Plasma HMGB-1 Levels in Subjects with Obesity and Type 2 Diabetes: A Cross-Sectional Study in China.
To detect the levels of plasma High-Mobility Group Box-1(HMGB1) in Chinese subject with obesity and type 2 diabetes mellitus (T2DM), and to investigate the correlations between plasma HMGB1 concentration and parameters of body fat, insulin resistance (IR) metabolism and inflammation. This study recruited 79 normal glucose tolerance (NGT) subjects and 76 newly diagnosed T2DM patients. NGT and T2DM groups were divided into normal weight (NW) and obese (OB)subgroups respectively. Anthropometric parameters such as height, weight, waist circumference, hip circumference and blood pressure were measured. Plasma concentrations of HMGB1, IL-6, fasting plasma glucose (FPG), 2 hours post challenge plasma glucose (2hPG), serum lipid, glycated hemoglobin (HbA1C) and fasting insulin (FINS) were examined. The homeostasis model assessment (HOMA) was performed to assess IR status. Plasma HMGB1 levels were higher in T2DM group than that in NGT group. The concentrations of serum HMGB1 were also higher in subjects with OB than those in subjects with NW both in NGT and T2DM groups. Plasma levels of HMGB1 were positively correlated with waist hip ratio (WHR), blood pressure, FPG, FINS, HOMA-IR, TG, IL-6 and negatively correlated with HOMA-βand high-density lipoprotein-cholesterol (HDL-c) independent of age, gender and BMI. Plasma levels of HMGB1 were significantly correlated with diabetes in fully adjusted models. Plasma HMGB1 levels were increased in Chinese subjects with pure T2DM, which might be caused by IR. Serum HMGB1 participated in the pathological process of obesity and T2DM via its proinflammatory effect.


UV-B-responsive association of the Arabidopsis bZIP transcription factor ELONGATED HYPOCOTYL5 with target genes, including its own promoter.
In plants subjected to UV-B radiation, responses are activated that minimize damage caused by UV-B. The bZIP transcription factor ELONGATED HYPOCOTYL5 (HY5) acts downstream of the UV-B photoreceptor UV RESISTANCE LOCUS8 (UVR8) and promotes UV-B-induced photomorphogenesis and acclimation. Expression of HY5 is induced by UV-B; however, the transcription factor(s) that regulate HY5 transcription in response to UV-B and the impact of UV-B on the association of HY5 with its target promoters are currently unclear. Here, we show that HY5 binding to the promoters of UV-B-responsive genes is enhanced by UV-B in a UVR8-dependent manner in Arabidopsis thaliana. In agreement, overexpression of REPRESSOR OF UV-B PHOTOMORPHOGENESIS2, a negative regulator of UVR8 function, blocks UV-B-responsive HY5 enrichment at target promoters. Moreover, we have identified a T/G-box in the HY5 promoter that is required for its UV-B responsiveness. We show that HY5 and its homolog HYH bind to the T/G(HY5)-box cis-acting element and that they act redundantly in the induction of HY5 expression upon UV-B exposure. Therefore, HY5 is enriched at target promoters in response to UV-B in a UVR8 photoreceptor-dependent manner, and HY5 and HYH interact directly with a T/G-box cis-acting element of the HY5 promoter, mediating the transcriptional activation of HY5 in response to UV-B.


Modeling carbon-nutrient interactions during the early recovery of tundra after fire.
Fire frequency has dramatically increased in the tundra of northern Alaska, USA, which has major implications for the carbon budget of the region and the functioning of these ecosystems, which support important wildlife species. We investigated the postfire succession of plant and soil carbon (C), nitrogen (N), and phosphorus (P) fluxes and stocks along a burn severity gradient in the 2007 Anaktuvuk River fire scar in northern Alaska. Modeling results indicated that the early regrowth of postfire tundra vegetation was limited primarily by its canopy photosynthetic potential, rather than nutrient availability, because of the initially low leaf area and relatively high inorganic N and P concentrations in soil. Our simulations indicated that the postfire recovery of tundra vegetation was sustained predominantly by the uptake of residual inorganic N (i.e., in the remaining ash), and the redistribution of N and P from soil organic matter to vegetation. Although residual nutrients in ash were higher in the severe burn than the moderate burn, the moderate burn recovered faster because of the higher remaining biomass and consequent photosynthetic potential. Residual nutrients in ash allowed both burn sites to recover and exceed the unburned site in both aboveground biomass and production five years after the fire. The investigation of interactions among postfire C, N, and P cycles has contributed to a mechanistic understanding of the response of tundra ecosystems to fire disturbance. Our study provided insight on how the trajectory of recovery of tundra from wildfire is regulated during early succession.


Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.
Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia. We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%. In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01994720.).


Thermoanaerobacter yonseiensis sp. nov., a novel extremely thermophilic, xylose-utilizing bacterium that grows at up to 85 degrees C.
A novel strictly anaerobic, extremely thermophilic, spore-forming and xylose-utilizing bacterium, designated strain KB-1TP (type and patent strain), was isolated from a geothermal hot stream at Sileri on Java island, Indonesia. The cells were rod-shaped, motile and had terminal spores. The newly isolated strain stained gram-positive and the cells occurred singly or in pairs during the exponential growth phase. The temperature optimum for growth was 75 degrees C and growth occurred in the range 50-85 degrees C. The pH range for growth was 4.5-9.0, with an optimum at pH 6.5. Strain KB-1TP grew chemo-organotrophically by fermenting a wide range of substrates such as glucose, fructose, D-xylose, lactose, maltose, sucrose, mannose, galactose, cellobiose, pullulan and soluble starch. Arabinose, xylan, cellulose, olive oil and Tween 80 were not fermented. The predominant fermentation end products after growth on glucose were lactate, acetate, ethanol, CO2 and small amounts of isovaleric acid, butyric acid, propionic acid, 1-pentanol and 2-propanol. Thiosulfate was reduced to H2S. Strain KB-1TP was sensitive to tetracycline, chloramphenicol, penicillin G, neomycin, kanamycin, vancomycin and rifampicin at concentrations of 100 microg ml(-1). No effect was observed with chloramphenicol and neomycin at concentrations of 10 microg ml(-1). This indicates that strain KB-1TP belongs to the bacterial domain. The G+C content of the DNA was 37 mol%. The comparison of the 165 rDNA sequence to that of closely related strains revealed that strain KB-1TP belonged to clostridial cluster V, showing highest sequence identities (92.7%) to members of the genus Thermoanaerobacter. Taking into account the physiological and molecular properties of the new isolate, it is proposed that strain KB-1TP should be classified as a new species of the genus Thermoanaerobacter, designated Thermoanaerobacter yonseiensis. The type strain, KB-1TP, has been deposited in the Korean Federation of Culture Collections (KFCC 11116P) as a patent strain and in the Deutsche Sammlung von Mikroorganismen und Zellkulturen as a type strain (= DSM 13777T).


Melanocortin receptor-mediated effects on obesity are distributed over specific hypothalamic regions.
Reduction of melanocortin signaling in the brain results in obesity. However, where in the brain reduced melanocortin signaling mediates this effect is poorly understood. We determined the effects of long-term inhibition of melanocortin receptor activity in specific brain regions of the rat brain. Melanocortin signaling was inhibited by injection of a recombinant adeno-associated viral (rAAV) vector that overexpressed Agouti-related peptide (AgRP) into the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH) or the accumbens shell (Acc). Overexpression of AgRP in the rat PVN, VMH or LH increased bodyweight, the percentage of white adipose tissue, plasma leptin and insulin concentrations and food intake. Food intake was mainly increased because of an increase in meal size in the light and dark phases, after overexpression of AgRP in the PVN, LH or VMH. Overexpression of AgRP in the PVN or VMH reduced average body core temperature in the dark on day 40 post injection, whereas AgRP overexpression in the LH did not affect temperature. In addition, overexpression of AgRP in the PVN, LH or VMH did not significantly alter mRNA expression of AgRP, neuropeptide Y (NPY), pro-opiomelanocortin (POMC) or suppressor of cytokine signaling 3 (SOCS3) in the arcuate. Overexpression of AgRP in the Acc did not have any effect on the measured parameters. Reduction of melanocortin signaling in several hypothalamic regions increased meal size. However, there were brain area-specific effects on other parameters such as core temperature and plasma leptin concentrations. In a previous study, where NPY was overexpressed with an rAAV vector in the PVN and LH, meal frequency and meal size were increased respectively, whereas locomotor activity was reduced by NPY overexpression at both nuclei. Taken together, AgRP and NPY have complementary roles in energy balance.


