Mechanism of cell death following thymidylate synthase inhibition: 2'-deoxyuridine-5'-triphosphate accumulation, DNA damage, and growth inhibition following exposure to CB3717 and dipyridamole.
The thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) inhibits the growth of human lung carcinoma A549 cells. The cytotoxicity of CB3717 is potentiated by the nucleoside transport inhibitor dipyridamole (DP), which not only inhibits the uptake and therefore salvage of thymidine but also inhibits the efflux of deoxyuridine, thereby enhancing the intracellular accumulation of deoxyuridine nucleotides. Measurement of intracellular deoxyuridine triphosphate (dUTP) pools, by sensitive radioimmunoassay, demonstrated a large increase in response to CB3717, in a dose- and time-related manner, and this accumulation was enhanced by coincubation with DP. In untreated cells and those treated with DP alone, dUTP was close to or below the limit of detection of the assay. In cells treated for 24 h with 3 microM CB3717 (concentration producing 50% growth inhibition) the intracellular dUTP was 46.1 +/- 9.6 (SEM) pmol/10(6) cells and after 24 h exposure to 30 microM CB3717, 337.5 +/- 37.9 pmol dUTP/10(6) cells was detected. There was significant enhancement by DP of the accumulation of dUTP in cells treated with CB3717; coincubation of cells with 1 microM DP + 3 microM CB3717 for 24 h resulted in intracellular dUTP levels of 174.7 +/- 57.7 pmol/10(6) cells. Accumulation of DNA strand breaks, measured by alkaline elution, also increased in response to CB3717 concentration and exposure period. Newly synthesized (nascent) DNA was more sensitive to damage by CB3717 than was mature DNA. As with the accumulation of dUTP, coincubation with DP also enhanced the accumulation of strand breaks, whereas DP alone had little or no effect on DNA fragmentation. When data for cells treated with CB3717 alone and CB3717 in combination with DP were combined, there was a significant correlation of intracellular dUTP levels with the level of DNA strand breaks. This strongly suggests that growth inhibition following thymidylate synthase inhibition is mediated through an increase in intracellular dUTP, leading to uracil misincorporation into DNA, its subsequent excision, and resultant strand breakage.


Yes-associated protein regulates the hepatic response after bile duct ligation.
Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Yes-associated protein (YAP), the effector of the Hippo tumor-suppressor pathway, has been shown to play a critical role in promoting cholangiocyte and hepatocyte proliferation and survival during embryonic liver development and hepatocellular carcinogenesis. Therefore, the aim of this study was to examine whether YAP participates in the regenerative response after cholestatic injury. First, we examined human liver tissue from patients with chronic cholestasis. We found more-active nuclear YAP in the bile ductular reactions of primary sclerosing cholangitis and primary biliary cirrhosis patient liver samples. Next, we used the murine bile duct ligation (BDL) model to induce cholestatic liver injury. We found significant changes in YAP activity after BDL in wild-type mice. The function of YAP in the hepatic response after BDL was further evaluated with liver-specific Yap conditional deletion in mice. Ablating Yap in the mouse liver not only compromised bile duct proliferation, but also enhanced hepatocyte necrosis and suppressed hepatocyte proliferation after BDL. Furthermore, primary hepatocytes and cholangiocytes isolated from Yap-deficient livers showed reduced proliferation in response to epidermal growth factor in vitro. Finally, we demonstrated that YAP likely mediates its biological effects through the modulation of Survivin expression. Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and thus may mediate the response to cholestasis-induced human liver disease.


Cardiovascular Risk Behavior among Students of a Medical College in Delhi.
Life style related behavioural risk factors are mainly implicated for increased burden of cardio- vascular diseases. Research related to these risk behaviours especially among medical students is essential, considering their role as future physicians and role models in public health intervention programmes. To evaluate the burden of cardiovascular risk behaviours among students of a medical college of Delhi, India. A cross sectional study was carried out among undergraduate medical students of a medical college in Delhi. Self administered questionnaire was used to collect information on identification data and risk behaviours in relation to cardiovascular diseases. Binary logistic regression analysis was done to calculate adjusted odds ratio to assess association between risk behaviours and covariates. The minimum recommendation of taking at least five servings per day of fruits and vegetables was complied only by 12% of students. Consumption of carbonated soft drinks either once or more on daily basis was present in 23.7% students and 32.0% reported frequent consumption of fast foods in past week. Consumption of alcohol was present in 28.8% students but only small proportion of students (7%) was current tobacco users. Large proportions of students (42.6%) were either not carrying out or were involved in only occasional physical activity in past week. Unhealthy behavioural practises are present and may progress as student advance through medical college. Developing strategies targeting at these risk behaviours and determining factors is necessary to promote healthy life style among medical students.


Geospatial modeling approach to monument construction using Michigan from A.D. 1000-1600 as a case study.
Building monuments was one way that past societies reconfigured their landscapes in response to shifting social and ecological factors. Understanding the connections between those factors and monument construction is critical, especially when multiple types of monuments were constructed across the same landscape. Geospatial technologies enable past cultural activities and environmental variables to be examined together at large scales. Many geospatial modeling approaches, however, are not designed for presence-only (occurrence) data, which can be limiting given that many archaeological site records are presence only. We use maximum entropy modeling (MaxEnt), which works with presence-only data, to predict the distribution of monuments across large landscapes, and we analyze MaxEnt output to quantify the contributions of spatioenvironmental variables to predicted distributions. We apply our approach to co-occurring Late Precontact (ca. A.D. 1000-1600) monuments in Michigan: (i) mounds and (ii) earthwork enclosures. Many of these features have been destroyed by modern development, and therefore, we conducted archival research to develop our monument occurrence database. We modeled each monument type separately using the same input variables. Analyzing variable contribution to MaxEnt output, we show that mound and enclosure landscape suitability was driven by contrasting variables. Proximity to inland lakes was key to mound placement, and proximity to rivers was key to sacred enclosures. This juxtaposition suggests that mounds met local needs for resource procurement success, whereas enclosures filled broader regional needs for intergroup exchange and shared ritual. Our study shows how MaxEnt can be used to develop sophisticated models of past cultural processes, including monument building, with imperfect, limited, presence-only data.


Epithelial-derived TGF-beta2 modulates basal and wound-healing subepithelial matrix homeostasis.
The epithelium influences the mesenchyme during dynamic processes such as embryogenesis, wound healing, fibrosis, and carcinogenesis. Since transforming growth factor-beta (TGF-beta) modulates these processes, we hypothesized that epithelial-derived TGF-beta also plays a critical role in maintaining the extracellular matrix at basal conditions. We utilized an in vitro model of the epithelial-mesenchymal trophic unit in the human airways to determine the role of epithelial-derived TGF-beta in modulating the extracellular matrix under basal and wound-healing conditions. When differentiated at an air-liquid interface, the human bronchial epithelium produces active TGF-beta2 at a concentration of 50-70 pg/ml, whereas TGF-beta1 is undetectable. TGF-beta2 increases two- to threefold following scrape injury in a dose-dependent fashion and significantly enhances both alpha-smooth muscle actin expression in the underlying collagen-embedded fibroblasts and secretion of tenascin-C into the matrix. Multiphoton microscopy demonstrates substantially enhanced second harmonic generation from fibrillar collagen in the matrix. Pretreatment of the matrix with either sirolimus (2.5 nM) or paclitaxel (10 nM) abolishes the increases in both TGF-beta2 and second harmonic generation in response to epithelial injury. In the absence of the epithelium, exogenous active TGF-beta2 (0-400 pg/ml) produces a biphasic response in the second harmonic signal with a minimum occurring at the epithelial-derived basal level. We conclude that epithelial-derived TGF-beta2 is secreted in response to injury, significantly alters the bulk optical properties of the extracellular matrix, and its tight regulation may be required for normal collagen homeostasis.


Ring 18 molecular assessment and clinical consequences.
Ring chromosome 18 is a rare condition which has predominantly been described by case reports and small case series. We assessed a cohort of 30 individuals with ring 18 using both microarray comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). We determined that each participant had a unique combination of hemizygosity for the p and q arms. Four ring chromosomes had no detectable deletion of one of the chromosome arms using aCGH. However, two of these ring chromosomes had telomeric sequences detected using FISH. These data confirm the importance of molecular and cytogenetic analysis to determine both chromosome content and morphology. We failed to find dramatic changes in mosaicism percentage between cytogenetic measurements made at the time of diagnosis and those made years later at the time of this study, demonstrating that dynamic ring mosaicism is unlikely to be a major cause of phenotypic variability in the ring 18 population. Lastly, we present data on the clinical features present in our cohort, though the extreme genotypic variability makes it impossible to draw direct genotype-phenotype correlations. Future work will focus on determining the role of specific hemizygous genes in order to create individualized projections of the effect of each person's specific ring 18 compliment.


Universal distance-scaling of nonradiative energy transfer to graphene.
The near-field interaction between fluorescent emitters and graphene exhibits rich physics associated with local dipole-induced electromagnetic fields that are strongly enhanced due to the unique properties of graphene. Here, we measure emitter lifetimes as a function of emitter-graphene distance d, and find agreement with a universal scaling law, governed by the fine-structure constant. The observed energy transfer rate is in agreement with a 1/d(4) dependence that is characteristic of two-dimensional lossy media. The emitter decay rate is enhanced 90 times (energy transfer efficiency of ~99%) with respect to the decay in vacuum at distances d ≈ 5 nm. This high energy transfer rate is mainly due to the two-dimensionality and gapless character of the monatomic carbon layer. Graphene is thus shown to be an extraordinary energy sink, holding great potential for photodetection, energy harvesting, and nanophotonics.


