term post-exercise recovery.


Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells.
Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neu+/- mice (neuT mice), IFNAR1-/- neu+/- mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuT+ mammospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDH+ cells, suggesting that IFN-I controls stemness in tumor cells. Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658-70. ©2018 AACR.


Mechanical Mitral Valve Replacement: A Multicenter Study of Outcomes With Use of 15- to 17-mm Prostheses.
The aim of this study was to evaluate early and mid-term outcomes (mortality and prosthetic valve reintervention) after mitral valve replacement with 15- to 17-mm mechanical prostheses. A multicenter, retrospective cohort study was performed among patients who underwent mitral valve replacement with a 15- to 17-mm mechanical prosthesis at 6 congenital cardiac centers: 5 in The Netherlands and 1 in the United States. Baseline, operative, and follow-up data were evaluated. Mitral valve replacement was performed in 61 infants (15 mm, n = 17 [28%]; 16 mm, n = 18 [29%]; 17 mm, n = 26 [43%]), of whom 27 (47%) were admitted to the intensive care unit before surgery and 22 (39%) required ventilator support. Median age at surgery was 5.9 months (interquartile range [IQR] 3.2-17.4), and median weight was 5.7 kg (IQR, 4.5-8.8). There were 13 in-hospital deaths (21%) and 8 late deaths (17%, among 48 hospital survivors). Major adverse events occurred in 34 (56%). Median follow-up was 4.0 years (IQR, 0.4-12.5) First prosthetic valve replacement (n = 27 [44%]) occurred at a median of 3.7 years (IQR, 1.9-6.8). Prosthetic valve endocarditis was not reported, and there was no mortality related to prosthesis replacement. Other reinterventions included permanent pacemaker implantation (n = 9 [15%]), subaortic stenosis resection (n = 4 [7%]), aortic valve repair (n = 3 [5%], and aortic valve replacement (n = 6 [10%]). Mitral valve replacement with 15- to 17-mm mechanical prostheses is an important alternative to save critically ill neonates and infants in whom the mitral valve cannot be repaired. Prosthesis replacement for outgrowth can be carried out with low risk.


The variant histone H2A.V of Drosophila--three roles, two guises.
Histone variants play important roles in eukaryotic genome organization, the control of gene expression, cell division and DNA repair. Unlike other organisms that employ several H2A variants for different functions, the parsimonious fruit fly Drosophila melanogaster gets along with just a single H2A variant, H2A.V. Remarkably, H2A.V unites within one molecule features and functions of two different mammalian H2A variants, H2A.Z and H2A.X. Accordingly, H2A.V is involved in diverse functions, as an element of a class of active promoter structure, as a foundation for heterochromatin assembly and as a DNA damage sensor. Here, we comprehensively review the current knowledge of this fascinating histone variant.


Axon guidance mechanisms for establishment of callosal connections.
Numerous studies have investigated the formation of interhemispheric connections which are involved in high-ordered functions of the cerebral cortex in eutherian animals, including humans. The development of callosal axons, which transfer and integrate information between the right/left hemispheres and represent the most prominent commissural system, must be strictly regulated. From the beginning of their growth, until reaching their targets in the contralateral cortex, the callosal axons are guided mainly by two environmental cues: (1) the midline structures and (2) neighboring? axons. Recent studies have shown the importance of axona guidance by such cues and the underlying molecular mechanisms. In this paper, we review these guidance mechanisms during the development of the callosal neurons. Midline populations express and secrete guidance molecules, and "pioneer" axons as well as interactions between the medial and lateral axons are also involved in the axon pathfinding of the callosal neurons. Finally, we describe callosal dysgenesis in humans and mice, that results from a disruption of these navigational mechanisms.


Historical comparison of gender inequality in scientific careers across countries and disciplines.
There is extensive, yet fragmented, evidence of gender differences in academia suggesting that women are underrepresented in most scientific disciplines and publish fewer articles throughout a career, and their work acquires fewer citations. Here, we offer a comprehensive picture of longitudinal gender differences in performance through a bibliometric analysis of academic publishing careers by reconstructing the complete publication history of over 1.5 million gender-identified authors whose publishing career ended between 1955 and 2010, covering 83 countries and 13 disciplines. We find that, paradoxically, the increase of participation of women in science over the past 60 years was accompanied by an increase of gender differences in both productivity and impact. Most surprisingly, though, we uncover two gender invariants, finding that men and women publish at a comparable annual rate and have equivalent career-wise impact for the same size body of work. Finally, we demonstrate that differences in publishing career lengths and dropout rates explain a large portion of the reported career-wise differences in productivity and impact, although productivity differences still remain. This comprehensive picture of gender inequality in academia can help rephrase the conversation around the sustainability of women's careers in academia, with important consequences for institutions and policy makers.


Rift Valley fever virus-induced encephalomyelitis and hepatitis in calves.
Three calves (Nos. 1, 2 = 7 days old; No. 3 = 21 days old) were inoculated subcutaneously with virulent Rift Valley fever (RVF) virus. All calves became viremic and clinically ill, but the two 7-day-old calves were moribund and were euthanatized subsequently on post-inoculation day (PID) 3. Highest viral titers were measured in the serum, with lesser concentrations in the brain, heart, spleen, and liver of these animals. Viral antigens were detected by immunohistochemical analysis only in the livers, where positive staining was localized in coalescing foci of hepatocellular necrosis. The 21-day-old calf appeared to recover after viremia and pyrexia but became lethargic and ataxic and was euthanatized on PID 9. The calf was no longer viremic, and RVF virus was isolated only from the brain. Microscopic examination of the central nervous system revealed diffuse perivascular infiltrates of lymphocytes and macrophages, multifocal meningitis, and focal areas of neuronal necrosis and aggregates of macrophages, lymphocytes, and neutrophils throughout all regions of the brain and cervical spinal cord. There was positive immunohistochemical staining for viral antigens within the cytoplasm of neurons and glial cells throughout the central nervous system. Thus, RVF virus can cause encephalomyelitis in calves, and the specific virologic diagnosis can be made by immunohistochemical localization of viral antigens in formalin-fixed tissues.


Safe staffing for nursing in emergency departments: evidence review.
Getting staffing levels wrong in hospitals is linked to excess mortality and poor patient experiences but establishing the safe nurse staffing levels in the emergency department (ED) is challenging because patient demand is so variable. This paper reports a review conducted for the National Institute for Health and Care Excellence (NICE) which sought to identify the research evidence to inform UK nursing workforce planning. We searched 10 electronic databases and relevant websites for English language studies published from 1994. Studies included reported a direct measure of nurse staffing relative to an activity measure (eg, attendances, patient throughput) or an estimate of nurse staffing requirements. Randomised or non-randomised trials, prospective or retrospective observational, cross-sectional or correlational studies, interrupted time-series, and controlled before and after studies were considered. We identified 16,132 items via databases and 2193 items through manual and other searching. After title/abstract screening (by one reviewer, checked by a second) 55 studies underwent full assessment by the review team. 18 studies met the inclusion criteria for the NICE review, however 3 simulation studies that reported simulated rather than measured outcomes are not reported here. The evidence is weak but indicates that levels of nurse staffing in the ED are associated with patients leaving without being seen, ED care time and patient satisfaction. Lower staffing is associated with worse outcomes. There remain significant gaps and in particular a lack of evidence on the impact of staffing on direct patient outcomes and adequate economic analyses to inform decisions about nurse staffing. Given that an association between nurse staffing levels and patient outcomes on inpatient wards has been demonstrated, this gap in the evidence about nurse staffing in EDs needs to be addressed.


The PecT repressor coregulates synthesis of exopolysaccharides and virulence factors in Erwinia chrysanthemi.
Erwinia chrysanthemi 3937 synthesizes an exopolysaccharide (EPS) composed of rhamnose, galactose, and galacturonic acid. Fourteen transcriptional fusions in genes required for EPS synthesis, named eps, were obtained by Tn5-B21 mutagenesis. Eleven of them are clustered on the chromosome and are repressed by PecT, a regulator of pectate lyase synthesis. In addition, expression of these fusions is repressed by the catabolite regulatory protein, CRP, and induced in low osmolarity medium. The three other mutations are located in genes that are not regulated by pecT. A 13-kb DNA fragment containing pecT-regulated eps genes has been cloned. All the genes identified on this fragment are transcribed in the same orientation and could form a large operon. The promoter region of this operon has been sequenced. It contains a JUMP-start sequence, a sequence required for the expression of polysaccharide-associated operons. E. chrysanthemi 3937 produces a systemic soft rot on its host Saintpaulia ionantha. An eps mutant was less efficient than the wild-type strain in initiating a maceration symptom, suggesting that production of EPS is required for the full expression of the E. chrysanthemi virulence.


