Modulation of the activity of central serotoninergic neurons by novel serotonin1A receptor agonists and antagonists: a comparison to adrenergic and dopaminergic neurons in rats.
In this study, we used a complementary in vivo electrophysiological and (in individual rats) neurochemical approach to characterize the actions of chemically diverse serotonin (5-HT)1A receptor ligands at central 5-HT1A autoreceptors as compared to dopamine (DA) D2 autoreceptors and presynaptic alpha-2 adrenergic receptors (ARs). The novel, high efficacy, 5-HT1A agonists, WY 48,723 (an arylpiperazine), (+)-flesinoxan (a benzodioxane) and S 14671 and S 14506 (methoxynaphtylpiperazines) mimicked the aminotetralin, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), in inhibiting the firing of dorsal raphe nucleus (DRN) neurons. Similarly, the firing rate of DRN neurons was reduced by the "partial" agonists, MDL 73005EF, BMY 7378, NAN-190, tandospirone and the novel pyrimidinylpiperazine, zalospirone. Furthermore, S 14489, S 15535 and S 15931, novel benzodioxopiperazines, which behave as antagonists at postsynaptic 5-HT1A receptors, inhibited completely DRN firing, whereas the methoxyphenylpiperazine, WAY 100,135, and the aryloxoarylamine, (-)-tertatolol, were ineffective. Indeed, in analogy to spiperone, both WAY 100,135 and (-)-tertatolol behaved as apparently competitive antagonists in that, in their presence, the dose-response curves for inhibition of DRN firing by S 14671, S 14506 or 8-OH-DPAT were shifted in parallel to the right with no loss of maximal effect. In distinction to WAY 100,135 and (-)-tertatolol, a further novel, putative "antagonist," SDZ 216-525 (a benzoisothiazolpiperazine) weakly inhibited the electrical activity of the DRN. With the exception of (-)-tertatolol, which behaved as a weak agonist, a very similar pattern of inhibition of 5-HT turnover was seen in the striatum (innervated by the DRN), the hippocampus and the hypothalamus (DRN and median raphe nucleus) and the spinal cord (nucleus raphe magnus), with the striatum displaying the greatest sensitivity. Drug potency for inhibition of firing and turnover was highly correlated (r = 0.80-0.82) and these actions were significantly correlated to affinity at (hippocampal) 5-HT1A receptors (r = 0.62-0.73). As concerns DA D2 autoreceptors, the agonist action of apomorphine in reducing DA turnover were mimicked only by 8-OH-DPAT, whereas the majority of the other 5-HT1A ligands, in analogy to raclopride, enhanced DA turnover. The facilitation of DA turnover appeared to reflect direct blockade of DA D2 autoreceptors because potency was correlated powerfully to affinity at these D2 sites (r = 0.89).(ABSTRACT TRUNCATED AT 400 WORDS)


Persistent organic pollutants in early pregnancy and risk of gestational diabetes mellitus.
Persistent organic pollutants (POPs) are a group of diverse substances, including polychlorinated biphenyls (PCBs) and organochlorine pesticides that are resistant to biodegradation and ubiquitously present in our environment. Exposure to endocrine disrupting chemicals such as POPs has been linked to type 2 diabetes and metabolic disturbances in epidemiological and animal studies, but little is known about POPs exposure during pregnancy and the development of gestational diabetes mellitus (GDM). The purpose of this study was to determine the extent to which exposure to current low levels of different POPs in the first trimester of pregnancy is associated with GDM risk in 939 women from the "Rhea" pregnancy cohort in Crete, Greece. Concentrations of several PCBs, dichlorodiphenyldichloroethene (DDE), and hexachlorobenzene (HCB) were determined in first trimester maternal serum by triple quadrupole mass spectrometry. We defined total PCBs as the sum of all congeners, nondioxin-like PCBs as the sum of PCB 153, 138, 170 and 180, and dioxin-like PCBs as the sum of PCB 118 and 156. Pregnant women were screened for gestational diabetes mellitus (GDM) between 24 and 28weeks of gestation, and GDM was defined by the criteria proposed by Carpenter and Coustan. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models. Of the 939 women, 68 (7%) developed GDM. Serum concentrations of POPs were higher in women with GDM. Women in the medium and high tertiles of PCBs had 3.90 (95% CI: 1.37, 11.06) and 3.60 (95% CI: 1.14, 11.39) fold respectively higher odds of developing GDM compared to women in the lowest tertile of PCB exposure after adjusting for pre-pregnancy BMI and several other confounders. Odds of GDM for women in the medium and high tertiles of dioxin-like PCBs was 5.63 (95% CI: 1.81, 17.51) and 4.71 (95% CI: 1.38, 16.01) and for nondioxin-like PCBs 2.36 (95% CI: 0.89, 6.23) and 2.26 (95% CI: 0.77, 6.68) respectively. Prenatal DDE and HCB exposure were not significantly associated GDM risk. These findings suggest that women with high PCBs levels in early pregnancy had higher risk for GDM. Further studies are needed to replicate these results and to evaluate potential biological mechanisms underlying the observed associations.


Endothelium dependency of contractile activity differs in infant and adult vertebral arteries.
Contractions to serotonin (5-HT) and endothelin-1 (ET-1) in infant (0-2 yr) and adult (38-71 yr) vertebral arteries were examined in the presence of either the cyclooxygenase inhibitor indomethacin or NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide production. In addition, endothelium-dependent relaxations to acetylcholine were characterized in arteries contracted with agonist. The results showed that: (a) Contractions of infant arteries to 5-HT or ET-1 decreased to 44 +/- 8% and 27 +/- 13%, respectively, within 10 min. Indomethacin or removal of endothelium abolished this decreased response, whereas L-NMMA had no effect. (b) Adult arteries produced sustained contractions to 5-HT or ET-1 that were unaffected by indomethacin, endothelium denudation, or L-NMMA. (c) Endothelium-dependent relaxations to acetylcholine were greater in infant than adult arteries and were abolished by indomethacin (but not L-NMMA) in infants and L-NMMA (but not indomethacin) in adults. Thus, endothelium-dependent responses in infant arteries are attenuated because of increased prostaglandin activity not observed in adult tissues. Additionally, there is an age-dependent change in the primary mechanism responsible for acetylcholine-induced vasodilation. Apparently, endothelium dependency of acetylcholine-induced relaxation is highly dependent on cyclooxygenase activity in the infant vertebral artery, but in the adult artery, nitric oxide is linked to the vasodilator response.


Outcomes of Pectoralis Major Tears in Active Duty US Military Personnel: A Comparison of Surgical Repairs Performed in the Forward Deployed Setting to Those Performed in the Continental United States.
The purpose of our study is to compare pectoralis major tears in active duty military personal repaired surgically in the forward deployed setting to those performed in the Continental United States. Retrospective comparison of all pectoralis major tendon repairs performed at Madigan Army Medical Center from 2000 to 2007 to a forward deployed series treated by two deployed United States Air Force orthopedic surgeons at one expeditionary medical treatment facility over a 4-month deployment cycle from December 2013 through March 2014. Fourteen patients from the CONUS group and eight patients from deployed group were compared; they had a mean age of 32 years (21-52) all with pectoralis major ruptures that underwent operative fixation. Nineteen of the 22 patients (86%) sustained their injuries during bench press. The average bench press weight was similar with 271.8 lbs in the CONUS group and 273.1 lbs in the deployed group. There were 9 complete tears and 5 partial tears in the CONUS cohort whereas 7 complete tears and 1 partial tear in the deployed cohort, with all tears in both groups occurring at the insertion of the humerus. All 22 patients in both cohorts denied the use of anabolic steroids. The average DASH score at final follow-up was 12.74 in the CONUS group and 36.44 in the deployed group. The CONUS group reported that 7 out of 8 immediate repair patients and 4 out of 6 delayed repair patients returned to functional work level within 6 months with the 2 patients in the delayed repair group taking longer than 9 months to return to work. The deployed members reported return to functional work level at an average of 6.5 months. Both cohorts had early return to weight lifting at 6 and 7 months, respectively. The CONUS group reported a 39% bench press weight reduction and 34% pushup maximum reduction whereas the deployed cohort reported a 20% and 8% reduction respectively. When comparing deployed to CONUS results, we demonstrated that surgical repairs at one permanent US military in-theater tertiary referral medical center were as successful as repairs performed at one CONUS US Army academic tertiary referral medical center. Although in-theater surgical repair was technically feasible and clinically successful, we believe the lengthy convalescence, stringent post-operative restrictions, demanding environment and impact on operational readiness should preclude deployed surgical repairs from becoming standard practice.


Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a 1H NMR based metabolomics approach.
Pyrazinamide (PZA) is a well-known first line anti-tuberculosis drug used in combination with other drugs such as isoniazid and rifampicin. Unfortunately, PZA suffered from a high rate of hepatotoxicity and hyperuricemia, which has not been clearly elucidated, hindering its wide application for therapeutic purposes. The purpose of this investigation was to develop a model of rat sub-acute hepatotoxicity induced by PZA and to explore the affected metabolic pathways by a 1H NMR-based metabolomics approach complemented with histopathological analysis and clinical chemistry. Rats of both genders were administered with PZA by gavage at doses of 1.0 and 2.0 g kg-1 for 4 weeks. PZA decreased the weights of dosed rats and induced liver injury dose-dependently. The female rats were more sensitive to PZA induced damage. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of the rat liver and serum revealed that PZA produced a status of oxidative stress and disturbances in purine metabolism, energy metabolism and NAD+ metabolism in a gender-specific and dose-dependent manner. These findings could be helpful to clarify the mechanism of PZA-induced hepatotoxicity and hyperuricemia. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organisms, providing a powerful and feasible tool to probe drug induced toxicity or side effects.