Neuroprotective effect of nicotine against kainic acid excitotoxicity is associated with alpha-bungarotoxin insensitive receptors subtype of nAChRs.
Our previous study showed that administration of nicotine is capable to protect the neurons of hippocampus against the kainic acid induced damage. Here we tested the hypotheses that multiple nicotine administration would prevent the effects of kainic acid on neuronal nicotinic receptor subtypes densities (α-bungarotoxin sensitive and α-bungarotoxin insentive) and on hippocampal cell degeneration. Radioligand binding study was used to detect the particular nAChR subtypes densities. Two histochemical methods (bis-benzimide staining and Fluoro-Jade B dye) were used to detect and evaluate neuronal degeneration. Our study shows that: a) kainic acid single administration increased the number of α-bungarotoxin insentive nicotinic receptors, b) nicotine was able to prevent such changes, c) repeated nicotine administration is capable to attenuate the damage of CA1 and CA3 areas of the hippocampus. No effect on α-bungarotoxin sentive nicotinic receptors was observed. Our data therefore reveal the importance of α-bungarotoxin insentive nicotinic receptors in the response to kainite and the ability of nicotine to prevent such changes both in the cell degeneration and in number of receptors. Nicotine administration influences α-bungarotoxin insensitive receptors and repeated administration is capable to protect against toxicity caused by kainic acid in hippocampal area.


Non-contrast imaging characteristics of papillary renal cell carcinoma: implications for diagnosis and subtyping.
Current radiographic guidelines suggest unenhanced renal lesions < 20 Hounsfield Units (HU) are overwhelmingly benign, requiring no further evaluation. We evaluate our experience with papillary renal cell carcinoma (pRCC) presenting with low pre-contrast attenuation and the relationship of attenuation with histologic pRCC subtype. We reviewed our institutional kidney cancer database for patients with pT1 or pT2 pRCC between 2003-2017. Tumors were categorized by papillary subtype by expert uropathologists. Preoperative CT images were analyzed at six regional tumor locations. Low, presumably benign, unenhanced median attenuation was defined as ≤ 20 HU. We calculated the frequency of pRCC with low attenuation and assessed the relationship between attenuation and pRCC subtype using logistic regression. Sixty-one patients with evaluable imaging were included. Median tumor size was 6 cm (1.7 cm-15.3 cm) with 39% (n = 24) type-1 and 61% (n = 37) type-2. Half of all pRCC tumors (n = 30) exhibited very low pre-contrast attenuation (< 20 HU), risking misdiagnosis as benign using current guidelines. Of these, 80% (n = 24) were type-2 with significant biological potential. Overall, type-2 tumors demonstrated a lower pre-contrast attenuation than type-1 (median HU: 19.8 (1.5-42.3) versus 29.6 HU (10-45.8), p < 0.01; max HU: 25.3 versus 36.5 HU, p < 0.01). After adjustment, lower pre-contrast HU was an independent predictor of pRCC subtype associated with a 5.5-fold increase of being type-2 (OR = 5.47, p < 0.01). pRCCs may exhibit very low attenuation on pre-contrast CT. This appears more common among the more aggressive type-2 subtype. These data suggest that low attenuation (< 20 HU) alone on non-contrast CT imaging is insufficient as a single parameter to rule out malignancy.


Lipoprotein-associated phospholipase A₂ activity and mass in relation to vascular disease and nonvascular mortality.
To assess whether associations of circulating lipoprotein-associated phospholipase A₂ (Lp-PLA₂) with vascular disease are independent of other risk factors. Lp-PLA₂ activity and mass, lipids and other characteristics were measured at baseline in 19,037 individuals at high risk of vascular disease in a randomized trial of simvastatin with 5-year average follow-up. Lp-PLA₂ activity and mass were correlated with each other (r = 0.56), lipids and other vascular risk factors. The moderate association of Lp-PLA₂ activity with occlusive coronary events (n = 2531) in analyses adjusted for nonlipid factors (hazard ratio per 1 SD [HR] 1.11, 95% CI 1.06-1.15) became nonsignificant after further adjustment for apolipoproteins (HR 1.02, 0.97-1.06). Such adjustment also attenuated HRs with Lp-PLA₂ mass from 1.08 (1.03-1.12) to 1.05 (1.01-1.09). By contrast, the HR with apolipoprotein-B100 of 1.15 (1.10-1.19) was only slightly attenuated to 1.14 (1.09-1.19) after further adjustment for apolipoprotein A₁ and Lp-PLA₂. Age- and sex-adjusted HRs for other cardiac events (n = 1007) with either Lp-PLA₂ activity or mass were about 1.20, but HRs reduced after adjustment for nonlipid factors (activity: 1.11, 1.04-1.18; mass: 1.08, 1.02-1.15). Adjusted HRs for ischaemic stroke (n = 900) were weak and nonsignificant and for nonvascular mortality (n = 1040) were 1.01 (0.94-1.09) with activity and 1.12 (1.05-1.19) with mass. Simvastatin reduced Lp-PLA₂ levels by about one-quarter, but simvastatin's vascular protection did not vary with baseline Lp-PLA₂ concentration. Associations of Lp-PLA₂ with occlusive coronary events depend considerably on lipid levels, whereas those with other cardiac events appear to reflect confounding from cardiovascular medication and prior vascular disease.


Hyper-activation of pp60Src limits nitric oxide signaling by increasing asymmetric dimethylarginine levels during acute lung injury.
The molecular mechanisms by which the endothelial barrier becomes compromised during lipopolysaccharide (LPS) mediated acute lung injury (ALI) are still unresolved. We have previously reported that the disruption of the endothelial barrier is due, at least in part, to the uncoupling of endothelial nitric oxide synthase (eNOS) and increased peroxynitrite-mediated nitration of RhoA. The purpose of this study was to elucidate the molecular mechanisms by which LPS induces eNOS uncoupling during ALI. Exposure of pulmonary endothelial cells (PAEC) to LPS increased pp60Src activity and this correlated with an increase in nitric oxide (NO) production, but also an increase in NOS derived superoxide, peroxynitrite formation and 3-nitrotyrosine (3-NT) levels. These effects could be simulated by the over-expression of a constitutively active pp60Src (Y527FSrc) mutant and attenuated by over-expression of dominant negative pp60Src mutant or reducing pp60Src expression. LPS induces both RhoA nitration and endothelial barrier disruption and these events were attenuated when pp60Src expression was reduced. Endothelial NOS uncoupling correlated with an increase in the levels of asymmetric dimethylarginine (ADMA) in both LPS exposed and Y527FSrc over-expressing PAEC. The effects in PAEC were also recapitulated when we transiently over-expressed Y527FSrc in the mouse lung. Finally, we found that the pp60-Src-mediated decrease in DDAH activity was mediated by the phosphorylation of DDAH II at Y207 and that a Y207F mutant DDAH II was resistant to pp60Src-mediated inhibition. We conclude that pp60Src can directly inhibit DDAH II and this is involved in the increased ADMA levels that enhance eNOS uncoupling during the development of ALI.


Cone-beam reconstruction by backprojection and filtering.
A new analytical method for tomographic image reconstruction from cone-beam projections acquired on the source orbits lying on a cylinder is presented. By application of a weighted cone-beam backprojection, the reconstruction problem is reduced to an image-restoration problem characterized by a shift-variant point-spread function that is given analytically. Assuming that the source is relatively far from the imaged object, a formula for an approximate shift-invariant inverse filter is derived; the filter is presented in the Fourier domain. Results of numerical experiments with circular and helical orbits are considered.


Evaluating the reliability and accuracy of the promotional brochures for the generic pharmaceutical companies in Iraq using World Health Organization guidelines.
Pharmaceutical industries worldwide are heavily involved in aggressive drug promotions. Physician targeted promotion through medical representatives is one of the most common tactic for drug promotion by pharmaceutical drug companies. WHO states that medical representatives to work in an ethical way should make available to prescribers and dispensers complete and unbiased information for each product discussed; therefore this study aimed to evaluate the ethics in the medical brochures of generic pharmaceutical companies that are given through medical representatives to physicians in Iraq. An observational, cross-sectional study was conducted in Iraq - Baghdad from February to April 2014. Promotional drug brochures were collected mainly from pharmaceutical exhibition during attendance of medical conferences that were sponsored by generic pharmaceutical companies. Evaluation of each brochure was based primarily on WHO criteria for ethical medicinal drug promotion. The availability of emotional pictures in each brochure was also examined. Furthermore, references were checked to find their retrievability, source, and authenticity of presentations. Most medical brochures were for antibiotics, and drugs for cardiovascular diseases. All brochures mention drug name, with its active ingredient and indication, but there is a significant absence for drug interaction, while drug side effects and contraindications if present were written in a small font. Emotional picture presented in 70% of brochures. Reference citation was present in 72% of brochures, however only 75% of references in these brochures were correct. The information that is provided in medical brochures is biased and mainly persuasive since it is mainly focusing on the positive aspect of drug therapy.


Diversity of Flavobacterium psychrophilum and the potential use of its phages for protection against bacterial cold water disease in salmonids.
Flavobacterium psychrophilum causes rainbow trout fry syndrome (RTFS) and cold water disease (CWD) in salmonid aquaculture. We report characterization of F. psychrophilum strains and their bacteriophages isolated in Chilean salmonid aquaculture. Results suggest that under laboratory conditions phages can decrease mortality of salmonids from infection by their F. psychrophilum host strain. Twelve F. psychrophilum isolates were characterized, with DNA restriction patterns showing low diversity between strains despite their being obtained from different salmonid production sites and from different tissues. We isolated 15 bacteriophages able to infect some of the F. psychrophilum isolates and characterized six of them in detail. DNA genome sizes were close to 50 Kbp and corresponded to the Siphoviridae and Podoviridae families. One isolate, 6H, probably contains lipids as an essential virion component, based on its chloroform sensitivity and low buoyant density in CsCl. Each phage isolate rarely infected F. psychrophilum strains other than the strain used for its enrichment and isolation. Some bacteriophages could decrease mortality from intraperitoneal injection of its host strain when added together with the bacteria in a ratio of 10 plaque-forming units per colony-forming unit. While we recognize the artificial laboratory conditions used for these protection assays, this work is the first to demonstrate that phages might be able protect salmonids from RTFS or CWD.


