Changes in Tinnitus Experiences During the COVID-19 Pandemic.
Introduction: The COVID-19 pandemic has disrupted delivery of healthcare, economic activity, and affected social interactions. Identifying and supporting those most affected by the pandemic is required. The purpose of this study was to determine the impact of the pandemic on individuals with tinnitus and to identify mediating factors. Methods: This is a mixed-methods exploratory cross-sectional study, using data collected via an online survey from 3,103 individuals with tinnitus from 48 countries. The greatest representation was from North America (49%) and Europe (47%) and other countries were only marginally represented. Results: Although the study was aimed at those with pre-existing tinnitus, 7 individuals reported having COVID-19 initiated tinnitus. Having COVID-19 symptoms exacerbated tinnitus in 40% of respondents, made no change in 54%, and improved tinnitus in 6%. Other mediating factors such as the social and emotional consequences of the pandemic made pre-existing tinnitus more bothersome for 32% of the respondents, particularly for females and younger adults, better for 1%, and caused no change to tinnitus for 67%. Pre-existing tinnitus was significantly exacerbated for those self-isolating, experiencing loneliness, sleeping poorly, and with reduced levels of exercise. Increased depression, anxiety, irritability, and financial worries further significantly contributed to tinnitus being more bothersome during the pandemic period. Conclusions: These findings have implications for tinnitus management, because they highlight the diverse response both internal and external factors have on tinnitus levels. Clinical services should be mindful that tinnitus may be caused by contracting COVID-19 and pre-existing tinnitus may be exacerbated, although in the majority of respondents there was no change. Additional support should be offered where tinnitus severity has increased due to the health, social, and/or emotional effects of the COVID-19 pandemic. Tinnitus may be more bothersome for those experiencing loneliness, having fewer social interactions, and who are more anxious or worried.


l-Theanine Prevents Long-Term Affective and Cognitive Side Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry.
Chronic adolescent exposure to Δ-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioral abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathologic alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. l-Theanine is an amino acid analog of l-glutamate and l-glutamine derived from various plant sources, including green tea leaves. l-Theanine has previously been shown to modulate levels of GABA, DA, and glutamate in various neural regions and to possess neuroprotective properties. Using a preclinical model of adolescent THC exposure in male rats, we report that l-theanine pretreatment before adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect that persists into adulthood. In addition, pretreatment with l-theanine blocked THC-induced downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and subcortical DAergic dysregulation. Finally, l-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of l-theanine in the mesocorticolimbic system.SIGNIFICANCE STATEMENT With the increasing trend of cannabis legalization and consumption during adolescence, it is essential to expand knowledge on the potential effects of adolescent cannabis exposure on brain development and identify potential pharmacological strategies to minimize Δ-9-tetrahydrocannabinol (THC)-induced neuropathology. Previous evidence demonstrates that adolescent THC exposure induces long-lasting affective and cognitive abnormalities, mesocorticolimbic dysregulation, and schizophrenia-like molecular biomarkers that persist into adulthood. We demonstrate for the first time that l-theanine, an amino acid analog of l-glutamate and l-glutamine, is capable of preventing long-term THC side effects. l-Theanine prevented the development of THC-induced behavioral aberrations, blocked cortical downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways, and normalized dysregulation of both PFC and VTA DAergic activity, demonstrating powerful and functional neuroprotective effects against THC-induced developmental neuropathology.


Strategies to alleviate poverty and grassland degradation in Inner Mongolia: intensification vs production efficiency of livestock systems.
Semi-nomadic pastoralism was replaced by sedentary pastoralism in Inner Mongolia during the 1960's in response to changes in land use policy and increasing human population. Large increases in numbers of livestock and pastoralist households (11- and 9-fold, respectively) during the past 60 yrs have variously degraded the majority of grasslands in Inner Mongolia (78 M ha) and jeopardize the livelihoods of 24 M human inhabitants. A prevailing strategy for alleviating poverty and grassland degradation emphasizes intensification of livestock production systems to maintain both pastoral livelihoods and large livestock numbers. We consider this strategy unsustainable because maximization of livestock revenue incurs high supplemental feed costs, marginalizes net household income, and promotes larger flock sizes to create a positive feedback loop driving grassland degradation. We offer an alternative strategy that increases both livestock production efficiency and net pastoral income by marketing high quality animal products to an increasing affluent Chinese economy while simultaneously reducing livestock impacts on grasslands. We further caution that this strategy be designed and assessed within a social-ecological framework capable of coordinating market expansion for livestock products, sustainable livestock carrying capacities, modified pastoral perceptions of success, and incentives for ecosystem services to interrupt the positive feedback loop that exists between subsistence pastoralism and grassland degradation in Inner Mongolia.


CBG, CBD, Δ9-THC, CBN, CBGA, CBDA and Δ9-THCA as antioxidant agents and their intervention abilities in antioxidant action.
Positive effect of some cannabinoids in the treatment and prophylaxis of a wide variety of oxidation-associated diseases and growing popularity of supplements containing cannabinoids, mainly cannabinoid oils (e.g. CBD oil, CBG oil), in the self-medication of humans cause a growing interest in the antioxidant properties of these compounds, especially those not showing psychotropic effects. Herein, we report the antioxidant activity of cannabigerol (CBG), cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), cannabinol (CBN), cannabigerolic acid (CBGA), cannabinolic acid (CBDA) and Δ9-tetrahydrocannabinolic acid (Δ9-THCA) estimated by spectrophotometric methods: ABTS, DPPH, ORAC, beta-carotene CUPRAC and FRAP. The presented data prove that all the examined cannabinoids exhibit antioxidant activity manifested in their ability to scavenge free radicals, to prevent the oxidation process and to reduce metal ions. Although the intensity of these activities is not the same for the individual cannabinoids it is comparable for all of them with that of E vitamin. As results from the research, the significance of the two types of electron sources presenting in examined cannabinoids, phenolic groups and double bonds transferring electrons, depends on the type of electron-accepting species - radicals/metal ions.


Prevalence of gall stones in Dundee: a necropsy study.
Necropsy records from two large general hospitals in Dundee showed short-term fluctuations in the prevalence of gall stones that had not previously been described. There was no evidence of a rise in the standardised prevalence rate between 1902-9 and 1953-73. A spurious increase was apparent from the crude prevalence rates for these periods, which resulted simply from the increased age of the patients in the later period. Since there was no real increase in prevalence no conclusions can be drawn about dietary or other changes. Patients with stones in the common bile duct were likely to die from an associated cause. This related mainly to a high mortality rate in women. In patients with established epilepsy the prevalence of gall stones was greater than expected, which suggests that phenobarbitone does not diminish the likelihood of gall stones.


Indicators of trustworthiness in lay-friendly research summaries: Scientificness surpasses easiness.
Lay readers' trust in scientific texts can be shaped by perceived text easiness and scientificness. The two effects seem vital in a time of rapid science information sharing, yet have so far only been examined separately. A preregistered online study was conducted to assess them jointly, to probe for author and text trustworthiness overlap, and to investigate interindividual influences on the effects. N = 1467 lay readers read four short research summaries, with easiness and scientificness (high vs low) being experimentally varied. A more scientific writing style led to higher perceived author and text trustworthiness. Higher personal justification belief, lower justification by multiple-sources belief, and lower need for cognitive closure attenuated the influence of scientificness on trustworthiness. However, text easiness showed no influence on trustworthiness and no interaction with text scientificness. Implications for future studies and suggestions for enhancing the perceived trustworthiness of research summaries are discussed.


Perceptions of environmental supports for physical activity in African American and white adults in a rural county in South Carolina.
This study examined the association between perceptions of social and safety-related environmental attributes and physical activity (PA) and walking in African American and white adults. In a random-digit-dial telephone survey, 1165 adults in a rural county in South Carolina answered questions about their perceptions of social and safety-related environmental supports for PA and their overall PA and walking behavior. Social perceptions included whether neighbors could be trusted or were perceived to be physically active. Safety-related perceptions included neighborhood safety, the safety of public recreation facilities, problems with unattended dogs, traffic volume, and streetlight quality. Logistic regression models were used to examine the associations between environmental supports and PA and walking stratified by race. No association between perceived neighborhood environmental supports and PA or walking was observed in African Americans. Among whites, individuals who perceived their neighbors as active were twice (95% confidence interval [CI], 1.19-3.25) as likely to report meeting the recommendation for PA compared with individuals who did not report their neighbors as active. Whites who perceived their neighbors as active were 2.5 times (95% CI, 1.54-4.08) as likely to report meeting the recommendations for walking than whites who did not, and whites who perceived their neighborhoods as safe were 1.8 times (95% CI, 1.03-3.12) as likely to report meeting the recommendations for walking than whites who did not. These data indicate that perceptions of certain social and safety-related environmental supports were strongly associated with meeting the recommendations for PA and walking among white but not African American adults.


Drivers of sociality in Gobiodon fishes: An assessment of phylogeny, ecology and life-history.
What drives the evolution of sociality in animals? Many robust studies in terrestrial organisms have pointed toward various kinship-based, ecological and life-history traits or phylogenetic constraint which have played a role in the evolution of sociality. These traits are not mutually exclusive and the exact combination of traits is likely taxon-specific. Phylogenetic comparative analyses have been instrumental in identifying social lineages and comparing various traits with non-social lineages to give broad evolutionary perspectives on the development of sociality. Few studies have attempted this approach in marine vertebrate systems. Social marine fishes are particularly interesting because many have a pelagic larval phase and non-conventional life-history strategies (e.g. bi-directional sex-change) not often observed in terrestrial animals. Such strategies provide novel insights into terrestrially-derived theories of social evolution. Here, we assess the strength of the phylogenetic signal of sociality in the Gobiodon genus with Pagel's lambda and Blomberg's K parameters. We found some evidence of a phylogenetic signal of sociality, but factors other than phylogenetic constraint also have a strong influence on the extant social state of each species. We then use phylogenetic generalized least squares analyses to examine several ecological and life-history traits that may have influenced the evolution of sociality in the genus. We found an interaction of habitat size and fish length was the strongest predictor of sociality. Sociality in larger species was more dependent on coral size than in smaller species, but smaller species were more social overall, regardless of coral size. Finally, we comment on findings regarding the validity of the species G. spilophthalmus which arose during the course of our research. These findings in a group of marine fishes add a unique perspective on the evolution of sociality to the excellent terrestrial work conducted in this field.


