Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells.
Walnuts have been gathering attention for their health-promoting properties. They are rich in polyphenols, mainly ellagitannins (ETs) that after consumption are hydrolyzed to release ellagic acid (EA). EA is further metabolized by microbiota to form urolithins, such as A and B, which are absorbed. ETs, EA and urolithins have shown to slow the proliferation and growth of different types of cancer cells but the mechanisms remain unclear. We investigate the role of urolithins in the regulatory mechanisms in prostate cancer, specifically those related to the androgen receptor (AR), which have been linked to the development of this type of cancer. In our study, urolithins down-regulated the mRNA and protein levels of both prostate specific antigen (PSA) and AR in LNCaP cells. The luciferase assay performed with a construct containing three androgen response elements (AREs) showed that urolithins inhibit AR-mediated PSA expression at the transcriptional level. Electrophoretic mobility shift assays revealed that urolithins decreased AR binding to its consensus response element. Additionally, urolithins induced apoptosis in LNCaP cells, and this effect correlated with a decrease in Bcl-2 protein levels. In summary, urolithins attenuate the function of the AR by repressing its expression, causing a down-regulation of PSA levels and inducing apoptosis. Our results suggest that a diet rich in ET-containing foods, such as walnuts, could contribute to the prevention of prostate cancer.


Characteristics of Salmonella Recovered From Stools of Children Enrolled in the Global Enteric Multicenter Study.
The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313. Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics. Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa.


Random peptide libraries: a source of specific protein binding molecules.
Libraries of random peptide sequences were constructed and screened to identify peptides that specifically bind to proteins. In one of these about 2 X 10(7) different 15-residue peptide sequences were expressed on the surface of the coliphage M13. Each phage encoded a single random sequence and expressed it as a fusion complex with pIII, a minor coat protein present at five molecules per phage. Phage encoding nine different streptavidin-binding peptide sequences were isolated from this library. The core consensus sequence was His-Pro-Gln and binding of these phage to streptavidin was inhibited by biotin. This type of library makes it possible to identify peptides that bind to proteins (or other macromolecules) that have no previously known affinity for peptides.


Analysis of linear and non-linear genotype × environment interaction.
The usual analysis of genotype × environment interaction (G × E) is based on the linear regression of genotypic performance on environmental changes (e.g., classic stability analysis). This linear model may often lead to lumping together of the non-linear responses to the whole range of environmental changes from suboptimal and super optimal conditions, thereby lowering the power of detecting G × E variation. On the other hand, the G × E is present when the magnitude of the genetic effect differs across the range of environmental conditions regardless of whether the response to environmental changes is linear or non-linear. The objectives of this study are: (i) explore the use of four commonly used non-linear functions (logistic, parabola, normal and Cauchy functions) for modeling non-linear genotypic responses to environmental changes and (ii) to investigate the difference in the magnitude of estimated genetic effects under different environmental conditions. The use of non-linear functions was illustrated through the analysis of one data set taken from barley cultivar trials in Alberta, Canada (Data A) and the examination of change in effect sizes is through the analysis another data set taken from the North America Barley Genome Mapping Project (Data B). The analysis of Data A showed that the Cauchy function captured an average of >40% of total G × E variation whereas the logistic function captured less G × E variation than the linear function. The analysis of Data B showed that genotypic responses were largely linear and that strong QTL × environment interaction existed as the positions, sizes and directions of QTL detected differed in poor vs. good environments. We conclude that (i) the non-linear functions should be considered when analyzing multi-environmental trials with a wide range of environmental variation and (ii) QTL × environment interaction can arise from the difference in effect sizes across environments.


Comparison of wiping and rinsing techniques after oral care procedures in critically ill patients during endotracheal intubation and after extubation: A prospective cross-over trial.
Endotracheal intubation of critically ill patients increases the risk of aspiration pneumonia, which can be reduced by regular oral care. However, the rinsing of the residual oral contaminants after mechanical cleaning carries the risk of aspirating the residue during the intubation period. Removing the contaminants by wiping with mouth wipes could be an alternative to rinsing with water because of no additional fluid. This study tested: (i) the amount of oral bacteria during endotracheal intubation and after extubation; and (ii) the changes in the bacterial count during oral care procedures. Thirty-five mechanically ventilated patients in the intensive care unit were enrolled. The amount of bacteria on the dorsal tongue surface was counted before and following oral care and then after the elimination of contaminants either by rinsing with water and suctioning or by wiping with mouth wipes. The oral bacterial amount was compared statistically between the intubation and extubation status and among set time points during the oral care procedure. The oral bacterial count was significantly decreased after extubation. During the oral care procedure, the oral bacterial amount was significantly lower after eliminating the contaminants either by rinsing or wiping, with no remarkable difference between the elimination techniques. The findings suggest that the oral bacterial amount is elevated during endotracheal intubation, which could increase the risk of aspiration pneumonia. The significant reduction in the bacterial count by wiping indicates that it might be a suitable alternative to rinsing for mechanically ventilated patients.


Procyanidins protect Caco-2 cells from bile acid- and oxidant-induced damage.
Procyanidins can exert cytoprotective, anti-inflammatory, and anticarcinogenic actions in the gastrointestinal tract. Previous evidence has shown that procyanidins can interact with synthetic membranes and protect them from oxidation and disruption. Thus, in this study we investigated the capacity of a hexameric procyanidin fraction (Hex) isolated from cocoa to protect Caco-2 cells from deoxycholic (DOC)-induced cytotoxicity, cell oxidant increase, and loss of monolayer integrity. Hex interacted with the cell membranes without affecting their integrity, as evidenced by a Hex-mediated increase in the transepithelial electrical resistance, and inhibition of DOC-induced cytotoxicity. DOC induced an increase in cell oxidants, alterations in the paracellular transport, and redistribution of the protein ZO-1 from cell-cell contacts into the cytoplasm. Hex partially inhibited all these events at concentrations ranging from 2.5 to 20 microM. Similarly, Hex (5-10 microM) inhibited the increase in cell oxidants, and the loss of integrity of polarized Caco-2 cell monolayers induced by a lipophilic oxidant (2,2'-azobis (2,4-dimethylvaleronitrile). Results show that the assayed procyanidin fraction can interact with cell membranes and protect Caco-2 cells from DOC-induced cytotoxicity, oxidant generation, and loss of monolayer integrity. At the gastrointestinal tract, large procyanidins may exert beneficial effects in pathologies such us inflammatory diseases, alterations in intestinal barrier permeability, and cancer.


New Methods for Personal Exposure Monitoring for Airborne Particles.
Airborne particles have been associated with a range of adverse cardiopulmonary outcomes, which has driven its monitoring at stationary central sites throughout the world. Individual exposures, however, can differ substantially from concentrations measured at central sites due to spatial variability across a region and sources unique to the individual, such as cooking or cleaning in homes, traffic emissions during commutes, and widely varying sources encountered at work. Personal monitoring with small, battery-powered instruments enables the measurement of an individual's exposure as they go about their daily activities. Personal monitoring can substantially reduce exposure misclassification and improve the power to detect relationships between particulate pollution and adverse health outcomes. By partitioning exposures to known locations and sources, it may be possible to account for variable toxicity of different sources. This review outlines recent advances in the field of personal exposure assessment for particulate pollution. Advances in battery technology have improved the feasibility of 24-h monitoring, providing the ability to more completely attribute exposures to microenvironment (e.g., work, home, commute). New metrics to evaluate the relationship between particulate matter and health are also being considered, including particle number concentration, particle composition measures, and particle oxidative load. Such metrics provide opportunities to develop more precise associations between airborne particles and health and may provide opportunities for more effective regulations.


Analysis of pulse modulation format in coded BOTDA sensors.
A theoretical and experimental analysis of the impact of pulse modulation format on Brillouin optical time-domain analysis (BOTDA) sensors using pulse coding techniques has been carried out. Pulse coding with conventional non-return-to-zero (NRZ) modulation format is shown to induce significant distortions in the measured Brillouin gain spectrum (BGS), especially in proximity of abrupt changes in the fiber gain spectra. Such an effect, as confirmed by the theoretical analysis, is due to acoustic wave pre-excitation and non-uniform gain which depends on the bit patterns defined by the different codewords. A successful use of pulse coding techniques then requires to suitably optimize the employed modulation format in order to avoid spurious oscillations causing severe penalties in the attained accuracy. Coding technique with return-to-zero (RZ) modulation format is analyzed under different duty-cycle conditions for a 25 km-long sensing scheme, showing that low duty-cycle values are able to effectively suppress the induced distortions in the BGS and allow for spatially-accurate, high-resolution strain and temperature measurements being able to fully exploit the provided coding gain (approximately 7.2 dB along 25 km distance) with unaltered spatial resolution (1 meter). Although Simplex coding is used in our analysis, the validity of the results is general and can be directly applied to any intensity-modulation coding scheme.