No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain.
Defective splicing of tau mRNA, promoting a shift between tau isoforms with (4R tau) and without (3R tau) exon 10, is believed to be a pathological consequence of certain tau mutations causing frontotemporal dementia. By assessing protein and mRNA levels of 4R tau and 3R tau in 27 AD and 20 control temporal cortex, we investigated whether altered tau splicing is a feature also in Alzheimer's disease (AD). However, apart from an expected increase of sarcosyl-insoluble tau in AD, there were no significant differences between the groups. Next, by laser-capture microscopy and quantitative PCR, we separately analyzed CA1 hippocampal neurons with and without neurofibrillary pathology from six of the AD and seven of the control brains. No statistically significant differences in 4R tau/3R tau mRNA were found between the different subgroups. Moreover, we confirmed the absence of significant ratio differences in a second data set with laser-captured entorhinal cortex neurons from four AD and four control brains. Finally, the 4R tau/3R tau ratio in CA1 neurons was roughly half of the ratio in temporal cortex, indicating region-specific differences in tau mRNA splicing. In conclusion, this study indicated region-specific and possibly cell-type-specific tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis.


Positive and negative experiences of breast pumping during the first 6 months.
For mothers with breastfeeding difficulties, pumping can be recommended to help establish milk production. However, pumping may present some barriers to successful breastfeeding. Mothers with milk supply concern may be at higher risk of barriers to successful breastfeeding. No previous studies have described experiences of pumping among mothers with milk supply concern. We conducted 10 focus groups of 56 mothers who had milk supply concern in the first month after birth. A paid, trained facilitator led groups in a semi-structured approach. Sessions were audiorecorded and transcribed verbatim. The transcripts were coded independently by two investigators and analysed using grounded theory. We identified five themes related to the experience of pumping among mothers with milk supply concern: (1) additional control over breastfeeding from pumping: 'I would feed and then give him … whatever I could manage to pump to him'. (2) Painful experience: 'The first time I pumped my boobs hurt so bad'. (3) Pumped volume affected milk supply concern: 'Pump and there was hardly anything coming out that's when I started to worry'. (4) Pumping interfered with other nurturing activities: 'While you're pumping, you can't touch the baby'. (5) Frustration from inconsistent provider advice: 'They told me to pump … and then said, "That's going to cause your milk to increase too much" '. Mothers had positive and negative experiences with pumping. Clinicians should assess a mother's experience shortly after she initiates pumping, as further management and counselling may be necessary to avoid barriers to successful breastfeeding.


Temporal stability of psychophysiological stress profiles: a re-analysis using intraclass correlation coefficients.
This is a re-analysis of data from a previous study which examined the temporal stability of three psychophysiological responses [frontal electromyographic activity (EMG), hand surface temperature, and heart rate]. Each response was recorded on 64 subjects over four sessions, each of which consisted of a 20-min, adaptation period, a baseline condition, and two stressors (one cognitive, the other physical). Rather than using Pearson product-moment correlations, as nearly all psychophysiological test-retest reliability studies have, we have now analyzed the data using intraclass correlation coefficients. This type of correlation allows one to incorporate more than two test-retest values on the same subjects. Analysis indicated that, with the exception of EMG during the physical stressor, the absolute values of the responses had quite significant reliability (.70 or greater). Treating the responses as relative measures (percent change from baseline or simple change scores from baseline) produced smaller and frequently less stable coefficients. It is concluded that statistical estimates of psychophysiological response reliability are functions of the design and particular reliability analysis employed.


Interatomic exchange interactions for finite-temperature magnetism and nonequilibrium spin dynamics.
We derive ab inito exchange parameters for general noncollinear magnetic configurations, in terms of a multiple scattering formalism. We show that the general exchange formula has an anisotropiclike term even in the absence of spin-orbit coupling, and that this term is large, for instance, for collinear configuration in bcc Fe, whereas for fcc Ni it is quite small. We demonstrate that keeping this term leads to what one should consider a biquadratic effective spin Hamiltonian even in the case of collinear arrangement. In noncollinear systems this term results in new tensor elements that are important for exchange interactions at finite temperatures, but they have less importance at low temperature. To illustrate our results in practice, we calculate for bcc Fe magnon spectra obtained from configuration-dependent exchange parameters, where the configurations are determined by finite-temperature effects. Our theory results in the same quantitative results as the finite-temperature neutron scattering experiments.


The Vapnik-Chervonenkis dimension of graph and recursive neural networks.
The Vapnik-Chervonenkis dimension (VC-dim) characterizes the sample learning complexity of a classification model and it is often used as an indicator for the generalization capability of a learning method. The VC-dim has been studied on common feed-forward neural networks, but it has yet to be studied on Graph Neural Networks (GNNs) and Recursive Neural Networks (RecNNs). This paper provides upper bounds on the order of growth of the VC-dim of GNNs and RecNNs. GNNs and RecNNs are from a new class of neural network models which are capable of processing inputs that are given as graphs. A graph is a data structure that generalizes the representational power of vectors and sequences, via the ability to represent dependencies or relationships between feature vectors. It was shown previously that the ability of recurrent neural networks to process sequences increases the VC-dim when compared to the VC-dim of Neural Networks, which are limited to processing vectors. Since graphs are a more general form than sequences, the question arises how this will affect the VC-dimension of GNNs and RecNNs. A main finding in this paper is that the upper bounds on the VC-dim for GNNs and RecNNs are comparable to the upper bounds for recurrent neural networks. The result also suggests that the generalization capability of such models increases with the number of connected nodes.


Responsive Asthma Care for Teens (ReACT): development protocol for an adaptive mobile health intervention for adolescents with asthma.
Asthma is a leading cause of youth morbidity in the USA, affecting >8% of youth. Adherence to inhaled corticosteroids (ICS) can prevent asthma-related morbidity; however, the typical adolescent with asthma takes fewer than 50% of their prescribed doses. Adolescents are uniquely vulnerable to suboptimal asthma self-management due to still-developing executive functioning capabilities that may impede consistent self-regulation and weaken attempts to use problem solving to overcome barriers to ICS adherence. The aims of this project are to improve adherence to ICS as an important step towards better self-management among adolescents aged 13-17 years diagnosed with asthma by merging the efficacious behaviour change strategies found in behavioural health interventions with scalable, adaptive mobile health (mHealth) technologies to create the Responsive Asthma Care for Teens programme (ReACT). ReACT intervention content will be developed through an iterative user-centred design process that includes conducting (1) one-on-one interviews with 20 teens with asthma; (2) crowdsourced feedback from a nationally representative panel of 100 adolescents with asthma and (3) an advisory board of youth with asthma, a paediatric pulmonologist and a behavioural health expert. In tandem, we will work with an existing technology vendor to programme ReACT algorithms to allow for tailored intervention delivery. We will conduct usability testing of an alpha version of ReACT with a sample of 20 target users to assess acceptability and usability of our mHealth intervention. Participants will complete a 4-week run-in period to monitor their adherence with all ReACT features turned off. Subsequently, participants will complete a 4-week intervention period with all ReACT features activated. The study started in October 2018 and is scheduled to conclude in late 2019. Institutional review board approval was obtained at the University of Kansas and the University of Florida. We will submit study findings for presentation at national research conferences that are well attended by a mix of psychologists, allied health professionals and physicians. We will publish study findings in peer-reviewed journals read by members of the psychology, nursing and pulmonary communities.


Studies of Charm Quark Diffusion inside Jets Using Pb-Pb and pp Collisions at sqrt[s_{NN}]=5.02 TeV.
The first study of charm quark diffusion with respect to the jet axis in heavy ion collisions is presented. The measurement is performed using jets with p_{T}^{jet}>60 GeV/c and D^{0} mesons with p_{T}^{D}>4 GeV/c in lead-lead (Pb-Pb) and proton-proton (pp) collisions at a nucleon-nucleon center-of-mass energy of sqrt[s_{NN}]=5.02 TeV, recorded by the CMS detector at the LHC. The radial distribution of D^{0} mesons with respect to the jet axis is sensitive to the production mechanisms of the meson, as well as to the energy loss and diffusion processes undergone by its parent parton inside the strongly interacting medium produced in Pb-Pb collisions. When compared to Monte Carlo event generators, the radial distribution in pp collisions is found to be well described by pythia, while the slope of the distribution predicted by sherpa is steeper than that of the data. In Pb-Pb collisions, compared to the pp results, the D^{0} meson distribution for 4<p_{T}^{D}<20 GeV/c hints at a larger distance on average with respect to the jet axis, reflecting a diffusion of charm quarks in the medium created in heavy ion collisions. At higher p_{T}^{D}, the Pb-Pb and pp radial distributions are found to be similar.


Ideomotor and ideational apraxia in corticobasal degeneration: a case study.
Corticobasal degeneration (CBD) is a progressive disorder that can be characterised by asymmetrical akinetic rigidity, involuntary movements, cortical sensory loss, alien limb syndrome and asymmetrical apraxia (Gibb et al., 1989; Rinnie et al., 1994). Diagnosis of praxic disabilities is thought to be essential for distinguishing CBD, in its early stage, from other akinetic-rigid syndromes. However, the nature of apraxia in CBD, and the relations between ideomotor and ideational apraxia, are not well understood. For example, if there is an ideational deficit in a given patient, does this deficit occur independently of any ideomotor disorder, or are the two impairments linked in some manner? In the present paper we report a case study of a patient with apraxia due to CBD. We examine whether the disorder is confined to production tasks, or whether there is also a related deficit in recognising the correct actions performed with objects (an ideational deficit). We also evaluate whether a disorder found for action with single objects dissociates from the ability to link multiple actions into more complex, everyday tasks. The performance of our patient showed an impairment in both action production and action recognition system, suggesting a component of ideational as well as ideomotor apraxia in CBD.


