Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis.
To investigate the contribution of the gut microbiota to the pathogenesis of uveitis. Experimental autoimmune uveitis (EAU) in B10.RIII mice was induced using interphotoreceptor binding protein peptide. Mice were treated with oral or intraperitoneal (IP) antibiotics. Effector (Teff) and regulatory (Treg) T lymphocytes were identified using flow cytometry; 16S rRNA gene sequencing and qPCR were performed on gastrointestinal (GI) contents. Broad-spectrum (four antibiotics given simultaneously) oral, but not IP, antibiotics reduced mean uveitis clinical scores significantly compared with water-treated animals (0.5 vs. 3.0, P < 0.0001 for oral; 3.4 vs. 3.4, P > 0.99 for IP). Both oral metronidazole (P = 0.02) and vancomycin (P < 0.0001) alone decreased inflammation, whereas neomycin (P = 0.7) and ampicillin (P = 0.4) did not change mean uveitis scores. Oral broad-spectrum antibiotics increased Tregs in the GI lamina propria of EAU animals at 1 week, and in extraintestinal lymphoid tissues later, whereas Teff and inflammatory cytokines were reduced. 16S sequencing of GI contents revealed altered microbiota in immunized mice compared with nonimmunized mice, and microbial diversity clustering in EAU mice treated with uveitis-protective antibiotics. Experimental autoimmune uveitis mice also demonstrated gut microbial diversity clustering associated with clinical score severity. Oral antibiotics modulate the severity of inducible EAU by increasing Tregs in the gut and extraintestinal tissues, as well as decreasing effector T cells and cytokines. 16S sequencing suggests that there may be protective and, conversely, potentially uveitogenic, gut microbiota. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiome.


Controls of nitrogen limitation in tallgrass prairie.
The relationship between fire frequency and N limitation to foliage production in tallgrass prairie was studied with a series of fire and N addition experiments. Results indicated that fire history affected the magnitude of the vegetation response to fire and to N additions. Sites not burned for over 15 years averaged only a 9% increase in foliage biomass in response to N enrichment. In contrast, foliage production increased an average of 68% in response to N additions on annually burned sites, while infrequently burned sites, burned in the year of the study, averaged a 45% increase. These findings are consistent with reports indicating that reduced plant growth on unburned prairie is due to shading and lower soil temperatures, while foliage production on frequently burned areas is constrained by N availability. Infrequent burning of unfertilized prairie therefore results in a maximum production response in the year of burning relative to either annually burned or long-term unburned sites.Foliage biomass of tallgrass prairie is dominated by C4 grasses; however, forb species exhibited stronger production responses to nitrogen additions than did the grasses. After four years of annual N additions, forb biomass exceeded that of grass biomass on unburned plots, and grasses exhibited a negative response to fertilizer, probably due to competition from the forbs. The dominant C4 grasses may out-compete forbs under frequent fire conditions not only because they are better adapted to direct effects of burning, but because they can grow better under low available N regimes created by frequent fire.


Peer review of the pesticide risk assessment of the active substance prosulfuron.
The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State, France, for the pesticide active substance prosulfuron are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions were reached on the basis of the evaluation of the representative uses of prosulfuron as a herbicide on maize and sweet corn. Following the renewal of approval, prosulfuron has been renewed with the restriction that the use shall be limited to one application every 3 years. This assessment follows the request of the applicant to lift the restriction of the approval conditions. The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified.


MOF-derived Mn doped porous CoP nanosheets as efficient and stable bifunctional electrocatalysts for water splitting.
Searching for highly active and stable bifunctional electrocatalysts for overall water splitting, e.g., for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER), is dominating in terms of bringing future renewable energy storage and conversion processes to reality. In this work, a kind of two-dimensional ultrathin manganese (Mn) doped polyhedral cobalt phosphide (Mn-CoP) has been synthesized via the etching-carbonization-phosphidation of Co-centered metal-organic frameworks. The as-prepared porous Mn-CoP nanosheets had a larger specific surface area and higher porosity, furnishing them with more plentiful catalytically active sites than their counterpart hollow CoP and Mn-CoP nanoparticles, and thus showed much better electrocatalytic activity for both HER and OER in acidic and alkaline media. In addition, the Mn-CoP nanosheets also demonstrated excellent durability after long-term operation. These high performances are attributed to the synergistic effects of the CoP nanosheets with intrinsic activity, the graphitic carbon and the controllable electronic structure doped by Mn and N elements. This synthetic methodology of using a classical MOF as a precursor to build a new 2D sheet-like composite may create opportunities to search for highly efficient and robust non-precious metal catalysts for energy-related reactions.


Calibration of fundus images using spectral domain optical coherence tomography.
Measurements performed on fundus images using current software are not accurate. Accurate measurements can be obtained only by calibrating a fundus camera using measurements between fixed retinal landmarks, such as the dimensions of the optic nerve, or by relying on a calibrated model eye provided by a reading center. However, calibrated spectral domain OCT (SD-OCT) could offer a convenient alternative method for the calibration of any fundus image. The ability to measure exact distances on SD-OCT fundus images was tested by measuring the distance between the center of the fovea and the optic nerve. Calibrated SD-OCT scans measuring 6 X 6 X 2 mm centered on the fovea and the optic nerve were analyzed in 50 healthy right eyes. The foveal center was identified using cross-sectional SD-OCT images, and the center of the optic nerve was identified manually. The SD-OCT scans were registered to each other, and the distances between the center of the optic nerve and fovea were calculated. The overlay of these SD-OCT fundus images on photographic fundus images was performed. Any image of the fundus could be calibrated by overlaying the SD-OCT fundus image, and the measurements were consistent with previously defined calibration methods. The mean distance between the center of the fovea and the center of the optic nerve was 4.32 +/-0.32 mm. The line from the center of the optic nerve to the foveal center had a mean declination of 7.67 +/- 3.88 degrees. Mean horizontal displacement and vertical displacement were 4.27 +/- 0.29 mm and 0.58 +/- 0.29 mm, respectively. The overlay of the SD-OCT fundus image provides a convenient method for calibrating any image of the fundus. This approach should provide a uniform standard when comparing images from different devices and from different reading centers.


Moderate-to-severe psoriasis and pregnancy: impact on fertility, pregnancy outcome and treatment perspectives.
Psoriasis affects 2-4% of the world's population, with no difference between men and women and 70% of patients experiencing disease onset before the age of 40, which coincides with the reproductive years. Few data are available from literature on impact of psoriasis on fertility, course and outcome of pregnancy and risk associated with treatments. Recent studies on other immune-mediated inflammatory diseases, among which psoriasis is also included, indicate that rheumatoid arthritis and inflammatory bowel diseases can impact female fertility and pregnancy outcomes especially during active disease episodes. In psoriasis hormonal and metabolic comorbidities, unhealthy lifestyles and systemic inflammation could also influence the ability to conceive, pregnancy course and birth outcomes. In this article we review current knowledge on reproductive function, course and outcome of pregnancy in women affected by moderate-to-severe psoriasis. Systemic treatments are also considered with a special focus on TNF-alpha blocking agents and implication of molecular structure on placental transportation and fetal exposure.


Nitrogen cycling in a Norway spruce plantation in Denmark--a SOILN model application including organic N uptake.
A dynamic carbon (C) and nitrogen (N) circulation model, SOILN, was applied and tested on 7 years of control data and 3 years of manipulation data from an experiment involving monthly N addition in a Norway spruce ( Picea abies, L. Karst) forest in Denmark. The model includes two pathways for N uptake: (1) as mineral N after mineralisation of organic N, or (2) directly from soil organic matter as amino acids proposed to mimic N uptake by mycorrhiza. The model was parameterised and applied to the data from the control plot both with and without the organic N uptake included. After calibration, the models performance was tested against data from the N-addition experiment by comparing model output with measurements. The model reproduced well the overall trends in C and N pools and the N concentrations in soil solutions in the top soil layers whereas discrepancies in soil-solution concentrations in the deeper soil layers are seen. In the control data, the needle-N concentration was well reproduced except for small underestimations in some years because of drought effects not included in the model. In the N-addition experiment, SOILN reproduces the observed changes; in particular, the changes in needle-N concentrations and the overall distribution within the ecosystem of the extra added 3.5 g N m(-2) year(-1) parallel the observations. When organic N uptake is included, the simulations indicate that in the control plot receiving c. 1.9 g N m(-2) year(-1), the organic N uptake in average supplies 35% of the total plant N uptake. By addition of an extra 35 kg N ha(-1) year(-1), the organic N uptake is reduced to 16% of the total N uptake. Generally, inclusion of the pathway for organic N uptake improves model performance compared with observations for both C and N. This is because mineral N uptake alone implies a larger mineralisation rate, leading to bigger concentrations of N in the soil and soil water, bigger N losses, and net loss of c. 100 kg C ha(-1) year(-1), thereby causing depletion of the organic soil layer.


New species of Hohenbuehelia, with comments on the Hohenbuehelia atrocoerulea - Nematoctonus robustus species complex.
Four new species of Hohenbuehelia (Fungi: Pleurotaceae) are described in the group of Hohenbuehelia atrocoerulea and Hohenbuehelia grisea. Hohenbuehelia algonquinensis, found on Pinus in Ontario, Canada, may be distinguished macroscopically from bluish collections of H. atrocoerulea and watery grey-brown collections of H. grisea by its coal-black pileus. Hohenbuehelia canadensis, on or associated with Pinus in both Ontario and Alberta, Canada, and Hohenbuehelia nimueae, on Salix in Ontario and Abies in Wyoming, USA, have similarly dark fruiting bodies and were previously misidentified as H. approximans (which we treat as a synonym of H. grisea), H. atrocoerulea, H. mustialensis or H. nigra. The latter species is shown to be a member of Resupinatus, despite the presence of prominent metuloid cystidia in its hymenium. Hohenbuehelia carlothornii has been found in Costa Rica; collections of the sexual fruiting bodies were previously identified as H. grisea and isolates from soil nematodes were identified by the anamorph name Nematoctonus robustus. That name has been treated as a synonym of H. atrocoerulea but, given the genetic and geographic variation within this complex, we transfer it to Hohenbuehelia as a distinct species. Sequences of the nuclear ribosomal DNA internal transcribed spacer region (ITS), the D1/D2 variable region of the large subunit gene, and a portion of the translation elongation factor (TEF1) gene provide good separation and support for these new species. A key to the dimidiate species of Hohenbuehelia of North America and Europe is provided.