Does perceptual belongingness affect lightness constancy?
The relation between perceptual belongingness and lightness perception has historically been studied in the contrast domain (Benary, 1924 Psychologische Forschung 5 131 - 142). However, scientists have shown that two equal grey patches may differ in lightness when belonging to different reflecting surfaces. We extend this investigation to the constancy domain. In a CRT simulation of a bipartite field of illumination, we manipulated the arrangement of twelve patches: six squares and six diamonds. Patches of the same shape could be placed: (i) all within the same illumination field; or (ii) forming a row across the illumination fields. Furthermore, we manipulated proximity between the innermost patches and the illumination edge. The patches could be (i) touching (forming an X-junction); or (ii) not touching (not forming an X-junction). Observers were asked to perform a lightness match between two additional patches, one illuminated and the other in shadow. We found better lightness constancy when the patches of the same shape formed a row across the fields, with no effect of X-junctions. Since lightness constancy is improved by strengthening the belongingness across the illumination fields, we conclude that belongingness might help the visual system to aggregate the differently illuminated surfaces, and facilitate the scission process.


Dye transfer between cells of the embryonic chick lens becomes less sensitive to CO2 treatment with development.
During the 3-h developmental stage 14 in the chick, intercellular transfer of iontophoresed fluorescent dyes becomes less sensitive to the lowering of intracellular pH by either CO2 or acetate ions. Up to developmental state 14, dye transfer between lens cells is reversibly blocked by exposure to 50% CO2. Beyond stage 14, dye transfer between these cells is no longer reversibly blocked by elevated pCO2. Electronic coupling is present throughout lens development and is not reversibly blocked by high pCO2 at any stage. The gap junctions joining the lens cells show morphological changes at developmental stage 14. Up to stage 14, all gap junctions observed between chick lens cells have connexon assemblies that appear condensed or crystalline following routine freeze-fracture microscopy. Beyond stage 14, chick lens cells express gap junctions with both the condensed assemblies and the dispersed assemblies characteristic of adult lens gap-junction structure.


Continuation treatment of chronic depression: a comparison of nefazodone, cognitive behavioral analysis system of psychotherapy, and their combination.
Little is known about the relative benefits of psychotherapy, medication, and combined treatment as continuation therapies for chronic forms of major depressive disorder (MDD) after a positive response to acute treatment. We hypothesize that combined treatment would demonstrate superior continuation phase outcomes compared to either monotherapy, as evidenced by lower relapse rates and greater rates of improvement from partial to full remission. We report 16-week continuation phase outcomes for 324 patients who had participated in either the acute phase of a randomized multicenter trial of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combination therapy (COMB) for chronic forms of MDD. Patients entering the continuation phase had either fully or partially remitted after 12 weeks of acute phase treatment. The primary efficacy measure was the 24-item Hamilton Rating Scale for Depression. For patients in remission at acute phase exit, 73.3% (107/146) maintained their remitted status at endpoint of the continuation phase. Of those having a partial remission at acute phase exit, 52.9% (92/174) achieved full remission by end of continuation. A greater proportion of patients maintained a partial or full remission status on COMB (90%) compared to nefazodone (80%, p=0.011) or to CBASP (82%, p=0.042). These differences reflected greater symptom re-emergence in the partial remission groups on CBASP and nefazodone monotherapy compared to COMB. Continuation treatment assignment was not randomized or blinded. There was no placebo group. Most patients with chronic forms of MDD sustained their acute phase response and more than 50% of partial remitters achieved full remission while continuing treatment with nefazodone, CBASP, or COMB. COMB was associated with less symptom re-emergence during the continuation phase than either monotherapy, particularly for partial remitters.


The properties of the International Classification of the External Cause of Injury when used as an instrument for injury prevention research.
To demonstrate properties of the International Classification of the External Cause of Injury (ICECI) as a tool for use in injury prevention research. The Childhood Injury Prevention Study (CHIPS) is a prospective longitudinal follow up study of a cohort of 871 children 5-12 years of age, with a nested case crossover component. The ICECI is the latest tool in the International Classification of Diseases (ICD) family and has been designed to improve the precision of coding injury events. The details of all injury events recorded in the study, as well as all measured injury related exposures, were coded using the ICECI. This paper reports a substudy on the utility and practicability of using the ICECI in the CHIPS to record exposures. Interrater reliability was quantified for a sample of injured participants using the Kappa statistic to measure concordance between codes independently coded by two research staff. There were 767 diaries collected at baseline and event details from 563 injuries and exposure details from injury crossover periods. There were no event, location, or activity details which could not be coded using the ICECI. Kappa statistics for concordance between raters within each of the dimensions ranged from 0.31 to 0.93 for the injury events and 0.94 and 0.97 for activity and location in the control periods. This study represents the first detailed account of the properties of the ICECI revealed by its use in a primary analytic epidemiological study of injury prevention. The results of this study provide considerable support for the ICECI and its further use.


The gonadotropin-inhibitory hormone system of fish: The case of sea bass (Dicentrarchus labrax).
Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide belonging to the RFamide peptide family that was first discovered in quail by Tsutsui and co-workers in the year 2000. Since then, different GnIH orthologues have been identified in all vertebrate groups, from agnathans to mammals. These GnIH genes synthesize peptide precursors that encompass two to four C-terminal LPXRFamide peptides. Functional and behavioral studies carried out in birds and mammals have demonstrated a clear inhibitory role of GnIH on GnRH and gonadotropin synthesis and secretion as well as on aggressive and sexual behavior. However, the effects of Gnih orthologues in reproduction remain controversial in fish with both stimulatory and inhibitory actions being reported. In this paper, we will review the main findings obtained in our laboratory on the Gnih system of the European sea bass, Dicentrarchus labrax. The sea bass gnih gene encodes two putative Gnih peptides (sbGnih1 and sbGnih2), and is expressed in the olfactory bulbs/telencephalon, diencephalon, midbrain tegmentum, rostral rhombencephalon, retina and testis. The immunohistochemical study performed using specific antibodies developed in our laboratory revealed Gnih-immunoreactive (ir) perikarya in the same central areas and Gnih-ir fibers that profusely innervated the brain and pituitary of sea bass. Moreover, in vivo studies revealed the inhibitory role of centrally- and peripherally-administered Gnih in the reproductive axis of male sea bass, by acting at the brain (on gnrh and kisspeptin expression), pituitary (on gnrh receptors and gonadotropin synthesis and release) and gonadal (on androgen secretion and gametogenesis) levels. Our results have revealed the existence of a functional Gnih system in sea bass, and have provided evidence of the differential actions of the two Gnih peptides on the reproductive axis of this species, the main inhibitory role in the brain and pituitary being exerted by the sbGnih2 peptide. Recent studies developed in our laboratory also suggest that Gnih might be involved in the transduction of photoperiod and temperature information to the reproductive axis, as well as in the modulation of daily and seasonal rhythmic processes in sea bass.


Saltation and stasis: a model of human growth.
Human growth has been viewed as a continuous process characterized by changing velocity with age. Serial length measurements of normal infants were assessed weekly (n = 10), semiweekly (n = 18), and daily (n = 3) (19 females and 12 males) during their first 21 months. Data show that growth in length occurs by discontinuous, aperiodic saltatory spurts. These bursts were 0.5 to 2.5 centimeters in amplitude during intervals separated by no measurable growth (2 to 63 days duration). These data suggest that 90 to 95 percent of normal development during infancy is growth-free and length accretion is a distinctly saltatory process of incremental bursts punctuating background stasis.


Imaging renal cell carcinoma with ultrasonography, CT and MRI.
The increased use of abdominal imaging techniques for a variety of indications has contributed to more-frequent detection of renal cell carcinoma (RCC). Ultrasonography has been used to characterize the solid versus cystic nature of renal masses. This modality has limitations, however, in further characterization of solid tumors and in staging of malignancy, although contrast-enhanced ultrasonography has shown promise. Cross-sectional imaging with multiplanar reconstruction capability via CT or MRI has become the standard-bearer in the diagnosis, staging and surveillance of renal cancers. The use of specific protocols and the exploitation of different imaging characteristics of RCC subtypes, including variations in contrast agent timing, MRI weighting and digital subtraction, have contributed to this diagnostic capability. Cystic renal masses are a special case, evaluation of which can require multiple imaging modalities. Rigorous evaluation of these lesions can provide information that is crucial to prediction of the likelihood of malignancy. Such imaging is not without risk, however, as radiation from frequent CT imaging has been implicated in the development of secondary malignancies, and contrast agents for CT and MRI can pose risks, particularly in patients with compromised renal function.


Oxygen-controlled regulation of the flavohemoglobin gene in Bacillus subtilis.
A gene, hmp, which encodes a ubiquitous protein homologous to hemoglobin was isolated among genes from Bacillus subtilis that are induced under anaerobic conditions. The hmp protein belongs to the family of two-domain flavohemoproteins, homologs of which have been isolated from various organisms such as Escherichia coli, Alcaligenes eutrophus, and Saccharomyces cerevisiae. These proteins consist of an amino-terminal hemoglobin domain and a carboxy-terminal redox active site domain with potential binding sites for NAD(P)H and flavin adenine dinucleotide. The expression of hmp is strongly induced upon oxygen limitation, and the induction is dependent on a two-component regulatory pair, ResD and ResE, an anaerobic regulator, FNR, and respiratory nitrate reductase, NarGHJI. The requirement of FNR and NarGHJI for hmp expression is completely bypassed by the addition of nitrite in the culture medium, indicating that fnr is required for transcriptional activation of narGHJI, which produces nitrite, leading to induction of hmp expression. In contrast, induction of hmp was still dependent on resDE in the presence of nitrite. A defect in hmp in B. subtilis has no significant effect on anaerobic growth.


Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial.
Trials of beta blockers in patients undergoing non-cardiac surgery have reported conflicting results. This randomised controlled trial, done in 190 hospitals in 23 countries, was designed to investigate the effects of perioperative beta blockers. We randomly assigned 8351 patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery to receive extended-release metoprolol succinate (n=4174) or placebo (n=4177), by a computerised randomisation phone service. Study treatment was started 2-4 h before surgery and continued for 30 days. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00182039. All 8351 patients were included in analyses; 8331 (99.8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group reached the primary endpoint (244 [5.8%] patients in the metoprolol group vs 290 [6.9%] in the placebo group; hazard ratio 0.84, 95% CI 0.70-0.99; p=0.0399). Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4.2%] vs 239 [5.7%] patients; 0.73, 0.60-0.89; p=0.0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3.1%] vs 97 [2.3%] patients; 1.33, 1.03-1.74; p=0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] vs 19 [0.5%] patients; 2.17, 1.26-3.74; p=0.0053). Our results highlight the risk in assuming a perioperative beta-blocker regimen has benefit without substantial harm, and the importance and need for large randomised trials in the perioperative setting. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.


Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action.
Individuals with a history of binge drinking have an increased risk of developing the metabolic syndrome and type 2 diabetes. Whether binge drinking impairs glucose homeostasis and insulin action is unknown. To test this, we treated Sprague-Dawley rats daily with alcohol (3 g/kg) for three consecutive days to simulate human binge drinking and found that these rats developed and exhibited insulin resistance even after blood alcohol concentrations had become undetectable. The animals were resistant to insulin for up to 54 hours after the last dose of ethanol, chiefly a result of impaired hepatic and adipose tissue insulin action. Because insulin regulates hepatic glucose production and white adipose tissue lipolysis, in part through signaling in the central nervous system, we tested whether binge drinking impaired brain control of nutrient partitioning. Rats that had consumed alcohol exhibited impaired hypothalamic insulin action, defined as the ability of insulin infused into the mediobasal hypothalamus to suppress hepatic glucose production and white adipose tissue lipolysis. Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. Intracerebroventricular infusion of CPT-157633, a small-molecule inhibitor of PTP1B, prevented binge drinking-induced glucose intolerance. These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B.


Evaluation of Matrix Metalloproteinase 9 Serum Concentration as a Biomarker in Malignant Mesothelioma.
Malignant mesothelioma (MM) is a rare, but fatal disease with few treatment options. The diagnosis and treatment response are challenging in MM. Therefore, the search for novel diagnostic and prognostic biomarkers is ongoing. The aim of our study was to investigate matrix metalloproteinase 9 (MMP9) as a potential serum biomarker of treatment response and survival in MM. We also investigated the influence of genetic polymorphisms on MMP9 serum levels. We included 110 patients with MM that have been previously genotyped for common MMP9 polymorphisms. Serum samples were collected before treatment, at the end of chemotherapy, and at the time of progression. MMP9 serum levels were measured using enzyme-linked immunosorbent assay kits. The role of serum MMP9 and MMP9 polymorphisms in treatment response was determined using the nonparametric tests and logistic or Cox regression. Median serum MMP9 was 706.7 (499.6-1224.9) ng/ml before treatment, 440.5 (255.9-685.2) ng/ml after chemotherapy, and 502.8 (307.2-851.4) ng/ml at disease progression. After chemotherapy, 87 (79.8%) patients had lower serum MMP9, with the median change of -286.3 (-607.3 to -70.2) ng/ml (P < 0.001). At disease progression, 47 (65.3%) patients had lower serum MMP9 compared to pretreatment values, with the median change of -163.7 (-466.6 to 108.6) ng/ml (P = 0.001). Patients with higher performance status had higher serum MMP9 before treatment (P = 0.010). Among investigated polymorphisms, only rs17576 was associated with serum MMP9 levels before treatment (P = 0.041). Median serum MMP9 levels differed significantly before and after treatment of MM, but failed to reach significance as a standalone biomarker. The contribution of MMP9 serum levels and MMP9 polymorphisms to a composite diagnostic and prognostic biomarker should be further tested.


Selenium fortification of infant formulas: does selenium form matter?
Selenium is a trace element essential for the health and development of the growing infant. It is a necessary component of proteins and enzymes required for a variety of functions, including antioxidant defense, modulation of the inflammatory response, and production of thyroid hormones. In breast-fed infants, selenium stores depend on the selenium content of the mother's diet. In formula-fed infants, selenium levels are correlated to the residual selenium stores accumulated in utero and the level and type of selenium fortification used in the formula. Today, the United States Food and Drug Administration (FDA) recommends that infant formulas contain selenium at levels between 2.0 and 7.0 μg per 100 kcal. While the US FDA does not recommend a particular selenium form for fortification, evidence indicates that organically bound selenium forms (e.g., selenomethionine and selenium-enriched yeast) are better absorbed and retained than inorganic forms (e.g., selenite and selenate). Preliminary data from studies in adults do suggest that fortification with standardized selenium-enriched yeast may offer benefits compared to fortification with other organically bound selenium forms. However, because most studies evaluating the impact of selenium fortification of infant formula have assessed inorganic selenium supplements, additional research into the bioavailability and outcomes associated with the use of selenium-enriched yeast in infants is needed.


Fluorescence intensity normalisation: correcting for time effects in large-scale flow cytometric analysis.
A next step to interpret the findings generated by genome-wide association studies is to associate molecular quantitative traits with disease-associated alleles. To this end, researchers are linking disease risk alleles with gene expression quantitative trait loci (eQTL). However, gene expression at the mRNA level is only an intermediate trait and flow cytometry analysis can provide more downstream and biologically valuable protein level information in multiple cell subsets simultaneously using freshly obtained samples. Because the throughput of flow cytometry is currently limited, experiments may need to span over several weeks or months to obtain a sufficient sample size to demonstrate genetic association. Therefore, normalisation methods are needed to control for technical variability and compare flow cytometry data over an extended period of time. We show how the use of normalising fluorospheres improves the repeatability of a cell surface CD25-APC mean fluorescence intensity phenotype on CD4(+) memory T cells. We investigate two types of normalising beads: broad spectrum and spectrum matched. Lastly, we propose two alternative normalisation procedures that are usable in the absence of normalising beads.


An investigation into the temporal dimension of the Mozart effect: evidence from the attentional blink task.
In the present study, we examined whether the 'Mozart effect' would influence participants' temporal attention using a visual attentional blink (AB) task that provides a reliable measure of the temporal dynamics of visual attention. The 'Mozart effect' refers to the specific claim that listening to Mozart's Sonata for Two Pianos in D Major, K.448 can improve the performance in spatio-temporal tasks. Participants had to try and identify two target digits (in their correct order of presentation) presented amongst a stream of distractor letters in three different conditions (presented in separate blocks of trials): while listening to the Mozart sonata played normally, while listening to the same Mozart sonata played in reverse, and while in silence. The results showed that the participants were able to detect the second target (T2) significantly more accurately (given the correct detection of the first target, T1) in the AB stream when the Mozart sonata was played normally than in either of the other two conditions. Possible explanations for the differential effects of Mozart's music being played normally and in reverse and potential confounds in previous studies reporting a facilitatory 'Mozart effect' are discussed. Our results therefore provide the first empirical demonstration supporting the existence of a purely temporal component to the 'Mozart effect' using a non-spatial visual AB task.


Significance of vascular endothelial growth factor messenger RNA expression in primary lung cancer.
The expression of mRNAs for vascular endothelial growth factor (VEGF) was examined in 42 cases of primary lung cancer tissues (18 adenocarcinomas, 18 squamous cell carcinomas, 2 large cell carcinomas, 3 small cell carcinomas, and 1 adenoid cystic carcinoma) and 4 human lung cancer cell lines. As seen by reverse transcription-PCR analysis, VEGF mRNAs were expressed predominantly as transcripts for the secretory forms of VEGF (VEGF121 and VEGF165), both in resected lung cancer tissues and in human lung cancer cell lines. The positive ratios of VEGF mRNA according to pathological type were 66.7% (12 of 18) in adenocarcinoma, 72.2% (13 of 18) in squamous cell carcinoma, 100% (2 of 2) in large cell carcinoma, and 67% (2 of 3) in small cell carcinoma. The relative antigen levels of VEGF detected by immunohistochemical examination almost coincided with the relative VEGF mRNA expression levels. Also, we examined the expression of basic fibroblast growth factor mRNA in the same tumor specimens. However, no significant correlation was found between the VEGF and basic fibroblast growth factor mRNA expression levels. We assessed the relationship between the VEGF121 mRNA expression level and the survival period in patients (n = 17) who underwent a curative operation at stage I of the disease. The median survival of the VEGF high-expression group was 8 months, and that of the VEGF low-expression group was 151 months. The 3- and 5-year survival rates of the high-expression group (n = 6) were 50.0% and 16.7%, respectively. On the other hand, those of the low expression group (n = 11) were 90.9% and 77.9%, respectively. The difference in survival between the two groups was significant (P < 0.05). Among eight cases of long-term survival beyond 5 years, seven cases had low or no VEGF121 mRNA expression. In contrast, among 18 cases with VEGF121 mRNA overexpression, 17 cases died due to recurrence. As a marker of tumor angiogenesis, the VEGF121 mRNA expression level may be a significant prognostic indicator of lung cancers in early stages.


