Fruit load modulates flowering-related gene expression in buds of alternate-bearing 'Moncada' mandarin.
Gene determination of flowering is the result of complex interactions involving both promoters and inhibitors. In this study, the expression of flowering-related genes at the meristem level in alternate-bearing citrus trees is analysed, together with the interplay between buds and leaves in the determination of flowering. First defruiting experiments were performed to manipulate blossoming intensity in 'Moncada' mandarin, Citrus clementina. Further defoliation was performed to elucidate the role leaves play in the flowering process. In both cases, the activity of flowering-related genes was investigated at the flower induction (November) and differentiation (February) stages. Study of the expression pattern of flowering-genes in buds from on (fully loaded) and off (without fruits) trees revealed that homologues of FLOWERING LOCUS T (CiFT), TWIN SISTER OF FT (TSF), APETALA1 (CsAP1) and LEAFY (CsLFY) were negatively affected by fruit load. CiFT and TSF activities showed a marked increase in buds from off trees through the study period (ten-fold in November). By contrast, expression of the homologues of the flowering inhibitors of TERMINAL FLOWER 1 (CsTFL), TERMINAL FLOWER 2 (TFL2) and FLOWERING LOCUS C (FLC) was generally lower in off trees. Regarding floral identity genes, the increase in CsAP1 expression in off trees was much greater in buds than in leaves, and significant variations in CsLFY expression (approx. 20 %) were found only in February. Defoliation experiments further revealed that the absence of leaves completely abolished blossoming and severely affected the expression of most of the flowering-related genes, particularly decreasing the activity of floral promoters and of CsAP1 at the induction stage. These results suggest that the presence of fruit affects flowering by greatly altering gene-expression not only at the leaf but also at the meristem level. Although leaves are required for flowering to occur, their absence strongly affects the activity of floral promoters and identity genes.


Phytoestrogens and breast cancer--promoters or protectors?
The majority of breast cancers are oestrogen dependent and in postmenopausal women the supply of oestrogens in breast tissue is derived from the peripheral conversion of circulating androgens. There is, however, a paradox concerning the epidemiology of breast cancer and the dietary intake of phytoestrogens that bind weakly to oestrogen receptors and initiate oestrogen-dependent transcription. In Eastern countries, such as Japan, the incidence of breast cancer is approximately one-third that of Western countries whilst their high dietary intake of phytoestrogens, mainly in the form of soy products, can produce circulating levels of phytoestrogens that are known experimentally to have oestrogenic effects. Indeed, their weak oestrogenicity has been used to advantage by herbalist medicine to promote soy products as a natural alternative to conventional hormone replacement therapy (HRT). Such usage could increase in light of recent evidence that long-term HRT usage may be associated with an increased risk of breast cancer with a consequent reduction in prescription rates. So, are phytoestrogens safe as a natural alternative to HRT and could they be promoters or protectors of breast cancer? If they are promoters, then we must assume that it is due to their oestrogenic effect. If they are protectors, then other actions of phytoestrogens, including their ability to inhibit enzymes that are responsible for converting androgens and weak oestrogens into oestradiol, must be considered. This paper addresses these questions by reviewing the actions of phytoestrogens on oestrogen receptors and key enzymes that convert androgens to oestrogens in relation to the growth of breast cancer cells. In addition, it compares the experimental and epidemiological evidence pertinent to the potential beneficial or harmful effects of phytoestrogens in relation to the incidence/progression of breast cancer and their efficacy as natural alternatives to conventional HRT.


Listeria meningitis: a case study.
This case illustrates that L monocytogenes should always be considered as a potential cause of clinical meningitis, especially in an immunocompromised patient. The incidence of undetected or misdiagnosed Listeria organisms (as revealed in autopsies) is high enough that extra caution should be taken to ensure that an organism is not simply disregarded as a contaminant.


Cardiac coherence and posttraumatic stress disorder in combat veterans.
The need for treatment of posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing concern. PTSD has been associated with reduced cardiac coherence (an indicator of heart rate variability [HRV]) and deficits in early stage information processing (attention and immediate memory) in different studies. However, the co-occurrence of reduced coherence and cognition in combat veterans with PTSD has not been studied before. A pilot study was undertaken to assess the covariance of coherence and information processing in combat veterans. An additional study goal was assessment of effects of HRV biofeedback (HRVB) on coherence and information processing in these veterans. A two-group (combat veterans with and without PTSD), pre-post study of coherence and information processing was employed with baseline psychometric covariates. The study was conducted at a VA Medical Center outpatient mental health clinic. Five combat veterans from Iraq or Afghanistan with PTSD and five active-duty soldiers with comparable combat exposure who were without PTSD. Participants met with an HRVB professional once weekly for 4 weeks and received visual feedback in HRV patterns while receiving training in resonance frequency breathing and positive emotion induction. Cardiac coherence, word list learning, commissions (false alarms) in go-no go reaction time, digits backward. Cardiac coherence was achieved in all participants, and the increase in coherence ratio was significant post-HRVB training. Significant improvements in the information processing indicators were achieved. Degree of increase in coherence was the likely mediator of cognitive improvement. Cardiac coherence is an index of strength of control of parasympathetic cardiac deceleration in an individual that has cardinal importance for the individual's attention and affect regulation.


Plasticizing Effects of Polyamines in Protein-Based Films.
Zeta potential and nanoparticle size were determined on film forming solutions of native and heat-denatured proteins of bitter vetch as a function of pH and of different concentrations of the polyamines spermidine and spermine, both in the absence and presence of the plasticizer glycerol. Our results showed that both polyamines decreased the negative zeta potential of all samples under pH 8.0 as a consequence of their ionic interaction with proteins. At the same time, they enhanced the dimension of nanoparticles under pH 8.0 as a result of macromolecular aggregations. By using native protein solutions, handleable films were obtained only from samples containing either a minimum of 33 mM glycerol or 4 mM spermidine, or both compounds together at lower glycerol concentrations. However, 2 mM spermidine was sufficient to obtain handleable film by using heat-treated samples without glycerol. Conversely, brittle materials were obtained by spermine alone, thus indicating that only spermidine was able to act as an ionic plasticizer. Lastly, both polyamines, mainly spermine, were found able to act as "glycerol-like" plasticizers at concentrations higher than 5 mM under experimental conditions at which their amino groups are undissociated. Our findings open new perspectives in obtaining protein-based films by using aliphatic polycations as components.


Species packing and the latitudinal gradient in beta-diversity.
The decline in species richness at higher latitudes is among the most fundamental patterns in ecology. Whether changes in species composition across space (beta-diversity) contribute to this gradient of overall species richness (gamma-diversity) remains hotly debated. Previous studies that failed to resolve the issue suffered from a well-known tendency for small samples in areas with high gamma-diversity to have inflated measures of beta-diversity. Here, we provide a novel analytical test, using beta-diversity metrics that correct the gamma-diversity and sampling biases, to compare beta-diversity and species packing across a latitudinal gradient in tree species richness of 21 large forest plots along a large environmental gradient in East Asia. We demonstrate that after accounting for topography and correcting the gamma-diversity bias, tropical forests still have higher beta-diversity than temperate analogues. This suggests that beta-diversity contributes to the latitudinal species richness gradient as a component of gamma-diversity. Moreover, both niche specialization and niche marginality (a measure of niche spacing along an environmental gradient) also increase towards the equator, after controlling for the effect of topographical heterogeneity. This supports the joint importance of tighter species packing and larger niche space in tropical forests while also demonstrating the importance of local processes in controlling beta-diversity.


Breast feeding and child behaviour in the Millennium Cohort Study.
To examine whether breast feeding is associated with behavioural development in children aged 5 years. The authors used data from a large, prospective, nationally representative UK cohort, the Millennium Cohort Study. 10 037 mother-child pairs from white ethnic background (9525 term and 512 preterm children) were included in the analyses. Duration of breast feeding (at all or exclusively) was ascertained from parental interview at study baseline, when the children were aged 9 months. Child behaviour was assessed using a parent-completed questionnaire, the Strengths and Difficulties Questionnaire (SDQ). The authors used logistic regression to investigate the associations of breastfeeding duration with abnormal parent-rated SDQ total and subscores at age 5 in term and preterm children separately. Abnormal SDQ scores were less common in term children (n=1129/9525, 12%) than pre-term (n=78/512, 15%) children. Term children breast fed for 4 months or longer (n=2741/9525, 29%) had lower odds of an abnormal total SDQ score (multivariable-adjusted OR compared with never breastfed children (n=3292/9525, 35%) 0.67, 95% CI: 0.54 to 0.83). This effect was similar for all the SDQ subscores. In preterm children, longer duration of breast feeding was generally associated with lower odds of abnormal SDQ total and subscores but the effect estimates were imprecise. The associations between exclusive breast feeding and abnormal SDQ scores were similar to those of any breast feeding and abnormal SDQ scores. The findings suggest that, at least in term children, longer duration of breast feeding is associated with fewer parent-rated behavioural problems in children aged 5 years.


Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation.
The small heat shock proteins (sHsps) from human (Hsp27) and mouse (Hsp25) form large oligomers which can act as molecular chaperones in vitro and protect cells from heat shock and oxidative stress when overexpressed. In addition, mammalian sHsps are rapidly phosphorylated by MAPKAP kinase 2/3 at two or three serine residues in response to various extracellular stresses. Here we analyze the effect of sHsp phosphorylation on its quaternary structure, chaperone function, and protection against oxidative stress. We show that in vitro phosphorylation of recombinant sHsp as well as molecular mimicry of Hsp27 phosphorylation lead to a significant decrease of the oligomeric size. We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. In parallel, Hsp27 and its mutants were analyzed for their ability to confer resistance against oxidative stress when overexpressed in L929 and 13.S.1.24 cells. While wild type Hsp27 confers resistance, the triple mutant S15D,S78D,S82D cannot protect against oxidative stress effectively. These data indicate that large oligomers of sHsps are necessary for chaperone action and resistance against oxidative stress whereas phosphorylation down-regulates these activities by dissociation of sHsp complexes to tetramers.