Unbiased discovery of in vivo imaging probes through in vitro profiling of nanoparticle libraries.
In vivo imaging reveals how proteins and cells function as part of complex regulatory networks in intact organisms, and thereby contributes to a systems-level understanding of biological processes. However, the development of novel in vivo imaging probes remains challenging. Most probes are directed against a limited number of pre-specified protein targets; cell-based screens for imaging probes have shown promise, but raise concerns over whether in vitro surrogate cell models recapitulate in vivo phenotypes. Here, we rapidly profile the in vitro binding of nanoparticle imaging probes in multiple samples of defined target vs. background cell types, using primary cell isolates. This approach selects for nanoparticles that show desired targeting effects across all tested members of a class of cells, and decreases the likelihood that an idiosyncratic cell line will unduly skew screening results. To adjust for multiple hypothesis testing, we use permutation methods to identify nanoparticles that best differentiate between the target and background cell classes. (This approach is conceptually analogous to one used for high-dimensionality datasets of genome-wide gene expression, e.g. to identify gene expression signatures that discriminate subclasses of cancer.) We apply this approach to the identification of nanoparticle imaging probes that bind endothelial cells, and validate our in vitro findings in human arterial samples, and by in vivo intravital microscopy in mice. Overall, this work presents a generalizable approach to the unbiased discovery of in vivo imaging probes, and may guide the further development of novel endothelial imaging probes.


Characterization of the facilitatory prejunctional purinoceptor on adrenergic nerves of the rabbit ear artery.
The effects of a number of purinoceptor agonists and antagonists on the release of endogenous norepinephrine (NE) from electrically field-stimulated (2 ms, 4 Hz) rabbit ear arteries were determined. NE was quantified by high-performance liquid chromatography and electrochemical detection techniques. Both P1- and P2-purinoceptor agonists enhanced the release of NE in a concentration-dependent manner (0.1 microM-100 microM), the relative order of potency being beta, gamma-methylene ATP (beta gamma-mATP) > 2-chloroadenosine (2CA) > ATP > L-phenylisopropyl-adenosine > 2-methylthio ATP > 5'N-ethylcarboxamido-adenosine. Adenosine and alpha, beta-methylene ATP (alpha beta-mATP) at 100 microM did not significantly enhance the electrical field stimulation-evoked release of NE. None of drugs changed the spontaneous overflow of NE. Pretreatment with alpha beta-mATP (1, 10 microM), a P2x-purinoceptor desensitizing agent, and 8-sulfophenyl theophylline (8SPT; 1 and 10 microM), a P1-purinoceptor antagonist, caused a shift to right of the concentration-release curve for beta gamma-mATP. alpha beta-mATP and 8SPT did not by themselves significantly affect the spontaneous overflow and the electrical field stimulation-evoked release of NE. Pretreatment of alpha beta-mATP (30 microM) and 8SPT (30 microM) antagonized facilitation of NE release by 2CA (10 microM). The concentration-contraction curve for beta gamma-mATP (1-300 microM) in the rabbit ear artery was shifted to the right by alpha beta-mATP (30 microM) but not by 8SPT (30 microM).(ABSTRACT TRUNCATED AT 250 WORDS)


Systemic activation of Toll-like receptor 2 suppresses mitochondrial respiration and exacerbates hypoxic-ischemic injury in the developing brain.
Infection and inflammation are known risk factors for neonatal brain injury. Mycoplasma and Gram-positive bacteria, for which Toll-like receptor 2 (TLR2) plays a key role in recognition and inflammatory response, are among the most common pathogens in the perinatal period. Here, we report that systemic activation of TLR2 by Pam3CSK4 (P3C) increases neural tissue loss and demyelination induced by subsequent hypoxia-ischemia (HI) in neonatal mice. High-resolution respirometry of brain isolated mitochondria revealed that P3C suppresses ADP-induced oxidative phosphorylation, the main pathway of cellular energy production. The results suggest that infection and inflammation might contribute to HI-induced energy failure.


Immunological effects of HIV-1 infection on the humoral response to malaria in an African population.
We conducted a cross-sectional study to determine the serological response to malaria in an HIV-1 infected population and in a control population in a region of high malaria transmission. The study group consisted of 66 hospitalized patients with clinical acquired immunodeficiency syndrome (AIDS) and 70 trauma patients without clinical AIDS (controls). Mean optical densities of antibody produced against RESA-4, RESA-8, RESA-11, (PNAN)5 and (NAAG)5 synthetic peptides of Plasmodium falciparum were compared between HIV-1 seropositive and HIV-1 seronegative patients using non-parametric statistics. HIV-1 seropositive patients with clinical AIDS had significantly less antibody to the synthetic P. falciparum ring stage peptide, RESA-8 (P = 0.001), than a comparable group of seronegative patients. Antibody levels were also low for the other ring stage peptides, RESA-4 (P = 0.024) and RESA-11 (P = 0.024). Although not statistically significant, antibody levels among the HIV-1 seropositive trauma patients were higher than among the HIV-1 seronegative trauma patients. During HIV-1 infection, a polyclonal B cell activation may occur as noted in the HIV-1 seropositive trauma patients, but with increased immunosuppression in advanced clinical AIDS, B cell stimulation appears to be diminished. This results in decreased production of malaria antibody.


Cell birth and survival following seasonal periods of cell proliferation in the chemosensory epithelia of red-backed salamanders, Plethodon cinereus.
In addition to the continuous low levels of neurogenesis typical of adult vertebrates to replace damaged chemoreceptor cells, red-backed salamanders (Plethodon cinereus) experience an up-regulation of chemoreceptor epithelial cell proliferation on a seasonal basis. Significantly more cell division occurs in late spring than at any other time of the year, and we investigated the fate and life span of these newly generated cells. We used 5-bromo-2'-deoxyuridine (BrdU) immunocytochemical cell birth dating to examine cell proliferation and cell migration in the main olfactory and vomeronasal epithelia of red-backed salamanders collected in late spring who were allowed to survive for one hour or three, four, 25, 28, 42, 49 and 100 days post-injection. We examined new neuron growth in the vomeronasal and olfactory epithelia using antibodies against Growth Associated Protein-43 (GAP-43), a protein whose synthesis is up-regulated during axon growth. We also tracked apoptosis within both types of chemosensory epithelia using terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL). BrdU-immunoreactive cells were located extensively throughout the vomeronasal epithelia, particularly in the area posterior to the entrance of the nasolacrimal duct, not only after three days of survival, but also all of the longer experimental survival periods as well; BrdU-ir cells within the olfactory epithelia were rarely located after longer survival periods. Salamanders collected in late spring displayed extensive GAP-43 labeling in the vomeronasal epithelia posterior to the entrance of the nasolacrimal duct, indicating a large population of young vomeronasal receptor neurons. Finally, apoptotic cells were evident in this same post-nasolacrimal-duct-area of the vomeronasal organ and in the olfactory epithelium. We suggest that vomeronasal receptor neurons born in late spring function throughout the summer and may be associated with the animals' extensive territoriality during that period.


Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia.
Bacterial infections of the lung are known to induce inflammatory responses, which lead to mucus hypersecretion. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and its activation. Furthermore, matrix metalloproteinases (MMPs), especially MMP-9, have been reported to promote the transmigration of activated neutrophils. In this study, we investigated the associations between lipopolysaccharide (LPS)-induced goblet cell (GC) metaplasia and EGFR expression and the effects of MMP inhibitor (MMPI). Various concentrations of LPS were instilled into the tracheas of pathogen-free Sprague-Dawley rats, and airways were examined at different times after LPS instillation. To examine the role of MMP-9, we treated rats 3 days before LPS instillation and daily thereafter with MMPI. Neutrophilic infiltration, Alcian blue/periodic acid-Schiff (AB/PAS) staining, and immunohistochemical staining for MUC5AC, EGFR, and MMP-9 were performed. The instillation of LPS increased AB/PAS and MUC5AC staining in time- and dose-dependent manners, and treatment with MMPI significantly prevented GC metaplasia. The instillation of LPS into the trachea also induced neutrophilic infiltration and EGFR and MMP-9 expression in the airway epithelium, and MMPI was found to significantly prevent neutrophil recruitment, GC metaplasia, and EGFR and MMP-9 expression. This study demonstrates that the MMP-9 and EGFR cascades are associated with LPS-induced mucus hypersecretion.


Human Radiation Dosimetry for Orally and Intravenously Administered 18F-FDG.
Intravenous access is difficult in some patients referred for 18F-FDG PET imaging. Extravasation at the injection site and accumulation in central catheters can lead to limited tumor 18F-FDG uptake, erroneous quantitation, and significant image artifacts. In this study, we compared the human biodistribution and dosimetry for 18F-FDG after oral and intravenous administrations sequentially in the same subjects to ascertain the dosimetry and potential suitability of orally administered 18F-FDG as an alternative to intravenous administration. We also compared our detailed intravenous 18F-FDG dosimetry with older dosimetry data. Methods: Nine healthy volunteers (6 male and 3 female; aged 19-32 y) underwent PET/CT imaging after oral and intravenous administration of 18F-FDG. Identical preparation and imaging protocols (except administration route) were used for oral and intravenous studies. During each imaging session, 9 whole-body PET scans were obtained at 5, 10, 20, 30, 40, 50, 60, 120, and 240 min after 18F-FDG administration (370 ± 16 MBq). Source organ contours drawn using CT were overlaid onto registered PET images to extract time-activity curves. Time-integrated activity coefficients derived from time-activity curves were given as input to OLINDA/EXM for dose calculations. Results: Blood uptake after orally administered 18F-FDG peaked at 45-50 min after ingestion. The oral-to-intravenous ratios of 18F-FDG uptake for major organs at 45 min were 1.07 ± 0.24 for blood, 0.94 ± 0.39 for heart wall, 0.47 ± 0.12 for brain, 1.25 ± 0.18 for liver, and 0.84 ± 0.24 for kidneys. The highest organ-absorbed doses (μGy/MBq) after oral 18F-FDG administration were observed for urinary bladder (75.9 ± 17.2), stomach (48.4 ± 14.3), and brain (29.4 ± 5.1), and the effective dose was significantly higher (20%) than after intravenous administration (P = 0.002). Conclusion:18F-FDG has excellent bioavailability after oral administration, but peak organ activities occur later than after intravenous injection. These data suggest PET at 2 h after oral 18F-FDG administration should yield images that are comparable in biodistribution to conventional clinical images acquired 1 h after injection. Oral 18F-FDG is a palatable alternative to intravenous 18F-FDG when venous access is problematic.


Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes.
Adenylate cyclase in plasma membranes was inhibited by micromolar concentrations of delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol and by levonantradol and desacetyllevonantradol. This inhibition was noncompetitive for stimulation of the enzyme at the prostanoid receptor by prostaglandin E1 or prostacyclin, or at the peptide receptor by secretin or vasoactive intestinal peptide. Forskolin-activated adenylate cyclase was also inhibited by cannabimimetic agents. Inhibition by cannabinoid compounds was neither synergistic nor additive with muscarinic or alpha-adrenergic agents when each was present at maximally inhibitory concentrations. Cannabinoid inhibition was not blocked by atropine, yohimbine, or naloxone, suggesting that muscarinic, alpha 2-adrenergic and certain opiate receptors may not be required for the response. The inhibition of adenylate cyclase was specific for psychoactive cannabinoids, since cannabinol and cannabidiol produced minimal or no response. Inhibition was also stereoselective, since dextronantradol did not produce the response. A biphasic log dose-response curve was observed for each of the cannabinoid drugs, such that reversal of the inhibition occurred at 3-10 microM. Possible mechanisms for the effects of cannabinoid drugs on adenylate cyclase activity are discussed.


Use of inspiratory profiles from patients with chronic obstructive pulmonary disease (COPD) to investigate drug delivery uniformity and aerodynamic dose emission of indacaterol from a capsule based dry powder inhaler.
Most patients using dry powder inhalers (DPIs) are unable to achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of indacaterol Breezhaler (IB) have been measured using COPD patients' inhalation profiles (IPs) when using IB and replayed in-vitro using a breath simulator attached to an Andersen Cascade Impactor. The peak inhalation flow (PIF) of the profiles ranged from 28.3 to 87.8 L/min and inhaled volumes (Vin) from 0.7 to 3 L. The indacaterol total emitted doses (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) were measured. TED varied between 61% to 83% of the 150 μg nominal dose, the FPD was found to vary between 19% and 30% and the MMAD from 3.7 μm to 2.3 μm with the increase of the profiles' PIF and Vin. The mean (SD) values were 113.4(8.9) μg, 39.7(5.0) μg and 2.7(0.5) μm, respectively. The quantity and the quality of the emitted dose from the indacaterol Breezhaler® are dependent on the capability of a patient generating an optimal inhalation profile. Therefore, when using the IB patients should be encouraged to inhale as fast as they can from the start of their inhalation and for as long as possible.


Lanthanide labeling offers fast NMR approach to 3D structure determinations of protein-protein complexes.
A novel nuclear magnetic resonance (NMR) strategy based on labeling with lanthanides achieves rapid determinations of accurate three-dimensional (3D) structures of protein-protein complexes. The method employs pseudocontact shifts (PCS) induced by a site-specifically bound lanthanide ion to anchor the coordinate system of the magnetic susceptibility tensor in the molecular frames of the two molecules. Simple superposition of the tensors detected in the two protein molecules brings them together in a 3D model of the protein-protein complex. The method is demonstrated with the 30 kDa complex between two subunits of Escherichia coli polymerase III, comprising the N-terminal domain of the exonuclease subunit epsilon and the subunit theta. The 3D structures of the individual molecules were docked based on a limited number of PCS observed in 2D 15N-heteronuclear single quantum coherence spectra. Degeneracies in the mutual orientation of the protein structures were resolved by the use of two different lanthanide ions, Dy3+ and Er3+.


Prostate cancer incidence among American Indian and Alaska Native men, US, 1999-2004.
American Indian and Alaska Native (AI/AN) men experience lower incidence of prostate cancer than other race/ethnic populations in the US, but racial misclassification of AI/AN men threatens the validity of these estimates. To the authors' knowledge, little is known concerning prostate-specific antigen (PSA) testing in AI/AN men. The authors linked cancer registry data with Indian Health Service enrollment records to improve race classification. Analyses comparing cancer incidence rates and stage at diagnosis for AI/AN and non-Hispanic white (NHW) men for 6 geographic regions focused on counties known to have less race misclassification. The authors also used Behavioral Risk Factors Surveillance System data to characterize PSA testing in AI/AN men. Prostate cancer incidence rates were generally lower in AI/AN than in NHW men for all regions combined (rate ratio of 0.68). However, regional variation was noted among AI/AN men, with incidence rates (per 100,000 population) ranging from 65.7 in the Southwest to 174.5 on the Northern Plains. The rate of distant stage disease was somewhat higher among AI/AN (7.8) than NHW (6.2) men. Nationally, AI/AN men were less likely than NHW men to have undergone recent PSA testing (48.4% vs 58.0%), with prominent regional variation in screening rates noted. Prostate cancer incidence rates and the proportion of men with recent PSA testing were lower for AI/AN men than for NHW men. However, incident rates and rate of distant stage varied by region more for AI/AN than for NHW. Further research is needed among AI/AN men to evaluate strategies for better understanding the causes of the regional variation in prostate cancer incidence.


Assessing nutritional diversity of cropping systems in African villages.
In Sub-Saharan Africa, 40% of children under five years in age are chronically undernourished. As new investments and attention galvanize action on African agriculture to reduce hunger, there is an urgent need for metrics that monitor agricultural progress beyond calories produced per capita and address nutritional diversity essential for human health. In this study we demonstrate how an ecological tool, functional diversity (FD), has potential to address this need and provide new insights on nutritional diversity of cropping systems in rural Africa. Data on edible plant species diversity, food security and diet diversity were collected for 170 farms in three rural settings in Sub-Saharan Africa. Nutritional FD metrics were calculated based on farm species composition and species nutritional composition. Iron and vitamin A deficiency were determined from blood samples of 90 adult women. Nutritional FD metrics summarized the diversity of nutrients provided by the farm and showed variability between farms and villages. Regression of nutritional FD against species richness and expected FD enabled identification of key species that add nutrient diversity to the system and assessed the degree of redundancy for nutrient traits. Nutritional FD analysis demonstrated that depending on the original composition of species on farm or village, adding or removing individual species can have radically different outcomes for nutritional diversity. While correlations between nutritional FD, food and nutrition indicators were not significant at household level, associations between these variables were observed at village level. This study provides novel metrics to address nutritional diversity in farming systems and examples of how these metrics can help guide agricultural interventions towards adequate nutrient diversity. New hypotheses on the link between agro-diversity, food security and human nutrition are generated and strategies for future research are suggested calling for integration of agriculture, ecology, nutrition, and socio-economics.


Unusual size-dependence of effective interactions between collapsed polymers in crowded environments.
We investigate the influence of macromolecular crowding on interactions between collapsed polymers using computer simulations, to gain insights into biomacromolecular interactions in crowded biological environments. The effective attraction is induced between two collapsed polymers due to the macromolecular crowding, and it is found that the strength of the effective attraction decreases as the crowder size is reduced for a fixed crowder volume fraction, which is sharply contrasted with the conventional viewpoint based on the depletion attraction observed for hard-core spherical colloids. This unusual trend of size-dependence is interpreted by dividing the effective interaction into the polymer-mediated repulsion and crowder-mediated attraction. It is found that the ranges of repulsive and attractive contributions overlap significantly due to the flexible nature of polymer boundaries, resulting in partial cancellation over this range which leads to the observed size-dependence. Thus, this work suggests that the effective interactions between biomacromolecules in crowded environments may be qualitatively different from the depletion interactions predicted for hard-core spherical colloids.


[A study on the biological effects of exposure mobile-phone frequency EMF].
Together with a growing number of cellular telephone users increases the interest in the effect of electromagnetic fields (EMF) emitted by them on live organisms. The surveys on subjective complaints of cellular telephone users carried out in Sweden, Norway, UK, USA, New Zealand and Australia showed that head ache is the major complain, and it is more pronounced with analogue than digital telephones. Apart from head ache, fatigue and general ill-being, muscular pains and nausea are reported. Human experimental studies reveal that EMF emitted by cellular telephones may be responsible for periodical increase in arterial blood pressure, changes in electric activity of the brain. However, no changes in secretion of cerebral pituitary hormones: adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), growth hormone, prolactin (PRL), lactogenic hormone (LH), follicle-stimulating hormone (FSH) and melatonine. The animal experimental studies indicated that exposure to EMF of the microwave frequency activates the endogenous opioid system in the brain, while the studies of the brain neurotransmitter activity have not produced univocal results, some of them showed decline, others increase in acetylcholinesterase activity. In vitro studies reveal that EMF even below maximum permissible levels may induce changes in the blood-brain permeability barrier and disorders in active transport of Na+, K+ ions and release of Ca++ ions by cellular membranes. The studies carried out thus far have not produced clear-cut results, but they indicate that EMF of the microwave frequency, including the frequency emitted by cellular telephones may be responsible for various measurable biological effects. It is essential to find out whether these effects may affect human health.


