Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration.
To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample. A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A-) and baseline hippocampal volume (N+ or N-). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups. At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A-N-), 29 (12%) amyloid negative and neurodegeneration positive (A-N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N-), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+. We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging-Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.


Short report: Human infection with Trichinella britovi in Granada, Spain.
An outbreak of trichinellosis caused by ingestion of pork infected with Trichinella britovi occurred in the province of Granada in southern Spain in April-May 2000. Thirty-eight people were affected and 15 of them were hospitalized at the University Hospital of San Cecilio (Granada). The probable source of infection was sausage made from uninspected wild boar meat and inspected pork. Ninety-two percent of the patients had myalgias, 47.6% had diarrhea and/or vomited, 78.6% had periorbital edema, and 76.0% had fever. Twenty-two patients (15 hospitalized and 7 nonhospitalized) were serologically studied. Eosinophil levels were less than 5% of the total leukocyte count in 86.7% of the patients. Levels of creatinine phosphokinase (range = 200-2,213 U/L) and lactate dehydrogenase (range = 560-7,558 U/L) were elevated in 85.7% and 78.6% of the patients, respectively. Sixteen (72.7%) and 20 (90.9%) patients were positive for T. britovi by indirect immunofluorescence and Western blot, respectively.


Real world cost of human epidermal receptor 2-positive metastatic breast cancer patients: a longitudinal incidence-based observational costing study in the Netherlands and Belgium.
Currently, no country-specific metastatic breast cancer (MBC) observational costing data are available for the Netherlands and Belgium. Our aim is to describe country-specific resource use and costs of human epidermal receptor 2 (HER-2)-positive MBC in the Netherlands and Belgium, making use of real-world data. The eligibility period for patient selection was from April 2004 to April 2010. Inclusion and retrospective data collection begins at the time of first diagnosis of HER-2-positive MBC during the eligibility period and ends 24 months post-index diagnosis of MBC or at patient death. We identified 88 eligible patients in the Netherlands and 44 patients in Belgium. The total costs of medical treatment and other resource use utilisation per patient was €48,301 in the Netherlands and €37,431 in Belgium. Majority of costs was related to the use of trastuzumab in both countries, which was 50% of the total costs in the Netherlands and 56% in Belgium respectively. Our study provides estimates of resource use and costs for HER-2-positive MBC in the Netherlands and Belgium. We noticed various differences in resource use patterns between both countries demonstrating caution is needed when transferring cost estimates between countries.


Genes for human catecholamine-synthesizing enzymes.
Catecholamine neurotransmitters--dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine)--are synthesized in catecholaminergic neurons from tyrosine, via dopa, dopamine and noradrenaline, to adrenaline. Four enzymes are involved in the biosynthesis of adrenaline: (1) tyrosine 3-mono-oxygenase (tyrosine hydroxylase, TH); (2) aromatic L-amino acid decarboxylase (AADC, or DOPA decarboxylase, DDC); (3) dopamine beta-mono-oxygenase (dopamine beta-hydroxylase, DBH); and (4) noradrenaline N-methyltransferase (phenylethanolamine N-methyltransferase, PNMT). We cloned full-length complementary DNAs (cDNAs) and genomic DNAs of human catecholamine-synthesizing enzymes (TH, AADC, DBH, PNMT) and determined the nucleotide sequences and the deduced amino acid sequences. We discovered multiple messenger RNAs (mRNAs) of human TH, human DBH, and human PNMT. Four types (types 1, 2, 3, and 4) of human TH mRNAs are produced by alternative mRNA splicing mechanism from a single gene. We found the multiple forms of TH in two species of monkeys, but only a single mRNA corresponding to human TH type 1 in Sunkus murinus and rat, suggesting that the multiplicity of TH mRNA is primate-specific. Total TH mRNA, especially the most abundant type 2 and type 1 mRNAs in the human brain, were found to be reduced during the process of aging. The multiple forms of human TH may give additional regulation to the human enzyme, probably through altered phosphorylation and activation. We have succeeded in producing transgenic mice carrying multiple copies of the human TH gene in brain and adrenal medulla. The level of human TH mRNA in brain was about 50-fold higher than that of endogenous mouse TH mRNA. In situ hybridization demonstrated an enormous region-specific expression of the transgene in substantia nigra and ventral tegmental area. TH immunoreactivity in these regions, Western blot analysis, and TH activity measurements proved definitely increased TH in transgenic mice, though not comparable to the increment of the mRNA. However, catecholamine levels in transgenics were not significantly different from those in non-transgenics. The results suggest complex regulatory mechanisms for human TH gene expression and for the catecholamine levels in transgenic mice. Kohsaka and Uchida in collaboration with us applied genetically engineered (human TH cDNA-transfected) non-neuronal cells to brain tissue transplantation in parkinsonian rat models. We isolated and sequenced a full-length cDNA encoding human AADC.(ABSTRACT TRUNCATED AT 400 WORDS)


Making iron-sulfur cluster: structure, regulation and evolution of the bacterial ISC system.
Iron sulfur (Fe-S) clusters rank among the most ancient and conserved prosthetic groups. Fe-S clusters containing proteins are present in most, if not all, organisms. Fe-S clusters containing proteins are involved in a wide range of cellular processes, from gene regulation to central metabolism, via gene expression, RNA modification or bioenergetics. Fe-S clusters are built by biogenesis machineries conserved throughout both prokaryotes and eukaryotes. We focus mostly on bacterial ISC machinery, but not exclusively, as we refer to eukaryotic ISC system when it brings significant complementary information. Besides covering the structural and regulatory aspects of Fe-S biogenesis, this review aims to highlight Fe-S biogenesis facets remaining matters of discussion, such as the role of frataxin, or the link between fatty acid metabolism and Fe-S homeostasis. Last, we discuss recent advances on strategies used by different species to make and use Fe-S clusters in changing redox environmental conditions.


Large cities get more for less: Water footprint efficiency across the US.
Many urban indicators and functional citywide properties have been shown to scale with population due to agglomeration effects. We hypothesize that scaling relations may also exist for water-related urban indicators such as the water footprint. The water footprint is an indicator of water use that measures humans' appropriation of freshwater resources. We analyze the scaling of the water footprint for 65 mid- to large-sized US cities using both empirical estimates and a social interaction network model of city functioning. The network model is used to explain the presence of any scaling exponent in the empirical estimates of the urban water footprint by linking to previous theories of urban scaling. We find that the urban water footprint tends to approximately show sublinear scaling behavior with both population and gross domestic product. Thus, large cities tend to be more water footprint efficient and productive than mid-sized cities, where efficiency and productivity are quantified, in a broad sense, as deviations from a linear scaling exponent. We find the sublinear scaling may be linked to changes in urban economic structure with city size, which lead to large cities shifting water intensive economic activities to less populated regions. In addition, we find that green water contributes to the scaling both positively by transferring the dependence of food consumption on population into the water footprint and negatively by increasing heterogeneity. Overall, the proposed scaling relations allow for the comparison of water footprint efficiency and productivity of cities. Comparing these properties and identifying deviations from the expected behavior has implications for water resources and urban sustainability.


Hyperexpandable, self-healing macromolecular crystals with integrated polymer networks.
The formation of condensed matter typically involves a trade-off between structural order and flexibility. As the extent and directionality of interactions between atomic or molecular components increase, materials generally become more ordered but less compliant, and vice versa. Nevertheless, high levels of structural order and flexibility are not necessarily mutually exclusive; there are many biological (such as microtubules1,2, flagella 3 , viruses4,5) and synthetic assemblies (for example, dynamic molecular crystals6-9 and frameworks10-13) that can undergo considerable structural transformations without losing their crystalline order and that have remarkable mechanical properties8,14,15 that are useful in diverse applications, such as selective sorption 16 , separation 17 , sensing 18 and mechanoactuation 19 . However, the extent of structural changes and the elasticity of such flexible crystals are constrained by the necessity to maintain a continuous network of bonding interactions between the constituents of the lattice. Consequently, even the most dynamic porous materials tend to be brittle and isolated as microcrystalline powders 14 , whereas flexible organic or inorganic molecular crystals cannot expand without fracturing. Owing to their rigidity, crystalline materials rarely display self-healing behaviour 20 . Here we report that macromolecular ferritin crystals with integrated hydrogel polymers can isotropically expand to 180 per cent of their original dimensions and more than 500 per cent of their original volume while retaining periodic order and faceted Wulff morphologies. Even after the separation of neighbouring ferritin molecules by 50 ångströms upon lattice expansion, specific molecular contacts between them can be reformed upon lattice contraction, resulting in the recovery of atomic-level periodicity and the highest-resolution ferritin structure reported so far. Dynamic bonding interactions between the hydrogel network and the ferritin molecules endow the crystals with the ability to resist fragmentation and self-heal efficiently, whereas the chemical tailorability of the ferritin molecules enables the creation of chemically and mechanically differentiated domains within single crystals.


