The rise and fall of civil unions: lessons from the Connecticut legislature's abandonment of gay and lesbian citizens.
On April 20, 2005, Connecticut Governor M. Jodi Rell signed into law "An Act Concerning Civil Unions" (Public Act No. 05-10, 2005). That Act did two things: First, it afforded to qualifying same-sex couples many of the rights and benefits that the state makes available to married heterosexual couples. Second, it "defended" heterosexual marriage by defining marriage as involving one man and one woman. Although it might seem that the legislature was moving in an obviously correct direction, its decision to establish a statutory scheme consigning same-sex couples to civil unions was integral to the ideological exclusion of gays and lesbians from marriage and, thereby, implied that they are unfit for family life. The Democrats' and Republicans' focus was on the formal equality guaranteed by the civil union legislation. But the heart of the legislation is disenfranchisement. Connecticut lawmakers placed the stamp of legitimacy on a policy that officially excluded lesbians and gays from full membership in civil society. To many gay and lesbian citizens in Connecticut, it was a slap in the face and awakened a realization that lawmakers' professed egalitarian ideals and the realities of defining who belonged to their communities may not coincide.


Oral contraceptive use and risk of suicidal behavior among young women.
Oral contraceptive use has been previously associated with an increased risk of suicidal behavior in some, but not all, samples. The use of large, representative, longitudinally-assessed samples may clarify the nature of this potential association. We used Swedish national registries to identify women born between 1991 and 1995 (N = 216 702) and determine whether they retrieved prescriptions for oral contraceptives. We used Cox proportional hazards models to test the association between contraceptive use and first observed suicidal event (suicide attempt or death) from age 15 until the end of follow-up in 2014 (maximum age 22.4). We adjusted for covariates, including mental illness and parental history of suicide. In a crude model, use of combination or progestin-only oral contraceptives was positively associated with suicidal behavior, with hazard ratios (HRs) of 1.73-2.78 after 1 month of use, and 1.25-1.82 after 1 year of use. Accounting for sociodemographic, parental, and psychiatric variables attenuated these associations, and risks declined with increasing duration of use: adjusted HRs ranged from 1.56 to 2.13 1 month beyond the initiation of use, and from 1.19 to 1.48 1 year after initiation of use. HRs were higher among women who ceased use during the observation period. Young women using oral contraceptives may be at increased risk of suicidal behavior, but risk declines with increased duration of use. Analysis of former users suggests that women susceptible to depression/anxiety are more likely to cease hormonal contraceptive use. Additional studies are necessary to determine whether the observed association is attributable to a causal mechanism.


Exploring the experiences of substitute decision-makers with an exception to consent in a paediatric resuscitation randomised controlled trial: study protocol for a qualitative research study.
Prospective informed consent is required for most research involving human participants; however, this is impracticable under some circumstances. The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS) outlines the requirements for research involving human participants in Canada. The need for an exception to consent (deferred consent) is recognised and endorsed in the TCPS for research in individual medical emergencies; however, little is known about substitute decision-maker (SDM) experiences. A paediatric resuscitation trial (SQUEEZE) (NCT01973907) using an exception to consent process began enrolling at McMaster Children's Hospital in January 2014. This qualitative research study aims to generate new knowledge on SDM experiences with the exception to consent process as implemented in a randomised controlled trial. The SDMs of children enrolled into the SQUEEZE pilot trial will be the sampling frame from which ethics study participants will be derived. Qualitative research study involving individual interviews and grounded theory methodology. SDMs for children enrolled into the SQUEEZE pilot trial. Up to 25 SDMs. Qualitative methodology: SDMs will be invited to participate in the qualitative ethics study. Interviews with consenting SDMs will be conducted in person or by telephone, taped and professionally transcribed. Participants will be encouraged to elaborate on their experience of being asked to consent after the fact and how this process occurred. Data gathering and analysis will be undertaken simultaneously. The investigators will collaborate in developing the coding scheme, and data will be coded using NVivo. Emerging themes will be identified. This research represents a rare opportunity to interview parents/guardians of critically ill children enrolled into a resuscitation trial without their knowledge or prior consent. Findings will inform implementation of the exception to consent process in the planned definitive SQUEEZE trial and support development of evidence-based ethics guidelines.


Using supervised learning to select audit targets in performance-based financing in health: An example from Zambia.
Independent verification is a critical component of performance-based financing (PBF) in health care, in which facilities are offered incentives to increase the volume of specific services but the same incentives may lead them to over-report. We examine alternative strategies for targeted sampling of health clinics for independent verification. Specifically, we empirically compare several methods of random sampling and predictive modeling on data from a Zambian PBF pilot that contains reported and verified performance for quantity indicators of 140 clinics. Our results indicate that machine learning methods, particularly Random Forest, outperform other approaches and can increase the cost-effectiveness of verification activities.


Digital concentration readout of single enzyme molecules using femtoliter arrays and Poisson statistics.
Methods for accurately quantifying the concentration of a particular analyte in solution are all based on ensemble responses in which many analyte molecules give rise to the measured signal. In this paper, single molecules of beta-galactosidase were monitored using a 1 mm diameter fiber optic bundle with 2.4 x 10(5) individually sealed, femtoliter microwell reactors. By observation of the buildup of fluorescent products from single enzyme molecule catalysis over the array of reaction vessels and by application of a Poisson statistical analysis, a digital concentration readout was obtained. This approach should prove useful for single molecule enzymology and ultrasensitive bioassays. More generally, the ability to determine concentration by counting individual molecules offers a new approach to analysis of dilute solutions.


Diverse origin of mitochondrial lineages in Iron Age Black Sea Scythians.
Scythians were nomadic and semi-nomadic people that ruled the Eurasian steppe during much of the first millennium BCE. While having been extensively studied by archaeology, very little is known about their genetic identity. To fill this gap, we analyzed ancient mitochondrial DNA (mtDNA) from Scythians of the North Pontic Region (NPR) and successfully retrieved 19 whole mtDNA genomes. We have identified three potential mtDNA lineage ancestries of the NPR Scythians tracing back to hunter-gatherer and nomadic populations of east and west Eurasia as well as the Neolithic farming expansion into Europe. One third of all mt lineages in our dataset belonged to subdivisions of mt haplogroup U5. A comparison of NPR Scythian mtDNA linages with other contemporaneous Scythian groups, the Saka and the Pazyryks, reveals a common mtDNA package comprised of haplogroups H/H5, U5a, A, D/D4, and F1/F2. Of these, west Eurasian lineages show a downward cline in the west-east direction while east Eurasian haplogroups display the opposite trajectory. An overall similarity in mtDNA lineages of the NPR Scythians was found with the late Bronze Age Srubnaya population of the Northern Black Sea region which supports the archaeological hypothesis suggesting Srubnaya people as ancestors of the NPR Scythians.


TGF-beta signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer: role of the beta-spectrin, ELF.
We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-beta signaling through Smad3 and Smad4 localization. Notably elf(+/-)/smad4(+/-) mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf(-/-) cells and elf(+/-)/smad4(+/-) mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf(-/-) MEFs show a disruption of G1/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G1/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation.


Systematic reviews.
Systematic reviews are a type of literature review in which authors systematically search for, critically appraise, and synthesize evidence from several studies on the same topic (Grant & Booth, 2009). The precise and systematic method differentiates systematic reviews from traditional reviews (Khan, Kunz, Kleijnen, & Antes, 2003). In all types of systematic reviews, a quality assessment is done of the individual studies that meet inclusion criteria. These individual assessments are synthesized, and aggregated results are reported. Systematic reviews are considered the highest level of evidence in evidence-based health care because the reviewers strive to use transparent, rigorous methods that minimize bias.


Powder diffraction and crystal structure prediction identify four new coumarin polymorphs.
Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and the need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.


Outcomes following transcatheter transseptal versus transapical mitral valve-in-valve and valve-in-ring procedures.
Introduction: Transcatheter mitral valve-in-valve (ViV) & valve-in-ring (ViR) are relatively novel therapeutic alternatives for patients with degenerated bioprostheses or failed annuloplasty rings whose reoperative risk is too high. The predominant procedural access for both procedures is transapical or transseptal. However, whether there are differences in outcomes of this procedure using transseptal versus transapical access has not yet been defined. Methods: We conducted a systematic review of all published articles from MEDLINE and EMBASE to explore the outcomes of these two procedural approaches. Results:total of 55 studies including 183 patients (154 ViV and 29 ViR) were included. Patients that underwent ViV (101 transapical and 53 transseptal) using the transseptal approach required more iatrogenic atrial septal defect (ASD) closure (19% versus 0.0 %; P < 0.001) and hence had a lower device success rate (68% versus 89%; P = 0.001). However, there was no significant difference between the two groups in procedural success and all-cause mortality at 30 days. Overall severe bleeding complications (major or life threatening) were not different the two groups (3.7% versus 7.9%; P = 0.321). In the ViR group (19 transapical and 10 transseptal), no difference in procedural success, device success or 30-day outcomes were identified between transseptal and transapical groups, although sample size was small. Conclusion: In conclusion, mitral ViV and ViR using the two different procedural approaches appear to confer equal and reasonable 30-day outcomes.


Isochronic carrier-envelope phase-shift compensator.
A concept for orthogonal control of phase and group delay inside a laser cavity by a specially designed compensator assembly is discussed. Similar to the construction of variable polarization retarder, this assembly consists of two thin wedge prisms made from appropriately chosen optical materials. Being shifted as a whole, the assembly allows changing the phase delay with no influence on the cavity round-trip time, whereas relative shifting of the prisms enables adjustment of the latter. This scheme is discussed theoretically and verified experimentally, indicating a factor 30 reduction of the influence on the repetition rate compared to the commonly used silica wedge pair. For a 2pi adjustment of the carrier-envelope phase shift, single-pass timing differences are reduced to the single-femtosecond regime. With negligible distortions of timing and dispersion, the described compensator device greatly simplifies carrier-envelope phase control and experiments in extreme nonlinear optics.


