Development and validation of risk prediction equations to estimate future risk of blindness and lower limb amputation in patients with diabetes: cohort study.
Is it possible to develop and externally validate risk prediction equations to estimate the 10 year risk of blindness and lower limb amputation in patients with diabetes aged 25-84 years? This was a prospective cohort study using routinely collected data from general practices in England contributing to the QResearch and Clinical Practice Research Datalink (CPRD) databases during the study period 1998-2014. The equations were developed using 763 QResearch practices (n=454,575 patients with diabetes) and validated in 254 different QResearch practices (n=142,419) and 357 CPRD practices (n=206,050). Cox proportional hazards models were used to derive separate risk equations for blindness and amputation in men and women that could be evaluated at 10 years. Measures of calibration and discrimination were calculated in the two validation cohorts. Risk prediction equations to quantify absolute risk of blindness and amputation in men and women with diabetes have been developed and externally validated. In the QResearch derivation cohort, 4822 new cases of lower limb amputation and 8063 new cases of blindness occurred during follow-up. The risk equations were well calibrated in both validation cohorts. Discrimination was good in men in the external CPRD cohort for amputation (D statistic 1.69, Harrell's C statistic 0.77) and blindness (D statistic 1.40, Harrell's C statistic 0.73), with similar results in women and in the QResearch validation cohort. The algorithms are based on variables that patients are likely to know or that are routinely recorded in general practice computer systems. They can be used to identify patients at high risk for prevention or further assessment. Limitations include lack of formally adjudicated outcomes, information bias, and missing data. Patients with type 1 or type 2 diabetes are at increased risk of blindness and amputation but generally do not have accurate assessments of the magnitude of their individual risks. The new algorithms calculate the absolute risk of developing these complications over a 10 year period in patients with diabetes, taking account of their individual risk factors. JH-C is co-director of QResearch, a not for profit organisation which is a joint partnership between the University of Nottingham and Egton Medical Information Systems, and is also a paid director of ClinRisk Ltd. CC is a paid consultant statistician for ClinRisk Ltd.


Conventional hematopoietic stem cell transplants from identical or alternative donors are feasible in recipients relapsing after an autograft.
The risk of relapse after autologous bone marrow transplantation (ASCT) is high and is related to the type of malignancy and phase of the disease. The outcome for the patient who relapses after an autologous transplant is poor. Some of these patients achieve a remission with conventional chemotherapy, but it is usually short-lasting. Most of them succumb to the original disease. One further therapeutic possibility is an allogeneic transplant which would confer the potential advantage of a graft-versus-leukemia effect in addition to the lack of tumor contamination of the graft and to a high-dose intensity conditioning regimen. We have studied the outcome of 31 patients with hematologic malignancies who underwent an allogeneic hematopoietic stem cell transplant (HSCT) after failing an autologous transplant because of relapse (n=29) or persistent aplasia (n=2). The median age at allograft was 36 years (18-55) and the interval from autograft to allograft was 21 months (3-141). The source of stem-cells was unmanipulated bone marrow (n=26) or growth-factor-mobilized peripheral blood (n=5). The donor was an HLA-identical sibling (n=7), or an alternative donor (n=24) (family mismatched n=11, or matched unrelated n=13). The conditioning regimen was cyclophosphamide and thiotepa (n=22), or cyclophosphamide and total body irradiation (n=9) Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine (CyA) + methotrexate (MTX). Acute GvHD was scored as 0-I, II, or III-IV in 39%, 48%, and 13% of the patients, respectively. Sixteen patients died of transplant-related complications and one of progressive disease. With a median follow-up of 220 days (9-2104) the actuarial 2-year transplant-related mortality (TRM) was 51%, the actuarial relapse risk 37%, the actuarial survival 46%. Fifteen patients (48%) are alive in complete remission, with a median follow-up of 32 months (range 2-71). These data suggest that patients relapsing after an autotransplant should be screened for potential related or unrelated donors: although TRM remains high there is a definite chance of long-term disease-free survival if these patients are allografted.


Effect of coronary occlusion on intracardiac electrogram morphology.
The effect of coronary occlusion on the morphology of intracardiac electrograms (IKG) may be of diagnostic value in recipients of cardiac implantable electronic device (CIED) and in other patients at risk of ischaemic heart disease (IHD), but remains grossly uncharacterized. The aim of the current study was to examine the effect of total occlusions in the major coronary artery distributions on the IKG. Domestic crossbred pigs (n= 11, 20-30 kg) were implanted with dual-coil right ventricular defibrillators, and bipolar right atrial and left ventricular leads. Through the femoral approach, percutaneous balloon total occlusion of the major coronary arteries was performed in random order in the left anterior descending, left circumflex, and right coronary arteries. Each occlusion was maintained for 3-5 min with 30 min periods of reperfusion in between. Simultaneous 15-vector IKG and 12-lead surface electrocardiograms (ECG) were recorded and analysed at baseline and during coronary occlusions. With coronary occlusions, significant ST-segment disturbances are consistently seen on both surface ECG leads and IKG tracings compared with baseline recordings and are reproducible over time. Given the multiple intracardiac recording vectors, each occluded vessel has a specific signature, allowing coronary localization from the IKG. Total coronary occlusion induces consistent IKG changes with injury patterns that allow the detection and localization of the culprit coronary artery. If duplicated in patients with IHD, these changes are likely to improve the time to diagnosis of acute coronary syndromes and thus favourably impact clinical outcomes.


The hubs of the human connectome are generally implicated in the anatomy of brain disorders.
Brain networks or 'connectomes' include a minority of highly connected hub nodes that are functionally valuable, because their topological centrality supports integrative processing and adaptive behaviours. Recent studies also suggest that hubs have higher metabolic demands and longer-distance connections than other brain regions, and therefore could be considered biologically costly. Assuming that hubs thus normally combine both high topological value and high biological cost, we predicted that pathological brain lesions would be concentrated in hub regions. To test this general hypothesis, we first identified the hubs of brain anatomical networks estimated from diffusion tensor imaging data on healthy volunteers (n = 56), and showed that computational attacks targeted on hubs disproportionally degraded the efficiency of brain networks compared to random attacks. We then prepared grey matter lesion maps, based on meta-analyses of published magnetic resonance imaging data on more than 20 000 subjects and 26 different brain disorders. Magnetic resonance imaging lesions that were common across all brain disorders were more likely to be located in hubs of the normal brain connectome (P < 10(-4), permutation test). Specifically, nine brain disorders had lesions that were significantly more likely to be located in hubs (P < 0.05, permutation test), including schizophrenia and Alzheimer's disease. Both these disorders had significantly hub-concentrated lesion distributions, although (almost completely) distinct subsets of cortical hubs were lesioned in each disorder: temporal lobe hubs specifically were associated with higher lesion probability in Alzheimer's disease, whereas in schizophrenia lesions were concentrated in both frontal and temporal cortical hubs. These results linking pathological lesions to the topological centrality of nodes in the normal diffusion tensor imaging connectome were generally replicated when hubs were defined instead by the meta-analysis of more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders.


Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo.
Does ibuprofen use during the first trimester of pregnancy interfere with the development of the human fetal ovary? In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells. In utero stages of ovarian development define the future reproductive capacity of a woman. In rodents, analgesics can impair the development of the fetal ovary leading to early onset of fertility failure. Ibuprofen, which is available over-the-counter, has been reported as a frequently consumed medication during pregnancy, especially during the first trimester when the ovarian germ cells undergo crucial steps of proliferation and differentiation. Organotypic cultures of human ovaries obtained from 7 to 12 developmental week (DW) fetuses were exposed to ibuprofen at 1-100 μM for 2, 4 or 7 days. For each individual, a control culture (vehicle) was included and compared to its treated counterpart. A total of 185 individual samples were included. Ovarian explants were analyzed by flow cytometry, immunohistochemistry and quantitative PCR. Endpoints focused on ovarian cell number, cell death, proliferation and germ cell complement. To analyze the possible range of exposure, ibuprofen was measured in the umbilical cord blood from the women exposed or not to ibuprofen prior to termination of pregnancy. Human ovarian explants exposed to 10 and 100 μM ibuprofen showed reduced cell number, less proliferating cells, increased apoptosis and a dramatic loss of germ cell number, regardless of the gestational age of the fetus. Significant effects were observed after 7 days of exposure to 10 μM ibuprofen. At this concentration, apoptosis was observed as early as 2 days of treatment, along with a decrease in M2A-positive germ cell number. These deleterious effects of ibuprofen were not fully rescued after 5 days of drug withdrawal. N/A. This study was performed in an experimental setting of human ovaries explants exposed to the drug in culture, which may not fully recapitulate the complexity of in vivo exposure and organ development. Inter-individual variability is also to be taken into account. Whereas ibuprofen is currently only contra-indicated after 24 weeks of pregnancy, our results points to a deleterious effect of this drug on first trimester fetal ovaries ex vivo. These findings deserve to be considered in light of the present recommendations about ibuprofen consumption pregnancy, and reveal the urgent need for further investigations on the cellular and molecular mechanisms that underlie the effect of ibuprofen on fetal ovary development.