Origin of corn: pollen evidence.
The origin of Indian corn remains controversial. Its closest wild relative is teosinte, with which it hybridizes freely to produce fertile progeny. Teosinte ears are smaller and simpler than those of corn. Searches for a more likely living ancestor have failed, but nine of its assumed pollen grains have been recovered in deep drillcore samples obtained from a stratum of soil under Mexico City, which is believed to antedate man in the Western Hemisphere. These nine largest grains are indistinguishable from pollen of modern corn. It has been assumed to be that of a postulated wild corn other than that of teosinte, but this does not account for the possibility that the pollen grains are those of a tetraploid teosinte-producing pollen with two sets of chromosomes. This likelihood has been examined by treating modern teosinte plants with colchicine, which induces tetraploidy. The result has been many teosinte pollen grains indistinguishable in size from modern corn. In interpreting thrs outcome it is important also to know that heat treatment of corn and other plants induces polyploidy, and that the deep drill-core pollen was recovered in a stratum of volcanic clay indicating the high temperature known to favor doubling of corn pollen volumes.


Antibody recognition of Shiga toxins (Stxs): computational identification of the epitopes of Stx2 subunit A to the antibodies 11E10 and S2C4.
We have recently developed a new method to predict the epitopes of the antigens that are recognized by a specific antibody. In this work, we applied the method to identify the epitopes of the Shiga toxin (Stx2 subunit A) that were bound by two specific antibodies 11E10 and S2C4. The predicted epitopes of Stx2 binding to the antibody 11E10 resembles the recognition surface constructed by the regions of Stx2 identified experimentally. For the S2C4, our results indicate that the antibody recognizes the Stx2 at two different regions on the protein surface. The first region (residues 246-254: ARSVRAVNE) is similar to the recognition region of the 11E10, while the second region is formed by two epitopes. The second region is particularly significant because it includes the amino acid sequence region that is diverse between Stx2 and other Stx (residues 176-188: QREFRQALSETAPV). This new recognition region is believed to play an important role in the experimentally observed selectivity of S2C4 to the Stx2.


Molecular imaging and targeted drug delivery using albumin-based nanoparticles.
Albumin has been used as a popular material for carrying imaging probes and/or drugs to provide efficient biomedical imaging and therapy. It is considered as an ideal material for in vivo applications, because albumin is naturally abundant in serum to show non-toxicity and non-immunogenicity. In addition, based on the convenience of chemical modifications, it is widely used for the delivery of diverse molecules including chemicals, proteins/peptides, and oligonucleotides. Albumin nanoparticles carrying these molecules have shown improved pharmacokinetic properties by providing longer circulation time and more disease-specific accumulation, and they are emerging as a promising carrier system for in vivo imaging and therapy. Constant efforts to improve the properties of albumin nanoparticles have led to a great progress in medical application, and recent examples of market approval and success are brightening the prospect of albumin-based nanocarrier formulations in the future. This article will summarize the developments in albumin nanocarriers for biomedical imaging and targeted drug delivery. This review will give an account of the different applications of albumin carriers with examples of some recent innovative works.


Psychiatric issues in renal failure and dialysis.
This article aims to bring to the fore, issues regarding the interface of psychiatry and renal failure. Depression, anxiety, suicide and delirium are common complications observed in patients with renal failure. Pharmacological management of these problems need stringent monitoring on part of the psychiatrist. This article examines the various complications that may be observed in patients with renal failure while discussing treatment approaches and also emphasizing the need for interdisciplinary team work in improving the quality of life of patients with renal failure and those on dialysis.


Bicyclic peptide ligands pulled out of cysteine-rich peptide libraries.
Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format X(m)CX(n)CX(o)CX(p) are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.


Transgenic Xenopus embryos from sperm nuclear transplantations reveal FGF signaling requirements during gastrulation.
We have developed a simple approach for large-scale transgenesis in Xenopus laevis embryos and have used this method to identify in vivo requirements for FGF signaling during gastrulation. Plasmids are introduced into decondensed sperm nuclei in vitro using restriction enzyme-mediated integration (REMI). Transplantation of these nuclei into unfertilized eggs yields hundreds of normal, diploid embryos per day which develop to advanced stages and express integrated plasmids nonmosaically. Transgenic expression of a dominant negative mutant of the FGF receptor (XFD) after the mid-blastula stage uncouples mesoderm induction, which is normal, from maintenance of mesodermal markers, which is lost during gastrulation. By contrast, embryos expressing XFD contain well-patterned nervous systems despite a putative role for FGF in neural induction.


Characterization of methicillin-susceptible and -resistant staphylococci in the clinical setting: a multicentre study in Nigeria.
The staphylococci are implicated in a variety of human infections; however, many clinical microbiology laboratories in Nigeria do not identify staphylococci (in particular coagulase negative staphylococci - CNS) to the species level. Moreover, data from multi-centre assessment on antibiotic resistance and epidemiology of the staphylococci are not available in Nigeria. This study investigated 91 non-duplicate staphylococcal isolates obtained from the microbiology laboratories of eight hospitals in Nigeria during the period January to April 2010. Identification and antibiotic susceptibility testing was performed using the VITEK 2 system, detection of resistance genes by PCR, and molecular characterization was determined by SCCmec typing, spa and multilocus sequence typing (MLST). All the isolates were susceptible to mupirocin, tigecycline, vancomycin and linezolid, but 72.5% of CNS and 82.3% of Staphylococcus aureus were resistant to cotrimoxazole, while multiresistance was observed in 37 of the 40 CNS isolates. Untypeable SCCmec types (ccrC/Class A mec and ccr-negative/Class C2 mec gene complex) in two methicillin-resistant S. aureus (MRSA) were identified. Additionally, ccr-negative/Class A mec and ccr type 4/Class C2 mec gene complex was detected in one isolate each of S. sciuri and S. haemolyticus, respectively. The S. aureus isolates were classified into 21 spa types including two new types (t8987, t9008) among the methicillin-susceptible S. aureus (MSSA) isolates. Two (CC8-SCCmecnon-typeable and CC88-SCCmec IV) and four (CC8-SCCmec III/IV/V; CC30-SCCmec II/III; CC88-SCCmec IV; and ST152-SCCmecnon-typeable) MRSA clones were identified in Maiduguri (North-East Nigeria) and South-West Nigeria, respectively. The proportion of Panton-Valentine leukocidin (PVL)-positive MSSA was high (44.4%) and 56.3% of these strains were associated with sequence type (ST) 152. The identification of multiresistant mecA positive S. haemolyticus and S. sciuri from clinical samples indicates that characterization of CNS is important in providing information on their diversity and importance in Nigeria. There is the need to develop new SCCmec classification methods for non-typeable methicillin-resistant staphylococci, and to curtail the spread and establishment of the S. aureus ST152 clone in Nigeria. The study presents the first report of a PVL-positive ST152-SCCmecnontypeable MRSA and SCCmec typing of methicillin-resistant CNS in Nigeria.


Characterising Complex Enzyme Reaction Data.
The relationship between enzyme-catalysed reactions and the Enzyme Commission (EC) number, the widely accepted classification scheme used to characterise enzyme activity, is complex and with the rapid increase in our knowledge of the reactions catalysed by enzymes needs revisiting. We present a manual and computational analysis to investigate this complexity and found that almost one-third of all known EC numbers are linked to more than one reaction in the secondary reaction databases (e.g., KEGG). Although this complexity is often resolved by defining generic, alternative and partial reactions, we have also found individual EC numbers with more than one reaction catalysing different types of bond changes. This analysis adds a new dimension to our understanding of enzyme function and might be useful for the accurate annotation of the function of enzymes and to study the changes in enzyme function during evolution.


