miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression.
The ability of osteosarcoma cells to form lung metastases has been inversely correlated to cell surface Fas expression. Downregulation of Fas allows osteosarcoma cells to circumvent FasL-mediated apoptosis upon entrance into the FasL(+) lung microenvironment. However, the mechanism of Fas regulation remains unclear. Here, we show that miRNA plays a role in the downregulation of Fas expression in osteosarcoma. Expression levels of several members of the miR-17-92 cluster including miR-20a and miR-19a were found to be higher in metastatic low-Fas-expressing LM7 cells than in the parental nonmetastatic high-Fas-expressing SAOS-2 cells. We also found an inverse correlation between Fas and miR-20a expression in all 8 cell lines derived from patient samples. Overexpression of miR-20a consistently resulted in the downregulation of Fas expression in SAOS-2 cells and thus in decreased sensitivity to FasL. Conversely, inhibiting miR-20a in LM7 cells increased Fas expression and their sensitivity to FasL. Mice injected with LM7 stably transfected with anti-miR-20a had fewer metastases than those with control plasmids. Taken together, our findings suggest that miR-20a, encoded by miR-17-92, downregulates Fas expression in osteosarcoma, thus contributing to the metastatic potential of osteosarcoma cells by altering the phenotype and allowing survival in the FasL(+) lung microenvironment.


Engineered Healing of Avascular Meniscus Tears by Stem Cell Recruitment.
Meniscus injuries are extremely common with approximately one million patients undergoing surgical treatment annually in the U.S. alone. Upon injury, the outer zone of the meniscus can be repaired and expected to functionally heal but tears in the inner avascular region are unlikely to heal. To date, no regenerative therapy has been proven successful for consistently promoting healing in inner-zone meniscus tears. Here, we show that controlled applications of connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) can induce seamless healing of avascular meniscus tears by inducing recruitment and step-wise differentiation of synovial mesenchymal stem/progenitor cells (syMSCs). A short-term release of CTGF, a selected chemotactic and profibrogenic cue, successfully recruited syMSCs into the incision site and formed an integrated fibrous matrix. Sustain-released TGFβ3 then led to a remodeling of the intermediate fibrous matrix into fibrocartilaginous matrix, fully integrating incised meniscal tissues with improved functional properties. Our data may represent a novel clinically relevant strategy to improve healing of avascular meniscus tears by recruiting endogenous stem/progenitor cells.


Chondroprotection and the prevention of osteoarthritis progression of the knee: a systematic review of treatment agents.
Structure-modifying medications or nutraceuticals may be an effective treatment for osteoarthritis. This study identified 12 treatments that may possess chondroprotective properties: oral glucosamine; chondroitin; nonsteroidal anti-inflammatory drugs (NSAIDs); polyunsaturated fatty acids; S-adenosylmethionine; avocado and soybean unsaponifiable fractions; methylsulfonylmethane; vitamins C, D, and E; intra-articular injections of hyaluronic acid; and platelet-rich plasma (PRP). To perform a systematic review of randomized controlled trials for the effectiveness of each agent in preserving articular cartilage of the knee and delaying the progression of osteoarthritis. Systematic review; Level of evidence, 2. A literature search was performed using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Searches were performed using "treatment," "osteoarthritis," and "knee" as keywords. Selection criteria included randomized controlled trials of ≥12 months, with a placebo control, measuring radiographic changes in joint space width, cartilage volume, or radiographic progression of osteoarthritis. The primary outcome was changes in joint integrity measures. A total of 3514 studies were identified from the initial search, 13 of which met inclusion criteria. Treatment with chondroitin sulfate showed a significant reduction in cartilage loss in 3 of 4 studies identified compared with placebo. Two of 3 trials identified for glucosamine also reported significant structural effects relative to placebo. Intra-articular hyaluronic acid was effective in lowering the rate of cartilage loss in only 1 of 3 studies identified versus placebo. Of the 6 studies identified for NSAIDs, vitamin E, and vitamin D, none showed any structural effect compared with placebo. No studies were found that met the inclusion criteria for polyunsaturated fatty acids, S-adenosylmethionine, avocado and soybean unsaponifiable fractions, methylsulfonylmethane, vitamin C, or PRP. For patients with or at risk for osteoarthritis, the use of glucosamine and chondroitin sulfate may serve as a nonoperative means to protect joint cartilage and delay osteoarthritis progression. Hyaluronic acid injections showed variable efficacy, while NSAIDs and vitamins E and D showed no effect on osteoarthritis progression. The other agents evaluated had no evidence in the literature to support or refute their use for chondroprotection.


Barriers to participation in a worksite wellness program.
THE PURPOSE OF THIS RESEARCH WAS TO DETERMINE BARRIERS THAT PREVENT PARTICIPATION IN AN EMPLOYEE WELLNESS PROGRAM, WELLNESS WEDNESDAYS: "Eat & Meet" About Healthy Living, conducted at East Carolina University (ECU) in Greenville, North Carolina. All ECU ARAMARK employees (n = 481) over the age of 18 were eligible to participate in the wellness program. Weekly 30 minute classes, taught by a Registered Dietitian, on various nutrition- and health-related topics were conducted for 10-weeks. Five question knowledge quizzes were administered to participants at the end of each class to determine the comprehension of material presented. Qualitative interviews (n = 19) were conducted with employees (participants and non-participants) and the program organizer after the completion of the 10-week program to identify barriers to program participation. A total of 50 (10.4% of the total number of potential participants) ECU ARAMARK employees, managers, and leadership team directors attended Wellness Wednesdays at least once during the 10-week program. Employees, on average, scored 71-100% on the weekly knowledge quizzes administered at the end of each class. The most common barriers to participation reported included (most often to least often reported): insufficient incentives, inconvenient locations, time limitations, not interested in topics presented, undefined reasons, schedule, marketing, health beliefs, and not interested in the program. Results showed that employee wellness programs can be effective in increasing knowledge of employees on nutrition- and health-related topics. However, program planning that addresses identified barriers including insufficient incentives, inconvenient locations, and time limitations may facilitate higher participation in future worksite wellness opportunities.


Ultrasonographic findings in a cow with vascular hamartoma of the liver: case report.
This is the first description of the ultrasonographic findings in a cow with vascular hamartoma of the liver. Ultrasonographic examination of a six-year-old Swiss Braunvieh cow revealed an excessive number of hypoechogenic blood vessels in the liver parenchyma and a thrombus in the right hepatic vein. The activities of the liver enzymes and the concentration of bilirubin were within the reference ranges. At postmortem examination, a poorly delineated, non-encapsulated lesion, measuring approximately 10 cm × 10 cm in diameter, was found in the right liver lobe. The cut surface of the lesion was sponge-like and contained extremely dilated blood vessels, one of which was occluded with a branching red thrombus. A vascular hamartoma of the liver with thrombosis was diagnosed based on the histological findings. To our knowledge, this is the first description of the ultrasonographic findings of vascular hamartoma of the liver in a cow. Hamartoma should be considered part of the differential diagnosis in cows with an abnormally large number of blood vessels in the liver parenchyma. This case report broadens the spectrum of liver diseases and ultrasonographic findings of the liver in cattle.


A Drosophila DEG/ENaC channel subunit is required for male response to female pheromones.
Odorants and pheromones as well as sweet- and bitter-tasting small molecules are perceived through activation of G protein-coupled chemosensory receptors. In contrast, gustatory detection of salty and sour tastes may involve direct gating of sodium channels of the DEG/ENaC family by sodium and hydrogen ions, respectively. We have found that ppk25, a Drosophila melanogaster gene encoding a DEG/ENaC channel subunit, is expressed at highest levels in the male appendages responsible for gustatory and olfactory detection of female pheromones: the legs, wings, and antennae. Mutations in the ppk25 gene reduce or even abolish male courtship response to females in the dark, conditions under which detection of female pheromones is an essential courtship-activating sensory input. In contrast, the same mutations have no effect on other behaviors tested. Importantly, ppk25 mutant males that show no response to females in the dark execute all of the normal steps of courtship behavior in the presence of visible light, suggesting that ppk25 is required for activation of courtship behavior by chemosensory perception of female pheromones. Finally, a ppk25 mutant allele predicted to encode a truncated protein has dominant-negative properties, suggesting that the normal Ppk25 protein acts as part of a multiprotein complex. Together, these results indicate that ppk25 is necessary for response to female pheromones by D. melanogaster males, and suggest that members of the DEG/ENaC family of genes play a wider role in chemical senses than previously suspected.


Quantifying the roles of cell motility and cell proliferation in a circular barrier assay.
Moving fronts of cells are essential features of embryonic development, wound repair and cancer metastasis. This paper describes a set of experiments to investigate the roles of random motility and proliferation in driving the spread of an initially confined cell population. The experiments include an analysis of cell spreading when proliferation was inhibited. Our data have been analysed using two mathematical models: a lattice-based discrete model and a related continuum partial differential equation model. We obtain independent estimates of the random motility parameter, D, and the intrinsic proliferation rate, λ, and we confirm that these estimates lead to accurate modelling predictions of the position of the leading edge of the moving front as well as the evolution of the cell density profiles. Previous work suggests that systems with a high λ/D ratio will be characterized by steep fronts, whereas systems with a low λ/D ratio will lead to shallow diffuse fronts and this is confirmed in the present study. Our results provide evidence that continuum models, based on the Fisher-Kolmogorov equation, are a reliable platform upon which we can interpret and predict such experimental observations.