Predictors of poor reading performance in student-athletes following sport-related concussion.
The goal of the current study was to determine which sport/recreation-related concussion (SRC) assessments predict academic reading performance following SRC. The study included 70 concussed students aged 14-22 years (M = 16.21, SD = 1.90) evaluated 2-30 days (M = 8.41, SD = 5.88) post-injury. SRC assessments included: Post-Concussion Symptom Scale, Immediate Post-Concussion Assessment and Cognitive Testing, Vestibular/Ocular Motor Screening, and King-Devick test. The Nelson-Denny Reading Test (NDRT) comprehension subtest measured academic reading accuracy and rate. Pearson correlations examined relationships among SRC assessments and reading accuracy/rate; those assessments that significantly correlated with the NDRT were included in multiple regressions (MRs) predicting reading accuracy and reading rate. Results supported positive correlations between visual motor speed and reading accuracy (r = .31, p = .01), and near point of convergence (NPC) and reading rate (r = .30, p = .01). The MRs for reading accuracy (F = 4.61, p = .01) and reading rate (F = 4.61, p = .01) were significant, and predicted approximately 40% of the variance, with visual motor speed and NPC as the only significant predictors in both models. Symptoms were not predictive of reading accuracy or rate. The present study indicates that visual motor speed and NPC are predictive of academic reading performance after SRC, suggesting clinicians should consider these clinical outcomes to better inform academic accommodations.


Protective Effects of Tormentic Acid, a Major Component of Suspension Cultures of Eriobotrya japonica Cells, on Acetaminophen-Induced Hepatotoxicity in Mice.
An acetaminophen (APAP) overdose can cause hepatotoxicity and lead to fatal liver damage. The hepatoprotective effects of tormentic acid (TA) on acetaminophen (APAP)-induced liver damage were investigated in mice. TA was intraperitoneally (i.p.) administered for six days prior to APAP administration. Pretreatment with TA prevented the elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-Bil), total cholesterol (TC), triacylglycerol (TG), and liver lipid peroxide levels in APAP-treated mice and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, TA attenuated the APAP-induced production of nitric oxide (NO), reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and IL-6. Furthermore, the Western blot analysis showed that TA blocked the protein expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as the inhibition of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) activation in APAP-injured liver tissues. TA also retained the superoxidase dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the liver. These results suggest that the hepatoprotective effects of TA may be related to its anti-inflammatory effect by decreasing thiobarbituric acid reactive substances (TBARS), iNOS, COX-2, TNF-α, IL-1β, and IL-6, and inhibiting NF-κB and MAPK activation. Antioxidative properties were also observed, as shown by heme oxygenase-1 (HO-1) induction in the liver, and decreases in lipid peroxides and ROS. Therefore, TA may be a potential therapeutic candidate for the prevention of APAP-induced liver injury by inhibiting oxidative stress and inflammation.


Designing biomimetic pores based on carbon nanotubes.
Biomimetic nanopores based on membrane-spanning single-walled carbon nanotubes have been designed to include selectivity filters based on combinations of anionic and cationic groups mimicking those present in bacterial porins and in voltage-gated sodium and calcium channels. The ion permeation and selectivity properties of these nanopores when embedded in a phospholipid bilayer have been explored by molecular dynamics simulations and free energy profile calculations. The interactions of the nanopores with sodium, potassium, calcium, and chloride ions have been explored as a function of the number of anionic and cationic groups within the selectivity filter. Unbiased molecular dynamics simulations show that the overall selectivity is largely determined by the net charge of the filter. Analysis of distribution functions reveals considerable structuring of the distribution of ions and water within the nanopores. The distributions of ions along the pore axis reveal local selectivity for cations around filter, even in those nanopores (C0) where the net filter charge is zero. Single ion free energy profiles also reveal clear evidence for cation selectivity, even in the C0 nanopores. Detailed analysis of the interactions of the C0 nanopore with Ca(2+) ions reveals that local interactions with the anionic (carboxylate) groups of the selectivity filter lead to (partial) replacement of solvating water as the ion passes through the pore. These studies suggest that a computational biomimetic approach can be used to evaluate our understanding of the design principles of nanopores and channels.


Excreted-secreted antigens of Toxoplasma gondii inhibit Foxp3 via IL-2Rγ/JAK3/Stats pathway.
Toxoplasma gondii excreted-secreted antigens (ESA) could lead to the fetal abortion especially in the early stage of pregnancy. Deficit in regulatory T cells is a critical event in the fetal abortion. Transcription factor forkhead box p3 (Foxp3) mediates differentiation and functional roles on regulatory T cells. Previously, we revealed that ESA inhibited Foxp3 through the suppression of transforming growth factor-β type II receptor, phosphorylation of Smad2, Smad3, and Smad4. Knockdown of Smad2 collaborated with ESA to further inhibit Foxp3. The decrease in Foxp3 caused by ESA reversed via forced expression of Smad2, Smad3, and Smad4, respectively. In this study, we investigate whether other signaling pathways are implicated in ESA-induced Foxp3 downregulation. EL4 cells were cultured and stimulated with ESA. Interleukin-2 receptor γ (IL-2Rγ) chain, Janus kinase 3 (JAK3), signal transducer and activator of transcription 5 (Stat5), Stat3, phosphorylation of Stat5 and Stat3 were assayed by Western blot analysis. Phosphorylation of Stat5 and Stat3 was further measured by cellular immunofluorescence. The expression plasmid of pcDNA3.1-Stat3 and pcDNA3.1-Stat5b was constructed, respectively. The concentration of interleukin-2 (IL-2) in the culture supernatants was detected by enzyme-linked immunosorbent assay. ESA inhibited the level of JAK3, phosphorylation of Stat5 and Stat3, and Foxp3 in EL4 cells. The suppressive effects of ESA on Foxp3 were attenuated by forced expression of Stat5 and Stat3. In addition, ESA suppressed IL-2Rγ in EL4 cells, while IL-2Rγ agonist could markedly reverse the diminished Foxp3 caused by ESA. Furthermore, ESA directly influenced the expression of IL-2Rγ, rather than the availability of IL-2 indirectly. ESA suppressed the level of Foxp3 via inhibiting IL-2Rγ/JAK3/Stats signaling pathway in EL4 cells.


Mononuclear cells in human lung parenchyma. Characterization of a potent accessory cell not obtained by bronchoalveolar lavage.
Human alveolar macrophages from bronchoalveolar lavage are usually poor accessory cells for antigen-induced T-lymphocyte proliferation and poor stimulators of allogeneic mixed leukocyte reactions (MLR) when compared to peripheral blood monocytes. In contrast, cells harvested from minced lungs are good stimulators of a MLR. We have characterized the accessory cells obtained after enzymatic digestion of human lung tissue. Pulmonary mononuclear cells were separated from the dissociated lung cell mixture on Ficoll-Hypaque. Loosely adherent cells (LAM) were obtained after an overnight incubation on plastic culture dishes of initially adherent mononuclear cells. LAM were significantly more effective than were pulmonary mononuclear cells (p less than 0.05), firmly adherent cells (p less than 0.05), alveolar macrophages obtained by bronchoalveolar lavage (p less than 0.05), or monocytes (p less than 0.05) in stimulating allogeneic resting T-cells. Addition of indomethacin and catalase markedly improved T-cell proliferation induced by LAM. Enrichment for Fc receptor negative or for nonphagocytic cells further enhanced the MLR-stimulating capacity of LAM. Phase-contrast studies demonstrated an enrichment in cells compatible with dendritic cells in LAM as compared to firmly adherent cells. We conclude that there are potent accessory cells in human lung that are loosely adherent, Fc receptor negative, and poorly phagocytic, and thus are dissimilar from classic macrophages. We hypothesize that cells similar to dendritic cells might play a role in the initiation of immune responses in lung parenchyma.


Imaging studies in metastatic urogenital cancer patients undergoing systemic therapy: recommendations of a multidisciplinary consensus meeting of the Association of Urological Oncology of the German Cancer Society.
Imaging studies are an integral and important diagnostic modality to stage, to monitor and follow-up patients with metastatic urogenital cancer. The currently available guidelines on diagnosis and treatment of urogenital cancer do not provide the clinician with evidence-based recommendations for daily practice. To develop scientifically valid recommendations with regard to the most appropriate imaging technique and the most useful time interval in metastatic urogenital cancer patients undergoing systemic therapy. A systematic literature review was performed searching MedLine, Embase and Web of Science databases using the terms prostate, renal cell, bladder and testis cancer in combination with the variables lymph node, lung, liver, bone metastases, chemotherapy and molecular therapy, and the search terms computed tomography, magnetic resonance imaging and positron emission tomography were applied. A total of 11,834 records were retrieved from all databases. The panel reviewed the records to identify articles with the highest level of evidence using the recommendation of the US Agency for Health Care Policy and Research. Contrast-enhanced computed tomography remains the standard imaging technique for monitoring of pulmonary, hepatic and lymph node metastases. Bone scintigraphy is still the most widely used imaging technique for the detection and follow-up of osseous lesions. For clinical trials it might be replaced by either PET-CT or MRI of the skeletal axis. Response assessment for patients treated with cytotoxic regime is best performed by the RECIST/WHO criteria; treatment response to molecular triggered therapy is best assessed by CT evaluating decrease in tumor size and density. Cross-sectional imaging studies for response assessment might be obtained after each 2 cycles of systemic therapy to early stratify responders from non-responders.