Anatomically plausible illusory posture affects mental rotation of body parts.
During mental rotation (MR) of body parts, people internally simulate the movement of their corresponding body segments. These sensory-motor mechanisms render MR sensitive to proprioceptive information (e.g., posture). Similar mechanisms can alter illusory hand ownership following synchronous visuotactile stimulation (e.g., the rubber hand illusion [RHI]). In the present study, we first showed that illusory ownership for a fake hand can also be induced when the posture of the fake hand (palm-up) does not correspond with the subject's physical hand posture (palm-down). Then we tested whether illusory ownership for a fake hand in such a posture impacts the MR of hands carried out immediately and repeatedly after the RHI. The results showed that MR was altered for the view corresponding to the fake hand's posture, but not for other views. Additionally, these effects depended on illusory ownership, as only synchronous visuotactile stimulation was found to lead to these changes, characterized by a modulation of the rotation-dependent profile of MR response times. These findings show that similar sensory-motor mechanisms are recruited during the MR of hands and illusory hand ownership manipulated through multisensory mismatch, and that bottom-up visuotactile stimulation interferes with high-level imagery processes.


The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women.
To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum. A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4-6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0. Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71-0.83) for TDF area under the curve (AUC0-24 h); 0.81 (0.68-0.96) for TDF Cmax and 0.79 (0.70-0.90) for TDF C24 h and 0.75 (0.68-0.82) for FTC AUC0-24 h; and 0.87 (0.77-0.99) for FTC Cmax and 0.77 (0.52-1.12) for FTC C24 h. The viral load close to delivery was less than 200 copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported. Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.


Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives.
Essential oils (EOs) are volatile and concentrated liquids extracted from different parts of plants. Bioactive compounds found in EOs, especially terpenes and terpenoids possess a wide range of biological activities including anticancer, antimicrobial, anti-inflammatory, antioxidant, and antiallergic. Available literature confirms that EOs exhibit antimicrobial and food preservative properties that are considered as a real potential application in food industry. Hence, the purpose of this review is to present an overview of current knowledge of EOs for application in pharmaceutical and medical industries as well as their potential as food preservatives in food industry.


Large-scale Functional Integration, Rather than Functional Dissociation along Dorsal and Ventral Streams, Underlies Visual Perception and Action.
Visual dual-stream theory posits that two distinct neural pathways of specific functional significance originate from primary visual areas and reach the inferior temporal (ventral) and posterior parietal areas (dorsal). However, there are several unresolved questions concerning the fundamental aspects of this theory. For example, is the functional dissociation between ventral and dorsal stream driven by features in input stimuli or is it driven by categorical differences between visuoperceptual and visuomotor functions? Is the dual stream rigid or flexible? What is the nature of the interactions between the two streams? We addressed these questions using fMRI recordings on healthy human volunteers and employing stimuli and tasks that can tease out the divergence between visuoperceptual and visuomotor variants of dual-stream theory. fMRI scans were repeated after seven practice sessions that were conducted in a non-MRI environment to investigate the effects of neuroplasticity. Brain activation analysis supports an input-based functional dissociation and existence of context-dependent neuroplasticity in dual-stream areas. Intriguingly, premotor cortex activation was observed in the position perception task and distributed deactivated regions were observed in all perception tasks, thus warranting a network-level analysis. Dynamic causal modeling analysis incorporating activated and deactivated brain areas during perception tasks indicates that the brain dynamics during visual perception and actions could be interpreted within the framework of predictive coding. Effectively, the network-level findings point toward the existence of more intricate context-driven functional networks selective of "what" and "where" information rather than segregated streams of processing along ventral and dorsal brain regions.


Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone.
The effect on linear growth of daily long-term inhaled corticosteroid therapy in preschool-aged children with recurrent wheezing is controversial. We sought to determine the effect of daily inhaled corticosteroid given for 2 years on linear growth in preschool children with recurrent wheezing. Children aged 2 and 3 years with recurrent wheezing and positive modified Asthma Predictive Index scores were randomized to a 2-year treatment period of chlorofluorocarbon-delivered fluticasone propionate (176 μg/d) or masked placebo delivered through a valved chamber with a mask and then followed for 2 years off study medication. Height growth determined by means of stadiometry was compared between treatment groups. In the study cohort as a whole, the fluticasone group did not have significantly less linear growth than the placebo group (change in height from baseline difference, -0.2 cm; 95% CI, -1.1 to 0.6) 2 years after discontinuation of study treatment. In post hoc analyses children 2 years old who weighed less than 15 kg at enrollment and were treated with fluticasone had less linear growth compared with those treated with placebo (change in height from baseline difference, -1.6 cm; 95% CI, -2.8 to -0.4; P = .009). Linear growth was not significantly different in high-risk preschool-aged children with recurrent wheezing treated with 176 μg/d chlorofluorocarbon-delivered fluticasone compared with placebo 2 years after fluticasone is discontinued. However, post hoc subgroup analyses revealed that children who are younger in age and of lesser weight relative to the entire study cohort had significantly less linear growth, possibly because of a higher relative fluticasone exposure.


Predicting predation through prey ontogeny using size-dependent functional response models.
The functional response is a critical link between consumer and resource dynamics, describing how a consumer's feeding rate varies with prey density. Functional response models often assume homogenous prey size and size-independent feeding rates. However, variation in prey size due to ontogeny and competition is ubiquitous, and predation rates are often size dependent. Thus, functional responses that ignore prey size may not effectively predict predation rates through ontogeny or in heterogeneous populations. Here, we use short-term response-surface experiments and statistical modeling to develop and test prey size-dependent functional responses for water bugs and dragonfly larvae feeding on red-eyed treefrog tadpoles. We then extend these models through simulations to predict mortality through time for growing prey. Both conventional and size-dependent functional response models predicted average overall mortality in short-term mixed-cohort experiments, but only the size-dependent models accurately captured how mortality was spread across sizes. As a result, simulations that extrapolated these results through prey ontogeny showed that differences in size-specific mortality are compounded as prey grow, causing predictions from conventional and size-dependent functional response models to diverge dramatically through time. Our results highlight the importance of incorporating prey size when modeling consumer-prey dynamics in size-structured, growing prey populations.


Photoelectric Silk via Genetic Encoding and Bioassisted Plasmonics.
Genetically encoded photoelectric silk that can convert photons to electrons (light to electricity) over a wide visible range in a self-power mode is reported. As silk is a versatile host material with electrical conductivity, biocompatibility, and processability, a photoelectric protein is genetically fused with silk by silkworm transgenesis. Specifically, mKate2, which is conventionally known as a far-red fluorescent protein, is used as a photoelectric protein. Characterization of the electrochemical and optical properties of mKate2 silk allows designing a photoelectric measurement system. A series of in situ photocurrent experiments support the sensitive and stable performance of photoelectric conversion. In addition, as a plasmonic nanomaterial with a broad spectral resonance, titanium nitride (TiN) nanoparticles are biologically hybridized into the silk glands, taking full advantage of the silkworms' open circulatory system as well as the absorption band of mKate2 silk. This biological hybridization via direct feeding of TiN nanoparticles further enhances the overall photoelectric conversion ability of mKate2 silk. It is envisioned that the biologically derived photoelectric protein, its ecofriendly scalable production by transgenic silkworms, and the bioassisted plasmonic hybridization can potentially broaden the biomaterial choices for developing next-generation biosensing, retina prosthesis, and neurostimulation applications.


Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors.
Activating mutations in the epidermal growth factor receptor (EGFR), localized in the activation loop within the kinase domain, have been discovered in non-small cell lung cancers (NSCLC). Most of these mutants are exquisitely sensitive to EGFR tyrosine kinase inhibitors, suggesting that they generate receptor dependence in the cancers that express them. 32D cells stably expressing EGFR-L861Q and EGFR-L858R but not wild-type EGFR exhibited ligand-independent receptor phosphorylation and viability. Ligand-induced receptor down-regulation (LIRD) was impaired in mutant-expressing cells. The EGFR mutants were constitutively associated with the E3 ubiquitin ligase Cbl but did not associate with the adaptor protein CIN85 on the addition of ligand. Inhibition of HSP90 activity with geldanamycin restored Cbl function as indicated by receptor ubiquitination and LIRD. These results suggest that EGFR mutants form defective endocytic complexes. In addition, HSP90 plays a role in maintaining the functional conformation of EGFR mutants and protecting activated receptors from LIRD.


Novel carotenoid-based biosensor for simple visual detection of arsenite: characterization and preliminary evaluation for environmental application.
A novel whole-cell arsenite biosensor was developed using the photosynthetic bacterium Rhodopseudomonas palustris no. 7 and characterized. A sensor plasmid containing the operator-promoter region of the ars operon and arsR gene from Escherichia coli and the crtI gene from R. palustris no. 7 was introduced into a blue-green mutant with crtI deleted, R. palustris no. 711. The biosensor changed color in response to arsenite, and the change was obvious to the naked eye after 24 h without further manipulation. Real-time reverse transcription-PCR showed that the crtI mRNA was induced 3-fold at 3 h and 2.5-fold at 6 h after addition of 50 microg/liter arsenite compared with the no-arsenite control, and consistent with this, the relative levels of lycopene and rhodopin also increased compared with the control. Colorimetric analysis of the bacteria showed that the hue angle had clearly shifted from green-yellow toward red in an arsenic dose-dependent manner at 24 h after arsenite addition. This obvious shift occurred irrespective of the culture conditions before arsenite was added, indicating that the color change of the biosensor is stable in water samples containing various concentrations of dissolved oxygen. Finally, assays using samples prepared in various types of mineral water indicated that this biosensor could be used to screen groundwater samples for the presence of arsenite in a variety of locations, even where electricity is not available.