Increased Risk of Stroke in Patients of Concussion: A Nationwide Cohort Study.
Long-term morbidities can develop after traumatic brain injury (TBI). Some studies have suggested that the risk of stroke is higher after TBI, but the association between concussion and stroke remains unclear. Using a national cohort, the authors analyzed the incidence of both hemorrhagic and ischemic strokes in patients with previous concussion. A representative cohort of approximately one million people was followed up for four years. Patients with new-onset concussion were identified (n = 13,652) as the concussion group. Subsequently, the incidence rates of later stroke events in the concussion group were compared to a sex-, age- and propensity score-matched comparison group (n = 13,652). The overall incidence rate of stroke in the concussion group was higher than that of the comparison group (9.63 versus 6.52 per 1000 person-years, p < 0.001). Significantly higher stroke risk was observed in the concussion group than in the comparison group (crude hazard ratio 1.48, p < 0.001; adjusted HR 1.65, p < 0.001). In the concussion group, the cumulative incidence rates of both ischemic stroke and hemorrhagic stroke were higher than those of the comparison group (8.9% vs. 5.8% and 2.7% vs. 1.6%, respectively, both p < 0.001). Concussion is an independent risk factor for both ischemic and hemorrhagic strokes. Prevention and monitoring strategies of stroke are therefore suggested for patients who have experienced concussion.


Public participation processes related to nuclear research installations: what are the driving factors behind participation intention?
This article addresses organised public participation processes related to installations for nuclear research. The aim was to determine predictors that could provide an empirical insight into the motivations underlying people's intended level of involvement. The results highlight attitude towards participation and moral norm as the strongest predictors for participation intention. Other significant predictors were time constraints, attitude towards nuclear energy, subjective and descriptive norms, and knowledge. An opposing relationship is noted between participation intention and attitude towards nuclear energy. At the same time, people who are more knowledgeable about the nuclear domain seem more willing to get involved. The analysis also revealed that financial benefits do not influence people's intended involvement in participation processes related to nuclear research installations. The results reported here are based on empirical data from a large-scale public opinion survey (N = 1020) carried out in Belgium during May-June 2011.


Low plasma iron status and akathisia.
Thirty patients were examined to test the hypothesis that a depletion of iron levels is associated with symptoms of akathisia. Fifteen akathisic patients were pair-matched with 15 non-akathisic patients. Plasma ferritin levels were significantly decreased in the akathisic patients, and there was a significant inverse correlation between plasma iron levels and akathisia rating. In addition, akathisia ratings were found to be correlated with a scale measuring symptoms of tardive dyskinesia.


Phase II study of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma.
The purpose of this prospective multicenter phase II study was to evaluate the efficacy and toxicity of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma. Patients with advanced soft tissue or bone sarcoma, previously treated with ifosfamide and anthracycline-based chemotherapies, were treated with docetaxel (35 mg/m(2) over 60 min) and gemcitabine (1,000 mg/m(2) over 100 min) on days 1 and 8 of every 3-week cycle. From September 2008 to August 2010, 30 patients were enrolled; 24 (80.0%) were men and median patient age was 45 years (range 17-70 years). The patients received a total of 136 cycles of therapy (median 4 cycles per patient; range 1-15 cycles). Of these 30 patients, none achieved complete response (CR) and 5 achieved a partial response (PR), making the overall response rate 16.7% (95% CI, 2.5-30.8%). Twelve patients had stable disease (SD), resulting in tumor control (CR or PR or SD) in 17 of 30 patients (56.7%). Median progression-free survival was 2.5 months (range 0.8-15.3 months), and median overall survival was 8.4 months (range 1.4-22.3 months). Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were observed in 17 (56.7%), 13 (43.4%), and 4 (13.3%) patients, respectively. None of these patients, however, had febrile neutropenia or bleeding events, and all non-hematologic toxicities were manageable. The combination of weekly docetaxel and fixed dose rate gemcitabine was tolerable and may be an active regimen in patients with previously treated advanced sarcoma.


False negative rates in Drosophila cell-based RNAi screens: a case study.
High-throughput screening using RNAi is a powerful gene discovery method but is often complicated by false positive and false negative results. Whereas false positive results associated with RNAi reagents has been a matter of extensive study, the issue of false negatives has received less attention. We performed a meta-analysis of several genome-wide, cell-based Drosophila RNAi screens, together with a more focused RNAi screen, and conclude that the rate of false negative results is at least 8%. Further, we demonstrate how knowledge of the cell transcriptome can be used to resolve ambiguous results and how the number of false negative results can be reduced by using multiple, independently-tested RNAi reagents per gene. RNAi reagents that target the same gene do not always yield consistent results due to false positives and weak or ineffective reagents. False positive results can be partially minimized by filtering with transcriptome data. RNAi libraries with multiple reagents per gene also reduce false positive and false negative outcomes when inconsistent results are disambiguated carefully.


What is the best proton energy for accelerator-based BNCT using the 7Li(p,n)7Be reaction?
With a growing interest in the use of accelerator-based epithermal neutron sources for BNCT programs, in particular those based upon the 7Li(p,n)7Be reaction, there is a need to address the question of "what is the best proton energy to use?" This paper considers this question by using radiation transport calculations to investigate a range of proton energies from 2.15 to 3.5 MeV and a range of moderator sizes. This study has moved away completely from the use of empty therapy beam parameters and instead defines the beam quality and optimizes the moderator design using widely accepted in-phantom treatment planning figures of merit. It is concluded that up to a proton energy of about 2.8 MeV there is no observed variation in the achievable therapy beam quality, but a price is paid in terms of treatment time for not choosing the upper limit of this range. For higher proton energies, the beam quality falls, but with no improvement in treatment time for optimum configurations.


Breathing life into dinosaurs: tackling challenges of soft-tissue restoration and nasal airflow in extinct species.
The nasal region plays a key role in sensory, thermal, and respiratory physiology, but exploring its evolution is hampered by a lack of preservation of soft-tissue structures in extinct vertebrates. As a test case, we investigated members of the "bony-headed" ornithischian dinosaur clade Pachycephalosauridae (particularly Stegoceras validum) because of their small body size (which mitigated allometric concerns) and their tendency to preserve nasal soft tissues within their hypermineralized skulls. Hypermineralization directly preserved portions of the olfactory turbinates along with an internal nasal ridge that we regard as potentially an osteological correlate for respiratory conchae. Fossil specimens were CT-scanned, and nasal cavities were segmented and restored. Soft-tissue reconstruction of the nasal capsule was functionally tested in a virtual environment using computational fluid dynamics by running air through multiple models differing in nasal soft-tissue conformation: a bony-bounded model (i.e., skull without soft tissue) and then models with soft tissues added, such as a paranasal septum, a scrolled concha, a branched concha, and a model combining the paranasal septum with a concha. Deviations in fluid flow in comparison to a phylogenetically constrained sample of extant diapsids were used as indicators of missing soft tissue. Models that restored aspects of airflow found in extant diapsids, such as appreciable airflow in the olfactory chamber, were judged as more likely. The model with a branched concha produced airflow patterns closest to those of extant diapsids. These results from both paleontological observation and airflow modeling indicate that S. validum and other pachycephalosaurids could have had both olfactory and respiratory conchae. Although respiratory conchae have been linked to endothermy, such conclusions require caution in that our re-evaluation of the reptilian nasal apparatus indicates that respiratory conchae may be more widespread than originally thought, and other functions, such as selective brain temperature regulation, could be important.


Extensive variation in nuclear mitochondrial DNA content between the genomes of Phytophthora sojae and Phytophthora ramorum.
Fragments of mitochondrial DNA (mtDNA) transferred to the nuclear genome are called nuclear mitochondrial DNAs (NUMTs). We report here a comparison of NUMT content between genomes from two species of the same genus. Analysis of the genomes of Phytophthora sojae and P. ramorum revealed large differences in the NUMT content of the two genomes: 16.27 x 10(-3) and 2.28 x 10(-3)% of each genome, respectively. Substantial differences also exist between the two species in the sizes of the NUMTs found in each genome, with ranges of 20 to 405 bp for P. sojae and 19 to 137 bp for P. ramorum. Furthermore, in P. sojae, fragments from the mitochondrial genes rns, rnl, coxl, and nad (various subunits) are found most frequently, whereas P. ramorum NUMTs most often originate from the cox3, rpsl4, nad4, and nad5 genes. The large differences in the presumptive mtDNA insertions suggest that the insertions occurred subsequent to the divergence of the two species, and this is supported by sequence comparisons among the NUMTs and the mtDNA sequences of the two species. P. sojae mtDNA sequences inserted in the nuclear genome appear to have been altered as a result of insertions, deletions, inversions, and translocations and provide insights into active mechanisms of sequence divergence in this plant pathogen. No clear examples were found of NUMTs forming functional nuclear genes or of NUMTs inserted into exons or introns of any nuclear gene.


Ellagic Acid Inhibits Bladder Cancer Invasiveness and In Vivo Tumor Growth.
Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.


Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults.
The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn's disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.