Continuous Exposure to 1.7 GHz LTE Electromagnetic Fields Increases Intracellular Reactive Oxygen Species to Decrease Human Cell Proliferation and Induce Senescence.
Due to the rapid development of mobile phone technology, we are continuously exposed to 1.7 GHz LTE radio frequency electromagnetic fields (RF-EMFs), but their biological effects have not been clarified. Here, we investigated the non-thermal cellular effects of these RF-EMFs on human cells, including human adipose tissue-derived stem cells (ASCs), Huh7 and Hep3B liver cancer stem cells (CSCs), HeLa and SH-SY5Y cancer cells, and normal fibroblast IMR-90 cells. When continuously exposed to 1.7 GHz LTE RF-EMF for 72 h at 1 and 2 SAR, cell proliferation was consistently decreased in all the human cells. The anti-proliferative effect was higher at 2 SAR than 1 SAR and was less severe in ASCs. The exposure to RF-EMF for 72 h at 1 and 2 SAR did not induce DNA double strand breaks or apoptotic cell death, but did trigger a slight delay in the G1 to S cell cycle transition. Cell senescence was also clearly observed in ASC and Huh7 cells exposed to RF-EMF at 2 SAR for 72 h. Intracellular ROS increased in these cells and the treatment with an ROS scavenger recapitulated the anti-proliferative effect of RF-EMF. These observations strongly suggest that 1.7 GHz LTE RF-EMF decrease proliferation and increase senescence by increasing intracellular ROS in human cells.


Evaluating fibre orientation dispersion in white matter: Comparison of diffusion MRI, histology and polarized light imaging.
Diffusion MRI is an exquisitely sensitive probe of tissue microstructure, and is currently the only non-invasive measure of the brain's fibre architecture. As this technique becomes more sophisticated and microstructurally informative, there is increasing value in comparing diffusion MRI with microscopic imaging in the same tissue samples. This study compared estimates of fibre orientation dispersion in white matter derived from diffusion MRI to reference measures of dispersion obtained from polarized light imaging and histology. Three post-mortem brain specimens were scanned with diffusion MRI and analyzed with a two-compartment dispersion model. The specimens were then sectioned for microscopy, including polarized light imaging estimates of fibre orientation and histological quantitative estimates of myelin and astrocytes. Dispersion estimates were correlated on region - and voxel-wise levels in the corpus callosum, the centrum semiovale and the corticospinal tract. The region-wise analysis yielded correlation coefficients of r = 0.79 for the diffusion MRI and histology comparison, while r = 0.60 was reported for the comparison with polarized light imaging. In the corpus callosum, we observed a pattern of higher dispersion at the midline compared to its lateral aspects. This pattern was present in all modalities and the dispersion profiles from microscopy and diffusion MRI were highly correlated. The astrocytes appeared to have minor contribution to dispersion observed with diffusion MRI. These results demonstrate that fibre orientation dispersion estimates from diffusion MRI represents the tissue architecture well. Dispersion models might be improved by more faithfully incorporating an informed mapping based on microscopy data.


Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5.
HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.


Paper-based fluorogenic RNA aptamer sensors for label-free detection of small molecules.
Sensors based on fluorogenic RNA aptamers have emerged in recent years. These sensors have been used for in vitro and intracellular detection of a broad range of biological and medical targets. However, the potential application of fluorogenic RNA-based sensors for point-of-care testing is still little studied. Here, we report a paper substrate-based portable fluorogenic RNA sensor system. Target detection can be simply performed by rehydration of RNA sensor-embedded filter papers. This affordable sensor system can be used for the selective, sensitive, and rapid detection of different target analytes, such as antibiotics and cellular signaling molecules. We believe that these paper-based fluorogenic RNA sensors show great potential for point-of-care testing of a wide range of targets from small molecules, nucleic acids, proteins, to various pathogens.


Molecular characterization of MHC class II in a nonmodel anuran species, the fire-bellied toad Bombina bombina.
While the anuran Xenopus comprises one of the best characterized nonmammalian taxa regarding the major histocompatibility complex (MHC), the organization of this gene complex has never been studied in other anurans, and information on amphibian MHC (other than Xenopus) is generally very scarce. Here, we describe the characterization of the first MHC class II B cDNA sequences from a nonmodel anuran species, the European fire-bellied toad (Bombina bombina). We isolated two transcript sequences differing substantially in amino acid composition and length within the beta2 domain. To investigate the variability of the peptide binding region in this species, we sequenced a 158-bp large fragment from wild B. bombina (n = 20) and identified eight distinct alleles. All substitutions but one were nonsynonymous, and many of the highly polymorphic sites corresponded with amino acid positions known to be involved in antigen binding. The level of variation we found in B. bombina was similar compared to that previously found in a comparable sample of a wild urodelan species, Ambystoma tigrinum, and to that found in Xenopus laevis. Based on the cDNA data and the individual's allelic diversity, we conclude that Bombina possesses at least two class II B loci. With our new beta1 primers, we were able to generate sequences in other species of anurans. We provide here a first phylogenetic analysis of this gene in amphibians.


The kinases PIG-1 and PAR-1 act in redundant pathways to regulate asymmetric division in the EMS blastomere of C. elegans.
The PAR-1 kinase of C. elegans is localized to the posterior of the one-cell embryo and its mutations affect asymmetric spindle placement and partitioning of cytoplasmic components in the first cell cycle. However, par-1 mutations do not cause failure to restrict the anterior PAR polarity complex to the same extent as mutations in the posteriorly localized PAR-2 protein. Further, it has been difficult to examine the role of PAR-1 in subsequent divisions due to the early defects in par-1 mutant embryos. Here we show that the PIG-1 kinase acts redundantly with PAR-1 to restrict the anterior PAR-3 protein for normal polarity in the one-cell embryo. By using a temperature sensitive allele of par-1, which exhibits enhanced lethality when combined with a pig-1 mutation, we have further explored roles for these genes in subsequent divisions. We find that both PIG-1 and PAR-1 regulate spindle orientation in the EMS blastomere of the four-cell stage embryo to ensure that it undergoes an asymmetric division. In this cell, PIG-1 and PAR-1 act in parallel pathways for spindle positioning, PIG-1 in the MES-1/SRC-1 pathway and PAR-1 in the Wnt pathway.


Health in the new scenarios for climate change research.
The climate change research community is developing a toolkit for creating new scenarios to explore and evaluate the extensive uncertainties associated with future climate change and development pathways. Components of the toolkit include pathways for greenhouse gas emissions over this century and their associated magnitude and pattern of climate change; descriptions of a range of possible socioeconomic development pathways, including qualitative narratives and quantitative elements; and climate change policies to achieve specific levels of radiative forcing and levels of adaptive capacity. These components are combined within a matrix architecture to create a scenario. Five reference socioeconomic development pathways have been described along axes describing increasing socioeconomic and environmental challenges to adaptation and to mitigation. This paper extends these global pathways to describe their possible consequences for public health and health care, and considers the additional elements that could be added to increase the relevance of the new scenarios to address a wider range of policy relevant questions than previously possible.


The 17th International Congress on Infectious Diseases workshop on developing infection prevention and control resources for low- and middle-income countries.
Hospital-acquired infections (HAIs) are a major concern to healthcare systems around the world. They are associated with significant morbidity and mortality, in addition to increased hospitalization costs. Recent outbreaks, including those caused by the Middle East respiratory syndrome coronavirus and Ebola virus, have highlighted the importance of infection control. Moreover, HAIs, especially those caused by multidrug-resistant Gram-negative rods, have become a top global priority. Although adequate approaches and guidelines have been in existence for many years and have often proven effective in some countries, the implementation of such approaches in low- and middle-income countries (LMICs) is often restricted due to limited resources and underdeveloped infrastructure. While evidence-based infection prevention and control (IPC) principles and practices are universal, studies are needed to evaluate simplified approaches that can be better adapted to LMIC needs, in order to guide IPC in practice. A group of experts from around the world attended a workshop held at the 17th International Congress on Infectious Diseases in Hyderabad, India in March 2016, to discuss the existing IPC practices in LMICs, and how best these can be improved within the local context.


Carotid endarterectomy benefits patients with CKD and symptomatic high-grade stenosis.
Endarterectomy is generally recommended for symptomatic high-grade (70 to 99%) stenosis of the internal carotid artery, but whether this procedure is beneficial among patients with chronic kidney disease (CKD) is unknown. In this re-analysis of data from the North American Symptomatic Carotid Endarterectomy Trial, we included patients with symptomatic stenosis and either stage 3 CKD (n = 524) or preserved kidney function (n = 966; estimated GFR > or = 60). For medically treated patients with high-grade stenosis, risk for ipsilateral stroke at 2 yr was significantly higher in patients with CKD than in those with preserved renal function (31.6 versus 19.3%; P = 0.042); carotid endarterectomy significantly reduced this risk by 82 and 51%, respectively. To prevent one ipsilateral stroke, the number needed to treat by endarterectomy was four for patients with CKD and 10 for patients with preserved renal function. Compared with patients with preserved renal function, those with CKD had similar rates of perioperative stroke and death but higher rates of cardiac events. In conclusion, patients with stage 3 CKD and symptomatic high-grade carotid stenosis gain a large benefit in stroke risk reduction after endarterectomy.


Policy Approaches for Regulating Alcohol Marketing in a Global Context: A Public Health Perspective.
Alcohol consumption is responsible for 3.3 million deaths globally or nearly 6% of all deaths. Alcohol use contributes to both communicable and noncommunicable diseases, as well as violence and injuries. The purpose of this review is to discuss, in the context of the expansion of transnational alcohol corporations and harms associated with alcohol use, policy options for regulating exposure to alcohol marketing. We first provide an overview of the public health problem of harmful alcohol consumption and describe the association between exposure to alcohol marketing and alcohol consumption. We then discuss the growth and concentration of global alcohol corporations and their marketing practices in low- and middle-income countries, as well as in higher-income societies. We review the use and effectiveness of various approaches for regulating alcohol marketing in various countries before discussing challenges and opportunities to protect public health.