Oral hydrogen water prevents chronic allograft nephropathy in rats.
Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation.


A retrieved context account of spacing and repetition effects in free recall.
Repeating an item in a list benefits recall performance, and this benefit increases when the repetitions are spaced apart (Madigan, 1969; Melton, 1970). Retrieved context theory incorporates 2 mechanisms that account for these effects: contextual variability and study-phase retrieval. Specifically, if an item presented at position i is repeated at position j, this leads to retrieval of its context from its initial presentation at i (study-phase retrieval), and this retrieved context will be used to update the current state of context (contextual variability). Here we consider predictions of a computational model that embodies retrieved context theory, the context maintenance and retrieval model (CMR; Polyn, Norman, & Kahana, 2009). CMR makes the novel prediction that subjects are more likely to successively recall items that follow a shared repeated item (e.g., i + 1, j + 1) because both items are associated with the context of the repeated item presented at i and j. CMR also predicts that the probability of recalling at least 1 of 2 studied items should increase with the items' spacing (Lohnas, Polyn, & Kahana, 2011). We tested these predictions in a new experiment, and CMR's predictions were upheld. These findings suggest that retrieved context theory offers an integrated explanation for repetition and spacing effects in free recall tasks.


Dynamic determinants of longevity and exceptional health.
It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity.


Na-ion Storage Performances of FeSe(x) and Fe2O3 Hollow Nanoparticles-Decorated Reduced Graphene Oxide Balls prepared by Nanoscale Kirkendall Diffusion Process.
Uniquely structured FeSe(x)-reduced graphene oxide (rGO) composite powders, in which hollow FeSe(x) nanoparticles are uniformly distributed throughout the rGO matrix, were prepared by spray pyrolysis applying the nanoscale Kirkendall diffusion process. Iron oxide-rGO composite powders were transformed into FeSe(x)-rGO composite powders by a two-step post-treatment process. Metallic Fe nanocrystals formed during the first-step post-treatment process were transformed into hollow FeSe(x) nanoparticles during the selenization process. The FeSe(x)-rGO composite powders had mixed crystal structures of FeSe and FeSe2 phases. A rGO content of 33% was estimated from the TG analysis of the FeSe(x)-rGO composite powders. The FeSe(x)-rGO composite powders had superior sodium-ion storage properties compared to those of the Fe2O3-rGO composite powders with similar morphological characteristics. The discharge capacities of the FeSe(x)- and Fe2O3-rGO composite powders for the 200(th) cycle at a constant current density of 0.3 A g(-1) were 434 and 174 mA h g(-1), respectively. The FeSe(x)-rGO composite powders had a high discharge capacity of 311 mA h g(-1) for the 1000(th) cycle at a high current density of 1 A g(-1).


Depression, Anxiety, and Lifestyle Among Essential Workers: A Web Survey From Brazil and Spain During the COVID-19 Pandemic.
Essential workers have been shown to present a higher prevalence of positive screenings for anxiety and depression during the COVID-19 pandemic. Individuals from countries with socioeconomic inequalities may be at increased risk for mental health disorders. We aimed to assess the prevalence and predictors of depression, anxiety, and their comorbidity among essential workers in Brazil and Spain during the COVID-19 pandemic. A web survey was conducted between April and May 2020 in both countries. The main outcome was a positive screening for depression only, anxiety only, or both. Lifestyle was measured using a lifestyle multidimensional scale adapted for the COVID-19 pandemic (Short Multidimensional Inventory Lifestyle Evaluation-Confinement). A multinomial logistic regression model was performed to evaluate the factors associated with depression, anxiety, and the presence of both conditions. From the 22,786 individuals included in the web survey, 3745 self-reported to be essential workers. Overall, 8.3% (n=311), 11.6% (n=434), and 27.4% (n=1027) presented positive screenings for depression, anxiety, and both, respectively. After adjusting for confounding factors, the multinomial model showed that an unhealthy lifestyle increased the likelihood of depression (adjusted odds ratio [AOR] 4.00, 95% CI 2.72-5.87), anxiety (AOR 2.39, 95% CI 1.80-3.20), and both anxiety and depression (AOR 8.30, 95% CI 5.90-11.7). Living in Brazil was associated with increased odds of depression (AOR 2.89, 95% CI 2.07-4.06), anxiety (AOR 2.81, 95%CI 2.11-3.74), and both conditions (AOR 5.99, 95% CI 4.53-7.91). Interventions addressing lifestyle may be useful in dealing with symptoms of common mental disorders during the strain imposed among essential workers by the COVID-19 pandemic. Essential workers who live in middle-income countries with higher rates of inequality may face additional challenges. Ensuring equitable treatment and support may be an important challenge ahead, considering the possible syndemic effect of the social determinants of health.


Greater Attendance at a Community Weight Loss Programme over the First 12 Weeks Predicts Weight Loss at 2 Years.
There is considerable heterogeneity in long-term weight loss among people referred to obesity treatment programmes. It is unclear whether attendance at face-to-face sessions in the early weeks of the programme is an independent predictor of long-term success. To investigate whether frequency of attendance at a community weight loss programme over the first 12 weeks is associated with long-term weight change. Participants were randomised to receive brief support only (control, n = 211), or a weight loss programme for 12 weeks (n = 530) or 52 weeks (n = 528). This study included participants with data on session attendance over the first 12 weeks (n = 889) compared to the control group. The association between attendance (continuously) and weight loss was explored using a linear model. A multi-level mixed-effects linear model was used to investigate whether attendance (categorised as 0, 1, 2-5, 6-9, and 10-12 sessions) was associated with weight loss at 3, 12, and 24 months compared to the control. For every session attended in the first 12 weeks, the average weight loss was -0.259 kg/session at 24 months (p = 0.005). Analysis by attendance group found only those attending 10-12 sessions had significantly greater weight loss (-7.5 kg [95% CI -8.1 to -6.9] at 12 months; -4.7 kg [95% CI -5.3 to -4.1] at 24 months) compared to the control group (-3.4 [95% CI -4.5 to -2.4] at 12 months, -2.5 [95% CI -3.5 to -1.5] at 24 months). Early attendance was higher for people ≥70 years, but there was no evidence of a difference by gender, ethnicity, education, or income. Greater attendance at a community weight loss programme in the first 12 weeks is associated with enhanced weight loss up to 24 months. Regular attendance at a programme could be used as a criterion for continued provision of weight loss services to maximise the cost-effectiveness of interventions.


The Chd1 chromatin remodeler shifts hexasomes unidirectionally.
Despite their canonical two-fold symmetry, nucleosomes in biological contexts are often asymmetric: functionalized with post-translational modifications (PTMs), substituted with histone variants, and even lacking H2A/H2B dimers. Here we show that the Widom 601 nucleosome positioning sequence can produce hexasomes in a specific orientation on DNA, providing a useful tool for interrogating chromatin enzymes and allowing for the generation of nucleosomes with precisely defined asymmetry. Using this methodology, we demonstrate that the Chd1 chromatin remodeler from Saccharomyces cerevisiae requires H2A/H2B on the entry side for sliding, and thus, unlike the back-and-forth sliding observed for nucleosomes, Chd1 shifts hexasomes unidirectionally. Chd1 takes part in chromatin reorganization surrounding transcribing RNA polymerase II (Pol II), and using asymmetric nucleosomes we show that ubiquitin-conjugated H2B on the entry side stimulates nucleosome sliding by Chd1. We speculate that biased nucleosome and hexasome sliding due to asymmetry contributes to the packing of arrays observed in vivo.


Predicting tooth color from facial features and gender: results from a white elderly cohort.
Clinicians providing edentulous patients with complete dentures are often confronted with the problem of not knowing the patient's natural tooth color. It would be valuable to be able to determine this from other facial features. The purpose of this study was to assess the possibility of predicting tooth color in the elderly from hair and eye color, facial skin complexion, and gender. The lightness (L*), chroma (C*), and hue (h*) of the color of 541 natural teeth were measured for a white study population (94 subjects, 75 to 77 years old, 55.3% male) by means of a single measurement with a clinically applicable spectrophotometer. Hair and eye color and facial skin complexion were recorded in categories. Mixed-effects regression models were calculated for each L*, C*, and h* value with hair and eye color, facial skin complexion, and gender as independent variables (alpha=.05). Only gender and hair color in univariate analysis and, additionally, eye color in multivariate analysis, were significant predictors of tooth color. Higher L* values (lighter color) were associated with lighter eye color and with female gender. The C* value was lower (less saturated) for women. More yellow/green than yellow/red h* values were associated with hair colors other than black and with female gender. However, the parameter estimates of the variables were rather low. Determination of tooth color from hair and eye color and from gender in the white elderly was only partially possible.