Breastfeeding patterns and exposure to suboptimal breastfeeding among children in developing countries: review and analysis of nationally representative surveys.
Suboptimal breastfeeding is associated with higher mortality among infants and young children in the developing world. We describe patterns in 'exclusive breastfeeding' and 'any breastfeeding' rates and quantify exposure to suboptimal breastfeeding among children aged two years or younger in developing countries. We reviewed nationally representative surveys that collected data on breastfeeding rates in 94 developing countries. Surveys were categorized by completeness and comprehensiveness of data. Complete and comprehensive data were analysed with minimum chi-square regression. With a fitting procedure, estimated parameters were used to impute missing observations for incomplete or non-comprehensive surveys. Breastfeeding indicators were calculated and are reported for 135 developing countries by UN region. Amongst infants aged six months or younger in the developing world, the prevalence of exclusive breastfeeding is 39% and the prevalence of no breastfeeding is 5.6%. The prevalence of continued breastfeeding is 86% and 68% for infants and children aged 6-11 and 12-23 months, respectively, in the developing world. Imputation expands population coverage of indicators, especially for infants. Breastfeeding trends are highly linear and estimated parameters defining the age-specific attrition hazard are robust. Survey-reported rates, particularly for exclusive breastfeeding, appear to have systematic upward bias, and exposure estimates must be considered conservative. Compliance with breastfeeding recommendations in developing countries is low, and more attention should be given to increasing breastfeeding - especially exclusive breastfeeding - and to monitoring trends. Although the introduction of more standardized and better validated survey instruments is desirable, since data coverage, completeness and comprehensiveness are extensive, global exposure assessment is relatively robust. Moreover, the regularity of breastfeeding patterns show existing survey data capture real biological and social phenomena. Our method for the analysis of breastfeeding rates provides a potent tool for summarizing trends, validating observations, translating and extrapolating indicators (as well as projecting and imputing estimates when necessary) and should support more effective child health monitoring.


Hemodynamic function at rest, during acute stress, and in the field: predictors of cardiac structure and function 2 years later in youth.
Left ventricular hypertrophy is an independent predictor of cardiovascular morbidity and mortality. However, predictors of cardiac structure and function in youth are not completely understood. On 2 occasions (2.3 years apart), we examined 146 youth aged initially 10 to 19 years (mean age, 14.2+/-1.8 years). On the initial visit, hemodynamic function was assessed at rest, during laboratory stress (ie, orthostasis, car-driving simulation, video game, and forehead cold), and in the field (ie, ambulatory blood pressure). Quantitative M-mode echocardiograms were obtained on both visits. On both visits, black compared with white youth had higher resting laboratory systolic blood pressure (P<0.02), greater relative wall thickness (P<0.003), greater left ventricular mass indexed by either body surface area or height(2.7) (P<0.01 for both), and lower midwall fractional shortening ratio (P<0.05). Hierarchical stepwise regression analysis indicated that significant independent predictors of follow-up left ventricular mass/height(2. 7) were the initial evaluation of left ventricular mass/height(2.7), body mass index, gender (males more than females), and supine resting total peripheral resistance (final model R(2)=0.53). Left ventricular mass/body surface area was predicted by initial left ventricular mass/body surface area, weight, gender, mean supine resting total peripheral resistance, and systolic pressure response to car-driving simulation (final model R(2)=0.48). Midwall fractional shortening was predicted by initial midwall fractional shortening, race (white more than black), and lower mean supine total peripheral resistance (final model R(2)=0.13). The clinical significance of these findings and their implications for improved prevention of cardiovascular diseases are yet to be determined.


Systolic Blood Pressure Intervention Trial (SPRINT) and Target Systolic Blood Pressure in Future Hypertension Guidelines.
The Systolic Blood Pressure (SBP, mm Hg) Intervention Trial (SPRINT) showed that targeting SBP <120 mm Hg (intensive treatment, mean SBP: 121.5 mm Hg) versus <140 (standard treatment, mean SBP: 134.6 mm Hg) reduced cardiovascular events 25%. SPRINT has 2 implicit assumptions that could impact future US hypertension guidelines: (1) standard therapy controlled SBP similarly to that in adults with treated hypertension and (2) intensive therapy produced a lower mean SBP than in adults with treated hypertension and SBP <140 mm Hg. To examine these assumptions, US National Health and Nutrition Examination Survey 2009 to 2012 data were analyzed on 3 groups of adults with treated hypertension: group 1 consisted of SPRINT-like participants aged ≥50 years; group 2 consisted of participants all aged ≥18 years; and group 3 consisted of participants aged ≥18 years excluding group 1 but otherwise similar to SPRINT-like participants except high cardiovascular risk. Mean SBPs in groups 1, 2, and 3 were 133.0, 130.1, and 124.6, with 66.2%, 72.2%, and 81.9%, respectively, controlled to SBP <140; 68.3%, 74.8%, and 83.4% of the controlled subset had SBP <130. Mean SBPs in those controlled to <140 were 123.3, 120.9, and 118.9, respectively. Among US adults with treated hypertension, (1) the SPRINT-like group had higher mean SBP than comparison groups, yet lower than SPRINT standard treatment group and (2) among groups 1 to 3 with SBP <140, SBP values were within <3 mm Hg of SPRINT intensive treatment. SPRINT results suggest that treatment should be continued and not reduced when treated SBP is <130, especially for the SPRINT-like subset. Furthermore, increasing the percentage of treated adults with SBP <140 could approximate SPRINT intensive treatment SBP without lowering treatment goals.


Two Sides of a Coin: a Zika Virus Mutation Selected in Pregnant Rhesus Macaques Promotes Fetal Infection in Mice but at a Cost of Reduced Fitness in Nonpregnant Macaques and Diminished Transmissibility by Vectors.
Although fetal death is now understood to be a severe outcome of congenital Zika syndrome, the role of viral genetics is still unclear. We sequenced Zika virus (ZIKV) from a rhesus macaque fetus that died after inoculation and identified a single intrahost substitution, M1404I, in the ZIKV polyprotein, located in nonstructural protein 2B (NS2B). Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at a subconsensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I has occurred rarely in humans since 2015. Since the primary ZIKV transmission cycle is human-mosquito-human, mutations in one host must be retained in the alternate host to be perpetuated. We hypothesized that ZIKV I1404 increases viral fitness in nonpregnant macaques and pregnant mice but is less efficiently transmitted by vectors, explaining its low frequency in humans during outbreaks. By examining competitive fitness relative to that of ZIKV M1404, we observed that ZIKV I1404 produced lower viremias in nonpregnant macaques and was a weaker competitor in tissues. In pregnant wild-type mice, ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, in contrast to ZIKV M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Aedes aegypti mosquitoes transmitted ZIKV I1404 more poorly than ZIKV M1404. Our data highlight the complexity of arbovirus mutation-fitness dynamics and suggest that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics.IMPORTANCE Although Zika virus infection of pregnant women can result in congenital Zika syndrome, the factors that cause the syndrome in some but not all infected mothers are still unclear. We identified a mutation that was present in some ZIKV genomes in experimentally inoculated pregnant rhesus macaques and their fetuses. Although we did not find an association between the presence of the mutation and fetal death, we performed additional studies with ZIKV with the mutation in nonpregnant macaques, pregnant mice, and mosquitoes. We observed that the mutation increased the ability of the virus to infect mouse fetuses but decreased its capacity to produce high levels of virus in the blood of nonpregnant macaques and to be transmitted by mosquitoes. This study shows that mutations in mosquito-borne viruses like ZIKV that increase fitness in pregnant vertebrates may not spread in outbreaks when they compromise transmission via mosquitoes and fitness in nonpregnant hosts.


Drug-resistant Salmonella from animals fed antimicrobials.
It has been difficult to document the postulated sequence of events that begins with the selection of drug-resistant organisms in animals fed subtherapeutic amounts of antimicrobials and ends with clinically important infections in human beings. In early 1983 we identified 18 persons in four Midwestern states who were infected with Salmonella newport that was resistant to ampicillin, carbenicillin, and tetracycline and characterized by a 38-kilobase R plasmid. Twelve of these patients had been taking penicillin derivatives for medical problems other than diarrhea in the 24 to 48 hours before the onset of salmonellosis. Eleven patients were hospitalized for salmonellosis for an average of eight days, and one had a fatal nosocomial infection. We compared plasmid profiles of all human (six-state area) and animal (United States) S. newport isolates over an 18-month period and examined selected records of meat distribution. The results indicated that the patients had been infected before they took antimicrobials, by eating hamburger originating from South Dakota beef cattle fed subtherapeutic chlortetracycline for growth promotion. This study demonstrates that antimicrobial-resistant organisms of animal origin cause serious human illness, and emphasizes the need for more prudent use of antimicrobials in both human beings and animals.


Diffusion engineering of ions and charge carriers for stable efficient perovskite solar cells.
Long-term stability is crucial for the future application of perovskite solar cells, a promising low-cost photovoltaic technology that has rapidly advanced in the recent years. Here, we designed a nanostructured carbon layer to suppress the diffusion of ions/molecules within perovskite solar cells, an important degradation process in the device. Furthermore, this nanocarbon layer benefited the diffusion of electron charge carriers to enable a high-energy conversion efficiency. Finally, the efficiency on a perovskite solar cell with an aperture area of 1.02 cm2, after a thermal aging test at 85 °C for over 500 h, or light soaking for 1,000 h, was stable of over 15% during the entire test. The present diffusion engineering of ions/molecules and photo generated charges paves a way to realizing long-term stable and highly efficient perovskite solar cells.