A potentized homeopathic drug, Arsenicum Album 200, can ameliorate genotoxicity induced by repeated injections of arsenic trioxide in mice.
Groundwater arsenic contamination has become a menacing global problem. No drug is available until now to combat chronic arsenic poisoning. To examine if a potentized homeopathic remedy, Arsenicum Album-200, can effectively combat chronic arsenic toxicity induced by repeated injections of Arsenic trioxide in mice, the following experimental design was adopted. Mice (Mus musculus) were injected subcutaneously with 0.016% arsenic trioxide at the rate of 1 ml/100 g body weight, at an interval of 7 days until they were killed at day 30, 60, 90 or 120 and were divided into three groups: (i) one receiving a daily dose of Arsenicum Album-200 through oral administration, (ii) one receiving the same dose of diluted succussed alcohol (Alcohol-200) and (iii) another receiving neither drug, nor succussed alcohol. The remedy or the placebo, as the case may be, was fed from the next day onwards after injection until the day before the next injection, and the cycle was repeated until the mice were killed. Two other control groups were also maintained: one receiving only normal diet, and the other receiving normal diet and succussed alcohol. Several toxicity assays, such as cytogenetical (chromosome aberrations, micronuclei, mitotic index, sperm head anomaly) and biochemical (acid and alkaline phosphatases, lipid peroxidation), were periodically made. Compared with controls, the drug fed mice showed reduced toxicity at statistically significant levels in respect of all the parameters studied, thereby indicating protective potentials of the homeopathic drug against chronic arsenic poisoning.


A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.
Epileptic disorders affect about 20-40 million people worldwide, and 40% of these are idiopathic generalized epilepsies (IGEs; ref. 1). Most of the IGEs that are inherited are complex, multigenic diseases. To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-dominant mode of inheritance: the benign familial neonatal convulsions (BFNC; refs 2,3). Genetic heterogeneity of BFNC has been observed. Two loci, EBN1 and EBN2, have been mapped by linkage analysis to chromosome 20q13 (refs 5,6) and chromosome 8q24 (refs 7,8), respectively. By positional cloning, we recently identified the gene for EBN1 as KCNQ2 (ref. 9). This gene, a voltage-gated potassium channel, based on homology, is a member of the KQT-like family. Here we describe an additional member, KCNQ3. We mapped this new gene to chromosome 8, between markers D8S256 and D8S284 on a radiation hybrid map. We screened KCNQ3 for mutations in the large BFNC family previously linked to chromosome 8q24 in the same marker interval. We found a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype. The same conserved amino acid is also mutated in KVLQT1 (KCNQ1) in an LQT patient. KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs.


Adjunct mifepristone for cervical preparation prior to dilation and evacuation: a randomized trial.
The objective was to investigate mifepristone as a potential adjunct to cervical preparation for surgical abortion after 19 weeks of gestation, with the aim of improving procedure access, convenience and comfort. This is a site-stratified, block-randomized, noninferiority trial of 50 women undergoing surgical abortion between 19 and 23 6/7 weeks of gestation randomized to receive either one set of osmotic dilators plus mifepristone the day prior to procedure (mifepristone group) or two sets of osmotic dilators (placed 18-24 h apart) in the 2 days prior to procedure (control group). All subjects received preprocedure misoprostol. Primary outcome was procedure time. Secondary outcomes included preoperative cervical dilation, ease of procedure, and side effects and pain experienced by subjects. Mean gestational age was similar between groups (20 weeks); more nulliparous subjects were randomized to the mifepristone group (46% vs. 12%, p=.009). Mean procedure times were similar: mifepristone group 11:52 (SD 5:29) vs. control group 10:56 (SD 5:08); difference in means -56s, with confidence interval (95% CI -4:09 to +2:16) not exceeding the 5-min difference we a priori defined as clinically significant. Preprocedure cervical dilation did not differ and was >3cm for the majority of subjects in both groups. There was no difference (p=.6) in ease of procedure reported by providers. Preoperative (postmisoprostol) pain and postoperative pain levels were greater with mifepristone (p = 0.02 and p= 0.04 respectively). Overall subject experience was not different (p=0.80), with most reporting a "better than expected" experience. Mifepristone with one set of osmotic dilators and misoprostol did not result in longer procedure times or less cervical dilation than serial (two sets) of osmotic dilators and misoprostol, and has the potential to improve access to second trimester abortion without compromising safety. Use of mifepristone for cervical preparation before surgical abortion after 19 weeks allows for fewer visits and fewer osmotic dilators without compromising cervical dilation or increasing procedure time.


Proteolysis of the docking protein HEF1 and implications for focal adhesion dynamics.
The dynamic regulation of focal adhesions is implicated in cellular processes of proliferation, differentiation, migration, and apoptosis. The focal adhesion-associated docking protein HEF1 is cleaved by caspases during both mitosis and apoptosis. Common to both of these cellular processes is the loss of focal adhesions, transiently during mitosis and permanently during apoptosis. The proteolytic processing of HEF1 during both mitosis and apoptosis therefore posits a general role for HEF1 as a sensor of altered adhesion states. In this study, we find that HEF1 undergoes proteolytic processing specifically in response to cellular detachment, while HEF1 proteolysis is prevented by specific integrin receptor ligation and focal adhesion formation. We show that overexpression of a C-terminal caspase-derived 28-kDa HEF1 peptide causes cellular rounding that is demonstrably separable from apoptosis. Mutation of the divergent helix-loop-helix motif found in 28-kDa HEF1 significantly reduces the induction of apoptosis by this peptide, while deletion of the amino-terminal 28 amino acids of 28-kDa HEF1 completely abrogates the induction of apoptosis. Conversely, these mutations have no effect on the rounding induced by 28-kDa HEF1. Finally, we detect a novel focal adhesion targeting domain located in the C terminus of HEF1 and show that this activity is necessary for HEF1-induced cell spreading. Together, these data suggest that proteolytic and other posttranslational modifications of HEF1 in response to loss of adhesion serve to modulate the disassembly of focal adhesions.


Immature remains and the first partial skeleton of a juvenile Homo naledi, a late Middle Pleistocene hominin from South Africa.
Immature remains are critical for understanding maturational processes in hominin species as well as for interpreting changes in ontogenetic development in hominin evolution. The study of these subjects is hindered by the fact that associated juvenile remains are extremely rare in the hominin fossil record. Here we describe an assemblage of immature remains of Homo naledi recovered from the 2013-2014 excavation season. From this assemblage, we attribute 16 postcranial elements and a partial mandible with some dentition to a single juvenile Homo naledi individual. The find includes postcranial elements never before discovered as immature elements in the sub-equatorial early hominin fossil record, and contributes new data to the field of hominin ontogeny.


[Evaluation of two guidelines for the management of hyperbilirubinemia in newborn babies weighing less than 2,000 g].
To evaluate the use of two phototherapy guidelines for the treatment of hyperbilirubinemia in newborn babies weighing less than 2,000 g. Eighty-one newborn infants with birth weight less than 2,000 g were studied. They were divided in two groups: the "early" group, which started phototherapy 12 hours after birth, undergoing treatment for at least 96 hours; and the "late" group, which received phototherapy whenever the transcutaneous bilirubin reached 8 mg/dl and phototherapy suspended when bilirubin levels fell to 5 mg/dl. The following factors were analyzed: maintenance of transcutaneous bilirubin levels below 10 mg/dl, mean value of daily transcutaneous bilirubin, the highest transcutaneous bilirubin value and the period it first occurred, and duration of treatment. In the early group, 20% of all patients showed transcutaneous bilirubin level higher than 10 mg/dl compared to 60% of patients in the late group. The highest daily mean rate of transcutaneous bilirubin in the early group was 6.6 mg/dl, which happened on the 7th day. In the late group, it was 8.6 mg/dl on the 2nd day after birth. The median duration of phototherapy treatment used in the early group was 96 hours (minimum of 96 and maximum of 156 hours) and in the late group, 51 hours (minimum of zero and maximum of 120 hours). None of the babies needed changes in the treatment (double phototherapy or exchange transfusion). The use of early phototherapy treatment for babies weighing less than 2,000 g is safer when compared to the late group, considering satisfactory the maintenance of transcutaneous bilirubin levels below 10 mg/dl.


Effects of SR141716A on diazepam substitution for delta9-tetrahydrocannabinol in rat drug discrimination.
Interaction of cannabinoids with GABAergic systems has been noted in a number of previous studies. In the present study, this interaction was examined in a drug-discrimination paradigm. Rats were trained to discriminate either delta9-tetrahydrocannabinol (delta9-THC; 3 mg/kg) or diazepam (2.5 mg/kg) from vehicle in two-lever drug discrimination procedures for food reinforcement. As in previous studies, diazepam partially substituted for delta9-THC, but only at high doses that also decreased response rates. In contrast, delta9-THC did not substitute for diazepam in any of the rats. Hence, cross-generalization of these two drugs was asymmetrical. When tested in combination with diazepam, the brain cannabinoid (CB1) receptor antagonist SR141716A did not block the partial substitution of diazepam for delta9-THC, nor did it antagonize the discriminative stimulus effects of diazepam in diazepam-trained rats. These results suggest that the partial overlap in the discriminative stimulus effects of delta9-THC and diazepam is not mediated by diazepam action at CB1 receptors. However, the fact that diazepam produced partial substitution for delta9-THC is consistent with a GABAergic component to cannabinoid drug discrimination.


Hypaxial motor patterns and the function of epipubic bones in primitive mammals.
Since the first description of epipubic bones in 1698, their functions and those of the associated abdominal muscles of monotremes and marsupial mammals have remained unresolved. We show that each epipubic bone is part of a kinetic linkage extending from the femur, by way of the pectineus muscle, to the epipubic bone, through the pyramidalis and rectus abdominis muscles on one side of the abdomen, and through the contralateral external and internal oblique muscles to the vertebrae and ribs of the opposite side. This muscle series is activated synchronously as the femur and contralateral forelimb are retracted during the stance phase in locomotion. The epipubic bone acts as a lever that is retracted (depressed) to stiffen the trunk between the diagonal limbs that support the body during each step. This cross-couplet kinetic linkage and the stiffening function of the epipubic bone appear to be the primitive conditions for mammals.