Functional interactions between heterologously expressed starch-branching enzymes of maize and the glycogen synthases of Brewer's yeast.
Starch-branching enzymes (SBEs) catalyze the formation of alpha(1-->6) glycoside bonds in glucan polymers, thus, affecting the structure of amylopectin and starch granules. Two distinct classes of SBE are generally conserved in higher plants, although the specific role(s) of each isoform in determination of starch structure is not clearly understood. This study used a heterologous in vivo system to isolate the function of each of the three known SBE isoforms of maize (Zea mays) away from the other plant enzymes involved in starch biosynthesis. The ascomycete Brewer's yeast (Saccharomyces cerevisiae) was employed as the host species. All possible combinations of maize SBEs were expressed in the absence of the endogenous glucan-branching enzyme. Each maize SBE was functional in yeast cells, although SBEI had a significant effect only if SBEIIa and SBEIIb also were present. SBEI by itself did not support glucan accumulation, whereas SBEIIa and SBEIIb both functioned along with the native glycogen synthases (GSs) to produce significant quantities of alpha-glucan polymers. SBEIIa was phenotypically dominant to SBEIIb in terms of glucan structure. The specific branching enzyme present had a significant effect on the molecular weight of the product. From these data we suggest that SBEs and GSs work in a cyclically interdependent fashion, such that SBE action is needed for optimal GS activity; and GS, in turn, influences the further effects of SBE. Also, SBEIIa and SBEIIb appear to act before SBEI during polymer assembly in this heterologous system.


Class A mode-locked semiconductor ring laser.
We experimentally demonstrate low-repetition-rate mode-locked operation of a macroscopic semiconductor ring laser. Since antiphase periodic pulses are observed only when the two directions of operation are constrained to spatially overlap in the semiconductor medium, we interpret this regime as a result of coupling and competition between clockwise and counterclockwise emission directions. Because of its time constants and the possibility of unidirectional operation, the device could be highly suitable for the generation of temporal cavity solitons.


Evaluation of MHC-II peptide binding prediction servers: applications for vaccine research.
Initiation and regulation of immune responses in humans involves recognition of peptides presented by human leukocyte antigen class II (HLA-II) molecules. These peptides (HLA-II T-cell epitopes) are increasingly important as research targets for the development of vaccines and immunotherapies. HLA-II peptide binding studies involve multiple overlapping peptides spanning individual antigens, as well as complete viral proteomes. Antigen variation in pathogens and tumor antigens, and extensive polymorphism of HLA molecules increase the number of targets for screening studies. Experimental screening methods are expensive and time consuming and reagents are not readily available for many of the HLA class II molecules. Computational prediction methods complement experimental studies, minimize the number of validation experiments, and significantly speed up the epitope mapping process. We collected test data from four independent studies that involved 721 peptide binding assays. Full overlapping studies of four antigens identified binding affinity of 103 peptides to seven common HLA-DR molecules (DRB1*0101, 0301, 0401, 0701, 1101, 1301, and 1501). We used these data to analyze performance of 21 HLA-II binding prediction servers accessible through the WWW. Because not all servers have predictors for all tested HLA-II molecules, we assessed a total of 113 predictors. The length of test peptides ranged from 15 to 19 amino acids. We tried three prediction strategies - the best 9-mer within the longer peptide, the average of best three 9-mer predictions, and the average of all 9-mer predictions within the longer peptide. The best strategy was the identification of a single best 9-mer within the longer peptide. Overall, measured by the receiver operating characteristic method (AROC), 17 predictors showed good (AROC > 0.8), 41 showed marginal (AROC > 0.7), and 55 showed poor performance (AROC < 0.7). Good performance predictors included HLA-DRB1*0101 (seven), 1101 (six), 0401 (three), and 0701 (one). The best individual predictor was NETMHCIIPAN, closely followed by PROPRED, IEDB (Consensus), and MULTIPRED (SVM). None of the individual predictors was shown to be suitable for prediction of promiscuous peptides. Current predictive capabilities allow prediction of only 50% of actual T-cell epitopes using practical thresholds. The available HLA-II servers do not match prediction capabilities of HLA-I predictors. Currently available HLA-II prediction servers offer only a limited prediction accuracy and the development of improved predictors is needed for large-scale studies, such as proteome-wide epitope mapping. The requirements for accuracy of HLA-II binding predictions are stringent because of the substantial effect of false positives.


Split-mouth designs in orthodontics: an overview with applications to orthodontic clinical trials.
Split-mouth designs first appeared in dental clinical trials in the late sixties. The main advantage of this study design is its efficiency in terms of sample size as the patients act as their own controls. Cited disadvantages relate to carry-across effects, contamination or spilling of the effects of one intervention to another, period effects if the interventions are delivered at different time periods, difficulty in finding similar comparison sites within patients and the requirement for more complex data analysis. Although some additional thought is required when utilizing a split-mouth design, the efficiency of this design is attractive, particularly in orthodontic clinical studies where carry-across, period effects and dissimilarity between intervention sites does not pose a problem. Selection of the appropriate research design, intervention protocol and statistical method accounting for both the reduced variability and potential clustering effects within patients should be considered for the trial results to be valid.


Water turnover of healthy children measured by deuterated water elimination.
For healthy children up to 15 years of age, no data exist regarding water turnover as directly measured using stable isotope techniques. Water turnover was measured in 171 healthy children (88 girls, 83 boys, age: 6 weeks-15 years) whilst living in their normal environment. Water turnover was calculated from the equilibrium of 2H2O concentration reached in the urine 2-3 h after an oral test load of 2 ml 2H2O/kg and the subsequent elimination rate of 2H2O. Daily water turnover decreased from 160 ml/kg (3 months), 100 ml/kg (12 months), 65 ml/kg (3 years) to 40 ml/kg at 15 years of age. Fluid intake was then calculated by subtracting the estimated metabolic water production from water turnover and this data was compared with recommended values. Our calculation of spontaneous daily fluid intake for these healthy children is within the recommended range during the 1st year of life, whereas for older children the recommendations exceed the spontaneous intake by a factor of 1.2-2.


Osthole, a potential antidiabetic agent, alleviates hyperglycemia in db/db mice.
Osthole is an agent isolated from Cnidium monnieri (L.) Cusson and Angelica pubescens and has been used to treat several diseases, including metabolic syndromes. To investigate the hypoglycemic effects of osthole in diabetic db/db mice and the underlying mechanisms of these effects by in vitro assay, diabetic db/db mice and cell experiments were utilized to understand its possible effects. Osthole significantly activated both PPARalpha and PPARgamma in a dose-dependent manner based on the results of the transition transfection assay. The activation of PPARalpha and PPARgamma by osthole also resulted in an increase in the expression of PPAR target genes such as PPAR itself, adipose fatty acid-binding protein 2, acyl-CoA synthetases, and carnitine palmitoyltransferase-1A. In vitro results suggested that osthole might be a dual PPARalpha/gamma activator, but its chemical structure differed from that of the thiazolidinedione class of antidiabetic drugs. In addition, osthole markedly activated the AMP-activated protein kinase and its downstream acetyl CoA carboxylase molecules by increasing their phosphorylation levels. Finally, obese diabetic db/db mice were treated with osthole by different administered routes, and osthole was found to markedly reduce blood glucose level. Interestingly, osthole did not reduce the blood insulin or lipid levels, two phenomena that did occur in animals treated with insulin sensitizers like PPAR agonists. These results suggest that osthole can alleviate hyperglycemia and could be potentially developed into a novel drug for treatment of diabetes mellitus.


Identification of Reduced Host Transcriptomic Signatures for Tuberculosis Disease and Digital PCR-Based Validation and Quantification.
Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate diagnostic test development. To identify minimal transcript signatures, we applied a transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were further investigated using reverse transcriptase (RT)-digital PCR (dPCR). A four-transcript signature (GBP6, TMCC1, PRDM1, and ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2-100%). A three-transcript signature (FCGR1A, ZNF296, and C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3-100%), regardless of HIV. These signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.


Mollusk shell: daily growth lines.
Ridges forming the concentric sculpture on the shells of laboratory-grown specimens of Pecten diegensis Dall show daily periodicity. Missing growth lines account for all scatter in the data, so that the maximum, not the average, line count is most representative. The variation in spacing between growth lines can be correlated among specimens.


The outlet patch: gastric heterotopia of the colorectum and anus.
Gastric heterotopia (GH) has been described throughout the gastrointestinal tract. However, the colorectal region is an extremely rare location for it. We describe the clinicopathological features of GH of the colon, rectum and anus. We identified 33 cases in 20 males and 13 females (median age = 54 years; range = 4 months-73 years). Sites included the rectum (n = 26), anus (n = 4), ileocaecal junction (n = 1), ascending colon (n = 1) and descending colon (n = 1). Presenting symptoms (n = 27) included haematochezia (41%) and altered bowel habits (4%); 15 patients (55%) were asymptomatic. On colonoscopy (n = 31), all appeared as solitary lesions (median size = 6.5 mm, range = 2-55 mm), either as polyps (61%), raised erythematous patches (23%), an ulcer (10%), within a rectal diverticulum (3%) or a haemorrhoid (3%). Patients were managed by polypectomy. One with an associated carcinoma in the area of GH underwent resection. No morbidity related to GH itself was reported following excision. Histologically, heterotopic gastric mucosa was oxyntic (85%), mixed oxyntic and non-oxyntic (12%) and not specified (3%) types. In five patients a pyloric gland adenoma (PGA) arose from heterotopic gastric mucosa, two of which contained a focus of invasive adenocarcinoma. One case had associated surface foveolar-type low-grade dysplasia. Another had associated adenocarcinoma arising from the heterotopic mucosa. One example harboured Helicobacter pylori organisms. We highlight the features of GH in the distal GIT - the 'outlet patch'. Association with PGA, surface dysplasia and adenocarcinoma suggests that lower tract GH can undergo neoplastic transformation.