Hemorheological and hemodynamic parameters in patients with essential hypertension and their modification by alpha-1 inhibitor drug treatment.
Hemorheological factors play an important role in the pathogenesis of different cardiovascular diseases. The hemorheological and hemodynamic parameters in essential hypertension and their possible modification by antihypertensive treatment were examined in the following two studies. In the first study the fundus appearance and hemorheological parameters (plasma and whole blood viscosity (WBV), fibrinogen level) of 33 hypertensive patients (mean age: 55 years) were examined. The fundus appearance showed retinopathy in all the cases between stages I-III. All the measured hemorheological parameters of the examined patients were in the pathological range (WBV at 90 s(-1): 5.18 mPa s) and were significantly (p < 0.01) higher than in healthy controls (WBV at 90 s(-1): 4.18 mPa s). The hemorheological factors showed a parallel deterioration with the fundus appearance, namely their values were significantly (p < 0.01) higher in patients with a fundus appearance stage III (WBV at 90 s(-1): 6.02 mPa s) than stage I (WBV at 90 s(-1): 4.51 mPa s). These results show that there is a correlation between hemorheological parameters and fundus appearance in hypertensives, and this suggests that hemorheological factors may play a role in the development of hypertensive retinopathy. In the second study the hemorheological and hemodynamical effects of Doxazosin, a selective alpha-1-adrenoreceptor blocker agent, was examined in twenty patients (mean age: 54 years) with essential hypertension. Hemorheologic (hematocrit, fibrinogen, plasma and whole blood viscosity) and hemodynamic (cardiac output and index, total peripheral resistance) parameters and plasma lipids were determined. The measurements were carried out before the beginning of the treatment, after 1 week and after 12 weeks treatment periods. Besides significant reduction of blood pressure and total peripheral resistance (p < 0.001), a decrease in cholesterol (p < 0.001) and triglycerides (p < 0.01) levels and a beneficial effect on hemorheological parameters was detected. Fibrinogen and plasma viscosity decreased significantly (p < 0.01). Hematocrit value was also lower after one week (p < 0.001), then an increase could be seen. Whole blood viscosity showed similar changes as hematocrit, but the degree of its final increase was slighter, which was supported by the significantly lower value of corrected blood viscosity (p < 0.05). All these findings indicate that hemorheological factors may play a role in the pathogenesis and in the development of organ damages in hypertension.


Impact of prognostic factors on clinical outcome after resection of colorectal pulmonary metastases.
Colorectal cancer is the second leading cause of cancer-related deaths in Western countries. Approximately 35% of patients will have metastatic disease at diagnosis, and an additional 25% of patients with resected stage II/III disease will develop recurrence. In approximately 30% of patients, metastatic disease will be restricted to a single organ, with the liver and lungs accounting for the majority of single organ-site metastases. In recent years, aggressive surgical resection of pulmonary metastases has become increasingly common with the recognition that this offers the best chance of long-term cure despite recent chemotherapeutic advances. Unfortunately, relapse after pulmonary resection remains approximately 70% despite advances in imaging and surgical technique. This review examines prognostic factors that influence survival after resection and repeat resection of pulmonary colorectal metastases and examines the impact of lymph node metastases, chemotherapy, and hepatic metastases on outcome. Pathologic markers that might determine outcome and current literature, which consists mainly of retrospective institutional reports, is reviewed.


The racial/ethnic distribution of heat risk-related land cover in relation to residential segregation.
We examined the distribution of heat risk-related land cover (HRRLC) characteristics across racial/ethnic groups and degrees of residential segregation. Block group-level tree canopy and impervious surface estimates were derived from the 2001 National Land Cover Dataset for densely populated urban areas of the United States and Puerto Rico, and linked to demographic characteristics from the 2000 Census. Racial/ethnic groups in a given block group were considered to live in HRRLC if at least half their population experienced the absence of tree canopy and at least half of the ground was covered by impervious surface (roofs, driveways, sidewalks, roads). Residential segregation was characterized for metropolitan areas in the United States and Puerto Rico using the multigroup dissimilarity index. After adjustment for ecoregion and precipitation, holding segregation level constant, non-Hispanic blacks were 52% more likely (95% CI: 37%, 69%), non-Hispanic Asians 32% more likely (95% CI: 18%, 47%), and Hispanics 21% more likely (95% CI: 8%, 35%) to live in HRRLC conditions compared with non-Hispanic whites. Within each racial/ethnic group, HRRLC conditions increased with increasing degrees of metropolitan area-level segregation. Further adjustment for home ownership and poverty did not substantially alter these results, but adjustment for population density and metropolitan area population attenuated the segregation effects, suggesting a mediating or confounding role. Land cover was associated with segregation within each racial/ethnic group, which may be explained partly by the concentration of racial/ethnic minorities into densely populated neighborhoods within larger, more segregated cities. In anticipation of greater frequency and duration of extreme heat events, climate change adaptation strategies, such as planting trees in urban areas, should explicitly incorporate an environmental justice framework that addresses racial/ethnic disparities in HRRLC.


Formation mechanisms of ZnO nanowires on polycrystalline Au seed layers for piezoelectric applications.
ZnO nanowires are considered as attractive building blocks for piezoelectric devices, including nano-generators and stress/strain sensors. However, their integration requires the use of metallic seed layers, on top of which the formation mechanisms of ZnO nanowires by chemical bath deposition are still largely open. In order to tackle that issue, the nucleation and growth mechanisms of ZnO nanowires on top of Au seed layers with a thickness in the range of 5-100 nm are thoroughly investigated. We show that the ZnO nanowires present two different populations of nano-objects with a given morphology. The majority primary population is made of vertically aligned ZnO nanowires, which are heteroepitaxially formed on top of the Au (111) grains. The resulting epitaxial strain is found to be completely relieved at the Au/ZnO interface. In contrast, the minority secondary population is composed of ZnO nanowires with a significant mean tilt angle around 20° with respect to the normal to the substrate surface, which are presumably formed on the (211) facets of the Au (111) grains. The elongation of ZnO nanowires is further found to be limited by the surface reaction at the c-plane top facet in the investigated conditions. By implementing the selective area growth using electron beam lithography, the position of ZnO nanowires is controlled, but the two populations still co-exist in the ensemble. These findings provide an in-depth understanding of the formation mechanisms of ZnO nanowires on metallic seed layers, which should be taken into account for their more efficient integration into piezoelectric devices.


Does Twitter trigger bursts in signature collections?
The quantification of social media impacts on societal and political events is a difficult undertaking. The Japanese Society of Oriental Medicine started a signature-collecting campaign to oppose a medical policy of the Government Revitalization Unit to exclude a traditional Japanese medicine, "Kampo," from the public insurance system. The signature count showed a series of aberrant bursts from November 26 to 29, 2009. In the same interval, the number of messages on Twitter including the keywords "Signature" and "Kampo," increased abruptly. Moreover, the number of messages on an Internet forum that discussed the policy and called for signatures showed a train of spikes. In order to estimate the contributions of social media, we developed a statistical model with state-space modeling framework that distinguishes the contributions of multiple social media in time-series of collected public opinions. We applied the model to the time-series of signature counts of the campaign and quantified contributions of two social media, i.e., Twitter and an Internet forum, by the estimation. We found that a considerable portion (78%) of the signatures was affected from either of the social media throughout the campaign and the Twitter effect (26%) was smaller than the Forum effect (52%) in total, although Twitter probably triggered the initial two bursts of signatures. Comparisons of the estimated profiles of the both effects suggested distinctions between the social media in terms of sustainable impact of messages or tweets. Twitter shows messages on various topics on a time-line; newer messages push out older ones. Twitter may diminish the impact of messages that are tweeted intermittently. The quantification of social media impacts is beneficial to better understand people's tendency and may promote developing strategies to engage public opinions effectively. Our proposed method is a promising tool to explore information hidden in social phenomena.


Testing models of sex ratio evolution in a gynodioecious plant: female frequency covaries with the cost of male fertility restoration.
In many gynodioecious species, cytoplasmic male sterility genes (CMS) and nuclear male fertility restorers (Rf) jointly determine whether a plant is female or hermaphrodite. Equilibrium models of cytonuclear gynodioecy, which describe the effect of natural selection within populations on the sex ratio, predict that the frequency of females in a population will primarily depend on the cost of male fertility restoration, a negative pleiotropic effect of Rf alleles on hermaphrodite fitness. Specifically, when the cost of restoration is higher, the frequency of females at equilibrium is predicted to be higher. To test this prediction, we estimated variation in the cost of restoration across 26 populations of Lobelia siphilitica, a species in which Rf alleles can have negative pleiotropic effects on pollen viability. We found that L. siphilitica populations with many females were more likely to contain hermaphrodites with low pollen viability. This is consistent with the prediction that the cost of restoration is a key determinant of variation in female frequency. Our results suggest that equilibrium models can explain variation in sex ratio among natural populations of gynodioecious species.


New Medicare Technology Add-On Payment Could Be Used As A Market Support Mechanism To Accelerate Antibiotic Innovation.
Despite growing antibiotic resistance, the clinical drug development pipeline for antibiotics has been sparse largely because of an unsustainable business model. We illustrate three models to accelerate antibiotic development, using Medicare new technology add-on payments as a market support mechanism. The first two models subsidize drug development for Medicare beneficiaries, and the third model applies a payment for every patient with a resistant infection to essentially create a funding pool. We found that the reimbursement required to sustain research and development would range from $637 to $121,365, depending on the payment model and the incidence of the resistant infection in question. With a $300 million public research subsidy, the payment for an antibiotic would drop to between $273 and $10,396 per course. Our market support model could increase the likelihood of attracting private investment for antibiotic development.


Characteristics and crystal structure of bacterial inosine-5'-monophosphate dehydrogenase.
IMP dehydrogenase (IMPDH) is an essential enzyme that catalyzes the first step unique to GTP synthesis. To provide a basis for the evaluation of IMPDH inhibitors as antimicrobial agents, we have expressed and characterized IMPDH from the pathogenic bacterium Streptococcus pyogenes. Our results show that the biochemical and kinetic characteristics of S. pyogenes IMPDH are similar to other bacterial IMPDH enzymes. However, the lack of sensitivity to mycophenolic acid and the Km for NAD (1180 microM) exemplify some of the differences between the bacterial and mammalian IMPDH enzymes, making it an attractive target for antimicrobial agents. To evaluate the basis for these differences, we determined the crystal structure of the bacterial enzyme at 1.9 A with substrate bound in the catalytic site. The structure was determined using selenomethionine-substituted protein and multiwavelength anomalous (MAD) analysis of data obtained with synchrotron radiation from the undulator beamline (19ID) of the Structural Biology Center at Argonne's Advanced Photon Source. S. pyogenes IMPDH is a tetramer with its four subunits related by a crystallographic 4-fold axis. The protein is composed of two domains: a TIM barrel domain that embodies the catalytic framework and a cystathione beta-synthase (CBS) dimer domain of so far unknown function. Using information provided by sequence alignments and the crystal structure, we prepared several site-specific mutants to examine the role of various active site regions in catalysis. These variants implicate the active site flap as an essential catalytic element and indicate there are significant differences in the catalytic environment of bacterial and mammalian IMPDH enzymes. Comparison of the structure of bacterial IMPDH with the known partial structures from eukaryotic organisms will provide an explanation of their distinct properties and contribute to the design of specific bacterial IMPDH inhibitors.