High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients.
The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer-guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.


Hydroboration of carbon dioxide with catechol- and pinacolborane using an Ir-CNP* pincer complex. Water influence on the catalytic activity.
Iridium complexes based on deprotonated lutidine-derived CNP* pincers 2a/2b selectively catalyzed the hydroboration of CO2 under mild conditions (1-2 bar CO2, 30 °C) to methoxyborane using HBcat (TOF up to 56 h-1) and to the formate level with HBpin (TOF up to 1245 h-1). Interestingly, an intriguing, positive water effect on the reaction rates has been observed. NMR spectroscopy and ESI-MS analysis of the hydroboration reactions have shown the formation of ligand-protonated [Ir(CNP)(CO)(BR2)H][B(R2)2] (R2 = catecholate, pinacolate) derivatives under catalytic conditions. Control experiments, however, have demonstrated that these derivatives are not catalytically competent species in the hydroboration of CO2.


Newer antidepressants: review of efficacy and safety of escitalopram and duloxetine.
Two antidepressants with different mechanisms of action, escitalopram and duloxetine, have recently been developed for the treatment of major depressive disorder. This article reviews the available controlled data on these agents with regard to efficacy, safety, and tolerability. We identified four 8-week, double-blind, placebo-controlled studies of escitalopram in the acute treatment of major depression. Three of the studies involved an active comparator, citalopram. We identified 6 placebo-controlled studies of duloxetine in major depressive disorder. Two of the studies included fluoxetine as an active comparator, and 2 included paroxetine as an active comparator. A review of the data from the controlled studies supports the efficacy of both escitalopram and duloxetine in the treatment of patients with major depression. Three of the 4 escitalopram studies were positive, and 1 was a failed study. Four of the 6 duloxetine studies were positive. Both escitalopram and duloxetine performed better than at least 1 selective serotonin reuptake inhibitor comparator. The safety and tolerability profiles of both drugs are quite benign. The reported incidence of treatment-emergent adverse events was somewhat lower with escitalopram than with duloxetine, with the possible exception of sexual dysfunction. Discontinuations due to adverse events were lower for escitalopram than for duloxetine, although rates were comparable with higher doses of escitalopram (20 mg/day). Both escitalopram and duloxetine are useful in the treatment of major depressive disorder.


Evidence-based practice, response to intervention, and the prevention of reading difficulties.
This article provides an evidence-based perspective on what school communities can do to lower the prevalence of reading difficulties among their pupils through preventive interventions. It also delineates the roles that speech-language pathologists (SLPs) might play in these interventions. This article is organized to first provide a broad overview of current directions in research, practice, and policy in educational interventions, with an emphasis on how the three are increasingly integrated to respond to evidence showing that American school children are underperforming in reading. Next, the concept of response to intervention (RTI) is described. RTI is an educational policy and practice that is grounded in the accumulated literature that focuses on how schools might better organize themselves to deliver multitiered reading interventions to reduce children's risk for reading disability. Last, this article provides three organizational principles that school-based professionals, including SLPs, might follow to deliver RTI interventions. This article provides an important and timely description of key concepts in the prevention of reading difficulties through proactive multitiered interventions. SLPs can draw on the suggestions presented here to inform their local efforts in implementing preventive literacy programs that are consistent with an RTI paradigm.


British HIV Association (BHIVA)/British Association for Sexual Health and HIV (BASHH) guidelines on provision of adherence support to individuals receiving antiretroviral therapy (2003).
The widespread use of highly active antiretroviral therapy (HAART) has dramatically reduced HIV-associated morbidity and mortality where treatment has been made available. Very high levels of adherence to HAART are a prerequisite for a successful virological and immunological response. Low adherence increases the risk of treatment failure and disease progression. It is also likely to lead to further transmission of resistant viruses, and to have a negative impact on the cost effectiveness of HAART. Low adherence is difficult to predict, and this has two key implications for service provision. Firstly, HAART should not be withheld on the basis of assumptions about adherence. Secondly, support with adherence should be provided to all patients prescribed HAART. Our understanding of barriers to and enablers of high adherence, and the evidence base regarding effective interventions, is limited. Meta-analysis of randomized controlled trials available from the general literature suggests multiple interventions are required to maintain high adherence to chronic therapy. This document recommends a series of measures for adoption within HIV clinical care settings, based on evaluation of existing data. High adherence is a process, not a single event, and therefore adherence support must be integrated into clinical follow up. Every prescribing unit should have a written policy on provision of adherence support, and ensure that staff are appropriately trained to make delivery of such services possible.


Perturbing the metabolic dynamics of myo-inositol in developing Brassica napus seeds through in vivo methylation impacts its utilization as phytate precursor and affects downstream metabolic pathways.
myo-Inositol (Ins) metabolism during early stages of seed development plays an important role in determining the distributional relationships of some seed storage components such as the antinutritional factors, sucrose galactosides (also known as raffinose oligosaccharides) and phytic acid (PhA) (myo-inositol 1,2,3,4,5,6-hexakisphosphate). The former is a group of oligosaccharides, which plays a role in desiccation at seed maturation. They are not easily digested by monogastric animals, hence their flatulence-causing properties. Phytic acid is highly negatively charged, which chelates positive ions of essential minerals and decreases their bioavailability. It is also a major cause of phosphate-related water pollution. Our aim was to investigate the influence of competitive diversion of Ins as common substrate on the biosynthesis of phytate and sucrose galactosides. We have studied the initial metabolic patterns of Ins in developing seeds of Brassica napus and determined that early stages of seed development are marked by rapid deployment of Ins into a variety of pathways, dominated by interconversion of polar (Ins phosphates) and non-polar (phospholipids) species. In a time course experiment at early stages of seed development, we show Ins to be a highly significant constituent of the endosperm and seed coat, but with no phytate biosynthesis occurring in either tissue. Phytate accumulation appears to be confined mainly within the embryo throughout seed development and maturation. In our approach, the gene for myo-inositol methyltransferase (IMT), isolated from Mesembryanthemum crystallinum (ice plant), was transferred to B. napus under the control of the seed-specific promoters, napin and phaseolin. Introduction of this new metabolic step during seed development prompted Ins conversion to the corresponding monomethyl ether, ononitol, and affected phytate accumulation. We were able to produce homozygous transgenic lines with 19%-35% average phytate reduction. Additionally, changes in the raffinose content and related sugars occurred along with enhanced sucrose levels. Germination rates, viability and other seed parameters were unaffected by the IMT transgene over-expression. Competitive methylation of Ins during seed development reduces seed antinutritional components and enhances its nutritional characteristics while maintaining adequate phosphate reserves. Such approach should potentially raise the canola market value and likely, that of other crops.


Are polygenic risk scores for systolic blood pressure and LDL-cholesterol associated with treatment effectiveness, and clinical outcomes among those on treatment?
Many studies have investigated associations between polygenic risk scores (PRS) and the incidence of cardiovascular disease (CVD); few have examined whether risk factor-related PRS predict CVD outcomes among adults treated with risk-modifying therapies. We assessed whether PRS for systolic blood pressure (PRSSBP) and for low-density lipoprotein cholesterol (PRSLDL-C) were associated with achieving SBP and LDL-C-related targets, and with major adverse cardiovascular events (MACE: non-fatal stroke or myocardial infarction, CVD death, and revascularization procedures). Using observational data from the UK Biobank (UKB), we calculated PRSSBP and PRSLDL-C and constructed two sub-cohorts of unrelated adults of White British ancestry aged 40-69 years and with no history of CVD, who reported taking medications used in the treatment of hypertension or hypercholesterolaemia. Treatment effectiveness in achieving adequate risk factor control was ascertained using on-treatment blood pressure (BP) or LDL-C levels measured at enrolment (uncontrolled hypertension: BP ≥ 140/90 mmHg; uncontrolled hypercholesterolaemia: LDL-C ≥ 3 mmol/L). We conducted multivariable logistic and Cox regression modelling for incident events, adjusting for socioeconomic characteristics, and CVD risk factors. There were 55 439 participants using BP lowering therapies (51.0% male, mean age 61.0 years, median follow-up 11.5 years) and 33 787 using LDL-C lowering therapies (58.5% male, mean age 61.7 years, median follow-up 11.4 years). PRSSBP was associated with uncontrolled hypertension (odds ratio 1.70; 95% confidence interval: 1.60-1.80) top vs. bottom quintile, equivalent to a 5.4 mmHg difference in SBP, and with MACE [hazard ratio (HR) 1.13; 1.04-1.23]. PRSLDL-C was associated with uncontrolled hypercholesterolaemia (HR 2.78; 2.58-3.00) but was not associated with subsequent MACE. We extend previous findings in the UKB cohort to examine PRSSBP and PRSLDL-C with treatment effectiveness. Our results indicate that both PRSSBP and PRSLDL-C can help identify individuals who, despite being on treatment, have inadequately controlled SBP and LDL-C, and for SBP are at higher risk for CVD events. This extends the potential role of PRS in clinical practice from identifying patients who may need these interventions to identifying patients who may need more intensive intervention.