COVID-19 and the Uncovering of Health Care Disparities in the United States, United Kingdom and Canada: Call to Action.
The coronavirus disease 2019 (COVID-19) pandemic created a crisis that disproportionately affected populations already disadvantaged with respect to access to health care systems and adequate medical care and treatments. Understanding how and where health care disparities are most widespread is an important starting point for exploring opportunities to mitigate such disparities, especially within our patient population with liver disease. In a webinar in LiverLearning, we discussed the impact of the pandemic on the United States, United Kingdom and Canada, highlighting the disproportionate effects on infection rates and death for certain ethnic minorities, those socioeconomically disadvantaged and living in higher density areas, and those working in health care and other essential jobs. We set forth a "call to action" for members of the American Association for the Study of Liver Diseases and the larger community of providers of liver disease care to generate viable solutions to improve access to care and vaccination rates of our patients against COVID-19, and in general help reduce health care disparities and improve the health of disadvantaged populations within their communities. Solutions will likely involve personalized interventions and messaging for communities that honor local leaders and embrace the diverse needs and different cultural sensitivities of our unique patient populations.


Is it feasible and desirable to collect voluntarily quality and outcome data nationally in palliative oncology care?
Hospice/palliative care is a critical component of cancer care. In Australia, more than 85% of people referred to specialized hospice/palliative care services (SHPCS) have a primary diagnosis of cancer, and 60% of people who die from cancer will be referred to SHPCS. The Palliative Care Outcomes Collaboration (PCOC) is an Australian initiative that allows SHPCS to collect nationally agreed-upon measures to better understand quality, safety, and outcomes of care. This article describes data (October 2006 through September 2007) from the first 22 SHPCS, with more than 100 inpatient admissions annually. Data include phase of illness, place of discharge, and, at each transition in place of care, the person's functional status, dependency, and symptom scores. Data are available for 5,395 people for 6,379 admissions. After categorizing by phase of illness and dependency, there remain at the end of each admission 12-fold differences (mean, 26%; range, 4% to 52%) in the percentage of patients who became stable after an unstable phase; seven-fold differences (mean, 22%; range, 6% to 41%) in the percentage of patients with improved symptom scores, five-fold differences (mean, 25%; range, 12% to 64%) in discharge back to the community, four-fold differences (mean, 10%; range, 4% to 16%) in improved function, and three-fold differences in the length of stay (mean, 14 days; range, 6 to 19 days). PCOC shows it is feasible to collect quality national palliative care outcome data voluntarily. Variations in outcomes justify continued enrollment of services. Benchmarking should include all patients whose cancer will cause death and explore observed variations.


Temporal-Spatial Variation in Questing Tick Activity in the Netherlands: The Effect of Climatic and Habitat Factors.
Longitudinal studies are fundamental in the assessment of the effect of environmental factors on tick population dynamics. In this study, we use data from a 10-year study in 11 different locations in the Netherlands to gauge the effects of climatic and habitat factors on the temporal and spatial variation in questing tick activity. Marked differences in the total number of ticks were found between locations and between years. We investigated which climatic and habitat factors might explain this variation. No effects of climatic factors on the total number of ticks per year were observed, but we found a clear effect of temperature on the onset of tick activity. In addition, we found positive associations between (1) humus layer thickness and densities of all three stages, (2) moss and blackberry abundance and larval densities, and (3) blueberry abundance and densities of larva and nymphs. We conclude that climatic variables do not have a straightforward association with tick density in the Netherlands, but that winter and spring temperatures influence the onset of tick activity. Habitats with apparently similar vegetation types can still differ in tick population densities, indicating that local composition of vegetation and especially of wildlife is likely to contribute considerably to the spatial variation in tick densities.


Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task.
Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments. Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made. TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses. These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.


Interdependent sampling and social influence.
Most explanations of social influence focus on why individuals might want to agree with the opinions or attitudes of others. The authors propose a different explanation that assumes the attitudes of others influence only the activities and objects individuals are exposed to. For example, individuals are likely to be exposed to activities that their friends enjoy. The authors demonstrate that such influence over sampling behavior is sufficient to produce a social influence effect when individuals form attitudes by learning from experience. Even if the experiences of 2 individuals, when they sample an object or event, are independent random variables, their attitudes will become positively correlated if their sampling processes are interdependent. Interdependent sampling of activities thus provides a different explanation of social influence with distinct empirical and theoretical implications.


Paired Box 5 (PAX5) Expression in Poorly Differentiated Neuroendocrine Carcinoma of the Gastrointestinal and Pancreatobiliary Tract: Diagnostic and Potentially Therapeutic Implications.
Paired Box 5 (PAX5), a well-established B-cell marker, is preferentially expressed in small cell lung carcinoma and regulates the transcription of c-Met, offering a potential for therapeutic target. Its expression in poorly differentiated neuroendocrine carcinoma (PDNEC) of the digestive system has not been systemically evaluated. Archived pathology materials from 38 PDNEC in the gastrointestinal (GI) and pancreatobiliary (PB) tract were reviewed. Representative tumor sections were subject to immunohistochemical stain for PAX5, c-Met, and CD20. The extent of the staining [focal (<10%), patchy (10% to 50%), and diffuse (>50%)] and intensity (1+ to 3+) was evaluated. In total, 38 cases of well-differentiated neuroendocrine tumors from GI/PB tract served as controls. Nuclear PAX5 staining was observed in 16 (42%) cases in total, in 46% (11/24) of large cell neuroendocrine carcinoma, 67% (4/6) of small cell neuroendocrine carcinoma, and 13% (1/8) of mixed adenoneuroendocrine carcinoma, with diffuse (8), patchy (4), or focal (4) staining. The intensity was 3+ (2), 2+ (6), and 1+ (8). PAX5 expression was common in ampullary (4/5) and gastroesophageal junctional/esophageal (5/9) PDNEC. Two (5%) of 38 well-differentiated neuroendocrine tumors were positive for PAX5. Three PAX5 positive PDNEC showed weak cytoplasmic c-Met immunolabeling. CD20 was negative in all tumors. Our data show that PAX5 is commonly expressed in PDNEC of the GI/PB tract including small cell neuroendocrine carcinoma. This observation warrants a cautious approach when interpreting small biopsy of poorly differentiated neoplasms, especially when lymphoma is considered in the differentials. Further study of PAX5/c-Met signaling pathway and its potential therapeutic value in GI/PB PDNEC is warranted.


Cardiac ischemia activates calcium-independent phospholipase A2beta, precipitating ventricular tachyarrhythmias in transgenic mice: rescue of the lethal electrophysiologic phenotype by mechanism-based inhibition.
Murine myocardium contains diminutive amounts of calcium-independent phospholipase A2 (iPLA2) activity (<5% that of human heart), and malignant ventricular tachyarrhythmias are infrequent during acute murine myocardial ischemia. Accordingly we considered the possibility that the mouse was a species-specific knockdown of the human pathologic phenotype of ischemiainduced lethal ventricular tachyarrhythmias. Transgenic mice were generated expressing amounts of iPLA2beta activity comparable to that present in human myocardium. Coronary artery occlusion in Langendorff perfused hearts from transgenic mice resulted in a 22-fold increase in fatty acids released into the venous eluent (29.4 nmol/ml in transgenic versus 1.35 nmol/ml of eluent in wild-type mice), a 4-fold increase in lysophosphatidylcholine mass in ischemic zones (4.9 nmol/mg in transgenic versus 1.1 nmol/mg of protein in wild-type mice), and malignant ventricular tachyarrhythmias within minutes of ischemia. Neither normally perfused transgenic nor ischemic wild-type hearts demonstrated these alterations. Pretreatment of Langendorff perfused transgenic hearts with the iPLA2 mechanism-based inhibitor (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one (BEL) just minutes prior to induction of ischemia completely ablated fatty acid release and lysolipid accumulation and rescued transgenic hearts from malignant ventricular tachyarrhythmias. Collectively these results demonstrate that ischemia activates iPLA2beta in intact myocardium and that iPLA2beta-mediated hydrolysis of membrane phospholipids can induce lethal malignant ventricular tachyarrhythmias during acute cardiac ischemia.