The relationship between age and risky injecting behaviours among a sample of Australian people who inject drugs.
Limited evidence suggests that younger people who inject drugs (PWID) engage in high-risk injecting behaviours. This study aims to better understand the relationships between age and risky injecting behaviours. Data were taken from 11 years of a repeat cross-sectional study of sentinel samples of regular PWID (The Australian Illicit Drug Reporting System, 2001-2011). Multivariable Poisson regression was used to explore the relationship between age and four outcomes of interest: last drug injection occurred in public, receptive needle sharing (past month), experiencing injecting-related problems (e.g. abscess, dirty hit; past month), and non-fatal heroin overdose (past six months). Data from 6795 first-time study participants were analysed (median age: 33 years, interquartile range [IQR]: 27-40; median duration of injecting: 13 years [IQR: 7-20]). After adjusting for factors including duration of injecting, each five year increase in age was associated with significant reductions in public injecting (adjusted incidence rate ratio [AIRR]: 0.90, 95% confidence interval [CI]: 0.88-0.92), needle sharing (AIRR: 0.84, 95% CI: 0.79-0.89) and injecting-related problems (AIRR: 0.96, 95% CI: 0.95-0.97). Among those who had injected heroin in the six months preceding interview, each five year increase in age was associated with an average 10% reduction in the risk of heroin overdose (AIRR: 0.90, 95% CI: 0.85-0.96). Older PWID report significantly lower levels of high-risk injecting practices than younger PWID. Although they make up a small proportion of the current PWID population, younger PWID remain an important group for prevention and harm reduction.


Relationship between intuition and emotional intelligence in occupational therapists in mental health practice.
Clinical reasoning studies have acknowledged tacit aspects of practice, and recent research suggests that clinical reasoning contains intuition informed by tacit knowledge. Intuition also appears to be influenced by awareness and understanding of emotions. This study investigated the relationship between intuition and emotional intelligence among occupational therapists in mental health practice. We mailed a survey containing measures of cognitive style and of use of emotional competencies at work and demographic questions to 400 members of the national occupational therapy association; 134 occupational therapists responded. A moderate relationship was found between intuitive cognitive style and emotional intelligence. Experienced therapists scored higher on the use of emotional competencies at work and reported a preference for an intuitive cognitive style to a greater extent than novices. This study represents the first attempt to explore occupational therapists' preferred cognitive style and self-reported emotional intelligence. Findings suggest that exploring emotions through reflective practice could enhance intuitive aspects of clinical reasoning.


p53 expression in cultured cells following radioisotope labelling.
p53 inhibits division following cellular damage. Cultured cells were found to express p53 protein following pulse labelling with radioisotopes, even at low doses normally used for growth and metabolic labelling studies. Some stem cells are exquisitely sensitive to radiation and thus p53 may have evolved as a major regulator of stem cell function. Therefore any genetic damage may be able to induce p53 expression, which in turn will affect the biochemical outcome of many experiments by both cell cycle arrest and other mechanisms. In some cases the use of radioisotopes may directly change the results of the experiment. This will require a careful re-evaluation of the current literature and experimental protocols utilising radioisotopes.


Measurement of liver tissue oxygenation after orthotopic liver transplantation using a multiparameter sensor. A pilot study.
The currently used methods of monitoring liver perfusion and oxygenation after liver transplantation have major limitations in clinical use. We describe the use of a multiparameter sensor to enable continuous monitoring of liver tissue oxygen tension, carbon dioxide tension and hydrogen ion concentration in the early postoperative period in 12 patients after liver transplantation. The sensor was inserted under direct vision via the falciform ligament into the liver before skin closure. Tissue oxygen tension values decreased in the first 24 h and subsequently increased to a mean (SD) = 7.3 (2.8) kPa at 48 h after surgery. This was associated with a decrease in the degree of acidosis. There were no complications attributable to the sensor. This study demonstrates that continuous measurement of liver oxygen tension, carbon dioxide tension and pH is possible. This technique may be useful as a continuous monitor to help identify grafts at risk of ischaemia.


Antiproliferative ability of a combination regimen of crocodile egg extract, wild radix ginseng and natural Ganoderma lucidum on acute myelogenous leukemia.
Chinese practitioners have employed the use of traditional Chinese medicine as an anti-cancer agent since the ancient period. Different combinations have been formulated for various purposes. Some have been claimed for post-chemotherapy use but their direct actions on cancer cells may not be significantly reported. In the present study, we have tested the possible anti-leukemia potential of a combination regimen including crocodile egg extract, wild radix ginseng and natural Ganoderma lucidum (CGG extract) on acute myelogenous leukemia (AML) in vitro. A water soluble CGG extract was prepared and its antiproliferative activity was tested on the KG1a AML cell line and two freshly prepared bone marrow aspirate samples isolated from patients with de novo AML during presentation by a MTS/PMS assay. Furthermore, the possible activity of the CGG extract on the regeneration potential of KG1a cells was also investigated using a semi-solid methyl-cellulose colony formation assay. Lastly, the acute toxicity of CGG extract was further examined by a single high-dose oral feeding to rats. We found that the CGG extract could possess significant antiproliferative activity on AML cells. A strong colony formation inhibition was further demonstrated on KG1a cells. After feeding the rats with an excessive dose of CGG extract, we observed no development of acute toxicity. We concluded that the CGG extract has growth inhibitory potential on KG1a cells and AML bone marrow samples in vitro. An in vivo toxicity test revealed that no acute toxicity was observed after feeding the rats a high dosage of the CGG extract. Further animal model tests are necessary to investigate the possible chronic toxicity of the CGG extract.


Binge eating among gastric bypass patients at long-term follow-up.
A better understanding of the relationship of eating behavior and attitudes to weight loss following gastric bypass (GBP) will enable the development of interventions to improve outcome. Thus, the present study sought to characterize the postoperative weight, eating behavior, and attitudes toward body shape and weight in a cross-section of GBP patients. A second objective was to examine the relationship of postoperative binge eating to surgery outcome. 99 patients who underwent GBP > 2 and < 7 years before the study start date completed the Eating Disorder Examination-Questionnaire (EDE-Q) and the Three-Factor Eating Questionnaire (TFEQ). Subjects self-reported their current body weight, weight change over the past 3 months, and lowest weight since surgery. BMI remained significantly below the preoperative level, but significant weight regain was reported at long-term follow-up. 46% of participants reported recurrent loss of control over eating (objective or subjective bulimic episodes) on the EDE-Q. These patients constituted a distinctive subgroup with a less favorable outcome, including greater weight regain. Self-reported loss of control over eating was related to weight regain after GBP and may be an important target for clinical intervention. The relationship of binge eating and related psychopathology to outcome following GBP warrants further investigation.


Towards Equitable and Resilient Digital Primary Care Systems: An International Comparison and Insight for Moving Forward.
While the COVID-19 pandemic provided a global stimulus for digital health capacity, its development has often been inequitable, short-term in planning, and lacking in health system coherence. Inclusive digital health and the development of resilient health systems are broad outcomes that require a systematic approach to achieving them. This paper from the IMIA Primary Care Informatics Working Group (WG) provides necessary first steps for the design of a digital primary care system that can support system equity and resilience. We report on digital capability and growth in maturity in four key areas: (1) Vaccination/Prevention, (2) Disease management, (3) Surveillance, and (4) Pandemic preparedness for Australia, Canada, and the United Kingdom (data from England). Our comparison looks at seasonal influenza management prior to COVID-19 (2019-20) compared to COVID-19 (winter 2020 onwards). All three countries showed growth in digital maturity from the 2019-20 management of influenza to the 2020-21 year and the management of the COVID-19 pandemic. However, the degree of progress was sporadic and uneven and has led to issues of system inequity across populations. The opportunity to use the lessons learned from COVID-19 should not be wasted. A digital health infrastructure is not enough on its own to drive health system transformation and to achieve desired outcomes such as system equity and resilience. We must define specific measures to track the growth of digital maturity, including standardized and fit-for-context data that is shared accurately across the health and socioeconomic sectors.


A randomized pilot study of acupuncture treatment for primary dysmenorrhea.
To compare the therapeutic effect of acupuncture and non-steroidal anti-inflammatory drug (NSAID) therapy in primary dysmenorrhea patients. Thirty-five young women with a diagnosis of primary dysmenorrhea were recruited for the study. Their dysmenorrhea severity was rated by visual analog scale (VAS) immediately prior to entry into the study. They were randomly divided into two groups; and the following month they were given NSAID (group 1, n=24) or acupuncture treatment (group 2, n=11). Pain was rated again using VAS during menstruation in both groups. After one month's treatment, pain scores were significantly lower in both groups (p<0.05). Mean pain scores decreased by 52.2% and 69.5% in the NSAID and acupuncture groups, respectively. Acupuncture was as effective as NSAID therapy for patients with primary dysmenorrhea. Since this was a pilot study with a small sample size and short follow-up period, larger studies are needed to clarify the effect of acupuncture in the treatment of primary dysmenorrhea.


Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis.
4-1BB, a member of the TNFR superfamily, is a costimulatory receptor primarily expressed on activated T cells. It has been shown that the administration of agonistic anti-4-1BB Abs enhances tumor immunity and allogenic immune responses. Paradoxically, we found that the administration of an agonistic anti-4-1BB mAb (2A) dramatically reduced the incidence and severity of experimental autoimmune encephalomyelitis (EAE). Adoptive transfer of T cells from such treated mice failed to induce EAE, whereas anti-4-1BB treatment following adoptive transfer of encephalitogenic T cells did not prevent EAE pathogenesis. These results suggest that anti-4-1BB treatment during the induction phase inhibits autoreactive T cell immune responses rather than preventing T cell trafficking into the CNS. This was substantiated by the observations that draining lymph node cells from anti-4-1BB-treated mice failed to respond to Ag stimulation in vitro. In addition, we found that such treatment initially promotes the activation and proliferation of Ag-specific CD4+ T cells but subsequently increases their probability of undergoing activation-induced cell death, thereby inhibiting effector T cell responses. More importantly, 2A treatment also inhibits the relapse of EAE in a clinically relevant murine model of multiple sclerosis. This study indicates that the agonistic Ab against 4-1BB can potentially be used as a novel immunotherapeutic agent for treating autoimmune diseases.