Dying of boredom: an exploratory case study of time use, apparent affect, and routine activity situations on two Alzheimer's special care units.
The objective of this instrumental case study was to explore interrelationships among routine activity situations on 2 Alzheimer's special care units (SCUs) and 2 resident quality-of-life (QoL) indicators: daily time use and emotional well-being. Fourteen residents participated. We collected data across four 12-hr days using computer-assisted direct observations and computed associations of activity situations with QoL indicators and mean durations of QoL indicators in activity situations and daily by facility. We compared mean durations of QoL indicators across facilities and analyzed time-use profiles of 2 residents. We found that participants' capacities for activity engagement and emotional vitality were infrequently expressed at both SCUs. Diminished QoL was attributable to participants' dementia-related impairments coupled with insufficient attention to their occupational needs, initiatives, and capacities. Findings call for occupational therapists' involvement as educators, mentors, and consultants to enhance the effectiveness of routine activity situations in promoting QoL through everyday occupations.


Dietary variables and glucose tolerance in pregnancy.
To investigate relationships between dietary macronutrient intakes and glucose tolerance in pregnancy Nulliparous pregnant Chinese women diagnosed with gestational diabetes mellitus (GDM) (n = 56) were compared to age-, gestational age-, height-, and parity-matched groups with normal glucose tolerance (n = 77) and glucose intolerance (IGT) (n = 38) based on the results of an oral glucose tolerance test (National Diabetes Data Group criteria), performed between 24 and 28 weeks of pregnancy. A 24-h recall dietary assessment was also obtained at the time of screening. Subjects with IGT and GDM were significantly heavier (66.1 +/- 1.4 and 68.6 +/- 1.2 kg, respectively, mean +/- SEM) (P < 0.0001) than the normal group (61.2 +/- 1.8 kg) and had a higher BMI. Overall energy intake was similar between groups, as were the intakes of each macronutrient (%kcal). However, there was a highly significant reduction in polyunsaturated fat intake in the IGT and GDM groups whether expressed as %kcal, % of total fat, or fat kcal. This effect was independent of body weight or BMI whether assessed by ordinal logistic regression or by analysis of a weight- and BMI-matched subgroup of the subjects (P = 0.002 for %kcal; n = 47 normal, 26 IGT, and 43 GDM subjects). In logistic regression analysis of the complete data set, increased body weight (P < 0.0001) and decreased polyunsaturated fat intake (P = 0.0014) were both independent predictors of glucose intolerance (IGT and GDM), as were increased body weight and a low dietary polyunsaturated to saturated fat ratio. Increased polyunsaturated fat intake is associated with a reduced incidence of glucose intolerance during pregnancy. This finding may have major implications for dietary management of women with or at risk of developing GDM.


Allogeneic blood transfusion reduction by risk-based protocol in total joint arthroplasty.
To evaluate the effect of a preoperative protocol that triages patients awaiting total joint arthroplasty to one of four strategies designed to mitigate the risk of allogeneic blood transfusion (ABT) based on a priori transfusion risk on perioperative exposure to allogeneic blood. We compared the transfusion experiences of a historical control series of 160 subjects with a study group of 160 subjects treated by protocol. Protocol subjects with hemoglobin (Hb) 100-129 g.L(-1) were given erythropoietin, dosed by weight. Subjects with Hb 130-139 g.L(-1) underwent preoperative autologous blood harvest and perioperative re-infusion as deemed clinically necessary. Subjects with Hb >139 g.L(-1) received no special intervention, unless they were aged >70 yr and weighed < 70 kg, in which case they received oral iron and folate supplementation. The relative risk of ABT in the Study group was 0.68 (95% confidence interval 0.54-0.85). The Control group received 104 units of allogeneic blood and the Study group received 35 units (P = 0.0007). These differences cannot be explained by differences in transfusion risk or autologous units transfused. There was no worsening of anemia or its consequences in the Study group. A simple protocol based on easily obtained preoperative clinical indices effectively targets interventions that mitigate the risk of ABT.


Linear and nonlinear optical waveguiding in bio-inspired peptide nanotubes.
Unique linear and nonlinear optical properties of bioinspired peptide nanostructures such as wideband transparency and high second-order nonlinear optical response, combined with elongated tubular shape of variable size and rapid self-assembly fabrication process, make them promising for diverse bio-nano-photonic applications. This new generation of nanomaterials of biological origin possess physical properties similar to those of biological structures. Here, we focus on new specific functionality of ultrashort peptide nanotubes to guide light at fundamental and second-harmonic generation (SHG) frequency in horizontal and vertical peptide nanotubes configurations. Conducted simulations and experimental data show that these self-assembled linear and nonlinear optical bio-waveguides provide strong optical power confinement factor, demonstrate pronounced directionality of SHG and high conversion efficiency of SHG ∼10(-5). Our study gives new insight on physics of light propagation in nanostructures of biological origin and opens the avenue towards new and unexpected applications of these waveguiding effects in bio-nanomaterials both for biomedical nonlinear microscopy imaging recognition and development of novel integrated nanophotonic devices.


Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia.
Switch therapy is defined as the early transition from intravenous to oral antibiotics during treatment of infection. This study was designed to evaluate the clinical outcome and length of stay of hospitalized patients with community-acquired pneumonia treated with an early switch from intravenous to oral third-generation cephalosporins. Patients with a new roentgenographic pulmonary infiltrate and at least two symptoms (cough, fever, or leukocytosis) were enrolled in this study and treated with intravenous ceftizoxime sodium (1 g every 12 hours) or ceftriaxone sodium (1 g every 24 hours). Patients were switched to oral cefixime (400 mg every 24 hours) as soon as they met the following criteria: (1) resolution of fever; (2) improvement of cough and respiratory distress; (3) improvement of leukocytosis; and (4) presence of normal gastrointestinal tract absorption. Of the 120 patients enrolled, 75 (62%) had clinical data evaluated. Long-term follow-up showed that 74 patients (99%) were cured; one patient required readmission for further intravenous therapy. Mean duration of hospital stay was 4 days. This investigation demonstrated that an early switch to oral cefixime may be reasonable in hospitalized patients with community-acquired pneumonia who have already shown a good clinical and laboratory response to therapy with intravenous third-generation cephalosporins. This approach is clinically effective and minimizes hospital stay.


Exploring the Effect of Attachment Styles and Winning or Losing a Status Contest on Testosterone Levels.
A person's ability to form relationships and seek and attain social status affects their chances of survival. We study how anxious and avoidant-attachment styles and subsequent winning or losing affects the testosterone (T) levels of team members playing two status contests. The first is a management game played by teams striving to earn the most profits. Winners and losers emerge due to the cognitive endeavor of the players, which provokes intense status dynamics. Avoidant-attached winners do not show higher T levels whereas anxious-attached winners do. The second is an economic game which is rigged and favors some teams to become richer than others; teams have the option though to trade with each other and reduce the self-perpetuating rich-poor dynamics embedded in the game. Besides attachment styles, we here also explore how authentic pride as a self-conscious emotion affects team members' T levels as players trade with others to create more fairness. As in the first status contest, players' T levels are not significantly affected by their avoidant attachment style, neither as a main effect nor in interaction with winning or losing the game. However, similar to the first game, players' anxious attachment style affects their T levels: anxious-attached players generate significantly higher T levels when winning the game, but only when experiencing high authentic pride during the game. In short, the moderating effects of attachment style on winners' T levels are partly replicated in both status games which allows us to better understand the functioning of working models of attachment styles during and after status contests and gives us a better understanding of working models of attachment styles in general.


Specific, sensitive and rapid detection of human plasmodium knowlesi infection by loop-mediated isothermal amplification (LAMP) in blood samples.
The emergence of Plasmodium knowlesi in humans, which is in many cases misdiagnosed by microscopy as Plasmodium malariae due to the morphological similarity has contributed to the needs of detection and differentiation of malaria parasites. At present, nested PCR targeted on Plasmodium ssrRNA genes has been described as the most sensitive and specific method for Plasmodium detection. However, this method is costly and requires trained personnel for its implementation. Loop-mediated isothermal amplification (LAMP), a novel nucleic acid amplification method was developed for the clinical detection of P. knowlesi. The sensitivity and specificity of LAMP was evaluated in comparison to the results obtained via microscopic examination and nested PCR. LAMP assay was developed based on P. knowlesi genetic material targeting the apical membrane antigen-1 (AMA-1) gene. The method uses six primers that recognize eight regions of the target DNA and it amplifies DNA within an hour under isothermal conditions (65°C) in a water-bath. LAMP is highly sensitive with the detection limit as low as ten copies for AMA-1. LAMP detected malaria parasites in all confirm cases (n = 13) of P. knowlesi infection (sensitivity, 100%) and none of the negative samples (specificity, 100%) within an hour. LAMP demonstrated higher sensitivity compared to nested PCR by successfully detecting a sample with very low parasitaemia (< 0.01%). With continuous efforts in the optimization of this assay, LAMP may provide a simple and reliable test for detecting P. knowlesi malaria parasites in areas where malaria is prevalent.