Safety of kidney biopsy in pediatric transplantation: a report of the Controlled Clinical Trials in Pediatric Transplantation Trial of Induction Therapy Study Group.
Historically, young children undergoing renal transplantation have lower allograft survival than adults, and potential causes of this are being addressed by the North American Pediatric Renal Transplant Cooperative Study through the National Institutes of Health-sponsored study Cooperative Clinical Trials in Pediatric Transplantation. Included in this study is evaluation of surveillance renal biopsies (SB) and clinically indicated biopsies (CB). Few data exist in children to identify the risk involved with renal transplant biopsies. Questionnaires were mailed to 21 participating centers asking for descriptions of adverse events associated with kidney biopsies, with choices limited to none, gross hematuria, perinephric hematoma, and other. Further clinical details were obtained from review of medical records of all patients with reported adverse events. Data were collected from 19 centers on 126 patients. Eighty-six patients had undergone 212 biopsies (75 SB and 137 CB). Nine biopsy-related adverse events were reported (4.2%): three SB (4.0%) and six CB (4.4%). Gross hematuria was reported in six patients (2.8%): two SB (2.7%) and four CB (2.9%). A perinephric hematoma was reported in one patient. Two patients with intraperitoneal kidneys developed significant bleeding after biopsy and required transfusions and surgical exploration. No patient lost kidney function or required nephrectomy after biopsy. No difference was noted in adverse events between SB at day 5 or 12 versus CB. Evaluation of transplanted kidney tissue may provide important information for the care of the transplantation patient. This analysis suggests that transplanted kidney biopsies can be performed with minimal risks in pediatric patients.


Efficient synthesis of six tri- to hexasaccharide fragments of Shigella flexneri serotypes 3a and/or X O-antigen, including a study on acceptors containing N-trichloroacetylglucosamine versus N-acetylglucosamine.
Six tri- to hexasaccharide fragments of the {2)-[alpha-D-Glcp-(1-->3)]-alpha-L-Rhap-(1-->2)-alpha-L-Rhap-(1-->3)-[Ac-->2]-alpha-L-Rhap-(1-->3)-beta-D-GlcpNAc-(1-->}(n) polymer ([(E)AB(Ac)CD](n)) were synthesized as their propyl glycosides. All targets share the (E)AB sequence. Following a thorough investigation on the use of N-trichloroacetylglucosamine- versus N-acetylglucosamine-containing tri- and tetrasaccharide acceptors, the successful strategy was based on an efficient combination of the trichloroacetimidate chemistry, a trichloroacetyl used as permanent N-protection, and an allyl aglycon as temporary and/or permanent anomeric protection of selected building blocks. Use of an EAB intermediate orthogonally protected at 2(A) provided both the trisaccharide target and acceptor 12, the condensation of which with a chain terminator D followed by full deprotection, gave tetrasaccharide D(E)AB. Alternatively, stepwise glycosylation of 12 with a D donor compatible with a selective deblocking at position 3(D) and a 2-O-acetyl C donor following exposure of OH-3(D) led to a pentasaccharide, which was partially and fully deprotected into free (Ac)CD(E)AB and CD(E)AB, respectively. Furthermore, chain elongation of the common D(E)AB acceptor with a 2(B)-O-levulinoyl rhamnobiose donor BC and subsequent partial or total deprotection of the resulting hexasaccharide provided B(Ac)CD(E)AB and BCD(E)AB, respectively. All of the synthesized oligosaccharides are parts of the O-antigen of Shigella flexneri 3a, a prevalent serotype. Moreover, the non-O-acetylated fragments are also parts of the S. flexneri serotype X O-antigen.


Swarms of diversity at the gene cox1 in Antarctic krill.
The Antarctic krill, Euphausia superba, is an abundant and key species found in the Southern Ocean that forms dense, discrete swarms. Despite over three decades of research on Antarctic krill, the genetics of individual swarms is yet to be specifically investigated. In this study, we address the genetic diversity, population structure and demographic history of nine Antarctic krill swarms by sequencing 1173 bases of the gene cytochrome c oxidase subunit I (cox1, COI) from 504 individuals. Both haplotype diversity (h=0.9974-1.0000) and nucleotide diversity (pi=0.010275-0.011537) of Antarctic krill swarm samples was consistently high compared with populations of other species reported in the literature. Analysis of molecular variance did not show any significant genetic structure, thus implying that the sampled swarms do not appear to reflect discrete genetic units. Fu's Fs and Bayesian Skyride analyses provided strong evidence for a large increase in the population size of Antarctic krill, or selection favouring a particular mitochondrial lineage, within the last few 100,000 years (Pleistocene). The swarm-level results presented in this study not only further our understanding of Antarctic krill biology but, because of the economical importance of this species, also provide data to consider for future krill stock management.