Insights into the role of specific lipids in the formation and delivery of lipid microdomains to the plasma membrane of plant cells.
The existence of sphingolipid- and sterol-enriched microdomains, known as lipid rafts, in the plasma membrane (PM) of eukaryotic cells is well documented. To obtain more insight into the lipid molecular species required for the formation of microdomains in plants, we have isolated detergent (Triton X-100)-resistant membranes (DRMs) from the PM of Arabidopsis (Arabidopsis thaliana) and leek (Allium porrum) seedlings as well as from Arabidopsis cell cultures. Here, we show that all DRM preparations are enriched in sterols, sterylglucosides, and glucosylceramides (GluCer) and depleted in glycerophospholipids. The GluCer of DRMs from leek seedlings contain hydroxypalmitic acid. We investigated the role of sterols in DRM formation along the secretory pathway in leek seedlings. We present evidence for the presence of DRMs in both the PM and the Golgi apparatus but not in the endoplasmic reticulum. In leek seedlings treated with fenpropimorph, a sterol biosynthesis inhibitor, the usual Delta(5)-sterols are replaced by 9beta,19-cyclopropylsterols. In these plants, sterols and hydroxypalmitic acid-containing GluCer do not reach the PM, and most DRMs are recovered from the Golgi apparatus, indicating that Delta(5)-sterols and GluCer play a crucial role in lipid microdomain formation and delivery to the PM. In addition, DRM formation in Arabidopsis cells is shown to depend on the unsaturation degree of fatty acyl chains as evidenced by the dramatic decrease in the amount of DRMs prepared from the Arabidopsis mutants, fad2 and Fad3+, affected in their fatty acid desaturases.


A review of technologies for rapid detection of bacteria in recreational waters.
Monitoring of recreational beaches for fecal indicator bacteria is currently performed using culture-based technology that can require more than a day for laboratory analysis, during which time swimmers are at risk. Here we review new methods that have the potential to reduce the measurement period to less than an hour. These methods generally involve two steps. The first is target capture, in which the microbial group of interest (or some molecular/chemical/or biochemical signature of the group) is removed, tagged or amplified to differentiate it from the remaining material in the sample. We discuss three classes of capture methods: 1) Surface and whole-cell recognition methods, including immunoassay techniques and molecule-specific probes; 2) Nucleic acid methods, including polymerase chain reaction (PCR), quantitative PCR (Q-PCR), nucleic acid sequence based amplification (NASBA) and microarrays; and 3) Enzyme/substrate methods utilizing chromogenic or fluorogenic substrates. The second step is detection, in which optical, electrochemical or piezoelectric technologies are used to quantify the captured, tagged or amplified material. The biggest technological hurdle for all of these methods is sensitivity, as EPA's recommended bathing water standard is less than one cell per ml and most detection technologies measure sample volumes less than 1 ml. This challenge is being overcome through addition of preconcentration or enrichment steps, which have the potential to boost sensitivity without the need to develop new detector technology. The second hurdle is demonstrating a relationship to health risk, since most new methods are based on measuring cell structure without assessing viability and may not relate to current water quality standards that were developed in epidemiology studies using culture-based methods. Enzyme/substrate methods may be the first rapid methods adopted because they are based on the same capture technology as currently-approved EPA methods and their relationship to health risk can be established by demonstrating equivalency to existing procedures. Demonstration of equivalency may also be possible for some surface and whole-cell recognition methods that capture bacteria in a potentially viable state. Nucleic acid technologies are the most versatile, but measure nonviable structure and will require inclusion in epidemiological studies to link their measurement with health risk.


Risk of sick leave and disability pension in working-age women and men with knee osteoarthritis.
To investigate sick leave and disability pension in working-age subjects with knee osteoarthritis (OA) compared with the general population. Population-based cohort study: individual-level inpatient and outpatient Skåne Health Care Register data were linked with data from the Swedish Social Insurance Agency. In 2009 all working-age (16-64 years) Skåne County residents who in 1998-2009 had been diagnosed with knee OA (International Classification of Diseases-10 code M17) were identified and their sick leave and disability pension in 2009 related to those of the general working-age population (n=789 366) standardised for age. 15 345 working-age residents (49.6% women) with knee OA were identified. Compared with the general population, the RR (95% CI) of having had one or more episodes of sick leave during the year was 1.82 (1.73 to 1.91) for women and 2.03 (1.92 to 2.14) for men with knee OA. The corresponding risk for disability pension was 1.54 (1.48 to 1.60) for women and 1.36 (1.28 to 1.43) for men with knee OA. The annual mean number of sick days was 87 for each patient with knee OA and 57 for the general population (age- and sex-standardised). Of all sick leave and disability pension in the entire population, 2.1% of days were attributable to knee OA or associated comorbidity in the patients with knee OA (3.1% for sick leave and 1.8% for disability pension). Subjects with doctor-diagnosed knee OA have an almost twofold increased risk of sick leave and about 40-50% increased risk of disability pension compared with the general population. About 2% of all sick days in society are attributable to knee OA.


Scanning electron microscope observations on surface changes occurring in murine granulocytes and macrophages during maturation in soft agar cultures.
The present work has been undertaken to study by scanning electron microscopy (SEM) the cell surface changes occurring in granulocytes and macrophages during the process of maturation in soft agar cultures. All stages of maturation of these cells can be seen in a single colony, with immature cells at the center and mature cells toward the periphery. Special emphasis was made, therefore, to maintain the integrity of the colonies during preparation of the specimens for the SEM. Colonies of granulocytes appeared as tight aggregates of cells. The surfaces of cells in such colonies in 3 to 4-day-old cultures contained many microvilli. Cells in colonies of 5 to 7-day-old cultures contained fewer microvilli on their surfaces. Colonies of macrophages appeared as loose aggregates of cells. The surfaces of cells in such colonies in 3 to 4-day-old cultures was slightly ruffled, while the surfaces of cells in 5 to 7-day-old colonies had well developed ruffles. Granulocyte and macrophage colonies showed the same internal organization of the colony: In granulocytes, cells with many microvilli were located in the center of the colony and cells with less microvilli were at the periphery of the colonies. In macrophages, cells slightly ruffled were located in the center of the colony, while cells highly ruffled were at the periphery of the colonies. These observations have been confirmed by transmission electron and light microscopy preparations.


Specific killing of cytotoxic T cells and antigen-presenting cells by CD4+ cytotoxic T cell clones. A novel potentially immunoregulatory T-T cell interaction in man.
Mycobacterial antigens not only stimulate Th cells that produce macrophage-activating factors, but also CD4+ and CD8+ CTL that lyse human macrophages. The mycobacterial recombinant 65-kD hsp was previously found to be an important target antigen for polyclonal CD4+ CTL. Because of the major role of 65-kD hsp in the immune response to mycobacterial as well as autoantigens, we have studied CTL activity to this protein at the clonal level. HLA-DR or HLA-DQ restricted, CD4+CD8- T cell clones that recognize different peptides of the M. leprae 65-kD hsp strongly lysed EBV-BLCL pulsed with specific but not irrelevant peptide. No bystander lysis of B cells, T cells, or tumor cells was seen. Target cell lysis could not be triggered by PMA + Ca2+ ionophore alone and depended on active metabolism. Interestingly, these CD4+ CTL also strongly lysed themselves and other HLA-class II compatible CD4+ (TCR-alpha/beta or -gamma/delta) or CD8+ CTL clones in the presence of peptide, suggesting that CTL are not actively protected from CTL-mediated lysis. Cold target competition experiments suggested that EBV-BLCL targets were more efficiently recognized than CD4+ CTL targets. These results demonstrate that hsp65 peptide-specific HLA class II-restricted CD4+ T cell clones display strong peptide-dependent cytolytic activity towards both APCs, and, unexpectedly, CD4+ and CD8+ CTL clones, including themselves. Since, in contrast to murine T cells human T cells express class II, CTL-mediated T cell killing may represent a novel immunoregulatory pathway in man.


Flexural properties, morphology and bond strength of fiber-reinforced posts: influence of post pretreatment.
The aim of this study was to assess the influence of surface pretreatments of fiber-reinforced posts on flexural strength (FS), modulus of elasticity (ME) and morphology of these posts, as well as the bond strength (BS) between posts and core material. Fifty-two fiber posts (smooth and serrated) were assigned to 4 groups (n=13): no treatment (control), 10% hydrogen peroxide (HP) for 10 min (HP-10), 24% HP for 1 min (HP-24) and airborne-particle abrasion (Al(2)O(3)). To evaluate FS and ME, a 3-point bending test was performed. Three posts of each group were examined by scanning electron microscopy. Composite resin was used as the core build-up and samples were sectioned to obtain microtensile sticks. Data were analyzed by ANOVA and Tukey's test (α=0.05). For FS, significant differences were observed between posts type and surface pretreatment (p<0.05), with the highest means for the smooth posts. Al2O3 provided higher FS than HP-24. Al(2)O(3) promoted higher ME than HP-24 and control. SEM images revealed partial dissolution of the resin matrix in all treated groups. The smooth posts had higher BS and FS than serrated posts (p<0.05). Mechanical properties of the glass fiber posts and the bond strength between posts and composite material were not altered by the surface treatments, except for airborne-particle abrasion that increased the post elastic modulus.