Novel antioxidant peptides obtained by alcalase hydrolysis of Erythrina edulis (pajuro) protein.
Oxidative reactions are responsible for the changes in quality during food processing and storage. Oxidative stress is also involved in multiple chronic diseases, such as cardiovascular and neurodegenerative disorders, diabetes, cancer, and aging. The consumption of dietary antioxidants has been demonstrated to help to reduce the oxidative damage in both the human body and food systems. In this study, the potential of Erythrina edulis (pajuro) protein as source of antioxidant peptides was evaluated. Pajuro protein concentrate hydrolyzed by alcalase for 120 min showed potent ABTS·+ and peroxyl radical scavenging activity with Trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC) values of 1.37 ± 0.09 µmol TE mg-1 peptide and 2.83 ± 0.07 µmol TE mg-1 peptide, respectively. Fractionation of the hydrolyzate to small peptides resulted in increased antioxidant activity. De novo sequencing of most active fractions collected by chromatographic analysis enabled 30 novel peptides to be identified. Of these, ten were synthesized and their radical activity evaluated, demonstrating their relevant contribution to the antioxidant effects observed for pajuro protein hydrolyzate. The sequences identified represent an important advance in the molecular characterization of the pajuro protein, demonstrating its potential as a source of antioxidant peptides for food and nutraceutical applications. © 2018 Society of Chemical Industry.


Preclinical multimodality phantom design for quality assurance of tumor size measurement.
Evaluation of changes in tumor size from images acquired by ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI) is a common measure of cancer chemotherapy efficacy. Tumor size measurement based on either the World Health Organization (WHO) criteria or the Response Evaluation Criteria in Solid Tumors (RECIST) is the only imaging biomarker for anti-cancer drug testing presently approved by the United States Food and Drug Administration (FDA). The aim of this paper was to design and test a quality assurance phantom with the capability of monitoring tumor size changes with multiple preclinical imaging scanners (US, CT and MRI) in order to facilitate preclinical anti-cancer drug testing. Three phantoms (Gammex/UTHSCSA Mark 1, Gammex/UTHSCSA Mark 2 and UTHSCSA multimodality tumor measurement phantom) containing tumor-simulating test objects were designed and constructed. All three phantoms were scanned in US, CT and MRI devices. The size of test objects in the phantoms was measured from the US, CT and MRI images. RECIST, WHO and volume analyses were performed. The smaller phantom size, simplified design and better test object CT contrast of the UTHSCSA multimodality tumor measurement phantom allowed scanning of the phantom in preclinical US, CT and MRI scanners compared with only limited preclinical scanning capability of Mark 1 and Mark 2 phantoms. For all imaging modalities, RECIST and WHO errors were reduced for UTHSCSA multimodality tumor measurement phantom (≤1.69 ± 0.33%) compared with both Mark 1 (≤ -7.56 ± 6.52%) and Mark 2 (≤ 5.66 ± 1.41%) phantoms. For the UTHSCSA multimodality tumor measurement phantom, measured tumor volumes were highly correlated with NIST traceable design volumes for US (R2 = 1.000, p < 0.0001), CT (R2 = 0.9999, p < 0.0001) and MRI (R2 = 0.9998, p < 0.0001). The UTHSCSA multimodality tumor measurement phantom described in this study can potentially be a useful quality assurance tool for verifying radiologic assessment of tumor size change during preclinical anti-cancer therapy testing with multiple imaging modalities.


The Photophysics of Three Naphthylmethylene Malononitriles.
The solvent dependence of the photophysical properties of three naphthylmethylene malononitriles, 1-(1-naphthalenylmethylene)-propanedinitrile (1-MN), 2-(2-naphthalenylmethylene)-propanedinitrile (2-MN), and 2-(3,4-dihydro-1(2H)-phenanthrenylidene)-propanedinitile (r2-MN), was studied in order to determine their potential utility as fluidity probes and to make comparisons to the better studied benzylidene malononitriles. Density functional calculations were used to understand the possible conformational states related to rotation about the vinyl-aromatic bond ("τ"). Absorption and emission frequencies, extinction coefficients, fluorescence quantum yields, and fluorescence lifetimes were measured in 11 representative solvents. Both the computational and experimental results indicate that the S0 → S1 transitions of these molecules have substantial charge-transfer character and produce highly polar excited states. Emission appears to result from relaxed S1 states which do not differ qualitatively from the Franck-Condon states reached by absorption. In 2-MN, time-resolved emission reveals the presence of two ground-state conformers ("a" and "b" differing by ∼180° rotation about τ) coexisting in low-polarity solvents. In contrast, 1-MN appears to exist primarily as a single dominant ground-state conformer. Fluorescence lifetimes vary from ∼1 ps in 1-MN to ∼200 ps in 2-MN(a) at room temperature. With the exception of 2-MN(a), the lifetimes vary systematically with solvent in a manner similar to what is observed in the benzylidene malononitriles. Both solvent polarity and fluidity appear to be important determinants of lifetime. The primary mechanism of fluorescence decay in naphthylmethylene malononitriles is likely to be the same as that of the benzylidene malononitriles-twisting about the double bond in S1, which leads to rapid internal conversion via a conical intersection with S0.


Water-Based Indium Tin Oxide Nanoparticle Ink for Printed Toluene Vapours Sensor Operating at Room Temperature.
This study is focused on the development of water-based ITO nanoparticle dispersions and ink-jet fabrication methodology of an indium tin oxide (ITO) sensor for room temperature operations. Dimensionless correlations of material-tool-process variables were used to map the printing process and several interpretational frameworks were re-examined. A reduction of the problem to the Newtonian fluid approach was applied for the sake of simplicity. The ink properties as well as the properties of the deposited layers were tested for various nanoparticles loading. High-quality films were prepared and annealed at different temperatures. The best performing material composition, process parameters and post-print treatment conditions were used for preparing the testing sensor devices. Printed specimens were exposed to toluene vapours at room temperature. Good sensitivity, fast responses and recoveries were observed in ambient air although the n-type response mechanism to toluene is influenced by moisture in air and baseline drift was observed. Sensing response inversion was observed in an oxygen and moisture-free N₂ atmosphere which is explained by the charge-transfer mechanism between the adsorbent and adsorbate molecules. The sensitivity of the device was slightly better and the response was stable showing no drifts in the protective atmosphere.


Management of severe hypercalcemia caused by primary hyperparathyroidism.
Hypercalcemic crisis is a rare but often fatal complication of hyperparathyroidism (HPT). The reported mortality of 60% has been related to delay in diagnosis and appropriate treatment. During a 16-year period (1961 to 1977), 29 patients with severe symptomatic hypercalcemia caused by primary HPT were treated at the Surgical Service at the University of Michigan Hospital. This group represents 6% of the patients with primary HPT treated during this period. All but one patient had an exploration of the neck when the serum calcium level had been decreased to 12 mg/100 ml by intravenous hydration with saline, furosemide diuresis, and mithramycin when a hypocalcemic agent was required. One comatose patient died of irreversible shock. All of the 28 patients who had parathyroidectomies survived the early postoperative period. One patient died three weeks later of a myocardial infarction. This study demonstrates that emergent nonoperative care of parathyroid crisis, followed promptly by parathyroidectomy, can be successful in nearly all cases.


Antibodies to Trichomonas vaginalis surface glycolipid.
Human trichomoniasis is the most common non-viral sexually transmitted disease, yet immune responses are not well studied. Since the Trichomonas vaginalis lipophosphoglycan (TvLPG) is an important virulence factor, a bank of eight monoclonal antibodies was generated to define the antigen in clinical isolates. The TvLPG-specific antibody response of women who were culture positive (n=33) or negative (n=33) for T vaginalis infection was determined by isotype-specific ELISA. The bank of monoclonal antibodies reacted with conserved surface TvLPG epitopes in 27 isolates from pregnant women at their first prenatal visit. Conserved TvLPG epitopes were shown to be surface exposed by immunofluorescence. Sera collected from the same patients at the same time were assayed for specific antibodies. Serum and vaginal secretions from 33 T vaginalis-positive women had statistically higher IgG anti-TvLPG levels than age-matched and race-matched negative controls in the same clinical study (p<0.01). Vaginal IgA anti-TvLPG levels of the women with trichomoniasis were almost significantly higher than controls (p=0.055). Infected women with normal pregnancies had significantly higher vaginal IgG anti-TvLPG values than infected women with adverse outcomes of pregnancy. These antibody responses show that infected women can respond to the conserved TvLPG antigen. Since antibodies to trichomonad surface LPG protect in a bovine model of trichomoniasis, the role of these antibodies in the human disease should be investigated.