Implementing Eccentric Resistance Training-Part 2: Practical Recommendations.
The purpose of this review is to provide strength and conditioning practitioners with recommendations on how best to implement tempo eccentric training (TEMPO), flywheel inertial training (FIT), accentuated eccentric loading (AEL), and plyometric training (PT) into resistance training programs that seek to improve an athlete's hypertrophy, strength, and power output. Based on the existing literature, TEMPO may be best implemented with weaker athletes to benefit positional strength and hypertrophy due to the time under tension. FIT may provide an effective hypertrophy, strength, and power stimulus for untrained and weaker individuals; however, stronger individuals may not receive the same eccentric (ECC) overload stimulus. Although AEL may be implemented throughout the training year to benefit hypertrophy, strength, and power output, this strategy is better suited for stronger individuals. When weaker and stronger individuals are exposed to PT, they are exposed to an ECC overload stimulus as a result of increases in the ECC force and ECC rate of force development. In conclusion, when choosing to utilize ECC training methods, the practitioner must integrate these methods into a holistic training program that is designed to improve the athlete's performance capacity.


DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia.
We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL. We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5. Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.


Preliminary characterization of hemolymph coagulation in Anopheles gambiae larvae.
Hemolymph coagulation is a first response to injury, impeding infection, and ending bleeding. Little is known about its molecular basis in insects, but clotting factors have been identified in the fruit fly Drosophila melanogaster. Here, we have begun to study coagulation in the aquatic larvae of the malaria vector mosquito Anopheles gambiae using methods developed for Drosophila. A delicate clot was seen by light microscopy, and pullout and proteomic analysis identified phenoloxidase and apolipophorin-I as major candidate clotting factors. Electron microscopic analysis confirmed clot formation and revealed it contains fine molecular sheets, most likely a result of lipophorin assembly. Phenoloxidase appears to be more critical in clot formation in Anopheles than in Drosophila. The Anopheles larval clot thus differs in formation, structure, and composition from the clot in Drosophila, confirming the need to study coagulation in different insect species to learn more about its evolution and adaptation to different lifestyles.


Syntenin, a syndecan adaptor and an Arf6 phosphatidylinositol 4,5-bisphosphate effector, is essential for epiboly and gastrulation cell movements in zebrafish.
Epiboly, the spreading and the thinning of the blastoderm to cover the yolk cell and close the blastopore in fish embryos, is central to the process of gastrulation. Despite its fundamental importance, little is known about the molecular mechanisms that control this coordinated cell movement. By a combination of knockdown studies and rescue experiments in zebrafish (Danio rerio), we show that epiboly relies on the molecular networking of syntenin with syndecan heparan sulphate proteoglycans, which act as co-receptors for adhesion molecules and growth factors. Furthermore, we show that the interaction of syntenin with phosphatidylinositol 4,5-bisphosphate (PIP2) and with the small GTPase ADP-ribosylation factor 6 (Arf6), which regulate the endocytic recycling of syndecan, is necessary for epiboly progression. Analysis of the earliest cellular defects suggests a role for syntenin in the autonomous vegetal expansion of the yolk syncytial layer and the rearrangement of the actin cytoskeleton in extra-embryonic tissues, but not in embryonic cell fate determination. This study identifies the importance of the syntenin-syndecan-PIP2-Arf6 complex for the progression of fish epiboly and establishes its key role in directional cell movements during early development.


Neuropsychological assessment of sport-related concussion.
Assessment of concussion can be challenging for medical practitioners given the different factors associated with each individual injury. The use of neuropsychological testing provides an objective method in the evaluation and management of concussion. Over the last 20 years it has become increasingly useful in the realm of sports concussion and has been deemed a cornerstone of concussion management by the Concussion in Sport group at the International Symposia on Concussion in Sport. Neuropsychological assessment has evolved to using computer-based neurocognitive testing, which has become increasingly common over the last decade, especially in organized sports. Neuropsychological assessment has also proven to be effective in the detection of differences based on several individual factors, including age, gender, and history of prior concussion. Despite its documented value, neuropsychological assessment should be one of several tools used as part of the concussion assessment/management process.


Effectiveness of early administration of tranexamic acid in patients with severe trauma.
A reduction in mortality with the early use of tranexamic acid has been demonstrated in severely injured patients who are bleeding. However, the modest treatment effect with no reduction in blood transfusion has raised concerns. The aim of the present study was to estimate the effectiveness of regular use of tranexamic acid in severely injured patients. This multicentre observational study used retrospectively collected data from consecutive injured patients (Injury Severity Score at least 16) treated in 15 Japanese academic institutions in 2012. A propensity score-matched analysis compared patients who did or did not receive tranexamic acid administration within 3 h of injury. Study outcomes included 28-day all-cause and cause-specific mortality, and need for blood transfusion. Of 796 eligible subjects, 281 were treated with tranexamic acid. Propensity score matching selected a total of 500 matched subjects (250 in each group). Tranexamic acid administration was associated with lower 28-day mortality (10·0 versus 18·4 per cent; difference -8·4 (95 per cent c.i. -14·5 to -2·3) per cent) and lower 28-day mortality from primary brain injury (6·0 versus 13·2 per cent; difference -7·2 (-12·3 to -2·1) per cent). However, there was no significant difference between groups in the need for blood transfusion (33·2 versus 34·8 per cent; difference -1·6 (-9·9 to 6·7) per cent). Early tranexamic acid use was associated with reduced mortality in severely injured patients, in particular those with a primary brain injury.


Fragmentation to epidural space: first documented complication of Gelstix(TM.).
The knowledge of minimal invasive spinal surgery has increased greatly in recent years. A current issue is the hydrogel implant inserted through nucleus pulposus. In this paper we present a case in which the hydrogel implant was found to be fragmented into the spinal canal at follow up. The patient was a 40-year-old female. She was examined at another clinic because of low back pain about four months ago, and a hydrogel implant was inserted at the L5-S1 level. She was admitted to our clinic due to severe radicular pain. Magnetic resonance imaging (MRI) showed a posterolateral annular tear only and she was explored microneurosurgically as she did not benefit from a foraminal injection. A fragmented hydrogel implant that compressed the spinal root was seen peroperatively and it was excised. Postoperatively the radicular complaints of the patient disappeared and she was discharged with total recovery. Although rare, complications causing compression of neural structures can be seen after placing implants into the disc. In this case, the assessment of the patient according to the clinical presentation and microsurgical exploration if necessary are important.


Intact p53-dependent responses in miR-34-deficient mice.
MicroRNAs belonging to the miR-34 family have been proposed as critical modulators of the p53 pathway and potential tumor suppressors in human cancers. To formally test these hypotheses, we have generated mice carrying targeted deletion of all three members of this microRNA family. We show that complete inactivation of miR-34 function is compatible with normal development in mice. Surprisingly, p53 function appears to be intact in miR-34-deficient cells and tissues. Although loss of miR-34 expression leads to a slight increase in cellular proliferation in vitro, it does not impair p53-induced cell cycle arrest or apoptosis. Furthermore, in contrast to p53-deficient mice, miR-34-deficient animals do not display increased susceptibility to spontaneous, irradiation-induced, or c-Myc-initiated tumorigenesis. We also show that expression of members of the miR-34 family is particularly high in the testes, lungs, and brains of mice and that it is largely p53-independent in these tissues. These findings indicate that miR-34 plays a redundant function in the p53 pathway and suggest additional p53-independent functions for this family of miRNAs.


Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4.
Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent.


Kcna1 gene deletion lowers the behavioral sensitivity of mice to small changes in sound location and increases asynchronous brainstem auditory evoked potentials but does not affect hearing thresholds.
Sound localization along the azimuth depends on the sensitivity of binaural nuclei in the auditory brainstem to small differences in interaural level and timing occurring within a submillisecond epoch and on monaural pathways that transmit level and timing cues with high temporal fidelity to insure their coincident arrival at the binaural targets. The soma and axons of these brainstem neurons are heavily invested with ion channels containing the low-threshold potassium channel subunit Kv1.1, which previous in vitro and in vivo studies suggest are important for regulating their high input-output correspondence and temporal synchrony. We compared awake Kcna1-null mutant (Kcna1-/-) mice lacking Kv1.1 with Kcna1+/+ mice to determine whether Kv1.1 activity contributes to sound localization and examined anesthetized mice for absolute hearing thresholds for suprathreshold differences that may be revealed in the waveforms of auditory brainstem response potentials. The awake -/- mice tested with reflex modification audiometry had reduced sensitivity to an abrupt change in the location of a broad band noise compared to +/+ mice, while anesthetized -/- mice had normal absolute thresholds for tone pips but a high level of stimulus-evoked but asynchronous background activity. Evoked potential waveforms had progressively earlier peaks and troughs in -/- mice, but the amplitude excursions between adjacent features were identical in the two groups. Their greater excitability and asynchrony in suprathreshold evoked potentials coupled with their normal thresholds suggests that a disruption in central neural processing in -/- mice and not peripheral hearing loss is responsible for their poor sound localization.