Analysis of Diversity in Pythium aphanidermatum Populations from a Single Greenhouse Reveals Phenotypic and Genotypic Changes over 2006 to 2011.
A study was conducted to investigate phenotypic and genotypic changes within Pythium aphanidermatum populations during the period 2006 to 2011. In total, 92 isolates of P. aphanidermatum (59 in 2006 and 33 in 2011) were obtained from different planting sites (soil) of cucumber from a single greenhouse. Generated sequences of the internal transcribed spacer (ITS) ribosomal DNA showed that all, except one isolate, share an identical sequence of the ITS region. Most (89%) P. aphanidermatum isolates were found to be aggressive on cucumber seedlings, with no significant differences in the aggressiveness level between populations obtained from different planting rows or different years. Sensitivity to metalaxyl among populations of P. aphanidermatum increased significantly from concentration resulting in 50% growth inhibition levels of 0.070 to 1.823 (average 0.824 μg ml-1) in 2006 to 0.002 to 0.564 (average 0.160 μg ml-1) in 2011. Amplified fragment length polymorphism analysis of the 92 isolates produced 92 different genotypes and 985 polymorphic loci. P. aphanidermatum populations from 2006 and 2011 were found to have low levels of genetic diversity (H = 0.1425), which implies introduction of the isolates into the greenhouse via common sources. Results from analysis of molecular variance (FST = 0.0307 in 2006 and 0.0222 in 2011) provided evidence for frequent exchange of Pythium inoculum between different planting locations within the same year. However, the analysis showed moderate levels (FST = 0.1731) of genetic differentiation among populations from the 2 years. This was supported by unweighted pair group method with arithmetic means analysis, which showed clustering of many of the 2006 isolates in separate clusters. The change in the metalaxyl sensitivity of the populations from 2006 to 2011 accompanied by the genetic differences among these two populations may suggest that many of the isolates from 2006 were lost and were replaced by new and highly sensitive P. aphanidermatum isolates by 2011.


Hearing and saying. The functional neuro-anatomy of auditory word processing.
The neural systems involved in hearing and repeating single words were investigated in a series of experiments using PET. Neuropsychological and psycholinguistic studies implicate the involvement of posterior and anterior left perisylvian regions (Wernicke's and Broca's areas). Although previous functional neuroimaging studies have consistently shown activation of Wernicke's area, there has been only variable implication of Broca's area. This study demonstrates that Broca's area is involved in both auditory word perception and repetition but activation is dependent on task (greater during repetition than hearing) and stimulus presentation (greater when hearing words at a slow rate). The peak of frontal activation in response to hearing words is anterior to that associated with repeating words; the former is probably located in Brodmann's area 45, the latter in Brodmann's area 44 and the adjacent precentral sulcus. As Broca's area activation is more subtle and complex than that in Wernicke's area during these tasks, the likelihood of observing it is influenced by both the study design and the image analysis technique employed. As a secondary outcome from the study, the response of bilateral auditory association cortex to 'own voice' during repetition was shown to be the same as when listening to "other voice' from a prerecorded tape.


Proteomic characterization of lipid raft proteins in amyotrophic lateral sclerosis mouse spinal cord.
Familial amyotrophic lateral sclerosis (ALS) has been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene. The mutant SOD1 protein exhibits a toxic gain-of-function that adversely affects the function of neurons. However, the mechanism by which mutant SOD1 initiates ALS is unclear. Lipid rafts are specialized microdomains of the plasma membrane that act as platforms for the organization and interaction of proteins involved in multiple functions, including vesicular trafficking, neurotransmitter signaling, and cytoskeletal rearrangements. In this article, we report a proteomic analysis using a widely used ALS mouse model to identify differences in spinal cord lipid raft proteomes between mice overexpressing wild-type (WT) and G93A mutant SOD1. In total, 413 and 421 proteins were identified in the lipid rafts isolated from WT and G93A mice, respectively. Further quantitative analysis revealed a consortium of proteins with altered levels between the WT and G93A samples. Functional classification of the 67 altered proteins revealed that the three most affected subsets of proteins were involved in: vesicular transport, and neurotransmitter synthesis and release; cytoskeletal organization and linkage to the plasma membrane; and metabolism. Other protein changes were correlated with alterations in: microglia activation and inflammation; astrocyte and oligodendrocyte function; cell signaling; cellular stress response and apoptosis; and neuronal ion channels and neurotransmitter receptor functions. Changes of selected proteins were independently validated by immunoblotting and immunohistochemistry. The significance of the lipid raft protein changes in motor neuron function and degeneration in ALS is discussed, particularly for proteins involved in vesicular trafficking and neurotransmitter signaling, and the dynamics and regulation of the plasma membrane-anchored cytoskeleton.


Living arrangements and place of death of older people with cancer in England and Wales: a record linkage study.
The main objectives of the study were to (1) see whether the household circumstances of people aged 50 years and over with cancer, and trends in these, differ from those of the rest of the population and (2) whether living arrangements and presence and health status of a primary coresident are associated with place of death among older people dying of cancer and those dying from other causes. The design included prospective record linkage study of people aged 50 years and over included in a 1% sample of the population of England and Wales (the Office for National Statistics Longitudinal Study). The main outcome measures comprised family and household type, and death at home. The household circumstances of older people with cancer were very similar to those of the rest of the population of the same age and both showed a large increase in living alone, and decrease in living with relatives, between 1981 and 1991. The primary coresident of cancer sufferers who did not live alone was in most cases a spouse, with much smaller proportions living with a child, sibling or other person. In all, 30% of spouse, and 23% of other, primary coresidents had a limiting long-term illness. Compared with people who lived alone in 1991, odds of a home death among those dying of cancer between 1991 and 1995 were highest for those who lived with a spouse who had no limiting long-term illness (odds ratio (OR) 2.52, 95% confidence interval (CI) 2.15-2.97) and raised for those living with a spouse with a long-term illness (OR 2.14, CI 1.79-2.56) and those living with someone else who was free of long-term illness (OR 2.13, CI 1.69-2.68). Higher socioeconomic status, both individual and area, was positively associated with increased chance of a home death, while older age reduced the chance of dying at home. The changing living arrangements of older people have important implications for planning and provision of care and treatment for cancer sufferers.


Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II-Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy.
Preeclamptic women produce agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) and exhibit increased blood pressure (mean arterial pressure), vascular sensitivity to angiotensin II (ANG II), and display a decrease in renal function. The objective of this study was to examine the renal hemodynamic changes during pregnancy in the presence of AT1-AAs with or without a slow pressor dose of ANG II. In this study, mean arterial pressure was elevated in all pregnant rats treated with ANG II with or without AT1-AA. Glomerular filtration rate was reduced from 1.90±0.16 mL/min in normal pregnant (NP) to 1.20±0.08 in ANG II+AT1-AA rats. Renal blood flow was decreased in ANG II+AT1-AA versus NP rats to 7.4±1.09 versus 15.4±1.75 mL/min. Renal vascular resistance was drastically increased between ANG II+AT1-AA versus NP rats (18.4±2.91 versus 6.4±0.77 mm Hg/mL per minute). Isoprostane excretion was increased by 3.5-fold in ANG II+AT1-AA versus NP (1160±321 versus 323±52 pg/mL). In conclusion, ANG II and AT1-AA together significantly decrease glomerular filtration rate by 37% and renal blood flow by 50% and caused a 3-fold increase in renal vascular resistance and isoprostane levels versus NP rats. These data indicate the importance of AT1-AAs to enhance ANG II-induced renal vasoconstriction and reduce renal function as mechanisms to cause hypertension as observed during preeclampsia.


Exploring the effects of spatial autocorrelation when identifying key drivers of wildlife crop-raiding.
Few universal trends in spatial patterns of wildlife crop-raiding have been found. Variations in wildlife ecology and movements, and human spatial use have been identified as causes of this apparent unpredictability. However, varying spatial patterns of spatial autocorrelation (SA) in human-wildlife conflict (HWC) data could also contribute. We explicitly explore the effects of SA on wildlife crop-raiding data in order to facilitate the design of future HWC studies. We conducted a comparative survey of raided and nonraided fields to determine key drivers of crop-raiding. Data were subsampled at different spatial scales to select independent raiding data points. The model derived from all data was fitted to subsample data sets. Model parameters from these models were compared to determine the effect of SA. Most methods used to account for SA in data attempt to correct for the change in P-values; yet, by subsampling data at broader spatial scales, we identified changes in regression estimates. We consequently advocate reporting both model parameters across a range of spatial scales to help biological interpretation. Patterns of SA vary spatially in our crop-raiding data. Spatial distribution of fields should therefore be considered when choosing the spatial scale for analyses of HWC studies. Robust key drivers of elephant crop-raiding included raiding history of a field and distance of field to a main elephant pathway. Understanding spatial patterns and determining reliable socio-ecological drivers of wildlife crop-raiding is paramount for designing mitigation and land-use planning strategies to reduce HWC. Spatial patterns of HWC are complex, determined by multiple factors acting at more than one scale; therefore, studies need to be designed with an understanding of the effects of SA. Our methods are accessible to a variety of practitioners to assess the effects of SA, thereby improving the reliability of conservation management actions.


Patients with postoperative atrial fibrillation have a doubled cardiovascular mortality.
To investigate the impact of postoperative AF on late mortality and cause of death in CABG patients. All CABG patients without preoperative AF surgically treated between January 1, 1997 and June 30, 2000 were included (N = 1419). Altogether, 419 patients (29.5%) developed postoperative AF. After a median follow-up of 8.0 years, survival data were obtained, causes of death were compared and Cox proportional hazard analysis was used to determine predictors of late mortality. The total mortality was 140 deaths/419 patients (33.4%) in postoperative AF patients and 191 deaths/1 000 patients (19.1%) in patients without AF. Death due to cerebral ischemia (2.6% vs. 0.5%), myocardial infarction (7.4% vs. 3.0%), sudden death (2.6% vs. 0.9%), and heart failure (6.7% vs. 2.7%) was more common among postoperative AF patients. Postoperative AF was an age-independent risk indicator for late mortality with a hazard ratio (HR) of 1.56 (95% confidence interval 1.23-1.98). Postoperative AF is an age-independent risk factor for late mortality in CABG patients, explained by an increased risk of cardiovascular death.