Impaired immune function in Gulf War Illness.
Gulf War Illness (GWI) remains a serious health consequence for at least 11,000 veterans of the first Gulf War in the early 1990s. Our understanding of the health consequences that resulted remains inadequate, and this is of great concern with another deployment to the same theater of operations occurring now. Chronic immune cell dysfunction and activation have been demonstrated in patients with GWI, although the literature is not uniform. We exposed GWI patients and matched controls to an exercise challenge to explore differences in immune cell function measured by classic immune assays and gene expression profiling. This pilot study enrolled 9 GWI cases identified from the Department of Veterans Affairs GWI registry, and 11 sedentary control veterans who had not been deployed to the Persian Gulf and were matched to cases by sex, body mass index (BMI) and age. We measured peripheral blood cell numbers, NK cytotoxicity, cytokines and expression levels of 20,000 genes immediately before, immediately after and 4 hours following a standard bicycle ergometer exercise challenge. A repeated-measures analysis of variance revealed statistically significant differences for three NK cell subsets and NK cytotoxicity between cases and controls (p < 0.05). Linear regression analysis correlating NK cell numbers to the gene expression profiles showed high correlation of genes associated with NK cell function, serving as a biologic validation of both the in vitro assays and the microarray platform. Intracellular perforin levels in NK and CD8 T-cells trended lower and showed a flatter profile in GWI cases than controls, as did the expression levels of the perforin gene PRF1. Genes distinguishing cases from controls were associated with the glucocorticoid signaling pathway. GWI patients demonstrated impaired immune function as demonstrated by decreased NK cytotoxicity and altered gene expression associated with NK cell function. Pro-inflammatory cytokines, T-cell ratios, and dysregulated mediators of the stress response (including salivary cortisol) were also altered in GWI cases compared to control subjects. An interesting and potentially important observation was that the exercise challenge augments these differences, with the most significant effects observed immediately after the stressor, possibly implicating some block in the NK and CD8 T-cells ability to respond to "stress-mediated activation". This has positive implications for the development of laboratory diagnostic tests for this syndrome and provides a paradigm for exploration of the immuno-physiological mechanisms that are operating in GWI, and similar complex syndromes. Our results do not necessarily elucidate the cause of GWI, but they do reveal a role for immune cell dysfunction in sustaining illness.


Rare case of a kidney and inferior vena cava abnormalities with extensive lower extremity deep vein thrombosis in a young healthy male.
Kidney and inferior vena cava (IVC) abnormalities with extensive deep vein thrombosis (DVT) is a very rare cause of DVT and has a diverse clinical presentation. Computed tomography (CT) angiography is the gold standard for diagnosis and treatment including thrombectomy, thrombolysis and systemic anticoagulation. We present a rare case of active young healthy male admitted with acute onset of right lower extremity pain and swelling who was found to have extensive DVT on doppler ultrasound. CT abdomen showed extensive clot burden involving right common femoral vein extending into internal and external iliac veins associated with IVC hypoplasia and hypoplastic left kidney. Patient underwent urgent thrombectomy, catheter directed thrombolysis and was discharged home in stable condition on oral anticoagulation.


Transposon-derived small RNAs triggered by miR845 mediate genome dosage response in Arabidopsis.
Chromosome dosage has substantial effects on reproductive isolation and speciation in both plants and animals, but the underlying mechanisms are largely obscure 1 . Transposable elements in animals can regulate hybridity through maternal small RNA 2 , whereas small RNAs in plants have been postulated to regulate dosage response via neighboring imprinted genes3,4. Here we show that a highly conserved microRNA in plants, miR845, targets the tRNAMet primer-binding site (PBS) of long terminal repeat (LTR) retrotransposons in Arabidopsis pollen, and triggers the accumulation of 21-22-nucleotide (nt) small RNAs in a dose-dependent fashion via RNA polymerase IV. We show that these epigenetically activated small interfering RNAs (easiRNAs) mediate hybridization barriers between diploid seed parents and tetraploid pollen parents (the 'triploid block'), and that natural variation for miR845 may account for 'endosperm balance' allowing the formation of triploid seeds. Targeting of the PBS with small RNA is a common mechanism for transposon control in mammals and plants, and provides a uniquely sensitive means to monitor chromosome dosage and imprinting in the developing seed.


Multi-Compartment Profiling of Bacterial and Host Metabolites Identifies Intestinal Dysbiosis and Its Functional Consequences in the Critically Ill Child.
Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children. Prospective multicenter cohort study. Three U.K.-based PICUs. Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55). Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls. Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = -0.2; p = 0.037). Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. Profiling of bacterial metabolites in fecal and urine samples may support identification and treatment of intestinal dysbiosis in critical illness.


A DFT study on nanocones, nanotubes (4,0), nanosheets and fullerene C60 as anodes in Mg-ion batteries.
In this article, we studied the interactions between Mg atom and Mg2+ ion and four nanostructures, including a nanocone, nanotube (4,0), nanosheet, and C60 nanocage, to obtain the cell voltages (V) for Mg-ion batteries (MIBs). Total energy, geometry optimization, frontier molecular orbital (FMO) and density of states (DOS) analyses have been performed using the ωB97XD level of theory and the 6-31G(d) basis set. The DFT calculations clarified that the changes in energy adsorption between Mg2+ ion and the nanostructures, E ad, are in the order tube > cone > sheet > cage. However, V cell for the nanocone is the highest. The changes in V cell of the MIBs are in the order cone > tube > sheet > cage. This study theoretically considers the possibilities of Mg as an anode in batteries due to its high V cell values.


Genetics of peripheral vestibular dysfunction: lessons from mutant mouse strains.
A considerable amount of research has been published about genetic hearing impairment. Fifty to sixty percent of hearing loss is thought to have a genetic cause. Genes may also play a significant role in acquired hearing loss due to aging, noise exposure, or ototoxic medications. Between 1995 and 2012, over 100 causative genes have been identified for syndromic and nonsyndromic forms of hereditary hearing loss. Mouse models have been extremely valuable in facilitating the discovery of hearing loss genes and in understanding inner ear pathology due to genetic mutations or elucidating fundamental mechanisms of inner ear development. Whereas much is being learned about hereditary hearing loss and the genetics of cochlear disorders, relatively little is known about the role genes may play in peripheral vestibular impairment. Here we review the literature with regard to genetics of vestibular dysfunction and discuss what we have learned from studies using mutant mouse models and direct measures of peripheral vestibular neural function. Several genes are considered that when mutated lead to varying degrees of inner ear vestibular dysfunction due to deficits in otoconia, stereocilia, hair cells, or neurons. Behavior often does not reveal the inner ear deficit. Many of the examples presented are also known to cause human disorders. Knowledge regarding the roles of particular genes in the operation of the vestibular sensory apparatus is growing, and it is clear that gene products co-expressed in the cochlea and vestibule may play different roles in the respective end organs. The discovery of new genes mediating critical inner ear vestibular function carries the promise of new strategies in diagnosing, treating, and managing patients as well as predicting the course and level of morbidity in human vestibular disease.


Adolescent Body Image Distortion: A Consideration of Immigrant Generational Status, Immigrant Concentration, Sex and Body Dissatisfaction.
Immigrant adolescents represent a significant and growing proportion of the population in the United States. Yet, little is known about their experiences of body image distortion. This is particularly concerning given that body image distortion has been identified as a significant and modifiable risk factor for a number of mental illnesses, including depression and eating disorders. This study uses multi-level modeling to examine the associations between immigrant generational status, neighborhood immigrant concentration, sex, body dissatisfaction and risk for body image distortion. Data come from the National Longitudinal Study of Adolescent Health and includes 10,962 11-19 year olds (49.6 % female). First generation immigrant females were significantly more likely than 3rd generation-or-later adolescents to experience underweight body image distortion. There was no association between neighborhood immigrant concentration and risk for body image distortion. Body dissatisfaction was associated with greater risk for underweight and overweight body image distortion, with the magnitude of underweight distortion risk significantly greater among 1st generation immigrants. Interventions that encourage the development of a healthy body image have the potential to reduce the onset and duration of body image distortion among immigrant and non-immigrant adolescents.


Rapid trench channeling of graphenes with catalytic silver nanoparticles.
We demonstrate trench channeling of mono- and multilayer graphenes with silver nanoparticles with high speed in ambient environment and at elevated temperatures. A silver nanoparticle located at a graphene edge catalyzes oxidation of neighboring carbon atoms, thereby burning a trench into the graphene layer. High-resolution scanning tunneling microscopy imaging reveals that the trench edges are very smooth with a peak-to-peak roughness below 2 nm. We discuss the channeling mechanism and demonstrate that channeling speeds of up to 250 nm/s and the smoothness of the resulting trenches indicate the prospect of a "catalytic pen" for high-precision lithography on graphenes.


Concerted proton transfer mechanism of Clostridium thermocellum ribose-5-phosphate isomerase.
Ribose-5-phosphate isomerase (Rpi) catalyzes the interconversion of D-ribose-5-phosphate and D-ribulose-5-phosphate and plays an essential role in the pentose phosphate pathway and the Calvin cycle of photosynthesis. RpiB, one of the two isoforms of Rpi, is also a potential drug target for some pathogenic bacteria. Clostridium thermocellum ribose-5-phosphate isomerase (CtRpi), belonging to the RpiB family, has recently been employed in the industrial production of rare sugars because of its fast reaction kinetics and narrow substrate specificity. It is known that this enzyme adopts a proton transfer mechanism. It was suggested that the deprotonated Cys65 attracts the proton at C2 of the substrate to initiate the isomerization reaction, and this step is the rate-limiting step. However the elaborate catalytic mechanism is still unclear. We have performed quantum mechanical/molecular mechanical simulations of this rate-limiting step of the reaction catalyzed by CtRpi with the substrate D-ribose. Our results demonstrate that the deprotonated Cys65 is not a stable reactant. Instead, our calculations revealed a concerted proton-transfer mechanism: Asp8, a highly conserved residue in the RpiB family, performs as the base to abstract the proton at Cys65 and Cys65 in turn abstracting the proton of the D-ribose simultaneously. Moreover, we found Thr67 cannot catalyze the proton transfer from O2 to O1 of the D-ribose alone. Water molecule(s) may assist this proton transfer with Thr67. Our findings lead to a clear understanding of the catalysis mechanism of the RpiB family and should guide experiments to increase the catalysis efficiency. This study also highlights the importance of initial protonation states of cysteines.