Volunteers improving person-centred dementia and delirium care in a rural Australian hospital.
The aim of the present study was to address the challenges faced by staff in an acute rural hospital in Australia when providing person-centred care for patients with dementia and/or delirium. This was done by training volunteers to provide personal support to these patients, then measuring the outcomes of this intervention. Volunteers were given training, then allocated patients with dementia/delirium or at risk of delirium. A quasi-experimental pre-post design assessed outcomes of the intervention. Quantitative measures were clinical outcome data for the 64 patients who passed through the program; questionnaire data related to the stress and attitudes of the 18 participating nurses; and attitudes, knowledge and confidence of the 18 volunteers. Qualitative measures assessed acceptability and feasibility of the intervention to staff and volunteers. There was a significant reduction over time in length of stay for patients, and an increase in the use of analgesic medications. Only one patient fell while volunteers were on duty. There were no effects on the stress of nursing staff or their attitudes to dementia. Volunteers gained significantly in confidence and attitudes to dementia. The program was highly acceptable, with 96% of staff and 100% of volunteers perceiving the program as beneficial for patients, staff and volunteers. The program has continued and is now being expanded to other rural sites. It is feasible to introduce and then sustain a relatively inexpensive program to improve quality of care for people with dementia and/or delirium in an acute rural hospital. Reasons for the program's effectiveness are canvassed in the paper, but further research is needed to investigate the effectiveness of a similar program in urban hospitals.


Observations of slow electron holes at a magnetic reconnection site.
We report in situ observations of high-frequency electrostatic waves in the vicinity of a reconnection site in the Earth's magnetotail. Two different types of waves are observed inside an ion-scale magnetic flux rope embedded in a reconnecting current sheet. Electron holes (weak double layers) produced by the Buneman instability are observed in the density minimum in the center of the flux rope. Higher frequency broadband electrostatic waves with frequencies extending up to f(pe) are driven by the electron beam and are observed in the denser part of the rope. Our observations demonstrate multiscale coupling during the reconnection: Electron-scale physics is induced by the dynamics of an ion-scale flux rope embedded in a yet larger-scale magnetic reconnection process.


Pathophysiology and clinical management of moderate and severe traumatic brain injury in the ICU.
Moderate and severe traumatic brain injury (TBI) is the leading cause of morbidity and mortality among young individuals in high-income countries. Its pathophysiology is divided into two major phases: the initial neuronal injury (or primary injury) followed by secondary insults (secondary injury). Multimodality monitoring now offers neurointensivists the ability to monitor multiple physiologic parameters that act as surrogates of brain ischemia and hypoxia, the major driving forces behind secondary brain injury. The heterogeneity of the pathophysiology of TBI makes it necessary to take into consideration these interacting physiologic factors when recommending for or against any therapies; it may also account for the failure of all the neuroprotective therapies studied so far. In this review, the authors focus on neuroclinicians and neurointensivists, and discuss the developments in therapeutic strategies aimed at optimizing intracranial pressure and cerebral perfusion pressure, and minimizing cerebral hypoxia. The management of moderate to severe TBI in the intensive care unit is moving away from a pure "threshold-based" treatment approach toward consideration of patient-specific characteristics, including the state of cerebral autoregulation. The authors also include a concise discussion on the management of medical and neurologic complications peculiar to TBI as well as an overview of prognostication.


A review of the application and contribution of discrete choice experiments to inform human resources policy interventions.
Although the factors influencing the shortage and maldistribution of health workers have been well-documented by cross-sectional surveys, there is less evidence on the relative determinants of health workers' job choices, or on the effects of policies designed to address these human resources problems. Recently, a few studies have adopted an innovative approach to studying the determinants of health workers' job preferences. In the absence of longitudinal datasets to analyse the decisions that health workers have actually made, authors have drawn on methods from marketing research and transport economics and used Discrete Choice Experiments to analyse stated preferences of health care providers for different job characteristics. We carried out a literature review of studies using discrete choice experiments to investigate human resources issues related to health workers, both in developed and developing countries. Several economic and health systems bibliographic databases were used, and contacts were made with practitioners in the field to identify published and grey literature. Ten studies were found that used discrete choice experiments to investigate the job preferences of health care providers. The use of discrete choice experiments techniques enabled researchers to determine the relative importance of different factors influencing health workers' choices. The studies showed that non-pecuniary incentives are significant determinants, sometimes more powerful than financial ones. The identified studies also emphasized the importance of investigating the preferences of different subgroups of health workers. Discrete choice experiments are a valuable tool for informing decision-makers on how to design strategies to address human resources problems. As they are relatively quick and cheap survey instruments, discrete choice experiments present various advantages for informing policies in developing countries, where longitudinal labour market data are seldom available. Yet they are complex research instruments requiring expertise in a number of different areas. Therefore it is essential that researchers also understand the potential limitations of discrete choice experiment methods.


Molecular phylogenetic analyses indicate multiple independent emergences of parasitism in Myzostomida (Protostomia).
The fossil record indicates that Myzostomida, an enigmatic group of marine worms, traditionally considered as annelids, have exhibited a symbiotic relationship with echinoderms, especially crinoids, for nearly 350 million years. All known extant myzostomids are associated with echinoderms and infest their integument, gonads, celom, or digestive system. Using nuclear (18S rDNA) and mitochondrial (16S and COI) DNA sequence data from 37 myzostomid species representing nine genera, we report here the first molecular phylogeny of the Myzostomida and investigate the evolution of their various symbiotic associations. Our analyses indicate that the two orders Proboscidea and Pharyngidea do not constitute natural groupings. Character reconstruction analyses strongly suggest that (1) the ancestor of all extant myzostomids was an ectocommensal that first infested crinoids, and then asteroids and ophiuroids, and (2) parasitism in myzostomids emerged multiple times independently.


Diverse styles of submarine venting on the ultraslow spreading Mid-Cayman Rise.
Thirty years after the first discovery of high-temperature submarine venting, the vast majority of the global mid-ocean ridge remains unexplored for hydrothermal activity. Of particular interest are the world's ultraslow spreading ridges that were the last to be demonstrated to host high-temperature venting but may host systems particularly relevant to prebiotic chemistry and the origins of life. Here we report evidence for previously unknown, diverse, and very deep hydrothermal vents along the approximately 110 km long, ultraslow spreading Mid-Cayman Rise (MCR). Our data indicate that the MCR hosts at least three discrete hydrothermal sites, each representing a different type of water-rock interaction, including both mafic and ultramafic systems and, at approximately 5,000 m, the deepest known hydrothermal vent. Although submarine hydrothermal circulation, in which seawater percolates through and reacts with host lithologies, occurs on all mid-ocean ridges, the diversity of vent types identified here and their relative geographic isolation make the MCR unique in the oceans. These new sites offer prospects for an expanded range of vent-fluid compositions, varieties of abiotic organic chemical synthesis and extremophile microorganisms, and unparalleled faunal biodiversity--all in close proximity.


Self-management for bronchiectasis.
Bronchiectasis is a long term respiratory condition with an increasing rate of diagnosis. It is associated with persistent symptoms, repeated infective exacerbations, and reduced quality of life, imposing a burden on individuals and healthcare systems. The main aims of therapeutic management are to reduce exacerbations and improve quality of life. Self-management interventions are potentially important for empowering people with bronchiectasis to manage their condition more effectively and to seek care in a timely manner. Self-management interventions are beneficial in the management of other airways diseases such as asthma and COPD (chronic obstructive pulmonary disease) and have been identified as a research priority for bronchiectasis. To assess the efficacy, cost-effectiveness and adverse effects of self-management interventions for adults and children with non-cystic fibrosis bronchiectasis. We searched the Cochrane Airways Specialised Register of trials, clinical trials registers, reference lists of included studies and review articles, and relevant manufacturers' websites up to 13 December 2017. We included all randomised controlled trials of any duration that included adults or children with a diagnosis of non-cystic fibrosis bronchiectasis assessing self-management interventions delivered in any form. Self-management interventions included at least two of the following elements: patient education, airway clearance techniques, adherence to medication, exercise (including pulmonary rehabilitation) and action plans. Two review authors independently screened searches, extracted study characteristics and outcome data and assessed risk of bias for each included study. Primary outcomes were, health-related quality of life, exacerbation frequency and serious adverse events. Secondary outcomes were the number of participants admitted to hospital on at least one occasion, lung function, symptoms, self-efficacy and economic costs. We used a random effects model for analyses and standard Cochrane methods throughout. Two studies with a total of 84 participants were included: a 12-month RCT of early rehabilitation in adults of mean age 72 years conducted in two centres in England (UK) and a six-month proof-of-concept RCT of an expert patient programme (EPP) in adults of mean age 60 years in a single regional respiratory centre in Northern Ireland (UK). The EPP was delivered in group format once a week for eight weeks using standardised EPP materials plus disease-specific education including airway clearance techniques, dealing with symptoms, exacerbations, health promotion and available support. We did not find any studies that included children. Data aggregation was not possible and findings are reported narratively in the review.For the primary outcomes, both studies reported health-related quality of life, as measured by the St George's Respiratory Questionnaire (SGRQ), but there was no clear evidence of benefit. In one study, the mean SGRQ total scores were not significantly different at 6 weeks', 3 months' and 12 months' follow-up (12 months mean difference (MD) -10.27, 95% confidence interval (CI) -45.15 to 24.61). In the second study there were no significant differences in SGRQ. Total scores were not significantly different between groups (six months, MD 3.20, 95% CI -6.64 to 13.04). We judged the evidence for this outcome as low or very low. Neither of the included studies reported data on exacerbations requiring antibiotics. For serious adverse events, one study reported more deaths in the intervention group compared to the control group, (intervention: 4 of 8, control: 2 of 12), though interpretation is limited by the low event rate and the small number of participants in each group.For our secondary outcomes, there was no evidence of benefit in terms of frequency of hospital admissions or FEV1 L, based on very low-quality evidence. One study reported self-efficacy using the Chronic Disease Self-Efficacy scale, which comprises 10 components. All scales showed significant benefit from the intervention but effects were only sustained to study endpoint on the Managing Depression scale. Further details are reported in the main review. Based on overall study quality, we judged this evidence as low quality. Neither study reported data on respiratory symptoms, economic costs or adverse events. There is insufficient evidence to determine whether self-management interventions benefit people with bronchiectasis. In the absence of high-quality evidence it is advisable that practitioners adhere to current international guidelines that advocate self-management for people with bronchiectasis.Future studies should aim to clearly define and justify the specific nature of self-management, measure clinically important outcomes and include children as well as adults.