Analysis of systemic lupus erythematosus-related interstitial pneumonia: a retrospective multicentre study.
Thoracic diseases in patients with systemic lupus erythematosus (SLE), especially interstitial pneumonia (SLE-IP), are rare and have been poorly studied. The aims of this multicentre study were to evaluate SLE-IP and elucidate its clinical characteristics and prognosis. Fifty-five patients with SLE-IP who had attended the respiratory departments of participating hospitals were retrospectively evaluated in this multicentre study. Clinical information, high-resolution computed tomography (HRCT), and surgical lung biopsy/autopsy specimens were analysed by respiratory physicians, pulmonary radiologists, and pulmonary pathologists. IP patterns on HRCT and lung specimens were classified based on the international classification statement/guideline for idiopathic interstitial pneumonias. The most frequent form of SLE-IP at diagnosis was chronic IP (63.6%), followed by subacute (20.0%), and acute IP (12.7%). Radiologically, the most common HRCT pattern was "Unclassifiable" (54%). Histologically, "Unclassifiable" was the most frequently found (41.7%) among 12 patients with histologically proven IP. Interestingly, accompanying airway diseases were present in nine of these patients (75%). In multivariate analysis, current smoking (hazard ratio [HR] 6.105, p = 0.027), thrombocytopenia (HR 7.676, p = 0.010), anti-double-strand DNA titre (HR 0.956, p = 0.027), and nonspecific interstitial pneumonia (NSIP) + organizing pneumonia (OP) pattern on HRCT (vs. NSIP, HR 0.089, p = 0.023) were significant prognostic factors. In conclusion, chronic IP was the most frequent form of IP in patients with SLE-IP, and "Unclassifiable" was the commonest pattern radiologically and histologically.


A close-up view on ITS2 evolution and speciation - a case study in the Ulvophyceae (Chlorophyta, Viridiplantae).
The second Internal Transcriber Spacer (ITS2) is a fast evolving part of the nuclear-encoded rRNA operon located between the 5.8S and 28S rRNA genes. Based on crossing experiments it has been proposed that even a single Compensatory Base Change (CBC) in helices 2 and 3 of the ITS2 indicates sexual incompatibility and thus separates biological species. Taxa without any CBC in these ITS2 regions were designated as a 'CBC clade'. However, in depth comparative analyses of ITS2 secondary structures, ITS2 phylogeny, the origin of CBCs, and their relationship to biological species have rarely been performed. To gain 'close-up' insights into ITS2 evolution, (1) 86 sequences of ITS2 including secondary structures have been investigated in the green algal order Ulvales (Chlorophyta, Viridiplantae), (2) after recording all existing substitutions, CBCs and hemi-CBCs (hCBCs) were mapped upon the ITS2 phylogeny, rather than merely comparing ITS2 characters among pairs of taxa, and (3) the relation between CBCs, hCBCs, CBC clades, and the taxonomic level of organisms was investigated in detail. High sequence and length conservation allowed the generation of an ITS2 consensus secondary structure, and introduction of a novel numbering system of ITS2 nucleotides and base pairs. Alignments and analyses were based on this structural information, leading to the following results: (1) in the Ulvales, the presence of a CBC is not linked to any particular taxonomic level, (2) most CBC 'clades' sensu Coleman are paraphyletic, and should rather be termed CBC grades. (3) the phenetic approach of pairwise comparison of sequences can be misleading, and thus, CBCs/hCBCs must be investigated in their evolutionary context, including homoplasy events (4) CBCs and hCBCs in ITS2 helices evolved independently, and we found no evidence for a CBC that originated via a two-fold hCBC substitution. Our case study revealed several discrepancies between ITS2 evolution in the Ulvales and generally accepted assumptions underlying ITS2 evolution as e.g. the CBC clade concept. Therefore, we developed a suite of methods providing a critical 'close-up' view into ITS2 evolution by directly tracing the evolutionary history of individual positions, and we caution against a non-critical use of the ITS2 CBC clade concept for species delimitation.


Accurate refinement of docked protein complexes using evolutionary information and deep learning.
One of the major challenges for protein docking methods is to accurately discriminate native-like structures from false positives. Docking methods are often inaccurate and the results have to be refined and re-ranked to obtain native-like complexes and remove outliers. In a previous work, we introduced AccuRefiner, a machine learning based tool for refining protein-protein complexes. Given a docked complex, the refinement tool produces a small set of refined versions of the input complex, with lower root-mean-square-deviation (RMSD) of atomic positions with respect to the native structure. The method employs a unique ranking tool that accurately predicts the RMSD of docked complexes with respect to the native structure. In this work, we use a deep learning network with a similar set of features and five layers. We show that a properly trained deep learning network can accurately predict the RMSD of a docked complex with 1.40 Å error margin on average, by approximating the complex relationship between a wide set of scoring function terms and the RMSD of a docked structure. The network was trained on 35000 unbound docking complexes generated by RosettaDock. We tested our method on 25 different putative docked complexes produced also by RosettaDock for five proteins that were not included in the training data. The results demonstrate that the high accuracy of the ranking tool enables AccuRefiner to consistently choose the refinement candidates with lower RMSD values compared to the coarsely docked input structures.


The risk of unintended pregnancy among young women with mental health symptoms.
Depression and stress have been linked with poor contraceptive behavior, but whether existing mental health symptoms influence women's subsequent risk of unintended pregnancy is unclear. We prospectively examined the effect of depression and stress symptoms on young women's pregnancy risk over one year. We used panel data from a longitudinal study of 992 U.S. women ages 18-20 years who reported a strong desire to avoid pregnancy. Weekly journal surveys measured relationship, contraceptive use and pregnancy outcomes. We examined 27,572 journal surveys from 940 women over the first study year. Our outcome was self-reported pregnancy. At baseline, we assessed moderate/severe depression (CESD-5) and stress (PSS-4) symptoms. We estimated the effect of baseline mental health symptoms on pregnancy risk with discrete-time, mixed-effects, proportional hazard models using logistic regression. At baseline, 24% and 23% of women reported moderate/severe depression and stress symptoms, respectively. Ten percent of young women not intending pregnancy became pregnant during the study. Rates of pregnancy were higher among women with baseline depression (14% versus 9%, p = 0.04) and stress (15% versus 9%, p = 0.03) compared to women without symptoms. In multivariable models, the risk of pregnancy was 1.6 times higher among women with stress symptoms compared to those without stress (aRR 1.6, CI 1.1,2.7). Women with co-occurring stress and depression symptoms had over twice the risk of pregnancy (aRR 2.1, CI 1.1,3.8) compared to those without symptoms. Among women without a prior pregnancy, having co-occurring stress and depression symptoms was the strongest predictor of subsequent pregnancy (aRR 2.3, CI 1.2,4.3), while stress alone was the strongest predictor among women with a prior pregnancy (aRR 3.0, CI 1.1,8.8). Depression symptoms were not independently associated with young women's pregnancy risk. In conclusion, stress, and especially co-occurring stress and depression symptoms, consistently and adversely influenced these young women's risk of unintended pregnancy over one year.


Semi-synthetic aequorins with improved sensitivity to Ca2+ ions.
Thirty-seven coelenterazine analogues were synthesized and incorporated into apo-aequorin, yielding 30 semi-synthetic aequorins that have the capacity to emit a significant amount of light in the presence of Ca2+. The properties of resultant photoproteins were investigated. The most prominent feature of those photoproteins was the wide range in their sensitivities to Ca2+ concentration. The relative intensity of Ca2+-triggered luminescence of the photoproteins ranged from 0.01 to 190 when compared with natural aequorin (relative intensity 1.0) at pCa 6 for the cases where the relative intensity is less than 1 and at pCa 7 for the cases where the relative intensity is higher than 1. Eight of the semi-synthetic aequorins belonged to the class of e-aequorin. With two of those photoproteins, the degree of dependence of the luminescence intensity ratio I400/I465 on pCa was greater than that with e-aequorin, suggesting that these two photoproteins are possibly superior to e-aequorin in measuring Ca2+ concentration by the ratio method.


Catalytic activity of bimetallic catalysts highly sensitive to the atomic composition and phase structure at the nanoscale.
The ability to determine the atomic arrangement in nanoalloy catalysts and reveal the detailed structural features responsible for the catalytically active sites is essential for understanding the correlation between the atomic structure and catalytic properties, enabling the preparation of efficient nanoalloy catalysts by design. Herein we describe a study of CO oxidation over PdCu nanoalloy catalysts focusing on gaining insights into the correlation between the atomic structures and catalytic activity of nanoalloys. PdCu nanoalloys of different bimetallic compositions are synthesized as a model system and are activated by a controlled thermochemical treatment for assessing their catalytic activity. The results show that the catalytic synergy of Pd and Cu species evolves with both the bimetallic nanoalloy composition and temperature of the thermochemical treatment reaching a maximum at a Pd : Cu ratio close to 50 : 50. The nanoalloys are characterized structurally by ex situ and in situ synchrotron X-ray diffraction, including atomic pair distribution function analysis. The structural data show that, depending on the bimetallic composition and treatment temperature, PdCu nanoalloys adopt two different structure types. One features a chemically ordered, body centered cubic (B2) type alloy consisting of two interpenetrating simple cubic lattices, each occupied with Pd or Cu species alone, and the other structure type features a chemically disordered, face-centered cubic (fcc) type of alloy wherein Pd and Cu species are intermixed at random. The catalytic activity for CO oxidation is strongly influenced by the structural features. In particular, it is revealed that the prevalence of chemical disorder in nanoalloys with a Pd : Cu ratio close to 50 : 50 makes them superior catalysts for CO oxidation in comparison with the same nanoalloys of other bimetallic compositions. However, the catalytic synergy can be diminished if the Pd50Cu50 nanoalloys undergo phase segregation into distinct chemically-ordered (B2-type) and disordered (fcc-type) domains. This finding is significant since it provides a rational basis for streamlining the design and preparation of Pd-based nanoalloy catalysts in terms of atomic structure and phase state.


Acute aortic dissection associated with use of cocaine.
Cocaine use can result in a variety of cardiovascular complications, including myocardial infarction, arterial thrombosis, coronary dissection, and cardiomyopathy. Cocaine-induced aortic dissection is uncommon and has been described largely in case reports. The purpose of this study was to review our experience with aortic dissection associated with cocaine abuse. A retrospective chart review was performed of all hospital records during a 15-year period in patients diagnosed with aortic dissection. Among the 164 cases of acute aortic dissection, 16 patients (9.8%) had used cocaine or its derivative, crack cocaine, within 24 hours prior to the onset of symptoms. The remaining 148 patients (90.2%) had no history of cocaine usage. Clinical features, management, and outcome in these two groups were compared. In the cocaine group, powder cocaine was inhaled intranasally in 11 patients (69%) and crack cocaine was smoked in five cases (31%). The mean duration between cocaine use and the onset of aortic dissection was 12.8 hours (range, 4 to 24 hours). Patients in the cocaine group were younger in age and more likely to have a history of polysubstance abuse than the non-cocaine cohort. In the cocaine group, the incidence of DeBakey dissection type I, II, IIIa, and IIIb was 19%, 25%, 38%, and 19%, respectively. In the group without cocaine use, the incidence of DeBakey dissection type I, II, IIIa, and IIIb was 18%, 23%, 39%, and 20%, respectively. Surgical intervention for aortic dissection was performed in 50% of the cocaine group and 45% of the non-cocaine group. In patients who underwent surgical repair, greater pulmonary complications occurred in the cocaine group than the non-cocaine group (n = 0.02). No difference was noted in the hospital length of stay or 30-day operative mortality among the two groups. Cocaine-associated aortic dissection occurs in predominantly male patients with illicit drug abuse who were younger than patients with aortic dissection without cocaine use. Greater pulmonary complications can occur in patients with cocaine-related aortic dissection following surgical interventions.