Do Appalachian women attending a mobile mammography program differ from those visiting a stationary mammography facility?
To compare the characteristics (demographic, access to care, health-related behavioral, self and family medical history, psychosocial) of women aged 40 years and above who utilize a mobile mammography unit with those women aged 40 years and above who obtain mammography screening at a stationary facility. A cross-sectional study design was used with participant cohorts comprised of women age 40 years and above throughout West Virginia (WV) who utilized mobile mammography unit to get mammogram and those who had mammography screening at the stationary facility and completed the Mammography Screening and Preventive Care Survey. A total of 1,161 women who utilized the mobile mammography unit and 1,104 women who utilized stationary facility were included in the analysis. In logistic regression after adjusting for all the variables, women who utilized mobile mammography unit were more likely to be in age group 40-49, with lower income, with no health insurance coverage, not visit doctor or obstetrician/gynecologist (OB/GYN) in the past year, not adherent to clinical breast exam and mammography screening guidelines, with lower perceived five-year risk of developing breast cancer and with high knowledge about mammography screening. Women who utilize mobile unit are not adherent to mammography screening guidelines thereby suggesting that the mobile mammography unit is indeed reaching a rural vulnerable population who may not routinely access preventive health services. Financial and insurance constraints, as well as access to medical care, restricted WV women from receiving mammography screening from the stationary screening facilities.


LD-cladding-pumped 50 pm linewidth Tm 3+ -doped silica fiber laser.
We report on a Tm(3+)-doped fiber laser source operating at 1936.4 nm with a very narrow linewidth (50 pm) laser output. Up to 2.4 W cw laser power was obtained from an 82 cm long Tm(3+)-doped multimode-core fiber cladding pumped by a 792 nm laser diode (LD). The fiber laser cavity included a high-reflective dichroic and a low-reflective FBG output coupler. The multimode fiber Bragg grating (FBG) transmission spectrum and output laser spectrum were measured. By adjusting the distance between the dichroic and the Tm(3+)-doped fiber end, the multipeak laser spectrum changed to a single-peak laser spectrum.


Exploring the Map of Medicine's potential in undergraduate medical education.
Map of Medicine is a web-based knowledge resource depicting evidence-based pathways of patient care. Recent publications suggest a possible role for the Map of Medicine as a training tool in postgraduate education. The aim of this study was to explore the potential of the Map of Medicine to enhance undergraduate medical education. A mixed-method study including a survey of UK medical schools, and the embedding of the resource at one medical school and the evaluation of its impact. The survey found that only 1 of 23 medical schools was using the Map of Medicine in its undergraduate curriculum. The Peninsula Medical School students' reaction to the resource was extremely positive. Students liked the Map of Medicine's navigability and help in accessing reliable information. Use of the resource by students grew steadily throughout the period of the study and peaked at 595 sessions a month. There was evidence that usage was directly linked to curricular events, particularly problem-based learning tutorials and medical knowledge assessments. There is clear potential for the Map of Medicine in undergraduate medical education and a short-active period of resource promotion led to its embedding within routine learning practice.


Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium.
Big efforts have been dedicated up to now to identify novel targets for cancer treatment. The peculiar biophysical profile and the atypical ionic channels activity shown by diverse types of human cancers suggest that ion channels may be possible targets in cancer therapy. Earlier studies have shown that melatonin exerts an oncostatic action on different tumors. In particular, it was shown that melatonin was able to inhibit growth/viability and proliferation, to reduce the invasiveness and metastatic properties of human estrogen-sensitive breast adenocarcinoma MCF-7 cell line cultured in growth medium, with substantial impairments of epidermal growth factor (EGF) and Notch-1-mediated signaling. The purpose of this work was to evaluate on MCF-7 cells the possible effects of melatonin on the biophysical features known to have a role in proliferation and differentiation, by using the patch-clamp technique. Our results show that in cells cultured in growth as well as in differentiation medium melatonin caused a hyperpolarization of resting membrane potential paralleled by significant changes of the inward Ca(2+) currents (T- and L-type), outward delayed rectifier K(+) currents and cell capacitance. All these effects are involved in MCF-7 growth and differentiation. These findings strongly suggest that melatonin, acting as a modulator of different voltage-dependent ion channels, might be considered a new promising tool for specifically disrupting cell viability and differentiation pathways in tumour cells with possible beneficial effects on cancer therapy.


Current status of theories of hearing.
In summing up the current status of the hearing theories, it may be said that each of the vibration patterns of the basilar membrane postulated by the four major theories of hearing can be obtained by varying two elastic properties of the membrane-namely, the coupling between adjacent parts and the absolute value of the elasticity. If these two variables are adjusted to their numerical values in the cochlea of a living animal or a fresh preparation of the human ear, traveling waves are observed along the membrane. These traveling waves have a flat maximum that shifts its location along the membrane with a change of frequency-the place of the maximum determining the pitch. An enlarged dimensional model of the cochlea in which the nerve supply of the sensory organs on the basilar membrane was replaced by the skin of the arm indicates that the inhibitory action in the nervous system can produce quite sharp local sensations, which shift their place with changes in the frequency of the vibrations.


Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway.
S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflammation by regulating the activity of nuclear factor κB (NF-κB) and actin polymerization. Vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) migration is inhibited by Glrx overexpression. In mice overexpressing Glrx, blood flow recovery, exercise function and capillary density were significantly attenuated after hindlimb ischaemia (HLI). Wnt5a and soluble Fms-like tyrosine kinase-1 (sFlt-1) were enhanced in the ischaemic-limb muscle and plasma respectively from Glrx transgenic (TG) mice. A Wnt5a/sFlt-1 pathway had been described in myeloid cells controlling retinal blood vessel development. Interestingly, a Wnt5a/sFlt-1 pathway was found also to play a role in EC to inhibit network formation. S-glutathionylation of NF-κB components inhibits its activation. Up-regulated Glrx stimulated the Wnt5a/sFlt-1 pathway through enhancing NF-κB signalling. These studies show a novel role for Glrx in post-ischaemic neovascularization, which could define a potential target for therapy of impaired angiogenesis in pathological conditions including diabetes.


Coupling Optical and Electrical Measurements in Artificial Membranes: Lateral Diffusion of Lipids and Channel Forming Peptides in Planar Bilayers.
Planar lipid bilayers (PLB) were prepared by the Montal-Mueller technique in a FRAP system designed to simultaneously measure conductivity across, and lateral diffusion of, the bilayer. In the first stage of the project the FRAP system was used to characterise the lateral dynamics of bilayer lipids with regards to phospholipid composition (headgroup, chain unsaturation etc.), presence of cholesterol and the effect of divalent cations on negatively-charged bilayers. In the second stage of the project, lateral diffusion of two fluorescently-labelled voltage-dependent pore-forming peptides (alamethicin and S4s from Shaker K(+) channel) was determined at rest and in the conducting state. This study demonstrates the feasibility of such experiments with PLBs, amenable to physical constraints, and thus offers new opportunities for systematic studies of structure-function relationships in membrane-associating molecules.


Structural stability and intriguing electronic properties of two-dimensional transition metal dichalcogenide alloys.
Based on the first-principles calculations, we systematically studied the structures and electronic properties of two-dimensional (2D) transition metal dichalcogenide (TMD) alloys with half-to-half mixing of S and Se. Using the chemical potentials of S and Se, the energetic phase diagrams for both single phases and mixed phases of TMD were constructed. A new heterolayer structure (for Sc and Ti) and alternating structure (for Cr, Mn, Fe, Zr, Mo, and W) were proposed for the first time, which were thermodynamically stable for MSSe alloys under the S-poor (relatively low chemical potential of S) and Se-rich (relatively high chemical potential of Se) conditions, and further compared with the disordered structures. Moreover, band gaps, carrier effective mass, and work functions were calculated for these stable mixed phases. Compared to the single phases of MS2 and MSe2, MSSe alloys showed superior electronic properties including tunable band gaps and work functions. Importantly, the significantly reduced effective mass of the carriers in the MSSe alloys may induce higher carrier mobility, providing better performance of TMD materials in electronic devices.


Trace elements and thyroid cancer.
To evaluate the importance of trace amounts of elements in thyroid cancer etiology and diagnostics, instrumental neutron activation analysis has been used to estimate Ag, Co, Cr, Fe, Hg, I,Rb, Sb, Sc, Se, and Zn concentrations in malignant and benign thyroid nodules as well as in apparently intact paranodular thyroid tissue. Resected material from 135 patients was obtained from operations. Forty-five cancer cases were diagnosed and the rest were of benign nodules. The thyroid glands of 65 people, 53 male and 12 female, who died and unexpected death or committed suicide, were used as a control group. Trace element contents of the International Atomic Energy Agency reference material H-4 (animal muscle) were analysed simultaneously with the thyroid tissue in order to evaluate the accuracy of the obtained data. No dependence of trace element contents on sex and age (14-80 years) was found for normal thyroids. In paranodular tissue, the Ag, Co, Hg, I and Rb contents were much higher for malignant and benign nodules than they were for the standard. There was also a slight deficiency of Se in the nodules compared with the standard. This result supports the hypothesis that the direct toxic heavy metal influence on thyrocytes plays a major role in thyroid cancer etiology, provided that an adequate level of the defence mechanisms is absent. Iodine concentrations are 15 times lower, on average, in malignant compared with benign nodules. It is also shown that the radio between the iodine concentration in nodular and paranodular tissue can be used for in vivo thyroid cancer diagnostics.


Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism.
The increased glucose metabolism in cancer cells is required to fulfill their high energetic and biosynthetic demands. Changes in the metabolic activity of cancer cells are caused by the activation of oncogenes or loss of tumor suppressors. They can also be part of the metabolic adaptations to the conditions imposed by the tumor microenvironment, such as the hypoxia response. Among the metabolic enzymes that are modulated by these factors are the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases (PFKFBs), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate (Fru-2,6-P2). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating the rate-limiting enzyme of glycolysis phosphofructokinase-1 (PFK-1). Therapeutic strategies designed to alter the levels of this metabolite are likely to interfere with the metabolic balance of cancer cells, and could lead to a reduction in cancer cell proliferation, invasiveness and survival. This article will review our current understanding of the role of PFKFB proteins in the control of cancer metabolism and discuss the emerging interest in these enzymes as potential targets for the development of antineoplastic agents.