Lack of heritability of exhaled volatile compound pattern: an electronic nose twin study.
Electronic noses can distinguish various disorders by analyzing exhaled volatile organic compound (VOC) pattern; however it is unclear how hereditary and environmental backgrounds affect the exhaled VOC pattern. A twin study enrolling monozygotic (MZ) and dizygotic (DZ) twins is an ideal tool to separate the influence of these factors on the exhaled breath pattern. Exhaled breath samples were collected in duplicates from 28 never smoking twin pairs (in total 112 samples) without lung diseases and processed with an electronic nose (Cyranose 320). Univariate quantitative hereditary modeling (ACE analysis) adjusted for age and gender was performed to decompose the phenotypic variance of the exhaled volatile compound pattern (assessing principal components (PCs) derived from electronic nose data) into hereditary (A), shared (C), and unshared (E) environmental effects. Exhaled VOC pattern showed good intra-subject reproducibility as assessed with the Bland-Altman plot. Significant correlations were found between exhaled VOC patterns of both MZ and DZ twins. The hereditary background did not influence the VOC pattern. The shared environmental effect on PC 1, 2 and 3 was estimated to be 93%, 94% and 54%, respectively. The unshared (unique) environmental influence explained a smaller variance (7%, 6% and 46%). For the first time using the twin design, we have shown that the environmental background largely affects the exhaled volatile compound pattern in never smoking volunteers without respiratory disorders. Further studies should identify these environmental factors and also assess their influence on exhaled breath patterns in patients with lung diseases.


The Autonomous Glycosylation of Large DNA Viruses.
Glycosylation of surface molecules is a key feature of several eukaryotic viruses, which use the host endoplasmic reticulum/Golgi apparatus to add carbohydrates to their nascent glycoproteins. In recent years, a newly discovered group of eukaryotic viruses, belonging to the Nucleo-Cytoplasmic Large DNA Virus (NCLDV) group, was shown to have several features that are typical of cellular organisms, including the presence of components of the glycosylation machinery. Starting from initial observations with the chlorovirus PBCV-1, enzymes for glycan biosynthesis have been later identified in other viruses; in particular in members of the Mimiviridae family. They include both the glycosyltransferases and other carbohydrate-modifying enzymes and the pathways for the biosynthesis of the rare monosaccharides that are found in the viral glycan structures. These findings, together with genome analysis of the newly-identified giant DNA viruses, indicate that the presence of glycogenes is widespread in several NCLDV families. The identification of autonomous viral glycosylation machinery leads to many questions about the origin of these pathways, the mechanisms of glycan production, and eventually their function in the viral replication cycle. The scope of this review is to highlight some of the recent results that have been obtained on the glycosylation systems of the large DNA viruses, with a special focus on the enzymes involved in nucleotide-sugar production.


The interaction of hepatitis A virus (HAV) with soluble forms of its cellular receptor 1 (HAVCR1) share the physiological requirements of infectivity in cell culture.
Hepatitis A virus (HAV), an atypical Picornaviridae that causes acute hepatitis in humans, usurps the HAV cellular receptor 1 (HAVCR1) to infect cells. HAVCR1 is a class 1 integral membrane glycoprotein that contains two extracellular domains: a virus-binding immunoglobulin-like (IgV) domain and a mucin-like domain that extends the IgV from the cell membrane. Soluble forms of HAVCR1 bind, alter, and neutralize cell culture-adapted HAV, which is attenuated for humans. However, the requirements of the HAV-HAVCR1 interaction have not been fully characterized, and it has not been determined whether HAVCR1 also serves as a receptor for wild-type (wt) HAV. Here, we used HAV soluble receptor neutralization and alteration assays to study the requirements of the HAV-HAVCR1 interaction and to determine whether HAVCR1 is also a receptor for wt HAV. Treatment of HAV with a soluble form of HAVCR1 that contained the IgV and two-thirds of the mucin domain fused to the Fc fragment of human IgG1 (D1 muc-Fc), altered particles at 37 degrees C but left a residual level of unaltered particles at 4 degrees C. The kinetics of neutralization of HAV by D1 muc-Fc was faster at 37 degrees C than at 4 degrees C. Alteration of HAV particles by D1 muc-Fc required Ca, which could not be replaced by Li, Na, Mg, Mn, or Zn. Neutralization of HAV by D1 muc-Fc occurred at pH 5 to 8 but was more efficient at pH 6 to 7. D1 muc-Fc neutralized wt HAV as determined by a cell culture system that allows the growth of wt HAV. The interaction of HAV with soluble forms of HAVCR1 shares the temperature, Ca, and pH requirements for infectivity in cell culture and therefore mimics the cell entry process of HAV. Since soluble forms of HAVCR1 also neutralized wt HAV, this receptor may play a significant role in pathogenesis of HAV.


Induction of host chemotactic response by Encephalitozoon spp.
Microsporidians are a group of emerging pathogens typically associated with chronic diarrhea in immunocompromised individuals. The number of reports of infections with these organisms and the disseminated pathology is growing as diagnostic tools become more readily available. However, little is known about the innate immune response induced by and generated against these parasites. Using a coculture chemotaxis system, primary human macrophages were infected with Encephalitozoon cuniculi or Encephalitozoon intestinalis, and the recruitment of naïve monocytes was monitored. Encephalitozoon spp. induced an average threefold increase in migration of naïve cells 48 h postinfection, which corresponded to optimal infection of monocyte-derived-macrophages. A limited microarray analysis of infected macrophages revealed several chemokines involved in the inflammatory responses whose expression was upregulated, including CCL1, CCL2, CCL3, CCL4, CCL7, CCL15, CCL20, CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8. The levels of 6 of 11 chemokines also present in the microarray were confirmed to be elevated by protein profiling. Kinetic studies confirmed that secreted CCL2, CCL3, and CCL4 were expressed as early as 6 h postinfection, with peak expression at 12 to 24 h and expression remaining until 48 h postinfection. Neutralization of these chemokines, specifically CCL4, significantly reduced the number of migrating cells in vitro, indicating their role in the induction of monocyte migration. This mechanism of recruitment not only supports the evidence that in vivo cellular infiltration occurs but also provides new hosts for the parasites, which escape macrophages by rupturing the host cell. To our knowledge, this is the first documentation that chemokine production is induced by microsporidian infections in human macrophages.


Functional response in ventral temporal cortex differentiates mild cognitive impairment from normal aging.
This study sought to identify altered brain activation patterns in amnestic mild cognitive impairment (MCI) that could precede frank task impairment and neocortical atrophy. A high-accuracy lexical decision (LD) task was therefore employed. Both MCI and normal seniors (NS) groups completed the LD task while functional magnetic resonance imaging (fMRI) was performed. Accuracy on the LD task was high (> or =89% correct for both groups), and both groups activated a network of occipitotemporal regions and inferior frontal cortex. However, compared with the NS group, the MCI group showed reduced fMRI activation in these regions and increased activation in bilateral portions of anterior cingluate cortex. The results from a voxel-based morphometry analysis indicated that altered activations in the MCI group were not within regions of atrophy. Receiver operating characteristic curves demonstrated that reduced fMRI response in the left and right midfusiform gyri accurately discriminated MCI from NS. When activation magnitude in both fusiform gyri were included in a single logistic regression model, group classification accuracy was very high (area under the curve = 0.93). These results showed that a disrupted functional response in the ventral temporal lobe accurately distinguishes individuals with MCI from NS, a finding which may have implications for identifying seniors at risk for cognitive decline.


Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection.
Toll-like receptor 9 (TLR9), its adaptor MyD88, the downstream transcription factor interferon regulatory factor 7 (IRF7), and type I interferons (IFN-I) are all required for resistance to infection with ectromelia virus (ECTV). However, it is not known how or in which cells these effectors function to promote survival. Here, we showed that after infection with ECTV, the TLR9-MyD88-IRF7 pathway was necessary in CD11c(+) cells for the expression of proinflammatory cytokines and the recruitment of inflammatory monocytes (iMos) to the draining lymph node (dLN). In the dLN, the major producers of IFN-I were infected iMos, which used the DNA sensor-adaptor STING to activate IRF7 and nuclear factor κB (NF-κB) signaling to induce the expression of IFN-α and IFN-β, respectively. Thus, in vivo, two pathways of DNA pathogen sensing act sequentially in two distinct cell types to orchestrate resistance to a viral disease.


Knowledge, attitude and perception/practices (KAP) of medical practitioners in India towards adverse drug reaction (ADR) reporting.
The objective was to assess knowledge, attitude and perceptions/practices (KAP) of medical practitioners (MPs) in India towards Adverse Drug Reaction (ADR) reporting. A questionnaire was designed for assessment of KAP of medical practitioners in India toward ADR reporting. This questionnaire was administered to 2-3 medical practitioners from each zone prior to administering final questionnaire which was approved by Disha Independent Ethics Committee, Mumbai. 1200 medical practitioners (about 300 from each zone) from India were selected randomly. 1000 medical practitioners out of 1200 (90%), selected at random were approached. A total of 870 provided responses to the questionnaire, giving a response rate of 73% of 1200 selected randomly. A total of 47.5% respondents reported that they were aware of Government ADR centers. A total of 59.2% reported that they are familiar with the procedure of reporting ADRs to Government centers. However, only 18.5% of MPs have reported the observed ADRs to Government ADR centers. As against this relatively large number of MPs (87.9%) have reported ADRs observed during their routine practice to medical representatives of pharmaceutical company and NGOs (non-Govt. Organizations). A total of 80.5% of respondents agreed that safety plays an important role and 96% reported that ADR centers are useful. However, only 55.6% of respondents have reported that there is a need for ADR centers. The study reveals that practitioners are aware of ADR reporting; their perception toward ADR reporting is right but it is not reflected when it comes to the act of reporting of ADRs. In our sample of 870 respondents only 18.5 % reported ADRs to some organizations. Only 5% of respondents recorded the details of ADR and reported to the manufacturer and 1% of respondents to government health ministry. Thus, medical practitioners in India appear to have a good knowledge about ADR reporting, the right perception toward ADR reporting. However, as far as practice of ADR reporting is concerned it is discouraging.