Human and murine steroid 5β-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid.
Mammalian steroid 5β-reductases belong to the Aldo-Keto Reductase 1D sub-family and are essential for the formation of A-ring 5β-reduced steroids. Steroid 5β-reduction is required for the biosynthesis of bile-acids and the metabolism of all steroid hormones that contain a Δ4-3-ketosteroid functionally to yield the 5β-reduced metabolites. In mammalian AKR1D enzymes the conserved catalytic tetrad found in all AKRs (Y55, H117, K84 and D50) has changed in that the conserved H117 is replaced with a glutamic acid (E120). E120 may act as a "superacid" to facilitate enolization of the Δ4-ketosteroid. In addition, the absence of the bulky imidazole side chain of histidine in E120 permits the steroid to penetrate deeper into the active site so that hydride transfer can occur to the steroid C5 position. In murine steroid 5β-reductase AKR1D4, we find that there is a long-form, with an 18 amino-acid extension at the N-terminus (AKR1D4L) and a short-form (AKR1D4S), where the latter is recognized as AKR1D4 by the major data-bases. Both enzymes were purified to homogeneity and product profiling was performed. With progesterone and cortisol, AKR1D4L and AKR1D4S catalyzed smooth conversion to the 5β-dihydrosteroids. However, with Δ4-androstene-3,17-dione as substrate, a mixture of products was observed which included, 5β-androstane-3,17-dione (expected) but 3α-hydroxy-5β- androstan-17-one was also formed. The latter compound was distinguished from its isomeric 3β-hydroxy-5β-androstan-17-one by forming picolinic acid derivatives followed by LC-MS. These data show that AKR1D4L and AKR1D4S also act as 3α-hydroxysteroid dehydrogenases when presented with Δ4-androstene-3,17-dione and suggest that E120 alters the position the steroid to enable a correct trajectory for hydride transfer and may not act as a "superacid".


Extraction and Purification of Pasteuria spp. Endospores.
Pasteuria penetrans is an endospore-forming bacterial parasite of root-knot nematodes that has potential as a biological control agent. Biochemical investigations of P. penetrans are limited because of difficulty in obtaining large quantities of endospores free of plant debris and contaminating microorganisms. Our objective was to develop a technique for extraction and purification of P. penetrans endospores from root-knot nematodes. Tomato roots infected with Meloidogyne arenaria that was parasitized by P. penetrans were digested with cytolase. The nematode females along with plant debris were washed with a jet stream of water onto an 800-microm-pore sieve nested on a 250-microm-pore sieve. The materials retained on the 250-microm-pore sieve were centrifuged through a 20% sucrose solution. The resulting loose pellet fraction was collected on a 250-microm-pore sieve and then centrifuged through a 47% sucrose solution. Endospore-filled females were handpicked from the 47% sucrose pellicle fraction. Endospores were released by grinding the females with a glass tissue grinder. The endospores were then filtered through a nylon filter with 8-microm openings, collected by centrifugation, and subjected to buoyant density centrifugation in different media. Further purification by buoyant density centrifugation in a linear gradient of sodium diatrizoate resulted in a preparation of endospores free of debris. This additional step may be desirable for the further characterization of components unique to the endospores.


Ventilatory management of infant baboons with hyaline membrane disease: the use of high frequency ventilation.
We tested the hypothesis that high frequency oscillatory ventilation (HFOV) would result in decreased pulmonary barotrauma in infants with hyaline membrane disease by comparing HFOV at 10 Hz to conventional positive pressure ventilation with continual distending airway pressure (PPV/PEEP) in premature baboons with hyaline membrane disease. Nineteen baboon fetuses were randomized to one of two treatment groups, delivered at 140 +/- 2 days, and, after stabilization and instrumentation of PPV/PEEP, placed in their respective ventilator group. Animals on conventional ventilation were managed by adjustment of tidal volume and frequency (to 1 Hz) to keep PaCO2 below 55 and by adjustment of the mean airway pressure. One of the "HFOV" group died of cardiovascular complications before going on HFOV and was eliminated from data analysis. The remaining HFOV baboons survived the 11-day experimental period without evidence of airleak. Six of the 11 prematures treated with PPV/PEEP developed pulmonary interstitial emphysema and/or pneumothorax and five of the animals died within 48 h. The intergroup differences in airleak were significant (p less than 0.05). Mean airway pressure (measured at the proximal airway) was higher initially with HFOV but then was lowered more rapidly than in the PPV/PEEP animals. The arterial to alveolar oxygen ratio rose and the FIO2 could be lowered more rapidly with HFOV than with conventional ventilation. These differences reached significance by 20 h. After 60 h there were no significant differences between HFOV and the PPV/PEEP survivors. HFOV resulted in more uniform saccular expansion, higher arterial to alveolar oxygen ratio, less oxygen exposure, and decreased acute barotrauma when compared to PPV/PEEP.(ABSTRACT TRUNCATED AT 250 WORDS)


Peroxisome proliferator-activated receptor-alpha activation reduces salt-dependent hypertension during chronic endothelin B receptor blockade.
Endothelin B (ETB) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, increases protein expression of cytochrome P450 4A (CYP4A), which is responsible for 20-HETE synthesis in the kidney. Experiments were designed to determine whether clofibrate reduces hypertension associated with chronic ETB receptor blockade. Male Sprague-Dawley rats received either normal-salt (0.8% NaCl) or high-salt (8% NaCl) diet for 10 days. Female rats were fed a high-salt (8% NaCl) diet for 10 days. During the last 7 days, rats of both sexes were divided into 3 treatment groups: (1) clofibrate in drinking water (80 mg per day), (2) ETB receptor antagonist A-192621 in food (10 mg/kg per day), or (3) clofibrate and A-192621. During ETB receptor blockade, clofibrate had no effect on mean arterial pressure (MAP) under normal salt conditions. In contrast, clofibrate significantly inhibited the increase in MAP produced by A-192621 in rats fed a high-salt diet (34+/-3 versus 19+/-4 mm Hg; P <0.05). Similar results were observed in female rats administered A-192621 and fed a high-salt diet. ETB receptor blockade significantly decreased CYP4A protein expression in the renal cortex of rats on high salt. Clofibrate significantly increased renal cortical and medullary CYP4A protein expression in A-192621-treated male rats on high salt. Therefore, chronic PPAR-alpha agonist treatment reduces salt-dependent hypertension produced by ETB receptor blockade in male and female Sprague-Dawley rats. This suggests a possible relationship between ETB receptor activation and the maintenance of CYP4A protein expression in the kidney of rats fed a high-salt diet.


Chiropractic treatment of frozen shoulder syndrome (adhesive capsulitis) utilizing mechanical force, manually assisted short lever adjusting procedures.
To describe treatment of frozen shoulder syndrome (adhesive capsulitis) via conservative chiropractic treatment to the shoulder joint, utilizing specific contact, low force, instrumental adjusting procedures. A case report, providing an illustrative example of the same, is presented along with a review of the relevant literature. A 53-yr-old woman suffered severe shoulder pain of over 6 months' duration. The patient had been diagnosed as having adhesive capsulitis and had undergone a variety of different treatment regimens without obtaining relief, including various NSAIDs, analgesics and physical therapy. At the time of her presentation, her condition had progressed to the point of near total immobility of the shoulder joint, accompanied by severe pain with resulting marked restriction in her normal activities of daily living. The patient's shoulder was conservatively managed with chiropractic adjustments to the affected shoulder joint, as well as to the cervicothoracic spine. Treatment consisted of mechanical force, manually assisted short lever chiropractic adjustments, delivered via an Activator Adjusting Instrument. Successful resolution of the presenting symptomatology was achieved. Chiropractic care may be able to provide an effective mode of therapeutic treatment for certain types of these difficult cases. Low force instrumental adjustments, in particular, may present certain benefits in these cases that the more forceful manipulations and/or mobilizations cannot. As such, further formal investigation of this type of therapeutic intervention for treatment of frozen shoulder may be warranted on a larger scale.