Novel Nut and Bolt Task Quantifies Motor Deficits in Premanifest and Manifest Huntington's Disease.
We investigated the use of a simple novel nut and bolt task in premanifest and manifest Huntington's disease (HD) patients to detect and quantify motor impairments at all stages of the disease. Premanifest HD (n=24), manifest HD (n=27) and control (n=32) participants were asked to screw a nut onto a bolt in one direction, using three different sized bolts with their left and right hand in turn. We identified some impairments at all stages of HD and in the premanifest individuals, deficits in the non-dominant hand correlated with disease burden scores. This simple, cheap motor task was able to detect motor impairments in both premanifest and manifest HD and as such might be a useful quantifiable measure of motor function for use in clinical studies.


Circulating levels and subcutaneous adipose tissue gene expression of pigment epithelium-derived factor in polycystic ovary syndrome and normal women: a case control study.
Polycystic ovary syndrome (PCOS) has been recognized as a metabolic disorder, manifested by abdominal obesity, insulin resistance, dyslipidemia and hypertension. Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor family, is a pleiotropic protein known for its antiangiogenic, antioxidant, and neuroprotective properties and has been shown to induce insulin resistance and play a role in glucose metabolism. Recent studies investigating circulating PEDF levels show elevated serum PEDF in association with insulin resistance in normal-weight women with PCOS, but not in obese PCOS patients. The aims of this study were 1) to assess PEDF gene expression in subcutaneous adipose tissue (scAT) from women with PCOS and nonhirsute, ovulatory controls, and 2) to determine the circulating levels of PEDF in these groups. Total RNA was extracted from adipose tissue biopsy samples and reverse-transcribed to cDNA. Real-time quantitative PCR was performed to determine relative gene expression levels. The 22 women with PCOS and 14 non-PCOS controls included in the study had similar age, BMI, and fasting glucose, triglycerides, and HDL-cholesterol levels. Participants with PCOS exhibited higher 2 h oral glucose tolerance test levels (p = 0.006), total (p = 0.026) and LDL-cholesterol (p = 0.036), Ferriman-Gallwey score (p = 0.003) and total testosterone (p = 0.001) as compared to controls. BMI-adjusted PEDF serum levels and scAT gene expression were similar in the PCOS and control groups (p = 0.622 and p = 0.509, respectively). Circulating PEDF levels were not associated with scAT PEDF gene expression. Multiple regression analysis revealed that, in women with PCOS, insulin contributed positively and significantly to serum PEDF (p = 0.027), independently of testosterone. Serum PEDF levels and scAT gene expression were associated with metabolic risk factors, but did not differ between women with PCOS and age- and BMI-matched controls. Circulating levels and scAT gene expression of PEDF were not associated in the study subjects, suggesting additional sources for PEDF in addition to or instead of fat tissue.


Chokeberry attenuates the expression of genes related to de novo lipogenesis in the hepatocytes of mice with nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD), which is characterized by steatosis, is a major public health concern. Previous studies have shown that chokeberry has anti-inflammatory, antimutagenic, hepatoprotective, cardioprotective, and antidiabetic effects. In this study, we hypothesized that chokeberry powder can attenuate the expression of genes related to de novo lipogenesis and the triglyceride levels in the hepatocytes of mice with high-fat diet-induced NAFLD. After coadministering chokeberry powder for 8weeks (0.5% and 1% powder) with a high-fat diet, mice that consumed chokeberry powder diets, regardless of the dose, had significantly lower liver triglyceride levels than control mice that were fed a high-fat diet (P=.0145 and P<.0012, respectively). Compared with mice that were fed a high-fat diet, mice that were given 1% chokeberry powder exhibited significantly decreased mRNA expression of sterol regulatory element-binding protein (P=.009) and acetyl-CoA carboxylase (P=.0032) in the liver. Compared with mice in the control group, fatty acid synthase (FAS) expression significantly increased in the mice that were fed a high-fat diet, but both chokeberry powder-treated groups had significantly decreased FAS expression (P=.0157 and P<.0001, respectively). The size of the fat droplets was decreased in the livers of the chokeberry-supplemented groups. In summary, the administration of chokeberry powder may help attenuate high-fat diet-induced NAFLD by regulating the expression levels of sterol regulatory element-binding protein, acetyl-CoA carboxylase, and FAS and by decreasing the size of the fat droplets in the liver.


Completion of guideline-recommended initial evaluation of atrial fibrillation.
Guidelines recommend evaluation of cardiac function, valvular and ischemic heart disease, and thyroid, kidney, and liver function on initial diagnosis of atrial fibrillation (AF). We hypothesized that initial workup of patients with newly identified AF would vary by age, sex, and burden of comorbid illness. In a retrospective analysis of a large sample of commercially insured patients 18 to 64 years old (n = 40 245) and a nationally representative 5% cohort of Medicare beneficiaries 65 years or older (n = 204 676), we measured claims for guideline-recommended services for initial evaluation of AF among patients with a new diagnosis between 2000 and 2008. From 30 days before through 90 days after AF diagnosis, basic evaluation, including physician visit, electrocardiogram, and echocardiography, was completed in up to 66.6% of patients. Completion rates for all guideline-recommended evaluations were 17.4% in the commercially insured sample and 18.5% in the Medicare cohort in 2007. Evaluation rates increased over time. Blood tests assessing thyroid function were documented for approximately one-third of patients in each cohort. Increasing the observation period to 1 year before through 3 months after the AF diagnosis markedly increased completion rates, but rates of thyroid function testing remained low (50%-60%). There were minor differences in evaluation completeness by sex, race, and geographic region. Differences in guideline-recommended evaluation rates by demographic characteristics after a new diagnosis of AF were of minor clinical importance. Basic evaluation had satisfactory completion rates; however, rates of laboratory testing were low.


Mycoplasma pneumoniae infection: role of a surface protein in the attachment organelle.
Attachment of Mycoplasma pneumoniae to host cell by means of a specialized terminus initiates infection. Monoclonal antibodies to a surface protein (Pl) inhibit this process, and react with a region of the tip covered with peplomer-like particles. Since antibodies against the Pl protein are generated by natural and experimental infection and by immunization, the substance may be an important determinant of protective immunity.


Melatonin and protection from whole-body irradiation: survival studies in mice.
The radioprotective ability of melatonin was investigated in mice exposed to an acute whole-body gamma radiation dose of 815 cGy (estimated LD50/30 dose). The animals were observed for mortality over a period of 30 days following irradiation. The results indicated 100% survival for unirradiated and untreated control mice, and for mice treated with melatonin or solvent alone. Forty-five percent of mice exposed to 815 cGy radiation alone, and 50% of mice pretreated with solvent and irradiated with 815 cGy were alive at the end of 30 days. Irradiated mice which were pretreated with 125 mg/kg melatonin exhibited a slight increase in their survival (60%) (p=0.3421). In contrast, 85% of irradiated mice which were pretreated with 250 mg/kg melatonin were alive at the end of 30 days (p=0.0080). These results indicate that melatonin (at a dose as high as 250 mg/kg) is non-toxic, and that high doses of melatonin are effective in protecting mice from lethal effects of acute whole-body irradiation.


The Role of an Inflammatory Bowel Disease Nurse in the Follow-Up of Patients From a Latin American Inflammatory Bowel Disease Program.
Inflammatory bowel disease requires long-term treatment to maintain disease control. Favorable follow-up of patients indicates attention from a multidisciplinary team, in which the nurse's responsibilities have great importance. The aim of this observational, descriptive study was to describe the role of an inflammatory bowel disease nurse in the management of patients in a tertiary center in Chile, including all patients in follow-up between January 2016 and April 2017. Inflammatory bowel disease nurse contacts were recorded and classified. Demographic data, clinical variables, and patient satisfaction were also analyzed. A total of 597 patients (51%) were in follow-up over the 16-month period; 63% had ulcerative colitis, with a median age of 35 years. The inflammatory bowel disease nurse performed 760 contacts in 253 patients (42% of the follow-up patients). The most frequent nurse interventions were reinforcement of medical indications (42%), assessment of laboratory results (17%), and disease follow-up (12%); 49% related to education. Nurse interventions were focused in more severely ill patients; flares during the follow-up, biological therapy, immunomodulators, and steroids were all statistically significant. Of a sample of 107 patients surveyed, 96% perceived the inflammatory bowel disease program as excellent/good. The inflammatory bowel disease nurse plays an important role in the follow-up and management, specifically in education, of more severely ill patients.


Triple P-Positive Parenting Program as a public health approach to strengthening parenting.
Parenting programs have considerable potential to improve the mental health and well-being of children, improve family relationships, and benefit the community at large. However, traditional clinical models of service delivery reach relatively few parents. A public health approach is needed to ensure that more parents benefit and that a societal-level impact is achieved. The Triple P-Positive Parenting Program is a comprehensive, multilevel system of parenting intervention that combines within a single intervention universal and more targeted interventions for high-risk children and their parents. With Triple P, the overarching goal is to enhance the knowledge, skills, and confidence of parents at a whole-of-population level and, in turn, to reduce the prevalence rates of behavioral and emotional problems in children and adolescents. The distinguishing features of the intervention and variables that influence its effective implementation are discussed. Self-regulation is a unifying concept that is applied throughout the entire system (e.g., to interactions between children, parents, service providers, and agencies involved in delivering the intervention). Challenges and future directions for the development of public health approaches to parenting are discussed.