Dietary fibre, exercise and serum lipids and lipoprotein cholesterols in 12 to 15 year olds.
Serum lipid and lipoprotein cholesterol levels track from childhood and are associated with risk of coronary heart disease. There is some evidence that these are influenced by dietary intake and exercise. Serum lipid and lipoprotein cholesterols were measured in a cohort of 119 British children aged 12-15 y who completed a dietary assessment and exercise questionnaire. The ratio of total- to high-density lipoprotein cholesterol fell with increasing fibre intake, but after adjustment for age, body mass index, sex and other dietary factors, this was not statistically significant. Children exercising at least once a day had significantly lower serum total cholesterol and low density lipoprotein cholesterol levels than those exercising less frequently, even after adjustment for the above factors and dietary fibre intake. No dietary factor was significantly associated with any lipid measure after adjustment for the above factors. The challenge is how to optimize exercise level in adolescent children.


Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.
Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.


Rapid detection of parainfluenza virus type 3 RNA in respiratory specimens: use of reverse transcription-PCR-enzyme immunoassay.
Parainfluenza virus type 3 (PIV-3), an important lower respiratory tract pathogen in young children and immunocompromised individuals, may be underdiagnosed because of the insensitivity of available culturing systems and delay in identification of virus in cell culture. We developed a reverse transcription-PCR-enzyme immunoassay (RT-PCR-EIA) for PIV-3, using primers specific for a highly conserved region of the hemagglutinin-neuraminidase gene. Testing of nasal washes spiked with PIV-3 or other respiratory viruses showed that this assay detected seven strains of PIV-3 but not other respiratory viruses. Of 103 respiratory tract samples obtained from children experimentally infected with a liver PIV-3 vaccine or naturally infected with wild-type PIV-3, 51 were positive by culture and 48 were positive by RT-PCR-EIA. Eleven of the culture-positive samples were negative by RT-PCR-EIA; however, none of these grew virus upon reinoculation into cell culture, indicating that virus was lost or was present at a very low titer. Eight of the culture-negative samples were positive by RT-PCR-EIA: two were obtained from a subject who was culture negative but had a serologic response to PIV-3, four were obtained 7 to 9 days after the first positive culture, and two were obtained 1 day prior to the first positive culture. Thus, this RT-PCR-EIA for PIV-3 is sensitive and specific and can detect viral RNA in samples from which virus cannot be cultivated. This assay could be used for diagnosis late in the course of PIV-3 infection and for accurate detection of disease outbreaks.


beta-blocker use and diabetes symptom score: results from the GEMINI study.
The Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two beta-blockers in people with type 2 diabetes and hypertension treated with renin-angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two beta-blockers on commonly reported symptoms. The Diabetes Symptom Checklist (DSC), a self-report questionnaire measuring the occurrence and perceived burden of diabetes-related symptoms, was completed by GEMINI participants at baseline and at the end of the study (maintenance month 5). The DSC assessed symptoms in eight domains: psychology (fatigue), psychology (cognitive), neuropathy (pain), neuropathy (sensory), cardiology, ophthalmology, hyperglycaemia and hypoglycaemia. Comparison of the mean change in self-reported diabetes-related symptoms indicated a significant treatment difference favouring carvedilol over metoprolol tartrate in overall symptom score (-0.08; 95% CI -0.15, -0.01; p = 0.02) and in the domains for hypoglycaemia symptoms (-0.12; 95% CI -0.23, -0.02; p = 0.02) and hyperglycaemia symptoms (-0.16; 95% CI -0.27, -0.05; p = 0.005). Carvedilol resulted in fewer perceived diabetes-related symptoms in patients with diabetes and hypertension. Carvedilol resulted in a lower perceived burden of diabetes-related symptoms in patients with type 2 diabetes and hypertension. The addition of a well-tolerated beta-blocker to RAS blockade may improve hypertension treatment and quality of life in patients with diabetes.


High-pathogenicity island of Yersinia spp. in Escherichia coli strains isolated from diarrhea patients in China.
The high-pathogenicity island (HPI) of Yersinia has been observed in 93% of 60 enteroadhesive Escherichia coli strains and 80% of E. coli strains isolated from blood samples. In the present study we investigated 671 fecal samples from patients with diarrhea in Shandong Province, China, and isolated HPI-harboring E. coli from 6. 26% of the samples. The isolation rates for patients with diarrhea in three age groups, 10 to 20, 30 to 40, and 50 to 60 years, were 6. 70, 12.35, and 10.81%, respectively. Therefore, HPI-harboring E. coli is the third most frequently isolated enteric pathogen from patients with diarrhea. Vomiting and abdominal pain were recorded for 33.33 and 66.67% of the patients, respectively. Stools with blood were observed for 9.52% of the patients. Twenty-four of 42 (57%) patients experienced a temperature over 37.4 degrees C. These observations indicate that HPI-harboring E. coli is one of the major causes of diarrheal disease in China and that the clinical symptoms caused by HPI-harboring E. coli differ from those caused by enteroadhesive E. coli.


Pseudomonas pseudomallei liver abscesses: a clinical, laboratory, and ultrasonographic study.
Ultrasonography revealed evidence of liver abscess in 126 patients who were admitted to one hospital in northeastern Thailand over a 3-year period. There were 50 cases for which a pyogenic bacterial etiology was confirmed; 34 cases (group 1) were caused by Pseudomonas pseudomallei (nine patients died) and 16 cases (group 2) were caused by other bacteria (two patients died). Melioidosis was associated with anemia and underlying diabetes or renal disease; right-upper-quadrant pain and jaundice were more common in group 2 (P less than .05). Blood cultures were positive for bacteria in 68% of group 1 and 50% of group 2. Chest radiographs revealed abnormalities in 17 of 30 group 1 patients and 6 of 12 group 2 patients. The radiographic appearances of a blood-borne pneumonia suggested melioidosis. The serum indirect hemagglutination assay for antibodies to P. pseudomallei was of limited value in differentiating the two types of abscesses. Multiple hypoechoic areas on ultrasonography were significantly associated with melioidosis (P less than .01); associated splenic abscess occurred in 19 group 1 patients but only one group 2 patient (2-107, 95% confidence interval; odds ratio, 19). In an area where P. pseudomallei is endemic, these characteristic ultrasonographic findings should prompt immediate treatment for melioidosis.


Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5-Triazine CFTR Activator for Dry Eye Disorders.
Pharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact-K267), fully activated human wildtype CFTR with EC50 ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits. CFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTRact-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration. Electrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTRact-K267. A single topical dose of 3 nmol CFTRact-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs. These studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders.


Drusen Ooze: A Novel Hypothesis in Geographic Atrophy.
To describe a subgroup of subjects with soft drusen associated with geographic atrophy (GA) and novel spectral-domain OCT (SD-OCT) findings consistent with presumed drusen leakage. We also propose a mechanism leading to GA progression in these patients. A retrospective, observational cohort study. Forty-eight eyes of 33 patients with soft drusen secondary to age-related macular degeneration (AMD). Drusen were evaluated with SD-OCT and retinal imaging to characterize the development of atrophy-associated drusen regression (drusen collapse) over a follow-up period of ≥18 months. The presence of isoreflective dots at the outer retinal layers associated with retinal pigment epithelium (RPE) defects. Percentages of previously reported hyperreflective RPE, and hyperreflective dots (HRDs) were also determined. Nineteen of 48 eyes (39.6%) showed a collapse of ≥1 druse during the follow-up period. Thirty-four foci of collapsed drusen were found to be associated with either isoreflective dots associated with RPE defects (32.4%), hyperreflectivity of the RPE (91.2%), or HRDs (79.4%). A post hoc showed the adjusted odds ratio of drusen collapse for isoreflective dots (65.8), for HRDs (6.0) or both (12.1). In soft drusen progressing to subsequent atrophy, approximately 33% were associated with isoreflective dots and RPE defects. In addition, overlying hyperreflectivity of the RPE and HRDs were noted with high frequency. Presence of isoreflective dots, with or without HRDs, was associated with a strong risk of developing atrophy compared with drusen without these findings. We hypothesize that these isoreflective dots associated with RPE defects may be debris extruded from the soft drusen into the subretinal space, which we have termed "drusen ooze". Drusen ooze may activate the RPE apical surfaces, leading to a marked increase in phagocytosis/endocytosis of extracellular debris that eventually overwhelms the RPE capacity, and leads to RPE death, subsequent release of intracellular RPE material and thereby propagate a cycle of cellular death resulting in GA development and progression. Therapeutic targeting of drusen material, prior to its extrusion into the subretinal space and prior to irreversible damage to the RPE, might prevent or delay onset and progression of GA.