Relationship between physical occupational exposures and health on semen quality: data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study.
To study the relationship among occupation, health, and semen quality in a cohort of men attempting to conceive. Observational prospective cohort. Not applicable. A total of 501 couples discontinuing contraception were followed for 1 year while trying to conceive; 473 men (94%) provided one semen sample, and 80% provided a second sample. None. Semen data obtained through at-home semen collection with next-day analysis/quantification. In all, complete data were available for 456 men, with a mean age of 31.8 years. Work-related heavy exertion was consistently associated with lower semen concentration and total sperm count. Thirteen percent of men who reported heavy exertion displayed oligospermia, compared with 6% who did not report workplace exertion. Shift work, night work, vibration, noise, heat, and prolonged sitting were not associated with semen quality. Men with high blood pressure had significantly lower strict morphology scores compared with normotensive men (17% vs. 21%). In contrast, hyperlipidemia, diabetes, and composite of total comorbidities were not associated with semen quality. The number of medications a man was taking as a proxy of health status was associated with semen quality. There was a negative association between number of medications and sperm count. A negative relationship among occupational exertion, hypertension, and the number of medications with semen quality was identified. As these are potentially modifiable factors, further research should determine whether treatment or cessation may improve male fecundity.


Characterization of Resistance to Stripe Rust in Contemporary Cultivars and Lines of Winter Wheat from the Eastern United States.
Stripe rust, caused by Puccinia striiformis f. sp. tritici, has been an important disease of winter wheat (Triticum aestivum) in the eastern United States since 2000, when a new strain of the pathogen emerged. The new strain overcame the widely used resistance gene, Yr9, and was more aggressive and better adapted to warmer temperatures than the old strain. Host resistance is the most effective approach to manage stripe rust. Winter wheat lines with resistance to the new strain in the field are common, but the genes conferring this resistance are mostly unknown. The objectives of this research were to characterize the all-stage resistance and adult-plant resistance (APR) to stripe rust in a representative group of contemporary winter wheat cultivars and breeding lines and to identify the resistance genes when possible. Of the 50 lines evaluated for all-stage resistance at the seedling stage, nearly all were susceptible to the new strain. Based on a linked molecular marker, seven lines had resistance gene Yr17 that confers resistance to both old and new strains; however, this resistance was difficult to identify in the seedling stage. Of the 19 lines evaluated for APR, all expressed APR compared with a very susceptible check. Nine had race-specific APR to the new strain and nine had APR to both old and new strains. The remaining line, 26R61, had all-stage resistance to the old strain (conferred by resistance gene Yr9) and a high level of APR to the new strain. APR was expressed as low infection type, low percent leaf area diseased, and long latent period at heading stage under both low and high temperature regimes and could be identified as early as jointing stage. Based on tests for linked molecular markers, the most widely used slow-rusting APR genes, Yr18 and Yr29, were not present in any of the lines. The results of this research indicate that effective all-stage resistance was conferred only by Yr17 and that APR was common and likely conferred by unknown race-specific genes rather than genes conferring slow rusting that are more likely to be durable.


A renewed focus on primary health care: revitalize or reframe?
The year 2008 celebrated 30 years of Primary Health Care (PHC) policy emerging from the Alma Ata Declaration with publication of two key reports, the World Health Report 2008 and the Report of the Commission on the Social Determinants of Health. Both reports reaffirmed the relevance of PHC in terms of its vision and values in today's world. However, important challenges in terms of defining PHC, equity and empowerment need to be addressed.This article takes the form of a commentary reviewing developments in the last 30 years and discusses the future of this policy. Three challenges are put forward for discussion (i) the challenge of moving away from a narrow technical bio-medical paradigm of health to a broader social determinants approach and the need to differentiate primary care from primary health care; (ii) The challenge of tackling the equity implications of the market oriented reforms and ensuring that the role of the State in the provision of welfare services is not further weakened; and (iii) the challenge of finding ways to develop local community commitments especially in terms of empowerment.These challenges need to be addressed if PHC is to remain relevant in today's context. The paper concludes that it is not sufficient to revitalize PHC of the Alma Ata Declaration but it must be reframed in light of the above discussion.


Therapeutic touch for healing acute wounds.
Therapeutic Touch (TT) is an alternative therapy that has gained popularity over the past two decades for helping wounds to heal. Practitioners enter a meditative state and pass their hands above the patient's body to find and correct any imbalances in the patient's 'life energy' or chi. Scientific instruments have been unable to detect this energy. The effect of TT on wound healing has been expounded in anecdotal publications. To identify and review all relevant data to determine the effects of TT on healing acute wounds. In January 2014, for this fifth update, we searched The Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. All randomised or quasi-randomised controlled trials, which compared the effect of TT with a placebo, another treatment, or no treatment control were considered. Studies which used TT as a stand-alone treatment, or as an adjunct to other therapies, were eligible. One author (DO'M) determined the eligibility for inclusion of all trials in the review. Both authors conducted data extraction and evaluation of trial validity independently. Each trial was assessed using predetermined criteria. No new trials were identified for this update. Four trials in people with experimental wounds were included. The effect of TT on wound healing in these studies was variable. Two trials (n = 44 & 24) demonstrated a significant increase in healing associated with TT, while one trial found significantly worse healing after TT and the other found no significant difference. All trials are at high risk of bias. There is no robust evidence that TT promotes healing of acute wounds.


Gastric cancer risk factors in subjects with family history.
Until now, it has been unclear whether there are differences in various risk factor profiles for familial gastric cancer, i.e., gastric cancer among subjects with a family history of the disease. A total of 722 gastric cancer patients and 2024 controls were admitted between 1985 and 1992 to a network of hospitals in the Greater Milan area. Of these, 88 cases and 103 controls who reported a family history of gastric cancer in first degree relatives were considered in the present analysis. There was no relationship between gastric cancer risk and tobacco smoking or alcohol drinking. Shorter duration of electrical refrigerator use was related to a nonsignificant increased risk and a high daily meal frequency was associated with an increased gastric cancer risk. Significant direct trends of risk were observed for pasta (odds ratio, OR = 4.20 for the highest versus the lowest tertile), bread (OR, 2.86), red meat (OR, 3.38), and preserved meat (OR, 1.90). Inverse associations were observed for increasing consumption of selected vegetables and fruits, chiefly peppers (OR = 0.31), total fruits (OR, 0.47), and citrus fruits (OR, 0.38). With reference to selected micronutrients, a significant inverse trend in risk with increasing consumption for beta-carotene (OR, 0.27) and ascorbic acid (OR, 0.20) was observed. These results suggest that dietary risk factors for subjects with a family history of gastric cancer in first-degree relatives are not appreciably different from well-established risk factors of the disease in the general population.


Lessons from the Canadian national health information technology plan for the United States: opinions of key Canadian experts.
To summarize the Canadian health information technology (HIT) policy experience and impart lessons learned to the US as it determines its policy in this area. Qualitative analysis of interviews with identified key stakeholders followed by an electronic survey. We conducted semi-structured interviews with 29 key Canadian HIT policy and opinion leaders and used a grounded theory approach to analyze the results. The informant sample was chosen to provide views from different stakeholder groups including national representatives and regional representatives from three Canadian provinces. Canadian informants believed that much of the current US direction is positive, especially regarding incentives and meaningful use, but that there are key opportunities for the US to emphasize direct engagement with providers, define a clear business case for them, sponsor large scale evaluations to assess HIT impact in a broad array of settings, determine standards but also enable access to resources needed for mid-course corrections of standards when issues are identified, and, finally, leverage implementation of digital imaging systems. Not all stakeholder groups were included, such as providers or patients. In addition, as in all qualitative research, a selection bias could be present due to the relatively small sample size. Based on Canadian experience with HIT policy, stakeholders identified as lessons for the US the need to increase direct engagement with providers and the importance of defining the business case for HIT, which can be achieved through large scale evaluations, and of recognizing and leveraging successes as they emerge.