Anthropogenic disturbance promotes hybridization between Banksia species by altering their biology.
Putative hybrids between Banksia hookeriana and B. prionotes were identified among 12 of 106 populations of B. hookeriana located at or near anthropogenically disturbed sites, mainly roadways, but none in 156 undisturbed populations. Morphometrics and AFLP markers confirmed that a hybrid swarm existed in a selected disturbed habitat, whereas no intermediates were present where the two species co-occurred in undisturbed vegetation. Individuals of both species in disturbed habitats at 12 sites were more vigorous, with greater size and more flower heads than their counterparts in undisturbed vegetation. These more fecund plants also showed a shift in season and duration of flowering. By promoting earlier flowering of B. hookeriana plants and prolonging flowering of B. prionotes, anthropogenic disturbance broke the phenological barrier between these two species. We conclude that anthropogenic disturbance promotes hybridization through increasing opportunities for gene flow by reducing interpopulation separation, increasing gamete production and, especially, promoting coflowering.


Long-segment Hirschsprung's disease.
We identified 21 children (14 boys and seven girls) with long-segment Hirschsprung's disease defined as aganglionosis extending proximal to the ileocecal valve. Long-segment Hirschsprung's disease is difficult to diagnose and treat; symptoms may be mild, and diagnosis delayed. Abdominal distention and constipation or delayed passage of meconium are the most common symptoms. Radiologic studies are unreliable in establishing the diagnosis. The morbidity rate is high because of the high transition zone and short gut. The long-term outcome of patients after the standard Duhamel procedure is satisfactory, except with extremely high transition zones. Pull-through procedures should not be performed in the small infant, but should be delayed until patients are old enough to be continent.


The association of serum lipid level with ischemic stroke in the elderly of Xinjiang.
The aim of the present study is to determine the association of serum lipid level in the above 55-year-old age elderly with ischemic stroke (IS) in Xinjiang regions, China. 408 patients with IS and 347 healthy individuals as control in the ≥55-year-old elderly were selected for the present study in Xinjiang province of China from July 2010 to July 2012. Patients were divided into different groups according to the IS subtypes (large-artery atherosclerosis, LAA; cardio-aortic embolism CE; small-artery occlusion, SAO), plague stability, hypertension and diabetes. The serum lipid level including total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), Lipoprotein(a) (Lp(a)) and their ratios(TC/HDL, LDL/HDL, ApoA1/ApoB) were measured. Patients in LAA group had higher ratio of TC/HDL, ApoA1/ApoB and lower level of ApoA1 than SAO group(p<0.05); higher level of TC, HDL, LDL, TC/HDL, LDL/HDL, ApoA1/ApoB and lower level of ApoB compared with CE group. Patients in SAO group had higher level of LDL, ApoA1, ApoB, TC/HDL, LDL/HDL and ApoA1/ApoB than CE group. Patients with stable plaque had higher level of HDL and low level of LDL, ApoB, Lp(a), TC/HDL, LDL/HDL and ApoA1/ApoB than unstable plaque group. Patients with hypertension had higher level of TG, ApoB, Lp(a), LDL/HDL and ApoA1/ApoB than non-hypertensive group. Patients with diabetes had higher level of TC, TG, ApoB, TC/HDL, LDL/HDL, ApoA1/ApoB and low level of ApoA1 than non-diabetic group. Multiple logistic regression analysis revealed that high LDL, ApoB, LDL/HDL and ApoA1/ApoB might be the risk factors for ischemic stroke. An abnormal serum lipid level of the patients with IS in older Xinjiang population is significantly associated with the stroke subtypes, plaque stability, hypertension and diabetes.


Polymorphisms in chemokine and receptor genes and gastric cancer risk and survival in a high risk Polish population.
To examine if genetic variations in chemokine receptor and ligand genes are associated with gastric cancer risk and survival. The study included 298 cases and 417 controls from a population-based study of gastric cancer conducted in Warsaw, Poland in 1994-1996. We investigated seven single nucleotide polymorphisms in a chemokine ligand (CXCL12) and chemokine receptor (CCR2, CCR5, CX3CR1) genes and one frameshift deletion (CCR5) in blood leukocyte DNA in relation to gastric cancer risk and survival. Genotyping was conducted at the NCI Core Genotyping Facility. Odds ratios and 95% confidence intervals were computed using univariate and multivariate logistic regression models. Survival analysis was performed using Cox proportional hazards models. Gastric cancer risk was not associated with single chemokine polymorphisms. A CCR5 haplotype that contained the common alleles of IVS1+151 G>T (rs2734648), IVS2+80 C>T (rs1800024) and minor allele of IVS1+246 A>G (rs1799987) was associated with a borderline significantly increased risk (OR = 1.5, 95% CI: 1.0?2.2). For gastric cancer cases, there was a greater risk of death for carriers of the minor alleles of CCR2 Ex2+241 G>A (rs1799864) (HR = 1.5, 95% CI: 1.1-2.1) and CCR5 IVS2+80 C>T (rs1800024) (HR = 1.5, 95% CI: 1.1-2.1). Carriers of the CCR5 minor allele of IVS1+151 G>T (rs2734648) had a decreased risk of death compared to homozygote carriers of the common allele (HR = 0.8, 95% CI: 0.6-1.0). Our findings do not support an association between gastric cancer risk and single chemokine genetic variation. The observed associations between cancer risk and a CCR5 haplotype and between survival and polymorphisms in CCR2 and CCR5 need replication in future studies.


Undernutrition is associated with perturbations in T cell-, B cell-, monocyte- and dendritic cell- subsets in latent Mycobacterium tuberculosis infection.
Undernutrition, as described by low body mass index (BMI), is a foremost risk factor for the progression of active Tuberculosis (TB). Undernutrition is also known to impact the baseline frequencies of innate and adaptive immune cells in animal models. To verify whether undernutrition has any influence on the baseline frequencies of immune cells in latent Mycobacterium tuberculosis infection (LTBI), we examined the frequencies of T cell-, B cell, monocyte- and dendritic cell (DC)- subsets in individuals with LTBI and low BMI (LBMI) and contrasted them with LTBI and normal BMI (NBMI) groups. LBMI was characterized by decreased frequencies and absolute cell counts of T cells, B cells and NK cells in comparison with NBMI. LBMI individuals demonstrated significantly enhanced frequencies of naïve and effector CD4+ and CD8+ T cells and significantly decreased frequencies of central memory, effector memory CD4+ and CD8+ T cells and regulatory T cells. Among B cell subsets, LBMI individuals demonstrated significantly diminished frequencies of naïve, immature, classical memory, activated memory, atypical memory and plasma cells. In addition, LBMI individuals showed significantly decreased frequencies of classical monocytes, myeloid DCs and plasmacytoid DCs and significantly increased frequencies of intermediate and non-classical monocytes and myeloid derived suppressor cells. BMI exhibited a positive correlation with B cell and NK cell counts. Our data, therefore, demonstrates that coexistent undernutrition in LTBI is characterized by the occurrence of a significant modulation in the frequency of innate and adaptive immune cell subsets.


[Hyperdynamic circulation in patients with liver cirrhosis and portal hypertension].
Hyperdynamic circulation in patients with liver cirrhosis is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure and currently focused on understanding the pathogenesis because of possibility of developing novel treatment modality. Basically, these hemodynamic alternations arise from portal hypertension. Portosystemic collaterals develop to counterbalance the increased intrahepatic vascular resistance to portal blood flow and induce an increase in venous return to heart. Increased shear stress in vascular endothelial cell related high blood flow by portosystemic shunting contributes to this upregulation of eNOS resulting in NO overproduction. Additionally, bypassing through portosystemic collaterals and escaping degradation of over-produced circulating vasodilators in the diseased liver can promote the peripheral arterial vasodilation. Vasodilation of the systemic and splanchnic circulations lead to a reduced systemic vascular resistance, and increased cardiac output and splanchnic blood flow. Furthermore, neurohumoral vasoconstrictive systems including systemic nervous system, rennin angiotensin aldosterone system, and vasopressin are intensively activated secondary to vasodilation. However, hyperdynamic circulation would be more aggravated by the activated vasoconstrictive systems. With the progression of the cirrhotic process, hyperdynamic alternations can be more profound due to hyporesponsiveness to vasoconstrictors and increased shunt formation in conjunction with autonomic neuropathy. Eventually, splanchnic arterial vasodilation results in an increase portal venous inflow, maintaining the elevated portal venous pressure. Hyperdynamic circulation is intimately involved in portal hypertension with liver cirrhosis, therefore it is reasonable to have an interest in complete understanding of the pathogenesis of hyperdynamic circulation to develop novel treatment modality.


Functional outcome following bone transport reconstruction of distal tibial defects.
Little has been written about the functional outcome of patients treated with bone transport to reconstruct a distal tibial defect. The aim of this study was to investigate the functional capabilities of patients who had undergone reconstruction with distraction osteogenesis for the treatment of a distal tibial defect in one lower limb. At least eighteen months after completion of treatment, eight patients who had no pain and were able to walk and climb stairs without difficulty performed isometric ankle plantar flexion maximum voluntary contractions while the electromyographic activity of the tibialis anterior and triceps surae muscles was simultaneously recorded. Seven of the patients also underwent gait analysis. Data for the involved limb were compared with those collected for the contralateral limb. During gait, stance time (p = 0.01), the plantar flexion angular displacement and peak moment developed during the second half of stance (p < 0.046), and the amount of ankle power generated (p = 0.02) were significantly decreased in the involved limb compared with the contralateral limb. Similar decreases were observed in the plantar flexion (p = 0.01) and dorsiflexion (p = 0.01) maximum voluntary contractions and the corresponding electromyographic activity (p = 0.01). These results suggest that adaptive changes had occurred at the level of the transported muscles, which affected both routine and maximal effort capabilities. These findings contribute to our understanding of the functional limitations of patients who have undergone bone transport with its obligatory shortening of muscle length.