A preliminary investigation into the genetic variation and population structure of Taenia hydatigena from Sardinia, Italy.
Cysticercosis caused by the metacestode stage of Taenia hydatigena is endemic in Sardinia. Information on the genetic variation of this parasite is important for epidemiological studies and implementation of control programs. Using two mitochondrial genes, the cytochrome c oxidase subunit 1 (cox1) and the NADH dehydrogenase subunit 1 (ND1) we investigated the genetic variation and population structure of Cysticercus tenuicollis from Sardinian intermediate hosts and compared it to that from other hosts from various geographical regions. The parsimony cox1 network analysis indicated the existence of a common lineage for T. hydatigena and the overall diversity and neutrality indices indicated demographic expansion. Using the cox1 sequences, low pairwise fixation index (Fst) values were recorded for Sardinian, Iranian and Palestinian sheep C. tenuicollis which suggested the absence of genetic differentiation. Using the ND1 sequences, C. tenuicollis from Sardinian sheep appeared to be differentiated from those of goat and pig origin. In addition, goat C. tenuicollis were genetically different from adult T. hydatigena as indicated by the statistically significant Fst value. Our results are consistent with biochemical and morphological studies that suggest the existence of variants of T. hydatigena.


Haploinsufficiency of protamine-1 or -2 causes infertility in mice.
Protamines are the major DNA-binding proteins in the nucleus of sperm in most vertebrates and package the DNA in a volume less than 5% of a somatic cell nucleus. Many mammals have one protamine, but a few species, including humans and mice, have two. Here we use gene targeting to determine if the second protamine provides redundancy to an essential process, or if both protamines are necessary. We disrupted the coding sequence of one allele of either Prm1 or Prm2 in embryonic stem (ES) cells derived from 129-strain mice, and injected them into blastocysts from C57BL/6-strain mice. Male chimeras produced 129-genotype sperm with disrupted Prm1 or Prm2 alleles, but failed to sire offspring carrying the 129 genome. We also found that a decrease in the amount of either protamine disrupts nuclear formation, processing of protamine-2 and normal sperm function. Our studies show that both protamines are essential and that haploinsufficiency caused by a mutation in one allele of Prm1 or Prm2 prevents genetic transmission of both mutant and wild-type alleles.


Intraductal oncocytic papillary neoplasm of the pancreas: a radio-pathological case study.
An intraductal oncocytic papillary neoplasm is a rare pancreatic tumor with the potential of developing invasive carcinoma. Its differentiation from other cystic-like neoplasms of the pancreas, such as intraductal papillary mucinous neoplasms, is a challenge for pancreatic imaging. We present the case of a 76-year-old male with painless jaundice caused by an intraductal oncocytic papillary neoplasm of the pancreas. The imaging findings on computed tomography, magnetic resonance including diffusion-weighted imaging, and (18)F-fluorodeoxyglucose positron emission tomography are presented and the radio-pathological correlations are discussed. An intraductal oncocytic papillary neoplasm of the pancreas appears as a cystic tumor communicating with the dilated pancreatic duct featuring intraductal tumor nodules. Intraductal oncocytic papillary neoplasms show a high (18)F-fluorodeoxyglucose-uptake in positron emission tomography and low diffusion values in diffusion-weighted imaging including apparent diffusion coefficient maps which may be a valuable attribute in distinguishing these rare lesions from intraductal papillary mucinous neoplasms.


Alveolar ridge augmentation by connective tissue grafting using a pouch method and modified connective tissue technique: A prospective study.
Localized alveolar ridge defect may create physiological and pathological problems. Developments in surgical techniques have made it simpler to change the configuration of a ridge to create a more aesthetic and more easily cleansable shape. The purpose of this study was to compare the efficacy of alveolar ridge augmentation using a subepithelial connective tissue graft in pouch and modified connective tissue graft technique. In this randomized, double blind, parallel and prospective study, 40 non-smoker individuals with 40 class III alveolar ridge defects in maxillary anterior were randomly divided in two groups. Group I received modified connective tissue graft, while group II were treated with subepithelial connective tissue graft in pouch technique. The defect size was measured in its horizontal and vertical dimension by utilizing a periodontal probe in a stone cast at base line, after 3 months, and 6 months post surgically. Analysis of variance and Bonferroni post-hoc test were used for statistical analysis. A two-tailed P < 0.05 was considered to be statistically significant. Mean values in horizontal width after 6 months were 4.70 ± 0.87 mm, and 4.05 ± 0.89 mm for group I and II, respectively. Regarding vertical heights, obtained mean values were 4.75 ± 0.97 mm and 3.70 ± 0.92 mm for group I and group II, respectively. Within the limitations of this study, connective tissue graft proposed significantly more improvement as compare to connective tissue graft in pouch.


Prey Limitation Drives Variation in Allometric Scaling of Predator-Prey Interactions.
Ecologists have long searched for a universal size-scaling constant that governs trophic interactions. Although this is an appealing theoretical concept, predator-prey size ratios (PPSRs) vary strikingly across and within natural food webs, meaning that predators deviate from their optimal prey size by consuming relatively larger or smaller prey. Here we suggest that this unexpected variation in allometric scaling of trophic interactions can be predicted by gradients of prey limitation consistent with predictions from optimal foraging theory. We analyzed >6,000 trophic interactions of 52 populations from four tropical frog species along a gradient of prey limitation. The mean of PPSR and its variance differed up to two orders of magnitude across and within food webs. Importantly, as prey availability decreased across food webs, PPSR and its variance became more size dependent. Thus, trophic interactions did not follow a fixed allometric scaling but changed predictably with the strength of prey limitation. Our results emphasize the importance of ecological contexts in arranging food webs and the need to incorporate ecological drivers of PPSR and its variance in food web and community models.


A novel cell-based binding assay system reconstituting interaction between SARS-CoV S protein and its cellular receptor.
Severe acute respiratory syndrome (SARS), a life-threatening disease, is caused by the newly identified virus SARS coronavirus (SARS-CoV). In order to study the spike (S) protein of this highly contagious virus, we established a clonal cell-line, CHO-SG, from the Chinese hamster ovary cells that stably expresses C-terminally EGFP-tagged SARS-CoV S protein (S-EGFP). The ectodomain of the S glycoprotein is localized on the surface of CHO-SG cells with N-acetyl-glucosamine-terminated carbohydrate structure. CHO-SG cells associated tightly with Vero E6 cells, a SARS-CoV receptor (ACE2) expressing cell-line, and the interaction remained stable under highly stringent condition (1M NaCl). This interaction could be blocked by either the serum from a SARS convalescent patient or a goat anti-ACE2 antibody, indicating that the interaction is specific. A binding epitope with lesser degree of glycosylation and native conformation was localized by using rabbit anti-sera raised against five denatured recombinant S protein fragments expressed in Escherichia coli. One of the sera obtained from the fragment encompassing amino acids 48-358 significantly blocked the interaction between CHO-SG and Vero E6 cells. The region is useful for studying neutralizing antibodies in future vaccine development. This paper describes an easy and safe cell-based assay suitable for studying the binding between SARS-CoV S protein and its receptor.


Outcomes of synchronous systemic and central nervous system (CNS) involvement of diffuse large B-cell lymphoma are dictated by the CNS disease: a collaborative study of the Australasian Lymphoma Alliance.
De novo diffuse large B-cell lymphoma (DLBCL) presenting with synchronous central nervous system (CNS) and systemic disease (synDLBCL) is not well described and is excluded from clinical trials. We performed a retrospective analysis of 80 synDLBCL patients treated across 10 Australian and UK centres. Of these patients, 96% had extranodal systemic disease. CNS-directed treatment with combination intravenous cytarabine and high-dose methotrexate ("CNS-intensive") (n = 38) was associated with favourable survival outcomes compared with "CNS-conservative" strategies such as intravenous high-dose methotrexate monotherapy, intrathecal therapy and/or radiotherapy (2-year progression-free survival [PFS] 50% vs. 31%, P = 0·006; 2-year overall survival [OS] 54% vs. 44%, P = 0·037). Outcomes were primarily dictated by the ability to control the CNS disease, with 2-year cumulative CNS relapse incidence of 42% and non-CNS relapse 21%. Two-year OS for CNS-relapse patients was 13% vs. 36% for non-CNS relapses (P = 0·02). Autologous stem cell transplantation as consolidation (n = 14) was not observed to improve survival in those patients who received CNS-intensive induction when matched for induction outcomes (2-year PFS 69% vs. 56%, P = 0·99; 2-year OS 66% vs. 56%, P = 0·98). Hyperfractionated or infusional systemic treatment did not improve survival compared to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) (2-year OS 49% for both groups). Our study suggests that adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.