Changes in regional brain morphology in neuropsychiatric systemic lupus erythematosus.
Neuropsychiatric lupus (NPSLE) is a severe and potentially life-threatening condition, reported to occur in 25%-70% of patients with systemic lupus erythematosus (SLE). Brain imaging, especially magnetic resonance imaging, is frequently used to diagnose or exclude overt cerebral pathologies such as edema, hemorrhage, and central thrombosis. More advanced imaging techniques have been applied to demonstrate subtle changes in regional cerebral blood flow and brain structure. We investigated changes in regional gray-matter (GM) volume in SLE patients without neurological manifestations and NPSLE patients at an acute stage of the disease. Using high-resolution structural images and voxel-based morphometry (VBM), we investigated regional GM volume in 20 NPSLE patients (within 2 weeks of the acute manifestation), 18 SLE patients without neurologic and/or psychiatric manifestations, and 18 healthy controls. VBM analyses revealed several regions of GM atrophy in various parts of the brain in NPSLE and SLE patients. GM atrophy was seen in both groups in the temporal and parietal lobes and was most pronounced in the posterior thalamus bilaterally. Both groups showed an increase in regional GM volume in the posterior parahippocampal gyrus. Our data suggest that changes in regional brain morphology are present in acute NPSLE, but also in SLE (as compared to controls), which might be indicative of a subclinical neurodegenerative process. Further research is needed to investigate whether specific neuropsychiatric symptoms are related to these changes.


An efficient test protocol for identification of a limited, sensitive frequency test range for early detection of ototoxicity.
A primary focus of research at the National Center for Rehabilitative Auditory Research (NCRAR) has been to develop methodology for rapid and efficient early detection of ototoxicity. It has been shown that an individualized, limited frequency range can be identified, which is sensitive to early ototoxic changes in the auditory system. In this study, a rapid identification protocol for identifying the uppermost target frequency within this sensitive range of ototoxicity (SRO) was investigated. In 36 of 42 ears, the target frequency found with the rapid identification protocol was the same as that found with the full-frequency baseline testing. Where differences occurred, target frequencies obtained by the two methods did not differ by more than one-half octave. This rapid identification protocol results in considerable time savings in ototoxicity monitoring, which will result in the capability to include more patients in a monitoring program.


Homeopathic Individualized Q-Potencies versus Fluoxetine for Moderate to Severe Depression: Double-Blind, Randomized Non-Inferiority Trial.
Homeopathy is a complementary and integrative medicine used in depression, The aim of this study is to investigate the non-inferiority and tolerability of individualized homeopathic medicines [Quinquagintamillesmial (Q-potencies)] in acute depression, using fluoxetine as active control. Ninety-one outpatients with moderate to severe depression were assigned to receive an individualized homeopathic medicine or fluoxetine 20 mg day(-1) (up to 40 mg day(-1)) in a prospective, randomized, double-blind double-dummy 8-week, single-center trial. Primary efficacy measure was the analysis of the mean change in the Montgomery & Åsberg Depression Rating Scale (MADRS) depression scores, using a non-inferiority test with margin of 1.45. Secondary efficacy outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society of Psychopharmacology. Mean MADRS scores differences were not significant at the 4th (P = .654) and 8th weeks (P = .965) of treatment. Non-inferiority of homeopathy was indicated because the upper limit of the confidence interval (CI) for mean difference in MADRS change was less than the non-inferiority margin: mean differences (homeopathy-fluoxetine) were -3.04 (95% CI -6.95, 0.86) and -2.4 (95% CI -6.05, 0.77) at 4th and 8th week, respectively. There were no significant differences between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between the side effects rates, although a higher percentage of patients treated with fluoxetine reported troublesome side effects and there was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. This study illustrates the feasibility of randomized controlled double-blind trials of homeopathy in depression and indicates the non-inferiority of individualized homeopathic Q-potencies as compared to fluoxetine in acute treatment of outpatients with moderate to severe depression.


Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster. Part II. Results of chronic exposure.
Fiberglass (FG) is the largest category of man-made mineral fibers (MMVFs). Many types of FG are manufactured for specific uses building insulation, air handling, filtration, and sound absorption. In the United States, > 95% of FG produced is for building insulation. Several inhalation studies in rodents of FG building insulation have shown no indication of pulmonary fibrosis or carcinogenic activity. However, because of increasing use and potential for widespread human exposure, a chronic toxicity/carcinogenicity inhalation study of a typical building insulation FG (MMVF 10a) was conducted in hamsters, which were shown to be highly sensitive to the induction of mesotheliomas with another MMVF. A special-application FG (MMVF 33) and amosite asbestos were used for comparative purposes. Groups of 140 weanling male Syrian golden hamsters were exposed via nose-only inhalation for 6 h/day, 5 days/wk for 78 wk to either filtered air (chamber controls) or MMVF 10a, MMVF 33, or amosite asbestos at 250-300 WHO fibers/cm(3) with two additional amosite asbestos groups at 25 and 125 WHO fibers/cm(3). They were then held unexposed for 6 wk until approximately 10-20% survival. After 13, 26, 52, and 78 wk, various pulmonary parameters and lung fiber burdens were evaluated. Groups hamsters were removed from exposure at 13 and 52 wk and were held until 78 wk (recovery groups). Initial lung deposition of long fibers (>20 microm in length) after a single 6-h exposure was similar for all 3 fibers exposed to 250-300 fibers/cm(3). MMVF 10a lungs showed inflammation (which regressed in recovery hamsters) but no pulmonary or pleural fibrosis or neoplasms. MMVF 33 induced more severe inflammation and mild interstitial and pleural fibrosis by 26 wk that progressed in severity until 52 wk, after which it plateaued. While the inflammatory lesions regressed in the recovery animals, pulmonary or pleural fibrosis did not. A single multicentric mesothelioma was observed at 32 wk. No neoplasms were found in the remainder of the study. Amosite asbestos produced dose-related inflammation and pulmonary and pleural fibrosis as early as 13 wk in all 3 exposure levels. The lesions progressed during the course of the study, and at 78 wk severe pulmonary fibrosis with large areas of consolidation was observed in the highest 2 exposure groups. Progressive pleural fibrosis with mesothelial hypertrophy and hyperplasia was present in the thoracic wall and diaphragm in most animals and increased with time in the recovery hamsters. While no pulmonary neoplasms were observed in the amosite exposed hamsters, a large number of mesotheliomas were found; 25 fibers/cm(3), 3.6%; 125 fibers/cm(3), 25.9%; and 250 fibers/cm(3), 19.5%. For the 3 fiber types, the severity of the lung and pleural lesions generally paralleled the cumulative fiber burden, especially those >20 microm length, in the lung, thoracic wall, and diaphragm. They also inversely paralleled the in vitro dissolution rates; that is, the faster the dissolution, the lower were the cumulative lung burdens and the less severe the effects.


Cardiac stem cells with electrical stimulation improve ischaemic heart function through regulation of connective tissue growth factor and miR-378.
In this study, we investigated whether pre-conditioning (PC) by electrical stimulation (EleS) induces cytoprotective effect on cardiac stem cells (CSCs) and determined its underlying molecular mechanisms. Sca-1(+) CSCs were isolated from male C57BL6 mice (12 weeks) hearts. PC of CSCs with EleS ((EleS)CSCs) was carried out for 3 h at 1.5 V followed by exposure to 300 µM H2O2 for 5 h. Cytoprotective effects and cell adhesion ability were significantly increased by EleS as evaluated by transferase-mediated dUTP nick-end labelling (TUNEL), lactate dehydrogenase (LDH) release assay, and adhesion assay. EleS increased phosphorylation of AKT, focal adhesion kinase (FAK), and glycogen synthase kinase (GSK3β), as well as decreased caspase-3 cleavage. Interestingly, inhibition of AKT or FAK abolished the pro-survival effects of EleS. We found that connective tissue growth factor (Ctgf) was responsible for EleS-induced CSC survival and adhesion.The survival rate of (EleS)CSCs after transplantation in the infarcted myocardium was significantly increased together with improvement in cardiac function. Importantly, knockdown of Ctgf abolished EleS-induced cytoprotective effects and recovery of cardiac function. Furthermore, we identified miR-378 as a potential Ctgf regulator in (EleS)CSCs. EleS enhanced CSC survival in vitro and in vivo as well as functional recovery of the ischaemic heart through an AKT/FAK/CTGF signalling pathway. It is suggested that Ctgf and miR-378 are novel therapeutic targets for stem cell-based therapy.


Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA).
This study aims to establish the benefits of lowering cholesterol in diabetic patients with well-controlled hypertension and average/below-average cholesterol concentrations, but without established coronary disease. In the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), 10,305 hypertensive patients with no history of coronary heart disease (CHD) but at least three cardiovascular risk factors were randomly assigned to receive 10 mg atorvastatin or placebo. Effects on total cardiovascular outcomes in 2,532 patients who had type 2 diabetes at randomization were compared. During a median follow-up of 3.3 years, concentrations of total and LDL cholesterol among diabetic participants included in ASCOT-LLA were approximately 1 mmol/l lower in those allocated atorvastatin compared with placebo. There were 116 (9.2%) major cardiovascular events or procedures in the atorvastatin group and 151 (11.9%) events in the placebo group (hazard ratio 0.77, 95% CI 0.61-0.98; P = 0.036). For the individual components of this composite end point, the number of events occurring in the diabetes subgroup was small. Therefore, although fewer coronary events (0.84, 0.55-1.29; P = 0.14) and strokes (0.67, 0.41-1.09; P = 0.66) were observed among the patients allocated atorvastatin, these reductions were not statistically significant. Atorvastatin significantly reduced the risk of major cardiovascular events and procedures among diabetic patients with well-controlled hypertension and without a history of CHD or markedly elevated cholesterol concentrations. The proportional reduction in risk was similar to that among participants who did not have diagnosed diabetes. Allocation to atorvastatin prevented approximately 9 diabetic participants from suffering a first major cardiovascular event or procedure for every 1,000 treated for 1 year.