Pollination by the locally endangered island flying fox (Pteropus hypomelanus) enhances fruit production of the economically important durian (Durio zibethinus).
Fruit bats provide valuable pollination services to humans through a unique coevolutionary relationship with chiropterophilous plants. However, chiropterophily in the Old World and the pollination roles of large bats, such as flying foxes (Pteropus spp., Acerodon spp., Desmalopex spp.), are still poorly understood and require further elucidation. Efforts to protect these bats have been hampered by a lack of basic quantitative information on their role as ecosystem service providers. Here, we investigate the role of the locally endangered island flying fox Pteropus hypomelanus in the pollination ecology of durian (Durio zibethinus), an economically important crop in Southeast Asia. On Tioman Island, Peninsular Malaysia, we deployed 19 stations of paired infrared camera and video traps across varying heights at four individual flowering trees in a durian orchard. We detected at least nine species of animal visitors, but only bats had mutualistic interactions with durian flowers. There was a clear vertical stratification in the feeding niches of flying foxes and nectar bats, with flying foxes feeding at greater heights in the trees. Flying foxes had a positive effect on mature fruit set and therefore serve as important pollinators for durian trees. As such, semi-wild durian trees-particularly tall ones-may be dependent on flying foxes for enhancing reproductive success. Our study is the first to quantify the role of flying foxes in durian pollination, demonstrating that these giant fruit bats may have far more important ecological, evolutionary, and economic roles than previously thought. This has important implications and can aid efforts to promote flying fox conservation, especially in Southeast Asian countries.


Oxidative stress and abdominal aortic aneurysm: potential treatment targets.
Abdominal aortic aneurysm (AAA) is a significant cause of mortality in older adults. A key mechanism implicated in AAA pathogenesis is inflammation and the associated production of reactive oxygen species (ROS) and oxidative stress. These have been suggested to promote degradation of the extracellular matrix (ECM) and vascular smooth muscle apoptosis. Experimental and human association studies suggest that ROS can be favourably modified to limit AAA formation and progression. In the present review, we discuss mechanisms potentially linking ROS to AAA pathogenesis and highlight potential treatment strategies targeting ROS. Currently, none of these strategies has been shown to be effective in clinical practice.


Transplantation of human umbilical cord blood mesenchymal stem cells improves survival rates in a rat model of acute hepatic necrosis.
Stem cell-based therapies are emerging as important and promising methods in the treatment of end-stage liver disease. This study is aimed to evaluate the effects of human umbilical cord blood mesenchymal stem cell (HUCBMSC) transplantation in acute hepatic necrosis (AHN). Green fluorescent protein (GFP)-labeled HUCBMSCs were injected into the liver of rats in which AHN was induced by carbon tetrachloride, and the migration of these cells in liver slices was evaluated from 48 hours to 4 weeks post-transplantation. The transdifferentiation status of the HUCBMSCs was evaluated using immunohistochemistry and real-time reverse transcription-polymerase chain reaction, and survival rates were statistically analyzed. Dispersed GFP fluorescence was observed along the portal area 48 hours after transplantation. One week post-transplantation, GFP-positive cells were found in necrotic liver areas, and GFP-positive cells persisted after 4 weeks. Immunohistochemistry and real-time polymerase chain reaction analysis showed that transplanted HUCBMSCs expressed several human liver tissue-specific markers in rats with AHN. Statistical analysis revealed that rats with AHN that were transplanted with HUCBMSCs had significantly lower death rates after 48 hours than those receiving no HUCBMSCs. HUCBMSC transplantation can significantly improve the survival of rats with AHN. The underlying mechanisms involved may include the transdifferentiation of HUCBMSCs into hepatocyte-like cells and targeted migration of these cells to liver lesion sites.


Solute-Solvent Interactions in Modern Physical Organic Chemistry: Supramolecular Polymers as a Muse.
Interactions between solvents and solutes are a cornerstone of physical organic chemistry and have been the subject of investigations over the last century. In recent years, a renewed interest in fundamental aspects of solute-solvent interactions has been sparked in the field of supramolecular chemistry in general and that of supramolecular polymers in particular. Although solvent effects in supramolecular chemistry have been recognized for a long time, the unique opportunities that supramolecular polymers offer to gain insight into solute-solvent interactions have become clear relatively recently. The multiple interactions that hold the supramolecular polymeric structure together are similar in strength to those between solute and solvent. The cooperativity found in ordered supramolecular polymers leads to the possibility of amplifying these solute-solvent effects and will shed light on extremely subtle solvation phenomena. As a result, many exciting effects of solute-solvent interactions in modern physical organic chemistry can be studied using supramolecular polymers. Our aim is to put the recent progress into a historical context and provide avenues toward a more comprehensive understanding of solvents in multicomponent supramolecular systems.


Discovery of a divergent HPIV4 from respiratory secretions using second and third generation metagenomic sequencing.
Molecular detection of viruses has been aided by high-throughput sequencing, permitting the genomic characterization of emerging strains. In this study, we comprehensively screened 500 respiratory secretions from children with upper and/or lower respiratory tract infections for viral pathogens. The viruses detected are described, including a divergent human parainfluenza virus type 4 from GS FLX pyrosequencing of 92 specimens. Complete full-genome characterization of the virus followed, using Single Molecule, Real-Time (SMRT) sequencing. Subsequent "primer walking" combined with Sanger sequencing validated the RS platform's utility in viral sequencing from complex clinical samples. Comparative genomics reveals the divergent strain clusters with the only completely sequenced HPIV4a subtype. However, it also exhibits various structural features present in one of the HPIV4b reference strains, opening questions regarding their lifecycle and evolutionary relationships among these viruses. Clinical data from patients infected with the strain, as well as viral prevalence estimates using real-time PCR, is also described.


Integrated undergraduate research experience for the study of brain injury.
We developed a series of hands-on laboratory exercises on "Brain Injury" designed around several pedagogical goals that included the development of: 1) knowledge of the scientific method, 2) student problem solving skills by testing cause and effect relationships, 3) student analytical and critical thinking skills by evaluating and interpreting data, identifying alternative explanations for data, and identifying confounding variables, and 4) student writing skills by reporting their findings in manuscript form. Students, facilitated by the instructor, developed a testable hypothesis on short-term effects of brain injury by analyzing lesion size and astrocytic activity. Four sequential laboratory exercises were used to present and practice ablation techniques, histological processing, microscopic visualization and image-capture, and computer aided image analysis. This exercise culminated in a laboratory report that mimicked a research article. The effectiveness of the laboratory sequence was assessed by measuring the acquisition of 1) content on anatomical, physiological, and cellular responses of the brain to traumatic brain injury, and 2) laboratory skills and methods of data-collection and analysis using surgical procedures, histology, microscopy, and image analysis. Post-course test scores, significantly greater than pre-course test scores and greater than scores from a similar but unstructured laboratory class, indicated that this hands-on approach to teaching an undergraduate research laboratory was successful. Potential variations in the integrated laboratory exercise, including multidisciplinary collaborations, are also noted.


Monoclonal antibody defining a molecule possibly identical to the p75 subunit of interleukin 2 receptor.
A mouse hybridoma cell line, TU27, producing an mAb was established. TU27 mAb reacted with various human and Gibbon ape T cell lines bearing the IL-2R p75 (IL-2Rp75), but not with cell lines expressing only Tac antigen, IL-2Rp55, and numbers of its binding sites on cell surfaces were similar to those of high-affinity IL-2R. Radioimmunoprecipitation with TU27 mAb defined a molecule with a molecular mass of 75 kD on the surface of IL-2Rp75 bearing cells. TU27 mAb completely blocked IL-2 binding to IL-2Rp75 and to the high-affinity IL-2R but not to IL-2Rp55 composing the low-affinity IL-2R. The IL-2-dependent growth of a human T cell line, ILT-Mat, was significantly inhibited by TU27 mAb only at low concentrations of IL-2, and combination of TU27 mAb and H-31 mAb specific for IL-2Rp55 completely inhibited the cell growth even at high concentrations of IL-2. These data strongly suggest that TU27 mAb is specific for the human IL-2Rp75.


Diet in relation to endometrial cancer risk: a case-control study in Greece.
The risk of endometrial cancer is positively associated with obesity, but the role of specific nutrients remains unclear. Given the distinct characteristics of the Greek diet and the low incidence of this form of cancer among Greek women, we undertook a case-control study to investigate the association of endometrial cancer with food groups and micronutrients. Cases were 84 women with histologically confirmed endometrial cancer and controls were 84 women with intact uterus admitted to the same teaching hospital in Athens, Greece. Consumption of pulses, nuts, and seeds was significantly inversely related to the risk for endometrial cancer. No other significant association with food groups was detected, although a protective effect of added lipids, which in the Greek diet are primarily represented by olive oil, was highly suggestive. Retinol, nicotinic acid, vitamin B- 6, and riboflavin were inversely associated with the disease. These findings need to be replicated, because this was a relatively small study with the statistical power to detect only strong associations between cases and controls; they appear, however, to support a role of diet in the etiology of endometrial cancer.


Acquired chromosomal anomalies in chronic lymphocytic leukemia patients compared with more than 50,000 quasi-normal participants.
Pretherapy patients with chronic lymphocytic leukemia (CLL) from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The four CLL-typical anomalies (11q-, +12, 13q-, and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected anomalies, and their number per participant has a significant effect on progression-free survival after adjusting for the effects of 17p- (and other covariates). These results were compared with those from a previous study of more than 50,000 participants from the GENEVA consortium of genome-wide association studies, which analyzed individuals with a variety of medical conditions and healthy controls. The percentage of individuals with acquired anomalies is vastly different between the two studies (GENEVA 0.8%; E2997 80%). The composition of the anomalies also differs, with GENEVA having a higher percentage of acquired uniparental disomies and a lower percentage of deletions. The four common CLL anomalies are among the most frequent in GENEVA participants, some of whom may have CLL-precursor conditions or early stages of CLL. However, the patients from E2997 (and other studies of symptomatic CLL) have recurrent acquired anomalies that were not found in GENEVA participants, thus identifying genomic changes that may be unique to symptomatic stages of CLL.