Precision grip and Parkinson's disease.
In order to investigate sensorimotor processing and force development in Parkinson's disease, 16 patients, four patients with hemiparkinsonism and 12 age-matched normal subjects were assessed during lifting and holding of an object in a precision grip between thumb and forefinger, or holding the object in this grip at a fixed height above a table. In the former case, object loading could be changed between lifts without warning. In the latter case, unexpected step load changes to the object were applied to the object with a torque motor. All procedures could be applied with or without visual control of the hand and the object. Normal subjects lifted an unpredictable load employing the grip force parameters used in the preceding lift. If a load change was encountered, the parameters became adapted to the new conditions during the lift, modulating grip forces to match the loading. Parkinsonian patients retained this strategy and the ability to regulate grip forces according to load. Under all conditions, however, parkinsonian subjects developed abnormally high grip forces in both the lift and the hold phase, although the ratio of these forces remained normal. Lifting height was normal in parkinsonian subjects, but the duration of the lifting task was significantly prolonged, due to a marked slowing in the rate of grip force development in the lead-up to object lift-off and to prolongation of the movement phase. Forewarning of object loading, with or without visual control, did not reduce timing deficits or improve the rate of grip force development. However, it did allow parkinsonian subjects to reduce the safety margin significantly. Responses to step load changes imposed during holding without visual control showed minor abnormalities in the parkinsonian patients: onset latencies and EMG activity in the first dorsal interosseus and thenar muscles were normal up to 140 ms after displacement. Subsequent EMG activity in the first dorsal interosseus remained largely normal, but activity later in the slip response (140-210 ms), subject to voluntary influence, was reduced in the thenar muscle. Differences were less marked under visual conditions, but remained significant. We concluded that the internal parameter set for lifting an object in a precision grip and the automatic processes adapting precision grip to actual conditions are intact in Parkinson's disease. However, parkinsonian subjects generate abnormally high grip forces and require longer than normal subjects to complete a lift, particularly with lighter loads. This deterioration in performance reflects both reduced effectiveness of sensorimotor processing and impairment in the rate of force development in Parkinson's disease.


Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.
Caveolin-3, the muscle-specific isoform of caveolins, plays important roles in signal transduction. Dominant-negative mutations of the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) with loss of caveolin-3. However, identification of the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient muscle has remained elusive. Myostatin, a member of the muscle-specific TGF-beta superfamily, negatively regulates skeletal muscle volume. Here we report that caveolin-3 inhibited myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophosphorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of caveolin-3 in P104L mutant caveolin-3 transgenic mice caused muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a myostatin target gene. Introduction of the myostatin prodomain, an inhibitor of myostatin, by genetic crossing or intraperitoneal administration of the soluble type II myostatin receptor, another inhibitor, ameliorated muscular atrophy of the mutant caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that caveolin-3 normally suppresses the myostatin-mediated signal, thereby preventing muscular atrophy, and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in a mouse model of LGMD1C. Myostatin inhibition may be a promising therapy for LGMD1C patients.


Changes in echocardiographic parameters according to the rate of residual renal function decline in incident peritoneal dialysis patients.
Residual renal function (RRF) is associated with left ventricular (LV) hypertrophy as well as all-cause and cardiovascular (CV) mortality in patients with end-stage renal disease. However, no studies have yet examined the serial changes in echocardiographic findings according to the rate of RRF decline in incident dialysis patients. A total of 81 patients who started peritoneal dialysis (PD) between 2005 and 2012 at Yonsei University Health System, Seoul, South Korea, and who underwent baseline and follow-up echocardiography within the first year of PD were recruited. Patients were dichotomized into "faster" and "slower" RRF decline groups according to the median values of RRF decline slope (-1.60 mL/min/y/1.73 m(2)). Baseline RRF and echocardiographic parameters were comparable between the 2 groups. During the first year of PD, there were no significant changes in LV end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), or LV mass index (LVMI) in the "faster" RRT decline group, while these indices decreased in the "slower" RRT decline group. The rate of RRF decline was a significant determinant of 1-year changes in LVEDVI, LAVI, and LVMI. The linear mixed model further confirmed that there were significant differences in the changes in LVEDVI, LAVI, and LVMI between the 2 groups (P = 0.047, 0.048, and 0.001, respectively). During a mean follow-up duration of 31.9 months, 4 (4.9%) patients died. Compared with the "slower" RRF decline group, CV composite (20.29/100 vs 7.18/100 patient-years [PY], P = 0.098), technique failure (18.80/100 vs 4.19/100 PY, P = 0.006), and PD peritonitis (15.73/100 vs 4.95/100 PY, P = 0.064) developed more frequently in patients with "faster" RRF decline rate. On multivariate Cox regression analysis, patients with "faster" RRF decline rate showed 4.82-, 4.44-, and 7.37-fold higher risks, respectively, for each clinical outcome. Preservation of RRF is important for conserving cardiac performance, resulting in an improvement in clinical outcomes of incident PD patients.


Psychological distress after the Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant accident: results of a mental health and lifestyle survey through the Fukushima Health Management Survey in FY2011 and FY2012.
On 11 March 2011, the Great East Japan Earthquake followed by a gigantic tsunami hit the Pacific coast of Northeast Japan (Tohoku) and damaged Tokyo Electric Power Company's Fukushima Daiichi Nuclear Power Plant, causing a radiation hazard in the entire Fukushima Prefecture. The radiation dose exposed either externally and internally in Fukushima residents have been evaluated to be low so far and it is hardly believed that they may have any direct radiation risk on physical condition. The purpose of this report is, therefore, to describe results of a mental health and lifestyle survey intended to facilitate adequate care for residents who are at a higher risk of developing mental health problems after the complicated accident. The target population of this survey is the residents of evacuation zones including Hirono Town, Naraha Town, Tomioka Town, Kawauchi Village, Okuma Town, Futaba Town, Namie Town, Katsurao Village, Minamisoma City, Tamura City, Yamakiya district of Kawamata Town, and Iitate Village. The targeted population was 210,189 in fiscal year 2011 (FY2011) and 211,615 in fiscal year 2012 (FY2012). Questionnaires have been mailed since January 2012, and subsequently, January 2013, 10 and 22 months after the disaster. Among of them, children 63.4%, adults 40.7% for FY2011, and children 41.0%, adults 29.7% for FY2012 responded to the questionnaires mailed. Sociodemographic data showed that many evacuee households were separated after the disaster and had to move several times. K6 was used in this survey to estimate general mental health. The proportion (14.6% in FY2011 and 11.9% inFY2012) of adults who scored above the K6 cut-off (≥13) for general mental health was higher than usual, indicating severe mental health problems among evacuees. The proportion (21.6% in FY2011 and 18.3% inFY2012) of adults who scored above the cut-off (≥44) of PTSD checklist (PCL), reflecting traumatic symptoms, was almost equal to that of the workers after the 9.11 World Trade Center attacks. These results also indicate the presence of severe traumatic problems among evacuees. The proportions of children (4-6 years old) and children of primary school age (6-12 years old) who scored above the cut-off (≥16) of Strengths and Difficulties Questionnaire (SDQ) reflecting the mental health status in children, 24.4% and 22.0% in the survey of FY2011, were double the usual state respectively, whereas 16.6% in children of 4-6 years old and 15.8% in children of 6-12 years old in FY2012 were 1.5 times. These findings also disclosed the presence of severe mental difficulties in children, with relative improvement year by year. As revealed by the present mental health survey, the earthquake and tsunami followed by the nuclear accident caused psychological distress among residents in Fukushima prefecture. Continuous survey and mental care programs are required.


Endoscopic detection of ischaemia with a new probe indicates low oxygenation of gastric epithelium in portal hypertensive gastropathy.
Changes in mucosal blood flow may be important in the pathogenesis of many conditions. Study of mucosal blood perfusion is difficult, and available methods have significant technical limitations. This study describes the development of an instrument for endoscopy, which indicates blood flow indirectly, by measuring the quantity of tissue oxygen that can diffuse from the mucosa to a luminal surface electrode. The instrument was used through an endoscope in patients with portal hypertension (n = 14), scleroderma (n = 3), disease controls (n = 7), and normal controls (n = 11). In portal hypertension readings were one quarter that in normal controls in both antrum (geometric mean (SEM) 35 (1.1)), nanoamps v 137 (1.1), and upper corpus 34 (1.1) v 125 (1.1)). Scleroderma patients showed greatly reduced oxygen readings in both antrum (18 (1.2)) and corpus (24 (1.2)), an expected but hitherto undiscovered result. These differences are highly significant (p = 0.0001), and the findings suggest that tissue hypoxia may contribute to mucosal changes in portal hypertensive gastropathy and in scleroderma.


Calibrated Breast Density Measurements.
Mammographic density is an important risk factor for breast cancer, but translation to the clinic requires assurance that prior work based on mammography is applicable to current technologies. The purpose of this work is to evaluate whether a calibration methodology developed previously produces breast density metrics predictive of breast cancer risk when applied to a case-control study. A matched case control study (n = 319 pairs) was used to evaluate two calibrated measures of breast density. Two-dimensional mammograms were acquired from six Hologic mammography units: three conventional Selenia two-dimensional full-field digital mammography systems and three Dimensions digital breast tomosynthesis systems. We evaluated the capability of two calibrated breast density measures to quantify breast cancer risk: the mean (PGm) and standard deviation (PGsd) of the calibrated pixels. Matching variables included age, hormone replacement therapy usage/duration, screening history, and mammography unit. Calibrated measures were compared to the percentage of breast density (PD) determined with the operator-assisted Cumulus method. Conditional logistic regression was used to generate odds ratios (ORs) from continuous and quartile (Q) models with 95% confidence intervals. The area under the receiver operating characteristic curve (Az) was also used as a comparison metric. Both univariate models and models adjusted for body mass index and ethnicity were evaluated. In adjusted models, both PGsd and PD were statistically significantly associated with breast cancer with similar Az of 0.61-0.62. The corresponding ORs and confidence intervals were also similar. For PGsd, the OR was 1.34 (1.09, 1.66) for the continuous measure and 1.83 (1.11, 3.02), 2.19 (1.28, 3.73), and 2.20 (1.26, 3.85) for Q2-Q4. For PD, the OR was 1.43 (1.16, 1.76) for the continuous measure and 0.84 (0.52, 1.38), 1.96 (1.19, 3.23), and 2.27 (1.29, 4.00) for Q2-Q4. The results for PGm were slightly attenuated and not statistically significant. The OR was 1.22 (0.99, 1.51) with Az = 0.60 for the continuous measure and 1.24 (0.78, 1.97), 0.98 (0.60, 1.61), and 1.26, (0.77, 2.07) for Q2-Q4 with Az = 0.60. The calibrated PGsd measure provided significant associations with breast cancer comparable to those given by PD. The calibrated PGm performed slightly worse. These findings indicate that the calibration approach developed previously replicates under more general conditions.