Women and heart attack: a study of women's experiences.
Cardiovascular disease in general, and myocardial infarction (MI) in particular, is the major health problem of females after 50 years of age. To date, heart disease research has focused primarily on males. The limited evidence suggests that the physical, psychological, and social ramifications of MI for women are significant, and different from those of men. Since the specific rehabilitation needs of women are not yet clear, this study was designed to explore the unique experiences and needs of women following a first MI. A phenomenological study using focus groups was used to explore the experiences, questions, concerns, and preferred interventions of women after a MI. Participants were female volunteers (n = 14) who had been hospitalized for a MI within the previous 6 months. Focus groups were audio taped and analysed by the investigators. Four major themes emerged: validation; perceived gender differences; role expectations/role tensions; and helps and hindrances to recovery.


Confined Dynamics of Water in Transmembrane Pore of TRPV1 Ion Channel.
Solvation effects play a key role in chemical and biological processes. The microscopic properties of water near molecular surfaces are radically different from those in the bulk. Furthermore, the behavior of water in confined volumes of a nanometer scale, including transmembrane pores of ion channels, is especially nontrivial. Knowledge at the molecular level of structural and dynamic parameters of water in such systems is necessary to understand the mechanisms of ion channels functioning. In this work, the results of molecular dynamics (MD) simulations of water in the pore and selectivity filter domains of TRPV1 (Transient Receptor Potential Vanilloid type 1) membrane channel are considered. These domains represent nanoscale volumes with strongly amphiphilic walls, where physical behavior of water radically differs from that of free hydration (e.g., at protein interfaces) or in the bulk. Inside the pore and filter domains, water reveals a very heterogeneous spatial distribution and unusual dynamics: It forms compact areas localized near polar groups of particular residues. Residence time of water molecules in such areas is at least 1.5 to 3 times larger than that observed for similar groups at the protein surface. Presumably, these water "blobs" play an important role in the functional activity of TRPV1. In particular, they take part in hydration of the hydrophobic TRPV1 pore by localizing up to six waters near the so-called "lower gate" of the channel and reducing by this way the free energy barrier for ion and water transport. Although the channel is formed by four identical protein subunits, which are symmetrically packed in the initial experimental 3D structure, in the course of MD simulations, hydration of the same amino acid residues of individual subunits may differ significantly. This greatly affects the microscopic picture of the distribution of water in the channel and, potentially, the mechanism of its functioning. Therefore, reconstruction of the full picture of TRPV1 channel solvation requires thorough atomistic simulations and analysis. It is important that the naturally occurring porous volumes, like ion-conducting protein domains, reveal much more sophisticated and fine-tuned regulation of solvation than, e.g., artificially designed carbon nanotubes.


Folnegović & Folnevogić-Smalc's "Schizophrenia in Croatia: inter-regional differences in prevalence and a comment on constant incidence".
"STUDY OBJECTIVE--The aim was to examine why differences exist in schizophrenia prevalence and risk in some areas of Croatia, when schizophrenia incidence rates do not appear to vary. DESIGN--Areas differing by schizophrenia admission rates in patients born in 1953 and admitted by the age of 31 years are compared using a number of indicators relating both to general population characteristics and to those of schizophrenic cases in these populations. SETTING--The study covers the whole of Croatia (4,601,469 inhabitants, 1981 census). SUBJECTS--By the age of 31 years, out of 80,445 individuals born in Croatia in 1953, 464 were admitted for and diagnosed as having schizophrenia. MAIN RESULTS--Admission risk rates are higher in those parts of Croatia where emigration rates are high and lower where immigration rates are high. There is also a positive correlation with schizophrenia prevalence and manic depressive psychosis rates. There is a negative correlation with age of onset of schizophrenia and with schizophrenic reproduction rates. In the study areas, hospital incidence rates are not significantly different. CONCLUSIONS--Economic migration and negative selection in the domestic population are likely to be the most significant factors leading to differences in schizophrenia prevalence. The approximately equal incidence rates in the population, with different prevalence and admission risks, are linked to differences in the disease onset among schizophrenics with a positive family history for this condition. In other words, these patients, when part of the population with a greater prevalence and a greater hereditary loading, experience the onset more often at an earlier age. Thus they have a lower reproduction rate than in a population with a lower prevalence and a lower hereditary loading. Thus incidence rates in populations with different prevalences and different hereditary loads are maintained roughly equal over generations."


Taste disorders in Australian Aboriginal and non-Aboriginal children.
To assess the prevalence and type of taste disorders in Aboriginal and non-Aboriginal children matched for age, gender and living in the same general and educational environment. Taste function was assessed in 432 Aboriginal (n = 166) and non-Aboriginal (n = 266) children aged 8-12 years from six public schools in a rural township using a three-choice taste identification test and a cross-sectional design. The prevalence of taste disorders was very high and significantly more common in Aboriginal (20/166; 12.0%) than in non-Aboriginal (21/266; 7.9%) children. Forty-one children had quality-specific disorders, of whom 27 (65.9%) had sweet disorders. Children often had more than one quality disorder. The prevalence of taste disorders in children was high and exceeded the level (4%) designated by the World Health Organisation as requiring immediate action by health authorities. As the cause of the disorders is unknown, there is a need for a wider investigation of the causes and the consequences.


Predicting the outcome of total knee arthroplasty.
The relief of pain and the restoration of functional activities are the main outcomes of primary total knee arthroplasty for the treatment of osteoarthritis. This paper examines the preoperative predictors of pain and functional outcome at one and two years following total knee arthroplasty. Patients were recruited for a prospective observational study of primary total knee arthroplasty for the treatment of osteoarthritis from centers in the United States, the United Kingdom, and Australia. Research assistants recruited the patients and collected the clinical history and physical examination data preoperatively and at three, twelve, and twenty-four months postoperatively. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Short Form-36 (SF-36), and demographic data were obtained by self-administered patient questionnaires. We recruited 860 patients and obtained one-year WOMAC data on 759 patients (88%) and two-year data on 701 (82%). The mean age was seventy years, and 59% of the patients were female. Using hierarchical regression models, we found that the most significant preoperative predictors of worse scores on the pain and function domains of the WOMAC scale and on the physical functioning domain of the SF-36 at one and two years postoperatively were low preoperative scores, a higher number of comorbid conditions, and a low SF-36 mental health score. After adjusting for these predictors, we found that the functional status of the patients from the United Kingdom was significantly worse than that of the patients from the other countries and the difference was clinically important at both the one-year and two-year follow-up examination (p < 0.0005). The mean WOMAC pain scores for the three countries were not significantly different at one year, and, although they were significantly different at two years (p = 0.025), the difference was not clinically important. Patients who have marked functional limitation, severe pain, low mental health score, and other comorbid conditions before total knee arthroplasty are more likely to have a worse outcome at one year and two years postoperatively. After adjusting for these predictors, it was found that patients from the United Kingdom had significantly worse functional outcomes but similar pain relief compared with those from the United States and Australia.


Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice.
Favipiravir (T-705 [6-fluoro-3-hydroxy-2-pyrazinecarboxamide]) and oseltamivir were combined to treat influenza virus A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), and A/Duck/MN/1525/81 (H5N1) infections. T-705 alone inhibited viruses in cell culture at 1.4 to 4.3 microM. Oseltamivir inhibited these three viruses in cells at 3.7, 0.02, and 0.16 microM and in neuraminidase assays at 0.94, 0.46, and 2.31 nM, respectively. Oral treatments were given twice daily to mice for 5 to 7 days starting, generally, 24 h after infection. Survival resulting from 5 days of oseltamivir treatment (0.1 and 0.3 mg/kg/day) was significantly better in combination with 20 mg/kg of body weight/day of T-705 against the H1N1 infection. Treatment of the H3N2 infection required 50 mg/kg/day of oseltamivir for 7 days to achieve 60% protection; 25 mg/kg/day was ineffective. T-705 was >or=70% protective at 50 to 100 mg/kg/day but inactive at 25 mg/kg/day. The combination of inhibitors (25 mg/kg/day each) increased survival to 90%. The H5N1 infection was not benefited by treatment with oseltamivir (<or=100 mg/kg/day for 7 days). T-705 was 30 to 70% protective at 25 to 100 mg/kg/day. Survival improved slightly with combination treatments. Increased activity was seen against H5N1 infection by starting treatments 2 h before infection. Oseltamivir was ineffective at <or=40 mg/kg/day. T-705 was 100% protective at 40 and 80 mg/kg/day and inactive at 20 mg/kg/day. Combining ineffective doses (20 mg/kg/day of T-705 and 10 to 40 mg/kg/day of oseltamivir) afforded 60 to 80% protection and improved body weights during infection. Thus, synergistic responses were achieved with low doses of T-705 combined with oseltamivir. These compounds may be viable candidates for combination treatment of human influenza infections.


Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice.
Inhibiting the synthesis of endogenous prostaglandins with nonsteroidal anti-inflammatory drugs exacerbates arterial hypertension. We hypothesized that the converse, i.e., raising the level of endogenous prostaglandins, might have anti-hypertensive effects. To accomplish this, we focused on inhibiting the prostaglandin transporter PGT (SLCO2A1), which is the obligatory first step in the inactivation of several common PGs. We first examined the role of PGT in controlling arterial blood pressure blood pressure using anesthetized rats. The high-affinity PGT inhibitor T26A sensitized the ability of exogenous PGE2 to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE2 T26A administered alone to anesthetized rats dose-dependently lowered blood pressure, and did so to a greater degree in spontaneously hypertensive rats than in Wistar-Kyoto control rats. In mice, T26A added chronically to the drinking water increased the urinary excretion and plasma concentration of PGE2 over several days, confirming that T26A is orally active in antagonizing PGT. T26A given orally to hypertensive mice normalized blood pressure. T26A increased urinary sodium excretion in mice and, when added to the medium bathing isolated mouse aortas, T26A increased the net release of PGE2 induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE2. We conclude that pharmacologically inhibiting PGT-mediated prostaglandin metabolism lowers blood pressure, probably by prostaglandin-induced natriuresis and vasodilation. PGT is a novel therapeutic target for treating hypertension.


Cell adhesion molecules, leukocyte trafficking, and strategies to reduce leukocyte infiltration.
Leukocyte-endothelial cell interactions are mediated by various cell adhesion molecules. These interactions are important for leukocyte extravasation and trafficking in all domestic animal species. An initial slowing of leukocytes on the vascular endothelium is mediated by selectins. This event is followed by (1) activation of beta2 integrins after leukocyte exposure to cytokines and pro-inflammatory mediators, (2) adherence of leukocyte beta2 integrins to vascular endothelial ligands (eg, intercellular adhesion molecule-1 [ICAM-1]), (3) extravasation of leukocytes into tissues through tight junctions of endothelial cells mediated by platelet and endothelial cell adhesion molecule-1 (PECAM-1), and (4) perivascular migration through the extracellular matrix via beta1 integrins. Inhibiting excessive leukocyte egress and subsequent free radical-mediated damage caused by leukocyte components may attenuate or eliminate tissue damage. Several methods have been used to modify leukocyte infiltration in various animal models. These methods include nonspecific inhibition of pro-inflammatory mediators and adhesion molecules by nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, inhibition of cytokines and cytokine receptors, and inhibition of specific types of cell adhesion molecules, with inhibitors such as peptides and antibodies to beta2 integrins, and inhibitors of selectins, ICAMs, and vascular cell adhesion molecule-1 (VCAM-1). By understanding the cellular and molecular events in leukocyte-endothelial cell interactions, therapeutic strategies are being developed in several animal models and diseases in domestic animal species. Such therapies may have clinical benefit in the future to overcome tissue damage induced by excessive leukocyte infiltration.


Herpes simplex virus type 2 infection among young uncircumcised men in Kisumu, Kenya.
To identify factors associated with herpes simplex virus type 2 (HSV-2) infection among men aged 18-24 in Kisumu, Kenya. Baseline data from a randomised trial of male circumcision were analysed. Participants were interviewed for sociodemographic and behavioural risks. The outcome was HSV-2 by antibody status. Risk factors were considered singly and in combination through logistic regression models. Among 2771 uncircumcised men, 766 (27.6%; 95% confidence interval (CI) 26.0% to 29.3%) tested antibody positive for HSV-2. The median age at first sex was 16 years, and the median number of lifetime sexual partners was four. HSV-2 seroprevalence increased from 19% among 18-year-olds to 43% among 24-year-olds (p<0.001). In multivariable analysis, statistically significant risks for infection were increasing age (adjusted odds ratio (AOR) = 1.22-2.58), being married or having a live-in female partner (AOR = 1.80; 95% CI 1.28 to 2.53), preferring "dry" sex (AOR = 1.39; 95% CI 1.14 to 1.69), reported penile cuts or abrasions during sex (AOR = 1.58; 95% CI 1.32 to 1.91), increasing lifetime sex partners (multiple response categories; AORs ranging from 1.65 to 1.97), and non-student occupation (multiple response categories; AORs ranging from 1.44 to 1.93). Risk decreased with reported condom used at last sex (AOR = 0.82; 95% CI 0.68 to 0.99). Primary prevention efforts should be initiated at an early age. The same behavioural interventions used currently for HIV prevention-abstinence, reducing the number of sex partners and increasing condom use-should be effective for HSV-2 prevention.


Birth defects after prenatal exposure to antiepileptic drugs.
Exposure to antiepileptic drugs (AEDs) in the first trimester of pregnancy has been associated with an increased risk of major congenital anomalies (MCAs) in offspring. Most of the studies, however, have been fraught with methodological shortcomings, and differences in ascertainment methods and classifications prevent meaningful data pooling. Individual studies lacked the statistical power to assess comparative risks associated with specific AEDs. Several larger-scale studies, including collaborative multinational registries, have been set up to compare MCA risks associated with different treatments, including newer generation AEDs. Results have largely been consistent with the notion that monotherapy with the most commonly used AEDs is associated with an increase in risk of MCAs by two to three times, and that the magnitude of risk increases in offspring exposed to polytherapy. Available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of MCAs. Almost all studies have suggested that exposure to valproic acid is associated with a greater incidence of MCAs than other AEDs. Valproic acid is also the only AED for which a dose-dependency has been confirmed in several studies: the increase in risk of MCAs, compared with other AEDs, is especially evident at doses above 800-1000 mg/day. Data from the North American registry have suggested that phenobarbital may also have a higher teratogenic risk compared with AEDs other than valproic acid, but evidence remains inconclusive. Information about effects on fetuses of newer generation AEDs other than lamotrigine and oxcarbazepine is scant. Although teratogenic effects of lamotrigine and oxcarbazepine have not been established with certainty, none of the investigations to date identified any statistically significant difference in rates of MCAs between infants exposed to lamotrigine or oxcarbazepine and infants exposed to carbamazepine. In the case of lamotrigine, moreover, a positive correlation between maternal dose and rates of MCAs has been identified. WHERE NEXT?: Collaborative pregnancy registries worldwide are at work to fill remaining gaps in knowledge. Issues to be addressed include the comparative risks associated with phenobarbital, with low-dose valproic acid, with newer generation AEDs, and with specific AED combinations; the influence of potential confounders; and the interaction of AED-associated risks with other risk factors, such as genetic profiles. Large scale studies may also clarify whether individual AEDs differ in their ability to cause specific anomalies. Finally, studies are urgently needed to investigate other potential adverse effects of AED exposure, with special reference to effects on postnatal intellectual development.


Regulation of expression of the pilA gene in Myxococcus xanthus.
Type IV pili are required for social gliding motility in Myxococcus xanthus. In this work, the expression of pilin (the pilA gene product) during vegetative growth and fruiting-body development was examined. A polyclonal antibody against the pilA gene product (prepilin) was prepared, along with a pilA-lacZ fusion, and was used to assay expression of pilA in M. xanthus in different mutant backgrounds. pilA expression required the response regulator pilR but was negatively regulated by the putative sensor kinase pilS. pilA expression did not require pilB, pilC, or pilT. pilA was also autoregulated; a mutation which altered an invariant glutamate five residues from the presumed prepilin processing site eliminated this autoregulation, as did a deletion of the pilA gene. Primer extension and S1 nuclease analysis identified a sigma54 promoter upstream of pilA, consistent with the homology of pilR to the NtrC family of response regulators. Expression of pilA was found to be developmentally regulated; however, the timing of this expression pattern was not entirely dependent on pilS or pilR. Finally, pilA expression was induced by high nutrient concentrations, an effect that was also not dependent on pilS or pilR.


Normative Data and Conversion Equation for Spectral-Domain Optical Coherence Tomography in an International Healthy Control Cohort.
Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration. Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline. The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 μm per decade in pRNFL thickness ( P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 μm per decade in GCIPL thickness ( P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 μm, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses. A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups.


Olfactory and amygdalar structures of the chicken ventral pallium based on the combinatorial expression patterns of LIM and other developmental regulatory genes.
We compared the combinatorial expression patterns of several LIM domain-containing regulatory genes in the ventrolateral pallium of mouse and chicken, in order to identify the homologues of the ventral pallial amygdala and other olfactory structures in birds. Lmo3, Lmo4, Lhx2, and Lhx9 showed comparable expression patterns in the telencephalon of mouse and chicken, which allowed distinction of the ventrolateral pallium and, particularly, the ventral pallial amygdala and entorhinal cortex. Lmo3 was expressed in most of the ventrolateral pallium in both species, including, in chicken, the piriform cortex and dorsal ventricular ridge (mesopallium, nidopallium, and arcopallium) and, in mouse, the piriform cortex, most of the claustral complex, and the pallial amygdala. Lhx9 was differentially expressed in the ventral pallium, where it was restricted to its rostral (olfactory bulb) and caudal (amygdalar and entorhinal) poles. In the caudal pole, expression of Lhx9 overlapped that of its paralog Lhx2. According to these expression patterns, the chicken ventral pallial amygdala appears to include the caudal dorsolateral pallium, the caudal nidopallium, and the whole arcopallium, and each one relates to a distinct ventricular sector. Finally, the combinatorial expression patterns of Lmo3, Lhx9, and Lmo4 distinguished four distinct subdivisions in the superficial, olfactorecipient area of the chicken ventral pallium, which appear comparable to the piriform, entorhinal, amygdalopiriform, and amygdalar cortices of mammals. The results are discussed in the context of the two existing, opposite views on the homology of the dorsal ventricular ridge of sauropsids and in terms of the evolution of pallial derivatives.