2014 AAHA weight management guidelines for dogs and cats.
Communicating and implementing a weight management program for dogs and cats can be a challenging endeavor for veterinarians, but a rewarding one. An effective individualized weight loss program provides a consistent and healthy rate of weight loss to reduce risk of disease, prevent malnutrition, and improve quality of life. Weight loss is achieved with appropriate caloric restriction, diet selection, exercise, and strategies to help modify behavior of both the pet and client. This document offers guidelines and tools for the management of weight loss and long-term maintenance of healthy weight.


Induction/activation and detection of occult viral agents present in mammalian cells.
Occult viral agents in cell cultures may include (i) known viruses present at a concentration too low for detection and (ii) unknown viruses. For maximal safety regarding adventitious agents, a strategy is proposed which involves cellular cloning of candidate cell substrates for vaccines. This will render occult viruses present in either all cells or none, thus greatly facilitating their detection. Known and unknown members of virus families known to establish latency are best detected by molecular methods based on broadly conserved sequences and low stringency conditions. The presence of retrovirus particles, known or unknown, in vaccine harvests can be excluded by the Product-Enhanced Reverse Transcriptase (PERT) assay which detects particle-associated reverse transcriptase with the sensitivity of nucleic acid amplification tests. Latent retroviruses can be activated by stimulation with halogenated pyrimidines and/or azacytidine. Endogenous proviruses with no release of particles are of no concern.


Development of a confocal rheometer for soft and biological materials.
We discuss the design and operation of a confocal rheometer, formed by integrating an Anton Paar MCR301 stress-controlled rheometer with a Leica SP5 laser scanning confocal microscope. Combining two commercial instruments results in a system which is straightforward to assemble that preserves the performance of each component with virtually no impact on the precision of either device. The instruments are configured so that the microscope can acquire time-resolved, three-dimensional volumes of a sample whose bulk viscoelastic properties are being measured simultaneously. We describe several aspects of the design and, to demonstrate the system's capabilities, present the results of a few common measurements in the study of soft materials.


Changing concepts of sudden infant death syndrome: implications for infant sleeping environment and sleep position. American Academy of Pediatrics. Task Force on Infant Sleep Position and Sudden Infant Death Syndrome.
The American Academy of Pediatrics has recommended since 1992 that infants be placed to sleep on their backs to reduce the risk of sudden infant death syndrome (SIDS). Since that time, the frequency of prone sleeping has decreased from >70% to approximately 20% of US infants, and the SIDS rate has decreased by >40%. However, SIDS remains the highest cause of infant death beyond the neonatal period, and there are still several potentially modifiable risk factors. Although some of these factors have been known for many years (eg, maternal smoking), the importance of other hazards, such as soft bedding and covered airways, has been demonstrated only recently. The present statement is intended to review the evidence about prone sleeping and other risk factors and to make recommendations about strategies that may be effective for further reducing the risk of SIDS. This statement is intended to consolidate and supplant previous statements made by this Task Force.


Fatal shark attacks on divers in Australia, 1960-2017.
The aim of this study was to identify the number, location and characteristics associated with fatal shark attacks on divers in Australian waters from 1960 to 2017, inclusive. Searches were made of the Divers Alert Network Asia-Pacific Diving Mortality Database; the International Shark Attack File website; the Australian Shark Attack File and the Global Shark Attack File to identify cases of fatal shark attacks on divers in Australia. In addition, a systematic search of published medical and sporting literature was conducted to identify relevant reports. The data collected were scrutinised for relevance and duplication. There were 187 recorded attacks on divers, comprising 112 snorkellers, 62 scuba divers and 13 on divers using surface-supplied breathing apparatus. These included 28 verified deaths: 13 involving snorkellers, eight involving scuba divers, and seven divers using surface-supply. The victims' ages ranged from 13-50 years (mean 31 years). All but three were males. The vast majority of attacks were by Carcharodon carcharias (Great White Shark). Spearfishing and other seafood collection, as well as diving near fishing activities and/or seals, were identified as major risk factors. However, shark attacks on divers are relatively rare and represent only 3% of diving-related fatalities in Australia over this 57-year period.


Metabolic Effects of Doxorubicin on the Rat Liver Assessed With Hyperpolarized MRI and Metabolomics.
Doxorubicin (DOX) is a successful chemotherapeutic widely used for the treatment of a range of cancers. However, DOX can have serious side-effects, with cardiotoxicity and hepatotoxicity being the most common events. Oxidative stress and changes in metabolism and bioenergetics are thought to be at the core of these toxicities. We have previously shown in a clinically-relevant rat model that a low DOX dose of 2 mg kg-1 week-1 for 6 weeks does not lead to cardiac functional decline or changes in cardiac carbohydrate metabolism, assessed with hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (MRS). We now set out to assess whether there are any signs of liver damage or altered liver metabolism using this subclinical model. We found no increase in plasma alanine aminotransferase (ALT) activity, a measure of liver damage, following DOX treatment in rats at any time point. We also saw no changes in liver carbohydrate metabolism, using hyperpolarized [1-13C]pyruvate MRS. However, using metabolomic analysis of liver metabolite extracts at the final time point, we found an increase in most acyl-carnitine species as well as increases in high energy phosphates, citrate and markers of oxidative stress. This may indicate early signs of steatohepatitis, with increased and decompensated fatty acid uptake and oxidation, leading to oxidative stress.


A comparison of PCR detection of mecA with oxacillin disk susceptibility testing in different media and sceptor automated system for both Staphylococcus aureus and coagulase-negative staphylococci isolates.
To evaluate three methods for 406 isolates of Staphylococcus aureus and coagulase-negative staphylococci (CNS) for the detection of methicillin resistance (MR) using National Committee for Clinical Laboratory Standards (NCCLS) new interpretive criteria. We used polymerase chain reaction (PCR) as a gold standard method to evaluate three methods [disk diffusion with Mueller-Hinton agar (MHA) and mannitol salt agar (MSA) and Sceptor system (Becton Dickinson, USA)] for the detection of mecA gene. The isolates that were methicillin-resistant with any of the three tests were evaluated further for MR by E-test. MHA, MSA and Sceptor showed sensitivities of 100, 100 and 99% for S. aureus and 100, 82.6 and 72.1% for CNS, respectively. The specificities of the same methods were found as 100, 90.1 and 99.3% for S. aureus and 79.2, 95.8 and 97.2% for CNS, respectively. E-test showed 100% sensitivity for both S. aureus and CNS. Forty-eight CNS and 16 S. aureus isolates, which presented discrepancies with the three phenotypic methods (MHA disk diffusion method, MSA disk diffusion method and Sceptor), were correctly classified as resistant/susceptible with the E-test when compared with PCR. Only five CNS isolates, which were mecA-negative with PCR were resistant with E-test. Analysis of 248 S. aureus revealed that MHA is superior to other phenotype-based susceptibility testing methods in detecting MR. When we examined the results of 158 CNS, none of the three methods proved efficient in detecting MR. We conclude that although the accuracy of the MHA disk diffusion test for the detection of MR approaches the accuracy of PCR for S. aureus isolates, the need for easy and reliable methods of detecting MR in CNS still remains.


Psychosocial function and life satisfaction after stroke.
This prospective study was designed to describe different aspects of psychosocial function after stroke and the development of changes over time. A major aim has been to identify mental, functional, and social factors associated with low life satisfaction late after stroke. Social network, functional ability, leisure-time activities, experience of ill health, major depression, and life satisfaction were assessed repeatedly over 3 years in a population-based sample of 50 long-term survivors of stroke (mean age 71.4 years). Compared with a general elderly population, patients 3 years poststroke had more psychiatric symptoms, lower functional ability, and reduced life satisfaction. Contacts with children were maintained over the 3-year follow-up period, whereas contacts with friends and neighbors declined early after stroke and remained lower than in the general elderly population (p less than 0.05). When time dependency was analyzed, activities of daily living and somatic/neurological symptoms were found to change little after 3 months, while psychiatric symptoms showed changes later. Between 3 and 12 months poststroke, the prevalence of major depression decreased, leisure-time activities and social contacts were partly resumed, and life satisfaction improved (p less than 0.01). Once good life satisfaction was restored it was maintained, and poor life satisfaction at 1 year remained poor for the entire 3 years. It is concluded that major depression early after stroke, functional disability, and an impaired social network interact to reduce life satisfaction for the long-term survivors of stroke.


NF-E2-related factor 2 over-expression in mesenchymal stem cells to improve cellular cardiomyoplasty.
Myocardial infarction (MI) is the leading cause of death worldwide. Various therapeutic strategies have been introduced for MI treatment. In recent years, interest in utilizing mesenchymal stem cells (MSCs) for MI therapy has increased. In fact, the use of MSCs for MI treatment, known as cellular cardiomyoplasty, is in the clinical trial stage. However, despite promising results, most MSCs die after transplantation as a result of exposure to various stresses. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a well-known cytoprotective transcription factor, protects MSCs against some stresses. Over-expression of Nrf2 in MSCs decreases their apoptosis in vitro without any adverse effects on their differentiation capacity. Therefore, we hypothesized that over-expression of Nrf2 in MSCs can improve cellular cardiomyoplasty.