Relevance of cognition to health-related quality of life in good-outcome survivors of out-of-hospital cardiac arrest.
For survivors of out-of-hospital cardiac arrest (OHCA) with good outcomes, it is not known whether and how health-related quality of life is affected by the cognitive impairments frequently observed in these patients. This study explores how neuropsychological tests of memory, exe-cutive and psychomotor functioning relate to the physical and mental aspects of health-related quality of life in functionally independent and community dwelling OHCA survivors discharged early from hospital. The study included 42 adult survivors (mean age 62 years, 38 males). Health-related quality of life was measured approximately 3 months post-OHCA with the Medical Outcome Study Short Form 36 (SF-36). Cognition was measured with established neuropsychological tests. Regression analyses were used to examine associations between neuropsychological domains and physical and mental health-related quality of life, respectively, when controlling for age, education and length of coma. The physical, but not the mental, component of the SF-36 was significantly worse than Norwegian population data. Neuropsychological tests showed frequent impairments most often in the memory domain. Worse psychomotor functioning was associated with worse physical health-related quality of life, whereas worse memory performance was associated with worse mental health-related quality of life. The cognitive impairments frequently reported in OHCA survivors with good outcomes may compromise health-related quality of life. Cognitive functioning should be addressed even in survivors with rapid recovery.


Intensive management of hyperglycaemia in acute coronary syndromes. Study design and rationale of the BIOMArCS 2 glucose trial.
Elevated admission plasma glucose is associated with increased mortality in patients who are admitted with an acute coronary syndrome. This may be mediated by increased inflammation, apoptosis and coagulation, and by a disturbed endothelial function that can be found in hyperglycaemic patients. Insulin has several characteristics that may potentially counteract these mechanisms. The BIOMArCS programme is a multi-centre initiative and currently consists of three different studies. The effects of acute coronary syndrome on acute biomarkers washout are studied in the BIOMArCS pilot and the value of biomarkers in predicting upcoming acute coronary syndrome events is studied in BIOMArCS 1. The third study (BIOMArCS 2 glucose), which will be presented here, investigates the effectiveness and safety of intensive glucose level control compared with conventional glucose management in patients with acute coronary syndrome and an admission plasma glucose of 7.8-16 mmol/l. In BIOMArCS 2 glucose, a total of 300 patients without insulin-treated diabetes mellitus will be randomized in a 1:1 ratio to either intensive or conventional glucose management on top of standard medical care. The primary endpoint is infarct size as expressed by the cardiac troponin T level 72 h after admission. To study the metabolic effects of insulin administration, we will investigate biomarker washout patterns of various metabolic mechanisms up to 7 days after admission. These markers will address inflammation, oxidative stress, hypercoagulability, endothelial activation and vasodilatation. Current acute coronary syndrome guidelines lack a clear strategy for hyperglycaemia treatment. This study will extend our knowledge on this matter as it may clarify mechanisms and generate hypotheses of if and how myocardial infarct size may be limited by glucose management at admission.


Inhibitory effects of methotrexate on spontaneous motility and Cajal-like type of tubal interstitial cells in rabbit oviduct.
To study the adverse biomechanical effects of methotrexate (MTX) on spontaneous tubal motility and on a widely distributed Cajal-like type of tubal interstitial cells (t-ICC) in rabbits. In our previous study, MTX was confirmed to cause acute endosalpingitis, and ultrastructural and steroid receptor damage in rat's endosalpinx in a dose-dependent manner. Differences in spontaneous tubal contractions and cellular distribution of t-ICC in isthmus were evaluated in response to MTX. Medical school research laboratory. Twenty nonpregnant female New Zealand albino rabbits in estrus stage were divided equally into four groups. Rabbits received IM MTX (1, 5, 10 mg/kg body weight) and controls received physiological saline. On day 7, in vitro motility studies measuring spontaneous tubal contractions were performed, and cellular distribution of t-ICC was determined by immunohistochemistry. Methotrexate produced a concentration-dependent inhibition of spontaneous isthmus contractions (frequency in 5, 10 mg/kg groups, and amplitude in 1, 5, 10 mg/kg MTX groups). It decreased significantly compared with the control group. Meanwhile, MTX at 5, 10 mg/kg decreased the population of c-kit immunoreactive t-ICC significantly. The decreased t-ICC may contribute to the diminished tubal smooth muscle contractility caused by MTX as observed. Tubal interstitial cells might be new potential targets for a variety of dysfunctional tubal motility diseases.


Biochemical markers in osteoarthritis with lessons learned from osteoporosis.
Osteoarthritis (OA) is a disease of the whole joint, including synovium, bone and cartilage. OA is a slow degenerative and very heterogeneous disease, with both varying levels of disease activity and progression. Biomarkers are urgently needed to assist drug developers in selecting and developing the projects with the highest chance of success. Biomarkers for enrichment of clinical studies, early efficacy as well as other diagnostic tools are needed. Osteoporosis and OA have many similarities. In osteoporosis an armamentarium of treatments are now available with high clinical efficacy and well-described effects on biomarkers. Possibly, lessons learned from the osteoporosis field in the use of biomarkers may be applied in the OA field, from both technical and scientific perspectives. To help guide the way, the FDA has recently published the BEST guidelines, to facilitate obtaining a common vocabulary to assist biomarker researchers. In the current review, we will review the biomarkers of OA, with emphasis on bone, cartilage and synovial biomarkers, and draw clear perspectives to the use of biomarkers for drug development and clinical practice in the osteoporosis field.


Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors.
The Mas-related G protein-coupled receptor D (Mrgprd) is selectively expressed in nonpeptidergic nociceptors that innervate the outer layers of mammalian skin. The function of Mrgprd in nociceptive neurons and the physiologically relevant somatosensory stimuli that activate Mrgprd-expressing (Mrgprd(+)) neurons are currently unknown. To address these issues, we studied three Mrgprd knock-in mouse lines using an ex vivo somatosensory preparation to examine the role of the Mrgprd receptor and Mrgprd(+) afferents in cutaneous somatosensation. In mouse hairy skin, Mrgprd, as marked by expression of green fluorescent protein reporters, was expressed predominantly in the population of nonpeptidergic, TRPV1-negative, C-polymodal nociceptors. In mice lacking Mrgprd, this population of nociceptors exhibited decreased sensitivity to cold, heat, and mechanical stimuli. Additionally, in vitro patch-clamp studies were performed on cultured dorsal root ganglion neurons from Mrgprd(-/-) and Mrgprd(+/-) mice. These studies revealed a higher rheobase in neurons from Mrgprd(-/-) mice than from Mrgprd(+/-) mice. Furthermore, the application of the Mrgprd ligand beta-alanine significantly reduced the rheobase and increased the firing rate in neurons from Mrgprd(+/-) mice but was without effect in neurons from Mrgprd(-/-) mice. Our results demonstrate that Mrgprd influences the excitability of polymodal nonpeptidergic nociceptors to mechanical and thermal stimuli.


Comparison of Systemic Exposure to Toxic and/or Carcinogenic Volatile Organic Compounds (VOC) during Vaping, Smoking, and Abstention.
Comparisons of systemic exposure to toxicants during monitored cigarette smoking, electronic cigarette (e-cigarette) use, and abstention are needed to enhance our understanding of the risks of e-cigarette use (vaping). In a cross-over study, we measured 10 mercapturic acid metabolites of volatile organic compounds (VOCs) in 24-hour urine samples collected from 36 dual users (8 women) of e-cigarettes and cigarettes during 2 days of ad libitum vaping or cigarette-only use, and 2 days of enforced abstention. Concentrations of VOC metabolites were higher during smoking compared with vaping, except for the methylating agents' metabolite. The fold-difference in concentrations when smoking relative to vaping ranged from 1.31 (1.06-1.61; geometric mean, 95% confidence interval; 1,3-butadiene) to 7.09 (5.88-8.54; acrylonitrile). Metabolites of acrylamide [fold difference of 1.21 (1.03-1.43)] and benzene [1.46 (1.13-1.90)] were higher during vaping compared with abstention. The 1,3-butadiene and propylene oxide metabolites were higher in variable-power tank users compared with users of cig-a-likes. E-cigarettes expose users to lower levels of toxic VOCs compared with cigarette smoking, supporting their harm reduction potential among smokers. However, some e-cigarettes expose users to VOCs such as acrylamide, benzene, and propylene oxide, and may pose health risks to nonsmoking users. The results of our study will inform regulators in assessing e-cigarettes with respect to the balance between its potential harm reduction for adult smokers and risk to nonsmoking users.


Tryptophan degradation in transplanted tumor cells undergoing rejection.
The depletion of an essential amino acid, tryptophan, caused by indoleamine 2,3-dioxygenase induction in vitro, has been shown to be due to a mechanism that is used in self-defense against inhaled microorganisms and tumor growth. In this communication, we report the results of measuring dioxygenase activity in the peritoneal exudate cells and tumor cytotoxicity at the transplantation loci after in vivo transplantation of tumor cells into the peritoneal cavity of syngeneic or allogeneic strains of mice. The enzyme was induced only when the tumor cells were being rejected from allogeneic animals and no change was observed when the cells continued to grow in syngeneic animals. Furthermore, when the syngeneic tumor cells in a diffusion chamber were i.p. transplanted simultaneously with i.p. injection of allogeneic tumor cells, the enzyme was induced not only in allografted tumor cells but also in the syngeneic tumor cells. Under these conditions, the tumor cells in the diffusion chamber ceased to grow and 50% of the cells were rejected. To determine the type of cells containing the induced enzyme, the peritoneal exudate cells (tumor cells and host cells--mostly small lymphocytes) were separated into six fractions by sedimentation under gravity and by differential centrifugation. Approximately 80% of total enzyme activity was localized in a tumor-rich fraction (98.9% purity), whereas only 0.2% of the activity was found in a lymphocyte-rich fraction (99.5% purity). The localization of indoleamine 2,3-dioxygenase in the tumor cells was confirmed by complement-dependent lysis with specific antibodies against tumor and host cells.