Tibial dyschondroplasia-associated proteomic changes in chicken growth plate cartilage.
Tibial dyschondroplasia (TD) is a poultry leg problem that affects the proximal growth plate of the tibia, preventing its transition to bone. To understand the disease-induced proteomic changes, we compared the protein extracts of cartilage from normal and TD-affected growth plates. TD was induced by feeding thiram to chickens 2 wk before tissue harvest. Proteins were extracted from whole tissues and from conditioned media (CM) prepared by incubating appropriate growth plate tissues in serum-free culture medium for 48 hr. The extracts were prefractionated to contain proteins ranging between 10 and 100 kD. Equal amounts of proteins were subjected to 2D gel electrophoresis with three individual samples per group. The gels were silver stained, and digital images were compared and analyzed with Melanie software to determine differentially expressed protein spots. On comparison of two sets of gels, 47 matching spots were detected in tissue extracts and 27 in CM extracts. Among the matching spots, 12 were determined to be down-regulated in tissue extracts (P < or = 0.05) and two in CM extracts (P < or = 0.05) of TD-affected growth plates. Altogether, 32 protein spots could be identified in both tissue and CM extracts by in-gel trypsin digestion, followed by peptide mass fingerprinting and mass spectrometry (MS)/MS fragmentation. The down-regulated proteins included alpha-enolase, G protein, origin recognition complex, peptidyl prolyl isomerase, calumenin, type II collagen precursor, and the expressed sequence tag pgm2n.pk014.f20, a protein with homology to human reticulocalbin-3 (RCN3). Most of the downregulated proteins are associated with signal transduction, energy metabolism, and secretory functions that are integral to cell viability. Consistent with our earlier findings that the TD chondrocytes are nonviable, the current results suggest that thiram very likely interferes with basic metabolic functions of chondrocytes, leading to their death and, consequently, to the pathogenesis of TD.


Gestational diabetes and subsequent growth patterns of offspring: the National Collaborative Perinatal Project.
Our objective was to test the hypothesis that intrauterine exposure to gestational diabetes [GDM] predicts childhood growth independent of the effect on infant birthweight. We conducted a prospective analysis of 28,358 mother-infant pairs who enrolled in the National Collaborative Perinatal Project between 1959 and 1965. The offspring were followed until age 7. Four hundred and eighty-four mothers (1.7%) had GDM. The mean birthweight was 3.2 kg (range 1.1-5.6 kg). Maternal characteristics (age, education, race, family income, pre-pregnancy body mass index and pregnancy weight gain) and measures of childhood growth (birthweight, weight at ages 4, and 7) differed significantly by GDM status (all P < 0.05). As expected, compared to their non-diabetic counterparts, mothers with GDM gave birth to offspring that had higher weights at birth. The offspring of mothers with GDM were larger at age 7 as indicated by greater weight, BMI and BMI z-score compared to the offspring of mothers without GDM at that age (all P < 0.05). These differences at age 7 persisted even after adjustment for infant birthweight. Furthermore, the offspring of mothers with GDM had a 61% higher odds of being overweight at age 7 compared to the offspring of mothers without GDM after adjustment for maternal BMI, pregnancy weight gain, family income, race and birthweight [OR = 1.61 (95%CI:1.07, 1.28)]. Our results indicate that maternal GDM status is associated with offspring overweight status during childhood. This relationship is only partially mediated by effects on birthweight.


Biochemical and physiochemical characterization of pepsin-solubilized type-II collagen from bovine articular cartilage.
Solubilization of collagen from bovine articular with pepsin requires the preliminary extraction of proteoglycans from the ground substance. Biochemical and physiochemical properties of this pepsin-solubilized collagen are independent of the pretreatment (extraction with 1.5M-CaCl2, 5M-guanidinium chloride or 0.2M-NaOH) and of the age range (2-4-year-old and 2-month-old animals). Characterization of the de-natured components, of the CNBr peptides and of the amino acid and cross-link composition shows that the collagen of the hyaline cartilage is all type II. Electrical birefringence measurements showed the presence of tropocollagen molecules (length 280nm) and molecules whose length is slightly less than twice that of the tropocollagen molecules. This latter molecule may be a dimer composed of two monomers linked by intermolecular head-to-tail bonds and whose theoretical length (530nm), according to the quarter-stagger theory, is in good agreement with our measured values (510-530nm). We have verified that the beta-components of this collagen are formed of two alpha-chains linked by the stable intermolecular bond, dehydrodihydroxylysinonorleucine. These dimeric molecules are absent from solutions of skin collagen whose beta-components possess only aldol-type intramolecular cross-links. Although reconstituted fibres from solutions of skin and cartilage collagen are similar, the segment-long spacing crystallites formed with pepsin-solubilized cartilage collagen present a symmetrical and dimeric form corresponding to the lateral aggregation of two monomers with an overlap (90nm) of the C-terminal ends.


Carbon Assimilation and Leaf Water Status in Sugar Beet Leaves during a Simulated Natural Light Regimen.
Carbon assimilation and leaf water status were studied in sugar beet (Beta vulgaris L., Klein E-type multigerm) leaves during a light period in which illumination either increased rapidly to full irradiance or changed gradually in a sinusoidal manner as generally occurs during a natural day. A light regimen that simulated the light of a natural day was produced by adjusting irradiance with a neutral-density filter under the control of a computer. Under this light regimen, photosynthesis, transpiration, and stomatal conductance followed the irradiance pattern very closely and ribulose bisphosphate carboxylase was nearly fully activated. When illumination was increased rapidly at the beginning of a light period, transpiration also increased quickly, causing leaves to wilt to some extent. The activation state of ribulose bisphosphate carboxylase increased to only 52%, but ribulose bisphosphate level was nearly twice as high as during the simulated natural day. In spite of the differences in activation state and ribulose bisphosphate levels, photosynthesis rates were very similar under both regimens. Nevertheless, differences in parameters between leaves under the two irradiance regimens can affect how a plant responds to internal or external factors, and therefore, the rate at which irradiance increases at the beginning of a light period is an important consideration when interpreting data.


In vitro modulation of LPS/calcimycin induced inflammatory and allergic mediators by pure compounds of Andrographis paniculata (King of bitters) extract.
The aim of the current study is to probe the anti-inflammatory/anti-allergic potential of seven phytoconstituents (andrographolide, neoandrographolide, isoandrographolide, andrograpanin, 14-deoxy-11,12-didehydroandrographolide, 7-O-methylwogonin and skullcapflavone-I) isolated from Andrographis paniculata (King of bitters) on the production of key inflammatory/allergic mediators (NO, PGE(2), IL-1 beta, IL-6, LTB(4), TXB(2) and histamine). The results demonstrated that andrographolide, isoandrographolide, 7-O-methylwogonin and skullcapflavone-I significantly inhibited LPS stimulated NO and PGE(2) release in J774A.1 macrophages. Andrographolide, isoandrographolide and 7-O-methylwogonin showed considerable inhibition of IL-1 beta production in LPS elicited macrophages. LPS induced IL-6 production was significantly inhibited by andrographolide, isoandrographolide and skullcapflavone-I in a concentration dependent manner. The results revealed that andrographolide, isoandrographolide and skullcapflavone-I significantly decreased TXB(2) release in A23187 activated HL-60 promyelocytic cells. Furthermore, the anti-allergic properties of the phytoconstituents was investigated on A23187 induced LTB(4) production (HL-60 cells) and histamine release (RBL-2H3 basophilic cells). The results showed that only skullcapflavone-I and 7-O-methylwogonin showed marked inhibitory effect on LTB(4) production, however, only 7-O-methylwogonin exerted dose-dependent inhibition towards histamine release. Therefore, this study indicates that some of these phytoconstituents exhibit potent anti-inflammatory/anti-allergic effects by modulating different inflammatory/allergic mediators. Hence, these phytoconstituents might provide useful phytomedical treatment against variety of inflammatory and allergic disorders.


Lifelong learning: Established concepts and evolving values.
To summarise the concepts critical for understanding the content and value of lifelong learning (LL). Ideas generated by personal experience were combined with those of philosophers, social scientists, educational institutions, governments and UNESCO, to facilitate an understanding of the importance of the basic concepts of LL. Autopoietic, continuous, self-determined, informal, vicarious, biographical, lifelong reflexive learning, from and for society, when supported by self-chosen formal courses, can build capacities and portable skills that allow useful responses to challenges and society's new structures of governance. The need for LL is driven by challenges. LL flows continuously in pursuit of one agenda, which could either be citizenship, as is conventional, or as this article proposes, health. LL cannot be wholly centred on vocation. Continuous medical education and continuous professional development, important in their own right, cannot supply all that is needed. LL aids society with its learning, and it requires an awareness of the environment and structures of society. It is heavily vicarious, draws on formal learning and relies for effectiveness on reflection, self-assessment and personal shaping of views of the world from different perspectives. Health is critical to rational thought and peace, and determines society's capacity to govern itself, and improve its health. LL should be reshaped to focus on health not citizenship. Therefore, embedding learning in society and environment is critical. Each urologist must develop an understanding of the numerous concepts in LL, of which 'biographicisation' is the seed that will promote innovative strategies.