Cost-effectiveness of low-dose rivaroxaban and aspirin versus aspirin alone in people with peripheral or carotid artery disease: An Australian healthcare perspective.
Peripheral artery disease affects 1.2% of the population globally and is associated with an increased risk of atherothrombotic cardiovascular events, major adverse limb events and mortality. The Cardiovascular Outcomes for People Using Anti-coagulation Strategies (COMPASS) trial demonstrated positive results of rivaroxaban plus aspirin therapy compared to aspirin therapy alone in those with peripheral artery disease or carotid artery disease. We sought to estimate the cost-effectiveness from the Australian healthcare system perspective. A Markov model was developed to simulate the experiences of a hypothetical population of 1000 individuals with peripheral artery disease or carotid artery disease, profiled on the COMPASS trial, treated with rivaroxaban plus aspirin therapy versus aspirin therapy alone. With each annual cycle, individuals were at risk of having non-fatal cardiovascular disease events, major adverse limb events, or dying. Individuals were also at risk of non-fatal major bleeding. The model had a lifetime time horizon. Costs and utilities were sourced from the literature and discounted at 5.0% annually. Rivaroxaban plus aspirin therapy prevented 143 non-fatal cardiovascular disease events, 118 major adverse limb events and 10 deaths compared to aspirin therapy alone. Conversely, 156 additional major non-fatal bleeds were accrued. With an additional 256 quality-adjusted life years gained, at an additional cost of AUD$6,858,103, the incremental cost-effectiveness ratio was AUD$26,769 (discounted) per quality-adjusted life year gained, which is below Australia's arbitrary willingness to pay threshold of AUD$50,000. In those with peripheral artery disease or carotid artery disease, rivaroxaban plus aspirin therapy is effective and cost-effective in the prevention of recurrent cardiovascular disease compared to aspirin therapy alone.


Haplotype diversity in mitochondrial genome in a Chinese Han population.
Investigations into the use of mitochondrial genome (mtGenome) typing by massively parallel sequencing technologies are well underway in many areas, including forensic genetics. Previous studies have demonstrated that mtGenome sequencing data generated from Ion torrent personal genome machine (PGM) system were highly viable and reliable in forensic research. In this study, 145 whole mtGenomes from unrelated Chinese Han population were sequenced using the Ion PGM system. Results showed that 145 distinct haplotypes were obtained at a relatively high coverage with limited strand bias. The distribution of variants across the entire mtGenomes was illustrated and 70.74% of the variants were observed outside of the control region. An overall increase in the number of unique haplotypes as well as haplotype diversity were observed by detection of mtGenome compared with hypervariable region I/II (HV I/II) and control region (CR). This study demonstrates the substantially higher degree of haplotype resolution with whole-mtGenome sequences in comparison to HV I/II or CR that historically targeted for forensic testing, which shows the potential value of mtGenome typing in forensic testing in the future.


Central and autonomic nervous system interaction is altered by short-term meditation.
Five days of integrative body-mind training (IBMT) improves attention and self-regulation in comparison with the same amount of relaxation training. This paper explores the underlying mechanisms of this finding. We measured the physiological and brain changes at rest before, during, and after 5 days of IBMT and relaxation training. During and after training, the IBMT group showed significantly better physiological reactions in heart rate, respiratory amplitude and rate, and skin conductance response (SCR) than the relaxation control. Differences in heart rate variability (HRV) and EEG power suggested greater involvement of the autonomic nervous system (ANS) in the IBMT group during and after training. Imaging data demonstrated stronger subgenual and adjacent ventral anterior cingulate cortex (ACC) activity in the IBMT group. Frontal midline ACC theta was correlated with high-frequency HRV, suggesting control by the ACC over parasympathetic activity. These results indicate that after 5 days of training, the IBMT group shows better regulation of the ANS by a ventral midfrontal brain system than does the relaxation group. This changed state probably reflects training in the coordination of body and mind given in the IBMT but not in the control group. These results could be useful in the design of further specific interventions.


Incorporating known sources of uncertainty to determine precautionary harvests of saltwater crocodiles.
It has been demonstrated repeatedly that the degree to which regulation operates and the magnitude of environmental variation in an exploited population will together dictate the type of sustainable harvest achievable. Yet typically, harvest models fail to incorporate uncertainty in the underlying dynamics of the target population by assuming a particular (unknown) form of endogenous control. We use a novel approach to estimate the sustainable yield of saltwater crocodile (Crocodylus porosus) populations from major river systems in the Northern Territory, Australia, as an example of a system with high uncertainty. We used multimodel inference to incorporate three levels of uncertainty in yield estimation: (1) uncertainty in the choice of the underlying model(s) used to describe population dynamics, (2) the error associated with the precision and bias of model parameter estimation, and (3) environmental fluctuation (process error). We demonstrate varying strength of evidence for density regulation (1.3-96.7%) for crocodiles among 19 river systems by applying a continuum of five dynamical models (density-independent with and without drift and three alternative density-dependent models) to time series of density estimates. Evidence for density dependence increased with the number of yearly transitions over which each river system was monitored. Deterministic proportional maximum sustainable yield (PMSY) models varied widely among river systems (0.042-0.611), and there was strong evidence for an increasing PMSY as support for density dependence rose. However, there was also a large discrepancy between PMSY values and those produced by the full stochastic simulation projection incorporating all forms of uncertainty, which can be explained by the contribution of process error to estimates of sustainable harvest. We also determined that a fixed-quota harvest strategy (up to 0.2K, where K is the carrying capacity) reduces population size much more rapidly than proportional harvest (the latter strategy requiring temporal monitoring of population size to adjust harvest quotas) and greatly inflates the risk of resource depletion. Using an iconic species recovering from recent extreme overexploitation to examine the potential for renewed sustainable harvest, we have demonstrated that incorporating major forms of uncertainty into a single quantitative framework provides a robust approach to modeling the dynamics of exploited populations.


Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy.
A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. To evaluate the rate of within-couple HIV transmission (heterosexual and men who have sex with men [MSM]) during periods of sex without condoms and when the HIV-positive partner had HIV-1 RNA load less than 200 copies/mL. The prospective, observational PARTNER (Partners of People on ART-A New Evaluation of the Risks) study was conducted at 75 clinical sites in 14 European countries and enrolled 1166 HIV serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex (September 2010 to May 2014). Eligibility criteria for inclusion of couple-years of follow-up were condomless sex and HIV-1 RNA load less than 200 copies/mL. Anonymized phylogenetic analysis compared couples' HIV-1 polymerase and envelope sequences if an HIV-negative partner became infected to determine phylogenetically linked transmissions. Condomless sexual activity with an HIV-positive partner taking virally suppressive ART. Risk of within-couple HIV transmission to the HIV-negative partner. Among 1166 enrolled couples, 888 (mean age, 42 years [IQR, 35-48]; 548 heterosexual [61.7%] and 340 MSM [38.3%]) provided 1238 eligible couple-years of follow-up (median follow-up, 1.3 years [IQR, 0.8-2.0]). At baseline, couples reported condomless sex for a median of 2 years (IQR, 0.5-6.3). Condomless sex with other partners was reported by 108 HIV-negative MSM (33%) and 21 heterosexuals (4%). During follow-up, couples reported condomless sex a median of 37 times per year (IQR, 15-71), with MSM couples reporting approximately 22,000 condomless sex acts and heterosexuals approximately 36,000. Although 11 HIV-negative partners became HIV-positive (10 MSM; 1 heterosexual; 8 reported condomless sex with other partners), no phylogenetically linked transmissions occurred over eligible couple-years of follow-up, giving a rate of within-couple HIV transmission of zero, with an upper 95% confidence limit of 0.30/100 couple-years of follow-up. The upper 95% confidence limit for condomless anal sex was 0.71 per 100 couple-years of follow-up. Among serodifferent heterosexual and MSM couples in which the HIV-positive partner was using suppressive ART and who reported condomless sex, during median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission (upper 95% confidence limit, 0.30/100 couple-years of follow-up). Additional longer-term follow-up is necessary to provide more precise estimates of risk.


Reliability of non-lethal surveillance methods for detecting ranavirus infection.
Ranaviruses have been identified as the etiologic agent in many amphibian die-offs across the globe. Polymerase chain reaction (PCR) is commonly used to detect ranavirus infection in amphibian hosts, but the test results may vary between tissue samples obtained by lethal and non-lethal procedures. Testing liver samples for infection is a common lethal sampling technique to estimate ranavirus prevalence because the pathogen often targets this organ and the liver is easy to identify and collect. However, tail clips or swabs may be more practicable for ranavirus surveillance programs compared with collecting and euthanizing animals, especially for uncommon species. Using PCR results from liver samples for comparison, we defined false-positive test results as occurrences when a non-lethal technique indicated positive but the liver sample was negative. Similarly, we defined false-negative test results as occurrences when a non-lethal technique was negative but the liver sample was positive. Using these decision rules, we estimated false-negative and false-positive rates for tail clips and swabs. Our study was conducted in a controlled facility using American bullfrog Lithobates catesbeianus tadpoles; false-positive and false-negative rates were estimated after different periods of time following exposure to ranavirus. False-negative and false-positive rates were 20 and 6%, respectively, for tail samples, and 22 and 12%, respectively, for swabs. False-negative rates were constant over time, but false-positive rates decreased with post-exposure duration. Our results suggest that non-lethal sampling techniques can be useful for ranavirus surveillance, although the prevalence of infection may be underestimated when compared to results obtained with liver samples.


Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis.
Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC(50) value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 microg mL(-1) (13 microM), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.


Plasmodium-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis.
In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for Plasmodium falciparum- and P. vivax-IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting hampers phagocytosis of IRBC by host phagocytes.