Development and feeding of fall armyworm on Miscanthus x giganteus and switchgrass.
Observations of fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), larvae infesting plots of Miscanthus x giganteus Greef and Deuter ex Hodkinson and Renvoize prompted laboratory-based tests of survival, development, and feeding preferences on leaf tissue from M. x giganteus and switchgrass, Panicum virgatum L. Survival from hatch to pupation was >70 and 50% for fall armyworms reared on switchgrass and M. x giganteus, respectively, although survival of the S. frugiperda rice strain was significantly greater than the corn strain on both crops. Developmental times from hatch to pupation or adult emergence showed effects of crop and S. frugiperda host strain, but analysis of an interaction revealed developmental times for the rice strain were similar on both crops, whereas corn strain larvae showed delayed development on M. x giganteus relative to switchgrass. Analysis of larval (10 d) and pupal masses showed a similar pattern, with effects of crop and an interaction (at 10 d), but only the mass of corn strain larvae feeding on M. x giganteus was reduced relative to the other crop and strain combinations. In choice tests, neonates of both corn and rice strains showed a strong preference for feeding on young tissues rather than mature leaves of M. x giganteus or switchgrass, but they also clearly favored corn, Zea mays L., leaves over either of the perennial grasses. Results indicate both plants are potential hosts for S. frugiperda, but additional information is needed to understand under which scenarios and to what degree fall armyworms may damage perennial grasses grown for biofuel production.


Anodizing of Self-Passivating W xTi1- x Precursors for W xTi1- xO n Oxide Alloys with Tailored Stability.
TiO2 and WO3 are two of the most important, industrially relevant earth-abundant oxides. Although both materials show complementary functionality and are promising candidates for similar types of applications such as catalysis, sensor technology, and energy conversion, their chemical stability in reactive environments differs remarkably. In this study, anodic barrier oxides are grown on solid-solution W xTi1- x alloy precursors covering a wide compositional range (0 ≤ x ≤ 1) with the goal of creating functional oxides with tailored stability. A strong Ti-cation enrichment in the surface region of the grown W xTi1- xO n layer is observed, which can be controlled by both the anodizing conditions and precursor composition. For Ti concentrations above 50 at. %, a continuous nanometer-thick TiO2 protective coating is achieved on top of a homogeneous W xTi1- xO n film as evidenced by X-ray photoelectron spectroscopy and transmission electron microscopy analyses. A comprehensive electrochemical assessment demonstrates a very stable passivation of the surface in both acidic and alkaline environments. This increase in chemical stability correlates directly with the presence of this protective TiO2 film. The results of this work provide insights into the oxidation behavior of W1- xTi x alloys, but more importantly demonstrate how controlled oxidation of self-passivating alloys can lead to oxide alloys with thin, protective surface layers that otherwise would require more sophisticated deposition methods.


Pacifier use and short breastfeeding duration: cause, consequence, or coincidence?
Pacifiers are related to a shorter duration of breastfeeding. However, it is unclear whether this association is causal, because confounding, reverse causality, and self-selection of mothers may play a role. These issues were investigated through a combination of epidemiologic and ethnographic research in southern Brazil. A population-based cohort of 650 mothers and infants were visited shortly after delivery and at 1, 3, and 6 months. The rate of complete follow-up was 96.8%. A subsample of 80 mothers and infants was selected for the ethnographic study, which included in-depth interviews and participant observations in the age range of 2 to 6 months with a mean of 4.5 visits. The epidemiologic study showed that pacifier use was common with 85% of users at 1 month. However, this was a dynamic process, with many infants starting or abandoning the pacifiers in any age range. Children who stopped breastfeeding in a given period were likely to take up the pacifier during that period. Further analyses excluded all infants not breastfed at 1 month of age and those who reportedly had breastfeeding problems, leaving 450 infants with full data. Intense pacifier users at 1 month (children who used the pacifiers during most of the day and at least until falling asleep) were four times more likely to stop breastfeeding by 6 months of age than nonusers. Users also had fewer daily breastfeedings than nonusers. After adjustment for several confounding variables, logistic regression showed that pacifier use was still associated with an odds ratio of 2.5 (95% confidence interval, 1.40 to 4.01) for stopping breastfeeding. The ethnographic analysis showed that pacifier use was widely regarded as a positive behavior and that mothers often strongly stimulated the infants to accept it. Although few mothers openly admitted that pacifiers might shorten breastfeeding, a considerable group effectively used pacifiers to get their infants off the breast or to increase the interval between feedings. The latter also had rigid breastfeeding styles that increased maternal-infant distance, had important concerns about objective aspects of infant growth and development, and were highly sensitive to infant crying. These behaviors were linked to intense comparison between themselves and other mothers and to a lack of self-confidence. Nonwhite mothers, those who delivered vaginally, and mothers of infant girls seemed to be more confident and less affected by these difficulties. The epidemiologic analysis confirmed that pacifier use was more closely associated with breastfeeding duration among nonwhite mothers and for normally delivered infants. Pacifiers may be an effective weaning mechanism used by mothers who have explicit or implicit difficulties in breastfeeding, but they are much less likely to affect infants whose mothers are confident about nursing. Breastfeeding promotion campaigns aimed specifically at reducing pacifier use will fail unless they also help women face the challenges of nursing and address their anxieties. The combination of epidemiologic and ethnographic methods was essential for understanding the complex relations between pacifier use and breastfeeding.


Reading with the rod visual system.
Using the scanned text technique developed by Legge and his colleagues, the present study demonstrates that visually normal subjects can read with the isolated rod visual system. The subjects were able to read text (albeit slowly) at luminances near their absolute thresholds. The peak reading rates increase with luminance at about 40 words per minute for every tenfold increase in luminance. The authors suggest that the study of scotopic reading performance in normal subjects might contribute to an understanding of reading problems in patients with bilateral central scotoma.


Health governance in India: citizenship as situated practice.
Despite the impressive growth of the Indian economy over the past decades, the country struggles to deal with multiple and overlapping forms of inequality. One of the Indian government's main policy responses to this situation has been an increasing engagement with the 'rights regime', witnessed by the formulation of a plethora of rights-based laws as policy instruments. Important among these are the National Rural Health Mission (NRHM). Grounded in ethnographic research in Rajasthan focused on the management of maternal and child health under NRHM, this paper demonstrates how women, as mothers and health workers, organise themselves in relation to rights and identities. I argue that the rights of citizenship are not solely contingent upon the existence of legally guaranteed rights but also significantly on the social conditions that make their effective exercise possible. This implies that while citizenship is in one sense a membership status that entails a package of rights, duties, and obligations as well as equality, justice, and autonomy, its development and nature can only be understood through a careful consideration and analysis of contextually specific social conditions.


Impact of prevalent and incident vertebral fractures on utility: results from a patient-based and a population-based sample.
Data are scarce on the impact of vertebral fractures (VFX) on utility. The objective of this study was to assess the impact of prevalent and incident VFX on utility in both a patient-based and population-based sample. Data from the Multiple Outcomes of Raloxifene Evaluation (MORE) study (n = 550 for prevalent VFX and n = 174 for incident VFX) and the European Prospective Osteoporosis Study (EPOS) (n = 236) were used. Utility was assessed by the index score of the EQ-5D. In the MORE study, highly statistically significant associations were found between utility and the presence of prevalent VFX (p < 0.001), number of prevalent VFX (p < 0.001), severity of prevalent VFX (p < 0.001), the combination of number and severity of prevalent VFX (p = 0.001) and location of prevalent VFX (p = 0.019). The mean utility was significantly lower among women who suffered an incident VFX (utility = 0.67) than among women who did not (utility = 0.77) (p = 0.005), although utility loss was not significantly different between the two groups (p = 0.142). In EPOS, the combination of number and severity of incident VFX was significantly related to utility (p = 0.030). In conclusion, utility is lower among persons with prevalent and incident VFX, especially in a patient-based sample. Utility loss was not significantly different between women without and with incident VFX.


Modified beta-D-N-acetylhexosaminidase isozymes for enzyme replacement in GM2 gangliosidosis.
The therapeutic potential of enzyme replacement in lysosomal storage disorders has remained largely unfulfilled, perhaps because of negative reactions to the initial disappointing results. Despite the existence of several animal models that can be utilized to explore solutions to the problems of exogenous enzyme targeting, the interest in ERT prevalent during the 1970's seems to have subsided to be replaced by active interest in bone marrow transplantation (BMT, Krivit and Paul [1986]). This is a logical approach to enzyme replacement in storage disorders of the RE system, and indeed some encouraging results have been obtained. However, in addition to having high morbidity and mortality, in the ultimate analysis BMT presents the same targeting problems as conventional ERT. In our opinion, these problems can be solved more easily in the case of ERT by exploiting the existing cellular uptake mechanisms and infusing enzymes whose structure has been suitably modified by simple biochemical manipulations. Accordingly, we have explored a methodology that takes advantage of negative charges on the cell surface to obtain nonspecific but effective membrane binding of beta-hex coupled to the highly positively charged PLL, followed by internalization and routing to the lysosomes. This system increases uptake of exogenous enzyme by some neurons in vitro and possibly in vivo, but its efficiency depends on the cells' endocytic activity that, in the case of neuronal soma, apparently is low. Thus, we have chosen as recognition marker for specific neuronal uptake a nontoxic fragment of TTx that is efficiently taken up by these cells. The initial results are encouraging; they support our contention that effective enzyme replacement methodologies can be devised, and encourage us to continue our work in this direction. Finally, recombinant DNA techniques are now being applied to a number of LSD, and the genes for several of the pertinent enzymes have been or are being isolated. In addition to representing a first step towards gene replacement therapy, the results of this work will permit the generation of large amounts of human enzymes from bacteria by recombinant DNA methods, thus obviating the problem of enzyme supply for ERT. Since human lysosomal enzymes obtained from bacteria will be nonglycosylated, to obtain cell uptake it will be necessary to resort to the type of modifications that we are trying to develop at this time, i.e., covalent linkage to moieties that allow non-glycosyl-mediated cellular uptake. Thus, our work on beta-hex may provide a model for biochemical manipulations of bacterially produced enzymes applicable to several LSD.


Estrogen metabolism and breast cancer risk among postmenopausal women: a case-cohort study within B~FIT.
Although elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992-93, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EMs were measured by liquid chromatography-tandem mass spectrometry. EMs (quintiles, Q) were analyzed individually, as metabolic pathways (C-2, -4 or -16) and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HRQ5vsQ1 = 1.86; 95% CI: 1.19-2.90; P trend = 0.04). An elevated ratio of the 2-hydroxylation pathway (HRQ5vsQ1 = 0.69; 95% CI: 0.46-1.05; P trend = 0.01) and 4-hydroxylation pathway (HRQ5vsQ1 = 0.61; 95% CI: 0.40-0.93; P trend = 0.004) to parent estrogens (estradiol and estrone) was inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HRQ5vsQ1 = 0.60; 95% CI: 0.40-0.90; P trend = 0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis.


Statistical analysis of ion mobility spectrometry. I. Unbiased and guided replica-exchange molecular dynamics.
Achieving (bio)macromolecular structural assignment from the interpretation of ion mobility spectrometry (IMS) experiments requires successful comparison with computer modeling. Replica-exchange molecular dynamics simulations with suitable force fields not only offer a convenient framework to locate relevant conformations, especially in the case of multiple-funnel energy landscapes, but they are also well suited to statistical analyses. In the present paper, we discuss two extensions of the method used to improve its efficiency in the context of IMS. Two doubly-protonated polyalanines [RA(4)XA(4)K + 2H](2+) with X=V and D appear as favorable cases for which the calculated collision cross-section distributions naturally agree with the measurements, providing reliable candidate structures. For these compounds, a careful consideration of other order parameters based on the weighted histogram method resolves several otherwise hidden underlying conformational families. In the case of a much larger peptide exhibiting bistability, assignment is more difficult but could be achieved by guiding the sampling with an umbrella potential using the square gyration radius as the biasing coordinate. Applied to triply protonated bradykinine, the two presented methods indicate that different conformations compatible with the measurements are very close in energy.


Functional mapping of dynamic traits with robust t-distribution.
Functional mapping has been a powerful tool in mapping quantitative trait loci (QTL) underlying dynamic traits of agricultural or biomedical interest. In functional mapping, multivariate normality is often assumed for the underlying data distribution, partially due to the ease of parameter estimation. The normality assumption however could be easily violated in real applications due to various reasons such as heavy tails or extreme observations. Departure from normality has negative effect on testing power and inference for QTL identification. In this work, we relax the normality assumption and propose a robust multivariate t-distribution mapping framework for QTL identification in functional mapping. Simulation studies show increased mapping power and precision with the t distribution than that of a normal distribution. The utility of the method is demonstrated through a real data analysis.


Interocular suppression in normal and amblyopic vision: spatio-temporal properties.
We measured the properties of interocular suppression in strabismic amblyopes and compared these to dichoptic masking in binocularly normal observers. We used a dichoptic version of the well-established probed-sinewave paradigm that measured sensitivity to a brief target stimulus (one of four letters to be discriminated) in the amblyopic eye at different times relative to a suppression-inducing mask in the fixing eye. This was done using both sinusoidal steady state and transient approaches. The suppression-inducing masks were either modulations of luminance or contrast (full field, just overlaying the target, or just surrounding the target). Our results were interpreted using a descriptive model that included contrast gain control and spatio-temporal filtering prior to excitatory binocular combination. The suppression we measured, other than in magnitude, was not fundamentally different from normal dichoptic masking: lowpass spatio-temporal properties with similar contributions from both surround and overlay suppression.


Predicting large CO2 adsorption in aluminosilicate zeolites for postcombustion carbon dioxide capture.
Large-scale simulations of aluminosilicate zeolites were conducted to identify structures that possess large CO(2) uptake for postcombustion carbon dioxide capture. In this study, we discovered that the aluminosilicate zeolite structures with the highest CO(2) uptake values have an idealized silica lattice with a large free volume and a framework topology that maximizes the regions with nearest-neighbor framework atom distances from 3 to 4.5 Å. These predictors extend well to different Si:Al ratios and for both Na(+) and Ca(2+) cations, demonstrating their universal applicability in identifying the best-performing aluminosilicate zeolite structures.


Neck pain in South Africa: An overview of the prevalence, assessment and management for the contemporary clinician.
Neck pain is a prevalent condition and is associated with high levels of disability and pain. The long-term prognosis can be poor, and therefore effective management in the acute stage is important. To provide an overview of the prevalence of neck pain and physiotherapy management and to provide evidence-informed recommendations for clinical practice within a South African context. The literature was reviewed considering prevalence, risk factors and examination. Management recommendations were derived from the highest levels of evidence of clinical practice guidelines, systematic reviews and randomised clinical trials. Neck pain is classified into four grades, and three trajectories of recovery have been identified. Although the incidence of neck pain globally is high, in the South African context the majority of the population have limited access to physiotherapy management. Sound clinical reasoning is important in the assessment and decision-making process for management. Exercise, and mobilisation or manipulation are effective treatment options in the management of most types of neck pain. Other physical modalities such as needling, transcutaneous electrical nerve stimulation, laser and intermittent traction may be used as an adjunct to management. The burden of neck pain globally is high; however, there is a lack of information on current practice, prevalence and burden of neck pain in the South African context. Sound evidence-informed clinical reasoning to inform a working diagnosis and to enable patient-centred management is important. A thorough assessment is essential to gather information to formulate hypotheses regarding diagnosis and prognosis for neck pain. Exercise, and mobilisation or manipulation are effective management options.


Association between serum 25-hydroxyvitamin D levels and bone mineral density in normal postmenopausal women.
This study was conducted with the objective of assessing serum 25-hydroxyvitamin D (25(OH)D) in postmenopausal women (PMW), to detect osteopenia or osteoporosis in PMW and to establish a correlation between serum 25(OH)D levels and bone mineral density (BMD). A total of 100 healthy PMW were selected, and a prospective observational study was conducted to correlate the BMD with serum 25(OH)D levels. Their laboratory investigations along with serum 25(OH)D levels were done. Their BMD was assessed with dual-energy X-ray absorptiometry at lumbar spine and neck of femur; T-scores were derived. Correlation analysis was done to investigate the relationship between serum 25(OH)D levels and BMD. The proportion of osteoporosis at the hip was 31.9% in deficient group, 16.1% in insufficient, and 18.2% in sufficient group and at lumbar spine, it was 27.7%, 16.1%, and 22.7%, respectively. Forty-seven percent of PMW had deficient (<20 ng/ml) serum 25(OH)D levels and 31% had insufficiency. T-score at hip in deficient group was -2.05 ± 0.25, and in an insufficient group, it was -1.79 ± 0.13; T-score at lumbar spine was -1.92 ± 0.12 and -1.79 ± 0.12, respectively, but both were not statistically significant. Osteoporosis was seen in 24%, osteopenia in 55% at hip level and 23% and 59% respectively at lumbar spine. There was no association between serum 25(OH)D levels and BMD neither at hip nor at lumbar spine (P = 0.51 and P = 0.79 respectively). In this study, among our cohort of patients there was no correlation between serum 25(OH)D levels and BMD. However, Vitamin D deficiency coexists with low BMD. Vitamin D insufficiency is a common risk factor for osteoporosis associated with increased bone remodeling and low bone mass.


Effect of non-surgical periodontal therapy on interleukin-29 levels in gingival crevicular fluid of chronic periodontitis and aggressive periodontitis patients.
Recently discovered interleukin 29 (IL-29) has antiviral properties and its production is induced by herpes viruses. This study was aimed at analyzing the effect of non-surgical periodontal treatment on IL-29 levels in gingival crevicular fluid (GCF) of chronic and aggressive periodontitis patients. A total of 60 participants were divided into healthy group (group 1; n=20), chronic periodontitis group (group 2; n=20), and aggressive periodontitis group (group 3; n=20). GCF samples collected from each subject at baseline and 6-8 weeks after scaling and root planing were quantified for IL-29 levels using ELISA. The mean IL-29 concentration in GCF was found to be highest in group 3 (92.37 pg/μl). The mean IL-29 level in group 1 and group 2 was 36.88 pg/μl and 69.35 pg/μl respectively. After scaling and root planing, the mean concentration of IL-29 in GCF was increased to 85.99 pg/μl in group 2 and to 114.64 pg/μl in group 3. Results of the present study indicate that antiviral IL-29 level was highest in GCF of aggressive periodontitis patients and least in subjects with healthy periodontium, while that of chronic periodontitis lying in between. After non-surgical periodontal therapy, IL-29 levels increased both in chronic and aggressive periodontitis patients and deserve further investigation as a potential therapeutic agent in treating periodontitis.