Gene Regulatory Variation in Drosophila melanogaster Renal Tissue.
Genetic variation influencing levels of gene expression is abundant in natural populations, and may exert its effects through complex mechanisms that depend on an organism's genetic background and the tissue in which expression is measured. We investigated natural variation in gene expression in the Malpighian tubules of three inbred Drosophila melanogaster strains and their F1 hybrids. One of the strains was from a population in the species' ancestral range (Zambia), while the other two were from a more recently derived population (Sweden). Although closely related, the two Swedish strains differed greatly in terms of their expression inheritance when hybridized with the Zambian strain, with one Swedish strain showing a large excess of genes with recessive expression inheritance, as well as a large number of genes with overdominant inheritance. Although most expression variation could be attributed to trans-regulation, there were ∼200 genes that showed allele-specific expression differences in each of the between-population hybrids, indicating that cis-regulation contributes as well. The cis-regulated genes were enriched with cytochrome P450 genes, and the upstream regions of six of these genes were incorporated into transgenic reporter gene constructs to test their effects on expression. Differential expression was observed for five of the six reporter genes in the Malpighian tubule, suggesting that a large proportion of cis-regulatory variation lies directly upstream of the affected gene. In most cases, the differential expression was specific to the Malpighian tubule or greater in this tissue than in the rest of the body, highlighting the importance of single-tissue studies of gene expression variation.


How the alignment of adsorbed ortho H pairs determines the onset of selective carbon nanotube etching.
Unlocking the enormous technological potential of carbon nanotubes strongly depends on our ability to specifically produce metallic or semiconducting tubes. While selective etching of both has already been demonstrated, the underlying reasons, however, remain elusive as yet. We here present computational and experimental evidence on the operative mechanisms at the atomic scale. We demonstrate that during the adsorption of H atoms and their coalescence, the adsorbed ortho hydrogen pairs on single-walled carbon nanotubes induce higher shear stresses than axial stresses, leading to the elongation of HC-CH bonds as a function of their alignment with the tube chirality vector, which we denote as the γ-angle. As a result, the C-C cleavage occurs more rapidly in nanotubes containing ortho H-pairs with a small γ-angle. This phenomenon can explain the selective etching of small-diameter semiconductor nanotubes with a similar curvature. Both theoretical and experimental results strongly indicate the important role of the γ-angle in the selective etching mechanisms of carbon nanotubes, in addition to the nanotube curvature and metallicity effects and lead us to clearly understand the onset of selective synthesis/removal of CNT-based materials.


NAT2 genotyping and efficacy of sulfasalazine in patients with chronic discoid lupus erythematosus.
Sulfasalazine is an effective agent for chronic discoid lupus erythematosus (CDLE) but the response to treatment is considerably variable between patients and is also unpredictable. The reason for this might relate to differences in metabolism of the drug which is extensively acetylated by the polymorphic enzyme N-acetyltransferase 2 (NAT2). To test this possibility, the N-acetylation phenotype of eleven patients with CDLE and treated by standard doses of sulfasalazine was retrospectively determined by genotyping. A clear-cut difference in the outcome of treatment was observed according to whether the patients were slow acetylators (SA) or rapid acetylators (RA). Eight out of 11 patients responded to treatment with a complete or marked remission of the disease. Seven of them were RA. The three other patients who did not respond at all to the drug were SA. In addition, SA seem to be more prone to toxic events. These findings strongly suggest that the genetic polymorphism of NAT2 is responsible for differences in the response to sulfasalazine in patients with CDLE. Therefore, candidates for sulfasalazine therapy should be genotyped to identify those patients who might benefit from the drug.


Bioenergetic shifts during transitions between stem cell states (2013 Grover Conference series).
Two defining characteristics of stem cells are their multilineage differentiation potential (multipotency or pluripotency) and their capacity for self-renewal. Growth factors are well-established regulators of stem cell differentiation and self renewal, but less is known about the influence of the metabolic state on stem cell function. Recent studies investigating cellular metabolism during the differentiation of adult stem cells, human embryonic stem cells (ESCs), and induced pluripotent stem cells have demonstrated that activation of specific metabolic pathways depends on the type of stem cells as well as the lineage cells are differentiating into and that these metabolic pathways can influence the differentiation process. However, some common patterns have emerged, suggesting that undifferentiated stem cells primarily rely on glycolysis to meet energy demands. Our own data indicate that undifferentiated ESCs not only exhibit a low mitochondrial membrane potential but also express high levels of the mitochondrial uncoupling protein 2 and of glutamine metabolism regulators when compared with differentiated cells. More importantly, interventions that target stem cell metabolism are able to either prevent or enhance differentiation. These findings suggest that the metabolic state of stem cells is not just a marker of their differentiation status but also plays an active role in regulating stem cell function. Regulatory metabolic pathways in stem cells may thus serve as important checkpoints that can be modulated to direct the regenerative capacity of stem cells.


Development and validation of a herring gull embryo toxicokinetic model for PCBs.
A toxicokinetic model was developed to describe polychlorinated biphenyl (PCB) accumulation by herring gull (Larus argentatus) embryos during development. The model consists of two components, a bioenergetics model that predicts the lipid mass balance of embryo and yolk compartments with time and an empirical toxicokinetic model that describes PCB partitioning between lipid compartments in the egg. The model was calibrated using data on PCB and lipid partitioning between embryo and yolk + albumen at four time points during incubation in herring gull eggs injected with a PCB mixture, combined with data sets on herring gull embryo growth rates and bioenergetic demands with time. The model was validated using independent data consisting of maternally exposed, field-incubated Lake Superior herring gull eggs that varied in incubation ages over the range of 8.5 d to pipping age (26-28 days). PCB concentrations in 6-9 d embryos were nearly an order of magnitude less than predicted by equilibrium lipid partitioning between the embryo and yolk + albumen compartments of the eggs. PCB concentrations in embryos were adequately predicted by equilibrium partitioning, however, for eggs incubated for 23-28 d. An empirical relationship was developed to account for the apparent nonequilibrium behaviour of PCBs during early development. The model was sensitive to the mass of yolk lipids and the mass of PCBs deposited to fresh eggs and much of the variability in embryo PCB concentrations could by explained by accounting for variability in these input parameters. Consistent with experimental data for other avian species, the model predicts that the highest PCB concentrations in the embryo/chick occur during pipping or soon after when yolk lipids have been completely resorbed by the embryo.


Comparative study of enzymatic activities of new KatG mutants from low- and high-level isoniazid-resistant clinical isolates of Mycobacterium tuberculosis.
Resistance to isoniazid (INH-R) in Mycobacterium tuberculosis is mainly due to mutations at position 315 (S315T) of the catalase-peroxidase KatG. We identified 16 mutations (including 13 biochemically uncharacterized mutations) in KatG from INH-R clinical isolates of M. tuberculosis showing mutations other than S315T. The KatG enzymatic activities (catalase, peroxidase, free radical production and isonicotinoyl-NAD formation) of wild-type KatG and the 16 mutants were determined and correlated to their spatial location in a KatG model structure. Of all mutations studied, H270R, which conferred a high level of INH-R and results in the disruption of a coordination bond with the heme, caused complete loss of all enzymatic KatG activities. The mutants generally associated with a very high level of INH-R were all characterized by a drastic reduction in catalase activity and a marked decrease in INH activation activities. One mutant, A162E, displayed a behavior similar to S315T, i.e. a moderate decrease in catalase activity and a drastic decrease in the formation of the radical form of INH. Finally, the mutants associated with a low level of INH-R showed a moderate reduction in the four catalytic activities, likely stemming from an overall alteration of the folding and/or stability of the KatG protein.


Resonators in insect sound production: how insects produce loud pure-tone songs.
In a resonant vibration, two reactive elements, such as a mass and a spring, interact: the resonant frequency depends on the magnitude of these two elements. The build-up and decay of the vibration depend on the way the resonator is driven and on the damping in the system. The evidence for the existence of resonators in insect sound production is assessed. The mechanics of different types of sound-producing system found in insects is described. Mechanical frequency-multiplier mechanisms, which convert the relatively slow contraction of muscles to the higher frequency of the sound, are commonly used to convert the comparatively slow muscle contraction rate to the higher frequency of the sound. The phasing and rate of mechanical excitation may also affect the frequency and duration of the sound that is produced. Although in many insects the song may appear to be produced by the excitation of a simple resonator, the song frequency may not be constant, suggesting that other factors, such as the mechanism of excitation, or variation of the effective mass or elasticity of the system during sound production, may be additional determinants of the song frequency. Loud, and hence efficient, transduction of the energy of a mechanical resonator into sound may involve a second stage of transduction which, by damping the resonator, may compromise tonal purity. Some insect singers resolve this problem by tuning both stages of transduction to the same frequency, thereby maintaining tonal purity.