Pomalidomide Reduces Ischemic Brain Injury in Rodents.
Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent neurological damage. Reactive oxygen species (ROS) are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Prior cellular studies demonstrate that POM can mitigate oxidative stress and lower levels of pro-inflammatory cytokines, particularly TNF-α, which plays a prominent role in ischemic stroke-induced brain damage and functional deficits. To evaluate the potential value of POM in cerebral ischemia, POM was initially administered to transgenic mice chronically over-expressing TNF-α surfactant protein (SP)-C promoter (SP-C/TNF-α mice) to assess whether systemically administered drug could lower systemic TNF-α level. POM significantly lowered serum levels of TNF-α and IL-5. Pharmacokinetic studies were then undertaken in mice to evaluate brain POM levels following systemic drug administration. POM possessed a brain/plasma concentration ratio of 0.71. Finally, rats were subjected to transient middle cerebral artery occlusion (MCAo) for 60 min, and subsequently treated with POM 30 min thereafter to evaluate action on cerebral ischemia. POM reduced the cerebral infarct volume in MCAo-challenged rats and improved motor activity, as evaluated by the elevated body swing test. POM's neuroprotective actions on ischemic injury represent a potential therapeutic approach for ischemic brain damage and related disorders, and warrant further evaluation.


[Surgical treatment for tuberculous tracheobronchial stenosis].
Thirty-nine patients with bronchial tuberculosis underwent bronchoplastic surgery. The modes of procedures were left upper sleeve lobectomy in 13 patients, sleeve resection of the left main bronchus in 11 patients, sleeve resection of the left main bronchus with concomitant left upper lobectomy in 2 patients, right upper sleeve lobectomy in 6 patients, sleeve resection of the right intermediate bronchus in 2 patients, right sleeve superior segmentectomy of the lower lobe in one patient, sleeve resection of the trachea with concomitant left pneumonectomy in one patient, left lower sleeve lobectomy in one patient, carinal resection with right upper sleeve lobectomy and middle lobectomy in one patient, and dilatation of the left main bronchus with a free skin graft reinforced with a steel wire in one patient. There were one operation death and one operation related death in 1950's. FEV 1.0% of 12 patients whose records of pulmonary function tests performed before and after surgery were available, were increased significantly from 67 +/- 10% to 82 +/- 8% in average. Three patients of laryngotracheal stenosis due to tuberculosis were treated with silicon T-tube. In 2 patients their stenotic lesions were repaired by stenting only, for 36 and 56 months. In one patient, T-tube could not be removed due to laryngeal malacia for more than 12 years.


Genital pain: algorithm for management.
Chronic testicular pain although becoming very common in our patient population poses a challenge to the physician, the patient and his family. The pathogenesis of chronic orchialgia (CO) is not well understood. The objective of this paper is to review the current literature on chronic testicular pain and its management and to propose an algorithm for its treatment. Abstracts, original papers and review articles were reviewed during a literature search using words such as testicular pain, CO, and microsurgical anatomy of spermatic cord. Chronic scrotal content pain (CSP) is a difficult condition to treat and could be idiopathic or secondary. Conservative therapy is the first line of treatment attempted to allow the patient to return to his routine activities. When conservative treatment fails, patients can now turn toward surgical options such as microsurgical denervation of the spermatic cord (MDSC) which has a success rate published in the 60-85% range and/or minimally invasive therapies such as microcryoablation of the spermatic cord, Botox or Amniofix injection. There is an increase in referrals for CO. The true pathogenesis is still unclear and the road to complete recovery is unsure for certain patients. This paper proposes an algorithm for the management of patients suffering with CO.


Molecular phenotypic profiling of a Saccharomyces cerevisiae strain at the single-cell level.
Studying cell-to-cell heterogeneity requires techniques which robustly deliver reproducible results with single-cell sensitivity. Through a new fabrication method for the microarrays for mass spectrometry (MAMS) platform, we now have attained robustness and reproducibility in our single-cell level mass spectrometry measurements that allowed us to combine single-cell MAMS-based measurements from different days and samples. By combining multiple measurements, we were able to identify three co-existing phenotypes in an isogenic population of Saccharomyces cerevisiae characterized by distinctively different levels of glycolytic intermediates.


Code-VEP vs. Eye Tracking: A Comparison Study.
Even with state-of-the-art techniques there are individuals whose paralysis prevents them from communicating with others. Brain⁻Computer-Interfaces (BCI) aim to utilize brain waves to construct a voice for those whose needs remain unmet. In this paper we compare the efficacy of a BCI input signal, code-VEP via Electroencephalography, against eye gaze tracking, among the most popular modalities used. These results, on healthy individuals without paralysis, suggest that while eye tracking works well for some, it does not work well or at all for others; the latter group includes individuals with corrected vision or those who squint their eyes unintentionally while focusing on a task. It is also evident that the performance of the interface is more sensitive to head/body movements when eye tracking is used as the input modality, compared to using c-VEP. Sensitivity to head/body movement could be better in eye tracking systems which are tracking the head or mounted on the face and are designed specifically as assistive devices. The sample interface developed for this assessment has the same reaction time when driven with c-VEP or with eye tracking; approximately 0.5⁻1 second is needed to make a selection among the four options simultaneously presented. Factors, such as system reaction time and robustness play a crucial role in participant preferences.


Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking.
We tested the hypothesis that green tea prevents diabetes-related tissue dysfunctions attributable to oxidation. Diabetic rats were treated daily with tap water, vitamins C and E, or fresh Japanese green tea extract. After 12 months, body weights were decreased, whereas glycated lysine in aorta, tendon, and plasma were increased by diabetes (P < 0.001) but unaffected by treatment. Erythrocyte glutathione and plasma hydroperoxides were improved by the vitamins (P < 0.05) and green tea (P < 0.001). Retinal superoxide production, acellular capillaries, and pericyte ghosts were increased by diabetes (P < 0.001) and improved by green tea and the vitamins (P variable). Lens crystallin fluorescence at 370/440 nm was ameliorated by green tea (P < 0.05) but not the vitamins. Marginal effects on nephropathy parameters were noted. However, suppressed renal mitochondrial NADH-linked ADP-dependent and dinitrophenol-dependent respiration and complex III activity were improved by green tea (P variable). Green tea also suppressed the methylglyoxal hydroimidazolone immunostaining of a 28-kDa mitochondrial protein. Surprising, glycoxidation in tendon, aorta, and plasma was either worsened or not significantly improved by the vitamins and green tea. Glucosepane cross-links were increased by diabetes (P < 0.001), and green tea worsened total cross-linking. In conclusion, green tea and antioxidant vitamins improved several diabetes-related cellular dysfunctions but worsened matrix glycoxidation in selected tissues, suggesting that antioxidant treatment tilts the balance from oxidative to carbonyl stress in the extracellular compartment.


Induced pluripotent stem cell reprogramming by integration-free Sendai virus vectors from peripheral blood of patients with craniometaphyseal dysplasia.
Studies of rare genetic bone disorders are often limited due to unavailability of tissue specimens and the lack of animal models fully replicating phenotypic features. Craniometaphyseal dysplasia (CMD) is a rare monogenic disorder characterized by hyperostosis of craniofacial bones concurrent with abnormal shape of long bones. Mutations for autosomal dominant CMD have been identified in the ANK gene (ANKH). Here we describe a simple and efficient method to reprogram adherent cells cultured from peripheral blood to human induced pluripotent stem cells (hiPSCs) from eight CMD patients and five healthy controls. Peripheral blood mononuclear cells (PBMCs) were separated from 5-7 mL of whole blood by Ficoll gradient, expanded in the presence of cytokines and transduced with Sendai virus (SeV) vectors encoding OCT3/4, SOX2, KLF4, and c-MYC. SeV vector, a cytoplasmic RNA vector, is lost from host cells after propagation for 10-13 passages. These hiPSCs express stem cell markers, have normal karyotypes, and are capable of forming embryoid bodies in vitro as well as teratomas in vivo. Further differentiation of these patient-specific iPSCs into osteoblasts and osteoclasts can provide a useful tool to study the effects CMD mutations on bone, and this approach can be applied for disease modeling of other rare genetic musculoskeletal disorders.


The development of cardiovascular and cerebral vascular control in preterm infants.
Over the past three decades there has been a steady increase in the incidence of preterm birth. The worldwide rate of preterm birth is estimated to be 9.6% of all births, a total of almost 13 million births annually. Preterm birth is associated with a range of adverse cardiovascular and central nervous system outcomes, which may be attributed to altered development of these systems following preterm birth. Preterm birth has a considerable impact on cardiovascular parameters with preterm infants displaying higher heart rates and reduced blood pressure when compared to term born infants at matched ages. Furthermore, premature infants have altered autonomic control of cardiovascular parameters which manifests as abnormalities in heart rate variability and baroreflex mediated control of heart rate and blood pressure. As a result, systemic cardiovascular parameters can be unstable following preterm birth which may place stress on the neonatal brain. The brain of a preterm infant is particularly vulnerable to these fluctuations due to immature cerebral haemodynamics. Preterm infants, particularly those who are very preterm or unwell, display fluctuating pressure-passivity between systemic blood pressure and cerebral blood flow representing a considerably increased risk of cerebral haemorrhage or hypoxia. This is further compounded by immaturity of cerebral blood flow-metabolism coupling, which means increased metabolic demand cannot adequately be met by increased cerebral blood flow. It has been suggested that adverse long-term outcomes following preterm birth may occur as a result of exposure to physiological stress either in-utero or early in infancy.