Ultra-broadband terahertz perfect absorber by exciting multi-order diffractions in a double-layered grating structure.
Terahertz (THz) perfect absorber, as a useful functional device, has attracted considerable attention. Traditional metamaterial perfect absorbers are usually in response to single-frequency or multi-frequency owing to the resonance features of the metal-based sub-wavelength structure. In this paper, a simple double-layered doped-silicon grating structure was designed to realize an ultra-broadband and polarization-independent THz perfect absorber. Both theoretical and experimental results demonstrate that the incident THz waves ranging from 0.59 to 2.58 THz can be efficiently absorbed with an absorptivity of more than 95% and a bandwidth of about 2.0 THz. The excellent characteristic of this broad-bandwidth THz perfect absorber is mainly resulted from the air gap mode resonance together with the first-order and the second-order grating diffractions.


A multiplexed gRNA piggyBac transposon system facilitates efficient induction of CRISPRi and CRISPRa in human pluripotent stem cells.
CRISPR-Cas9-mediated gene interference (CRISPRi) and activation (CRISPRa) approaches hold promise for functional gene studies and genome-wide screens in human pluripotent stem cells (hPSCs). However, in contrast to CRISPR-Cas9 nuclease approaches, the efficiency of CRISPRi/a depends on continued expression of the dead Cas9 (dCas9) effector and guide RNA (gRNA), which can vary substantially depending on transgene design and delivery. Here, we design and generate new fluorescently labeled piggyBac (PB) vectors to deliver uniform and sustained expression of multiplexed gRNAs. In addition, we generate hPSC lines harboring AAVS1-integrated, inducible and fluorescent dCas9-KRAB and dCas9-VPR transgenes to allow for accurate quantification and tracking of cells that express both the dCas9 effectors and gRNAs. We then employ these systems to target the TCF4 gene in hPSCs and assess expression levels of the dCas9 effectors, individual gRNAs and targeted gene. We also assess the performance of our PB system for single gRNA delivery, confirming its utility for library format applications. Collectively, our results provide proof-of-principle application of a stable, multiplexed PB gRNA delivery system that can be widely exploited to further enable genome engineering studies in hPSCs. Paired with diverse CRISPR tools including our dual fluorescence CRISPRi/a cell lines, this system can facilitate functional dissection of individual genes and pathways as well as larger-scale screens for studies of development and disease.


Mannose-binding lectin genotypes: lack of association with susceptibility to thoracic empyema.
The role of the innate immune protein mannose-binding lectin (MBL) in host defence against severe respiratory infection remains controversial. Thoracic empyema is a suppurative lung infection that arises as a major complication of pneumonia and is associated with a significant mortality. Although the pathogenesis of thoracic empyema is poorly understood, genetic susceptibility loci for this condition have recently been identified. The possible role of MBL genotypic deficiency in susceptibility to thoracic empyema has not previously been reported. To investigate this further we compared the frequencies of the six functional MBL polymorphisms in 170 European individuals with thoracic empyema and 225 healthy control individuals. No overall association was observed between MBL genotypic deficiency and susceptibility to thoracic empyema (2 x 2 Chi square = 0.02, P = 0.87). Furthermore, no association was seen between MBL deficiency and susceptibility to the Gram-positive or pneumococcal empyema subgroups. MBL genotypic deficiency did not associate with progression to death or requirement for surgery. Our results suggest that MBL genotypic deficiency does not associate with susceptibility to thoracic empyema in humans.


High-resolution CT scan findings in familial interstitial pneumonia do not conform to those of idiopathic interstitial pneumonia.
The aim of this study was to describe the high-resolution CT (HRCT) scan features that characterize familial interstitial pneumonia (FIP). FIP was defined by the presence of two or more cases of probable or definite idiopathic interstitial pneumonia (IIP) in individuals related within three degrees. The cases were collected consecutively from three centers. We identified 371 individuals with potential FIP from 289 families, including 340 individuals who had HRCT scans. Two chest radiologists independently reviewed the HRCT scans, scoring the extent and distribution of HRCT scan findings, and assessed the overall radiologic diagnosis. HRCT scan abnormalities suggestive of IIP were present in 85% (289 of 340 subjects). The most frequent findings were reticular pattern (n = 238, 82%) and ground-glass opacity (GGO) associated with reticular abnormality (n = 231, 80%). Other changes included GGO in 116 (40%), honeycombing in 92 (32%), and micronodules in 65 (22%). In the 289 cases with evidence of IIP, the findings were diffusely distributed in the craniocaudal plane in 186 (64%), and the lower lung zones were predominantly involved in 89 (31%). In the axial plane, 194 (67%) had a subpleural distribution; 88 (30%) were diffuse. The imaging pattern was classified as definite or probable usual interstitial pneumonia (UIP) in only 62 subjects (22%) and definite or probable nonspecific interstitial pneumonia (NSIP) in 35 subjects (12%). In 160 subjects (55%), the imaging findings did not conform to previously described UIP or NSIP patterns. Reticulation and a mixed GGO/reticular pattern are the most common HRCT scan findings in FIP. The parenchymal abnormalities are most often diffuse in the craniocaudal dimension and have a predominantly peripheral distribution in the axial dimension. Although a radiologic UIP pattern is not uncommon, most cases do not conform to typical UIP or NSIP patterns.


The detection of faked identity using unexpected questions and mouse dynamics.
The detection of faked identities is a major problem in security. Current memory-detection techniques cannot be used as they require prior knowledge of the respondent's true identity. Here, we report a novel technique for detecting faked identities based on the use of unexpected questions that may be used to check the respondent identity without any prior autobiographical information. While truth-tellers respond automatically to unexpected questions, liars have to "build" and verify their responses. This lack of automaticity is reflected in the mouse movements used to record the responses as well as in the number of errors. Responses to unexpected questions are compared to responses to expected and control questions (i.e., questions to which a liar also must respond truthfully). Parameters that encode mouse movement were analyzed using machine learning classifiers and the results indicate that the mouse trajectories and errors on unexpected questions efficiently distinguish liars from truth-tellers. Furthermore, we showed that liars may be identified also when they are responding truthfully. Unexpected questions combined with the analysis of mouse movement may efficiently spot participants with faked identities without the need for any prior information on the examinee.


Review of a computer based telephone Helpline in an A&E department.
An audit of use of the telephone Helpline in the accident and emergency (A&E) department was conducted to establish the type of call, time, by whom the calls were made, appropriateness of advice given, and whether callers attended or not as advised, and also to obtain feedback from callers as to the degree of satisfaction with the advice given. All calls over a four week period were included in the study. The information logged comprised name, age, telephone number, date and time of call, nature of query, advice given, and name of advisor. Callers whose telephone number had been noted were contacted for feedback. There were 300 calls over the four week period, and 150 callers were available for feedback. Most calls were received between 12.00 and 20.00 hours. The majority of callers were parent or self, 52% of calls were for problems concerning adults, and 40% for children; no age was recorded in 8%. Nursing staff answered 90.7% of the calls. Queries were wide ranging but commonly involved open and closed wounds and head injuries, with 29.3% being advised to attend A&E, 32.3% to ring or see their GP, and 38.4% were reassured or given other advice; 4% of callers attended A&E despite being advised otherwise, 97% were judged to have received appropriate advice, and 91.3% of callers were satisfied with the advice given. The Helpline has proved of benefit to the public. It is necessary and important to have protocols for common problems and to document all details carefully. It is also necessary that nursing staff are trained in handling the telephone queries and using the protocols. The use of a PC based system has improved data collection and also allows immediate access to protocols.