Mature oligodendrocytes actively increase in vivo cytoskeletal plasticity following CNS damage.
Oligodendrocytes are myelinating cells of the central nervous system which support functionally, structurally, and metabolically neurons. Mature oligodendrocytes are generally believed to be mere targets of destruction in the context of neuroinflammation and tissue damage, but their real degree of in vivo plasticity has become a matter of debate. We thus investigated the in vivo dynamic, actin-related response of these cells under different kinds of demyelinating stress. We used a novel mouse model (oLucR) expressing luciferase in myelin oligodendrocyte glycoprotein-positive oligodendrocytes under the control of a β-actin promoter. Activity of this promoter served as surrogate for dynamics of the cytoskeleton gene transcription through recording of in vivo bioluminescence following diphtheria toxin-induced oligodendrocyte death and autoimmune demyelination. Cytoskeletal gene expression was quantified from mature oligodendrocytes directly isolated from transgenic animals through cell sorting. Experimental demyelinating setups augmented oligodendrocyte-specific in vivo bioluminescence. These changes in luciferase signal were confirmed by further ex vivo analysis of the central nervous system tissue from oLucR mice. Increase in bioluminescence upon autoimmune inflammation was parallel to an oligodendrocyte-specific increased transcription of β-tubulin. Mature oligodendrocytes acutely increase their cytoskeletal plasticity in vivo during demyelination. They are therefore not passive players under demyelinating conditions but can rather react dynamically to external insults.


Polymethylmethacrylate and titanium alloy particles activate peripheral monocytes during periprosthetic inflammation and osteolysis.
We investigated the interactions of particulate PMMA or titanium alloy, patient blood monocytes, and periprosthetic tissues using a SCID-hu model of aseptic loosening. Periprosthetic tissues and bone chips obtained at revision surgery for loosening were transplanted into muscles of SCID mice. Peripheral blood monocytes (PBMCs) isolated from the same donors were fluorescently labeled and co-cultured with PMMA or Ti-6Al-4V particles before intraperitoneal injection. Control mice with periprosthetic tissue or non-inflammatory ligament xenografts received naive PBMCs transfusion. Mice were euthanized 2 weeks after PBMC transfusion. The human tissues were well accepted in SCID mice. Transfused fluorescent-labeled PBMCs were markedly accumulated in transplanted periprosthetic tissues. Multinucleated osteoclast-like cells were commonly seen within retrieved xenograft tissue, and focal bone erosions were ubiquitous. Total cell densities and CD68+ cells within the xenograft were significantly increased in mice transfused with PMMA and Ti-provoked PBMCs compared to the naïve PBMC animals (p < 0.05). Immunohistochemical staining identified much stronger positive IL-1 and TNF stains in xenografts from either PMMA or Ti-stimulated monocytes transfusion groups (p < 0.05). TRAP+ cells were found around bone chips in both activated-PBMCs groups, although markedly more aggregated TRAP+ cells in the PMMA-challenged group than in the titanium group (p < 0.05). MicroCT assessment confirmed the significant decrease of bone mineral density in chips interacted with activated-monocytes/osteoclasts. In conclusion, PMMA or titanium particles readily activate peripheral monocytes and promote the cell trafficking to the debris-containing prosthetic tissues. Particles-provoked PBMCs participated in and promoted the local inflammatory process, osteoclastogenesis, and bone resorption.


Indicators of ocean health and human health: developing a research and monitoring framework.
We need to critically assess the present quality of the marine ecosystem, especially the connection between ecosystem change and threats to human health. In this article we review the current state of indicators to link changes in marine organisms with eventual effects to human health, identify research opportunities in the use of indicators of ocean and human health, and discuss how to establish collaborations between national and international governmental and private sector groups. We present a synthesis of the present state of understanding of the connection between ocean health and human health, a discussion of areas where resources are required, and a discussion of critical research needs and a template for future work in this field. To understand fully the interactions between ocean health and human health, programs should be organized around a "models-based" approach focusing on critical themes and attributes of marine environmental and public health risks. Given the extent and complex nature of ocean and human health issues, a program networking across geographic and disciplinary boundaries is essential. The overall goal of this approach would be the early detection of potential marine-based contaminants, the protection of marine ecosystems, the prevention of associated human illness, and by implication, the development of products to enhance human well-being. The tight connection between research and monitoring is essential to develop such an indicator-based effort.


Language spoken at home and parental birthplace moderate the association of race/ethnicity and distorted weight perception.
Distorted weight perception (DWP), specifically overestimating weight status, is common in adolescents and may lead to eating disorders. The authors examined the role of acculturation proxies as effect modifiers of the relationship between race/ethnicity and DWP in a diverse adolescent population. Analysis of the 2005 California Health Interview Survey showed that of 2955 adolescents with underweight or healthy weight status, 10.6% reported DWP. Latino adolescents had increased odds of DWP compared with white adolescents (adjusted odds ratio [aOR] = 3.02; 95% confidence interval [CI] = 2.00, 4.57). Latinos who spoke English and other language(s) at home (aOR = 3.38; 95% CI = 2.11, 5.41) and Latino (aOR = 5.00; 95% CI = 2.34, 10.72) and Asian (aOR = 3.10, 95% CI = 1.15, 8.35) adolescents who spoke no English at home had increased odds of DWP compared with white, English-only speakers. Latino adolescents had increased odds (aOR = 3.98, 95% CI = 2.45, 6.47) of DWP if neither parent was US born. Assessing acculturation proxies may help identify adolescents at risk of DWP.


Quantitative imaging of lateral ErbB1 receptor signal propagation in the plasma membrane.
Evidence for a new signaling mechanism consisting of ligand-independent lateral propagation of receptor activation in the plasma membrane is presented. We visualized the phosphorylation of green fluorescent protein (GFP)-tagged ErbB1 (ErbB1-GFP) receptors in cells focally stimulated with epidermal growth factor (EGF) covalently attached to beads. This was achieved by quantitative imaging of protein reaction states in cells by fluorescence resonance energy transfer (FRET) with global analysis of fluorescence lifetime imaging microscopy (FLIM) data. The rapid and extensive propagation of receptor phosphorylation over the entire cell after focal stimulation demonstrates a signaling wave at the plasma membrane resulting in full activation of all receptors.


Linkage of acquired quinolone resistance (qnrS1) and metallo-beta-lactamase (blaVIM-1) genes in multiple species of Enterobacteriaceae from Bolzano, Italy.
Twenty-four of 209 oxyimino-cephalosporin- and/or aztreonam-resistant Enterobacteriaceae collected around Bolzano had reduced susceptibility or resistance to carbapenems and gave positive metallo-beta-lactamase (MBL) tests. Their resistance mechanisms were investigated. Resistances were identified by Vitek 2 and MIC tests and isolates were genotyped by PFGE. Resistance genes were identified by PCR and sequencing, and plasmids were transferred by conjugation and/or transformation. Plasmid-borne genes were identified by Southern blotting, and their genetic surroundings were investigated by PCR mapping. The 24 isolates with positive EDTA/imipenem synergy tests had bla(VIM-1) carried on 40-150 kb plasmids. Imipenem MICs ranged from 2 to >32 mg/L, while those of meropenem and ertapenem were lower. The isolates included a clonal cluster of 10 Klebsiella pneumoniae, two other K. pneumoniae isolates, and diverse isolates of Escherichia coli (seven), Klebsiella oxytoca (three) and Citrobacter freundii (two). Six MBL producers were aztreonam-susceptible; the 18 aztreonam-resistant isolates had co-resident extended-spectrum beta-lactamases. bla(VIM-1) occurred as the first cassette in class 1 integrons, with aacA4 as the second cassette. Quinolone resistance gene qnrS1 was detected in 21 of 24 (87.5%) bla(VIM-1)-positive isolates versus 14 of 185 (7.6%) bla(VIM)-negative isolates (P < 0.0001), with 13 of the latter belonging to a clonal cluster of E. coli. qnrS1 was located on the same plasmids as bla(VIM-1) and aacA4, but was not closely linked, as judged by PCR mapping. bla(VIM-1) has become disseminated among enterobacteria in a small Italian town. The frequent association of genes conferring carbapenem, aminoglycoside and quinolone resistance on single plasmids will facilitate co-selection.


The Arabidopsis ppi1 mutant is specifically defective in the expression, chloroplast import, and accumulation of photosynthetic proteins.
The import of nucleus-encoded proteins into chloroplasts is mediated by translocon complexes in the envelope membranes. A component of the translocon in the outer envelope membrane, Toc34, is encoded in Arabidopsis by two homologous genes, atTOC33 and atTOC34. Whereas atTOC34 displays relatively uniform expression throughout development, atTOC33 is strongly upregulated in rapidly growing, photosynthetic tissues. To understand the reason for the existence of these two related genes, we characterized the atTOC33 knockout mutant ppi1. Immunoblotting and proteomics revealed that components of the photosynthetic apparatus are deficient in ppi1 chloroplasts and that nonphotosynthetic chloroplast proteins are unchanged or enriched slightly. Furthermore, DNA array analysis of 3292 transcripts revealed that photosynthetic genes are moderately, but specifically, downregulated in ppi1. Proteome differences in ppi1 could be correlated with protein import rates: ppi1 chloroplasts imported the ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit and 33-kD oxygen-evolving complex precursors at significantly reduced rates, but the import of a 50S ribosomal subunit precursor was largely unaffected. The ppi1 import defect occurred at the level of preprotein binding, which is consistent with a role for atToc33 during preprotein recognition. The data suggest that atToc33 is involved preferentially in the import of photosynthetic proteins and, by extension, that atToc34 is involved in the import of nonphotosynthetic chloroplast proteins.