The use of honey in cochlear implant associated wounds in pediatric patients.
The use of honey in wound care is becoming more common due to the proven benefit in all three phases of wound healing, as well as the antibacterial and antibiofilm properties. We present our experience using TheraHoney gel, a medical grade honey, for the successful treatment of cochlear implant associated skin breakdown. To describe the role of TheraHoney gel in the management of cutaneous infection and ulceration associated with cochlear implants. Three cases of wounds treated traditionally with antibiotics, plus the addition of TheraHoney, were retrospectively reviewed. The first patient had a superficial 1 × 1 cm ulcer, the second patient had bilateral ulcers: one superficial 1.5 × 1.5 cm ulcer and the other a 1.5 × 2 cm stage III pressure ulcer with an exposed receiver stimulator, and the third patient with a 3 × 3.5 cm stage III ulcer with an exposed receiver stimulator. With the addition of TheraHoney gel, complete wound closure was achieved at all three patients without the need for surgical reconstruction. Cutaneous infection with or without skin breakdown is a common delayed complication after cochlear implantation. We demonstrate the efficacy of adding medical grade honey in promoting healing in infected scalp pressure ulcers overlying the cochlear implant site.


The evolutionary convergence of mid-Mesozoic lacewings and Cenozoic butterflies.
Mid-Mesozoic kalligrammatid lacewings (Neuroptera) entered the fossil record 165 million years ago (Ma) and disappeared 45 Ma later. Extant papilionoid butterflies (Lepidoptera) probably originated 80-70 Ma, long after kalligrammatids became extinct. Although poor preservation of kalligrammatid fossils previously prevented their detailed morphological and ecological characterization, we examine new, well-preserved, kalligrammatid fossils from Middle Jurassic and Early Cretaceous sites in northeastern China to unravel a surprising array of similar morphological and ecological features in these two, unrelated clades. We used polarized light and epifluorescence photography, SEM imaging, energy dispersive spectrometry and time-of-flight secondary ion mass spectrometry to examine kalligrammatid fossils and their environment. We mapped the evolution of specific traits onto a kalligrammatid phylogeny and discovered that these extinct lacewings convergently evolved wing eyespots that possibly contained melanin, and wing scales, elongate tubular proboscides, similar feeding styles, and seed-plant associations, similar to butterflies. Long-proboscid kalligrammatid lacewings lived in ecosystems with gymnosperm-insect relationships and likely accessed bennettitalean pollination drops and pollen. This system later was replaced by mid-Cretaceous angiosperms and their insect pollinators.


Interaction between the autophagy protein Beclin 1 and Na+,K+-ATPase during starvation, exercise, and ischemia.
Autosis is a distinct form of cell death that requires both autophagy genes and the Na+,K+-ATPase pump. However, the relationship between the autophagy machinery and Na+,K+-ATPase is unknown. We explored the hypothesis that Na+,K+-ATPase interacts with the autophagy protein Beclin 1 during stress and autosis-inducing conditions. Starvation increased the Beclin 1/Na+,K+-ATPase interaction in cultured cells, and this was blocked by cardiac glycosides, inhibitors of Na+,K+-ATPase. Increases in Beclin 1/Na+,K+-ATPase interaction were also observed in tissues from starved mice, livers of patients with anorexia nervosa, brains of neonatal rats subjected to cerebral hypoxia-ischemia (HI), and kidneys of mice subjected to renal ischemia/reperfusion injury (IRI). Cardiac glycosides blocked the increased Beclin 1/Na+,K+-ATPase interaction during cerebral HI injury and renal IRI. In the mouse renal IRI model, cardiac glycosides reduced numbers of autotic cells in the kidney and improved clinical outcome. Moreover, blockade of endogenous cardiac glycosides increased Beclin 1/Na+,K+-ATPase interaction and autotic cell death in mouse hearts during exercise. Thus, Beclin 1/Na+,K+-ATPase interaction is increased in stress conditions, and cardiac glycosides decrease this interaction and autosis in both pathophysiological and physiological settings. This crosstalk between cellular machinery that generates and consumes energy during stress may represent a fundamental homeostatic mechanism.


The meninges is a source of retinoic acid for the late-developing hindbrain.
One general function for retinoic acid (RA) is pattern organization in the CNS. This regulatory factor has an essential role in spinal cord motor neuron and early posterior hindbrain development. In the anterior CNS, however, there is only a limited number of foci of RA synthesis, and less attention has been placed on regions such as the anterior hindbrain where RA synthesizing enzymes are absent. This study shows that a rich source of RA lies around the hindbrain from the RA synthetic enzyme retinaldehyde dehydrogenase-2 (RALDH2) present in the surrounding meninges and mesenchyme by embryonic day 13. RALDH2 is not distributed uniformly throughout the meninges but is restricted to territories over the developing hindbrain, suggesting that RA signaling may be localized to those regions. Further regulation of RA signaling is provided by the presence of a RA sink in the form of the CYP26B1 RA catabolic enzyme expressed in deeper regions of the brain. As a guide to the neural anatomy of hindbrain RA signaling, we used a mouse transgenic for a lacZ reporter gene driven by a RA response element (RAREhsplacZ) to identify regions of RA signaling. This reporter mouse provides evidence that RA signaling in the hindbrain after embryonic day 13 occurs in the regions of the cerebellum and precerebellar system adjacent to sources of RA, including the inferior olive and the pontine nuclei.


Flexibility vs. robustness in cell cycle regulation of timing of M-phase entry in Xenopus laevis embryo cell-free extract.
During the cell cycle, cyclin dependent kinase 1 (CDK1) and protein phosphatase 2A (PP2A) play major roles in the regulation of mitosis. CDK1 phosphorylates a series of substrates triggering M-phase entry. Most of these substrates are dephosphorylated by PP2A. To allow phosphorylation of CDK1 substrates, PP2A is progressively inactivated upon M-phase entry. We have shown previously that the interplay between these two activities determines the timing of M-phase entry. Slight diminution of CDK1 activity by the RO3306 inhibitor delays M-phase entry in a dose-dependent manner in Xenopus embryo cell-free extract, while reduction of PP2A activity by OA inhibitor accelerates this process also in a dose-dependent manner. However, when a mixture of RO3306 and OA is added to the extract, an intermediate timing of M-phase entry is observed. Here we use a mathematical model to describe and understand this interplay. Simulations showing acceleration and delay in M-phase entry match previously described experimental data. CDC25 phosphatase is a major activator of CDK1 and acts through CDK1 Tyr15 and Thr14 dephosphorylation. Addition of CDC25 activity to our mathematical model was also consistent with our experimental results. To verify whether our assumption that the dynamics of CDC25 activation used in this model are the same in all experimental variants, we analyzed the dynamics of CDC25 phosphorylation, which reflect its activation. We confirm that these dynamics are indeed very similar in control extracts and when RO3306 and OA are present separately. However, when RO3306 and OA are added simultaneously to the extract, activation of CDC25 is slightly delayed. Integration of this parameter allowed us to improve our model. Furthermore, the pattern of CDK1 dephosphorylation on Tyr15 showed that the real dynamics of CDK1 activation are very similar in all experimental variants. The model presented here accurately describes, in mathematical terms, how the interplay between CDK1, PP2A and CDC25 controls the flexible timing of M-phase entry.


Short biodegradable polyamines for gene delivery and transfection of brain capillary endothelial cells.
With the goal of rational design of systemic gene delivery system and efficient transfection of capillary endothelial cells forming the blood-brain barrier (BBB), we synthesized several short polyamines with reducible disulfide backbones for pDNA packaging, internalization and consequent release from endosomal compartments. The synthetic cationic polymers prepared from short linear PEI (pLPEI), triethylenetetramine (pTETA), and spermine (pSPE), demonstrated very low toxicity, good condensation capacity, and high levels of pDNA protection, producing small particulate nanoformulations. Mild reduction of the disulfide backbone allowed complete release of pDNA from these polyplexes. In vitro transfection of murine brain capillary endothelial bEnd.3 cells with pSPE, pTETA, and pLPEI polyplexes was 2.3-4.9 times more effective compared with the non-degradable LPEI 22kDa reagent (ExGen500) in the presence of serum. Their transfection ability was noticeably decreased following inhibition of the cellular reduced glutathione (GSH). After cellular uptake of biodegradable polyplexes, a disperse distribution of labeled pDNA in the cytoplasm of transfected cells was observed in contrast to ExGen500. Based on these polyamines, novel multifunctional polyplexes have been developed for efficient nuclear delivery of pDNA by co-application of NLS peptide and PEG-modified intercalating conjugates. Significant increase of nuclear accumulation was observed, and the transfection of bEnd.3 cells was additionally enhanced nearly 2-fold, demonstrating 8.5-, 6.3- and 3.7-fold better levels for pLPEI, pTETA, and pSPE, respectively, compared to ExGen500. Following brain-specific targeting, these safe and effective polyplexes may be converted into systemic nanocarriers for gene delivery and transfection of the BBB.


Planetary boundaries and Veterinary Services.
National Veterinary Services (NVS) play a crucial role in animal health, production and welfare. They are also intimately involved with safeguarding global health security and the health of the planet. Climate change is just one of the nine planetary boundaries (PBs), i.e. Earth system processes, that can be used to monitor the vital signs of our living planet. In this paper, the authors identify the positive and negative impacts of humaninduced management of aquatic and terrestrial animals in relation to these PBs. In the context of NVS, the authors provide an overview of the real and potential impacts of NVS policies on Earth systems and offer suggestions as to how new sustainability paradigms may assist with reviewing and revising NVS mandates and facilitating stakeholder engagement. Opportunities are proposed for the World Organisation for Animal Health to contribute to the global debate on the role of aquatic and terrestrial animal agriculture and wildlife in sustainable development. In addition, the paper suggests that a wider debate is required in relation to recent significant increases in domestic animal populations and PBs. Intersectoral and interdisciplinary collaboration are required to achieve the transformation of the framework in which NVS operate. While such transformations cannot be driven by the veterinary profession alone, veterinarians have proven very effective operators in the One Health arena. By building on these intersectoral linkages, it will be possible for our profession and NVS to actively contribute to the crucial discussions and transformations required to pull Earth system metrics back within safe boundaries.