Establishment of Specialized Clinical Cardiovascular Genetics Programs: Recognizing the Need and Meeting Standards: A Scientific Statement From the American Heart Association.
Cardiovascular genetics is a rapidly evolving subspecialty within cardiovascular medicine, and its growth is attributed to advances in genome sequencing and genetic testing and the expanding understanding of the genetic basis of multiple cardiac conditions, including arrhythmias (channelopathies), heart failure (cardiomyopathies), lipid disorders, cardiac complications of neuromuscular conditions, and vascular disease, including aortopathies. There have also been great advances in clinical diagnostic methods, as well as in therapies to ameliorate symptoms, slow progression of disease, and mitigate the risk of adverse outcomes. Emerging challenges include interpretation of genetic test results and the evaluation, counseling, and management of genetically at-risk family members who have inherited pathogenic variants but do not yet manifest disease. With these advances and challenges, there is a need for specialized programs combining both cardiovascular medicine and genetics expertise. The integration of clinical cardiovascular findings, including those obtained from physical examination, imaging, and functional assessment, with genetic information allows for improved diagnosis, prognostication, and cascade family testing to identify and to manage risk, and in some cases to provide genotype-specific therapy. This emerging subspecialty may ultimately require a new cardiovascular subspecialist, the genetic cardiologist, equipped with these combined skills, to permit interpretation of genetic variation within the context of phenotype and to extend the utility of genetic testing. This scientific statement outlines current best practices for delivering cardiovascular genetic evaluation and care in both the pediatric and the adult settings, with a focus on team member expertise and conditions that most benefit from genetic evaluation.


Thioredoxin reductase and cancer cell growth inhibition by organotellurium compounds that could be selectively incorporated into tumor cells.
The thioredoxins are small ubiquitous redox proteins with the conserved redox catalytic sequence-Trp-Cys-Gly-Pro-Cys-Lys, where the Cys residues undergo reversible NADPH dependent reduction by selenocysteine containing flavoprotein thioredoxin reductases. Thioredoxin expression is increased in several human primary cancers including lung, colon, cervix, liver, pancreatic, colorectal and squamous cell cancer. The thioredoxin/thioredoxin reductase pathway therefore provides an attractive target for cancer drug development. Organotellurium steroid, lipid, amino acid, nucleic base, and polyamine inhibitors were synthesized on the basis that they might be selectively or differentially incorporated into tumor cells. Some of the newly prepared classes of tellurium-based inhibitors (lipid-like compounds 3b and 3e, amino acid derivative 5b, nucleic base derivative 8b, and polyamine derivatives 14a and 14b) inhibited TrxR/Trx and cancer cell growth in culture with IC(50) values in the low micromolar range.


[Evaluation of glucose metabolism in acromegalic patients before and after treatment with octreotide LAR].
To evaluate the glucose metabolism in acromegalic patients before and after treatment with octreotide LAR. This was a prospective and longitudinal study involving 30 patients from the acromegaly research outpatient clinic of the Endocrinology unit of the HUCFF/UFRJ. They underwent clinical and laboratorial evaluations, with measurements of growth hormone (GH), insulin-like growth factor type I (IGF-I), insulin, proinsulin, C peptide, glycosylated hemoglobin (HbA1c), IGF binding protein type 1 (IGFBP-1) and glucose, during oral glucose tolerance test (OGTT), before and after six months of treatment with octreotide LAR. The Wilcoxon signed-rank test was used and values of 5% were considered statistically significant. We found 16 (54%) patients with normal glucose tolerance, 7 (23%) with impaired glucose tolerance and 7 (23%) diabetics. Twelve patients completed the six-month treatment, out of which three showed worsening of glucose tolerance and two (diabetics) had worse blood glucose control. Whereas there was an increase in waist circumference (p=0.03), there was a decrease in GH (p=0.04), with %IGF-I above the upper limit of reference values (% ULRV) [p=0.001], insulin (p=0.019), C peptide levels (p=0.002) and homeostatic model assessment (HOMA-IR) [p=0.039]. In this series, treatment with octreotide LAR led to a worsening of glucose tolerance in three non-diabetic patients and worsened glycemic control in two diabetics, in spite of reducing insulin resistance.


Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.
Primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) are BCR ABL-negative myeloproliferative neoplasms (MPN). Published epidemiology data are scarce, and multiple sources are needed to assess the disease burden. We assembled the most recent information available on the incidence and prevalence of myelofibrosis (MF), ET, and PV by conducting a structured and exhaustive literature review of the published peer-reviewed literature in EMBASE and by reviewing online documentation from disease registries and relevant health registries in European countries. The search was restricted to human studies written in English or French and published between January 1, 2000, and December 6, 2012. Eleven articles identified from EMBASE, three online hematology or oncology registries, and two Web-based databases or reports were used to summarize epidemiological estimates for MF, PV, and ET. The incidence rate of MF ranged from 0.1 per 100,000 per year to 1 per 100,000 per year. Among the various registries, the incidence of PV ranged from 0.4 per 100,000 per year to 2.8 per 100,000 per year, while the literature estimated the range of PV incidence to be 0.68 per 100,000 to 2.6 per 100,000 per year. The estimated incidence of ET was between 0.38 per 100,000 per year and 1.7 per 100,000 per year. While a few studies reported on the MPNs' prevalences, it is difficult to compare them as various types of prevalence were calculated (point prevalence vs. period prevalence) and standardization was made according to different populations (e.g., the world population and the European population). There is a wide variation in both prevalence and incidence estimates observed across European data sources. Carefully designed studies, with standardized definitions of MPNs and complete ascertainment of patients including both primary and secondary MFs, should be conducted so that estimates of the population aimed to receive novel treatments for these neoplasms are better understood assist public health planning and provide valuable information about the burden of illness to policy makers, funding agencies, resource planners, healthcare insurers, and pharmaceutical manufacturers.


Spironaphthoxazine switchable dyes for biological imaging.
Recent developments in super-resolution microscopy have significantly expanded the requirements for switchable dyes, leading to demand for specially designed molecular switches. We report the synthesis and characterization of a spironaphthoxazine photochromic switch (a derivative of palatinate purple) displaying high photoconversion (85-95%) under readily accessible 405 nm light, broad absorption in the visible, and excellent fatigue resistance. The indole substituent on this spironaphthoxazine is twisted out of conjugation with the naphthalene unit, yet it is crucial for activation with visible light. The open colored merocyanine form of the spironaphthoxazine reverts to the closed form with a lifetime of 4.7 s in dichloromethane at 20 °C; this thermal reversion is even faster in more polar solvents. The photochemical quantum yields for ring-opening and ring-closing are approximately 8% and 1%, respectively, in dichloromethane. The ring-opening and ring-closing reactions have been characterized by time-resolved infrared and transient absorption spectroscopies. Ring opening occurs rapidly (τ = 2.1 ns) and efficiently (∼90%) from the singlet excited state to form an intermediate (assigned as a cisoid merocyanine), which returns to the closed ground state (τ = 4.5 ns) in competition with relaxation to the transoid open form (τ = 40 ns). Photochemical ring closing is a faster and simpler process: the excited state proceeds to the closed spirooxazine with a time constant of 0.28 ns. This photochromic switch can be used in conjunction with commercial fluorescent dyes to create a small-molecule switchable fluorescent dyad that shows high contrast and good fatigue resistance in living cells. These properties make the dyads suitable for application in RESOLFT microscopy.


Two common tests of dexterity can stratify upper limb motor function after stroke.
Neurological deficits after a stroke are commonly classified according to motor function for clinical decision making regarding discharge and rehabilitation. Participants in clinical stroke studies are also stratified by motor function to avoid a sampling bias. This post hoc analysis examined a suite of upper limb functional assessment tools to test the hypothesis that motor function of survivors of stroke can be stratified using 2 simple tests of manual dexterity despite the heterogeneity of the population. The functional ability of the more affected hand and arm was assessed for 67 hemiparetic patients, aged 18 to 83 years (mean ± standard deviation, 59.8 ± 14.0 years), at 1 to 264 months after a stroke (23.6 ± 39.6 months) using the Wolf Motor Function Test (WMFT), upper limb motor Fugl-Meyer Assessment (F-M), Box and Block Test (BBT), grooved pegboard test, and wrist range of motion. We tested the strength of our proposed stratification scheme with a hypothesis-driven hierarchical cluster analysis using standardized raw scores and dichotomous BBT and grooved pegboard test values. The most salient discriminator between low and higher motor function was the ability to move >1 block on the BBT. Within the higher function group, the ability to place all 25 pegs on the grooved pegboard test discriminated between moderate and high motor function. The derived scheme was congruent with clinical observations. The WMFT timed tasks, F-M scores, and range of motion did not discriminate functional groups. Two simple unambiguous and objective tests of gross (BBT) and fine (grooved pegboard test) manual dexterity discriminated 3 groups of motor function ability for a heterogeneous group of patients after stroke.


Use of Spectroscopic Techniques to Monitor Changes in Food Quality during Application of Natural Preservatives: A Review.
Consumer demand for food of high quality has driven research for alternative methods of food preservation on the one hand, and the development of new and rapid quality assessment techniques on the other hand. Recently, there has been a growing need and interest in healthier food products, which has led to an increased interest in natural preservatives, such as essential oils, plant extracts, and edible films and coatings. Several studies have shown the potential of using biopreservation, natural antimicrobials, and antioxidant agents in place of other processing and preservation techniques (e.g., thermal and non-thermal treatments, freezing, or synthetic chemicals). Changes in food quality induced by the application of natural preservatives have been commonly evaluated using a range of traditional methods, including microbiology, sensory, and physicochemical measurements. Several spectroscopic techniques have been proposed as promising alternatives to the traditional time-consuming and destructive methods. This review will provide an overview of recent studies and highlight the potential of spectroscopic techniques to evaluate quality changes in food products following the application of natural preservatives.