A Healthcare-Associated Outbreak of HCV Genotype 2a at a Clinic in Seoul.
An epidemiological investigation was conducted into a hepatitis C virus (HCV) outbreak at an outpatients clinic in Seoul (2011-2012). The aim of the study was to analyze the scale of infection, identify the source of infection, and route of transmission to prevent hepatitis C transmission in the future. A retrospective study of the outpatients and health care workers (n = 7,285) in the target outpatient clinic during 2011-2012 was conducted. The history of the study population infection with hepatitis C, electronic medical records, field visits, and health care worker interviews were examined for the period between March 1st, 2006 and March 25th, 2016. The blood samples were collected and tested for anti-HCV antibodies, HCV RNA and HCV gene in 2016. The rate of anti-HCV positive results was 4.4% in the study population. The risk factors associated with an anti-HCV positive result were ≥ 10 clinic visits, and receiving an invasive procedure including a nerve block and a block of the peripheral branch of the spinal nerve (p < 0.05). There were 112 HCV RNA positive cases out of 320 anti-HCV positive test result cases, amongst which 100 cases had the dominant HCV genotype 2a which formed either 1 cluster (n = 56) or 2 clusters (n = 25). This result indicated exposure to a high-association infection source. Anti-HCV antibodies and genotypic analysis showed an epidemiological association between the outbreak of HCV and invasive procedures performed (2011-2012) at an outpatients clinic in Seoul.


Patients' perspective of financial benefits following head and neck cancer in Merseyside and Cheshire.
The aim of this interview study was to ask patients with head and neck cancer in the Mersey region about their need for financial benefits, the advice they were given about benefits and financial matters, and the financial burden of the disease. Stratified quota sampling was by employment status, whether work had been affected by the cancer, and by sex. Of 51 interviewees (mean (SD) age 61(8) years) 20 were retired, 11 were unemployed, 13 worked full-time, and 7 worked part-time. Cancer had affected the work status of 24. Since diagnosis 57% had suffered financially; this was particularly high in those who had retired (65%), and in those whose work had been affected by cancer (79%). Quality of life had decreased in 53% as a result of the financial impact of the disease. This was most common in the unemployed (64%), and in those whose work was affected by cancer (83%). Only a quarter had been given adequate help and information about finance; this was lowest in the unemployed (18%) and highest in those who were fully employed (39%). One third (17/51) had never claimed benefits. The most common benefits were Disability Living Allowance and Incapacity Benefit. Two-thirds (21/31) had applied for benefits after diagnosis, 18 of these were directly as a result of the disease. The median (IQR) weekly income from benefits was £88 (£60-170). Patients and carers need better access to financial advice. We suggest that each multidisciplinary team should have a designated benefits or financial advisor who is readily available to patients in the clinic and on the ward.


Massive uric acid nephrolithiasis with progressive renal failure due to spontaneous tumour lysis syndrome.
Tumour lysis syndrome (TLS) is a constellation of meta- bolic complications due to the rapid destruction of malignant cells, causing renal, cardiac or cerebral dysfunction. Electrolyte abnormalities include hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. TLS-induced renal failure is mainly caused by uric acid and calcium phosphate crystal deposition and usually develops following cytotoxic chemotherapy. Here, we present a case of spontaneous TLS in a patient with chronic myelomonocytic leukaemia (CMML) with massive uric acid stone and crystal formation and rapidly worsening renal failure. Autopsy revealed underlying tumourous kidney infiltration. Risk factors for occurrence of TLS and current therapeutic management are discussed.


Elastosonographic evaluation of endometrium in women using tamoxifen for breast cancer.
A prospective case-control study was carried out to assess the value of elastosonography in identifying endometrial pathology in women using Tamoxifen (TAM) for breast cancer. In total, 66 women using TAM for breast cancer were enrolled for the study with 61 premenopausal and 61 postmenopausal healthy controls. Ultrasonographic findings (strain ratio, endometrial thickness) were evaluated in regard to the duration of TAM usage, histopathological findings, and menopausal status. Patients with endometrial cancer (EC) and cystic endometrial hyperplasia (CEH) were found to have longer duration of TAM usage, increased endometrial thickness, and higher strain ratios compared with controls. A significant positive correlation was found between duration of TAM usage, endometrial thickness, and the strain ratios. Endometrial thickness and the strain ratios were significant predictors for groups under risk. Cutoff values for endometrial thickness, strain ratios, and duration of TAM usage were 12.55 mm, 2.46, and 18 months in premenopausal group and 7.75 mm, 7.70, and 32 months in postmenopausal group to predict risky population, respectively. Endometrial tissue strain ratio was found to be significantly increased in cases with endometrial pathologies. Addition of elastosonography modality to B-mode may improve the diagnostic accuracy during the follow-up of women using TAM for breast cancer.


Iron deficient and manganese supplemented diets alter metals and transporters in the developing rat brain.
Manganese (Mn) neurotoxicity in adults can result in psychological and neurological disturbances similar to Parkinson's disease, including extrapyramidal motor system defects and altered behaviors. Iron (Fe) deficiency is one of the most prevalent nutritional disorders in the world, affecting approximately 2 billion people, especially pregnant and lactating women, infants, toddlers, and adolescents. Fe deficiency can enhance brain Mn accumulation even in the absence of excess Mn in the environment or the diet. To assess the neurochemical interactions of dietary Fe deficiency and excess Mn during development, neonatal rats were exposed to either a control diet, a low-Fe diet (ID), or a low-Fe diet supplemented with Mn (IDMn) via maternal milk during the lactation period (postnatal days [PN] 4-21). In PN21 pups, both the ID and IDMn diets produced changes in blood parameters characteristic of Fe deficiency: decreased hemoglobin (Hb) and plasma Fe, increased plasma transferrin (Tf), and total iron binding capacity (TIBC). Treated ID and IDMn dams also had decreased Hb throughout lactation and ID dams had decreased plasma Fe and increased Tf and TIBC on PN21. Both ID and IDMn pups had decreased Fe and increased copper brain levels; in addition, IDMn pups also had increased brain levels of several other essential metals including Mn, chromium, zinc, cobalt, aluminum, molybdenum, and vanadium. Concurrent with altered concentrations of metals in the brain, transport proteins divalent metal transporter-1 and transferrin receptor were increased. No significant changes were determined for the neurotransmitters gamma aminobutyric acid and glutamate. The results of this study confirm that there is homeostatic relationship among several essential metals in the brain and not simply between Fe and Mn.


Family and population effects on disease resistance in a reptile.
Despite its importance in evolutionary biology, studies of the pattern of disease resistance in natural populations are rare. In this paper, we report patterns of infection of a viral eye disease in juvenile Swedish common lizards (Lacerta vivipara). Females were sampled at random from natural populations immediately prior to parturition with equal exposure of pathogens for all lizards once in captivity. No causative agents could be found that linked risk of disease to maternal/interfollicular transfer of pathogens. The results show that a major factor influencing offspring susceptibility is family identity, suggesting heritable variation in pathogen resistance. Our interpopulation comparison provides additional support for a link between genetics and disease resistance. Lizards in northern Sweden were not only more susceptible to the disease but were also more health compromised once infected, with relatively more reduced growth rate and increased mortality than lizards from the south. This scenario suggests that southern lizards have been under selection for resistance to this pathogen, whereas northern lizards have not, or at least not to the same degree. Thus, this study confirms the importance of genetic (family) effects on pathogen resistance with variation in this trait among natural populations.


Acetaminophen increases blood pressure in patients with coronary artery disease.
Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.


Amplification of light collection in solid-state dye-sensitized solar cells via the antenna effect through supramolecular assembly.
This study demonstrates that the concept of molecular antenna is a relevant strategy to improve the power conversion efficiency of solid-state dye-sensitized solar cells by extending their spectral sensitivity over a broad region of the solar spectrum. In this work, we have associated a BODIPY antenna to a bi-chromophoric sensitizer made of a squaraine unit linked to a zinc porphyrin by axial ligation onto the zinc. Using steady-state and transient photoluminescence spectroscopy, we demonstrate that efficient energy transfers occur from the antenna to the dyad, extending its visible photosensitivity. We also show that direct electron injection from the antenna to TiO2 is possible. A drastic improvement in the device performance by a factor of three is observed under illumination using the spiro-OMeTAD molecular glass as the solid-state electrolyte, leading to a panchromatic response of the device. The influence of the solid-state hole transporter on the supramolecular assembly is also discussed.


Altered and asymmetric default mode network activity in a "hypnotic virtuoso": an fMRI and EEG study.
Very highly hypnotizable subjects are rare, easily induced, and able to manifest the whole spectrum of hypnotic phenomena, including post-hypnotic amnesia. The aim of this study was to detect and localize by means of quantitative functional MRI and EEG changes in cortical activity during hypnosis induction and deep "pure hypnosis" in a hypnotic "virtuoso" subject. We focused on areas forming the default mode network (DMN), since previous studies found that very highly suggestible subjects in hypnosis showed decreased activity in anterior DMN. During undisturbed hypnosis, our "virtuoso" subject showed not only detectable changes in DMN, but also peculiar activations of non-DMN areas and hemispheric asymmetries of frontal lobe connectivity. Our findings confirm that hypnosis is associated with significant modulation of connectivity and activity which involve the DMN but are not limited to it, depending on the depth of the hypnotic state, the type of mental content and emotional involvement.