Does aspartic acid racemization constrain the depth limit of the subsurface biosphere?
Previous studies of the subsurface biosphere have deduced average cellular doubling times of hundreds to thousands of years based upon geochemical models. We have directly constrained the in situ average cellular protein turnover or doubling times for metabolically active micro-organisms based on cellular amino acid abundances, D/L values of cellular aspartic acid, and the in vivo aspartic acid racemization rate. Application of this method to planktonic microbial communities collected from deep fractures in South Africa yielded maximum cellular amino acid turnover times of ~89 years for 1 km depth and 27 °C and 1-2 years for 3 km depth and 54 °C. The latter turnover times are much shorter than previously estimated cellular turnover times based upon geochemical arguments. The aspartic acid racemization rate at higher temperatures yields cellular protein doubling times that are consistent with the survival times of hyperthermophilic strains and predicts that at temperatures of 85 °C, cells must replace proteins every couple of days to maintain enzymatic activity. Such a high maintenance requirement may be the principal limit on the abundance of living micro-organisms in the deep, hot subsurface biosphere, as well as a potential limit on their activity. The measurement of the D/L of aspartic acid in biological samples is a potentially powerful tool for deep, fractured continental and oceanic crustal settings where geochemical models of carbon turnover times are poorly constrained. Experimental observations on the racemization rates of aspartic acid in living thermophiles and hyperthermophiles could test this hypothesis. The development of corrections for cell wall peptides and spores will be required, however, to improve the accuracy of these estimates for environmental samples.


Polymeric capsule-cushioned leukocyte cell membrane vesicles as a biomimetic delivery platform.
We report a biomimetic delivery of microsized capsule-cushioned leukocyte membrane vesicles (CLMVs) through the conversion of freshly reassembled leukocyte membrane vesicles (LMVs), including membrane lipids and membrane-bound proteins onto the surface of layer-by-layer assembled polymeric multilayer microcapsules. The leukocyte membrane coating was verified by using electron microscopy, a quartz crystal microbalance, dynamic light scattering, and confocal laser scanning microscopy. The resulting CLMVs have the ability to effectively evade clearance by the immune system and thus prolong the circulation time in mice. Moreover, we also show that the right-side-out leukocyte membrane coating can distinctly improve the accumulation of capsules in tumor sites through the molecular recognition of membrane-bound proteins of CLMVs with those of tumor cells in vitro and in vivo. The natural cell membrane camouflaged polymeric multilayer capsules with the immunosuppressive and tumor-recognition functionalities of natural leukocytes provide a new biomimetic delivery platform for disease therapy.


Scaling-up malaria treatment: a review of the performance of different providers.
Despite great progress towards malaria control, the disease continues to be a major public health problem in many developing countries, especially for poor women and children in remote areas. Resistance to artemisinin combination therapy (ACT) emerged in East Asia. Its spread would threaten the only effective malaria treatment currently available. Improvement in availability of diagnosis as part of malaria control has highlighted the fact that many fevers are not due to malaria. These fevers also need to be promptly diagnosed and adequately treated in order to improve public health outcomes in developing countries. This review looked for evidence for the most effective approach to deliver malaria treatment in developing countries, by public sector, formal and informal private sector, and community health workers (CHWs). The authors analysed 31 studies to assess providers based on six parameters: knowledge and practice of provider, diagnosis, referral practices, price of medicine, availability of ACT, and treatment coverage and impact on morbidity and mortality. The public sector has made progress in prevention and treatment in many countries, but facilities are inaccessible to some communities, and the sector suffers shortages of health workers and stock-outs of medicines. Despite wide outreach, the private sector, especially informal facilities, presents public health risks. This is due to an inability to diagnose and treat non-malarial fevers, and an innate motive to over-prescribe malaria treatment. The need to pay for treatment is a major factor in deterring poor women and children from accessing the medicines they need. A system that depends on ability to pay risks a repeat of the chloroquine story, where an effective and cheap anti-malarial drug was rendered useless partly due to under-treatment. CHWs have proved to be effective agents in providing correct diagnosis and treatment of malaria and other common fevers, even in remote areas. The evidence shows that there is no short-cut to investing in training and supervision of providers, or in treating malaria within a public health context rather than as a separate disease. The studies highlighted that all outlets face challenges in delivering their services, but that CHWs scored highly in almost all parameters. CHWs have proved to be effective agents in providing correct diagnosis and treatment of malaria and other common fevers, even in remote areas. Their role should be recognized and expanded.


Fluorescence properties of tryptophan residues in the monomeric d-chain of Glossoscolex paulistus hemoglobin: an interpretation based on a comparative molecular model.
The primary structure of the 142 residue Glossoscolex paulistus d-chain hemoglobin has been determined from Edman degradation data of 11 endo-Glu-C peptides and 11 endo-Lys-C peptides, plus the results of Edman degradation of the intact globin. Tryptophan occupies positions 15, 33 and 129. Homology modeling allowed us to assign the positions of these Trp residues relative to the heme and its environment. The reference coordinates of the indole rings (average coordinates of the C(varepsilon2) and C(delta2) atoms) for W15 and W129 were 16.8 and 18.5 A, respectively, from the geometric center of the heme, and W33 was located in close proximity to the heme group at a distance which was approximately half of that for W15 and W129. It was possible to identify three rotamers of W33 on the basis of electrostatic and Van der Waals energy criteria. The calculated distances from the center of the heme were 8.3, 8.4 and 9.1 A for Rot1, Rot2 and Rot3, respectively. Radiationless energy transfer from the excited indole to the heme was calculated on the basis of Förster theory. For W33, the distance was more important than the orientation factor, kappa(2), due to its proximity to the heme. However, based on kappa(2), Rot2 (kappa(2)=0.945) was more favorable for the energy transfer than Rot1 (kappa(2)=0.433) or Rot3 (kappa(2)=0.125). In contrast, despite its greater distance from the heme, the kappa(2) of W129 (2.903) established it as a candidate to be more efficiently quenched by the heme than W15 (kappa(2)=0.191). Although the Förster approach is powerful for the evaluation of the relative efficiency of quenching, it can only explain pico- and sub-nanosecond lifetimes. With the average lifetime, <tau>=3 ns, measured for the apomonomer as the reference, the lifetimes calculated for each emitter were: W33-1 (1 ps), W33-2 (2 ps), W33-3 (18 ps), W129 (100 ps), and W15 (600 ps). Experimentally, there are four components for oxymonomers at pH 7: two long ones of 4.6 and 2.1 ns, which contribute approximately 90% of the total fluorescence, one of 300 ps (4%), and the last one of 33 ps (7.4%). It is clear that the equilibrium structure resulting from homology modeling explains the sub-nanosecond fluorescence lifetimes, while the nanosecond range lifetimes require more information about the protein in solution, since there is a significant contribution of lifetimes that resemble the apo molecule.


Effects of vaccination by a recombinant antigen ureB138 (a segment of the beta-subunit of urease) against Helicobacter pylori infection.
Helicobacter pylori has to counteract acidity during colonization in the stomach. The most important region for the enzymic activity of H. pylori urease, consisting of 138 aa (ureB138), was determined by a comparison of the homology of amino acid sequences, and a structural analysis, between urease of H. pylori and various other species. This region was expressed in Escherichia coli as a fusion protein with glutathione S-transferase (GST), which was cleaved by PreScission protease between the GST moiety and ureB138. The ureB138 protein was then purified by gel filtration. The polyclonal antibody (pAb) induced by immunization with the purified ureB138 could suppress urease activity by about 50 %, while the pAb against the H. pylori urease did not show any inhibitory effect at all. Immunohistochemical analysis indicated that the ureB138-specific pAb specifically recognized the H. pylori infecting human gastric tissues. The effects of vaccination of recombinant ureB138 against infection by this organism were also examined. Specific IgG and IgA antibodies against H. pylori urease were induced in the serum of mice immunized with ureB138. A reduction in the number of colonizing H. pylori was observed in mice treated with ureB138 compared to ones treated with BSA and infection control mice. In the protected mice, severe gastritis characterized by marked infiltration of mononuclear cells was noted compared with the gastritis observed in unprotected mice. Immunohistochemical staining for IgA in gastric mucosa showed that the number of mice positively stained with IgA was significantly higher in ureB138-vaccinated mice than in non-vaccinated mice. This indicates that local IgA antibody and severe post-immunization gastritis correlate well with the protection of mice against H. pylori infection.


Modelling the effects of dispersal mechanisms and hydrodynamic regimes upon the structure of microbial communities within fluvial biofilms.
The spatial distribution of microbial taxa is determined primarily by physical and chemical environments and by dispersal. In a homogeneous landscape with limited dispersal, the similarity in abundance of taxa in samples declines with separation distance. We present a one-dimensional model for the spatial autocorrelation in abundances arising from immigration from some remote community and dispersal between environmentally similar landscape patches. Spatial correlation in taxa abundances were calculated from biofilms from the beds of two flumes which differed only in their bedform profiles; one flat and the other a periodic sawtooth shape. The hydraulic regime is approximately uniform over the flat bed, whereas the sawtooth induces fast flow over the peaks and recirculation in the troughs. On the flat bed, the correlation decline between samples was reproduced by a model using one biologically reasonable parameter. A decline was apparent in the other flume; however, a better fit was achieved when dispersal was not assumed constant everywhere. However, analysis of finer-resolution data for the heterogeneous flume suggested even this model did not adequately capture the community's complexity. We conclude that hydrodynamics are a strong driver of taxa-abundance patterns in stream biofilms. However, local adaptability must also be considered to build up a complete mechanistic model.