Child health promotion in developing countries: the case for integration of environmental and social interventions?
In spite of improving epidemiological knowledge in relation to child health, the challenge of promoting the survival and quality of life of infants and children in most parts of the developing world remains an abiding public health problem, for both the countries and the international agencies involved. Current infant and child health programmes largely reflect western style medical care, with emphasis placed on reducing mortality, and the preventive aspects confined mainly to immunisation, improved nutrition, provision of micronutrients, promotion of breast-feeding and birth spacing. In contrast, environmental and social factors which underpin the proliferation of disease agents are receiving minimal attention. This paper presents a critical review of current strategies for promoting child health in developing countries, and examines the environmental, social, and political factors that influence child health. Presenting a specific example of infant and childhood diarrhoea, the authors argue that in order for a real reduction in mortality, and improvements in quality of life to be sustained, attention needs to be focused equally on the environmental and social factors that underlie much of the childhood diseases in the developing world. This will involve the adoption of a broader strategy aimed at reducing childhood diarrhoea, using the hazard analysis critical control point (HACCP) system in combination with other methods.


Rosmarinic Acid, a Rosemary Extract Polyphenol, Increases Skeletal Muscle Cell Glucose Uptake and Activates AMPK.
Skeletal muscle is a major insulin-target tissue and plays an important role in glucose homeostasis. Impaired insulin action in muscles leads to insulin resistance and type 2 diabetes mellitus. 5' AMP-activated kinase (AMPK) is an energy sensor, its activation increases glucose uptake in skeletal muscle and AMPK activators have been viewed as a targeted approach in combating insulin resistance. We previously reported AMPK activation and increased muscle glucose uptake by rosemary extract (RE). In the present study, we examined the effects and the mechanism of action of rosmarinic acid (RA), a major RE constituent, in L6 rat muscle cells. RA (5.0 µM) increased glucose uptake (186 ± 4.17% of control, p < 0.001) to levels comparable to maximum insulin (204 ± 10.73% of control, p < 0.001) and metformin (202 ± 14.37% of control, p < 0.001). Akt phosphorylation was not affected by RA, while AMPK phosphorylation was increased. The RA-stimulated glucose uptake was inhibited by the AMPK inhibitor compound C and was not affected by wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). The current study shows an effect of RA to increase muscle glucose uptake and AMPK phosphorylation. RA deserves further study as it shows potential to be used as an agent to regulate glucose homeostasis.


Cells may feel a hard substrate even on a grafted layer of soft hydrogel.
Introducing or grafting molecules onto biomaterial surfaces to regulate cell destination via biophysical cues is one of the important steps for biomaterial design in tissue engineering. Understanding how cells feel the substrate makes it easier to learn the mechanism behind cell-material interaction. In this study, on a glass substrate, we constructed poly-phenoxyethyl methacrylate (PHEMA) brushes having different lengths via a surface-induced atom transfer radical polymerization (SI-ATRP) method. FTIR-ATR and XPS tests of the formed polymer brushes indicate that these brushes have characteristic chemical structures of PHEMA; the polymer brush length revealed by the AFM tests increases linearly with reaction time. Cell lines of BMSCs, ATDC5, and human chondrocytes (HC) were cultured on these substrates to evaluate proliferation, adhesion, and differentiation. Our results demonstrated that the cells cultured on the substrates with short PHEMA brushes developed a spread morphology and organized actin fibers as compared to the cells cultured on those with long brushes. Different cell lines showed different responses depending on the PHEMA brush length. Cells cultured on long PHEMA brushes displayed a more rounded shape, higher gene expression of FAK and integrin, and lower gene expression of NCAM and N-cadherin as compared to those, especially ATDC5 cells, cultured on short PHEMA brushes. On PHEMA brushes with a long length, the cell lines express higher cartilage-specific genes including Sox9 and Col2 and GAG in ECM. The results suggest that polymer brushes having different lengths may interfere with the behavior of the cells cultured on them.


Accelerometer measured level of physical activity indoors and outdoors during preschool time in Sweden and the United States.
It is important to understand the correlates of physical activity (PA) to influence policy and create environments that promote PA among preschool children. We compared preschoolers' PA in Swedish and in US settings and objectively examined differences boys' and girls' indoor and outdoor PA regarding different intensity levels and sedentary behavior. Accelerometer determined PA in 50 children with mean age 52 months, (range 40-67) was recorded during preschool time for 5 consecutive weekdays at 4 sites. The children wore an Actigraph GTIM Monitor. Raleigh preschool children, opposite to Malmö preschoolers spent significantly more time indoors than outdoors (P<.001). Significantly more moderate-to-vigorous intensity physical activity (MVPA) was observed outdoors (P<.001) in both settings. Malmö children accumulated significantly more counts/min indoors (P<.001). The percent of MVPA during outdoor time did not differ between children at Raleigh and Malmö. Physical activity counts/minutes was significantly higher outdoors vs. indoors in both Malmö and Raleigh. Malmö preschoolers spent 47% of attendance time outdoors compared with 18% for Raleigh preschoolers which could have influenced the difference in preschool activity between the 2 countries. Time spent in MVPA at preschool was very limited and predominantly adopted outdoors.


A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation.
The C. elegans insulin/IGF-1 signaling (IIS) cascade plays a central role in regulating life span, dauer, metabolism, and stress. The major regulatory control of IIS is through phosphorylation of its components by serine/threonine-specific protein kinases. An RNAi screen for serine/threonine protein phosphatases that counterbalance the effect of the kinases in the IIS pathway identified pptr-1, a B56 regulatory subunit of the PP2A holoenzyme. Modulation of pptr-1 affects IIS pathway-associated phenotypes including life span, dauer, stress resistance, and fat storage. We show that PPTR-1 functions by regulating worm AKT-1 phosphorylation at Thr 350. With striking conservation, mammalian B56beta regulates Akt phosphorylation at Thr 308 in 3T3-L1 adipocytes. In C. elegans, this ultimately leads to changes in subcellular localization and transcriptional activity of the forkhead transcription factor DAF-16. This study reveals a conserved role for the B56 regulatory subunit in regulating insulin signaling through AKT dephosphorylation, thereby having widespread implications in cancer and diabetes research.


Light-driven reversible surface functionalization with anthracenes: visible light writing and mild UV erasing.
We introduce a methodology to reversibly pattern planar surfaces via the light-induced dimerization of anthracenes, particularly involving a 9-triazolylanthracene motif. Specifically, we demonstrate that the visible light-induced forward reaction can be employed to pattern small molecule species as well as polymers in a spatially resolved fashion. Under UV irradiation, the generated patterns can be erased to regenerate reactive areas, which are then available for a new functionalization step. The dynamic change in surface chemistry is evidenced by ToF-SIMS.


A group of low molecular weight (<30 kDa) antigens of heat-killed Mycobacterium tuberculosis H37Rv confer better protection against experimental tuberculosis in guinea pigs.
Heat-killed Mycobacterium tuberculosis (Mtb) H37Rv-derived antigens were purified by electroelution, and their efficacy was evaluated in conferring protection against Tb in guinea pigs in order to identify those protein antigens as a subunit vaccine. A total sonicate extract of Mtb H37Rv (MTSE) was prepared by growing bacteria on Lowenstein-Jensen (LJ) solid medium to its mid-log phase, harvested, and subjected to ultrasonication. Fractions of MTSE were resolved on 10% polyacrylamide gel electrophoresis into as high (HMW, >60 kDa), middle (MMW, 31-59 kDa), and low molecular weight (LMW, <30 kDa) antigens and were purified by electroelution. The protection efficacy of each purified fraction was assessed in a placebo-controlled study by injecting them separately into a group of two animals. After two booster doses, animals were challenged on day 84, and autopsy of all animals was performed on day 126. On autopsy, animals were scored for formation of tubercles in lungs and their dissemination to organs such as spleen, liver, kidney, and lymph nodes. Viable counts (determined as colony forming unit or CFU) of lung and spleen from each animal were performed on LJ solid medium. Results of this study show that CFU of animals that received LMW antigens were significantly low with respect to control animals when compared to MMW and HMW. In conclusion, LMW of Mtb has greater potential in prevention of tubercle formation and thus could be viewed as a possible vaccine candidate in designing alternative subunit vaccines.


In vivo evidence that 5-HT(2C) receptors inhibit 5-HT neuronal activity via a GABAergic mechanism.
Recent evidence suggests that 5-HT(2C) receptor activation may inhibit midbrain 5-HT neurones by activating neighbouring GABA neurones. This hypothesis was tested using the putative selective 5-HT(2C) receptor agonist, WAY 161503. The effect of WAY 161503 on 5-HT cell firing in the dorsal raphe nucleus (DRN) was investigated in anaesthetised rats using single unit extracellular recordings. The effect of WAY 161503 on DRN GABA neurones was investigated using double label immunohistochemical measurements of Fos, glutamate decarboxylase (GAD) and 5-HT(2C) receptors. Finally, drug occupancy at 5-HT(2A) receptors was investigated using rat positron emission tomography and ex vivo binding studies with the 5-HT(2A) receptor radioligand [(11)C]MDL 100907. WAY 161503 caused a dose-related inhibition of 5-HT cell firing which was reversed by the 5-HT(2) receptor antagonist ritanserin and the 5-HT(2C) receptor antagonist SB 242084 but not by the 5-HT(1A) receptor antagonist WAY 100635. SB 242084 pretreatment also prevented the response to WAY 161503. The blocking effects of SB 242084 likely involved 5-HT(2C) receptors because the drug did not demonstrate 5-HT(2A) receptor occupancy in vivo or ex vivo. The inhibition of 5-HT cell firing induced by WAY 161503 was partially reversed by the GABA(A) receptor antagonist picrotoxin. Also, WAY 161503 increased Fos expression in GAD positive DRN neurones and DRN GAD positive neurones expressed 5-HT(2C) receptor immunoreactivity. These findings indicate that WAY 161503 inhibits 5-HT cell firing in the DRN in vivo, and support a mechanism involving 5-HT(2C) receptor-mediated activation of DRN GABA neurones.


Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis.
Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics. A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild ( n = 143; 16.8%), moderate ( n = 378; 44.3%), or severe ( n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively. Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis.


Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature.
To evaluate the possibility that fibrinogen represents a cardiovascular risk factor. A computerized literature search (1980 to 1992) identified all published epidemiologic studies on fibrinogen and cardiovascular disease. Clinical and basic research data were found by separate searches. References of all papers thus obtained were studied and relevant papers included. Six prospective epidemiologic studies were included in a meta-analysis (one study was excluded because the study population was non-representative). Clinical papers were reviewed separately for other evidence of causation. The correlation of fibrinogen levels on the subsequent incidence of myocardial infarction, stroke, and peripheral arterial occlusive disease was assessed and the causality of the association was analyzed. Calculations were made to examine fibrinogen level (in tertiles) versus cardiovascular risk. Odds ratios of high versus low tertile were computed. All prospective studies showed that fibrinogen was associated with subsequent myocardial infarction or stroke. A total of 92,147 person-years was covered by these investigations. Odds ratios varied between 1.8 (95% CI, 1.2 to 2.5) in the Framingham and 4.1 (CI, 2.3 to 6.9) in the GRIPS study, with a summary odds ratio of 2.3 (CI, 1.9 to 2.8). Associations existed between fibrinogen and other cardiovascular risk factors, but after multivariate analysis, only the association between fibrinogen and cardiovascular events remained. The majority of the preconditions for causality were fulfilled, indicating that fibrinogen is pathophysiologically related to cardiovascular events. Fibrinogen can be considered a major cardiovascular risk factor. Future studies of cardiovascular morbidity and death should include this variable.


Contemporary Management of Increased Intraoperative Intracranial Pressure: Evidence-Based Anesthetic and Surgical Review.
Increased intracranial pressure (ICP) is frequently encountered in the neurosurgical setting. A multitude of tactics exists to reduce ICP, ranging from patient position and medications to cerebrospinal fluid diversion and surgical decompression. A vast amount of literature has been published regarding ICP management in the critical care setting, but studies specifically tailored toward the management of intraoperative acute increases in ICP or brain bulk are lacking. Compartmentalizing the intracranial space into blood, brain tissue, and cerebrospinal fluid and understanding the numerous techniques available to affect these individual compartments can guide the surgical team to quickly identify increased brain bulk and respond appropriately. Rapidly instituting measures for brain relaxation in the operating room is essential in optimizing patient outcomes. Knowledge of the efficacy, rapidity, feasibility, and risks of the various available interventions can aid the team to properly tailor their approach to each individual patient. In this article, we present the first evidence-based review of intraoperative management of ICP and brain bulk.


Acquired Stuttering in Veterans of the Wars in Iraq and Afghanistan: The Role of Traumatic Brain Injury, Post-Traumatic Stress Disorder, and Medications.
Determine the association between acquired stuttering (AS), traumatic brain injury (TBI), and post-traumatic stress disorder (PTSD) in a cohort of 309,675 U.S. Iraq and Afghanistan veterans. The secondary aim was to determine the association between AS and medication patterns for veterans in the sample. Retrospective study using data from the Veterans Health Administration National Repository for veterans deployed in support of combat operations in Iraq and Afghanistan and who received Veterans Health Administration care in 2010 and 2011. We identified stuttering using ICD-9 codes to establish the association between AS, TBI, and PTSD, controlling for demographic characteristics and other comorbidities. Multivariable logistic regression was used to determine the association between comorbid conditions and potentially problematic medications associated with stuttering. Two hundred thirty-five veterans (0.08%) were diagnosed with AS in the cohort. There was the greater likelihood of an AS diagnosis for veterans with concomitant TBI and PTSD when compared with veterans without these diagnoses. Over 66% of those with stuttering were prescribed at least one medication that affected speech fluency (antidepressants, anxiolytics, and antiepileptic drugs) compared with 35% of those without AS. Veterans with a comorbid diagnosis of TBI and PTSD were more likely to be diagnosed with AS AOR: 9.77 (95% CI = 6.93-13.78, p < 0.05) and more likely to have been prescribed medications known to affect speech production OR: 3.68 (95% CI = 2.81-4.82, p < 0.05). Clinicians treating veterans with these complex comorbid conditions should consider the impact of medications on speech fluency.


The influence of five monoamine genes on trajectories of depressive symptoms across adolescence and young adulthood.
The influence of five monoamine candidate genes on depressive symptom trajectories in adolescence and young adulthood were examined in the Add Health genetic sample. Results indicated that, for all respondents, carriers of the dopamine receptor D4 5-repeat allele were characterized by distinct depressive symptom trajectories across adolescence and early adulthood. Similarly, for males, individuals with the monoamine oxidase A 3.5-repeat allele exhibited unique depressive symptom trajectories. Specifically, the trajectories of those with the dopamine receptor D4 5-repeat allele were characterized by rising levels in the transition to adulthood, while their peers were experiencing a normative drop in depressive symptom frequency. Conversely, males with the monoamine oxidase A 3.5-repeat allele were shown to experience increased distress in late adolescence. An empirical method for examining a wide array of allelic combinations was employed, and false discovery rate methods were used to control the risk of false positives due to multiple testing. Special attention was given to thoroughly interrogate the robustness of the putative genetic effects. These results demonstrate the value of combining dynamic developmental perspectives with statistical genetic methods to optimize the search for genetic influences on psychopathology across the life course.


Genome-Wide Dissection of the MicroRNA Expression Profile in Rice Embryo during Early Stages of Seed Germination.
The first 24 hours after imbibition (HAI) is pivotal for rice seed germination, during which embryo cells switch from a quiescent state to a metabolically active state rapidly. MicroRNAs (miRNAs) have increasingly been shown to play important roles in rice development. Nevertheless, limited knowledge about miRNA regulation has been obtained in the early stages of rice seed germination. In this study, the small RNAs (sRNAs) from embryos of 0, 12, and 24 HAI rice seeds were sequenced to investigate the composition and expression patterns of miRNAs. The bioinformatics analysis identified 289 miRNA loci, including 59 known and 230 novel miRNAs, and 35 selected miRNAs were confirmed by stem-loop real-time RT-PCR. Expression analysis revealed that the dry and imbibed seeds have unique miRNA expression patterns compared with other tissues, particularly for the dry seeds. Using three methods, Mireap, psRNATarget and degradome analyses, 1197 potential target genes of identified miRNAs involved in various molecular functions were predicted. Among these target genes, 39 had significantly negative correlations with their corresponding miRNAs as inferred from published transcriptome data, and 6 inversely expressed miRNA-target pairs were confirmed by 5'-RACE assay. Our work provides an inventory of miRNA expression profiles and miRNA-target interactions in rice embryos, and lays a foundation for further studies of miRNA-mediated regulation in initial seed germination.


Effect of endotoxin on leukocyte activation and migration into laminar tissue of isolated perfused equine limbs.
To investigate effects of endotoxin on leukocyte activation and infiltration of the laminar tissue in isolated perfused equine limbs. 10 right forelimbs and 3 left forelimbs collected from 10 healthy adult horses after slaughter at a licensed abattoir. procedures: Isolated right forelimbs were randomly assigned to 2 groups (5 forelimbs/group): perfusion of the distal portion for 10 hours with 80 ng of endotoxin/L and perfusion under the same conditions without endotoxin. After perfusion, samples for immunohistochemical detection of leukocytes (by use of antibodies against calprotectin and myeloperoxidase) and transmission electron microscopy were collected from the laminar tissue of the dorsal aspect of the hooves. Additionally, control samples were collected from the 3 nonperfused left forelimbs. Samples of laminar tissue from the endotoxin perfusion group had significantly higher scores for calprotectin and myeloperoxidase staining than did control samples and samples perfused without endotoxin. Ultrastructural examination revealed endotoxin-induced damage of the epidermal basal cells with loss of cell contacts including hemidesmosomes and anchoring filaments and a resulting separation of parts of the basement membrane. Additionally, local breakdown of the basement membrane was detected at the location of leukocyte adherence. In isolated perfused equine limbs, endotoxin at a clinically relevant concentration induced a distinct inflammatory reaction with intravascular and extravascular accumulation of leukocytes in the laminar tissue, similar to that seen during the developmental phase of laminitis. Therefore, endotoxin should be considered as a causative factor for some types of laminitis.


Therapeutic time window of anti-high mobility group box-1 antibody administration in mouse model of spinal cord injury.
Spinal cord injury (SCI) is a devastating neurologic disorder that often leads to permanent disability, and there is no effective treatment for it. High mobility group box-1 (HMGB1) is a damage-associated molecular protein that triggers sterile inflammation upon injuries. We have previously shown that two administrations of neutralizing monoclonal antibody (mAb) against HMGB1 (immediately after (0 h) and 6 h after) SCI dramatically improves functional recovery after SCI in mice. However, when considering clinical application, 0 h after SCI is not practical. Therefore, in this study, we examined the therapeutic time window of the mAb administration. Injection at 3 h after SCI significantly improved the functional recovery comparably to injection immediately after SCI, while injection at 6 h was less effective, and injection at 9 or 12 h had no therapeutic effect. We also found beneficial effects of injection at 3 h after injury on blood-spinal cord barrier maintenance, inflammatory-related gene expression and preservation of the damaged spinal cord tissue. Taken together, our results suggest that a single administration of anti-HMGB1 mAb within a proper time window could be a novel and potential therapeutic strategy for SCI.