Extranodal NK/T-cell lymphoma presenting as a pituitary mass. Case report and review of the literature.
Primary pituitary lymphomas (PPLs) are rare tumors of the central nervous system, and most are of B-cell origin. Extranodal NK/T-cell lymphomas are uncommon neoplasms that are highly aggressive and show a strong association with Epstein-Barr virus. They most commonly affect the nasal cavity and paranasal sinuses; manifestation as a primary pituitary tumor has never been described. The authors report a case of NK/T-cell lymphoma of the pituitary gland and review 17 cases of PPL from the literature. All patients had been evaluated at presentation for clinical, neuroimaging, and histopathological findings. Patients who had systemic lymphoma with secondary involvement of the pituitary gland were excluded. The mean patient age was 55.5 years (range 26-86 years); the male/female ratio was 13:5. The most common presentation was pituitary insufficiency (72%), followed by headache (56%), diplopia (39%), visual loss (28%), and fever (22%). Thirteen patients (72%) exhibited anterior hypopituitarism and seven (39%) had diabetes insipidus at presentation. Magnetic resonance imaging demonstrated enhancing parasellar masses with diffuse enlargement of the pituitary gland (94%), suprasellar extension (44%), cavernous sinus extension (39%), and stalk thickening (22%). Thirteen patients (72%) had B-cell lymphoma, four (22%) had T-cell lymphoma, and one (6%) had NK/T-cell lymphoma. Primary pituitary lymphomas are rare entities with a range of clinical presentations and neuroimaging findings that are unique from those of patients who present with pituitary adenomas. The pathological entity of NK/T-cell lymphoma is distinct, and its course is very aggressive with a poor prognosis.


Plasmodium falciparum var gene expression homogeneity as a marker of the host-parasite relationship under different levels of naturally acquired immunity to malaria.
Acquired immunity to Plasmodium falciparum infection causes a change from frequent, sometimes life-threatening, malaria in young children to asymptomatic, chronic infections in older children and adults. Little is known about how this transition occurs but antibodies to the extremely diverse PfEMP1 parasite antigens are thought to play a role. PfEMP1 is encoded by a family of 60 var genes that undergo clonal antigenic variation, potentially creating an antigenically heterogeneous infecting population of parasites within the host. Previous theoretical work suggests that antibodies to PfEMP1 may play a role in "orchestrating" their expression within infections leading to sequential, homogeneous expression of var genes, and prolonged infection chronicity. Here, using a cloning and sequencing approach we compare the var expression homogeneity (VEH) between isolates from children with asymptomatic and clinical infections. We show that asymptomatic infections have higher VEH than clinical infections and a broader host antibody response. We discuss this in relation to the potential role of host antibodies in promoting chronicity of infection and parasite survival through the low transmission season.


Comparative and demographic analysis of orang-utan genomes.
'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts.


Selective increase of cyclooxygenase-2 expression in a model of renal ablation.
Previous studies have suggested a possible role for prostaglandins (PGs) in mediating alterations in nephron structure and function ensuing after renal ablation. Two isoforms of cyclooxygenase (COX) have been described: constitutive (COX-1) and inducible (COX-2). We examined expression of these isoforms following subtotal renal ablation (5/6 ablation, RA) in rats. In renal cortex, COX-2 mRNA and immunoreactive protein (IP) increased progressively compared with sham-operated littermates. In contrast, there were no significant changes in COX-1 mRNA expression. In normal kidney, cortical COX-1 IP was immunolocalized predominantly to mesangial cells and collecting tubules, whereas COX-2 IP was found in a subset of cortical thick ascending limb of Henle's loop (CTAL) cells in the region of the macula densa (MD). Following RA, significantly increased COX-2 IP was detected in the MD and surrounding CTAL cells. In addition, fainter immunoreactive COX-2 was detected in scattered visceral epithelial cells and mesangial cells of the glomerulus. Immunoblotting of isolated glomeruli demonstrated a selective increase of glomerular immunoreactive COX-2 expression following RA. No change of COX-1 expression was seen. To determine COX activity, isolated glomeruli were incubated with arachidonic acid and PGE2 measured by enzyme immunoassay (EIA). Compared with sham, glomeruli from 2 wk RA produced significantly more PGs. SC-58560, a selective COX-1 inhibitor, did not inhibit PG production in the remnant glomeruli at concentrations up to 10(-4) M, whereas SC-58236, a relatively selective COX-2 inhibitor, significantly inhibited PG production by RA glomeruli. In preliminary studies, to define mechanisms of altered expression of glomerular COX-2, rat mesangial cells were incubated with serum from sham or 2 wk RA. There were significant increases in COX-2 expression in response to 2 wk RA serum. In summary, these results indicate selective increases in renal cortical COX-2 expression following renal ablation.


Mapping orientational order in a bulk heterojunction solar cell with polarization-dependent photoconductive atomic force microscopy.
New methods connecting molecular structure, self-organization, and optoelectronic performance are important for understanding the current generation of organic photovoltaic (OPV) materials. In high power conversion efficiency (PCE) OPVs, light-harvesting small-molecules or polymers are typically blended with fullerene derivatives and deposited in thin films, forming a bulk heterojunction (BHJ), a self-assembled three-dimensional nanostructure of electron donors and acceptors that separates and transports charges. Recent data suggest micrometer-scale orientational order of donor domains exists within this complex nanomorphology, but the link to the optoelectronic properties is yet unexplored. Here we introduce polarization-dependent, photoconductive atomic force microscopy (pd-pcAFM) as a combined probe of orientational order and nanoscale optoelectronic properties (∼20 nm resolution). Using the donor 7,7'-(4,4-bis(2-ethylhexyl)-4H-silolo[3,2-b:4,5-b']dithiophene-2,6-diyl)bis(6-fluoro-4-(5'-hexyl[2,2'-bithiophen]-5-yl)benzo[c][1,2,5]thiadiazole), p-DTS(FBTTh2)2, we show significant spatial dependence of the nanoscale photocurrent with polarized light in both pristine and BHJ blends (up to 7.0% PCE) due to the local alignment of the molecular transition dipoles. By mapping the polarization dependence of the nanoscale photocurrent, we estimate the molecular orientation and orientational order parameter. Liquid crystalline disclinations are observed in all films, in agreement with complementary electron microscopy experiments, and the order parameter exceeds 0.3. The results demonstrate the utility of pd-pcAFM to investigate the optical/structural anisotropy that exists within a well-performing BHJ system and its relationship to optoelectronic properties on both the nanometer and micrometer length scales.


Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases.
Epithelial-mesenchymal transition (EMT) is a term applied to the process whereby cells undergo a switch from an epithelial phenotype with tight junctions, lateral, apical, and basal membranes, and lack of mobility into mesenchymal cells that have loose interactions with other cells, are non-polarized, motile and produce an extracellular matrix. The importance of this process was initially recognized from a very early step in embryology, but more recently as a potential mechanism for the progression and spread of epithelial cancers. As the sequence of morphological changes has become understood in molecular terms, diseases characterized by alterations in stromal elements and fibrosis are being considered as examples of EMT. This review will focus on the pathogenetic features of immune-mediated renal disease, systemic sclerosis and rheumatoid arthritis that could be explained by EMT.


Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3.
In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.


Chemokines in the ischemic myocardium: from inflammation to fibrosis.
Myocardial infarction is associated with an inflammatory response leading to leukocyte recruitment, healing and formation of a scar. Members of the chemokine superfamily are rapidly induced in the infarcted myocardium and may critically regulate the post-infarction inflammatory response. CXCL8/Interleukin (IL)-8 is upregulated in the infarcted area and may induce neutrophil infiltration. In addition, mononuclear cell chemoattractants, such as the CC chemokines CCL2/Monocyte Chemoattractant Protein (MCP)-1, CCL3/Macrophage Inflammatory Protein (MIP)1alpha, and CCL4/MIP-1beta are expressed in the ischemic area, and may regulate monocyte and lymphocyte recruitment. However, chemokines may have additional effects on healing infarcts beyond their leukotactic properties. The CXC chemokine CXCL10/Interferon-y inducible Protein (IP)-10, a potent angiostatic factor with antifibrotic properties, is induced in the infarct and may prevent premature angiogenesis and fibrous tissue deposition, until the infarct is debrided and provisional matrix necessary to support granulation tissue ingrowth is formed. Chemokine induction in the infarct is transient, suggesting that inhibitory mediators (such as transforming growth Factor (TGF)-beta) may be activated suppressing chemokine synthesis and leading to resolution of inflammation and transition to fibrosis. Brief repetitive ischemia in mice also results in chemokine upregulation followed by suppression of chemokine synthesis and interstitial fibrosis, in the absence of myocardial infarction. Chemokine expression may play a role in the pathogenesis of non-infarctive ischemic cardiomyopathy, where early ischemia-induced chemokine expression may be followed by activation of inhibitory mediators that suppress inflammation, but induce fibrosis.