Skin eruptions associated with microscopic polyangiitis.
Microscopic polyangiitis (MPA) is a systemic vasculitis histologically characterized by small-vessel involvement. Antineutrophil cytoplasmic antibodies (especially anti-myeloperoxidase antibodies) (MPO-ANCA) are often positive in serum. Although the skin is affected in 20-70% of patients, the precise description has been limited. This retrospective study analyzed clinical manifestations in patients of MPA with skin eruptions. Ten patients with skin eruptions diagnosed as MPA according to Chapel Hill consensus criteria consisted of 6 men and 4 women aged from 38 to 80 years (62.1 +/- 13.3). Clinical manifestations, laboratory data, and histological findings were examined. Purpura and petechiae in 6 patients, livedo in 2 patients, and erythema in 7 patients, especially erythema on the hands and\or fingers in 4 patients, were observed. Histological findings from the eruptions in 7 patients showed perivascular lymphocyte infiltration in the upper dermis in 4 patients, and infiltration of lymphocytes and a few neutrophils around small arteries in the middle to deep dermis in 2 patients and diffuse infiltration of histiocytes and lymphocytes in the middle dermis in 1 patient. Cutaneous involvements in MPA showed a wide spectrum of clinical and histological findings.


A model of violence.
The assessment of the violent individual presents a challenge to psychiatrists. Many theoretical approaches contribute to the understanding of violence, but none are totally adequate for the clinician's purposes. The assessment of violent behaviour can be undertaken using three separate dimensions--"Dehumanisation", "Acceptance of Violence" and "Rage and its Control"--which together form a framework for the formulation of clinical data. This framework is described and the relevance of theoretical contributions to the three dimensions is discussed. It is suggested that this framework assists in the classification of violent individuals and in the prediction of the potential for future violence.


Phosphonoformic acid inhibits viral replication by trapping the closed form of the DNA polymerase.
Phosphonoformic acid (PFA, foscarnet) belongs to a class of antiviral drugs that inhibit the human cytomegalovirus DNA polymerase (UL54) by mimicking the pyrophosphate leaving group of the nucleotide transfer reaction. Difficulties expressing UL54 have hampered investigation of the precise structural requirements rendering inhibition by this drug. However, a previously engineered chimeric DNA polymerase, constructed by mutating the homologous polymerase from bacteriophage RB69 (gp43) to express several variable elements from UL54, can bypass this obstacle because of its favorable expression and acquired sensitivity to PFA (Tchesnokov, E. P., Obikhod, A., Schinazi, R. F., and Götte, M. (2008) J. Biol. Chem. 283, 34218-34228). Here, we compare two crystal structures that depict the chimeric DNA polymerase with and without PFA bound. PFA is visualized for the first time in the active site of a DNA polymerase, where interactions are resolved between the PP(i) mimic and two basic residues absolutely conserved in the fingers domain of family B polymerases. PFA also chelates metal ion B, the cation that contacts the triphosphate tail of the incoming nucleotide. These DNA complexes utilize a primer-template pair enzymatically chain-terminated by incorporation of acyclo-GMP, the phosphorylated form of the anti-herpes drug acyclovir. We postulate that the V478W mutation present in the chimera is critical in that it pushes the fingers domain to more readily adopt the closed conformation whether or not the drug is bound. The closed state of the fingers domain traps the variant polymerase in the untranslocated state and increases affinity for PFA. This finding provides a model for the mechanism of UL54 stalling by PFA.


Negative Urinalyses in Febrile Infants Age 7 to 60 Days Treated for Urinary Tract Infection.
The role of the urinalysis (UA) in the management of young, febrile infants is controversial. To assess how frequently infants are treated for urinary tract infection (UTI) despite having normal UA values and to compare the characteristics of infants treated for UTI who have positive versus negative UAs, we reviewed 20,570 wellappearing febrile infants 7-60 days of age evaluated at 124 hospitals in the United States who were included in a national quality improvement project. Of 19,922 infants without bacteremia and meningitis, 2,407 (12.1%) were treated for UTI, of whom 2,298 (95.5%) had an initial UA performed. UAs were negative in 337/2,298 (14.7%) treated subjects. The proportion of infants treated for UTI with negative UAs ranged from 0%-35% across hospitals. UA-negative subjects were more likely to have respiratory symptoms and less likely to have abnormal inflammatory markers than UA+ subjects, indicating that they are mounting less of an inflammatory response to their underlying illness and/or might have contaminated specimens or asymptomatic bacteriuria.


Surface plasmon polariton enhanced by optical parametric amplification in nonlinear hybrid waveguide.
We theoretically studied nonlinear interactions between surface plasmon polariton (SPP) and conventional waveguide mode in nonlinear hybrid waveguide and proposed a possible method to enhance SPP wave via optical parametric amplification (OPA). The phase matching condition of this OPA process is fulfilled by carefully tailoring the dispersions of SPP and guided mode. The influences of incident intensity and phase of guided wave on the OPA process are comprehensively analyzed. It is found that not only a strong enhancement of SPP but also modulations on this enhancement can be achieved. This result indicates potential applications in nonlinear optical integration and modulations.


Additional financial costs borne by cancer patients: a narrative review.
To review out-of-pocket costs related to cancer that are borne by patients and their families. A literature search using key terms relating to out-of-pocket costs incurred by cancer patients and their families was undertaken to generate a comprehensive narrative synthesis of the information available. Four themes were identified: measuring costs; sources of costs; the impact of costs and reducing costs. The wide variety of measures for ascertaining hidden costs makes comparison of findings difficult; some articles cover a very narrow range of costs. Qualitative research is useful for elucidating a wide range of costs. Costs pertaining to hospital visits, nutrition and clothing are widely mentioned. Low additional expenditure may indicate that needs/wants are going unmet. Financial capacity to cope and subjective perception of impact are important. Low income, younger age, chemotherapy and living rurally are associated with greater impact. Extra expense can exert long-term effects on family finances. Primary care follow-up, telemedicine and treatments that entail fewer visits may serve to reduce patient costs. The key question is how to organise/deliver cancer care in order to reduce additional expenses to patients and families. Future research could identify critical time-points and demographic groups susceptible to significant additional costs, in order to target support at those most in need.


Physical Examination-Indicated Cerclage: A Systematic Review and Meta-analysis.
To estimate the effectiveness of physical examination-indicated cerclage in the setting of second-trimester cervical dilatation by systematic review and meta-analysis of published studies. We searched MEDLINE, EMBASE, Scopus, ClinicalTrials.gov, Web of Science, and the Cochrane Library for studies published between 1966 and 2014 that evaluated cervical cerclage for the treatment of cervical insufficiency. The search yielded 6,314 citations. We included cohort studies and randomized controlled trials comparing cerclage placement with expectant management of women with cervical dilatation between 14 and 27 weeks of gestation. Two investigators independently reviewed each citation for inclusion or exclusion and discordant decisions were arbitrated by a third reviewer. Summary estimates were reported as the mean difference and 95% confidence interval (CI) for continuous variables or relative risk and with 95% CI for dichotomous outcomes. Fixed- and random-effects meta-analysis was used, depending on heterogeneity. Ten studies met inclusion criteria and were included in the final analysis. One was a randomized controlled trial, two were prospective cohort studies, and the remaining seven were retrospective cohort studies. Of the 757 women, 485 (64%) underwent physical examination-indicated cerclage placement and 272 (36%) were expectantly managed. Cerclage was associated with increased neonatal survival (71% compared with 43%; relative risk 1.65, 95% CI 1.19-2.28) and prolongation of pregnancy (mean difference 33.98 days, 95% CI 17.88-50.08). Physical examination-indicated cerclage is associated with a significant increase in neonatal survival and prolongation of pregnancy of approximately 1 month when compared with no such cerclage. The strength of this conclusion is limited by the potential for bias in the included studies.


Mining the bitter melon (momordica charantia l.) seed transcriptome by 454 analysis of non-normalized and normalized cDNA populations for conjugated fatty acid metabolism-related genes.
Seeds of Momordica charantia (bitter melon) produce high levels of eleostearic acid, an unusual conjugated fatty acid with industrial value. Deep sequencing of non-normalized and normalized cDNAs from developing bitter melon seeds was conducted to uncover key genes required for biotechnological transfer of conjugated fatty acid production to existing oilseed crops. It is expected that these studies will also provide basic information regarding the metabolism of other high-value novel fatty acids. Deep sequencing using 454 technology with non-normalized and normalized cDNA libraries prepared from bitter melon seeds at 18 DAP resulted in the identification of transcripts for the vast majority of known genes involved in fatty acid and triacylglycerol biosynthesis. The non-normalized library provided a transcriptome profile of the early stage in seed development that highlighted the abundance of transcripts for genes encoding seed storage proteins as well as for a number of genes for lipid metabolism-associated polypeptides, including Δ12 oleic acid desaturases and fatty acid conjugases, class 3 lipases, acyl-carrier protein, and acyl-CoA binding protein. Normalization of cDNA by use of a duplex-specific nuclease method not only increased the overall discovery of genes from developing bitter melon seeds, but also resulted in the identification of 345 contigs with homology to 189 known lipid genes in Arabidopsis. These included candidate genes for eleostearic acid metabolism such as diacylglycerol acyltransferase 1 and 2, and a phospholipid:diacylglycerol acyltransferase 1-related enzyme. Transcripts were also identified for a novel FAD2 gene encoding a functional Δ12 oleic acid desaturase with potential implications for eleostearic acid biosynthesis. 454 deep sequencing, particularly with normalized cDNA populations, was an effective method for mining of genes associated with eleostearic acid metabolism in developing bitter melon seeds. The transcriptomic data presented provide a resource for the study of novel fatty acid metabolism and for the biotechnological production of conjugated fatty acids and possibly other novel fatty acids in established oilseed crops.