The effect of protein energy malnutrition on plasma renin and oedema in the pig.
Five litter-mate male pigs, aged 7 days and fed a standard Pig Industry Board diet containing 190 g/kg dry mass of digestible protein, were compared with 10 male pigs from two litters fed a protein-deficient diet (50 g/kg) for a period of 70 days. The 10 experimental animals developed oedema between the 42nd and 70th days of the study and 4 of them became lethargic. Although the 10 experimental animals showed the typical biochemical changes characteristic of protein energy malnutrition (PEM), including changes in muscle electrolytes, liver fat and plasma albumin, the 4 lethargic animals showed a significant increase in effective plasma renin activity (EPRA) only by the 70th day of the study. Since oedema preceded any increase in EPRA in some pigs and developed in others without any change in EPRA, it is suggested that the increased renin activity is not responsible for the initial fluid retention and oedema.


Molecular circadian rhythm shift due to bright light exposure before bedtime is related to subthreshold bipolarity.
This study examined the link between circadian rhythm changes due to bright light exposure and subthreshold bipolarity. Molecular circadian rhythms, polysomnography, and actigraphy data were studied in 25 young, healthy male subjects, divided into high and low mood disorder questionnaire (MDQ) score groups. During the first 2 days of the study, the subjects were exposed to daily-living light (150 lux) for 4 hours before bedtime. Saliva and buccal cells were collected 5 times a day for 2 consecutive days. During the subsequent 5 days, the subjects were exposed to bright light (1,000 lux), and saliva and buccal cell samples were collected in the same way. Molecular circadian rhythms were analyzed using sine regression. Circadian rhythms of cortisol (F = 16.956, p < 0.001) and relative PER1/ARNTL gene expression (F = 122.1, p < 0.001) showed a delayed acrophase in both groups after bright light exposure. The high MDQ score group showed a significant delay in acrophase compared to the low MDQ score group only in salivary cortisol (F = 8.528, p = 0.008). The high MDQ score group showed hypersensitivity in cortisol rhythm shift after bright light exposure, suggesting characteristic molecular circadian rhythm changes in the high MDQ score group may be related to biological processes downstream from core circadian clock gene expression.


A review of LCA assessments of forest-based bioeconomy products and processes under an ecosystem services perspective.
The emergence of politically driven bioeconomy strategies worldwide calls for considering the ecological issues associated with bio-based products. Traditionally, life cycle analysis (LCA) approaches are key tools used to assess impacts through product life cycles, but they present limitations regarding the accounting of multiple ecosystem service-related issues, at both the land-use and supply chain levels. Based on a systematic review of empirical articles, this study provides insights on using LCA assessments to account for ecosystem service-related impacts in the context of bioeconomy activities. We address the following research questions: what is the state of the art of the literature performing LCA assessments of forest-based bioeconomy activities, including the temporal distribution, the geographic areas and products/processes at study, and the approaches and methods used? 2. Which impacts and related midpoints are considered by the reviewed studies and what types of ecosystem service- related information do they bear? Out of over 600 articles found through the Scopus search, 155 were deemed relevant for the review. The literature focuses on North-America and Europe. Most of the articles assessed the environmental impact of lower-value biomass uses. Climate change was assessed in over 90% of the studies, while issues related to ozone, eutrophication, human toxicity, resource depletion, acidification, and environmental toxicity were assessed in 40% to 60% of the studies. While the impact categories accounted for in the reviewed LCA studies bear information relevant to certain provisioning and regulating services, several ecosystem services (especially cultural ones) remain unaccounted for. The implications of our study are relevant for professionals working in the ecosystem services, circular bioeconomy, and/or LCA communities.


Geographic and Ethnic Variations in Radiographic Disability Thresholds: Analysis of North American and Japanese Operative Adult Spinal Deformity Populations.
Thresholds for spinal pelvic parameters in adult spinal deformity (ASD) were previously defined in North American patients and are commonly used to guide surgical planning. However, it is unclear whether these same threshold parameters can be more widely applied in other geographic regions and in other ethnicities. To evaluate the variation in the radiographic disability thresholds between North American and Japanese ASD populations and to adjust sagittal modifier thresholds accordingly. Retrospective case series of 717 patients with ASD who had baseline radiographs and Oswestry Disability Index (ODI) from North America (n = 518) and Japan (n = 199) were studied. Patients were compared at baseline for ODI, ODI offset from age- and ethnic-specific values (ODIni), and radiographic parameters. Significant differences in classification were observed: A greater proportion of Japanese patients had marked pelvic tilt deformity, whereas a greater proportion of US patients had marked SVA deformity; no difference in the pelvic incidence-lumbar lordosis mismatch sagittal modifier was observed. Health-related quality-of-life scores also differed, with a greater ODI raw value observed in the US patients but similar ODIni scores between cohorts. Stratifying ODIni scores by sagittal modifier grades revealed similar disability scores corresponding to the 0 to + thresholds for pelvic tilt, pelvic incidence-lumbar lordosis mismatch, and sagittal vertical axis across ethnicities. Finally, linear regression analysis demonstrated that compared with US patients, Japanese patients had a lower estimated ODI corresponding to established thresholds of radiographic deformity. Our findings demonstrate significant variability in health-related quality-of-life measures and radiographic parameters between North American and Japanese patients, supporting the need for population-adjusted sagittal modifiers to more accurately classify deformity. ASD, adult spinal deformityHRQOL, health-related quality of lifeLL, lumbar lordosisODI, Oswestry Disability IndexODIni, Oswestry Disability Index need for improvementPCS, physical component summaryPI, pelvic incidencePI-LL, pelvic incidence-lumbar lordosis mismatchPT, pelvic tiltSRS, Scoliosis Research SocietySVA, sagittal vertical axisTK, thoracic kyphosis.


Analysis of the quality of online resources for parents of children who are late to talk.
Internet usage worldwide has become a primary source of health-related information and an important resource for parents to find advice on how to promote their child's development and well-being. It is important that healthcare professionals understand what information is available to parents online to best support families and children. The current study evaluated the quality of online resources accessible for parents of children who are late to talk. Fifty-four web pages were evaluated for their usability and reliability using the LIDA instrument and Health on the Net Foundation code of conduct certification, and readability using the Flesch Reading Ease Score and Flesch-Kincaid Grade Level. Origin, author(s), target audience, topics discussed, terminology used, and recommendations were also examined. The majority of websites scored within the moderate range (50-90%) for total LIDA scores and usability, but scored in the low range for reliability (<50%). Significantly higher reliability scores (p < 0.001) were found for sites with Health on the Net Foundation code of conduct certification. Readability fell within the standard range. The largest proportion of websites were American, written by speech-language pathologists, with the most common topics being milestones, tips and strategies, and red flags. Discrepancies were mostly seen in terminology and misinformation, and when present, usually related to risk factors and causes. Prior to recommending websites to parents, health professionals should consider readability of the content, check that information is up-to-date, and confirm website sources and reputable authorship. Health professionals should also be aware of the types of unclear or inaccurate information to which parents of children who are late to talk may be exposed online.


Immunoprophylactic effects of administering honeybee (Apis melifera) venom spray against Salmonella gallinarum in broiler chicks.
Antibiotics continue to be used as growth promoters in the poultry industry. Honeybee (Apis melifera) venom (HBV) possesses a number of beneficial biological activities, particularly for regulating the immune system. The aim of the present study was to evaluate the immunoprophylactic effects of HBV against Salmonella Gallinarum in broiler chicks as an initial step towards developing eco-friendly alternatives to reduce antibiotic use. HBV was administered using a spray technique. HBV improved body weight gain, particularly in the presence of infection. Moreover, HBV enhanced antibody production activity against formalin-killed S. Gallinarum. The CD4(+):CD8(+) T lymphocyte ratio, relative mRNA expression levels of interleukin-18 and interferon-γ, and serum lysozyme activity also increased following HBV administration before the infection period as well as during infection. HBV reinforced bacterial clearance and increased survivability against S. Gallinarum. Corresponding pathological analyses demonstrated that the HBV-sprayed group displayed mild and less severe abnormal changes compared with those in the control group. It was presumed that the prophylactic effects of HBV against S. Gallinarum were associated with its non-specific immune response stimulating activity. Thus, HBV may provide an alternative to reduce antibiotic use in the poultry industry.


Molecular basis of DNA sequence recognition by the catabolite gene activator protein: detailed inferences from three mutations that alter DNA sequence specificity.
Previously, we reported that substitution of Glu-181 of the catabolite gene activator protein (CAP) by lysine, leucine, or valine results in a protein that has specificity for A X T base pairs at positions 7 and 16 of the DNA recognition site, rather than G X C base pairs as is the case with the wild-type CAP. In this paper, we deduce from these genetic data both (i) the specific chemical interactions by which amino acid side chains at position 181 interact with base pairs 7 and 16 and (ii) the precise alignment between the structures of the CAP and DNA in the intermolecular CAP-DNA complex. Our analysis supports the idea that the two symmetry-related F alpha-helices of the CAP dimer interact with successive major grooves of right-handed B-type DNA [Pabo, C. & Lewis, M. (1982) Nature (London) 298, 443-447; and Steitz, T., Weber, I. & Matthew, J. (1983) Cold Spring Harbor Symp. Quant. Biol. 47, 419-426].


Factors associated with arm swelling after breast cancer surgery.
As life expectancy improves for women with breast cancer, more women will be living with symptoms of lymphedema. This study reports the incidence of arm or hand swelling and associated risk factors in women with invasive breast cancer following surgery. Data were obtained from baseline and follow-up interviews of women with invasive breast cancer (n = 145), and mammography and pathology records. The Kaplan-Meier method was used to estimate the probability of developing arm or hand swelling over time. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for arm or hand swelling. Of women in this study, 38% self-reported arm or hand swelling. There was a significantly increased risk of arm swelling if women were under 50 years of age, had axillary node dissection, received chemotherapy, worked outside the home, and had a high household income. There was no association of body weight with swelling. A significantly decreased risk of arm swelling was found in women who were on treatment for high blood pressure. After adjustment for nodal dissection, only age had a significant independent effect. Our study highlights two important areas of future research that could reduce the incidence of lymphedema. There is a need to better understand the role that treatment for high blood pressure may play in protecting women from arm edema. Second, the potential effect of weight as a modifiable lymphedema risk factor needs to be studied in more detail in light of the conflicting results of different studies.