Heterogeneous Idealization of Ion Channel Recordings - Open Channel Noise.
We propose a new model-free segmentation method for idealizing ion channel recordings. This method is designed to deal with heterogeneity of measurement errors. This in particular applies to open channel noise which, in general, is particularly difficult to cope with for model-free approaches. Our methodology is able to deal with lowpass filtered data which provides a further computational challenge. To this end we propose a multiresolution testing approach, combined with local deconvolution to resolve the lowpass filter. Simulations and statistical theory confirm that the proposed idealization recovers the underlying signal very accurately at presence of heterogeneous noise, even when events are shorter than the filter length. The method is compared to existing approaches in computer experiments and on real data. We find that it is the only one which allows to identify openings of the PorB porine at two different temporal scales. An implementation is available as an R package.


Adhesion of resin cement to dentin: effects of adhesive promoters, immediate dentin sealing strategies, and surface conditioning.
This study evaluated the shear bond strength (SBS) of resin cement to dentin after applying two adhesive (A) systems with a combination of four different immediate dentin sealing (IDS) strategies, and two surface conditioning (SC) methods. Human third molars (n = 140) were collected and randomly split (n = 70 each) between the two A systems (Clearfil SE Bond; Kuraray [AC] and Optibond FL; Kerr [AO]). The A groups were further divided into four IDS strategies (2 x one adhesive layer (IDS-1L); 2 x two adhesive layers (IDS-2L); 2 x one adhesive layer and one flowable layer (IDS-F); 2 x no adhesive layer (delayed dentin sealing [DDS]). Finally, each strategy group was categorized into one of the two SC methods (only pumice [SC-P] or pumice and silica coating [SC-PS]), except the DDS group, where only SC-P was used. This resulted in 14 groups of 10 specimens each. The occlusal coronal third was removed from each molar crown with a diamond saw (Isomet 1000), and IDS was applied, followed by temporary restorations. These were removed after 2 weeks of water storage, and the IDS surfaces were subsequently conditioned. The standard adhesive procedure (Syntac Primer and Adhesive, Heliobond; Ivoclar Vivadent) was executed, followed by the application of a resin cement (Variolink II; Ivoclar Vivadent) and photopolymerization. All specimens were subjected to thermocyclic aging (10,000 cycles, 5°C to 55°C). Shear force was applied to the adhesive interface in a universal testing machine (1 mm/min). Fracture types and locations after loading were classified. The data were analyzed using analysis of variance (ANOVA) and independent samples t tests. AO groups exhibited higher mean SBS values (14.4 ± 6.43) than AC groups (12.85 ± 4.97) (P = 0.03). ANOVA showed the main effect of the applications on the SBS in the different groups (P = 0.00). Both DDS groups showed significantly lower SBS values compared with all the IDS groups (IDS-1L, IDS-2L, IDS-F). No significant differences in SBS results were found between the IDS groups (P = 0.43) and between the SC methods (P = 0.76). Dentin-cement interface failures diminished with the application of IDS. IDS improves the SBS compared with DDS. No significant differences were found between the tested conditioning methods.


Tomato Whole Genome Transcriptional Response to Tetranychus urticae Identifies Divergence of Spider Mite-Induced Responses Between Tomato and Arabidopsis.
The two-spotted spider mite Tetranychus urticae is one of the most significant mite pests in agriculture, feeding on more than 1,100 plant hosts, including model plants Arabidopsis thaliana and tomato, Solanum lycopersicum. Here, we describe timecourse tomato transcriptional responses to spider mite feeding and compare them with Arabidopsis in order to determine conserved and divergent defense responses to this pest. To refine the involvement of jasmonic acid (JA) in mite-induced responses and to improve tomato Gene Ontology annotations, we analyzed transcriptional changes in the tomato JA-signaling mutant defenseless1 (def-1) upon JA treatment and spider mite herbivory. Overlay of differentially expressed genes (DEG) identified in def-1 onto those from the timecourse experiment established that JA controls expression of the majority of genes differentially regulated by herbivory. Comparison of defense responses between tomato and Arabidopsis highlighted 96 orthologous genes (of 2,133 DEG) that were recruited for defense against spider mites in both species. These genes, involved in biosynthesis of JA, phenylpropanoids, flavonoids, and terpenoids, represent the conserved core of induced defenses. The remaining tomato DEG support the establishment of tomato-specific defenses, indicating profound divergence of spider mite-induced responses between tomato and Arabidopsis.


Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203.
Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective.


Is social jetlag associated with an adverse endocrine, behavioral, and cardiovascular risk profile?
Social jetlag represents the discrepancy between circadian and social clocks, which is measured as the difference in hours in midpoint of sleep between work days and free days. Previous studies have shown social jetlag to be associated with body mass index (BMI), glycated hemoglobin levels, heart rate, depressive symptoms, smoking, mental distress and alcohol use. The objective of our current study was to investigate, in a group of 145 apparently healthy participants (67 men and 78 women, aged 18-55 years, BMI 18-35 kg/m(2)), the prevalence of social jetlag and its association with adverse endocrine, behavioral and cardiovascular risk profiles as measured in vivo. participants with ≥2 h social jetlag had higher 5-h cortisol levels, slept less during the week, were more often physically inactive and had an increased resting heart rate, compared with participants who had ≤1 h social jetlag. We therefore concluded that social jetlag is associated with an adverse endocrine, behavioral and cardiovascular risk profile in apparently healthy participants. These adverse profiles put healthy participants at risk for development of metabolic diseases and mental disorders, including diabetes and depression, in the near future.


Observer variation in the histological grading of rectal carcinoma.
The variation between two observers in grading 100 biopsies and the corresponding main specimens of rectal carcinomas has been examined. Using kappa statistics, which take account of chance agreement, we found a highly significant level of agreement. As expected, higher levels were obtained for intraobserver agreement. However, disagreements between observers were in many instances "haphazard" and there were differences in bias between them. Fifty paired biopsies and main tumours were graded by five observers and the results analysed for bias and by kappa statistics for overall and conditional agreement. These methods revealed significant overall agreement but the levels for some observer pairs did not differ significantly from chance. Examination for observer bias indicated differing standards of grading, and haphazard disagreements reached high levels for some observer pairs. The intraobserver agreement between the grade of the biopsy and the corresponding main tumour varied from 56-69% but only 52% of the poorly differentiated tumours were diagnosed as such in the preoperative biopsy by the "specialist" observer. The poor predictive value was not improved by taking multiple biopsies. We conclude that the grade of a rectal carcinoma cannot be accurately assessed on a preoperative biopsy and that this has serious implications for the management of low rectal cancers. Furthermore the wide discrepancies in diagnostic standards between some pathologists mean that studies on the treatment and prognosis of rectal cancer which utilise histological grade for comparison purposes must be viewed with considerable skepticism.


British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis.
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. Major advances were made in its management based on controlled trials performed in England and the USA in the 1970s and 1980s. Unfortunately, in recent decades there has been a dearth of controlled clinical trials and, thus, many questions regarding the optimal management of this disease remain unanswered. Many promising newer immunosuppressive therapies await formal comparison with standard therapies and also many important details in relation to the application of standard therapies remain unclear. These guidelines describe the optimal management strategies in adults based on available published evidence, including the American Association for the Study of Liver Diseases practice guidelines for the diagnosis and treatment of AIH published in 2002 and recently updated.


Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice.
Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.


A new insight into postsurgical objective voice quality evaluation: application to thyroplastic medialization.
This paper aims at providing new objective parameters and plots, easily understandable and usable by clinicians and logopaedicians, in order to assess voice quality recovering after vocal fold surgery. The proposed software tool performs presurgical and postsurgical comparison of main voice characteristics (fundamental frequency, noise, formants) by means of robust analysis tools, specifically devoted to deal with highly degraded speech signals as those under study. Specifically, we address the problem of quantifying voice quality, before and after medialization thyroplasty, for patients affected by glottis incompetence. Functional evaluation after thyroplastic medialization is commonly based on several approaches: videolaryngostroboscopy (VLS), for morphological aspects evaluation, GRBAS scale and Voice Handicap Index (VHI), relative to perceptive and subjective voice analysis respectively, and Multi-Dimensional Voice Program (MDVP), that provides objective acoustic parameters. While GRBAS has the drawback to entirely rely on perceptive evaluation of trained professionals, MDVP often fails in performing analysis of highly degraded signals, thus preventing from presurgical/postsurgical comparison in such cases. On the contrary, the new tool, being capable to deal with severely corrupted signals, always allows a complete objective analysis. The new parameters are compared to scores obtained with the GRBAS scale and to some MDVP parameters, suitably modified, showing good correlation with them. Hence, the new tool could successfully replace or integrate existing ones. With the proposed approach, deeper insight into voice recovering and its possible changes after surgery can thus be obtained and easily evaluated by the clinician.


The Beneficial Effects of Principal Polyphenols from Green Tea, Coffee, Wine, and Curry on Obesity.
Several epidemiological studies and clinical trials have reported the beneficial effects of green tea, coffee, wine, and curry on human health, with its anti-obesity, anti-cancer, anti-diabetic, and neuroprotective properties. These effects, which have been supported using cell-based and animal studies, are mainly attributed to epigallocatechin gallate found in green tea, chlorogenic acid in coffee, resveratrol in wine, and curcumin in curry. Polyphenols are proposed to function via various mechanisms, the most important of which is related to reactive oxygen species (ROS). These polyphenols exert conflicting dual actions as anti- and pro-oxidants. Their anti-oxidative actions help scavenge ROS and downregulate nuclear factor-κB to produce favorable anti-inflammatory effects. Meanwhile, pro-oxidant actions appear to promote ROS generation leading to the activation of 5'-AMP-activated protein kinase, which modulates different enzymes and factors with health beneficial roles. Currently, it remains unclear how these polyphenols exert either pro- or anti-oxidant effects. Similarly, several human studies showed no beneficial effects of these foods, and, by extension polyphenols, on obesity. These inconsistencies may be attributed to different confounding study factors. Thus, this review provides a state-of-the-art update on these foods and their principal polyphenol components, with an assumption that it prevents obesity.