An electron-spin-resonance spin-label study of the interaction of purified Mojave toxin with synaptosomal membranes from rat brain.
The structural properties of isolated purified rat brain synaptosomal membranes, both in the presence and absence of purified active toxin of the Mojave snake Crotalus scutulatus scutulatus, were studied by spin-label electron spin resonance techniques. The spectra from eight different positional isomers of nitroxide-labelled stearic acids, a rigid steroid androstanol, and a spin-labelled phosphatidylcholine intercalated into the synaptosomal membranes, were obtained as a function of temperature from 4-40 degrees C. The flexibility gradient (from spin-label order parameters) and polarity profile (from isotropic splitting factors) across the synaptosomal membranes, was characteristic for lipid bilayers. The nitroxide spin-labelled steroid, androstanol, intercalated into the synaptosomal membrane, revealed the abrupt onset of rapid cooperative rotation about the long axis of the molecule at 12 degrees C showing that the lipid molecules are rotating rapidly around their long axes at physiological temperatures. The presence of the Mojave toxin affected the synaptosomal membrane in a complex manner, depending upon the temperature and the position of the nitroxide label on the alkyl chain of the stearic acid probe. Mojave toxin exerted little effect on the flexibility gradient of the synaptosomal membrane at 20 degrees C, a temperature at which the acyl chain labels detected a structural change in the membranes. At temperatures lower than 20 degrees C, the Mojave toxin produced a change in the flexibility gradient of the synaptosomal membrane which indicated an increased disordering in the upper region of the membrane and a concomitant increased ordering of the acyl chains in the deeper regions of the membrane. At temperatures higher than 20 degrees C, the order profile of the synaptosomal membrane was shifted by the presence of the Mojave toxin in a manner which indicated that the outer parts of the membrane were more rigid and the inner regions more fluid, than in controls. A cross-over point for the perturbation occurred at C8-9, which is about 12-14 A into the membrane. This is the approximate depth of the hydrophobic pocket shown in pancreatic phospholipase A2 [Drenth et al. (1976) Nature (Lond.) 264, 373-377], a protein likely to be homologous to the basic subunit of the toxin. At all temperatures, rotational lipid motion was inhibited by the toxin as indicated by the steroid probe. The electron spin-resonance spin-label results are interpreted in terms of the partial penetration of the basic subunit of the intact toxin into the membrane, disordering the ordered chains at low temperature and ordering the disordered chains at physiological temperatures. The purified individual toxin subunits did not perturb the membrane lipids at physiological temperatures implying that both subunits must be associated for activity of the toxin which is confirmed by toxicity studies.


Frustrated ferroelectricity in niobate pyrochlores.
The crystal structures of the A(2)B(2)O(7-x) niobium based pyrochlores Y(2)(Nb(0.86)Y(0.14))(2)O(6.91), CaYNb(2)O(7), and Y(2)NbTiO(7) are reported, determined by means of powder neutron diffraction. These compounds represent the first observation of B-site displacements in the pyrochlore structure: the B-site ions are found to be displaced from the ideal pyrochlore positions, creating electric dipoles. The orientations of these dipoles are fully analogous to orientations of the magnetic moments in Ising spin based magnetically frustrated pyrochlores. Diffuse scattering in electron diffraction patterns shows that the displacements are only short range ordered, indicative of geometric frustration of the collective dielectric state of the materials. Comparison to the crystal structure of the Nb(5+) (d(0)) pyrochlore La(2)ScNbO(7) supports the prediction that charge singlets, driven by the tendency of Nb to form metal-metal bonds, are present in these pyrochlores. The observed lack of long range order to these singlets suggests that Nb(4+) based pyrochlores represent the dielectric analogy to the geometric frustration of magnetic moments observed in rare earth pyrochlores.


Aboriginal premature mortality within South Australia 1999-2006: a cross-sectional analysis of small area results.
This paper initially describes premature mortality by Aboriginality in South Australia during 1999 to 2006. It then examines how these outcomes vary across area level socio-economic disadvantage and geographic remoteness. The retrospective, cross-sectional analysis uses estimated resident population by sex, age and small areas based on the 2006 Census, and Unit Record mortality data. Premature mortality outcomes are measured using years of life lost (YLL). Subsequent intrastate comparisons are based on indirect sex and age adjusted YLL results. A multivariate model uses area level socio-economic disadvantage rank, geographic remoteness, and an interaction between the two variables to predict premature mortality outcomes. Aboriginal people experienced 1.1% of total deaths but 2.2% of YLL and Aboriginal premature mortality rates were 2.65 times greater than the South Australian average. Premature mortality for Aboriginal and non-Aboriginal people increased significantly as area disadvantage increased. Among Aboriginal people though, a significant main effect for area remoteness was also observed, together with an interaction between disadvantage and remoteness. The synergistic effect shows the social gradient between area disadvantage and premature mortality increased as remoteness increased. While confirming the gap in premature mortality rates between Aboriginal South Australians and the rest of the community, the study also found a heterogeneity of outcomes within the Aboriginal community underlie this difference. The results support the existence of relationship between area level socio-economic deprivation, remoteness and premature mortality in the midst of an affluent society. The study concludes that vertically equitable resourcing according to population need is an important response to the stark mortality gap and its exacerbation by area socio-economic position and remoteness.


Ovarian cancer incidence and mortality in American Indian, Hispanic, and non-Hispanic white women in New Mexico.
Although ethnic and racial differences in ovarian cancer incidence and mortality have been reported worldwide, few published data have addressed the epidemiology of ovarian cancer among U.S. American Indians and Hispanics. We reviewed ovarian cancer incidence and survival data from New Mexico's population-based cancer registry collected from 1969 to 1992, and examined state vital records data for ovarian cancer deaths collected from 1958 to 1992, focusing on ethnic differences in occurrence and outcomes of ovarian malignancies. Non-Hispanic white women had age-adjusted incidence rates that were slightly higher (13.3/100,000) than rates for American Indians (11.4) and Hispanics (10.7) over the 24-year period. Ovarian cancer mortality rates were also higher for non-Hispanic whites than for minority women. Neither incidence rates nor mortality rates for ovarian cancer improved over the span of the study period. In addition, the stage at diagnosis did not shift substantially over time for any of the ethnic groups studied, nor did the distribution of various histopathological types shift proportionately. Only slight improvement was observed in 5-year survival over the time period of the study, with greater gains among younger (50 years old or less) versus older women. Ethnic differences in ovarian cancer incidence and mortality were apparent in our population-based data. However, our analysis indicated no reduction in ovarian cancer incidence or mortality in our state over the past quarter century and only slight improvement in 5-year survival.


Fluorescence lifetime endoscopy using TCSPC for the measurement of FRET in live cells.
Development of remote imaging for diagnostic purposes has progressed dramatically since endoscopy began in the 1960's. The recent advent of a clinically licensed intensity-based fluorescence micro-endoscopic instrument has offered the prospect of real-time cellular resolution imaging. However, interrogating protein-protein interactions deep inside living tissue requires precise fluorescence lifetime measurements to derive the Förster resonance energy transfer between two tagged fluorescent markers. We developed a new instrument combining remote fiber endoscopic cellular-resolution imaging with TCSPC-FLIM technology to interrogate and discriminate mixed fluorochrome labeled beads and expressible GFP/TagRFP tags within live cells. Endoscopic-FLIM (e-FLIM) data was validated by comparison with data acquired via conventional FLIM and e-FLIM was found to be accurate for both bright bead and dim live cell samples. The fiber based micro-endoscope allowed remote imaging of 4 microm and 10 microm beads within a thick Matrigel matrix with confident fluorophore discrimination using lifetime information. More importantly, this new technique enabled us to reliably measure protein-protein interactions in live cells embedded in a 3D matrix, as demonstrated by the dimerization of the fluorescent protein-tagged membrane receptor CXCR4. This cell-based application successfully demonstrated the suitability and great potential of this new technique for in vivo pre-clinical biomedical and possibly human clinical applications.


Stability of vitamins A, C, and E, carotenoids, lipids, and testosterone in whole blood stored at 4 degrees C for 6 and 24 hours before separation of serum and plasma.
To investigate whether overnight storage causes significant changes in whole blood, we measured serum and plasma concentrations of vitamins A, C, and E, carotenoids, lipids, and testosterone in whole blood samples stored in a refrigerator at 4 degrees C for 6 and 24 h before centrifugation, aliquoting and freezing them at -70 degrees C or below. In comparison with baseline samples prepared within 2 h, the mean percentage changes at 24 h were: -3.0% to +1.0% for retinol, alpha-tocopherol, and gamma-tocopherol in plasma; -8.7% to -0.1% for carotenoids in plasma; -7.2% for vitamin C in plasma and -1.8% for vitamin C in serum; -2.7% to +2.4% for lipids in serum; and +0.4% to +6.2% for testosterone in serum and plasma from men and women. Spearman's rank correlation coefficients between measurements made in the baseline samples and those made after storage for 24 h were greater than 0.9 for 11 analytes, between 0.8 and 0.9 for 7 analytes, and less than 0.8 for only 1 analyte (vitamin C in serum). The ratio of between-subject to within-subject coefficients of variation was greater than 3.0 for all analytes except lutein (ratio, 1.6), alpha-cryptoxanthin (ratio, 2.4) and vitamin C (ratio in serum, 3.0; ratio in plasma, 2.2). We conclude that storage of whole blood at 4 degrees C for 24 h before freezing does not cause important changes in the analytes studied and that this delay in processing may be incorporated in the design of large prospective studies.


Empirical measures of harbor seal behavior and avoidance of an operational tidal turbine.
There is global interest in marine renewable energy from underwater tidal turbines. Due to overlap in animal habitat with locations for tidal turbines, the potential for collisions has led to concern around strike risk. Using data from tagged harbor seals collected before construction and after operation of the SeaGen tidal turbine in Northern Ireland, this study quantifies risks of an operational turbine to harbor seals by taking into account turbine characteristics, tidal state, and seal behavior. We found 68% spatial avoidance (95% C.I., 37%, 83%) by harbor seals within 200 m of the turbine. When additionally accounting for variation in seal occupancy over depth and tidal flows, there is an overall reduction in collision risk from 1.29 to 0.125 seals per tidal cycle (90.3% reduction; (95% C.I., 83%, 98%)) compared to risk calculated under assumptions of uniform habitat use. This demonstrates the need to incorporate environmental conditions to properly assess strike risk.


Quantifying the impacts of stratification and nutrient loading on hypoxia in the northern Gulf of Mexico.
Stratification and nutrient loading are two primary factors leading to hypoxia in coastal systems. However, where these factors are temporally correlated, it can be difficult to isolate and quantify their individual impacts. This study provides a novel solution to this problem by determining the effect of stratification based on its spatial relationship with bottom-water dissolved oxygen (BWDO) concentration using a geostatistical regression. Ten years (1998-2007) of midsummer Gulf of Mexico BWDO measurements are modeled using stratification metrics along with trends based on spatial coordinates and bathymetry, which together explain 27-61% of the spatial variability in BWDO for individual years. Because stratification effects explain only a portion of the year-to-year variability in mean BWDO; the remaining variability is explained by other factors, with May nitrate plus nitrite river concentration the most important. Overall, 82% of the year-to-year variability in mean BWDO is explained. The results suggest that while both stratification and nutrients play important roles in determining the annual extent of midsummer hypoxia, reducing nutrient inputs alone will substantially reduce the average extent.


Multisensory brand search: How the meaning of sounds guides consumers' visual attention.
Building on models of crossmodal attention, the present research proposes that brand search is inherently multisensory, in that the consumers' visual search for a specific brand can be facilitated by semantically related stimuli that are presented in another sensory modality. A series of 5 experiments demonstrates that the presentation of spatially nonpredictive auditory stimuli associated with products (e.g., usage sounds or product-related jingles) can crossmodally facilitate consumers' visual search for, and selection of, products. Eye-tracking data (Experiment 2) revealed that the crossmodal effect of auditory cues on visual search manifested itself not only in RTs, but also in the earliest stages of visual attentional processing, thus suggesting that the semantic information embedded within sounds can modulate the perceptual saliency of the target products' visual representations. Crossmodal facilitation was even observed for newly learnt associations between unfamiliar brands and sonic logos, implicating multisensory short-term learning in establishing audiovisual semantic associations. The facilitation effect was stronger when searching complex rather than simple visual displays, thus suggesting a modulatory role of perceptual load. (PsycINFO Database Record


A cDNA encoding Tc-MUC-5, a mucin from Toxocara canis larvae identified by expression screening.
Toxocara canis is an ascarid nematode parasite of canids. Larvae infect a wide range of accidental hosts including humans, in whom they are the aetiologic agent of visceral and ocular Larva migrans. The labile surface coat of T. canis larvae consists of a family of mucin glycoproteins termed TES-120, for which the cDNAs have recently been cloned. In this paper, we describe the identification of a novel cDNA (Tc-muc-5) encoding an apomucin by expression screening of a cDNA library with antiserum raised to T. canis excretory/secretory products, and compare the predicted Tc-MUC-5 protein with those of other T. canis mucins (Tc-MUC-1-Tc-MUC-4) that include the TES-120 surface coat glycoproteins. Tc-MUC-5 has both a larger open reading frame and a more divergent sequence than the other T. canis mucins. It contains a putative signal peptide followed by two six-cysteine (SXC) domains, an extended threonine-rich central mucin core domain and two C-terminal SXC domains. Amino acid composition analysis of secreted TES-120 glycoproteins revealed a distinct lack of lysine residues; while this finding is in agreement with the primary sequences of Tc-MUC-1-Tc-MUC-4, Tc-MUC-5 is conspicuous by its relative abundance of lysines (6.7%), suggesting that this protein is not part of the TES-120 family of surface coat proteins.


Occluding junction structure-function relationships in a cultured epithelial monolayer.
Electrical circuit analysis was used to study the structural development of occluding junctions (OJs) in cultured monolayers composed to T84 cells. The magnitude of the increments in transepithelial resistance predicted by such analysis was compared with the magnitude of the measured increments in resistance. Confluent sheets of epithelial cells were formed after cells were plated at high density on collagen-coated filters. Using Claude's OJ strand count-resistance hypothesis (1978, J. Membr. Biol. 39:219-232), electrical circuit analysis of histograms describing OJ strand count distribution at different time points after plating predicted that junctional resistance should rise in a proportion of 1:21:50 from 18 h to 2 d to 5 d. This reasonably paralleled the degree of rise in transepithelial resistance over this period, which was 1:29:59. The ability to predict the observed resistance rise was eliminated if only mean strand counts were analyzed or if electrical circuit analysis of OJ strand counts were performed using an OJ strand count-resistance relationship substantially different from that proposed by Claude. Measurements of unidirectional fluxes of inulin, mannitol, and sodium indicated that restriction of transjunctional permeability accounted for the observed resistance rise, and that T84 junctional strands have finite permeability to molecules with radii less than or equal to 3.6 A but are essentially impermeable to molecules with radii greater than or equal to 15 A. The results suggest that general correlates between OJ structure and OJ ability to resist passive ion flow do exist in T84 monolayers. The study also suggests that such correlates can be obtained only if OJ structural data are analyzed as an electrical circuit composed of parallel resistors.


A Dual-Process Examination of Alcohol-Related Consequences Among First-Year College Students.
Despite showing reductions in college student drinking, interventions have shown some inconsistency in their ability to successfully decrease consequences. With the goal of improving prevention efforts, the purpose of this study was to examine the role of consequence-specific constructs, in addition to drinking, that influence students' experiences with alcohol-related problems. The study examined how drinking and protective behaviors mediated the relationships between students' willingness to experience consequences, intentions to avoid them, and four categories of alcohol-related problems (physiological, social, sexual, and academic). First-year college student drinkers (n = 2,024) at a large northeastern university completed surveys during the fall and spring of their freshman year. As expected, different patterns of associations emerged for physiological and nonphysiological consequences. When physiological consequences (e.g., hangover, vomiting) were examined, drinking significantly mediated the effect of willingness on the consequences. Drinking-specific protective behaviors indirectly influenced consequences through drinking behaviors whereas general protective behaviors did not. When nonphysiological (e.g., social, sexual, academic) consequences were examined, drinking and general protective behaviors emerged as significant mediators of the effects of willingness and intentions on the consequences, whereas drinking-specific protective behaviors did not. The results suggest that prevention efforts (e.g., personalized feedback) could be tailored to address specific types of protective behaviors as well as specific types of consequences frequently experienced by college students.


A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results.
In US cervical screening, immediate colposcopy is recommended for women with HPV-positive ASC-US (equivocal) cytology. We evaluated whether partial typing by Onclarity™ (BD) might identify HPV-positive women with low enough CIN3+ risk to permit 1-year follow-up instead. The NCI-Kaiser Permanente Northern California Persistence and Progression cohort includes a subset of 13,890 women aged 21+ with HC2 (Qiagen)-positive ASC-US at enrollment; current median follow-up is 3.0years. Using stratified random sampling, we typed 2079 archived enrollment specimens including 329 women subsequently diagnosed with CIN3+, 563 with CIN2, and 1187 with <CIN2. Adjusting for sampling, we computed 3-year cumulative CIN3+ risks for each Onclarity typing channel, using Kaplan-Meier methods. The 3-year CIN3+ risk for all HC2-positive women with ASC-US was 5.2%; this establishes the "benchmark" risk for colposcopic referral. Hierarchically, 3-year cumulative risks for each typing channel were 16.0% for HPV16, 7.4% for HPV18, 7.0% for HPV31, 7.1% for grouped HPV33/58, 4.3% for HPV52, 3.9% for HPV45, 2.7% for HPV51, 1.6% for HPV39/68/35, and 1.3% for HPV59/56/66. ASC-US linked to HPV16, HPV18, HPV31, or HPV33/58 warrants immediate colposcopy. Optimal management of women with HPV52 or HPV45 is uncertain. Risk of women with only HPV51, HPV39/68/35, or HPV59/56/66 might be low enough to recommend 1-year retesting permitting viral clearance. This strategy would defer colposcopy for 40% of women with HPV-positive ASC-US, half of whom would be cotest-negative at 1-year return. Approximately 10% of those with CIN3 diagnosable at enrollment would be delayed 1year instead. Cost-effectiveness analyses are needed.


"Electronic Cigarettes" Are Not Cigarettes, and Why That Matters.
As the prevalence rates of cigarette use have declined over the past decade, use of electronic cigarettes (e-cigarettes) continues to increase, and companies are heavily invested in manufacturing new e-cigarette products. Scientists are therefore studying e-cigarette use at a rapid rate, generally by conceptualizing e-cigarettes as similar to traditional cigarettes in their use and effects. Thinking of e-cigarettes as largely comparable with cigarettes, however, fails to capture the unique e-cigarette capabilities, user experiences, and effects on nicotine dependence and even health. Assuming that e-cigarette users puff on their devices as they do cigarettes to attain doses of nicotine comparable in magnitude and asking questions about e-cigarette use modeled after how smoking behavior has been usually assessed (eg, puff number, duration, number of cigarettes per day) may miss important differences. A greater appreciation of the distinct uniqueness of e-cigarettes, as compared with cigarettes, will help to accelerate innovative research on e-cigarettes and other electronic devices, leading to new theoretical models and behavioral measures. With research about electronic cigarettes (e-cigarettes) rapidly increasing, this commentary addresses the conceptualization of e-cigarettes as similar to traditional cigarettes. The more we attempt to understand and measure e-cigarettes as equivalent to cigarettes, the more likely research may err in conclusions about these unique devices. Our commentary notes how using unique conceptualizations and measures for e-cigarettes will help accelerate new research.


Community Primary Care Diabetes Pathway.
IN BRIEF "Quality Improvement Success Stories" are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc., and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an initiative to provide more intensive diabetes care and support in a primary care setting and thereby improve patients' glycemic, blood pressure, and lipid control, as well as BMI and psychosocial well-being.


A genetically encoded multifunctional TRAIL trimer facilitates cell-specific targeting and tumor cell killing.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L) has been shown to exhibit potent and specific apoptotic activity against tumor cells. Several TRAIL constructs have been tried in patients, and the molecule remains under active clinical investigation. Native and recombinant TRAIL must form a homotrimer to become biologically active. However, noncovalently associated TRAIL displays a high degree of sensitivity to degradation, which limits its therapeutic potential. To enforce trimerization of the recombinant protein, we developed a covalently linked TRAIL trimer (TR3) by genetic fusion. This molecular drug design conferred improved stability without altering the native killing ability of TRAIL. Target specificity was shown by blocking TR3 activity with soluble death receptor 5 (DR5-Fc). In addition, we have shown that TR3 is amenable to further, genetic modifications. The incorporation of additional functional domains to TR3, such as antibody fragments (scFvs) that allow for a more cell-specific delivery of the agent, is stoichiometrically controlled and inconsequential with regard to the bioactivity of TRAIL. As proof of this concept, TR3 activity was targeted to the mouse RBC membrane. TR3-decorated RBCs were effectively capable of target cell killing in a model of pancreatic cancer. TR3 represents a generally applicable platform tool to study basic mechanisms along the death receptor pathway. More importantly, the ability to target TR3 to a cell surface presents the opportunity to create a cancer-selective drug with fewer off-target toxicities and enhanced killing capacities.


Sexual desire in women presenting for antiandrogen therapy.
Women presenting with hirsuties/polycystic ovary syndrome have increased production of androgens. Clinical lore suggests that these women may have increased sexual desire. Treatment of hirsuties commonly involves antiandrogen therapy, a form of therapy with a potential for reducing sexual desire. The present study investigated sexual desire in 29 hirsute women aged 19 to 43 years presenting for therapy. We conducted a questionnaire appraisal of the women's sexual desire, body and self-esteem, and affect at baseline, 3 months, and 12 months and compared the data with a control group of 30 nonhirsute women of similar mean age. Those in the treatment group also had their Ferriman and Gallwey scores and body mass indices calculated at baseline and end of study for those in the treatment group. We determined hormone levels for those in the treatment group with baseline blood tests. Our hypotheses were that the hirsute women would experience different levels of sexual desire than the control group prior to therapy and that therapy would have a demonstrable effect on the self-reported sexual desire of these women. The study demonstrated that women with hirsuties had mean levels of sexual desire and body esteem that were significantly lower than the control group women. During the year-long course of therapy, the sexual desire levels of the hirsute women decreased progressively, while their self-esteem increased. The women's Ferriman and Gallwey scores fell, indicating diminishing hirsutism. These findings provide empirical data upon which clinicians can base advice to patients seeking therapy.


The Rpe65 rd12 allele exerts a semidominant negative effect on vision in mice.
The rd12 mouse was reported as a recessively inherited Rpe65 mutation. We asked if the rd12 mutation resides in Rpe65 and how the mutation manifests itself. A complementation test was performed by mating Rpe65(KO) (KO/KO) and rd12 mice together to determine if the rd12 mutation is in the Rpe65 gene. Visual function of wild-type (+/+), KO/+, rd12/+, KO/KO, rd12/rd12, and KO/rd12 mice was measured by optokinetic tracking (OKT) and ERG. Morphology was assessed by retinal cross section. qRT-PCR quantified Rpe65 mRNA levels. Immunoblotting measured the size and level of RPE65 protein. Rpe65 mRNA localization was visualized with RNA fluorescence in situ hybridization (FISH). Fractions of Rpe65 mRNA-bound proteins were separated by linear sucrose gradient fractionation. The KO and rd12 alleles did not complement. The rd12 allele induced a negative semidominant effect on visual function; OKT responses became undetectable 120 days earlier in rd12/rd12 mice compared with KO/KO mice. rd12/+ mice lost approximately 21% visual acuity by P210. rd12/rd12 mice had fewer cone photoreceptor nuclei than KO/KO mice at P60. rd12/rd12 mice expressed 71% +/+ levels of Rpe65 mRNA, but protein was undetectable. Mutant mRNA was appropriately spliced, exported to the cytoplasm, trafficked, and contained no other coding mutation aside from the known nonsense mutation. Mutant mRNA was enriched on ribosome-free messenger ribonucleoproteins (mRNPs), whereas wild-type mRNA was enriched on actively translating polyribosomes. The rd12 lesion is in Rpe65. The rd12 mutant phenotype inherits in a semidominant manner. The effects of the mutant mRNA on visual function may result from inefficient binding to ribosomes for translation.


A Process Model of Causal Reasoning.
How do we make causal judgments? Many studies have demonstrated that people are capable causal reasoners, achieving success on tasks from reasoning to categorization to interventions. However, less is known about the mental processes used to achieve such sophisticated judgments. We propose a new process model-the mutation sampler-that models causal judgments as based on a sample of possible states of the causal system generated using the Metropolis-Hastings sampling algorithm. Across a diverse array of tasks and conditions encompassing over 1,700 participants, we found that our model provided a consistently closer fit to participant judgments than standard causal graphical models. In particular, we found that the biases introduced by mutation sampling accounted for people's consistent, predictable errors that the normative model by definition could not. Moreover, using a novel experimental methodology, we found that those biases appeared in the samples that participants explicitly judged to be representative of a causal system. We conclude by advocating sampling methods as plausible process-level accounts of the computations specified by the causal graphical model framework and highlight opportunities for future research to identify not just what reasoners compute when drawing causal inferences, but also how they compute it.


An uncommon procedure for a rare ailment: massive bronchoalveolar lavage in a patient with pulmonary alveolar proteinosis.
As a rare procedure, massive bronchoalveolar lavage (MBAL) is a large-volume lavage which necessitates general anesthesia and one-lung ventilation (OLV). During MBAL isotonic saline is instilled into one lung and drained through one lumen of a double-lumen tube. MBAL is the most effective treatment for symptomatic pulmonary alveolar proteinosis (PAP). A 27-year-old male with PAP was scheduled for therapeutic MBALs. After standard preoxygenation, monitoring and anesthesia induction, a double-lumen tube was placed. Tube position was verified by a fiberoptic bronchoscope. The internal jugular vein, radial and pulmonary arteries were cannulated. A temperature probe and foley catheter were inserted. The nonventilated lung was filled with 1000 mL saline and then drained in each session. The left and right lung were lavaged with an interval of 2 weeks. A total of 20 L saline was used in each MBAL without retention. MBALs were terminated after the effluent became clear. Duration of the left and right MBALs were 325 and 275 minutes, respectively. Despite increased shunt fraction, oxygenation was within acceptable limits during OLV. The trachea was extubated in the operating room uneventfully after each MBAL. The patient's clinical and laboratory findings were evidently improved. Consequently, if proper conditions are provided, MBAL is safe and beneficial despite its risks and the long duration.


Traveling Across Time Zones With Type 1 Diabetes: A Pilot Study Comparing Insulin Degludec With Insulin Glargine U100.
For people with type 1 diabetes, there are limited evidence-based resources to support self-management when traveling across multiple time zones. Here, we compared glycemic control on insulin degludec versus glargine U100 as the basal insulin for adults using multiple daily injections (MDI) while traveling across multiple time zones. This randomized crossover pilot study compared insulin degludec versus glargine U100 for adults with type 1 diabetes using MDI insulin during long-haul travel to and from Hawaii to New York. Insulin degludec was administered daily at the same time regardless of time zone, and glargine was administered per travel algorithm. Primary end point was the percentage of time in range (TIR) between 70 and 140 mg/dL during the initial 24 h after each direction of travel. Secondary end points included standard continuous glucose monitoring metrics, jet lag, fatigue, and sleep. The study enrolled 25 participants (56% women, mean ± SD age of 35 ± 14.5 years, HbA1c of 7.4 ± 1.2% [57 ± 13.1 mmol/mol], and diabetes duration of 20.6 ± 15 years). There was no significant difference in glycemic outcomes between the two arms of the study, including TIR, hypoglycemia, or hyperglycemia. Neither group achieved >70% TIR 70-180 mg/dL during travel. Jet lag was greater on glargine U100 in eastward travel but not westward. Fatigue was greater after westward travel on glargine. Sleep was not significantly different between basal insulins. In adults with type 1 diabetes using MDI of insulin and traveling across multiple time zones, glycemic outcomes were similar comparing insulin degludec and glargine U100.


Deuterium-Depleted Water as Adjuvant Therapeutic Agent for Treatment of Diet-Induced Obesity in Rats.
In this study, we present the potential application of deuterium-depleted water (DDW) for the prevention and adjuvant treatment of obesity in rats. We tested the hypothesis that DDW can alleviate diet-induced obesity (DIO) and its associated metabolic impairments. Rats fed a high-fat diet had an increased body weight index (BWI), glucose concentration, and level of certain proinflammatory cytokines; decreased levels of insulin in the serum; decreased tryptophan and serotonin in the brain, and a decreased concentration of some heavy metals in the liver. Drinking DDW at a concentration of 10 ppm deuterium/protium (D/H) ad libitum for 3 weeks restored the BWI, glucose (serum), tryptophan (brain), and serotonin (brain) levels and concentration of Zn in the liver in the DIO animals to those of the controls. The levels of proinflammatory cytokines (IL-1β, IL-6, IFNγ) and anti-inflammatory TNFα were decreased in DIO rats, while anti-inflammatory cytokine (IL-4, IL-10) levels remained at the control levels, which is indicative of a pathophysiological syndrome. In contrast, in groups of rats treated with DDW, a significant increase in anti-inflammatory (IL-4, IL-10) and proinflammatory cytokines (IFNγ) was observed. This finding indicates a reduction in systemic inflammation in obese animals treated with DDW. Similarly, the high-fat diet caused an increased level of oxidative stress products, which was accompanied by decreased activity of both superoxide dismutase and catalase, whereas the administration of DDW decreased the level of oxidative stress and enhanced antioxidant enzyme activities.


Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes.
Mice deficient in various mismatch repair (MMR) enzymes were examined to determine whether this repair pathway is involved in antibody class switch recombination. Splenic B cells from mice deficient in Msh2, Mlh1, Pms2, or Mlh1 and Pms2 were stimulated in culture with lipopolysaccharide (LPS) to induce immunoglobulin (Ig)G2b and IgG3, LPS and interleukin (IL)-4 to induce IgG1, or LPS, anti-delta-dextran, IL-4, IL-5, and transforming growth factor (TGF)-beta1 to induce IgA. After 4 d in culture, cells were surface stained for IgM and non-IgM isotypes and analyzed by FACS((R)). B cells from MMR-deficient mice show a 35-75% reduction in isotype switching, depending on the isotype and on the particular MMR enzyme missing. IgG2b is the most affected, reduced by 75% in Mlh1-deficient animals. The switching defect is not due to a lack of maturation of the B cells, as purified IgM(+)IgD(+) B cells show the same reduction. MMR deficiency had no effect on cell proliferation, viability, or apoptosis, as detected by [(3)H]thymidine incorporation and by propidium iodide staining. The reduction in isotype switching was demonstrated to be at the level of DNA recombination by digestion-circularization polymerase chain reaction (DC-PCR). A model of the potential role for MMR enzymes in class switch recombination is presented.


A new species of salamander of the genus Hynobius (Amphibia, Caudata, Hynobiidae) from South Korea.
We describe a new species of lentic-breeding Hynobius salamander from the Naro Islands, near the village of Bongrae-myeon, Goheung-gun, Jeollanam-do, South Korea, on the basis of results of morphological, ecological and genetic analyses. Hynobius unisacculus sp. nov. is distinguished from its congeners by a combination of the following morphological attributes: (1) comparatively small size (adult SVL up to 61 mm; range 38.3-60.3 mm in males and 37.5-59.9 mm in females); (2) relatively slender short limbs; tips of fore- and hindlimbs adpressed on body never meeting, but separated by a large gap (gap of -3.0 to -1.5 costal folds in males and -3.5 to -1.5 in females); (3) comparatively short tail (TL/SVL ratio in adult males varying from 0.54-0.98, in adult females from 0.55 to 0.89), tail flattened and with a low dorsal fin extending to the posterior one-third of tail length; (4) usually 11 (occasionally 12) costal grooves; (5) in adults, dark brown dorsum with indistinct bronze or dark copper spots, lighter greyish-white or pinkish belly; (6) well developed fifth toe; (7) comparatively shallow vomerine tooth series with 13-23 vomerine teeth; (8) small, pigmented ova, located in one, occasionally two, strings in a small, curved egg sac with folded envelope, lacking distinct mucous stalks or whiptail-like structures on both ends. The molecular differentiation among Korean Hynobius is high; Hynobius unisacculus sp. nov. is genetically highly divergent from the morphologically similar H. leechii, H. yangi and H. quelpaertensis: pairwise distances are 9.7%, 9.1% and 8.0% of sequence divergence at the COI mtDNA gene respectively, and 10.9%, 10.9% and 9.4% of sequence divergence at the cyt b mtDNA gene, respectively. At present, the new species is known from coastal areas and offshore islands in southeastern part of Jeollanam-do in South Korea. We suggest the species should be considered as Vulnerable (Vu2a) in accordance with IUCN's Red List categories. Our study supports the presence of undiagnosed taxonomic diversity among Korean Hynobius.


Caffeine release and absorption from caffeinated gums.
The objectives of this study were to estimate the impact of chewing time on caffeine release from gum and to understand caffeine pharmacokinetics. Caffeine release increased with chewing time (2 min < 5 min < 10 min). Furthermore, two plasma caffeine concentration peaks were observed suggesting that caffeine absorption occurs both through the oral mucosa and gastrointestinal tract. This is of practical relevance to maximise caffeine doses and to synchronise effort with peak caffeine concentration.


Post-conception heat exposure increases clinically unobserved pregnancy losses.
Evidence of the relationship between temperature during pregnancy and human embryo mortality is limited. Most importantly, the literature lacks causal estimations and studies on early pregnancy losses. Here, we estimate the impact of early pregnancy temperature exposure on the clinically unobserved pregnancy loss rate. We use administrative data of clinically observed pregnancies from more than three decades for Hungary. We apply an empirical approach that allows us to infer the impact of temperature on the clinically unobserved pregnancy loss rate from the estimated effects on the clinically observed conception rate. The results show that exposure to hot temperatures during the first few weeks after the conception week increases the clinically unobserved pregnancy loss rate, whereas exposure to colder temperatures seems to decrease it. Importantly, the temperature-induced changes represent changes in the total number of pregnancy losses rather than a compositional change between clinically observed and clinically unobserved pregnancy losses.


Expression of target and reference genes in Daphnia magna exposed to ibuprofen.
Transcriptomic techniques are now being applied in ecotoxicology and toxicology to measure the impact of stressors and develop understanding of mechanisms of toxicity. Microarray technology in particular offers the potential to measure thousands of gene responses simultaneously. However, it is important that microarrays responses should be validated, at least initially, using real-time quantitative polymerase chain reaction (QPCR). The accurate measurement of target gene expression requires normalisation to an invariant internal control e.g., total RNA or reference genes. Reference genes are preferable, as they control for variation inherent in the cDNA synthesis and PCR. However, reference gene expression can vary between tissues and experimental conditions, which makes it crucial to validate them prior to application. We evaluated 10 candidate reference genes for QPCR in Daphnia magna following a 24 h exposure to the non-steroidal anti-inflammatory drug (NSAID) ibuprofen (IB) at 0, 20, 40 and 80 mg IB l-1. Six of the 10 candidates appeared suitable for use as reference genes. As a robust approach, we used a combination normalisation factor (NF), calculated using the geNorm application, based on the geometric mean of three selected reference genes: glyceraldehyde-3-phosphate dehydrogenase, ubiquitin conjugating enzyme and actin. The effects of normalisation are illustrated using as target gene leukotriene B4 12-hydroxydehydrogenase (Ltb4dh), which was up-regulated following 24 h exposure to 63-81 mg IB l-1. As anticipated, use of the NF clarified the response of Ltb4dh in daphnids exposed to sublethal levels of ibuprofen. Our findings emphasise the importance in toxicogenomics of finding and applying invariant internal QPCR control(s) relevant to the study conditions.


Adaptive intrapatient dose escalation of cisplatin in patients with advanced head and neck cancer.
The purpose of this study was to explore the feasibility and toxicity of intrapatient dose adjustment using predefined levels of exposure to cisplatin, with the ultimate goal to further improve the antitumor activity of the treatment. The primary parameter for adaptive dosing was the level of platinum DNA adducts in peripheral white blood cells (WBC) and the secondary parameter the area under the curve (AUC) of unbound platinum in plasma, which were determined during the applied courses. Target levels had been defined in a previously performed pharmacologic study. The concept of adaptive dosing was tested in 16 patients with locally advanced head and neck (H/N) cancer who would receive six weekly courses of cisplatin at a starting dose level of 80 mg/m(2), which was previously investigated in a phase II study. Forty-seven percent of patients received a dose increase varying from 10 to 40%. Only two patients had exposure levels significantly below the defined target levels for DNA adducts and AUC. The majority of patients reached the defined target levels by modest dose increases of 10-20% during course 2. Relevant but reversible ototoxicity (temporary grade 3 in two patients) and renal toxicity (temporary grade 2 in two other patients) were observed. The pattern and severity of the toxicity was comparable to that encountered in the previous phase II study in H/N cancer patients. We conclude that the strategy of intrapatient dose adjustment for cisplatin is practically feasible in a research setting even when a short turn around time of 1 week is the limit for reporting results. Although in some patients the dose increase that had to be applied to reach target levels was substantial (up to 40%), this approach in H/N cancer patients is not expected to improve the response rate significantly, because these significantly underdosed patients represented only a small percentage of the investigated population. The great majority of patients needed only limited (10-20%) dose increases which very likely will not improve the response rate to a clinically significant extent. The outlined concept is currently being explored in other tumor types and schedules of cisplatin.


Rapid identification of Candida glabrata in Candida bloodstream infections.
Candida species are the fourth most common cause of bloodstream infection (BSI) in the hospitalized patient. Candida glabrata is the most common non-Candida albicans Candida species in England and Wales with an attributed mortality of 48%. C. glabrata is known to demonstrate reduced susceptibility to fluconazole, resulting in treatment failures when employing this agent for empirical treatment of Candida BSI. The first part of this study demonstrated a technique utilizing a blood culture system commonly used by many laboratories (BACTEC 9240 automated detection system) that reduced the time to identification of this potentially resistant organism by up to 72 h. A presumptive identification was achieved by observing a difference in the duration of incubation required before growth was detected automatically between Lytic Anaerobic and Plus Aerobic culture bottles. Secondly, experiments exploring the growth characteristics of C. glabrata in BACTEC blood culture bottles containing various media were carried out to explore possible reasons underpinning this clinical observation. The detection of yeast in the anaerobic bottle of a blood culture pair consisting of Lytic Anaerobic and Plus Aerobic in a BACTEC 9240 system was found to be highly predictive of the isolation of C. glabrata (positive predictive value 93.3%, negative predictive value 98.3%). The reason for this appeared to be a component of the Lytic Anaerobic blood culture medium enhancing the growth of C. glabrata in that medium.


Suppression of SCARA5 by Snail1 is essential for EMT-associated cell migration of A549 cells.
Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT) might be a key event for cancer progression. The upregulation of Snail1, one of the most extensively studied EMT regulators, has been implicated in cancer metastasis, but the underlying mechanisms remain unclear. This study aims to identify that Snail1 targets regulating EMT-associated cancer cell migration. Human lung carcinoma A549 cells were treated with transforming growth factor beta 1 (TGF-β1), and EMT-associated phenotypic and functional alterations were monitored. TGF-β1 induced typical EMT-like morphological changes, 'cadherin switching' and cell migration in A549 cells. TGF-β1 stimulation induced rapid and persistent upregulation of Snail1. Moreover, Snail1 upregulation was required for EMT-associated cell migration. Several metastasis suppressors with putative Snail1-binding sites in their promoters were dramatically repressed in A549 cells during TGF-β1-induced EMT. Gain- and loss-of Snail1 function experiments demonstrated that scavenger receptor class A member 5 (SCARA5) was negatively regulated by Snail1. Importantly, SCARA5 downregulation was essential for EMT-induced migration in A549 cells. The chromatin immunoprecipitation assay revealed that Snail1 could bind to the E-box elements in SCARA5 promoter, implying that SCARA5 is a direct Snail1 target modulating cancer cell mobility during EMT. In addition, we showed that DNA methyltransferase 1 was physically associated with Snail1 to silence SCARA5 expression with an unidentified DNA methylation-independent mechanism, suggesting the complexity of Snail1-mediated epigenetic regulation. Collectively, our data demonstrated that EMT-regulator Snail1 suppresses the expression of SCARA5 to promote cancer progression, highlighting the possibility to target Snail1 and SCARA5 for cancer treatment.


Sexual Health Help-Seeking Behavior among Migrants from Sub-Saharan Africa and South East Asia living in High Income Countries: A Systematic Review.
The number of migrants has increased globally. This phenomenon has contributed to increasing health problems amongst migrants in high-income countries, including vulnerability for HIV acquisition and other sexual health issues. Adaptation processes in destination countries can present difficulties for migrants to seek help from and gain access to health services. This study examined migrants' from sub-Saharan Africa (SSA) and South East Asia (SEA) sexual health help-seeking behavior in high-income countries with universal health coverage. The systematic review followed PRISMA guidelines and was registered with PROSPERO. Several databases were searched from 2000 to 2017. Of 2824 studies, 15 met the inclusion criteria. These consisted of 12 qualitative and three quantitative studies conducted in Australia, Spain, the United Kingdom, Belgium, Scotland, Ireland, and Sweden. Migrants experienced a range of difficulties accessing health services, specifically those related to sexual health, in high-income countries. Few studies described sources of sexual health help-seeking or facilitators to help-seeking. Barriers to access were numerous, including: stigma, direct and indirect costs, difficulty navigating health systems in destination countries and lack of cultural competency within health services. More culturally secure health services, increased health service literacy and policy support to mitigate costs, will improve health service access for migrants from SSA and SEA. Addressing the structural drivers for stigma and discrimination remains an ongoing and critical challenge.


Evidence for high taxonomic and morphologic tyrannosauroid diversity in the Late Cretaceous (late Campanian) of the American Southwest and a new short-skulled tyrannosaurid from the Kaiparowits Formation of Utah.
The fossil record of late Campanian tyrannosauroids of western North America has a geographic gap between the Northern Rocky Mountain Region (Montana, Alberta) and the Southwest (New Mexico, Utah). Until recently, diagnostic tyrannosauroids from the Southwest were unknown until the discovery of Bistahieversor sealeyi from the late Campanian of New Mexico. Here we describe an incomplete skull and postcranial skeleton of an unusual tyrannosaurid from the Kaiparowits Formation (Late Cretaceous) of Utah that represents a new genus and species, Teratophoneus curriei. Teratophoneus differs from other tyrannosauroids in having a short skull, as indicated by a short and steep maxilla, abrupt angle in the postorbital process of the jugal, laterally oriented paroccipital processes, short basicranium, and reduced number of teeth. Teratophoneus is the sister taxon of the Daspletosaurus + Tyrannosaurus clade and it is the most basal North American tyrannosaurine. The presence of Teratophoneus suggests that dinosaur faunas were regionally endemic in the west during the upper Campanian. The divergence in skull form seen in tyrannosaurines indicates that the skull in this clade had a wide range of adaptive morphotypes.


Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction.
BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8(+) T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs. Freshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data. Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and Treg-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage. The current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases.


Autism spectrum disorder symptoms in children with ADHD: A community-based study.
This study examined the prevalence of autism spectrum disorder (ASD) symptoms in a community-based sample of children with attention-deficit/hyperactivity disorder (ADHD) and non-ADHD controls. We also examined the relationship between ASD symptoms and ADHD subtype, ADHD symptom severity and child gender. Participants were 6-10-year-old children (164 ADHD; 198 non-ADHD control) attending 43 schools in Melbourne, Australia, who were participating in the Children's Attention Project. ADHD was assessed in two stages using the parent and teacher Conners' 3 ADHD index and the Diagnostic Interview Schedule for Children IV (DISC-IV). ASD symptoms were identified using the Social Communication Questionnaire (SCQ). Unadjusted and adjusted linear and logistic regression examined continuous and categorical outcomes, respectively. Children with ADHD had more ASD symptoms than non-ADHD controls (adjusted mean difference=4.0, 95% confidence interval (CI) 2.8; 5.3, p<0.001, effect size=0.7). Boys with ADHD had greater ASD symptom severity than girls with ADHD (adjusted mean difference=2.9, 95% CI 0.8; 5.2, p=0.01, effect size=0.4). Greater ADHD symptom severity was associated with greater ASD symptom severity (regression co-efficient=1.6, 95% CI 1.2; 2.0, p<0.001). No differences were observed by ADHD subtype. Greater hyperactive/impulsive symptoms were associated with greater ASD symptoms (regression coefficient=1.0; 95% CI 0.0; 2.0, p=0.04) however, this finding attenuated in adjusted analyses (p=0.45). ASD symptoms are common in children with ADHD. It is important for clinicians to assess for ASD symptoms to ensure appropriate intervention.


Examining Variations in the Prevalence of Diagnosed Mood or Anxiety Disorders Among Migrant Groups in Ontario, 1995-2015: A Population-Based, Repeated Cross-Sectional Study.
International evidence on the frequency of mood or anxiety disorders among migrant groups is highly variable, as it is dependent on the time since migration and the socio-political context of the host country. Our objective was to estimate trends in the prevalence of diagnosed mood or anxiety disorders among recent (<5 years in Canada) and settled (5-10 years in Canada) migrant groups, relative to the general population of Ontario, Canada. We used a repeated cross-sectional design consisting of four cross-sections spanning 5 years each, constructed using health administrative databases from 1995 to 2015. We included all Ontario residents between the ages of 16 and 64 years. We assessed differences in the prevalence of mood or anxiety disorders adjusting for age, sex, and neighbourhood-level income. We further evaluated the impact of migrant class and region of birth. The prevalence of mood or anxiety disorders was lower among recent (weighted mean = 4.10%; 95% confidence interval [CI], 3.59% to 4.60%) and settled (weighted mean = 4.77%; 95% CI, 3.94% to 5.61%) migrant groups, relative to the general population (weighted mean = 7.39%; 95% CI, 6.83% to 7.94%). Prevalence estimates varied greatly by region of birth and migrant class. We found variation in prevalence estimates over time, with refugee groups having the largest increases between 1995 and 2015. Our findings highlight the complexity of mood and anxiety disorders among migrant groups, and that not all groups share the same risk profile. These results can be used to help inform health service allocation and the development of supportive programs for specific migrant groups.


Response of Resistant Soybean Plant Introductions to Meloidogyne arenaria Races 1 and 2.
Resistant plant introductions, PI 230977 and PI 200538, and partially resistant Jackson and susceptible CNS were evaluated for seed yield in response to races 1 and 2 of Meloidogyne arenaria. Initial soil population densities (Pi) of the nematode were 0, 31, 125, and 500 eggs/100 cm(3) soil. At the highest Pi, yield suppressions of CNS, Jackson, PI 230977, and PI 200538 were 55, 28, 31, and 29%, and 99, 86, 66, and 58% for races 1 and 2 compared with uninfested controls. Numbers of second-stage juveniles (J2) present in roots 14 days after planting increased as Pi increased, but did not differ between the two races. At the highest Pi, fewer race 1 (40-57%) and race 2 (53-68%) J2 were present in roots of the plant introductions than in roots of Jackson. Soil population densities of race 1 J2 at 135 days after planting were 83-89% lower on the resistant genotypes than on CNS. These numbers did not differ for race 2. Reproductive factors were considerably higher for race 2 compared to race 1 for all genotype by Pi combinations, except for CNS at the highest Pi.


Hepatoprotective activity of white horehound (Marrubium vulgare) extract against cyclophosphamide toxicity in male rats.
The hepatoprotective activity of Marrubium vulgare against cyclophosphamide toxicity in Wistar rats was evaluated. Adult male rats were divided into 4 groups of 6 each: a control group, a group injected with cyclophosphamide (150 mg·kg(-1)) for 3 days, a group orally given a M. vulgare aqueous extract ((500 mg of dry leaves)·kg(-1)·day(-1)) for 30 days then treated with cyclophosphamide, and a group receiving only M. vulgare for 30 days. After 33 days of treatment, activities of alanine amino transferase (ALAT), aspartate amino transferase (ASAT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) were determined in serum. Moreover, lipid peroxidation level and superoxide dismutase (SOD) activities, catalase (CAT) and glutathione peroxidase (GPx) were measured in liver. Alterations of these hepatic biomarkers and increased lipid peroxidation confirmed cyclophosphamide-induced liver toxicity. Cyclophosphamide also decreased the enzymatic defense system against oxidative stress. However, when this drug was administered in rats given M. vulgare extract, all the biological parameters underwent much less alteration. Administration of M. vulgare extract was found to be beneficial by attenuating cyclophosphamide-induced liver damage. The protective effect of the plant is mainly attributed to its antioxidant properties and the existence of phenolic acids and flavonoids, as highlighted by HPLC-based analysis.