Associations between adult attachment style, emotion regulation, and preschool children's food consumption.
The goal of this study was to test 3 serial mediation models of how caregiver adult attachment style influences children's food consumption through its influence on emotion regulation. Three mediators that have been shown to increase the risk for pediatric obesity and that are likely to be influenced by negative emotion regulation strategies in everyday family interactions were chosen: (1) caregiver feeding practices (2) family mealtime routines, and (3) child television (TV) viewing. A total of 497 primary caregivers of 2.5- to 3.5-year-old children reported on their own attachment style, typical responses to their children's negative affect, feeding styles, mealtime and TV viewing routines, and their children's consumption of healthful and unhealthful foods. Insecure mothers were more likely to use punishing or dismissing responses to their children's negative affect, and negative emotion regulation predicted the increased use of emotion-related feeding styles and fewer mealtime routines. These variables, in turn, were found to predict children's unhealthful food consumption, documenting serial mediational influences. With respect to TV viewing, caregiver insecurity influenced child food consumption indirectly through its direct effect on child TV viewing. Taken together, these data suggest that insecure attachment may put parents at a risk for using negative emotion regulation strategies in response to their children's distress, which may also have important implications for the interpersonal environment surrounding food and the development of children's early eating behaviors.


Correlation of Pain and Fluoride Concentration in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Voriconazole.
Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible after drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain.


The effect of electromagnetic waves on the growth of Entamoeba histolytica and Entamoeba dispar.
The aim of this study was to investigate the influence of electromagnetic radiation of a digital Global System for Mobile Communication mobile telephone (900 MHz) on Entamoeba histolytica (E. histolytica) and Entamoeba dispar (E. dispar) (cysts or trophozoites, or both) in a 24-hour period. This study was carried out from April 2004 to May 2004 at the Department of Parasitology, Medical Faculty of Dokuz Eylul University in Izmir, Turkey. The cultivated isolate tubes, which were exposed to electromagnetic field at 37 degrees C, were evaluated as study group, whereas the tubes without exposure were assessed as control group. Finally, only living parasites in all tubes were counted using a hemacytometer. The effect of the temperature was evaluated for both control and study groups. The influence of electromagnetic field and temperature was assessed separately for the study group. The parasite number of E. histolytica decreased after exposure at 37 degrees C and room temperature (p=0.009) compared to the decrease in the control group (p=0.009). The parasite number of E. dispar also decreased after exposure at 37 degrees C and room temperature (p=0.009). In comparison to control tubes, this was a significant decrease (p=0.008). In the case of exposure of E. histolytica the results did not reveal any significant difference between temperature degrees to magnetic field (p=0.459) and E. dispar (p=0.172). Our findings show that exposure to electromagnetic field for a certain period of time may cause damage that can lead to death in single-cell organisms.


Synergism and Antagonism of Proximate Mechanisms Enable and Constrain the Response to Simultaneous Selection on Body Size and Development Time: An Empirical Test Using Experimental Evolution.
Natural selection acts on multiple traits simultaneously. How mechanisms underlying such traits enable or constrain their response to simultaneous selection is poorly understood. We show how antagonism and synergism among three traits at the developmental level enable or constrain evolutionary change in response to simultaneous selection on two focal traits at the phenotypic level. After 10 generations of 25% simultaneous directional selection on all four combinations of body size and development time in Manduca sexta (Sphingidae), the changes in the three developmental traits predict 93% of the response of development time and 100% of the response of body size. When the two focal traits were under synergistic selection, the response to simultaneous selection was enabled by juvenile hormone and ecdysteroids and constrained by growth rate. When the two focal traits were under antagonistic selection, the response to selection was due primarily to change in growth rate and constrained by the two hormonal traits. The approach used here reduces the complexity of the developmental and endocrine mechanisms to three proxy traits. This generates explicit predictions for the evolutionary response to selection that are based on biologically informed mechanisms. This approach has broad applicability to a diverse range of taxa, including algae, plants, amphibians, mammals, and insects.


Acoustic effects accurately predict an extreme case of biological morphology.
The biosonar system of bats utilizes physical baffle shapes around the sites of ultrasound emission for diffraction-based beam forming. Among these shapes, some extreme cases have evolved that include a long noseleaf protrusion (sella) in a species of horseshoe bat. We have evaluated the acoustic cost function associated with sella length with a computational physics approach and found that the extreme length can be predicted accurately from a fiducial point on this function. This suggests that some extreme cases of biological morphology can be explained from their physical function alone.


Increasing HIV/AIDS knowledge among urban ethnic minority youth: Findings from a community-based prevention intervention program.
HIV (Human Immunodeficiency Virus)/AIDs (Acquired immunodeficiency syndrome) prevention and research are imperative. Prevention-intervention programming is minimal in low-income communities of color. Additional research is needed that uncovers points of support and prevention to increase HIV knowledge and awareness and limit new HIV infections among adolescents of color. This study presents preliminary findings from a community-based HIV/AIDS, substance abuse, and viral hepatitis (VH) prevention education intervention for ethnic minority youth in a northeastern urban community. We evaluated HIV/AIDS knowledge and factors associated with knowledge. Participants (N = 599) completed a baseline survey followed by an exit survey measuring HIV/AIDS knowledge. Exit survey findings indicated that there was an increase in HIV/AIDs knowledge. Multivariate regression analyses showed that change scores in VH knowledge accuracy, sexual negotiation skills, risk perception, and ethnic identity were positively associated with change in HIV/AIDs knowledge score. The development and implementation of HIV/AIDS knowledge interventions can be crucial in alleviating new infections in the U.S.


Smartphone usage and increased risk of mobile phone addiction: A concurrent study.
This study aimed to study the mobile phone addiction behavior and awareness on electromagnetic radiation (EMR) among a sample of Malaysian population. This online study was conducted between December 2015 and 2016. The study instrument comprised eight segments, namely, informed consent form, demographic details, habituation, mobile phone fact and EMR details, mobile phone awareness education, psychomotor (anxious behavior) analysis, and health issues. Frequency of the data was calculated and summarized in the results. Totally, 409 respondents participated in the study. The mean age of the study participants was 22.88 (standard error = 0.24) years. Most of the study participants developed dependency with smartphone usage and had awareness (level 6) on EMR. No significant changes were found on mobile phone addiction behavior between the participants having accommodation on home and hostel. The study participants were aware about mobile phone/radiation hazards and many of them were extremely dependent on smartphones. One-fourth of the study population were found having feeling of wrist and hand pain because of smartphone use which may lead to further physiological and physiological complication.


Spin-locking in low-frequency reaction yield detected magnetic resonance.
The purported effects of weak magnetic fields on various biological systems from animal magnetoreception to human health have generated widespread interest and sparked much controversy in the past decade. To date the only well established mechanism by which the rates and yields of chemical reactions are known to be influenced by magnetic fields is the radical pair mechanism, based on the spin-dependent reactivity of radical pairs. A diagnostic test for the operation of the radical pair mechanism was proposed by Henbest et al. [J. Am. Chem. Soc., 2004, 126, 8102] based on the combined effects of weak static magnetic fields and radiofrequency oscillating fields in a reaction yield detected magnetic resonance experiment. Here we investigate the effects on radical pair reactions of applying relatively strong oscillating fields, both parallel and perpendicular to the static field. We demonstrate the importance of understanding the effect of the strength of the radiofrequency oscillating field; our experiments demonstrate that there is an optimal oscillating field strength above which the observed signal decreases in intensity and eventually inverts. We establish the correlation between the onset of this effect and the hyperfine structure of the radicals involved, and identify the existence of 'overtone' type features appearing at multiples of the expected resonance field position.


Monocyte chemotactic and activating factor is a potent histamine-releasing factor for human basophils.
Recombinant monocyte chemotactic-activating factor (MCAF) has been shown to induce histamine release from human basophils with a dose response between 10(-9) and 10(-6) M. The peak of activity was reached at 10(-7) M. Histamine release by MCAF was rapid with an initial rate comparable with histamine release by an optimal dose of anti-IgE. MCAF led to peak histamine release within 1 min. 80% of the subjects tested were responsive to MCAF or anti-IgE, while all were responsive to FMLP. The percentage histamine release by MCAF was, however, less than that seen with anti-IgE or FMLP, but this was attributable to a lesser percent release in nonatopic subjects; atopic subjects responded similarly to all three agonists. MCAF was also shown to activate highly purified human basophils more readily than mixed leukocytes, and its activity was inhibited by a polyclonal rabbit antibody. At a suboptimal concentration (2.5 x 10(-9) M), MCAF was unable to prime the basophil to histamine release by other secretagogues. However, interleukin 3 (IL-3) and IL-5 could each prime basophils for MCAF-induced secretion. Therefore, our results suggest that MCAF may be a major contributor to the histamine-releasing activity seen in peripheral blood mononuclear cell supernatants that has been designated histamine releasing factor(s).


Factors Associated With Seeking Physician Care by Medicare Beneficiaries Who Receive All Their Primary Care From Nurse Practitioners.
A shortage of primary care physicians has led to the alternative strategy of nurse practitioners (NPs) as primary care providers for the growing elderly population. Many states have implemented policies that allow NPs to practice independently with no physician oversight. Little is known about the continuity of primary care provided by NPs. To examine rate and correlates of switching from exclusive NP primary care to receiving some or all primary care from physicians. A retrospective cohort study. Medicare beneficiaries (n = 38 618) with diabetes, congestive heart failure, or chronic obstructive pulmonary disease who received all their primary care from NPs in 2007. Multivariable logistic regression model was used to assess patient and disease characteristics associated with switching from sole NP primary care in 2007 to receiving some or all primary care from physicians between 2008 and 2010. Of elderly patients receiving all their primary care from NPs in 2007, 53.8% switched to receiving some or all primary care from physicians in 2008-2010. The switching patients had less comorbidity before the switch and were more likely to reside in metropolitan areas, ZIP code areas with high education or states with the most restriction on NP scope of practice. In multivariable analyses, significant predictors of switching included one of the following within 30 days before the switch: emergency room visits (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.44-1.68), hospitalization (OR = 1.13, 95% CI = 1.02-1.25), new diagnosis of heart attacks (OR = 5.52, 95% CI = 4.33-7.02), pneumonia (OR = 4.84, 95% CI = 3.71-6.32), atrial fibrillation (OR = 3.99, 95% CI = 2.93-5.44), stroke (OR = 2.94, 95% CI = 2.31-3.74), or cancer (OR = 2.65, 95% CI = 1.94-3.63). About half of Medicare patients under exclusive NP primary care switched to physicians for some or all primary care over a 3-year period. Future study is needed to understand the reasons for switching.


Affine parameter estimation from the trace transform.
In this paper, we assume that we are given the images of two segmented objects, one of which may be an affinely distorted version of the other, and wish to recover the values of the parameters of the affine transformation between the two images. The images may also differ by the overall level of illumination. The multiplicative constant of such difference may also be recovered. We present a generic theoretical framework to solve this problem. In terms of this framework, other proposed methods may be interpreted. We show how, in this framework, one can recover the affine parameters in a way that is robust to various effects, such as occlusion and illumination variation. The proposed method is generic enough to be applicable also to matching two images that do not depict the same scene or object.


Comparing the traditional and Multiple Mini Interviews in the selection of post-graduate medical trainees.
The traditional, panel style interview and the multiple mini interview (MMI) are two options to use in the selection of medical trainees with each interview format having inherent advantages and disadvantages. Our aim was to compare the traditional and MMI on the same cohort of postgraduate applicants to the Department of Otolaryngology - Head & Neck Surgery at the University of Toronto. Twenty-seven applicants from the 2010 Canadian Residency Matching Service selected for interview at the University of Toronto, Department of Otolaryngology - Head & Neck Surgery were included in the study. Each applicant participated in both a traditional interview and MMI. Traditional interviews marked out of a total maximum score of 570. On the traditional interview, scores ranged from 397-543.5 (69.6 - 95.3%), the mean was 460.2. The MMI maximum score was out of 180. MMI scores ranged from 93 - 146 (51.7 - 81.1%) with a mean of 114.8. Traditional interview total scores were plotted against MMI total scores. Scores correlated reasonably well, Pearson Correlation = 0.315 and is statistically significant at p = 0.001. Inter-interview reliability for the two interview methods was 0.038, with poor overall agreement 0.07%. MMI and traditional interview scores are correlated but do not reliably lead to the same rank order. We have demonstrated that these two interview formats measure different characteristics. One format may also be less reliable leading to greater variation in final rank. Further validation research is certainly required.


Three-dimensional remote sensing by optical scanning holography.
A technique is presented by which holograms can be recorded when an object or scene is scanned with an optically heterodyned Fresnel zone pattern. The experimental setup, based on optical scanning holography, is described and experimental results are presented. We apply the scanning holography technique to three-dimensional reflective objects for the first time to our knowledge and address the unique requirements for such a system. We discuss holographic recording and numerical image reconstruction using a system point-spread function (PSF) approach. We demonstrate numerical image reconstruction of experimentally recorded holograms by two techniques: deconvolution with a simulated PSF and an experimentally acquired PSF.


On a new species of titi monkey (Primates: Plecturocebus Byrne et al., 2016), from Alta Floresta, southern Amazon, Brazil.
The taxonomy of the titi monkeys (Callicebinae) has recently received considerable attention. It is now recognised that this subfamily is composed of three genera with 33 species, seven of them described since 2002. Here, we describe a new species of titi, Plecturocebus, from the municipality of Alta Floresta, Mato Grosso, Brazil. We adopt an integrative taxonomic approach that includes phylogenomic analyses, pelage characters, and locality records. A reduced representation genome-wide approach was employed to assess phylogenetic relationships among species of the eastern Amazonian clade of the Plecturocebus moloch group. Using existing records, we calculated the Extent of Occurrence (EOO) of the new species and estimated future habitat loss for the region based on predictive models. We then evaluated the species' conservation status using the IUCN Red list categories and criteria. The new species presents a unique combination of morphological characters: (1) grey agouti colouration on the crown and dorsal parts; (2) entirely bright red-brown venter; (3) an almost entirely black tail with a pale tip; and (4) light yellow colouration of the hair on the cheeks contrasting with bright red-brown hair on the sides of the face. Our phylogenetic reconstructions based on maximum-likelihood and Bayesian methods revealed well-supported species relationships, with the Alta Floresta taxon as sister to P. moloch + P. vieirai. The species EOO is 10,166,653 ha and we predict a total habitat loss of 86% of its original forest habitat under a "business as usual" scenario in the next 24 years, making the newly discovered titi monkey a Critically Endangered species under the IUCN A3c criterion. We give the new titi monkey a specific epithet based on: (1) clear monophyly of this lineage revealed by robust genomic and mitochondrial data; (2) distinct and diagnosable pelage morphology; and (3) a well-defined geographical distribution with clear separation from other closely related taxa. Urgent conservation measures are needed to safeguard the future of this newly discovered and already critically endangered primate.


Global tracking control of strict-feedback systems using neural networks.
Most existing adaptive neural controllers ensure semiglobally uniform ultimately bounded stability on the condition that the neural approximation remains valid for all time. However, such a condition is difficult to verify beforehand. As a result, deterioration of tracking performance or even instability may occur in real applications. A common recourse is to activate an extra robust controller outside the neural active region to pull back the transient. Such an approach, however, has been restricted to dynamic systems with matched uncertainty. We extend it to strict-feedback systems with mismatched uncertainties via multiswitching-based backstepping methodology. Each virtual and actual controller of the proposed design switches between an adaptive neural controller and a robust controller, with the switching algorithm being sufficiently smooth and, hence, able to be incorporated with the backstepping tool. The overall controller ensures globally uniform ultimate boundedness while simultaneously avoiding the possible control singularity. Simulation results demonstrate the validity of the proposed designs.


A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth.
The stromal microenvironment and particularly the macrophage component of primary tumors influence their malignant potential. However, at the metastatic site the role of these cells and their mechanism of actions for establishment and growth of metastases remain largely unknown. Using animal models of breast cancer metastasis, we show that a population of host macrophages displaying a distinct phenotype is recruited to extravasating pulmonary metastatic cells regardless of species of origin. Ablation of this macrophage population through three independent means (genetic and chemical) showed that these macrophages are required for efficient metastatic seeding and growth. Importantly, even after metastatic growth is established, ablation of this macrophage population inhibited subsequent growth. Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation. These data indicate a direct enhancement of metastatic growth by macrophages through their effects on tumor cell extravasation, survival and subsequent growth and identifies these cells as a new therapeutic target for treatment of metastatic disease.


Randomised trial of face-washing to develop a standard definition of a clean face for monitoring trachoma control programmes.
Surgery, antibiotics, facial cleanliness and environmental improvements (SAFE) are recommended for trachoma control. Programmes assess clean faces in children, but no standard definition of a clean face exists. We conducted a randomised controlled trial of face-washing to develop a valid and repeatable definition of a clean face. A total of 424 children were randomised to washed and unwashed groups after a first observation. Three additional observations were made throughout the day. Photographs were taken at each observation. No difference was observed in wet nasal discharge, dust, food or flies on the face between the face washed and unwashed groups at baseline or after washing. A difference was observed in the presence of ocular discharge (P < 0.001) and dry nasal discharge (P < 0.001) after washing. Agreement among observers was highest for flies (Kappa = 0.89, 95% CI = 0.87-0.91), followed by nasal (Kappa = 0.64, 0.62-0.66) and ocular (Kappa = 0.48, 0.46-0.50) discharge. The ability of any definition to identify whether a face had been washed decreased at each observation. This study suggests that the absence of ocular and dry nasal discharge can be used as an indicator of 'clean face', although it is not a good predictor of whether a face has been washed and is difficult to recommend.


Improving Clinical Manufacturing of IL-15 Activated Cytokine-Induced Killer (CIK) Cells.
Cytokine-induced killer (CIK) cells are an immunotherapeutic approach to combat relapse following allogeneic hematopoietic stem cell transplantation (HSCT) in acute leukemia or myelodysplastic syndrome (MDS) patients. Prompt and sequential administration of escalating cell doses improves the efficacy of CIK cell therapy without exacerbating graft vs. host disease (GVHD). This study addresses manufacturing-related issues and aimed to develop a time-, personal- and cost-saving good manufacturing process (GMP)-compliant protocol for the generation of ready-for-use therapeutic CIK cell doses starting from one unstimulated donor-derived peripheral blood (PB) or leukocytapheresis (LP) products. Culture medium with or without the addition of either AB serum, fresh frozen plasma (FFP) or platelet lysate (PL) was used for culture. Fresh and cryopreserved CIK cells were compared regarding expansion rate, viability, phenotype, and ability to inhibit leukemia growth. Cell numbers increased by a median factor of 10-fold in the presence of FFP, PL, or AB serum, whereas cultivation in FFP/PL-free or AB serum-free medium failed to promote adequate CIK cell proliferation (p < 0.01) needed to provide clinical doses of 1 × 106 T cells/kG, 5 × 106 T cells/kG, 1 × 107 T cells/kG, and 1 × 108 T cells/kG recipient body weight. CIK cells consisting of T cells, T- natural killer (T-NK) cells and a minor fraction of NK cells were not significantly modified by different medium supplements. Moreover, neither cytotoxic potential against leukemic THP-1 cells nor cell activation shown by CD25 expression were significantly influenced. Moreover, overnight and long-term cryopreservation had no significant effect on the composition of CIK cells, their phenotype or cytotoxic potential. A viability of almost 93% (range: 89-96) and 89.3% (range: 84-94) was obtained after freeze-thawing procedure and long-term storage, respectively, whereas viability was 96% (range: 90-97) in fresh CIK cells. Altogether, GMP-complaint CIK cell generation from an unstimulated donor-derived PB or LP products was feasible. Introducing FFP, which is easily accessible, into CIK cell cultures was time- and cost-saving without loss of viability and potency in a 10-12 day batch culture. The feasibility of cryopreservation enabled storage and delivery of sequential highly effective ready-for-use CIK cell doses and therefore reduced the number of manufacturing cycles.


Impeded protein folding and function in active inflammatory bowel disease.
The intestinal tract is covered by a total of 300 square metres of IECs (intestinal epithelial cells) that covers the entire intestinal mucosa. For protection against luminal xenobiotics, pathogens and commensal microbes, these IECs are equipped with membrane-bound transporters as well as the ability to secrete specific protective proteins. In patients with active IBD (inflammatory bowel disease), the expression of these proteins, e.g. ABC (ATP-binding cassette) transporters such as ABCG2 (ABC transporter G2) and defensins, is decreased, thereby limiting the protection against various luminal threats. Correct ER (endoplasmic reticulum)-dependent protein folding is essential for the localization and function of secreted and membrane-bound proteins. Inflammatory triggers, such as cytokines and nitric oxide, can impede protein folding, which causes the accumulation of unfolded proteins inside the ER. As a result, the unfolded protein response is activated which can lead to a cellular process named ER stress. The protein folding impairment affects the function and localization of several proteins, including those involved in protection against xenobiotics. In the present review, we discuss the possible inflammatory pathways affecting protein folding and eventually leading to IEC malfunction in patients with active IBD.


Structural convergence properties of amorphous InGaZnO4 from simulated liquid-quench methods.
The study of structural properties of amorphous structures is complicated by the lack of long-range order and necessitates the use of both cutting-edge computer modeling and experimental techniques. With regards to the computer modeling, many questions on convergence arise when trying to assess the accuracy of a simulated system. What cell size maximizes the accuracy while remaining computationally efficient? More importantly, does averaging multiple smaller cells adequately describe features found in bulk amorphous materials? How small is too small? The aims of this work are: (1) to report a newly developed set of pair potentials for InGaZnO4 and (2) to explore the effects of structural parameters such as simulation cell size and numbers on the structural convergence of amorphous InGaZnO4. The total number of formula units considered over all runs is found to be the critical factor in convergence as long as the cell considered contains a minimum of circa fifteen formula units. There is qualitative agreement between these simulations and X-ray total scattering data - peak trends and locations are consistently reproduced while intensities are weaker. These new IGZO pair potentials are a valuable starting point for future structural refinement efforts.


Drivers of and Obstacles to the Adoption of Toxicogenomics for Chemical Risk Assessment: Insights from Social Science Perspectives.
Some 20 y ago, scientific and regulatory communities identified the potential of omics sciences (genomics, transcriptomics, proteomics, metabolomics) to improve chemical risk assessment through development of toxicogenomics. Recognizing that regulators adopt new scientific methods cautiously given accountability to diverse stakeholders, the scope and pace of adoption of toxicogenomics tools and data have nonetheless not met the ambitious, early expectations of omics proponents. Our objective was, therefore, to inventory, investigate, and derive insights into drivers of and obstacles to adoption of toxicogenomics in chemical risk assessment. By invoking established social science frameworks conceptualizing innovation adoption, we also aimed to develop recommendations for proponents of toxicogenomics and other new approach methodologies (NAMs). We report findings from an analysis of 56 scientific and regulatory publications from 1998 through 2017 that address the adoption of toxicogenomics for chemical risk assessment. From this purposeful sample of toxicogenomics discourse, we identified major categories of drivers of and obstacles to adoption of toxicogenomics tools and data sets. We then mapped these categories onto social science frameworks for conceptualizing innovation adoption to generate actionable insights for proponents of toxicogenomics. We identify the most salient drivers and obstacles. From 1998 through 2017, adoption of toxicogenomics was understood to be helped by drivers such as those we labeled Superior scientific understanding, New applications, and Reduced cost & increased efficiency but hindered by obstacles such as those we labeled Insufficient validation, Complexity of interpretation, and Lack of standardization. Leveraging social science frameworks, we find that arguments for adoption that draw on the most salient drivers, which emphasize superior and novel functionality of omics as rationales, overlook potential adopters' key concerns: simplicity of use and compatibility with existing practices. We also identify two perspectives-innovation-centric and adopter-centric-on omics adoption and explain how overreliance on the former may be undermining efforts to promote toxicogenomics. https://doi.org/10.1289/EHP6500.


EuroQol EQ-5D and condition-specific measures of health outcome in women with urinary incontinence: reliability, validity and responsiveness.
To evaluate the measurement properties of the EuroQoL EQ-5D and two condition-specific patient-reported outcome measures--the Symptom Severity Index (SSI) and the Urinary Incontinence-Specific Quality of Life instrument (I-QoL)--in women with urinary incontinence. A questionnaire comprising all instruments was completed by women taking part in a clinical trial of physiotherapy for urinary incontinence. Follow-up questionnaires were at 6 weeks and 5 months. Data quality, internal consistency reliability, validity and responsiveness were assessed. One hundred and seventy-four patients taking part in the clinical trial completed the questionnaire. Instruments had low levels of missing data. The EQ-5D had a large ceiling effect and poor responsiveness. The SSI had poor validity and responsiveness. The I-QoL had levels of reliability that supported application in group assessment, and in some cases, individual assessment, and good evidence of validity. The I-QoL was the most responsive instrument at both 6 weeks and 5 months. The I-QoL was the best performing instrument and is recommended as a continence-specific measure of quality of life in a clinical trial setting. The SSI and EQ-5D are not recommended. Alternative generic instruments, which support economic evaluation, require further evaluation in trials of female urinary incontinence.


Serum lipid peroxide and alpha-tocopherol concentrations and superoxide dismutase activity in captive bottle-nosed dolphins.
To evaluate serum lipid peroxide (LPO) and alpha-tocopherol concentrations and superoxide dismutase (SOD) activity in captive bottle-nosed dolphins and to evaluate effects of storage on production of LPO in various marine fish. 16 bottle-nosed dolphins. 8 dolphins (group A) were fed chub mackerel and herring (high fat) and arabesque greenling and banded blue-sprat (low fat); the other 8 dolphins (group B) were fed chub mackerel and Pacific saury (high fat) and shishamo smelt and Japanese horse mackerel (low fat). Each group had been on these respective diets for 3 years. Serum LPO and alpha-tocopherol concentrations, serum SOD activity, and superoxide production by neutrophils were measured. All types of marine fish were frozen at -20 C for 6 months, and concentrations of LPO were measured at various time points. Serum LPO concentrations in group-A dolphins were significantly higher than those in group B. Serum alpha-tocopherol concentrations and SOD activity in group A were significantly lower than those in group B. A significant negative correlation was found between serum LPO and alpha-tocopherol concentrations in all 16 dolphins. The LPO concentrations in mackerel and herring fed to group-A dolphins were higher than those of other fish. Concentrations of LPO in herring stored for 3 and 6 months at -20 C were higher than those in herring before freezing and in herring stored for 1 month. Serum LPO and alpha-tocopherol concentrations in captive bottle-nosed dolphins may be strongly influenced by high amounts of polyunsaturated fatty acid and LPO found in marine fatty fishes. High concentrations of serum LPO, as found in group-A dolphins, were associated with decreased antioxidative states. Monitoring of serum LPO and alpha-tocopherol concentrations and serum SOD activity may be useful for the management of captive marine mammals.


Mercury in freshwater fish of northeast North America--a geographic perspective based on fish tissue monitoring databases.
As part of an initiative to assemble and synthesize mercury (Hg) data from environmental matrices across northeastern North America, we analyzed a large dataset comprised of 15,305 records of fish tissue Hg data from 24 studies from New York State to Newfoundland. These data were summarized to provide mean Hg concentrations for 40 fish species and associated families. Detailed analyses were carried out using data for 13 species. Hg in fishes varied by geographic area, waterbody type, and waterbody. The four species with the highest mean Hg concentrations were muskellunge (Esox masquinongy), walleye (Sander vitreus), white perch (Morone americana), and northern pike (Esox luscius). Several species displayed elevated Hg concentrations in reservoirs, relative to lakes and rivers. Normalized deviations from mean tissue levels for yellow perch (Perca flavescens) and brook trout (Salvelinus fontinalis) were mapped, illustrating how Hg concentrations in these species varied across northeastern North America. Certain geographic regions showed generally below or above-average Hg concentrations in fish, while significant heterogeneity was evident across the landscape. The proportion of waterbodies exhibiting exceedances of USEPA's criterion for fish methylmercury ranged from 14% for standard-length brook trout fillets to 42% for standard-length yellow perch fillets. A preliminary correlation analysis showed that fish Hg concentrations were related to waterbody acidity and watershed size.