Structural changes of Schistosoma mansoni adult worms recovered from C57BL/6 mice treated with radiation-attenuated vaccine and/or praziquantel against infection.
Although the current treatment of schistosomiasis relies largely on praziquantel (PZQ), it has not significantly reduced the overall number of disease cases, perhaps due to inevitable resistance to PZQ. Previous studies showed that radiation-attenuated vaccine gives protection levels for Schistosoma mansoni in host various species. In the present study, we evaluated the effect of various vaccination strategies in C57BL/6 mice, including single or multiple vaccination strategy, subcurative dose (20 mg/kg) of PZQ, and a combination of single vaccination with subcurative dose of PZQ. Groups of five mice were sacrificed postinfection in 42 days and schistosomes were collected by perfusion and examined by scanning electron microscopy. Treatment either with subcurative dose of PZQ or with a single vaccination of attenuated cercariae (500 per mouse), caused significant reduction in total worm burden, hepatic and intestinal ova counts 43.03%, 73.2%, 59.5% and 37.97%, 52.02%, 26.3%, respectively. Furthermore, tegumental changes were observed, including severe swelling, fusion of tegumental folds, vesicle formation, and loss or shortening of the spines on the tubercles. However, multiple vaccination strategy resulted in much higher reduction in total worm burden, hepatic and intestinal ova count. However, multiple vaccination strategy resulted in high reduction of worm burden, hepatic and intestinal ova counts 72.5%, 90.7%, 65.79%, respectively, and further causing swollen, disruption of tubercles teguments and erosion, extensive peeling, fusion of tegumental folds. Our findings suggest that multiple vaccination strategy is the most effective strategy to clear schistosomal infection, indicating its potential in guiding the design of appropriate therapeutic strategy against schistosomes.


Role of hypoxia on increased blood pressure in patients with obstructive sleep apnoea.
Cyclical changes in systemic blood pressure occur during apnoeic episodes in patients with obstructive sleep apnoea (OSA). Although several factors including arterial hypoxaemia, intrathoracic pressure changes, and disruption of sleep architecture have been reported to be responsible for these changes in blood pressure, the relative importance of each factor remains unclear. This study assessed the role of hypoxaemia on the increase in blood pressure during apnoeic episodes. The blood pressure in apnoeic episodes during sleep and the blood pressure response to isocapnic intermittent hypoxia whilst awake were measured in 10 men with OSA. While asleep the blood pressure was measured non-invasively using a Finapres blood pressure monitor with polysomnography. The response of the blood pressure to hypoxia whilst awake was also measured while the subjects intermittently breathed a hypoxic (5% or 7% oxygen) gas mixture. Each hypoxic gas exposure was continued until a nadir arterial oxygen saturation (nSaO2) of less than 75% was reached, or for a period of 100 seconds. The exposure was repeated five times in succession with five interposed breaths of room air in each run. The mean (SD) increase in blood pressure (delta MBP) during apnoeic episodes was 42.1 (17.3) mm Hg during rapid eye movement (REM) sleep and 31.9 (12.5) mm Hg during non-REM sleep. The delta MBP during apnoeic episodes showed a correlation with the decrease of nSaO2 (delta SaO2) (r2 = 0.30). The change in blood pressure in response to intermittent hypoxia whilst awake was cyclical and qualitatively similar to that during apnoeic episodes. Averaged delta MBP at an SaO2 of 7% and 5% oxygen was 12.6 (5.7) and 13.4 (3.6) mm Hg, respectively, whereas the averaged delta MBP at the same delta SaO2 during apnoeic episodes was 38.4 (15.5) and 45.2 (20.5) mm Hg, respectively. The blood pressure response to desaturation whilst awake was about one third of that during apnoeic episodes. These results suggest that factors other than hypoxia may play an important part in raising the blood pressure during obstructive sleep apnoea.


Mitochondria-coupled glucose phosphorylation develops after birth to modulate H2 O2 release and calcium handling in rat brain.
The adult brain is a high-glucose and oxygen-dependent organ, with an extremely organized network of cells and large energy-consuming synapses. To reach this level of organization, early stages in development must include an efficient control of cellular events and regulation of intracellular signaling molecules and ions such as hydrogen peroxide (H2 O2 ) and calcium (Ca2+ ), but in cerebral tissue, these mechanisms of regulation are still poorly understood. Hexokinase (HK) is the first enzyme in the metabolism of glucose and, when bound to mitochondria (mtHK), it has been proposed to have a role in modulation of mitochondrial H2 O2 generation and Ca2+ handling. Here, we have investigated how mtHK modulates these signals in the mitochondrial context during postnatal development of the mouse brain. Using high-resolution respirometry, western blot analysis, spectrometry and resorufin, and Calcium Green fluorescence assays with brain mitochondria purified postnatally from day 1 to day 60, we demonstrate that brain HK increases its coupling to mitochondria and to oxidative phosphorylation to induce a cycle of ADP entry/ATP exit of the mitochondrial matrix that leads to efficient control over H2 O2 generation and Ca2+ uptake during development until reaching plateau at day 21. This contrasts sharply with the antioxidant enzymes, which do not increase as mitochondrial H2 O2 generation escalates. These results suggest that, as its use of glucose increases, the brain couples HK to mitochondria to improve glucose metabolism, redox balance and Ca2+ signaling during development, positioning mitochondria-bound hexokinase as a hub for intracellular signaling control.


Antihyperglycemic Medications: A Claims-Based Estimate of First-line Therapy Use Prior to Initialization of Second-line Medications.
The American Diabetes Association recommends metformin as first-line therapy for type 2 diabetes. However, nonadherence to antihyperglycemic medication is common, and a clinician could confuse nonadherence with pharmacologic failure, potentially leading to premature prescribing of second-line therapies. We measured metformin use prior to second-line therapy initialization. This retrospective cross-sectional study used unidentifiable member claims data from individuals covered from 2010 to 2015 by Aetna, a U.S. health benefits company. Beneficiaries with two physician claims or one hospitalization with a type 2 diabetes diagnosis were included. Recommended use of metformin was measured by the proportion of days covered over 60 days. Through sensitivity analysis, we varied estimates of the percentage of beneficiaries who used low-cost generic prescription medication programs. A total of 52,544 individuals with type 2 diabetes were eligible. Of 22,956 patients given second-line treatment, only 1,875 (8.2%) had evidence of recommended use of metformin in the prior 60 days, and 6,441 (28.0%) had no prior claims evidence of having taken metformin. At the top range of sensitivity, only 49.5% patients could have had recommended use. Patients were more likely to be given an additional second-line antihyperglycemic medication or insulin if they were given their initial second-line medication without evidence of recommended use of metformin (P < 0.001). Despite published guidelines, second-line therapy often is initiated without evidence of recommended use of first-line therapy. Apparent treatment failures, which may in fact be attributable to nonadherence to guidelines, are common. Point-of-care and population-level processes are needed to monitor and improve guideline adherence.


The Drosophila homolog of the mammalian imprint regulator, CTCF, maintains the maternal genomic imprint in Drosophila melanogaster.
CTCF is a versatile zinc finger DNA-binding protein that functions as a highly conserved epigenetic transcriptional regulator. CTCF is known to act as a chromosomal insulator, bind promoter regions, and facilitate long-range chromatin interactions. In mammals, CTCF is active in the regulatory regions of some genes that exhibit genomic imprinting, acting as insulator on only one parental allele to facilitate parent-specific expression. In Drosophila, CTCF acts as a chromatin insulator and is thought to be actively involved in the global organization of the genome. To determine whether CTCF regulates imprinting in Drosophila, we generated CTCF mutant alleles and assayed gene expression from the imprinted Dp(1;f)LJ9 mini-X chromosome in the presence of reduced CTCF expression. We observed disruption of the maternal imprint when CTCF levels were reduced, but no effect was observed on the paternal imprint. The effect was restricted to maintenance of the imprint and was specific for the Dp(1;f)LJ9 mini-X chromosome. CTCF in Drosophila functions in maintaining parent-specific expression from an imprinted domain as it does in mammals. We propose that Drosophila CTCF maintains an insulator boundary on the maternal X chromosome, shielding genes from the imprint-induced silencing that occurs on the paternally inherited X chromosome. See commentary: http://www.biomedcentral.com/1741-7007/8/104.


Levofloxacin inhalation solution for the treatment of chronic Pseudomonas aeruginosa infection among patients with cystic fibrosis.
Chronic pulmonary infections are common among patients with cystic fibrosis. By 10 years of age, Pseudomonas aeruginosa is the predominant pathogen. Inhaled levofloxacin solution (MP-376) is a promising new therapy that exhibits rapid antibacterial activity and excellent biofilm penetration against P. aeruginosa. In the largest trial to date, 151 patients were randomized to receive MP-376 or placebo. At the end of the 28-day treatment period, patients who received MP-376 had decreased P. aeruginosa density in sputum, improved lung function parameters and improved respiratory symptoms. MP-376 also appeared to be safe and well tolerated. The results of two recently completed Phase III trials have not yet been released; however, these data will be critical in determining whether MP-376 is a safe and effective maintenance therapy for chronic pulmonary P. aeruginosa infections among patients with cystic fibrosis.


A Comparison of the Match Demands of International and Provincial Rugby Sevens.
To compare the running demands and match activity profiles of international and provincial rugby sevens players. 84 rugby sevens players, consisting of 16 international players from 1 team and 68 provincial players from 8 teams. Global positioning system analysis was completed during international and provincial tournament matches. Video analysis was also used to quantify the individual match activities during tournament matches. Trivial to moderate differences were found in the running demands of international and provincial players, with internationals covering a greater distance at very high speed (ES = 0.30) and performing a greater number of sprints (ES = 0.80). Small differences were found between the 2 levels in all but total tackles (ES = 0.07) and defensive ruck effectiveness (ES = 0.64). International matches incurred a greater overall ball-in-play time than provincial matches (proportion ratio = 1.32). These findings demonstrate that both physical and technical factors distinguish international and provincial rugby sevens, although overall match demands are similar.