Novel and known signals of selection for fat deposition in domestic sheep breeds from Africa and Eurasia.
Genomic regions subjected to selection frequently show signatures such as within-population reduced nucleotide diversity and outlier values of differentiation among differentially selected populations. In this study, we analyzed 50K SNP genotype data of 373 animals belonging to 23 sheep breeds of different geographic origins using the Rsb (extended haplotype homozygosity) and FST statistical approaches, to identify loci associated with the fat-tail phenotype. We also checked if these putative selection signatures overlapped with regions of high-homozygosity (ROH). The analyses identified novel signals and confirmed the presence of selection signature in genomic regions that harbor candidate genes known to affect fat deposition. Several genomic regions that frequently appeared in ROH were also identified within each breed, but only two ROH islands overlapped with the putative selection signatures. The results reported herein provide the most complete genome-wide study of selection signatures for fat-tail in African and Eurasian sheep breeds; they also contribute insights into the genetic basis for the fat tail phenotype in sheep, and confirm the great complexity of the mechanisms that underlie quantitative traits, such as the fat-tail.


Physical activity in relation to total, advanced, and fatal prostate cancer.
Physical activity has been inconsistently related to total prostate cancer and few studies have examined whether this association varies by disease aggressiveness. We examined physical activity in relation to total, advanced, and fatal prostate cancer in the NIH-AARP Diet and Health Study. At baseline (1995-1996), 293,902 men ages 50 to 71 years completed a questionnaire inquiring about current frequency of vigorous exercise of at least 20 min of duration, as well as frequency of exercise during adolescence (ages 15-18). We used proportional hazards regression to calculate multivariate relative risks (RR) and 95% confidence intervals (95% CI). During up to 8.2 years of follow-up, 17,872 prostate cancer cases were identified, including 1,942 advanced and 513 fatal cases. Comparing frequent (5+ times per week) versus infrequent (less than once per week) vigorous exercise, exercise at baseline was not associated with risk of total prostate cancer (RR, 1.01; 95% CI, 0.96-1.07; P(trend) = 0.78), advanced prostate cancer (RR, 1.14; 95% CI, 0.97-1.33; P(trend) = 0.25), or fatal prostate cancer (RR, 0.90; 95% CI, 0.67-1.20; P(trend) = 0.12). Increasing level of vigorous exercise during adolescence was associated with a small 3% reduction in total prostate cancer risk (frequent versus infrequent exercise during adolescence: RR, 0.97; 95% CI, 0.91-1.03; P(trend) = 0.03) but was not associated with risk of advanced prostate cancer (RR, 0.95; 95% CI, 0.78-1.14; P(trend) = 0.18) or fatal prostate cancer (RR, 0.96; 95% CI, 0.67-1.36; P(trend) = 0.99). Neither vigorous exercise at baseline nor exercise during adolescence was related to risk of total, advanced, or fatal prostate cancer in this large prospective cohort.


Characterisation and validation of farmers' knowledge and practice of cattle trypanosomosis management in the cotton zone of West Africa.
We carried out a knowledge, attitude, practice (KAP) survey on how farmers (n=895) manage cattle trypanosomosis in Burkina Faso, Mali and Guinea. Most farmers (96%) recognised the common signs of trypanosomosis, 70% knew the role of tsetse flies in transmitting the disease and 96% had knowledge of drugs used for treatment. Farmers reported that trypanosomosis was the most important cattle disease and estimated that 25% of their herd fall sick each year and 18% of the sick animals die. Nearly all sick animals (90%) were treated with trypanocides and most treatments were administered by untrained farmers. Giving drugs was the strategy most used as primary means of protection (50% of farmers) followed by avoiding high risk areas (32% of farmers) and keeping trypanotolerant cattle (7% of farmers). Few farmers knew about communal tsetse control methods and those who did, rarely practiced them. Farmer diagnosis of trypanosomosis in cattle presented at clinics (n=113) was in most cases (84%) supported by laboratory tests. However, the signs that most farmers considered indicative of trypanosomosis (staring coat and emaciation) were poor predictors of trypanosomosis. We tested farmer knowledge of injection sites and trypanocide dilutions (n=423 cattle), and while few (15%) farmers gave under-dosages or over-dosage (2% of farmers), injection techniques were poor with injection-related side effects in 24% of cattle treated by farmers. Despite this, therapeutic outcomes were both objectively (clinical parameters) and subjectively (carer assessment) satisfactory in 89% of cattle treated by farmers. This study found that farmers play a major role in successfully managing trypanosomosis and recommends the recognition and support for community based treatment.


Non-attendees' attitudes to the design of a cardiac rehabilitation programme focused on information of risk factors and professional involvement.
Enhancing the accuracy of the content of cardiac rehabilitation programmes (CRPs) and providing the mediators preferred by patients can increase attendance rates in line with secondary prevention goals. The aim of this study was therefore to explore non-attendees' attitudes to the design of a CRP focused on information of risk factors and professional involvement. Consecutive patients with coronary heart disease (n=100) who declined to participate in a CRP answered a questionnaire focusing on patients' attitudes to risk factors and cardiac rehabilitation. Non-attendees considered that information of hypertension and information of sedentary lifestyle constituted the most important content of a CRP. Physicians, nurses and social workers were considered the most suitable professional categories. Females preferred nurses when discussing smoking issues while males preferred physicians. More males compared to females preferred occupational therapists for dealing with stress, physicians for depression and social workers for social isolation. Non-attendees' attitudes are similar to those of attendees and quite traditional in that they favour physician or nurse-led activities. There is a difference in attitude between male and female.


Numerical Priming Between Touch and Vision Depends on Tactile Discrimination.
Although the interaction between vision and touch is of crucial importance for perceptual and bodily self-consciousness, only little is known regarding the link between conscious access and tactile processing. Here, we tested whether the numerical encoding of tactile stimuli depends on conscious discrimination. On each trial, participants received between zero and three taps at low, medium, or high intensity and had to enumerate the number of visual items subsequently presented as a visual target. We measured tactovisual numerical priming, that is, the modulation of reaction times according to the numerical distance between the visual target and tactile prime values. While numerical priming and repetition priming were respectively elicited by high and medium intensity stimuli, no effect was found for low intensity stimuli that were not discriminable. This suggests that numerical priming between touch and vision depends on tactile discrimination. We discuss our results considering recent advances in unconscious visual numerical priming.


Plasma and urine dopamine in man given sodium chloride in the diet.
1. Plasma and urine free dopamine were measured daily for 5 days in six normal subjects maintained on a low sodium diet. The subjects were then given dietary supplements of sodium chloride for 5 days and the measurements repeated. 2. Throughout the experiment the 24 h free dopamine excretion rates for all the subjects were higher than could be accounted for by renal clearance. Dopamine excretion increased significantly in response to the added sodium chloride whereas plasma dopamine remained unchanged. The rise in dopamine excretion preceded that of sodium excretion. 3. It is concluded that free dopamine is formed within the kidney in response to increased dietary sodium and may have a role in the control of sodium excretion.


Effects of telomerase and telomere length on epidermal stem cell behavior.
A key process in organ homeostasis is the mobilization of stem cells out of their niches. We show through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted stem cell mobilization, hair growth, and stem cell proliferation in vitro. The effects of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging.