Manuscript prepared for submission to environmental toxicology and pharmacology pollution in drinking water source areas: Microplastics in the Danjiangkou Reservoir, China.
As the source of water for the South-to-North Water Diversion Project of China, the water quality of the Danjiangkou Reservoir (DJKR) is related to the safety of drinking water for billions of residents. Consequently, microplastics in surface water and sediment samples of the DJKR were investigated in this study. Microplastics were observed in all water and sediment samples with abundances varying from 467 to 15,017 n/m3 and 15 to 40 n/kg wet weight, respectively. Microplastics were rich in colour and dominated by fibrous items. Small-sized particles (< 2 mm) were more frequently observed than other sizes. Analysis by micro-Raman spectroscopy showed that polypropylene was the major polymer type. These systematic results demonstrated that the DJKR is suffering from the pollution of microplastics, which should be paid more attention based on its potential threat to the aquatic organisms and residents impacted by the drinking water source pollution.


Validation of global rating scale and checklist instruments for the infant lumbar puncture procedure.
The Patient Outcomes in Simulation Education network has developed tools for the assessment of competency to perform the infant lumbar puncture (ILP) procedure. The objective of this study was to evaluate the validity and reliability of these tools in a simulated setting. We developed a 4-point anchored global rating scale (GRS) and 15-item dichotomous checklist instrument to assess ILP performance in a simulated environment. Video recordings of 60 subjects performing an unsupervised lumbar puncture on an infant bench top simulator were collected prospectively; 20 performed by subjects in each of 3 categories (beginner, intermediate experienced, or expert). Three blinded, expert raters independently scored each subject's video recording using the GRS and checklist instruments. The final version of the scoring instruments is presented. Across all subject groups, higher GRS scores were found with advancing level of experience (P < 0.01). Total checklist scores were similar between the expert and intermediate experienced groups (P = 0.54). Both groups scored higher than the beginner group on the checklist instrument (P < 0.01). For each rater, a significant positive correlation was found between GRS scores and total checklist scores (median ρ = 0.75, P < 0.01). Cronbach α coefficient for the checklist was 0.77. The intraclass correlation coefficients between raters for the GRS and total checklist scores were 0.71 and 0.52, respectively. This study provides some initial evidence to support the validity and reliability of the ILP-anchored GRS. Acceptable internal consistency was found for the checklist instrument. The GRS instrument outperformed the checklist in its discriminant ability and interrater agreement.


Correlation between TRAIL and caspase-8 expression and their relationship with cell proliferation and apoptosis in human osteosarcoma.
Osteosarcoma is a common malignant bone tumor that mainly affects children and adolescents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily. Caspase-8 appears in the upstream of apoptosis signaling pathway among caspases. We investigated TRAIL and caspase-8 levels in osteosarcoma patients to determine their correlation with cell proliferation and apoptosis. Osteosarcoma and osteochondroma patients receiving surgery in our hospital were selected. TRAIL and caspase-8 expression levels in tissue were determined by immunohistochemistry, and protein levels in cells were evaluated by western blotting. Human osteosarcoma cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The osteosarcoma and osteochondroma cell cycles and apoptosis were investigated by flow cytometry. Correlation analysis was applied to TRAIL and caspase-8 levels during cell apoptosis. Positive TRAIL and caspase-8 expression rates in osteosarcoma tissue were significantly lower than in the controls (P < 0.05). TRAIL (0.114 ± 0.002) and caspase-8 (0.352 ± 0.124) levels in experimental cells were obviously lower than in the controls (P < 0.05). Osteosarcoma cells in the experimental group demonstrated higher proliferation and lower apoptosis at 24, 48, and 72 h (P < 0.05). The experimental cell number increased in the G1 stage and decreased in the S stage (P < 0.05). TRAIL and caspase-8 proteins showed positive correlation with apoptosis in osteosarcoma (P < 0.05). Human osteosarcoma presented reduced TRAIL and caspase-8 levels with enhanced cell proliferation and reduced apoptosis. TRAIL and caspase-8 expression levels were positively correlated with apoptosis in osteosarcoma.


Technique for enhanced rare earth separation
A process is demonstrated for the efficient separation of rare earth elements, using a combination of selective reduction and vacuum distillation of halides. The large differences in the redox chemistry of the rare earth elements and in the vapor pressures of rare earth di- and trihalides are exploited for separation. Experimental proof of concept is provided for the binary systems praseodymium-neodymium and neodymium-samarium. This process enhances the separation factor for the isolation of samarium and neodymium from their mixture by more than an order of magnitude.


Social stimulation and corticolimbic reactivity in premenstrual dysphoric disorder: a preliminary study.
Premenstrual dysphoric disorder (PMDD), characterized by luteal phase-induced negative affect and loss of impulse control, often results in compromised social interactions. Although amygdala activation is generally linked to negative affect, increased amygdala reactivity to aversive stimuli in the luteal phase has not been consistently reported in PMDD. We tested the hypothesis that amygdala hyper-reactivity in PMDD is symptom specific, rather than generalized, and linked to socially relevant stimuli. Blood oxygenation level dependent signal changes during exposure to negative images with social and non-social content were evaluated in the mid-follicular and late luteal phase of the menstrual cycle. Fourteen women with PMDD and 13 healthy controls participated. When compared with healthy controls, women with PMDD in the luteal phase had enhanced reactivity to social stimuli compared to non-social stimuli in the amygdala and insula, but attenuated reactivity in the anterior cingulate cortex. Functional couplings between emotion processing and controlling areas were significantly different, being positive in women with PMDD and negative in healthy controls. Changes in progesterone levels in women with PMDD correlated positively with altered amygdala reactivity. Socially relevant aversive stimulation elicited enhanced activity in affective processing brain regions that were functionally coupled to compromised activity in cognitive control areas. Because increased reactivity correlated positively with alterations in ovarian steroid levels, data preliminary support the hypothesis that enhanced progesterone sensitivity in PMDD affects corticolimbic processing of social emotions.


Medical care costs and quality of life after randomization to coronary angioplasty or coronary bypass surgery. Bypass Angioplasty Revascularization Investigation (BARI) Investigators.
Randomized trials comparing coronary angioplasty with bypass surgery in patients with multivessel coronary disease have shown no significant differences in overall rates of death and myocardial infarction. We compared quality of life, employment, and medical care costs during five years of follow-up among patients treated with angioplasty or bypass surgery. A total of 934 of the 1829 patients enrolled in the randomized Bypass Angioplasty Revascularization Investigation participated in this study. Detailed data on quality of life were collected annually, and economic data were collected quarterly. During the first three years of follow-up, functional-status scores on the Duke Activity Status Index, which measures the ability to perform common activities of daily living, improved more in patients assigned to surgery than in those assigned to angioplasty (P<0.05). Other measures of quality of life improved equally in both groups throughout the follow-up period. Patients in the angioplasty group returned to work five weeks sooner than did patients in the surgery group (P<0.001). The initial mean cost of angioplasty was 65 percent that of surgery ($21,113 vs. $32,347, P<0.001), but after five years the total medical cost of angioplasty was 95 percent that of surgery ($56,225 vs. $58,889), a difference of $2,664 (P = 0.047). The five-year cost of angioplasty was significantly lower than that of surgery among patients with two-vessel disease ($52,930 vs. $58,498, P<0.05), but not among patients with three-vessel disease ($60,918 vs. $59,430). After five years of follow-up, surgery had an overall cost-effectiveness ratio of $26,117 per year of life added, but unacceptable ratios of $100,000 or more per year of life added could not be excluded (P=0.13). Surgery appeared particularly cost effective in treating diabetic patients because of their significantly improved survival. In patients with multivessel coronary disease, coronary-artery bypass surgery is associated with a better quality of life for three years than coronary angioplasty, after the initial morbidity caused by the procedure. Coronary angioplasty has a lower five-year cost than bypass surgery only in patients with two-vessel coronary disease.


Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-alpha for Crohn's disease in Japan: evaluation by rapid turnover proteins, and radiologic and endoscopic findings.
Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)-alpha (Infliximab) is extremely valuable in the treatment of Crohn's disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohn's disease. A 12-week multicenter, open trial of Infliximab was carried out and involved 25 patients with moderate to severe Crohn's disease who were resistant to conventional treatment. Patients received a single 2-h intravenous infusion of Infliximab at a dose of 1, 3, 5 or 10 mg/kg bodyweight. Clinical evaluation of this treatment response was defined as a reduction in the index of the inflammatory bowel disease (IOIBD) and of the Crohn's disease activity index scores (CDAI), and in serum levels of C-reactive protein (CRP) at 2, 4, 8 and 12 weeks, and as an increase in serum levels of rapid turnover proteins as well as improvement of radiologic and endoscopic findings at 4 weeks. The IOIBD score was reduced after 4 weeks in 66.7% of the group receiving 1 mg/kg Infliximab, 71.4% in the group receiving 3 mg/kg, 80.0% in the group receiving 5 mg/kg, and 85.7% in the group receiving 10 mg/kg. Improvement was better maintained over 12 weeks in the 5 and 10 mg/kg groups compared with the 1 and 3 mg/kg groups. Similar results were obtained for the CDAI scores. Serum levels of rapid turnover proteins significantly increased to within the normal ranges after infusion in all groups. Seven of the 11 (63.6%) patients evaluated showed improvement of radiologic and endoscopic findings. A single infusion of Infliximab was effective for the treatment of Japanese patients with Crohn's disease. Serum rapid turnover proteins reflected the clinical response to antibody for TNF-alpha well.


Monitoring and benchmarking population diet quality globally: a step-wise approach.
INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support) aims to monitor and benchmark the healthiness of food environments globally. In order to assess the impact of food environments on population diets, it is necessary to monitor population diet quality between countries and over time. This paper reviews existing data sources suitable for monitoring population diet quality, and assesses their strengths and limitations. A step-wise framework is then proposed for monitoring population diet quality. Food balance sheets (FBaS), household budget and expenditure surveys (HBES) and food intake surveys are all suitable methods for assessing population diet quality. In the proposed 'minimal' approach, national trends of food and energy availability can be explored using FBaS. In the 'expanded' and 'optimal' approaches, the dietary share of ultra-processed products is measured as an indicator of energy-dense, nutrient-poor diets using HBES and food intake surveys, respectively. In addition, it is proposed that pre-defined diet quality indices are used to score diets, and some of those have been designed for application within all three monitoring approaches. However, in order to enhance the value of global efforts to monitor diet quality, data collection methods and diet quality indicators need further development work.


[Use of thermostable DNA polymerase from Thermus thermophilus KTP in a combined reverse transcription and amplification reaction of detecting interleukin 2alpha RNA and determining expression of the multidrug resistance gene (MDR-1)].
According to our data native Tth DNA polymerase displays higher reverse transcription activity than Taq DNA polymerase. This allows one to use Tth DNA polymerase in the complete reaction of reverse transcription and amplification (RT/PCR). We used this enzyme to synthesize the interleukine (IL-2 alpha) RNA template synthesized by the RT/PCR method in vitro. The conditions for RNA IL-2 alpha detection were optimized. The maximum yield of the specific product was obtained at pH 8.5-9.0. The influence of bivalent cations on the efficiency of RT reaction of coupled RT/PCR can be expressed as: Mn2+ > or = Cu2+ > Mg2+ > Cd2+ >> Co2+. The optimal ratio is 1.25-1.88 for Mn2+/dNTPs and 1.88-2.5 for Cu2+/dNTPs and Cd2+/dNTPs. The maximum yield of the RT/PCR product is found at Mg2+/dNTPs = 3.75. When Mn2+ is used instead of Mg2+ in the PCR reaction the efficiency of RT/PCR decreases. The RT/PCR method embracing thermostable Tth DNA-polymerase provides detection of 10(3) copies of RNA IL-2 alpha. An efficient method of the express-diagnostics of MDR-1 gene expression by coupled RT/PCR using Tth DNA polymerase is described.


Recombinant CD40L treatment protects allogeneic murine bone marrow transplant recipients from death caused by herpes simplex virus-1 infection.
Posttransplant infection associated with host immune deficiency is the major cause of nonrelapse mortality of human bone marrow transplant recipients. In a new murine model of posttransplant infection, allogeneic bone marrow transplant recipients were infected with herpes simplex virus-1 (HSV-1) via intraperitoneal inoculation 12 weeks after transplantation. Allogeneic transplant recipients with graft-versus-host disease (GVHD) had significantly increased mortality from HSV-1 encephalitis, with deficiencies of both specific anti-HSV-1 antibody and total serum IgG2a. GVHD mice displayed a Th2 cytokine profile (increased interleukin-4 [IL-4] and decreased interferon-gamma) and decreased lipopolysaccharide (LPS) responses, suggesting that both T-cell and B-cell defects contributed to the impaired production of antibody. Because passive transfer of hyperimmune serum protected mice from HSV-1 infection, we hypothesized that CD40 ligand (CD40L), which induces B-cell maturation, would protect mice from HSV-1 infection. CD40L-treated GVHD mice showed elevated IgG2a levels and increased survival compared with vehicle-treated transplant recipients.


The extent of population genetic subdivision differs among four co-distributed shark species in the Indo-Australian archipelago.
The territorial fishing zones of Australia and Indonesia are contiguous to the north of Australia in the Timor and Arafura Seas and in the Indian Ocean to the north of Christmas Island. The area surrounding the shared boundary consists of a variety of bio-diverse marine habitats including shallow continental shelf waters, oceanic trenches and numerous offshore islands. Both countries exploit a variety of fisheries species, including whaler (Carcharhinus spp.) and hammerhead sharks (Sphyrna spp.). Despite their differences in social and financial arrangements, the two countries are motivated to develop complementary co-management practices to achieve resource sustainability. An essential starting point is knowledge of the degree of population subdivision, and hence fisheries stock status, in exploited species. Populations of four commercially harvested shark species (Carcharhinus obscurus, Carcharhinus sorrah, Prionace glauca, Sphyrna lewini) were sampled from northern Australia and central Indonesia. Neutral genetic markers (mitochondrial DNA control region sequence and allelic variation at co-dominant microsatellite loci) revealed genetic subdivision between Australian and Indonesian populations of C. sorrah. Further research is needed to address the possibility of genetic subdivision among C. obscurus populations. There was no evidence of genetic subdivision for P. glauca and S. lewini populations, but the sampling represented a relatively small part of their distributional range. For these species, more detailed analyses of population genetic structure is recommended in the future. Cooperative management between Australia and Indonesia is the best option at present for P. glauca and S. lewini, while C. sorrah and C. obscurus should be managed independently. On-going research on these and other exploited shark and ray species is strongly recommended. Biological and ecological similarity between species may not be a predictor of population genetic structure, so species-specific studies are recommended to provide new data to assist with sustainable fisheries management.


Administration of alfacalcidol for patients with predialysis chronic kidney disease may reduce cardiovascular disease events.
Besides its effect on calcium metabolism, vitamin D may play a part in preventing the onset and progression of cardiovascular disease (CVD) events. Only a few reports on the studies relating to whether vitamin D may reduce CVD events in patients with predialysis chronic kidney disease (CKD) are available, and many ambiguities remain. We conducted a retrospective cohort study of 665 patients with predialysis CKD. With log-rank test using the Kaplan-Meyer survival curve, comparison of incidences of CVD events, CVD-related mortality, and all-cause mortality were made between patients in the alfacalcidol treatment group (107 patients) in the predialysis stage to whom alfacalcidol 0.25-0.5 microg/day was orally administered for at least 24 weeks, and patients in the nontreatment group (558 patients) who received no administration of alfacalcidol or other type of activated vitamin D and its analogues. Patients to whom alfacalcidol administration was discontinued within 24 weeks as well as initiation of dialysis of <24 weeks were excluded for this study. Factors relating to CVD events were examined using Cox's proportional hazards analysis. The mean follow-up period was 55.1 +/- 38.9 months in the alfacalcidol treatment group and 41.9 +/- 38.4 months in the nontreatment group. CVD events occurred in 172 patients during the follow-up period, and 74 of those occurred during the predialysis period. In the alfacalcidol treatment group, the incidence of cumulative CVD events was significantly lower. In relation to all-cause deaths and CVD-related deaths, the cumulative mortality rate was significantly lower in the alfacalcidol treatment group during the follow-up period. Throughout the follow-up period, the association between CVD events and alfacalcidol use was detected when adjusted for age, sex, diabetes, hypertension, use of renin-angiotensin system inhibitors, estimated glomerular filtration rate, and albumin and parathyroid hormone. These data showed that oral administration of alfacalcidol for predialysis CKD patients was associated with reduced risk for CVD.


Esophageal reflexes modulate frontoparietal response in neonates: Novel application of concurrent NIRS and provocative esophageal manometry.
Central and peripheral neural regulation of swallowing and aerodigestive reflexes is unclear in human neonates. Functional near infrared spectroscopy (NIRS) is a noninvasive method to measure changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbD). Pharyngoesophageal manometry permits evaluation of aerodigestive reflexes. Modalities were combined to investigate feasibility and to test neonatal frontoparietal cortical changes during pharyngoesophageal (visceral) stimulation and/or swallowing. Ten neonates (45.6 ± 3.0 wk postmenstrual age, 4.1 ± 0.5 kg) underwent novel pharyngoesophageal manometry concurrent with NIRS. To examine esophagus-brain interactions, we analyzed cortical hemodynamic response (HDR) latency and durations during aerodigestive provocation and esophageal reflexes. Data are presented as means ± SE or percent. HDR rates were 8.84 times more likely with basal spontaneous deglutition compared with sham stimuli (P = 0.004). Of 182 visceral stimuli, 95% were analyzable for esophageal responses, 38% for HDR, and 36% for both. Of analyzable HDR (n = 70): 1) HbO concentration (μmol/l) baseline 1.5 ± 0.7 vs. 3.7 ± 0.7 poststimulus was significant (P = 0.02), 2) HbD concentration (μmol/l) between baseline 0.1 ± 0.4 vs. poststimulus -0.5 ± 0.4 was not significant (P = 0.73), and 3) hemispheric lateralization was 21% left only, 29% right only, and 50% bilateral. During concurrent esophageal and NIRS responses (n = 66): 1) peristaltic reflexes were present in 74% and HDR in 61% and 2) HDR was 4.75 times more likely with deglutition reflex vs. secondary peristaltic reflex (P = 0.016). Concurrent NIRS with visceral stimulation is feasible in neonates, and frontoparietal cortical activation is recognized. Deglutition contrasting with secondary peristalsis is related to cortical activation, thus implicating higher hierarchical aerodigestive protective functional neural networks.


Survey of physicians' practices in the control of cardiovascular risk factors: the EURIKA study.
To assess the practices of physicians in 12 European countries in the primary prevention of cardiovascular disease (CVD). In 2009, 806 physicians from 12 European countries answered a questionnaire, delivered electronically or by post, regarding their assessment of patients with cardiovascular risk factors, and their use of risk calculation tools and clinical practice guidelines (ClinicalTrials.gov number: NCT00882336). Approximately 60 physicians per country were selected (participation rate varied between 3.1% in Sweden and 22.8% in Turkey). Among participating physicians, 85.2% reported using at least one clinical guideline for CVD prevention. The most popular were the ESC guidelines (55.1%). Reasons for not using guidelines included: the wide choice available (47.1%), time constraints (33.3%), lack of awareness of guidelines (27.5%), and perception that guidelines are unrealistic (23.5%). Among all physicians, 68.5% reported using global risk calculation tools. Written charts were the preferred method (69.4%) and the most commonly used was the SCORE equation (35.4%). Reasons for not using equations included time constraints (59.8%), not being convinced of their usefulness (21.7%) and lack of awareness (19.7%). Most physicians (70.8%) believed that global risk-equations have limitations; 89.8% that equations overlook important risk factors, and 66.5% that they could not be used in elderly patients. Only 46.4% of physicians stated that their local healthcare framework was sufficient for primary prevention of CVD, while 67.2% stated that it was sufficient for secondary prevention of CVD. A high proportion of physicians reported using clinical guidelines for primary CVD prevention. However, time constraints, lack of perceived usefulness and inadequate knowledge were common reasons for not using CVD prevention guidelines or global CVD risk assessment tools.


Staining human lymphocytes and onion root cell nuclei with madder root.
We performed staining experiments on cells using natural dyes and different mordants using techniques that are used for wool and silk dyeing. The natural dye sources were madder root, daisy, corn cockle and yellow weed. Ferrous sulfate, copper sulfate, potassium tartrate, urea, potassium aluminum sulfate and potassium dichromate were used as mordants. Distilled water, distilled water plus ethanol, heptane, and distilled water plus methanol were used as solvents. All dye-mordant-solvent combinations were studied at pH 2.4, 3.2 and 4.2. The generic staining procedure was to boil 5-10 onion roots or stimulated human lymphocyte (SHL) preparations in a dye bath on a hot plate. Cells were examined at every half hour. For multicolor staining, madder-dyed lymphocytes were decolorized, then stained with Giemsa. The AgNOR technique was performed following the decolorization of Giemsa stained lymphocytes. Good results were obtained for both onion root cells and lymphocytes that were boiled for 3 h in a dye bath that included 4 g madder root, 4 g ferrous sulfate as mordant in 50 ml of 1:1 (v/v) methanol:distilled water. The pH was adjusted to 4.2 with 6 ml acetic acid. We conclude that madder root has potential as an alternative dye for staining biological materials.


Response of endangered plant species to inoculation with arbuscular mycorrhizal fungi and soil bacteria.
Three endangered plant species, Plantago atrata and Pulsatilla slavica, which are on the IUCN red list of plants, and Senecio umbrosus, which is extinct in the wild in Poland, were inoculated with soil microorganisms to evaluate their responsiveness to inoculation and to select the most effective microbial consortium for application in conservation projects. Individuals of these taxa were cultivated with (1) native arbuscular mycorrhizal fungi (AMF) isolated from natural habitats of the investigated species, (2) a mixture of AMF strains available in the laboratory, and (3) a combination of AMF lab strains with rhizobacteria. The plants were found to be dependent on AMF for their growth; the mycorrhizal dependency for P. atrata was 91%, S. umbrosus-95%, and P. slavica-65%. The applied inocula did not significantly differ in the stimulation of the growth of P. atrata and S. umbrosus, while in P. slavica, native AMF proved to be the less efficient. We therefore conclude that AMF application can improve the ex situ propagation of these three threatened taxa and may contribute to the success of S. umbrosus reintroduction. A multilevel analysis of chlorophyll a fluorescence transients by the JIP test permitted an in vivo evaluation of plant vitality in terms of biophysical parameters quantifying photosynthetic energy conservation, which was found to be in good agreement with the results concerning physiological parameters. Therefore, the JIP test can be used to evaluate the influence of AMF on endangered plants, with the additional advantage of being applicable in monitoring in a noninvasive way the acclimatization of reintroduced species in nature.


Diurnal Variation in Straylight in Patients With Fuchs Endothelial Corneal Dystrophy and Controls.
The goal of this study was to investigate diurnal changes in intraocular straylight in relation to other corneal parameters and subjective complaints in patients with Fuchs endothelial dystrophy and healthy controls. This is a prospective study conducted in 2 tertiary care hospitals in Germany and the Netherlands. Patients with Fuchs endothelial dystrophy (n = 71) and healthy controls (n = 34) were included. Patients with Fuchs dystrophy were grouped by the presence of subjective complaints and measured over multiple time points during the day. Measurements included intraocular straylight using the C-Quant and corneal thickness and backscatter using a Scheimpflug camera. A separate group of healthy controls was measured intensively with repeated straylight measurements directly after waking. An exponential decay model was used to model the diurnal change. Healthy controls showed an average straylight baseline of 1.17 log(s) with an increase in straylight after waking of 0.22 log(s). In the repeated measurements subgroup, the increase in morning straylight lasted for 22 minutes. Patients with Fuchs dystrophy showed a morning increase in straylight of 0.21 log(s) present up to 4 hours after waking before reaching an average baseline of 1.30 log(s). Straylight was positively correlated with anterior corneal backscatter, r = 0.21, P = 0.022, and corneal thickness, r = 0.46, P < 0.01. Healthy eyes experience a diurnal straylight increase similar to patients with Fuchs dystrophy in intensity. However, in Fuchs dystrophy, the resolution of increased straylight is prolonged over multiple hours compared with minutes in healthy eyes. This suggests pathological exacerbation of a physiological diurnal change. This mechanism can play a role in subjective complaints experienced by patients with Fuchs dystrophy.


Burkholderia pseudomallei Evades Nramp1 (Slc11a1)- and NADPH Oxidase-Mediated Killing in Macrophages and Exhibits Nramp1-Dependent Virulence Gene Expression.
Bacterial survival in macrophages can be affected by the natural resistance-associated macrophage protein 1 (Nramp1; also known as solute carrier family 11 member a1 or Slc11a1) which localizes to phagosome membranes and transports divalent cations, including iron. Little is known about the role of Nramp1 in Burkholderia infection, in particular whether this differs for pathogenic species like Burkholderia pseudomallei causing melioidosis or non-pathogenic species like Burkholderia thailandensis. Here we show that transfected macrophages stably expressing wild-type Nramp1 (Nramp1+) control the net replication of B. thailandensis, but not B. pseudomallei. Control of B. thailandensis was associated with increased cytokine responses, and could be abrogated by blocking NADPH oxidase-mediated production of reactive oxygen species but not by blocking generation of reactive nitrogen species. The inability of Nramp1+ macrophages to control B. pseudomallei was associated with rapid escape of bacteria from phagosomes, as indicated by decreased co-localization with LAMP1 compared to B. thailandensis. A B. pseudomallei bipB mutant impaired in escape from phagosomes was controlled to a greater extent than the parent strain in Nramp1+ macrophages, but was also attenuated in Nramp1- cells. Consistent with reduced escape from phagosomes, B. thailandensis formed fewer multinucleated giant cells in Nramp1+ macrophages at later time points compared to B. pseudomallei. B. pseudomallei exhibited elevated transcription of virulence-associated genes of Type VI Secretion System cluster 1 (T6SS-1), the Bsa Type III Secretion System (T3SS-3) and the bimA gene required for actin-based motility in Nramp1+ macrophages. Nramp1+ macrophages were found to contain decreased iron levels that may impact on expression of such genes. Our data show that B. pseudomallei is able to evade Nramp1- and NADPH oxidase-mediated killing in macrophages and that expression of virulence-associated genes by pathogenic B pseudomallei is enhanced in macrophages expressing wild-type compared to non-functional Nramp1. B. thailandensis has been proposed as surrogate for B. pseudomallei in the study of melioidosis however our study highlights important differences in the interaction of these bacteria with macrophages.


P2X7 antagonism using Brilliant Blue G reduces body weight loss and prolongs survival in female SOD1G93A amyotrophic lateral sclerosis mice.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterised by the accumulation of aggregated proteins, microglia activation and motor neuron loss. The mechanisms underlying neurodegeneration and disease progression in ALS are unknown, but the ATP-gated P2X7 receptor channel is implicated in this disease. Therefore, the current study aimed to examine P2X7 in the context of neurodegeneration, and investigate whether the P2X7 antagonist, Brilliant Blue G (BBG), could alter disease progression in a murine model of ALS. Human SOD1G93A transgenic mice, which normally develop ALS, were injected with BBG or saline, three times per week, from pre-onset of clinical disease (62-64 days of age) until end-stage. During the course of treatment mice were assessed for weight, clinical score and survival, and motor coordination, which was assessed by rotarod performance. Various parameters from end-stage mice were assessed as follows. Motor neuron loss and microgliosis were assessed by immunohistochemistry. Relative amounts of lumbar spinal cord SOD1 and P2X7 were quantified by immunoblotting. Serum monocyte chemoattractant protein-1 was measured by ELISA. Splenic leukocyte populations were assessed by flow cytometry. Relative expression of splenic and hepatic P2X7 mRNA was measured by quantitative real-time PCR. Lumbar spinal cord SOD1 and P2X7 were also quantified by immunoblotting in untreated female SOD1G93A mice during the course of disease. BBG treatment reduced body weight loss in SOD1G93A mice of combined sex, but had no effect on clinical score, survival or motor coordination. BBG treatment reduced body weight loss in female, but not male, SOD1G93A mice. BBG treatment also prolonged survival in female, but not male, SOD1G93A mice, extending the mean survival time by 4.3% in female mice compared to female mice treated with saline. BBG treatment had no effect on clinical score or motor coordination in either sex. BBG treatment had no major effect on any end-stage parameters. Total amounts of lumbar spinal cord SOD1 and P2X7 in untreated female SOD1G93A mice did not change over time. Collectively, this data suggests P2X7 may have a partial role in ALS progression in mice, but additional research is required to fully elucidate the contribution of this receptor in this disease.


"Blurred lines?" Sexual aggression and barroom culture.
Meeting potential sexual/romantic partners for mutual pleasure is one of the main reasons young adults go to bars. However, not all sexual contacts are positive and consensual, and aggression related to sexual advances is a common experience. Sometimes such aggression is related to misperceptions in making and receiving sexual advances while other times aggression reflects intentional harassment or other sexually aggressive acts. This study uses objective observational research to assess quantitatively gender of initiators and targets and the extent that sexual aggression involves intentional aggression by the initiator, the nature of responses by targets, and the role of third parties and intoxication. We analyzed 258 aggressive incidents involving sexual advances observed as part of a larger study on aggression in large capacity bars and clubs, using variables collected as part of the original research (gender, intoxication, intent) and variables coded from narrative descriptions (invasiveness, persistence, targets' responses, role of third parties). Hierarchical linear modeling analyses were used to account for nesting of incidents in evening and bars. Ninety percent of incidents involved male initiators and female targets, with almost all incidents involving intentional or probably intentional aggression. Targets mostly responded nonaggressively, usually using evasion. Staff rarely intervened; patron third parties intervened in 21% of incidents, usually to help the target but sometimes to encourage the initiator. initiators' level of invasiveness was related to intoxication of the targets, but not their own intoxication, suggesting intoxicated women were being targeted. Sexual aggression is a major problem in bars often reflecting intentional sexual invasiveness and unwanted persistence rather than misperceptions in sexual advances. Prevention needs to focus on addressing masculinity norms of male patrons and staff who support sexual aggression and better management of the highly sexualized and sexist environments of most bars.


Dietary patterns and colorectal cancer in a Japanese population: the Fukuoka Colorectal Cancer Study.
Few studies have addressed the relation between dietary patterns and colorectal cancer in Japan. We investigated dietary patterns in relation to colorectal cancer risk in a community-based case-control study. The association with dietary patterns was also examined for different sites of colorectal cancer. Data were derived from the Fukuoka Colorectal Cancer Study, including 800 cases and 775 controls interviewed from September 2000 to December 2003. The cases were admitted to one of the participating hospitals for the first surgical treatment during this period. We identified dietary patterns using principal component analysis of intakes of twenty-nine items of food groups and specific foods. Quartile categories of each dietary pattern were used, and non-dietary lifestyle factors and total energy intake were adjusted for in the analysis. We identified three dietary patterns: prudent, high-fat and light-meal patterns. The prudent dietary pattern characterised by high intakes of vegetables, fruits, seafoods and soya foods showed a nearly significant protective association with the overall risk of colorectal cancer (trend P = 0.054), and it was statistically significantly related to a decreased risk of distal colon cancer (trend P = 0.002), but not to that of either proximal colon or rectal cancer. The high-fat and light-meal dietary patterns were not materially related to the overall or site-specific risk of colorectal cancer. In summary, a prudent dietary pattern was associated with a decreased risk of colorectal cancer, especially with that of distal colon cancer, in a fairly large case-control study in Japan.


Accuracy of five self-report screening instruments for substance use in pregnancy.
The accuracy of current screening instruments for identification of substance use in pregnancy is unclear, particularly given methodological shortcomings in existing research. This diagnostic accuracy study compared five existing instruments for ability to identify illicit drug, opioid and alcohol use, under privacy expectations consistent with applied practice and using a gold standard incorporating toxicological analysis. Prospective cross-sectional screening accuracy study. Three sites encompassing four prenatal care clinics in the United States. Convenience sample of 1220 racially, ethnically and socio-economically diverse pregnant women aged 18 years and over. In Phase I, participants completed the five screening instruments in counterbalanced order. Instruments included the Substance Use Risk Profile-Pregnancy (SURP-P), CRAFFT (acronym for five-item screener with items related to car, relax, alone, forget, friends and trouble), 5Ps (parents, peers, partner, pregnancy, past), Wayne Indirect Drug Use Screener (WIDUS) and the National Institute on Drug Abuse (NIDA) Quick Screen. In Phase II, participants provided a urine sample and completed a calendar recall-based interview regarding substance use. These screeners were tested, using receiver operating characteristic (ROC) analysis and accuracy statistics, against a reference standard consisting of substance use in three classes (illicit drugs, opioids and alcohol), considered positive if use was evident via 30-day calendar recall or urine analysis. Three hundred and fifteen of 1220 participants (26.3%) met reference standard criteria for positivity. The single-item screening questions from the NIDA Quick Screen showed high specificity (0.99) for all substances, but very poor sensitivity (0.10-0.27). The 5Ps showed high sensitivity (0.80-0.88) but low specificity (0.35-0.37). The CRAFFT, SURP-P and 5Ps had the highest area under the curve (AUC) for alcohol (0.67, 0.66 and 0.62, respectively), and the WIDUS had the highest AUC for illicit drugs and opioids (0.70 and 0.69, respectively). Performance of all instruments varied significantly with race, site and economic status. Of five screening instruments for substance use in pregnancy tested (Substance Use Risk Profile-Pregnancy (SURP-P), CRAFFT, 5Ps, Wayne Indirect Drug Use Screener (WIDUS) and the National Institute on Drug Abuse (Quick Screen), none showed both high sensitivity and high specificity, and area under the curve was low for nearly all measures.


Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors.
A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC50 = 1.9-7.4 μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking.


Tobacco proliferating cell nuclear antigen binds directly and stimulates both activity and processivity of ddNTP-sensitive mungbean DNA polymerase.
PCNA is well known as a component of DNA replication system and plays important roles in multiple cellular pathways in addition to replication and repair. In this work we have demonstrated the physical and functional interaction between tobacco PCNA and mungbean ddNTP-sensitive DNA polymerase which shares many physicochemical properties with family X-DNA polymerases except with the moderately processive mode of nucleotide incorporation. We have shown here that recombinant PCNA binds directly to mungbean DNA polymerase as revealed in affinity chromatography, pull-down and co-immunoprecipitation approaches. In vitro DNA polymerase activity assay and processivity analyses indicated recombinant PCNA specifically stimulates both activity and processivity of mungbean DNA polymerase. These observations lead to interesting speculation about the functional significance of the ddNTP-sensitive enzyme in replication event in higher plants since the enzyme has been shown to be active and expressed at an elevated level during the endoreduplication stages in developing mungbean seeds.


IQ, the Urban Environment, and Their Impact on Future Schizophrenia Risk in Men.
Exposure to an urban environment during early life and low IQ are 2 well-established risk factors for schizophrenia. It is not known, however, how these factors might relate to one another. Data were pooled from the North Jutland regional draft board IQ assessments and the Danish Conscription Registry for men born between 1955 and 1993. Excluding those who were followed up for less than 1 year after the assessment yielded a final cohort of 153170 men of whom 578 later developed a schizophrenia spectrum disorder. We found significant effects of having an urban birth, and also experiencing an increase in urbanicity before the age of 10 years, on adult schizophrenia risk. The effect of urban birth was independent of IQ. However, there was a significant interaction between childhood changes in urbanization in the first 10 years and IQ level on the future adult schizophrenia risk. In short, those subjects who moved to more or less urban areas before their 10th birthday lost the protective effect of IQ. When thinking about adult schizophrenia risk, the critical time window of childhood sensitivity to changes in urbanization seems to be linked to IQ. Given the prediction that by 2050, over 80% of the developed world's population will live in an urban environment, this represents a major future public health issue.


Molecular Basis and Genetic Modifiers of Thalassemia.
Thalassemia is a disorder of hemoglobin characterized by reduced or absent production of one of the globin chains in human red blood cells with relative excess of the other. Impaired synthesis of β-globin results in β-thalassemia, whereas defective synthesis of α-globin leads to α-thalassemia. Despite being a monogenic disorder, thalassemia exhibits remarkable clinical heterogeneity that is directly related to the intracellular imbalance between α- and β-like globin chains. Novel insights into the genetic modifiers have contributed to the understanding of the correlation between genotype and phenotype and are being explored as therapeutic pathways to cure this life-limiting disease.


Time dependency of foamy virus evolutionary rate estimates.
It appears that substitution rate estimates co-vary very strongly with their timescale of measurement; the shorter the timescale, the higher the estimated value. Foamy viruses have a long history of co-speciation with their hosts, and one of the lowest estimated rates of evolution among viruses. However, when their rate of evolution is estimated over short timescales, it is more reminiscent of the rapid rates seen in other RNA viruses. This discrepancy between their short-term and long-term rates could be explained by the time-dependency of substitution rate estimates. Several empirical models have been proposed and used to correct for the time-dependent rate phenomenon (TDRP), such as a vertically-translated exponential rate decay model and a power-law rate decay model. Nevertheless, at present, it is still unclear which model best describes the rate dynamics. Here, we use foamy viruses as a case study to empirically describe the phenomenon and to determine how to correct rate estimates for its effects. Four empirical models were investigated: (i) a vertically-translated exponential rate decay model, (ii) a simple exponential rate decay model, (iii) a vertically-translated power-law rate decay model, and (iv) a simple power-law rate decay model. Our results suggest that the TDRP is likely responsible for the large discrepancy observed in foamy virus short-term and long-term rate estimates, and the simple power-law rate decay model is the best model for inferring evolutionary timescales. Furthermore, we demonstrated that, within the Bayesian phylogenetic framework, currently available molecular clocks can severely bias evolutionary date estimates, indicating that they are inadequate for correcting for the TDRP. Our analyses also suggest that different viral lineages may have different TDRP dynamics, and this may bias date estimates if it is unaccounted for. As evolutionary rate estimates are dependent on their measurement timescales, their values must be used and interpreted under the context of the timescale of rate estimation. Extrapolating rate estimates across large timescales for evolutionary inferences can severely bias the outcomes. Given that the TDRP is widespread in nature but has been noted only recently the estimated timescales of many viruses may need to be reconsidered and re-estimated. Our models could be used as a guideline to further improve current phylogenetic inference tools.


The pH of spontaneously beating cultured rat heart cells is regulated by an ATP-calmodulin-dependent Na+/H+ antiport.
We investigated the mechanisms by which spontaneously beating cultured rat ventricular cells regulate intracellular pH (pHi). Specifically, the relative contributions of the Na+/H+ antiport, Cl-/HCO3- exchange, ATP, and calmodulin-dependent processes in regulating the pHi of cells loaded with the intracellular fluorescent pH indicator BCECF were investigated. The pHi of ventricular cells bathed in HEPES-buffered medium averaged 7.30 +/- 0.02. Subsequent exposure of the cells to CO2-HCO3- -buffered medium resulted in intracellular acidification followed by recovery to pHi levels approximately 0.1 pH units lower than in controls. Recovery was inhibited by the Na+/H+ antiport inhibitor 5-(N-ethyl-N-isopropyl)amiloride (EIPA). The recovery from intracellular acidification, induced by a 15-mM ammonium chloride prepulse, was also dependent solely upon activation of the Na+/H+ antiport. Recovery was dependent upon extracellular sodium, was completely inhibited by EIPA, and could be modulated by changes in extracellular pH (pHo). At low pHo values (6.3) the recovery of pHi was greatly attenuated, while at high pHo (8.0) the recovery process was accelerated. The final pHi to which the cells recovered was also dependent upon pHo. Preincubation of the cells with 2-deoxy-D-glucose to deplete cellular ATP levels reduced pHi by approximately 0.2 pH units and greatly impaired the cells' ability to recover from 15-mM ammonium chloride-induced acid load. Similarly, preincubation of cells with the calmodulin inhibitors W-7 and trifluoperazine also impaired their ability to recover from the acid load. The Cl- -HCO3- exchange played no role in the cells' ability to recover from intracellular acidosis. However, the presence of HCO3- significantly increased the resistance of myocardial cells to changes in pHi by approximately doubling their buffer capacity. These results demonstrated that a Na+/H+ antiport is the major pHi-regulating system in spontaneously beating rat ventricular cells. The ability of the Na+/H+ antiport to regulate myocardial pHi is dependent upon the cells' ability to maintain adequate levels of ATP. The antiport's dependency on ATP, in conjunction with its dependency on calmodulin, suggests that activation of the antiport in ventricular cells involves phosphorylation processes.


Predisposing factors for recurrent shoulder dislocation after arthroscopic treatment.
Arthroscopic repair of anterior dislocation of the shoulder can fail. We hypothesized that patients who are at higher risk for redislocation following repair could be recognized preoperatively on the basis of their clinical history. The purpose of the present study was to identify the risk factors for recurrence in a community-based population of patients with traumatic unidirectional instability that was treated with a single arthroscopic technique. From January 2000 to December 2003, 625 patients with anterior unidirectional instability were managed with an arthroscopic Bankart technique, and 385 met the criteria for inclusion in the study. Demographic data were collected, and clinical follow-up was performed at three, six, twelve, twenty-four, and thirty-six months. At thirty-six months, thirty-one patients (8.1%) had experienced a redislocation; the rate was 13.3% among patients who were twenty-two years of age and younger and 6.3% among older patients. Age at the time of the first dislocation, male sex, and the time from the first dislocation until surgery were significant risk factors for recurrence (p < 0.05 for all). Patients who are more likely to have a redislocation following arthroscopic repair of an anterior shoulder dislocation can be identified preoperatively on the basis of sex, age, and the time from the first dislocation to surgery.


Light propagation from a fluorescent particle embedded in a photonic cluster of micrometer-sized dielectric spheres.
In self-assembled multilayer arrays of micrometer-sized spheres that include small amounts of fluorescent particles, unique six-dot-triangular and seven-dot-hexagonal patterns have been known to appear in the fluorescence microscopic images. Although it has been suggested that these two types of patterns correspond to local domain structures, i.e., face centered cubic (fcc) or hexagonal closed packed (hcp), no conclusive evidence has been provided to support this claim. In this study, we systematically investigated the relationship between the propagation patterns and the arrangement of the particles. Through a cross-check between an experiment using well-defined clusters fabricated by a micromanipulation technique and a rigorous calculation based on the expansion of vector spherical harmonics, we confirmed that the six-dot-triangular and seven-dot-hexagonal patterns correspond to the fcc and hcp domains, respectively. Further, we also found that the propagation patterns depend on the size of the clusters. As a result of a quantitative discussion on the light propagation in clusters with various sizes, it was clarified that a sufficient domain size is necessary for the appearance of clear triangular or hexagonal patterns.


Ultrafast interfacial energy transfer and interlayer excitons in the monolayer WS2/CsPbBr3 quantum dot heterostructure.
The idea of fabricating artificial solids with band structures tailored to particular applications has long fascinated condensed matter physicists. Heterostructure (HS) construction is viewed as an effective and appealing approach to engineer novel electronic properties in two dimensional (2D) materials. Different from common 2D/2D heterojunctions where energy transfer is rarely observed, CsPbBr3 quantum dots (0D-QDs) interfaced with 2D materials have become attractive HSs for exploring the physics of charge transfer and energy transfer, due to their superior optical properties. In this paper, a new 0D/2D HS is proposed and experimentally studied, making it possible to investigate both light utilization and energy transfer. Specifically, this HS is constructed between monolayer WS2 and CsPbBr3 QDs, and exhibits a hybrid band alignment. The dynamics of energy transfer within the investigated 0D/2D HS is characterized by femtosecond transient absorption spectrum (TAS) measurements. The TAS results reveal that ultrafast energy transfer caused by optical excitation is observed from CsPbBr3 QDs to the WS2 layer, which can increase the exciton fluence within the WS2 layer up to 69% when compared with pristine ML WS2 under the same excitation fluence. Moreover, the formation and dynamics of interlayer excitons have also been investigated and confirmed in the HS, with a calculated recombination time of 36.6 ps. Finally, the overall phenomenological dynamical scenario for the 0D/2D HS is established within the 100 ps time region after excitation. The techniques introduced in this work can also be applied to versatile optoelectronic devices based on low dimensional materials.


In vivo evaluation of zinc oxide-propolis mixture as root canal filling material in the primary molars: A 24-month follow-up randomized controlled trial.
Pulpectomy is a routine practice in children with pulpal and periapical infections, the success of which depends on the elimination of bacteria from the root canals. Propolis, a natural product with proven antibacterial and anti-inflammatory properties when mixed with zinc oxide powder as root canal filling material, it could provide good success in endodontic therapy of primary teeth. The aim was to evaluate and compare the clinical effectiveness of zinc oxide-propolis mixture with zinc oxide eugenol (ZOE) as root canal filling material in nonvital primary molars. This was a 2-arm, parallel group randomized controlled trial with blinded outcome assessment. Forty primary molars from children aged 4-8 years requiring pulpectomy treatment were randomly allocated into two groups according to the obturating material used: zinc oxide-propolis mixture (test group) and ZOE (control group). All the pulpectomy treated teeth were finally restored with stainless steel crowns, and the children were recalled at 6, 12, and 24 months for postoperative clinical and radiographic evaluation. Chi-square test was used to analyze the data. The overall success rate of pulpectomy with zinc oxide-propolis mixture and ZOE was found to be 95% and 70%, respectively, and the difference was statistically significant (P = 0.037). Zinc oxide-propolis mixture has shown a success rate of 100% at 6 months and 95% at 12 and 24 months follow-up, whereas ZOE has shown 80% success rate at 6 and 12 months, and it declined to 70% at 24-month follow-up. Zinc oxide-propolis mixture demonstrated good clinical and radiographic success at the end of 24 months, and hence, it can be considered as an alternate root canal filling material in the primary teeth.


The improvement of the dissolution rate of ziprasidone free base from solid oral formulations.
This work aims at increasing solubility and dissolution rate of ziprasidone free base-Biopharmaceutics Classifaction System (BCS) class II compound. The authors describe a practical approach to amorphization and highlight problems that may occur during the development of formulations containing amorphous ziprasidone, which was obtained by grinding in high-energy planetary ball mills or cryogenic mills. The release of ziprasidone free base from the developed formulations was compared to the reference drug product containing crystalline ziprasidone hydrochloride-Zeldox® hard gelatin capsules. All preparations were investigated using compendial tests (USP apparatuses II and IV) as well as novel, biorelevant dissolution tests. The novel test methods simulate additional elements of mechanical and hydrodynamic stresses, which have an impact on solid oral dosage forms, especially during gastric emptying. This step may prove to be particularly important for many formulations of BCS class II drugs that are often characterized by narrow absorption window, such as ziprasidone. The dissolution rate of the developed ziprasidone free base preparations was found to be comparable or even higher than in the case of the reference formulation containing ziprasidone hydrochloride, whose water solubility is about 400 times higher than its free base.


Exposure to traffic and mortality risk in the 1991-2011 Canadian Census Health and Environment Cohort (CanCHEC).
There is evidence that local traffic density and living near major roads can adversely affect health outcomes. We aimed to assess the relationship between local road length, proximity to primary highways, and cause-specific mortality in the 1991 Canadian Census Health and Environment Cohort (CanCHEC). In this long-term study of 2.6 million people, based on completion of the long-form census in 1991 and followed until 2011, we used annual residential addresses to determine the total length of local roads within 200 m of postal code representative points and the postal code's distance to primary highways. The association between exposure to traffic and cause-specific non-accidental mortality was estimated using Cox proportional hazards models, adjusting for individual covariates and contextual factors, including census division-level proportion in high school, the percentage of recent immigrants, and neighborhood income. We performed sensitivity analyses, including adjustment for exposure to PM2.5, NO2, or O3, restricting to subjects in core urban areas, and spatial variation by climatic zone. The hazard ratio (HR) for all non-accidental mortality associated with an interquartile increase in length of local roads was 1.05 (95% CI 1.04, 1.05), while for an interquartile range increase in proximity to primary highways, the HR was 1.03 (95% CI 1.02, 1.04). HRs by traffic quartile increased with increasing lengths of local roads, as well as with closer proximity to primary highways, for all mortality causes. The associations were stronger within subjects' resident in urban core areas, attenuated by adjustment for PM2.5, and HRs showed limited spatial variation by climatic zone. In the CanCHEC cohort, exposure to higher road density and proximity to major traffic roads was associated with increased mortality risk from cerebrovascular and cardiovascular disease, ischemic heart disease, COPD, respiratory disease, and lung cancer, with unclear results for diabetes.


Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development.
The development of TCRαβ and TCRγδ T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC-sequencing and ChIPmentation on well-defined thymocyte subsets that represent the continuum of human T cell development. The chromatin accessibility dynamics show clear stage specificity and reveal that human T cell-lineage commitment is marked by GATA3- and BCL11B-dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for β-selection, whereas emerging γδ T cells, which originate from common precursors of β-selected cells, show large chromatin accessibility changes due to strong T cell receptor (TCR) signaling. Furthermore, we unravel distinct chromatin landscapes between CD4+ and CD8+ αβ-lineage cells that support their effector functions and reveal gene-specific mechanisms that define mature T cells. This resource provides a framework for studying gene regulatory mechanisms that drive normal and malignant human T cell development.


Endogenous CO imaging in bacterial pneumonia with a NIR fluorescent probe.
Bacterial pneumonia is a serious respiratory illness that poses a great threat to human life. Rapid and precise diagnosis of bacterial pneumonia is crucial for symptomatic clinical treatment. Endogenous carbon monoxide (CO) is regarded as a significant indicator of bacterial pneumonia; herein, we developed a near-infrared (NIR) probe for fluorescence and photoacoustic (PA) dual-mode imaging of endogenous CO in bacterial pneumonia. NO2-BODIPY could rapidly and specifically react with CO to produce strong NIR fluorescence as well as ratiometric PA signals. NO2-BODIPY has outstanding features including fast response, fluorescence/PA dual mode signals, good specificity, and a low limit of detection (LOD = 20.3 nM), which enables it to image endogenous CO in cells and bacterial pneumonia mice with high sensitivity and high contrast ratio. In particular, NO2-BODIPY has two-photon excited (1340 nm, σ1 = 1671 GM) NIR fluorescence and has been utilized to image endogenous CO in bacterial pneumonia mice with deep tissue penetration. NO2-BODIPY has been demonstrated a good capability of fluorescence/PA dual-mode imaging of CO in bacterial pneumonia mice, providing a precise manner to diagnose bacterial pneumonia.


Fetal growth and risk of stillbirth: a population-based case-control study.
Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary.


Similarities in the Metabolic Reprogramming of Immune System and Endothelium.
Cellular metabolism has been known for its role in bioenergetics. In recent years, much light has been shed on the reprogrammable cellular metabolism underlying many vital cellular processes, such as cell activation, proliferation, and differentiation. Metabolic reprogramming in immune and endothelial cells (ECs) is being studied extensively. These cell compartments are implicated in inflammation and pathogenesis of many diseases but their similarities in metabolic reprogramming have not been analyzed in detail. One of the most notable metabolic reprogramming is the Warburg-like effect, famously described as one of the hallmarks of cancer cells. Immune cells and ECs can display this phenotype that is characterized by a metabolic switch favoring glycolysis over oxidative phosphorylation (OXPHOS) in aerobic conditions. Though energy-inefficient, aerobic glycolysis confers many benefits to the respiring cells ranging from higher rate of adenosine triphosphate production to maintaining redox homeostasis. Chemical and biological regulators either promote or perturb this effect. In this review, nitric oxide, hypoxia-inducible factor, and adenosine monophosphate-activated protein kinase have been discussed for their common involvement in metabolic reprogramming of both systems. From in vitro and animal studies, various discrepancies exist regarding the effects of those regulators on metabolic switch. However, it is generally accepted that glycolysis favors inflammatory reactions while OXPHOS favors anti-inflammatory processes. The reasons for such observation are currently subject of intense studies and not completely understood. Finally, metabolic reprogramming in immune cells and ECs does not limit to the physiological state in health but can also be observed in pathological states, such as atherosclerosis and cancer. These new insights provide us with a better understanding of the similarities in metabolic reprogramming across a number of cell types, which could pave the way for future research and possible metabolic-based therapeutics.


Comparison of heat shock response in Brucella abortus and Brucella melitensis.
Heat shock protein (hsp) is highly conserved, that serves a wide range of function in protein folding and transport. It protect from various type of stress including heat shocks. However, it is well known that the virulence of B. melitensis is more than B. abortus, but there is not any strong evidence to verify it. For this purpose, in refer to potent antigenicity of hsps in various infectious as well as some hsp molecules act as potent activator of macrophage (danger signal), we hypothesized that difference in virulence between B. abortus and B. melitensis may be originated from difference in pattern of response to heat shock induced by high degree of fever that usually present in brucellosis. To this end, five B. abortus and five B. melitensis strains isolated from cows and human, were subjected to 39, 40 and 42 degrees C heat shocks. The bacterial whole cell proteins were extracted and resolved by SDS-PAGE. Western blotting was used to detect antibody production against the extracted bacterial proteins especially hsp60 in both control and patient sera. SDS-PAGE gels revealed protein bands mainly in the range of 10-100 kDa. The amounts of a 60 kDa protein band (hsp60) was significantly enhanced following heat shock at 42 degrees C in relation to the unheated cells in both bacterial species. The heat shock responses in B. abortus and B. melitensis point to the higher production of a 60 kDa protein (hsp60) in both bacterial species, especially in B. abortus. It seems that, lower hsp60 production by B. melitensis would induce a relatively much lower immune response against the bacterium leading to its greater virulence potentials; the sera from Brucellosis patients reacted with several of these cell derived protein bands in western blots, none of which were reactive with sera from healthy individuals. The western blot protein bands showed striking differences. This observation points to the immunogenic properties of hsps, specially the overwhelming response to hsp-60. Therefore, hsp-60 can be a good antigenic candidate for engineering subunit vaccine against Brucella, as well as for ELISA test development.


Cardiovascular involvement in psoriatic arthritis.
Psoriasis is a chronic, genetically determined and immunomediated inflammatory skin disease that affects 2-3% of the Caucasian population. A considerable proportion of these patients develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), although the prevalence of this has not been well defined. Patients with PsA have a higher mortality rate than the general population and the risk of mortality is related to disease severity at the time of presentation. Endothelial dysfunction and early atherosclerosis have been found in patients with PsA without any cardiovascular disease (CVD) risk factors, and experts believe that CVD is one of the leading causes of death, as it is in patients with rheumatoid arthritis (RA). Various disease-related mechanisms may be involved in the development of premature vascular damage in both cases, including an increased synthesis of proinflammatory mediators (such as cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors. In a recent study of 22 patients with PsA without any signs of CVD, we found that the plasma concentration of asymmetric dimethylarginine (ADMA) levels were significantly high and coronary flow reserve (CFR) was significantly reduced. Moreover, there was a significant correlation between CFR and plasma ADMA levels in the PsA group. The significant correlation between the reduced CRF and increased ADMA levels suggests that, like patients with early RA, PsA patients suffer from endothelial dysfunction and impaired coronary microcirculation. Active PsA is a risk factor for CVD, and so PsA patients should be screened for subclinical forms of the disease and its risk factors, and an early treatment approach should be adopted.


Selenium levels in whole blood of Finnish volunteers before and during organic and inorganic selenium supplementation.
High selenium barley biscuits containing 1 mumol (70 micrograms) organic Se were administered to healthy male volunteers for 5 weeks at doses of 2.1 mumol Se (group A) or 6.4 mumol (group B). In addition, 2 mg Na-selenate capsules (5.4 mumol Se) were given to two other groups at daily doses of 2 mg (group C) or 8 mg (group D). Groups A, B and C each comprised eight healthy men and group D eight healthy women and three men. The initial median concentration of whole blood selenium (B-Se for groups A, B and C were 1.0-1.1 mumol/l (range 0.7-1.7) and for group D 1.3 mumol/l (range 0.9-1.8). In 1-2 weeks time the B-Se concentrations rose to 1.6 mumol/l for groups A and C, to 1.8 mumol/l for group B, and to 2.2 mumol/l for group D. There was no decrease 1 week after the Se intake ceased. As expected, the level of B-Se increased more (in relation to dose) in those given organic Se than in those given inorganic Se. Groups A, B and C, however, had rather moderate increases. The daily dose required to raise the B-Se of Finns up to the North American level (2.2 mumol/l) was as high as 8 mg Na-selenate (21.5 mumol or 1700 micrograms Se), but the dose of organic Se which would be required to achieve this level is not yet known.


A comparison of phosphonothioic acids with phosphonic acids as phosphatase inhibitors.
Phosphorothioates, analogues of phosphate esters in which a sulfur replaces an oxygen atom in the phosphoryl group, are competent surrogate substrates for a number of phosphatases. In some cases the thio analogues show similar binding (as estimated by K(m)) while other phosphatases show quite different K(m) values for phosphate compared to phosphorothioate esters. On this basis it was hypothesized that there might be different inhibitory tendencies by the nonhydrolyzable analogues, phosphonothioic acids compared with phosphonic acids. A series of phosphonothioic acids and corresponding phosphonic acids were synthesized and their inhibitory properties were compared toward human placental and E. coli alkaline phosphatases, the protein-tyrosine phosphatase from Yersinia, and the serine/threonine protein phosphatases PP2C and lambda. Sulfur substitution for oxygen gives the phosphonothioic acids pK(a) values that are close to those of phosphate esters, in contrast to the higher pK(a) values typical of phosphonic acids. Despite different steric requirements and differences in charge distribution in the anions of phosphonothioic acids compared with phosphonic acids, it was found that, with some exceptions, differences in inhibitory properties were modest.


Influenza vaccine: awareness and barriers to immunization in families of children with chronic medical conditions other than asthma.
Children with chronic medical conditions (CMCs) are considered to be at increased risk for influenza and its related complications. Despite this, influenza immunization rates in the United States for children with CMCs in the primary care setting remain between 7-10%. This was a survey study looking at the barriers to influenza immunization among children with CMCs other than asthma. We examined caregiver knowledge and perceptions regarding influenza vaccine in addition to assessing other barriers, such as availability and perceived safety of the vaccine. The study was conducted during the fall-winter influenza seasons of 2002-2003 and 2003-2004 at five academic institutions across the southeastern US. Convenience samples of 100-150 families attending pediatric subspecialty clinics were surveyed. A total of 794 surveys were completed. Controlling for disease, failure to recommend vaccination was significantly associated with failure to get the vaccine (P < 0.0001). Of the children who did not receive the vaccine, 61% of their parents believed that the vaccine itself could give influenza, 54% cited other safety concerns, and 30% thought it did not work. Among vaccine recipients, 163 (43%) reported that the primary care provider had given the vaccine, whereas 171 (45%) reported that the vaccine had been given at the subspecialty clinic. This study highlights the importance of physician recommendation, as well as parental education, as some of the key elements crucial to the receipt of influenza vaccination in children with CMCs.


Identification of Host Fruit Volatiles from Snowberry (Symphoricarpos albus), Attractive to Rhagoletis zephyria Flies from the Western United States.
A mixture of behaviorally active volatiles was identified from the fruit of snowberry, Symphoricarpos albus laevigatus, for Rhagoletis zephyria flies reared from snowberry fruit. A nine-component blend containing 3-methylbutan-1-ol (3%), dimethyl trisulfide (1%), 1-octen-3-ol (40%), myrcene (8%), nonanal (9%), linalool (13%), (3E)-4,8-dimethyl-1,3,7-nonatriene (DMNT, 6%), decanal (15%), and β-caryophyllene (5%) was identified that gave consistent electroantennogram activity and was behaviorally active in flight tunnel tests. In other flight tunnel assays, snowberry flies from two sites in Washington state, USA, displayed significantly greater levels of upwind oriented flight to sources with the snowberry volatile blend compared with previously identified volatile blends from domestic apple (Malus domestica) and downy hawthorn (Crataegus mollis) fruit from the eastern USA, and domestic apple, black hawthorn (C. douglasii) and ornamental hawthorn (C. monogyna) from Washington state. Selected subtraction assays showed that whereas removal of DMNT or 1-octen-3-ol significantly reduced the level of upwind flight, removal of myrcene and β-caryophyllene, or dimethyl trisulfide alone did not significantly affect the proportion of upwind flights. Our findings add to previous studies showing that populations of Rhagoletis flies infesting different host fruit are attracted to unique mixtures of volatile compounds specific to their respective host plants. Taken together, the results support the hypothesis that differences among flies in their behavioral responses to host fruit odors represent key adaptations involved in sympatric host plant shifts, contributing to host specific mating and generating prezygotic reproductive isolation among members of the R. pomonella sibling species complex.


Yoga practice is associated with superior motor imagery performance.
Yoga is an activity that aims to integrate physical, mental and spiritual elements and is an increasingly popular approach to enhancing physical fitness. The integration of imagery within yoga practice is considered an important component and may be critical in contributing to the benefits of yoga that have been reported. In this study, we tested whether individuals who practice yoga demonstrate superior performance on an objective measure of implicit motor imagery. Thirty-six participants (18 yoga, 18 non-yoga) matched for age, sex and handedness, undertook the hand laterality recognition task; an objective measure of implicit motor imagery performance. Accuracy and response times were gathered and analysed to determine any group differences as well as any differences relating to the typical hallmarks of imagery (i.e. dominance and awkwardness effects) on the task. Response Times (RTs) in the yoga group were significantly faster than controls (p < 0.05) and there was also a trend towards greater accuracy for the Yoga group (p = 0.073). Dominance effects (faster responses to images corresponding with the dominant limb) and Awkwardness effects (faster responses to images corresponding with natural compared with awkward postures) were evident across groups, supporting the participants' use of motor imagery in undertaking the task. Additionally, a Group × Awkwardness interaction (p < 0.05) revealed that the enhanced imagery performance for the yoga group was most pronounced for awkward postures. This is the first study to show that yoga practice is associated with superior motor imagery performance; an association that may be important in explaining the established rehabilitative value of yoga for chronic pain.


N4 component responses to pre-pulse startle stimuli in young adults: relationship to alcohol dependence.
Both physiological and behavioral studies provide evidence to suggest that deficits in frontal cortical control circuits may contribute to the risk for developing alcohol dependence. Event-related potential (ERP) and eye blink responses to startle and short delay prepulse-plus-startle stimuli, and psychiatric diagnoses were investigated in young adult (age 18-30 years) men (n=135) and women (n=205) Mexican Americans. Women displayed a significant increase in the amplitude of the eye blink response to both the startle and pre-pulse-plus-startle stimuli. None of the psychiatric diagnoses were associated with differences in eye blink responses. ERP responses to the startle and prepulse-plus startle stimuli included a negative polarity wave at approximately 400 ms that was of the highest amplitude in the frontal leads (N4S). Women were found to have significantly higher amplitude N4S responses than men. Participants with alcohol dependence demonstrated significantly less inhibition and more facilitation of the N4S component by the pre-pulse stimuli. This finding was not associated with a diagnosis of: any other drug dependence disorder (including nicotine), anxiety or affective disorder, or conduct/antisocial personality disorder. The present study suggests that gender and a lifetime diagnosis of alcohol dependence may selectively contribute to this frontal late wave electrophysiological response to prepulse-plus-startle stimuli.


Translational cross talk in gene networks.
It has been shown experimentally that competition for limited translational resources by upstream mRNAs can lead to an anticorrelation between protein counts. Here, we investigate a stochastic model for this phenomenon, in which gene transcripts of different types compete for a finite pool of ribosomes. Throughout, we utilize concepts from the theory of multiclass queues to describe a qualitative shift in protein count statistics as the system transitions from being underloaded (ribosomes exceed transcripts in number) to being overloaded (transcripts exceed ribosomes in number). The exact analytical solution of a simplified stochastic model, in which the numbers of competing mRNAs and ribosomes are fixed, exhibits weak positive correlations between steady-state protein counts when total transcript count slightly exceeds ribosome count, whereas the solution can exhibit strong negative correlations when total transcript count significantly exceeds ribosome count. Extending this analysis, we find approximate but reasonably accurate solutions for a more realistic model, in which abundances of mRNAs and ribosomes are allowed to fluctuate randomly. Here, ribosomal fluctuations contribute positively and mRNA fluctuations contribute negatively to correlations, and when mRNA fluctuations dominate ribosomal fluctuations, a strong anticorrelation extremum reliably occurs near the transition from the underloaded to the overloaded regime.


The role of motion streaks in the perception of the kinetic Zollner illusion.
In classic geometric illusions such as the Zollner illusion, vertical lines superimposed on oriented background lines appear tilted in the direction opposite to the background. In kinetic forms of this illusion, an object moving over oriented background lines appears to follow a titled path, again in the direction opposite to the background. Existing literature does not proffer a complete explanation of the effect. Here, it is suggested that motion streaks underpin the illusion; that the effect is a consequence of interactions between detectors tuned to the orientation of background lines and those sensing the motion streaks that arise from fast object motion. This account was examined in the present study by measuring motion-tilt induction under different conditions in which the strength or salience of motion streaks was attenuated: by varying object speed (Experiment 1), contrast (Experiment 2), and trajectory/length by changing the element life-time within the stimulus (Experiment 3). It was predicted that, as motion streaks become less available, background lines would less affect the perceived direction of motion. Consistent with this prediction, the results indicated that, with a reduction in object speed below that required to generate motion streaks (< 1.12°/s), Weber contrast (< 0.125) and motion streak length (two frames) reduced or extinguished the motion-tilt-induction effect. The findings of the present study are consistent with previous reports and computational models that directly combine form and motion information to provide an effective determinant of motion direction.


Application of long read sequencing to determine expressed antigen diversity in Trypanosoma brucei infections.
Antigenic variation is employed by many pathogens to evade the host immune response, and Trypanosoma brucei has evolved a complex system to achieve this phenotype, involving sequential use of variant surface glycoprotein (VSG) genes encoded from a large repertoire of ~2,000 genes. T. brucei express multiple, sometimes closely related, VSGs in a population at any one time, and the ability to resolve and analyse this diversity has been limited. We applied long read sequencing (PacBio) to VSG amplicons generated from blood extracted from batches of mice sacrificed at time points (days 3, 6, 10 and 12) post-infection with T. brucei TREU927. The data showed that long read sequencing is reliable for resolving variant differences between VSGs, and demonstrated that there is significant expressed diversity (449 VSGs detected across 20 mice) and across the timeframe of study there was a clear semi-reproducible pattern of expressed diversity (median of 27 VSGs per sample at day 3 post infection (p.i.), 82 VSGs at day 6 p.i., 187 VSGs at day 10 p.i. and 132 VSGs by day 12 p.i.). There was also consistent detection of one VSG dominating expression across replicates at days 3 and 6, and emergence of a second dominant VSG across replicates by day 12. The innovative application of ecological diversity analysis to VSG reads enabled characterisation of hierarchical VSG expression in the dataset, and resulted in a novel method for analysing such patterns of variation. Additionally, the long read approach allowed detection of mosaic VSG expression from very few reads-the earliest in infection that such events have been detected. Therefore, our results indicate that long read analysis is a reliable tool for resolving diverse gene expression profiles, and provides novel insights into the complexity and nature of VSG expression in trypanosomes, revealing significantly higher diversity than previously shown and the ability to identify mosaic gene formation early during the infection process.


Justice and justiciability: advancing solidarity and justice through South Africans' right to health jurisprudence.
The South African Constitutional Court's jurisprudence provides a path-breaking illustration of the social justice potential of an enforceable right to health. It challenges traditional objections to social rights by showing that their enforcement need not be democratically unsound or make zero-sum claims on limited resources. Indeed the South African experience suggests that enforcing health rights may in fact contribute to greater degrees of collective solidarity and justice as the Court has sought to ensure that the basic needs of the poor are not unreasonably restricted by competing public and private interests. This approach has seen the Court adopt a novel fights paradigm which locates individual civil and social rights within a communitarian framework drawing from the traditional African notion of'ubuntu', denoting collective solidarity, humaneness and mutual responsibilities to recognize the respect, dignity and value of all members of society. Yet this jurisprudence also illustrates the limits of litigation as a tool of social transformation, and of social rights that remain embedded in ideological baggage even where they have been constitutionally entrenched and enforced. This paper explores the Constitutional Court's unfolding jurisprudence on the right to health, providing background to the constitutional entrenchment of a justiciable right to health; exploring early Constitutional Court jurisprudence on this right; turning to the forceful application of this right in relation to government policy on AIDS treatment; and concluding with thoughts about the strengths and limits of this jurisprudence in light of subsequent case-law.


Population based epidemiology and prognosis of mesothelioma in Leeds, UK.
Malignant mesothelioma is a fatal neoplasm, which is rapidly increasing in incidence throughout Western Europe. To date there have been no studies reporting on the natural history and interventional practices on a comprehensive unselected population, as opposed to reports from referral institutions or compensation claimants. We present a population based study capturing data on all patients with mesothelioma presenting within a defined geographical area over a 4 year period in the UK. Data of all cases occurring in Leeds with a population of 750 000 were collected retrospectively from 2002 to 2003 and prospectively from 2004 to 2005. All patients' hospital records and the Trust histology database were reviewed, as well as coroner's reports on all patients with a post mortem diagnosis of mesothelioma. Over the 4 year study period, there were a total of 146 cases in Leeds; 77% were male. Median age was 74 years (range 36-93). Median survival from diagnosis was 8.9 months. 92% and 8% had histological or cytological confirmation, respectively. 85% had documented evidence of definite or probable exposure to asbestos. 110/146 (75%) had symptomatic pleural effusions at presentation. Twice the number of patients (42 vs 17) were managed with surgical rather than bedside pleurodesis and these had a lower recurrence rate (14% vs 47%; p = 0.02). 122 patients had video assisted thoracoscopic surgery/cutting CT biopsies or chest drains. 73/122 (60%) had prophylactic radiotherapy to these sites. There were seven cases (5%) of tract invasion by tumour and six of these had received prophylactic radiotherapy. Median time to seeding was 174 days. 92/146 (63%) had a performance status of 2 or better at diagnosis but only 54/146 were considered fit for chemotherapy. Of these, 28 (52%) declined chemotherapy; the overall uptake of chemotherapy or entry into a trial was 18%. No patient had radical surgery. This comprehensive population based audit has shown that the median age at presentation of malignant mesothelioma is increasing and baseline performance status and survival is worse than in selected series. 37% of patients were considered suitable for palliative chemotherapy but less than 20% accepted this offer. Thorascopic pleurodesis appears to be associated with fewer recurrences. The role of prophylactic radiotherapy to chest drain and biopsy sites needs reappraisal.


Project quality rating by experts and practitioners: experience with Preffi 2.0 as a quality assessment instrument.
Preffi 2.0 is an evidence-based Dutch quality assessment instrument for health promotion interventions. It is mainly intended for both planning and assessing one's own projects but can also be used to assess other people's projects (external use). This article reports a study on the reliability of Preffi as an external quality assessment instrument. Preffi is used to assess quality at three levels: (i) specific criteria, (ii) clusters of criteria and (iii) entire projects. The study compared Preffi-based assessments of 20 projects by three practitioners with their intuitive assessments of the same projects and with assessments by three experts, which were to be used as external criteria. The intuitive assessments only related to the cluster and project levels. Our main hypothesis was that intuitive assessments by practitioners would be less reliable and accurate than their Preffi-based assessments and the experts' assessments. On the whole, we failed to confirm this hypothesis: the experts' assessments proved less reliable and accurate than the practitioners' intuitive and Preffi-based assessments and differed too much from each other to be used as external criteria. The Preffi-based assessments by the practitioners had an acceptable generalizability coefficient (G) and accuracy (standard error of measurement). At the level of the entire project, two assessors are needed to produce sufficiently reliable and accurate assessments, whereas three are needed for assessment at cluster level. The study also showed that different assessors use different perspectives and base their assessment on a variety of aspects. This was regarded as inevitable and even useful by the assessors themselves. Discussions between assessors are important to achieve consensus. The article suggests some improvements to Preffi to further increase its reliability.


The moral standing of animals: Towards a psychology of speciesism.
We introduce and investigate the philosophical concept of 'speciesism' -the assignment of different moral worth based on species membership -as a psychological construct. In five studies, using both general population samples online and student samples, we show that speciesism is a measurable, stable construct with high interpersonal differences, that goes along with a cluster of other forms of prejudice, and is able to predict real-world decision-making and behavior. In Study 1 we present the development and empirical validation of a theoretically driven Speciesism Scale, which captures individual differences in speciesist attitudes. In Study 2, we show high test-retest reliability of the scale over a period of four weeks, suggesting that speciesism is stable over time. In Study 3, we present positive correlations between speciesism and prejudicial attitudes such as racism, sexism, homophobia, along with ideological constructs associated with prejudice such as social dominance orientation, system justification, and right-wing authoritarianism. These results suggest that similar mechanisms might underlie both speciesism and other well-researched forms of prejudice. Finally, in Studies 4 and 5, we demonstrate that speciesism is able to predict prosociality towards animals (both in the context of charitable donations and time investment) and behavioral food choices above and beyond existing related constructs. Importantly, our studies show that people morally value individuals of certain species less than others even when beliefs about intelligence and sentience are accounted for. We conclude by discussing the implications of a psychological study of speciesism for the psychology of human-animal relationships. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Opioid receptors and endogenous opioids in diverse human and animal cancers.
Receptor binding studies demonstrated specific high-affinity, saturable binding of a number of opioid ligands to a wide variety of neural and nonneural human and animal tumors. Radioimmunoassays revealed the presence of beta-endorphin and methionine-enkephalin in these tumors. Both methionine- and leucine-enkephalin were detected in tumor tissue by immunocytochemistry, with immunoreactivity related to the cortical cytoplasm of tumor cells, but not to cell nuclei. Endogenous opioids and receptors were found in benign and malignant tumors representative of ectodermal, mesodermal, and endodermal origin. Receptors and endogenous opioid peptides were present in tumors from many different species, including those transplanted into nude mice. These results suggest that opioid receptors and endogenous opioids are fundamental features of human and animal cancers.


The Use of "Optimal Cytoreduction" Nomenclature in Ovarian Cancer Literature: Can We Move Toward a More Optimal Classification System?
The objective of this study is to explore how cytoreductive surgical outcomes such as residual disease (RD) and use of the term "optimal cytoreduction" (OCR) have changed over time in the ovarian cancer literature. We identified all English-language publications referring to ovarian cancer cytoreduction for a 12-year period. Publications were evaluated for how the diameter of RD was categorized and whether OCR was defined. In addition, the use of RD and OCR terminology trends over time and associations between terminology and the region of corresponding author, study type, and journal impact factor were explored. Of the 772 publications meeting inclusion criteria, the RD stratification points used to demarcate patient groups were as follows: 0 mm (45%), 5 mm (3.6%), 10 mm (65%), and 20 mm (24%). The use of 0-mm RD (odds ratio [OR], 1.1; 95% confidence interval, 1.05-1.15) and 10-mm RD (OR, 1.1; 95% confidence interval, 1.09-1.20) to delineate patient outcomes increased over time. The use of OCR terminology did not change over time but was more commonly used in clinical studies as well as those from North America. Many studies (70%) defined OCR as less than or equal to 10-mm RD, whereas 30% defined OCR differently or not at all. Optimal cytoreduction terminology remains ambiguous and inconsistently used in the ovarian cancer surgical literature. On the basis of this literature review, we propose a novel classification system to categorize RD without reference to OCR while accurately and succinctly identifying meaningful clinical subgroups and minimizing bias.


External validation of the QCovid risk prediction algorithm for risk of COVID-19 hospitalisation and mortality in adults: national validation cohort study in Scotland.
The QCovid algorithm is a risk prediction tool that can be used to stratify individuals by risk of COVID-19 hospitalisation and mortality. Version 1 of the algorithm was trained using data covering 10.5 million patients in England in the period 24 January 2020 to 30 April 2020. We carried out an external validation of version 1 of the QCovid algorithm in Scotland. We established a national COVID-19 data platform using individual level data for the population of Scotland (5.4 million residents). Primary care data were linked to reverse-transcription PCR (RT-PCR) virology testing, hospitalisation and mortality data. We assessed the performance of the QCovid algorithm in predicting COVID-19 hospitalisations and deaths in our dataset for two time periods matching the original study: 1 March 2020 to 30 April 2020, and 1 May 2020 to 30 June 2020. Our dataset comprised 5 384 819 individuals, representing 99% of the estimated population (5 463 300) resident in Scotland in 2020. The algorithm showed good calibration in the first period, but systematic overestimation of risk in the second period, prior to temporal recalibration. Harrell's C for deaths in females and males in the first period was 0.95 (95% CI 0.94 to 0.95) and 0.93 (95% CI 0.92 to 0.93), respectively. Harrell's C for hospitalisations in females and males in the first period was 0.81 (95% CI 0.80 to 0.82) and 0.82 (95% CI 0.81 to 0.82), respectively. Version 1 of the QCovid algorithm showed high levels of discrimination in predicting the risk of COVID-19 hospitalisations and deaths in adults resident in Scotland for the original two time periods studied, but is likely to need ongoing recalibration prospectively.