Molecular and morphological diversity in locally grown non-commercial (heirloom) mango varieties of North India.
Mango (Mangifera indica L.) has been cultivated and conserved in different agro-ecologies including Malihabad region in northern part of India, that is well known for housing diverse types (heirloom and commercial varieties). In the present study, 37 mango types comprising of 27 heirloom varieties from Malihabad region and 10 commercial varieties grown in North and Eastern India were assessed for morphological attributes and molecular diversity. The employed SSR markers amplified 2-13 alleles individually, cumulatively amplifying 124 alleles. These were studied for allelic diversity and genetic dissimilarity ranged from 0.035 to 0.892 arranging the varieties in three major clusters. The results revealed that majority of unique heirloom mangoes from Malihabad were different from the eastern part of the country. It is interesting to note Dashehari, a commercial variety from Malihabad was not aligned with heirloom varieties. Commercial varieties like Gulabkhas and Langra were placed in a separate group including Bombay Green, Himsagar, Dashehari, etc., indicating their dissimilarity with heirloom varieties at molecular level and thus, indicating importance for later from conservation point of view. Furthermore, the hierarchical clustering of varieties based on fruit morphology, assembled these into four groups largely influenced by fruit size. The maximum agreement subtree indicated seemingly good fit as thirteen varieties were arrayed in common grouping pattern. Appreciable dissimilarity among the heirloom varieties demonstrated by molecular analysis, underlines the importance for their on-farm conservation.


Throwing performance in water polo is related to in-water shoulder proprioception.
Water polo players require a high level of upper-extremity strength, flexibility and coordination to achieve a peak level of throwing performance. Increased levels of shoulder proprioceptive acuity, strength and range of motion (ROM) have been previously associated with higher sporting performance. A coach-rating scale, used to quantify an athlete's kicking proficiency in soccer; was adapted in the current study to measure each coach's subjective expert opinion regarding athletes' throwing mechanics, velocity, and accuracy. To examine this hypothesis shoulder proprioception acuity of 18 water polo players was measured both in-water and on-land using an AMEDA apparatus and correlated with coach-rated throwing performance and clinical measures of shoulder strength and ROM. There was a moderate positive correlation between the in-water and the on-land proprioception acuity (r = 0.47, p < 0.05). The in-water score showing a strong positive correlation with coach rated throwing mechanics (r = 0.68, p < 0.05) and velocity (r = 0.75, p = 0.02), suggesting that superior proprioception acuity contributed to fast, mechanically-efficient throwing. These findings support the notion that in-water proprioceptive acuity is an important determinant of the throwing performance achieved by water polo athletes and its measurement may be a valuable adjunct to current athlete screening.


Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial.
This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation. http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).


The role of health-related claims and health-related symbols in consumer behaviour: Design and conceptual framework of the CLYMBOL project and initial results.
Health claims and symbols are potential aids to help consumers identify foods that are healthier options. However, little is known as to how health claims and symbols are used by consumers in real-world shopping situations, thus making the science-based formulation of new labelling policies and the evaluation of existing ones difficult. The objective of the European Union-funded project Role of health-related CLaims and sYMBOLs in consumer behaviour (CLYMBOL) is to determine how health-related information provided through claims and symbols, in their context, can affect consumer understanding, purchase and consumption. To do this, a wide range of qualitative and quantitative consumer research methods are being used, including product sampling, sorting studies (i.e. how consumers categorise claims and symbols according to concepts such as familiarity and relevance), cross-country surveys, eye-tracking (i.e. what consumers look at and for how long), laboratory and in-store experiments, structured interviews, as well as analysis of population panel data. EU Member States differ with regard to their history of use and regulation of health claims and symbols prior to the harmonisation of 2006. Findings to date indicate the need for more structured and harmonised research on the effects of health claims and symbols on consumer behaviour, particularly taking into account country-wide differences and individual characteristics such as motivation and ability to process health-related information. Based on the studies within CLYMBOL, implications and recommendations for stakeholders such as policymakers will be provided.


[Two-Year Results of Modified AMIC Technique for Treatment of Cartilage Defects of the Knee].
PURPOSE OF THE STUDY Damage to hyaline cartilage represents a serious problem due to its limited capacity of regeneration. Currently, there are several treatment options available. The purpose of this study is to evaluate the success rate of treatment of chondral and osteochondral defects of the knee joint using the modified AMIC (Autologous Matrix-Induced Chondrogenesis) technique, combining microfractures of the base and the implantation of the type I collagen-based cell-free implant over a two-year period. MATERIAL AND METHODS The prospective study of the success rate of treatment by the modified AMIC technique included 15 patients (13 men and 2 women) with a defect confirmed by MRI and appropriate indication criteria. The mean age at the time of implantation was 33.4 years (range 19-47 years). The mean size of a treated defect was 3.66 ± 1.71 cm2 (range 2.00-7.05 cm2). The clinical outcomes were monitored through the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Lysholm score and the Tegner activity scale preoperatively and subsequently at 6, 12 and 24 months postoperatively. Control MRI was conducted at 6, 12 and 18 months postoperatively. The MRI finding was evaluated using the Magnetic Observation of Cartilage Repair Tissue (MOCART) score. RESULTS The total KOOS score was 44.69 ± 7.71 preoperatively, while postoperatively it gradually increased up to 80.45 ± 8.97 (p < 0.001) at 24 months. The Lysholm score significantly rise from 43.47 ± 11.87 preoperatively to the mean value of 81.60 ± 13.07 (p < 0.001) at 24 months postoperatively. The preoperative Tegner score was 3.53 ± 1.41. At 24 months, there was a statistically significant increase to 5.40 ± 1.70 (p = 0.003). The mean MOCART score at 18 months postoperatively was 74.67 ± 14.08. At the end of the monitored period, a complete filling of the defect site by tissue was achieved in 73.33% patients. A complete integration with adjacent cartilage was seen in 66.67% patients and homogenous structure of newly formed tissue was reported in 80% of patients. DISCUSSION In recent years, cell-free implants (the so-called scaffolds or carriers) have been used ever more frequently in treating localised cartilage defects. Their main effect should consist in helping the cells penetrate the defect site and support new cartilage tissue formation. In order to improve the efficacy of cell-free implants, a new therapeutic technique was developed, combining the microfractures of the base with the use of cell-free scaffold AMIC (Autologous Matrix-Induced Chondrogenesis). Our modification of the original AMIC technique consists in the use of a type I collagen-based scaffold instead of the original collagen membrane constituted by collagen type I and III. Based on the statistical processing of results, the modified AMIC technique has shown a statistically significant improvement compared to the preoperative values of the KOOS questionnaire and all its sub-groups, the Lysholm core and the Tegner activity scale. These good clinical outcomes correlate with the results obtained by other authors using both the original method and the modified AMIC technique. CONCLUSIONS The modified AMIC technique using the cell-free type I collagen-based implant appears to be a safe, accessible and onestage technique to treat localised chondral and osteochondral defects of the knee joint up to the size of 8 cm2. Key words: hyaline cartilage, chondral defect, AMIC, scaffold, knee.


Transplantable hematopoietic stem cells in human fetal liver have a CD34(+) side population (SP)phenotype.
Cells with a verapamil-sensitive ability to efflux Hoechst 33342 (termed side population [SP] cells) have been identified in adult marrow from several species including humans and in several tissues from adult mice. In mice, the SP phenotype appears to be a common feature of stem cells, but human SP cells have been less well characterized. We show here, for the first time to our knowledge, that SP cells are present in the second-trimester human fetal liver. They include all of the transplantable human hematopoietic stem cell activity detectable in NOD/SCID mice and also certain other, more differentiated hematopoietic cell types. Notably, the stem cell activity was confined to the CD34(+)CD38(-) SP(+) population, and isolation of these cells gave an approximately tenfold enrichment of transplantable stem cells. This subset was not, however, coenriched in hematopoietic progenitors detectable by either short- or long-term in vitro assays, indicating most of these to be distinct from transplantable stem cells. These findings suggest that the SP phenotype is an important and distinguishing property of human hematopoietic stem cells and that early in ontogeny they express CD34.


Adjuvant stereotactic body radiotherapy for resected pancreatic adenocarcinoma with close or positive margins.
The aim of this study was to evaluate the role of stereotactic body radiotherapy (SBRT) as adjuvant therapy for resected pancreatic adenocarcinoma with close or positive margins. Between September 2006 and January 2010, 24 patients were treated with adjuvant SBRT following surgical resection. Eight (33.3%) patients had close margins of 1-2.5 mm to the retroperitoneal, vascular structures, and periduodenal adipose tissue. Sixteen (66.7%) patients had positive margins at retroperitoneal margin and vascular structures. Twenty-three patients received 24 Gy (20-24 Gy) in one fraction, and one had 30 Gy in three fractions. The median target volume was 11 cc (4.5-30 cc). Eighteen patients were treated with the Cyberknife® Robotic Radiosurgery System and six patients were treated with Trilogy™ intensity-modulated radiosurgery. Kaplan-Meier survival analyses were used to estimate freedom-from-local-progression (FFLP), and overall survival (OS) rates. PET/CT or CT was used to monitor disease recurrence following SBRT. The median follow-up for all patients was 12.5 months (1.4-39.5 months), and among surviving patients it was 16.3 months (2-39.5 months). The FFLP rates at 6 months, 1 and 2 years were 94.7%, 66%, and 44%, respectively. Overall, FFLP was achieved in seven (87.5%) patients with close margins, and 10 (62.5%) with positive margins. After SBRT, 19 patients resumed or started a 6-month course of gemcitabine-based chemotherapy at a median interval of 18 days (range, 9-31 days) post-SBRT. The median OS was 26.7 months and the 1- and 2-year OS rates were 80.4% and 57.2%, respectively. Of the 24 patients, 12 (50%) developed distant metastases of whom two (25%) had close margins and 10 (62.5%) had positive margins. Ten patients (41.7%) were free of progression at last follow-up (range, 3-39.5 months). Three patients (12.5%) had grade 1-2 acute GI toxicities, and two patients (8.3%) had grade 1 and 2 late toxicities. No patients experienced grade 3 or 4 toxicity, including bowel perforation, secondary to SBRT. Our data suggest that adjuvant SBRT for resected pancreatic cancer can be achieved with minimal toxicity. This shorter treatment course allowed initiation of systemic chemotherapy shortly after the completion of SBRT.