Synchronous and metachronous bilateral breast cancer: clinicopathologic characteristics and prognostic outcomes.
The incidence of bilateral breast cancer (BBC) reportedly ranges from 1.4 to 11.8%. Women with a first primary breast cancer are at a 2- to 6-fold increased risk of developing contralateral BC. However, there have been limited studies analyzing the clinicopathologic features of BBC and conflicting data exist on the prognostic significance of BBC. In this study, we sought to analyze the incidence of BBC in the era of modern medicine and assess the clinicopathologic characteristics and prognostic outcomes compared to unilateral BC (UBC). Of the 5941 patients with stage I-III BC diagnosed between 1998 and 2013 at our institution, 110 developed BBC, including 58 synchronous BBC (SBBC, interval between the first and the contralateral BC ≤3 months) and 52 metachronous BBC (MBBC, interval >3 months). The median time to the second tumor was 67.9 months among patients with MBBC. BBC was associated with a significantly lower rate of having a ductal type, high grade, HER2-positive or node-positive disease when compared to UBC, while no difference was found for age, race, ER/PR status, or pathologic tumor stage. When compared to MBBC, SBBC was strongly associated with a lobular phenotype, non-high grade, and ER/PR-positive disease; and further demonstrated a significantly higher concordant rate for ER, PR, and HER2 status. Patients with BBC had a significantly worse distant relapse-free survival (RFS) but a similar disease-specific survival (DSS) when compared to those with UBC. Being African American, having a high histologic grade and higher pathologic tumor or node stage was significantly associated with a worse prognosis, while SBBC was associated with a favorable RFS by multivariate analysis. Nodal status was the only independent prognosticator for DSS in patients with BBC. Further investigation into the complex biologic and clinical behavior of BBC may provide novel insights into the therapeutic strategies in the pursuit of precision medicine in this unique subset of patients.


Hidden diversity in deep-water bandfishes: review of Owstonia with descriptions of twenty-one new species (Teleostei: Cepolidae: Owstoniinae).
The bandfish family Cepolidae, comprising the subfamilies Owstoniinae and Cepolinae, is characterized, and defining characters of the three groups are identified and discussed. Characters of larvae of both subfamilies are described and illustrated. Six nominal genera of owstoniines had been proposed by various authors, but we recognize only Owstonia Tanaka. Utility of selected identification characters of the genus are discussed. Differences in lateral-line patterns have been the primary character used by some recent authors for recognition of two owstoniine genera, with Sphenanthias Weber possessing the plesiomorphic lateral-line condition. Several other patterns also occur in these fishes bringing into question the phylogenetic significance of lateral line plasticity. Sexual dimorphism in pelvic fin lengths is also present in several species. Identification keys, descriptions, synonymies, distribution maps and photographs or illustrations are provided for all Owstonia species for which adults are available. Although only 15 valid species were previously known, a remarkable hidden diversity of these fishes was discovered in major museum collections with the following 21 species here described as new: O. ainonaka (eastern Australia), O. contodon (Philippines), O. crassa (New Caledonia and Solomon Islands), O. dispar (Solomon Islands), O. elongata (New Caledonia and Vanuatu), O. fallax (eastern Australia and New Caledonia), O. geminata (Vanuatu and Philippines), O. hastata (eastern Australia), O. hawaiiensis (Hawaiian Islands); O. ignota (Mariana Islands), O. lepiota (Tanzania), O. melanoptera (Philippines), O. merensis (eastern Australia, Torres Strait), O. mundyi (Kiribati, Christmas Island), O. nalani (eastern Australia and New Caledonia), O. nudibucca (eastern Indian Ocean, Mentawai Islands and off Myanmar), O. psilos (Western Australia), O. raredonae (Mozambique), O. rhamma (Vanuatu), O. scottensis (Western Australia, Scott Reefs) and O. similis (Madagascar). Several specimens based on small juveniles, which we describe as Owstonia sp., appear to be additional new species but are not formally described as such.


Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data.
Although displacement from plasma protein binding (dPB) is usually of little clinical significance, it should be taken into account when interpreting changes in total plasma concentrations of drugs subject to metabolically based drug-drug interactions (mDDI). The aim of this study was to develop an approach to predict changes in the free fractions (fu) of pairs of drugs that compete for plasma binding, knowing their binding affinity constants, and to consider the implications of associated concentration- and time-dependence of such changes with respect to drug exposure. Experimental fu values of valproic acid and phenytoin in the presence of ibuprofen, diflunisal, or naproxen were predicted successfully (within 0.99- to 1.36-fold) by the model. In addition, the simulation of time-dependent changes in fu of valproic acid following administration of ibuprofen indicated different extents of dPB during 'first-pass' through the liver after oral absorption and on systemic recirculation. To understand the impact of the time-dependent change in fu, a full physiologically based pharmacokinetic model, that accounts for concentration-time profile of displacee and displacer and their mutual effect on each other, is required. The approach developed in this study is a first step towards the development of such a model.


Pressor response to electrical and chemical stimulation of nucleus raphe dorsalis in the cat.
The dorsal raphe nucleus was stimulated electrically and chemically in 57 cats with blood pressure being measured by an arterial catheter. Blood pressure rose by a mean of 119.5 +/- 8.9% on stimulation of the dorsal raphe nucleus at a frequency of 200 sec-1. This pressor response was frequency-dependent over the range 0.2 to 200 sec-1 and the site of origin was localized to the dorsal raphe nucleus. The pressor response could also be obtained by the injection of D,L-homocysteic acid into the nucleus, and is therefore likely to be due to activation of cell bodies rather than axons of passage. The response was blocked by high spinal cord section but was not affected by bilateral clamping of the adrenal glands or supracollicular decerebration. The pressor response was significantly reduced by pretreatment of the cats with parachlorophenylalanine (PCPA) and abolished by the alpha receptor blocker phentolamine, suggesting that both serotonergic and noradrenergic synapses are involved.


Outcome in juvenile idiopathic arthritis: a population-based study from Sweden.
As the treatment arsenal for children with juvenile idiopathic arthritis (JIA) has expanded during the last decades, follow-up studies are needed on children diagnosed in the era of biological treatment to evaluate if this has improved the outcome. Our aim was to study the epidemiology and outcome of JIA in southern Sweden using a population-based cohort of children with a validated diagnosis of JIA collected over 9 years. Potential cases of JIA between 2002 and 2010 were collected after a database search, using the ICD codes M08-M09. The study area was Skåne, the southernmost county of Sweden (population 1.24 million; 17.6% aged < 16 years). The JIA diagnosis was validated and subcategorized through medical record review based on the criteria defined by the International League of Associations for Rheumatism (ILAR). Parameters on disease activity and pharmacologic treatment were recorded annually until the end of the study period (December 31, 2015). In total, 251 cases of JIA were confirmed. The mean annual incidence rate for JIA was estimated to be 12.8/100,000 children < 16 years, with the highest age-specific annual incidence at the age of 2 years (36/100,000). Oligoarthritis was the largest subgroup (44.7%), and systemic JIA was the smallest subgroup (2.8%). Methotrexate was the most common disease-modifying anti-rheumatic drug prescribed (60.6%). Tumor necrosis factor alpha inhibitors were used as treatment for 23.9% of the children. Only 40.0% of the follow-up years, with a median follow-up time of 8 years, were free of arthritis or uveitis. Uveitis occurred in 10.8% of the children (8.0% chronic uveitis), and the need for joint corrective orthopedic surgery was 9.2%. The incidence of JIA in this well-defined, population-based cohort is slightly lower than in previously published studies from Scandinavia. The need for orthopedic surgery and the presence of uveitis are diminished compared to studies with patients diagnosed more than 20 years ago. Children with JIA however still experience disease activity more than 50% of the time. In conclusion, we still have long-term challenges in the care for children with JIA, in spite of state-of-the-art treatment.


Is dental erosion really a problem?
Dental erosion is the non-carious dental substance loss induced by direct impact of exogenous or endogenous acids. It results in a loss of dental hard tissue, which can be serious in some groups, such as those with eating disorders, in patients with gastroesophageal reflux disease, and also in persons consuming high amounts of acidic drinks and foodstuffs. For these persons, erosion can impair their well-being, due to changes in appearance and/or loss of function of the teeth, e.g., the occurrence of hypersensitivity of teeth if the dentin is exposed. If erosion reaches an advanced stage, time- and money-consuming therapies may be necessary. The therapy, in turn, poses a challenge for the dentist, particularly if the defects are diagnosed at an advanced stage. While initial and moderate defects can mostly be treated non- or minimally invasively, severe defects often require complex therapeutic strategies, which often entail extensive loss of dental hard tissue due to preparatory measures. A major goal should therefore be to diagnose dental erosion at an early stage, to avoid functional and esthetic impairments as well as pain sensations and to ensure longevity of the dentition.


Association of active oncologic treatment and risk of death in cancer patients with COVID-19: a systematic review and meta-analysis of patient data.
Cancer patients suffer from worse coronavirus disease-2019 (COVID-19) outcomes. Whether active oncologic treatment is an additional risk factor in this population remains unclear. Therefore, here we have conducted a systematic review and meta-analysis to summarize the existing evidence for the effect of active oncologic treatment on COVID-19 outcomes. Systematic search of databases (PubMed, Embase) was conducted for studies published from inception to July 1, 2020, with a subsequent search update conducted on 10 October 2020. In addition, abstracts and presentations from major conference proceedings (ASCO, ESMO, AACR) as well as pre-print databases (medxriv, bioxriv) were searched. Retrospective and prospective studies reporting clinical outcomes in cancer patients with laboratory confirmation or clinical diagnosis of COVID-19 and details of active or recent oncologic treatment were selected. Random-effects model was applied throughout meta-analyses. Summary outcome measure was the pooled odds ratio (OR) of death for active cancer therapy versus no active cancer therapy for each of the following modalities: recent surgery, chemotherapy, targeted therapy, immunotherapy, or chemoimmunotherapy. Sixteen retrospective and prospective studies (3558 patients) were included in the meta-analysis. Active chemotherapy was associated with higher risk of death compared to no active chemotherapy (OR, 1.60, 95% CI, 1.14-2.23). No significant association with risk of death was identified for active targeted therapy, immunotherapy, chemoimmunotherapy, or recent surgery. Meta-analysis of multivariate adjusted OR of death for active chemotherapy was consistently associated with higher risk of death compared to no active chemotherapy (OR, 1.42, 95% CI, 1.01-2.01). Active chemotherapy appears to be associated with higher risk of death in cancer patients with COVID-19. Further research is necessary to characterize the complex interactions between active cancer treatment and COVID-19.