Assessment of Pyrexia and Associated Sickness Behavior in Patients with Chronic Periodontitis.
The purpose of this study was to assess pyrexia and sickness behavior such as anxiety, depression, lethargy, and weight loss in subjects with chronic periodontitis, and evaluate inflammatory mediators such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the patients with fever. This was a cross-sectional study that consisted of 150 chronic periodontitis and 150 healthy subjects. Sublingual and subgingival temperatures were assessed using a digital temperature probe. Associated sickness behavior was assessed for all the subjects. Pathological tests, i.e., ESR and CRP were done for subjects with fever. Evaluating the presence of fever with the severity of periodontal disease, 66.7% of the subjects with fever were in the group diagnosed with severe periodontitis, 20.4% had with moderate periodontitis, and 5.3% were in the healthy group. Subjects diagnosed with periodontitis comprised 66.2% of the subjects with higher (i.e., > 36.3°C) subgingival temperatures and healthy subjects made up the remaining 33.8% (p < 0.001). A correlation between the sublingual and subgingival temperature with the Pearson ρ correlation coefficient of 0.227 (p < 0.001) was observed. A statistically significant mean value of 37.05 ± 11.24 of ESR and 1.59 ± 1.11 mg/L of CRP was reported amongst the subjects with fever (p < 0.001). The association of sickness behavior with the severity of periodontitis was found to be significant: depression 40.006, anxiety 50.857, reported weight loss 76.463, and lethargy 141.581 (p < 0.001). The study demonstrated that there is a significant increase in the sublingual temperature amongst patients with severe chronic periodontitis. The subgingival temperature has a positive correlation with the sublingual temperature. There was a linear trend of an association of sickness behavior with the severity of chronic periodontitis. A significant increase in the circulating inflammatory mediators, CRP and ESR, were noticed in subjects with elevated body temperature.


Diabetes in tropical Africa: a prospective study, 1981-7. I. Characteristics of newly presenting patients in Dar es Salaam, Tanzania, 1981-7.
To study the clinical characteristics of newly diagnosed diabetic patients in tropical Africa. Prospective study of all newly diagnosed diabetic patients registered at a major urban hospital between 1 June 1981 and 31 May 1987. Muhimbili Medical Centre, Dar es Salaam, Tanzania. 1250 Patients: 874 men, 376 women. 272 (21.8%) Patients had diabetes requiring insulin, 825 (66.0%) had diabetes not requiring insulin, and 153 (12.2%) had diabetes of uncertain type. Most patients (1103, 88.2%) presented with the classic symptoms of diabetes. The peak time of presentation of diabetic patients requiring insulin was at age 15 to 19 years. Male manual workers and peasant farmers with diabetes not requiring insulin presented at a significantly older age and had a lower body mass index than sedentary office workers. Forty six (18.1%) of the patients requiring insulin diabetes and 111 (14.4%) not requiring insulin had first degree relative with diabetes. Twenty seven per cent of patients were underweight (body mass index less than 20 kg/m2) and 14.6% were obese (body mass index greater than 30 kg/m2). Hypertension was diagnosed in 211 (26.7%) of 791 patients not requiring insulin. Nine (3.3%) of those requiring insulin may have had the protein deficient type of diabetes related to malnutrition. The fibrocalculous variety of diabetes related to malnutrition was not observed. Newly presenting diabetic patients in Tanzania with diabetes requiring insulin are older at presentation than those in Britain; most diabetic patients present with diabetes not requiring insulin and a smaller proportion of Tanzanian patients are obese. Most have a lower socioeconomic state than diabetic patients in Britain. There are often delays in diagnosis in Tanzania, and there is a higher incidence of death shortly after presentation.


A case report of mantle cell lymphoma manifesting as a foot lesion.
Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma that most commonly affects men above the age of 60 years. The disease is called MCL because the tumor cells originate from the mantle zone of the lymph node. The most commonly affected sites are the lymph nodes, bone marrow, gastrointestinal tract, Waldeyer's ring and rarely the skin, breast and central nervous system. Only 22 cases with skin manifestation of MCL have been reported so far. We report the case of a 73-year-old woman who was diagnosed with MCL and underwent treatment, but later relapsed and presented with an ulcerated mass over her right foot. She underwent 6 cycles of chemotherapy with bendamustine plus rituximab and responded with resolution of the foot lesion. MCL is an aggressive lymphoma with a median overall survival of 3-5 years for advanced disease, while early-stage disease has a better prognosis. It rarely involves the skin. Since cutaneous lesions can be the first manifestation of MCL, awareness of this less common presentation is crucial to establish an early diagnosis and pursue treatment as early as possible, as it significantly impacts the survival rate.


Impact of ocean acidification on the early development and escape behavior of marine medaka (Oryzias melastigma).
Ocean acidification is predicted to affect a wide diversity of marine organisms. However, no studies have reported the effects of ocean acidification on Indian Ocean fish. We have used the Indian Ocean medaka (Oryzias melastigma) as a model species for a marine fish that lives in coastal waters. We investigated the impact of ocean acidification on the embryonic development and the stereotyped escape behavior (mediated by the Mauthner cell) in newly hatched larvae. Newly fertilized eggs of medaka were reared in seawater at three different partial pressures of carbon dioxide (pCO2): control at 450 μatm, moderate at 1160 μatm, and high at 1783 μatm. Hatch rates, embryonic duration, and larval malformation rates were compared and were not significantly different between the treatments and the control. In the high pCO2 group, however, the yolks of larvae were significantly smaller than in the control group, and the newly hatched larvae were significantly longer than the larvae in the control. In the moderate pCO2 group, the eye distance decreased significantly. No significantly negative growth effects were observed in the larvae when exposed to pCO2 levels that are predicted as a result of ocean acidification in the next 100-200 years. Larvae reared under control conditions readily produced C-start escape behavior to mechanosensory stimuli; however, in the moderate and high pCO2 experimental groups, the probabilities of C-start were significantly lower than those of the control group. Therefore, the sensory integration needed for the C-start escape behavior appears to be vulnerable to ocean acidification. Altered behavior in marine larval fish, particularly behaviors involved in escape from predation, could have potentially negative implications to fish populations, and, further, to the marine ecosystems at the levels of CO2 projected for the future.


Trace elements in hemodialysis patients: a systematic review and meta-analysis.
Hemodialysis patients are at risk for deficiency of essential trace elements and excess of toxic trace elements, both of which can affect health. We conducted a systematic review to summarize existing literature on trace element status in hemodialysis patients. All studies which reported relevant data for chronic hemodialysis patients and a healthy control population were eligible, regardless of language or publication status. We included studies which measured at least one of the following elements in whole blood, serum, or plasma: antimony, arsenic, boron, cadmium, chromium, cobalt, copper, fluorine, iodine, lead, manganese, mercury, molybdenum, nickel, selenium, tellurium, thallium, vanadium, and zinc. We calculated differences between hemodialysis patients and controls using the differences in mean trace element level, divided by the pooled standard deviation. We identified 128 eligible studies. Available data suggested that levels of cadmium, chromium, copper, lead, and vanadium were higher and that levels of selenium, zinc and manganese were lower in hemodialysis patients, compared with controls. Pooled standard mean differences exceeded 0.8 standard deviation units (a large difference) higher than controls for cadmium, chromium, vanadium, and lower than controls for selenium, zinc, and manganese. No studies reported data on antimony, iodine, tellurium, and thallium concentrations. Average blood levels of biologically important trace elements were substantially different in hemodialysis patients, compared with healthy controls. Since both deficiency and excess of trace elements are potentially harmful yet amenable to therapy, the hypothesis that trace element status influences the risk of adverse clinical outcomes is worthy of investigation.


The contribution of nearshore fish aggregating devices (FADs) to food security and livelihoods in Solomon Islands.
Fish aggregating devices, or FADs, are used widely in developing countries to concentrate pelagic fish, making them easier to catch. Nearshore FADs anchored close to the coast allow access for rural communities, but despite their popularity among policy makers, there is a dearth of empirical analysis of their contributions to the supply of fish and to fisheries management. In this paper we demonstrate that nearshore FADs increased the supply of fish to four communities in Solomon Islands. Estimated total annual fish catch ranged from 4300 to 12,000 kg across the study villages, with nearshore FADs contributing up to 45% of the catch. While it is clear that FADs increased the supply of fish, FAD catch rates were not consistently higher than other fishing grounds. Villages with limited access to diverse or productive fishing grounds seemingly utilized FADs to better effect. Villagers believed FADs increased household income and nutrition, as well as providing a source of fish for community events. FADs were also perceived to increase intra-household conflict and reduce fishers' participation in community activities. FADs need to be placed within a broader rural development context and treated as another component in the diversified livelihoods of rural people; as with other livelihood options they bring trade-offs and risks.