Stillbirth evaluation: a stepwise assessment of placental pathology and autopsy.
The American Congress of Obstetricians and Gynecologists places special emphasis on autopsy as one of the most important tests for evaluation of stillbirth. Despite a recommendation of an autopsy, many families will decline the autopsy based on religious/cultural beliefs, fear of additional suffering for the child, or belief that no additional information will be obtained or of value. Further, many obstetric providers express a myriad of barriers limiting their recommendation for a perinatal autopsy despite their understanding of its value. Consequently, perinatal autopsy rates have been declining. Without the information provided by an autopsy, many women are left with unanswered questions regarding cause of death for their fetus and without clear management strategies to reduce the risk of stillbirth in future pregnancies. To avoid this scenario, it is imperative that clinicians are knowledgeable about the benefit of autopsy so they can provide clear information on its diagnostic utility and decrease potential barriers; in so doing the obstetrician can ensure that each family has the necessary information to make an informed decision. We sought to quantify the contribution of placental pathologic examination and autopsy in identifying a cause of stillbirth and to identify how often clinical management is modified due to each result. This is a cohort study of all cases of stillbirth from 2009 through 2013 at a single tertiary care center. Records were reviewed in a stepwise manner: first the clinical history and laboratory results, then the placental pathologic evaluation, and finally the autopsy. At each step, a cause of death and the certainty of that etiology were coded. Clinical changes that would be recommended by information available at each step were also recorded. Among the 144 cases of stillbirth examined, 104 (72%) underwent autopsy and these cases constitute the cohort of study. The clinical and laboratory information alone identified a cause of death in 35 (24%). After placental pathologic examination, 88 (61%) cases had a probable cause of death identified. The addition of autopsy resulted in 78 (74%) cases having an identifiable probable cause of death. Placental examination alone changed clinical management in 52 (36%) cases. Autopsy led to additional clinical management changes in 6 (6%) cases. This stepwise assessment of the benefit of both placental pathological examination and autopsy in changing probable cause of death beyond traditional clinical history and laboratory results emphasizes the need to implement more comprehensive evaluation of all stillbirths. With the aim of providing a cause of stillbirth to the parents, and to prevent future stillbirths, it behooves health care professionals to understand the value of this more comprehensive approach and convey that information to the bereaved parents.


Arctic seabirds and shrinking sea ice: egg analyses reveal the importance of ice-derived resources.
In the Arctic, sea-ice plays a central role in the functioning of marine food webs and its rapid shrinking has large effects on the biota. It is thus crucial to assess the importance of sea-ice and ice-derived resources to Arctic marine species. Here, we used a multi-biomarker approach combining Highly Branched Isoprenoids (HBIs) with δ13C and δ15N to evaluate how much Arctic seabirds rely on sea-ice derived resources during the pre-laying period, and if changes in sea-ice extent and duration affect their investment in reproduction. Eggs of thick-billed murres (Uria lomvia) and northern fulmars (Fulmarus glacialis) were collected in the Canadian Arctic during four years of highly contrasting ice conditions, and analysed for HBIs, isotopic (carbon and nitrogen) and energetic composition. Murres heavily relied on ice-associated prey, and sea-ice was beneficial for this species which produced larger and more energy-dense eggs during icier years. In contrast, fulmars did not exhibit any clear association with sympagic communities and were not impacted by changes in sea ice. Murres, like other species more constrained in their response to sea-ice variations, therefore appear more sensitive to changes and may become the losers of future climate shifts in the Arctic, unlike more resilient species such as fulmars.


The impact of BMI and smoking on risk of revision following knee and hip replacement surgery: evidence from routinely collected data.
The aim of this study was to assess the association of body mass index (BMI) and smoking with risk of revision following total knee replacement (TKR) and total hip replacement (THR). Primary care data, from the Clinical Practice Research Datalink (CPRD), was linked to inpatient hospital records, from Hospital Episode Statistics Admitted Patient Care (HES APC), and covered 1997 to 2014. Parametric survival models, with BMI and smoking status included as explanatory variables, were estimated for 10-year risk of revision and mortality, and were extrapolated to estimate lifetime risk of revision. TKR and THR cohorts included 10,260 and 10,961 individuals, respectively. For a change in BMI from 25 to 35, the 10-year risk of revision is expected change from 4.6% (3.3-6.4%) to 3.7% (2.6-5.1%) for TKR and 3.7% (2.8-5.1%) to 4.0% (2.8-5.7%) for THR for an otherwise average patient profile. Meanwhile, changing from a non-smoker to a current smoker is expected to change the risk of revision from 4.1% (3.1-5.5%) to 2.8% (1.7-4.7%) for TKR and from 3.8% (2.8-5.3%) to 2.9% (1.9-4.7%) for THR for an otherwise average patient profile. Estimates of lifetime risk were also similar for different values of BMI or smoking status. Obesity and smoking do not appear to have a meaningful impact on the risk of revision following TKR and THR.


Genetic mapping and exome sequencing identify variants associated with five novel diseases.
The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.


Role of color memory in successive color constancy.
We investigate color constancy for real 2D paper samples using a successive matching paradigm in which the observer memorizes a reference surface color under neutral illumination and after a temporal interval selects a matching test surface under the same or different illumination. We find significant effects of the illumination, reference surface, and their interaction on the matching error. We characterize the matching error in the absence of illumination change as the "pure color memory shift" and introduce a new index for successive color constancy that compares this shift against the matching error under changing illumination. The index also incorporates the vector direction of the matching errors in chromaticity space, unlike the traditional constancy index. With this index, we find that color constancy is nearly perfect.


HIV-induced loss of CD44 expression in monocytic cell lines.
We have found that HIV-1 infection of monocytic cell lines results in a new adhesion phenotype. Whereas uninfected cells grow as single cell suspensions, HIV-infected cells grow as large aggregates. When the expression of adhesion molecules was investigated, CD44 was almost completely depleted from the surface of HIV-infected cells. Immunoprecipitation with mAb confirmed the loss of CD44 from the surface of infected cells. In addition, loss of surface CD44 was not due to formation of internal complexes or release into the culture supernatant. Soluble CD44 was not detected in culture supernatant from HIV-infected cells. Northern blot analysis showed an altered RNA pattern in HIV-infected cells. The high molecular mass CD44 RNA (7.0 kb) was lost from infected cells, and the low molecular mass CD44 RNA (1.2 kb) remained. We have previously shown that anti-CD44 mAb induces homotypic adhesion in CD44+ cell lines. In this report, we show that homotypic adhesion of the HIV-infected cells occurs through a different mechanism than anti-CD44 mAb-induced aggregation. The homotypic adhesion in infected cells was CD18-mediated, but anti-CD44 mAb-induced homotypic adhesion in uninfected cells was CD18-independent. The change in adhesion phenotype and the loss of CD44 from the surface of HIV-1-infected monocytic cells are discussed in terms of their potential implications in cell-to-cell transmission of HIV.


Calcium causes a conformational change in lamin A tail domain that promotes farnesyl-mediated membrane association.
Lamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchinson Gilford progeria syndrome is a premature aging disorder wherein a mutant version of lamin A, Δ50 lamin A, retains its farnesylation. We report here that membrane association of farnesylated Δ50 lamin A tail domains requires calcium. Experimental evidence and molecular dynamics simulations collectively suggest that the farnesyl group is sequestered within a hydrophobic region in the tail domain in the absence of calcium. Calcium binds to the tail domain with an affinity KD ≈ 250 μM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl2, the affinity of the farnesylated protein to a synthetic membrane is KD ≈ 2 μM, as measured with surface plasmon resonance, but showed a combination of aggregation and binding. Membrane binding in the absence of calcium could not be detected. We suggest that a conformational change induced in Δ50 lamin A with divalent cations plays a regulatory role in the posttranslational processing of lamin A, which may be important in disease pathogenesis.


Pliocene paleoenvironments of southeastern Queensland, Australia inferred from stable isotopes of marsupial tooth enamel.
The Chinchilla Local Fauna is a diverse assemblage of both terrestrial and aquatic Pliocene vertebrates from the fluviatile Chinchilla Sand deposits of southeastern Queensland, Australia. It represents one of Australia's few but exceptionally rich Pliocene vertebrate localities, and as such is an important source of paleoecological data concerning Pliocene environmental changes and its effects on ecosystems. Prior inferences about the paleoenvironment of this locality made on the basis of qualitative observations have ranged from grassland to open woodland to wetland. Examination of the carbon and oxygen isotopes in the tooth enamel of marsupials from this site represents a quantitative method for inferring the paleoenvironments and paleoecology of the fossil fauna. Results from Chinchilla show that Protemnodon sp. indet. consumed both C3 and C4 photosynthesis plant types (mean δ(13)C = -14.5±2.0‰), and therefore probably occupied a mixed vegetation environment. Macropus sp. indet. from Chinchilla also consumed a mixed diet of both C3 and C4 plants, with more of a tendency for C4 plant consumption (mean δ(13)C = -10.3±2.3‰). Interestingly, their isotopic dietary signature is more consistent with tropical and temperate kangaroo communities than the sub-tropical communities found around Chinchilla today. Other genera sampled in this study include the extinct kangaroo Troposodon sp. indet. and the fossil diprotodontid Euryzygoma dunense each of which appear to have occupied distinct dietary niches. This study suggests that southeastern Queensland hosted a mosaic of tropical forests, wetlands and grasslands during the Pliocene and was much less arid than previously thought.