Gender/Sex Differences in the Relationship between Psychosocial Work Exposures and Work and Life Stress.
Stress is an important factor affecting the health of working population. While work exposures are determinants of levels of work and life stress, we do not know whether similar or different exposures are related to stress levels for men and women. This study aimed to formally examine male/female differences in the relationships between psychosocial work exposures and work and life stress in a representative sample of Canadian labour market participants. We used data from 2012 cycle of the Canadian Community Health Survey (CCHS), a representative population-based survey conducted by Statistics Canada. The sample was restricted to employed labour force participants working 15+ hours per week (N = 8328, 48% female). To examine the relationship between work exposures and work and life stress, we conducted path analyses. Psychosocial work exposures included social support, job insecurity, job control, and job strain. Differences between estimates for men and women were explored using multigroup analyses, constraining paths between male and female models to be equivalent and examining the impact on change in model fit. Male/female differences were observed in the relationships between supervisor support and work stress levels as well as between job control, job insecurity, job strain, and life stress levels. Higher levels of supervisor support at work were associated with lower work stress among women, but not among men. Low job control had a direct protective effect on life stress for men but not for women, while high job strain had a direct adverse effect on life stress among women but not among men. Higher job insecurity was more strongly associated with higher life stress among men compared with women. The relationship between work stress and life stress was similar among men and women. The findings of this study suggest that the relationships between psychosocial exposures and work and life stress differ for men and women. Our study also raised important questions about which work exposures are considered when assessing work stress, with level of job control not related to work stress but associated with levels of life stress among men. Our study highlights the role of psychosocial work environment for both work and life stress and suggests differences in the importance of specific psychosocial work dimensions for feelings of stress among men and women, and for work stress versus life stress. Future study designs should ensure that measures are included to better disentangle the relative contribution of social and biological factors in explaining these differences among men and women.


[Exposure to asbestos dust in agricultural environment. Some significant exposure forms documented by the Hospital Unit of Occupational Medicine of Hospital Institute of Cremona].
Although it is difficult to document the exposition to asbestos in the agricultural workers, mesotelioma has however been noticed in the rural environment that may seem to have low risk because of its nature. This work describes the systematic diffusion of asbestos dust in the rural environment near Cremona due to the activity of "non-agricultural" workers who have fallen ill with mesothelioma. The patient described their work in details to the occupational medical doctor underlining the circumstances and the ways asbestos dust has been diffused in the rural environment. These ways were carefully analysed by the occupational medical doctor. They explain the onset of the mesothelioma in patients and they prove a systematic and long contamination of the involved rural areas. The described diffusion of dust has probably provoked a noteworthy exposure to the agricultural workers. At the moment there aren't full-blown asbestos-linked pathology but these workers are potentially at risk of getting them. So it has an importance both on individual and global level for the rural area near Cremona.


Clustering of voltage-sensitive sodium channels on axons is independent of direct Schwann cell contact in the dystrophic mouse.
The distribution of voltage-sensitive sodium channels on axons in the dorsal and ventral spinal roots of the dystrophic mouse 129/ReJ-Lama2dy was determined via immunocytochemistry. In these nerves there are regions in which Schwann cells fail to proliferate and myelinate axons in a normal manner, leaving bundles of closely packed large-diameter amyelinated axons. We have identified discrete and focal concentrations of sodium channel immunoreactivity on these axons by both confocal immunofluorescence and immunoelectron microscopy, using a peptide-derived polyclonal antibody. In addition, simultaneous labeling with an antibody recognizing neuronal-specific ankyrinG revealed a distinct colocalization with the sodium channels on both normal and amyelinated axons. The presence of patches of sodium channels along with their anchoring protein on amyelinated axons in the absence of intervening Schwann cells demonstrates that axons can form and maintain independently these initial aggregations. This confirms that direct contact between Schwann cell and axon is not required for the formation of sodium channel patches of nodal dimensions and density. Furthermore, this strongly suggests that local transfer of sodium channels from Schwann cells to axons is not required for this process.


Fasciclin 2, the Drosophila orthologue of neural cell-adhesion molecule, inhibits EGF receptor signalling.
Adhesion proteins not only control the degree to which cells adhere to each other but are increasingly recognised as regulators of intercellular signalling. Using genetic screening in Drosophila, we have identified Fasciclin 2 (Fas2), the Drosophila orthologue of neural cell adhesion molecule (NCAM), as a physiologically significant and specific inhibitor of epidermal growth factor receptor (EGFR) signalling in development. We find that loss of fas2 genetically interacts with multiple genetic conditions that perturb EGFR signalling. Fas2 is expressed in dynamic patterns during imaginal disc development, and in the eye we have shown that this depends on EGFR activity, implying participation in a negative-feedback loop. Loss of fas2 causes characteristic EGFR hyperactivity phenotypes in the eye, notum and wing, and also leads to downregulation of Yan, a transcriptional repressor targeted for degradation by EGFR activity. No significant genetic interactions were detected with the Notch, Wingless, Hedgehog or Dpp pathways, nor did Fas2 inhibit the FGF receptor or Torso, indicating specificity in the inhibitory role of Fas2 in EGFR signalling. Our results introduce a new regulatory interaction between an adhesion protein and a Drosophila signalling pathway and highlight the extent to which the EGFR pathway must be regulated at multiple levels.


Associations between human leukocyte antigen type and nasopharyngeal carcinoma in Caucasians in the United States.
A genetic component to nasopharyngeal carcinoma (NPC) has been suggested by associations of the malignancy with human leukocyte antigens (HLAs) in Southern Chinese populations, among which NPC is a major cancer. Data from other races are inconclusive. We have investigated associations between NPC and HLA antigens at the HLA-A, B, C, and DQ loci and alleles at the DRB1 locus in a population-based, multicenter investigation in the United States. Data from 82 cases and 140 controls are presented, making this the largest study population analyzing data from Caucasians to date. HLA frequencies from study cases were also compared with external control groups from the 11th International Histocompatibility Workshop and the National Marrow Donor Program. Logistic regression methods were used to investigate the effects of the joint occurrence of multiple HLA types and to assay for differences in HLA-associated risk in different age groups. A meta-analysis was undertaken to compare and summarize our results with previously published findings. The meta-analysis found a protective association with A2 antigen in non-Chinese [odds ratio (OR), 0.63; P < 0.001], a protective association with A11 across all races (OR, 0.54; P < 0.001), and an increased risk associated with B5 in Caucasians (OR, 2.81; P < 0.001). The present study also found independent associations, in a logistic regression model, between NPC and DRB1*1501 (OR, 0.33), DRB1*0405 (OR, 7.57), and Cw3 (OR, 0.42), although these data must be interpreted cautiously due to multiple-testing considerations. Associations were found to be more pronounced in younger patients for A2, A11, A28, B8, and B51.


The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of β-catenin and cell proliferation.
The short half-life protooncogene β-catenin acquires a remarkable stability in a large subset of cancers, mainly from mutations affecting its proteasomal degradation. In this sense, colorectal cancers (CRC) form a group of pathologies in which early steps of development are characterized by an aberrant expression of β-catenin and an uncontrolled proliferation of epithelial cells. Diet has long been described as an influence in the emergence of CRC, but the molecular events that link metabolic disorders and CRC remain elusive. Part of the explanation may reside in hexosamine biosynthetic pathway (HBP) flux. We found that fasted mice being force-fed with glucose or glucosamine leads to an increase of β-catenin and O-GlcNAcylation levels in the colon. MCF7 cells possessing intact Wnt/β-catenin signaling heavily expressed β-catenin when cultured in high glucose; this was reversed by the HBP inhibitor azaserine. HBP inhibition also decreased the expression of β-catenin in HT29 and, to a lesser extent, HCT116 cells. The same observation was made with regard to the transcriptional activity of β-catenin in HEK293 cells. Inhibition of HBP also blocked the glucose-mediated proliferation capacity of MCF7 cells, demonstrating that glucose affects both β-catenin expression and cell proliferation through the HBP. The ultimate element conducting these events is the dynamic posttranslational modification O-GlcNAcylation, which is intimately linked to HBP; the modulation of its level affected the expression of β-catenin and cell proliferation. In accordance with our findings, we propose that metabolic disorders correlate to CRC via an upregulation of HBP that reverberates on high O-GlcNAcylation levels including modification of β-catenin.


Image processing applied to the interactive analysis of interferometric fringes.
A computer software system for performing interferometric fringe analysis interactively (FAI) is described. FAI is based on a general-purpose image-processing system running on a DEC PDP-11. The images contain 144 x 144 pixels with 64 gray levels. FAI permits manual definition of difficult fringe-pattern boundaries. The fringes are traced by an algorithm which makes use of the 2-D gray-level image information. The user can interactively guide the system and correct errors. The application of the system to analyzing moiré fringes defining eardrum shape is described.