Lipid raft endocytosis and exosomal transport facilitate extracellular trafficking of annexin A2.
Annexin A2 (AnxA2), a Ca(2+)-dependent phospholipid-binding protein, is known to associate with the plasma membrane and the endosomal system. Within the plasma membrane, AnxA2 associates in a Ca(2+) dependent manner with cholesterol-rich lipid raft microdomains. Here, we show that the association of AnxA2 with the lipid rafts is influenced not only by intracellular levels of Ca(2+) but also by N-terminal phosphorylation at tyrosine 23. Binding of AnxA2 to the lipid rafts is followed by the transport along the endocytic pathway to be associated with the intralumenal vesicles of the multivesicular endosomes. AnxA2-containing multivesicular endosomes fuse directly with the plasma membrane resulting in the release of the intralumenal vesicles into the extracellular environment, which facilitates the exogenous transfer of AnxA2 from one cell to another. Treatment with Ca(2+) ionophore triggers the association of AnxA2 with the specialized microdomains in the exosomal membrane that possess raft-like characteristics. Phosphorylation at Tyr-23 is also important for the localization of AnxA2 to the exosomal membranes. These results suggest that AnxA2 is trafficked from the plasma membrane rafts and is selectively incorporated into the lumenal membranes of the endosomes to escape the endosomal degradation pathway. The Ca(2+)-dependent exosomal transport constitutes a novel pathway of extracellular transport of AnxA2.


Isoform-specific complementation of the yeast sac6 null mutation by human fimbrin.
The actin cytoskeleton is a fundamental component of eukaryotic cells, with both structural and motile roles. Actin and many of the actin-binding proteins found in different cell types are highly conserved, showing considerable similarity in both primary structure and biochemical properties. To make detailed comparisons between homologous proteins, it is necessary to know whether the various proteins are functionally, as well as structurally, conserved. Fimbrin is an example of a cytoskeletal component that, as shown by sequence determinations and biochemical characterizations, is conserved between organisms as diverse as Saccharomyces cerevisiae and humans. In this study, we examined whether the human homolog can substitute for the yeast protein in vivo. We report here that two isoforms of human fimbrin, also referred to as T- and L-plastin, can both substitute in vivo for yeast fimbrin, also known as Sac6p, whereas a third isoform, I-fimbrin (or I-plastin), cannot. We demonstrate that the human T- and L-fimbrins, in addition to complementing the temperature-sensitive growth defect of the sac6 null mutant, restore both normal cytoskeletal organization and cell shape to the mutant cells. In addition, we show that human T- and L-fimbrins can complement a sporulation defect caused by the sac6 null mutation. These findings indicate that there is a high degree of functional conservation in the cytoskeleton, even between organisms as diverse as S. cerevisiae and humans.


Genetic interaction between DNA polymerase beta and DNA-PKcs in embryogenesis and neurogenesis.
DNA polymerase beta (Polbeta) has been implicated in base excision repair. Polbeta knockout mice exhibit apoptosis in postmitotic neuronal cells and die at birth. Also, mice deficient in nonhomologous end-joining (NHEJ), a major pathway for DNA double-strand break repair, cause massive neuronal apoptosis. Severe combined immunodeficiency (SCID) mice have a mutation in the gene encoding DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the component of NHEJ, and exhibit defective lymphogenesis. To study the interaction between Polbeta and DNA-PKcs, we generated mice doubly deficient in Polbeta and DNA-PKcs. Polbeta(-/-)DNA-PKcs(scid/scid) embryos displayed greater developmental delay, more extensive neuronal apoptosis, and earlier lethality than Polbeta(-/-) and DNA-PKcs(scid/scid) embryos. Furthermore, to study the involvement of p53 in the phenotype, we generated Polbeta(-/-)DNA-PKcs(scid/scid)p53(-/-) triple-mutant mice. The mutants did not exhibit apoptosis but were lethal with defective neurulation at midgestation. These results suggest a genetic interaction between Polbeta and DNA-PKcs in embryogenesis and neurogenesis.


The Threat of Aerobic Vaginitis to Pregnancy and Neonatal Morbidity.
Aerobic vaginitis (AV) is an endogenous opportunistic infection brought about by the disruption of the normal vaginal microbiota. Its early diagnosis and treatment during pregnancy may reduce the risk of negative pregnancy outcomes. The aim of this review was to report on the aerobic bacteria most prevalent in AV and to provide evidence of the threat of untreated AV on pregnancy outcomes. More than 300 papers on preterm delivery were extracted from several research domains and filtered to include only AV-associated bacteria such as Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Group B streptococci and their association with adverse pregnancy outcomes. Due to the diverse sample groups, study techniques and outcomes, a meta-analysis was not conducted. The review revealed that the association of AV with adverse pregnancy outcomes has not been as widely researched as bacterial vaginosis (BV) and needs further investigation. Furthermore, the frequent misdiagnosis of AV coupled with the emerging antimicrobial resistance associated with bacteria implicated in AV and neonatal nosocomial infections pose a problem for prophylaxis and treatment to reduce the risk of maternal and neonatal morbidity and mortality.


Trends in observation care among Medicare fee-for-service beneficiaries at critical access hospitals, 2007-2009.
Observation care is used to evaluate patients prior to admission or discharge. Often beneficial, such care also imposes greater financial liability on Medicare beneficiaries. While the use of observation care has increased recently, critical access hospitals (CAHs) face different policies than prospective payment (PPS) hospitals, which may influence their observation care use. We used 100% Medicare inpatient and outpatient claims files and enrollment data for years 2007 to 2009, and the 2007 American Hospital Association data to compare trends in the likelihood, prevalence and duration of observation stays between CAHs and PPS hospitals in metro and non-metro areas among fee-for-service Medicare beneficiaries over age 65. While PPS hospitals are more likely to provide any observation care, the 3-year increase in the proportion of CAHs providing any observation care is approximately 5 times as great as the increase among PPS hospitals. Among hospitals providing any observation care in 2007, the prevalence at CAHs was 35.7% higher than at non-metro PPS hospitals and 72.8% higher than at metro PPS hospitals. By 2009, these respective figures had increased to 63.1% and 111%. Average stay duration increased more slowly for CAHs than for PPS hospitals. These data suggest that a growing proportion of CAHs are providing observation care and that CAHs provide relatively more observation care than PPS hospitals, but they have shorter average stays. This may have important financial implications for Medicare beneficiaries.


Impact of PET/CT system, reconstruction protocol, data analysis method, and repositioning on PET/CT precision: An experimental evaluation using an oncology and brain phantom.
In longitudinal oncological and brain PET/CT studies, it is important to understand the repeatability of quantitative PET metrics in order to assess change in tracer uptake. The present studies were performed in order to assess precision as function of PET/CT system, reconstruction protocol, analysis method, scan duration (or image noise), and repositioning in the field of view. Multiple (repeated) scans have been performed using a NEMA image quality (IQ) phantom and a 3D Hoffman brain phantom filled with 18 F solutions on two systems. Studies were performed with and without randomly (< 2 cm) repositioning the phantom and all scans (12 replicates for IQ phantom and 10 replicates for Hoffman brain phantom) were performed at equal count statistics. For the NEMA IQ phantom, we studied the recovery coefficients (RC) of the maximum (SUVmax ), peak (SUVpeak ), and mean (SUVmean ) uptake in each sphere as a function of experimental conditions (noise level, reconstruction settings, and phantom repositioning). For the 3D Hoffman phantom, the mean activity concentration was determined within several volumes of interest and activity recovery and its precision was studied as function of experimental conditions. The impact of phantom repositioning on RC precision was mainly seen on the Philips Ingenuity PET/CT, especially in the case of smaller spheres (< 17 mm diameter, P < 0.05). This effect was much smaller for the Siemens Biograph system. When exploring SUVmax , SUVpeak , or SUVmean of the spheres in the NEMA IQ phantom, it was observed that precision depended on phantom repositioning, reconstruction algorithm, and scan duration, with SUVmax being most and SUVpeak least sensitive to phantom repositioning. For the brain phantom, regional averaged SUVs were only minimally affected by phantom repositioning (< 2 cm). The precision of quantitative PET metrics depends on the combination of reconstruction protocol, data analysis methods and scan duration (scan statistics). Moreover, precision was also affected by phantom repositioning but its impact depended on the data analysis method in combination with the reconstructed voxel size (tissue fraction effect). This study suggests that for oncological PET studies the use of SUVpeak may be preferred over SUVmax because SUVpeak is less sensitive to patient repositioning/tumor sampling.


Motion - colonoscopic surveillance is more cost effective than colectomy in patients with ulcerative colitis: arguments against the motion.
There are insufficient data upon which to base recommendations about surveillance colonoscopy and prophylactic colectomy for the prevention of colorectal cancer in patients with ulcerative colitis. Case series, analyses of intermediate results and extrapolations from other patient groups do not constitute reliable evidence. Available studies are susceptible to several biases: the 'healthy worker' effect, surveillance bias and selection bias. Patients who are enrolled in surveillance programs are more likely to be thoroughly evaluated beforehand, are more likely to be given a diagnosis of dysplasia or neoplasm even when asymptomatic and are more likely to comply with medical treatment, including maintenance anti-inflammatory medication. Comparisons of the rates of neoplasia or death between surveyed and nonsurveyed patients are, therefore, of questionable validity. Prophylactic colectomy, unlike surveillance colonoscopy, prevents death from colorectal cancer. Moreover, it is difficult to keep patients in surveillance programs, and those who withdraw from programs appear to be at high risk of developing cancer. Prophylactic colectomy should be strongly considered for patients with dysplasia, sclerosing cholangitis, longstanding pancolitis (especially if it began early in life) or a positive family history of colorectal cancer. This procedure is underused in clinical practice and is a good alternative to colonoscopic surveillance in high risk patients.


Venezuela's humanitarian crisis, resurgence of vector-borne diseases, and implications for spillover in the region.
In the past 5-10 years, Venezuela has faced a severe economic crisis, precipitated by political instability and declining oil revenue. Public health provision has been affected particularly. In this Review, we assess the impact of Venezuela's health-care crisis on vector-borne diseases, and the spillover into neighbouring countries. Between 2000 and 2015, Venezuela witnessed a 359% increase in malaria cases, followed by a 71% increase in 2017 (411 586 cases) compared with 2016 (240 613). Neighbouring countries, such as Brazil, have reported an escalating trend of imported malaria cases from Venezuela, from 1538 in 2014 to 3129 in 2017. In Venezuela, active Chagas disease transmission has been reported, with seroprevalence in children (<10 years), estimated to be as high as 12·5% in one community tested (n=64). Dengue incidence increased by more than four times between 1990 and 2016. The estimated incidence of chikungunya during its epidemic peak is 6975 cases per 100 000 people and that of Zika virus is 2057 cases per 100 000 people. The re-emergence of many vector-borne diseases represents a public health crisis in Venezuela and has the possibility of severely undermining regional disease elimination efforts. National, regional, and global authorities must take action to address these worsening epidemics and prevent their expansion beyond Venezuelan borders.


A methodology for inferring the causes of observed impairments in aquatic ecosystems.
Biological surveys have become a common technique for determining whether aquatic communities have been injured. However, their results are not useful for identifying management options until the causes of apparent injuries have been identified. Techniques for determining causation have been largely informal and ad hoc. This paper presents a logical system for causal inference. It begins by analyzing the available information to generate causal evidence; available information may include spatial or temporal associations of potential cause and effect, field or laboratory experimental results, and diagnostic evidence from the affected organisms. It then uses a series of three alternative methods to infer the cause: Elimination of causes, diagnostic protocols, and analysis of the strength of evidence. If the cause cannot be identified with sufficient confidence, the reality of the effects is examined, and if the effects are determined to be real, more information is obtained to reiterate the process.


Posterior reperfusion T-waves: Wellens' syndrome of the posterior wall.
Reperfusion after coronary occlusion (myocardial infarction, MI), as in Wellens' syndrome, is often represented on ECG as T-wave inversion in the leads overlying the affected myocardial wall(s). As an extension of this logic, reperfusion of the posterior wall should manifest on right precordial leads (which are opposite the posterior wall) as enlarged T-waves. We sought to determine whether T-wave amplitude (TWa) in leads V2 and V3 after reperfusion in posterior MI (PMI) is greater than in patients without PMI. Review of ECGs from patients with ST elevation MI of the left circumflex or right coronary artery with post-procedure thrombolysis in MI (TIMI) flow >0 between 2007 and 2009. Blinded experts reviewed admission ECGs to determine the presence of PMI and measure TWa before and after reperfusion. Maximum TWa in V2 and V3 and the difference between maximum and admission V2 and V3 TWa were compared between those with and without PMI. Of 72 patients, 48 had PMI. Values expressed are medians and IQRs. Maximum TWa after reperfusion was greater in PMI than in non-PMI in V2 (5.00 mm (3.5 to 8.25) vs 3.9 mm (2.75 to 5.5), p=0.04), but not in V3 (4.0 mm (2 to 5.5) vs 3.0 mm (1.75 to 4), p=0.09). The increase in TWa in V2 and V3 after reperfusion was greater in PMI compared with non-PMI: (V2, 3.4 mm (2 to 5.25) vs 1.25 mm (-0.25 to 2), p=0.0005; V3, 2 mm (-0.5 to 3.25) vs 0.25 mm (-1 to 1.75), p=0.03). Reperfusion of the posterior wall results in higher right precordial TWa, and an even greater increase in TWa, as measured in leads V2 and V3. This observation has important implications for emergency physicians to accurately identify recent posterior infarction in patients who may be symptom free on presentation but at risk of reocclusion.


Two side chains, three supramolecules: exploration of fluorenone derivatives towards crystal engineering.
Structural diversity obtained through two-dimensional molecular self-assembly induced by the chain length effect has gained immense attention, not only because of its significance in crystal engineering but also for its potential application in nanoscience and nanotechnology. Three kinds of fluorenone derivative, named F-C7C7, F-C14C7, and F-C14C14, were synthesized and used for systematic exploration of their crystalline difference. At first, scanning electron microscopy and X-ray powder diffraction were performed to investigate their differences in morphology and three-dimensional crystal structure. Then scanning tunneling microscopy experiments were conducted to compare the self-assembled monolayers. Moreover, different solvents were used to repeatedly investigate the occurrence of structural diversity. F-C7C7 could not self-assemble into a stable monolayer on the graphite surface under ambient conditions due to its weak molecule-substrate interaction. F-C14C7 was observed to self-assemble into twist, plier-like, octamer-curve, and random structures in 1-octanoic acid, 1-phenyloctane, n-tetradecane, and dichloromethane, respectively. However, when the same solvents were used and at similar concentrations, the F-C14C14 molecules were arranged into interval, mixed, linear, and plier-like configurations. These self-assembled nanopatterns formed under the driving forces of dipole-dipole interactions, hydrogen bonds, and chain-chain, molecule-substrate, and molecule-solvent van der Waals interactions. Furthermore, from the viewpoint of thermal analysis, differential scanning calorimetry, as well as polarized optical microscopy, was performed to further elucidate the difference between these three compounds in the solid and liquid crystal states. The present system is believed to provide understanding of how the chain length effect induces different crystalline properties, and to open up the possibility of fabricating diverse self-assembled networks for crystal engineering.


Effects of biofeedback-aided relaxation on the psychological stress symptoms of college students.
The purpose of this study was to compare the effects of Benson's relaxation technique (BRT) with Benson's technique augmented with GSR biofeedback (i.e., biofeedback-aided relaxation, BAR) on the psychological stress symptoms of well college students. Seventy-eight normotensive college students were randomly assigned to one of three groups: the BRT group, the BAR group, and a control group. The BRT and BAR students were asked to practice their respective relaxation technique daily for an eight-week period. Pre- and postintervention, all subjects were administered a state-anxiety inventory and a profile-of-mood state (POMS) test. Posttest analysis indicated that the BAR group had significantly lower state anxiety and POMS than the BRT and control groups (p less than 0.05). It was evident from the results that BAR did augment BRT in lowering psychological stress symptoms. Part of the effectiveness was due to the expectation of relief on the part of the BAR group. It was recommended that nurses study the effects of BAR in clinical settings.


Bayesian optimization for conformer generation.
Generating low-energy molecular conformers is a key task for many areas of computational chemistry, molecular modeling and cheminformatics. Most current conformer generation methods primarily focus on generating geometrically diverse conformers rather than finding the most probable or energetically lowest minima. Here, we present a new stochastic search method called the Bayesian optimization algorithm (BOA) for finding the lowest energy conformation of a given molecule. We compare BOA with uniform random search, and systematic search as implemented in Confab, to determine which method finds the lowest energy. Energetic difference, root-mean-square deviation, and torsion fingerprint deviation are used to quantify the performance of the conformer search algorithms. In general, we find BOA requires far fewer evaluations than systematic or uniform random search to find low-energy minima. For molecules with four or more rotatable bonds, Confab typically evaluates [Formula: see text] (median) conformers in its search, while BOA only requires [Formula: see text] energy evaluations to find top candidates. Despite using evaluating fewer conformers, 20-40% of the time BOA finds lower-energy conformations than a systematic Confab search for molecules with four or more rotatable bonds.


An Altered aroA Gene Product Confers Resistance to the Herbicide Glyphosate.
The hypothesis that the herbicide glyphosate (N-phosphonomethylglycine) acts on plants and microorganisms by inhibiting synthesis of 5-enolpyruvyl-3-phosphoshikimate, a precursor to aromatic amino acids, was tested. Salmonella typhimurium was treated with ethyl methanesulfonate, and mutants mapping at the aroA locus, which encodes 5-enolpyruvyl-3-phosphoshikimate synthetase, were isolated by selection for glyphosate resistance. One of the mutants results in the synthesis of a 5-enolpyruvyl-3-phosphoshikimate synthetase that is resistant to inhibition by glyphosate. The mutant aroA gene and the corresponding wild-type allele were cloned. The mutation confers high resistance to glyphosate when introduced in Escherichia coli in the presence or absence of the wild-type aroA allele.