Construction grammar.
Construction grammar, or constructionist approaches more generally, emphasize the function of particular constructions as well as their formal properties. Constructions vary in their degree of generality, from words to idioms to more abstract patterns such as argument structure constructions, topicalization, and passive. There is also no division drawn between semantics and pragmatics, as all conventional aspects of constructions are encoded within the constructions themselves; thus constructions can include information about information structure, register, or genre. The majority of constructionist approaches are also usage based, in that they recognize that we retain a great deal of item-specific information. An important desideratum of constructionist approaches is that they interface naturally with what we know about language acquisition, language change, and language typology. In order to capture generalizations within a given language, constructions are related via an inheritance hierarchy, with more abstract, productive constructions being directly related to their more idiomatic instantiations. The functions of particular constructions as well as domain general cognitive and social cognition are appealed in order to capture cross-linguistically valid typological generalizations. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.


Elementary sensory-motor transformations underlying olfactory navigation in walking fruit-flies.
Odor attraction in walking Drosophila melanogaster is commonly used to relate neural function to behavior, but the algorithms underlying attraction are unclear. Here, we develop a high-throughput assay to measure olfactory behavior in response to well-controlled sensory stimuli. We show that odor evokes two behaviors: an upwind run during odor (ON response), and a local search at odor offset (OFF response). Wind orientation requires antennal mechanoreceptors, but search is driven solely by odor. Using dynamic odor stimuli, we measure the dependence of these two behaviors on odor intensity and history. Based on these data, we develop a navigation model that recapitulates the behavior of flies in our apparatus, and generates realistic trajectories when run in a turbulent boundary layer plume. The ability to parse olfactory navigation into quantifiable elementary sensori-motor transformations provides a foundation for dissecting neural circuits that govern olfactory behavior.


Intraosseous screw-supported upper molar distalization.
The aims of the present study were to investigate (1) the efficiency of intraosseous screws for anchorage in maxillary molar distalization and (2) the sagittal and vertical skeletal, dental, and soft tissue changes after maxillary molar distalization using intraosseous screw-supported anchorage. Twenty-five subjects (18 girls and seven boys; 11.3 to 16.5 years of age) with skeletal Class I, dental Class II malocclusion participated in the study. An anchorage unit was prepared for molar distalization by placing an intraosseous screw behind the incisive canal at a safe distance from the midpalatal suture following the palatal anatomy. The screws were placed and immediately loaded to distalize upper first molars or the second molars when they were present. The average distalization time to achieve an overcorrected Class I molar relationship was 4.6 months. The skeletal and dental changes were measured on cephalograms and dental casts obtained before and after the distalization. In the cephalograms, the upper first molars were tipped 8.8 degrees and moved 3.9 mm distally on average. On the dental casts, the mean distalization was five mm. The upper molars were rotated distopalatally. Mild protrusion (mean 0.5 mm) of the upper central incisors was also recorded. However, there was no change in overjet, overbite, or mandibular plane angle measurements. In conclusion, immediately loaded intraosseous screw-supported anchorage unit was successful in achieving sufficient molar distalization without major anchorage loss.


The impact of point-of-care testing for influenza A and B on patient flow and management in a medical assessment unit of a general hospital.
Timely implementation of influenza infection control and treatment can significantly reduce the impact on Hospital resources and patient management when demand is at peak. Turnaround times of Laboratory based screening tests for the diagnosis of influenza may have an impact on the implementation of infection control measures and treatment. In this study the objectives included determining the correlation between the Abbott ID NOW point-of-care testing (POCT) instrument using the Influenza A&B2 test and the laboratory based GeneXpert Flu+RSV kit. In addition the impact of the POCT instrument on the prescription of antivirals and antibiotics was evaluated by comparing with practice when the instrument was not in place. The results of the correlation study with a cohort of 54 patients revealed the Abbott ID NOW POCT has 92% sensitivity for the detection of Influenza A, while specificity was 100% for both Influenza A and B. The impact of the POCT instrument on the frequency of prescription of antivirals and amount of antibiotics consumed (33% reduction in antibiotic consumption in a cohort of 65 (2017) and 61 (2018)) was significant. In addition the average patient length of Hospital stay was significantly reduced from 5.26 days to 3.73 days.


Upper-limit luminance for the surface-color mode appearance.
A series of experiments were carried out to reveal determinants for the mode of color appearance by measuring the upper-limit luminance of a color chip for the surface-color mode. We used a CRT color monitor to present test and surround stimuli in the surface-color mode. The stimuli were composed of a three-by-three array of color chips on a gray background with a white frame. The observer increased the luminance of a center test color until it just ceased to appear in the surface-color mode. Our results show that this upper-limit luminance was different among test colors, but their brightnesses, calculated from the luminance and brightness/ luminance values, were almost the same and were slightly below the brightness of the white frame. The existence of the surrounding color chips affected the results, but their sizes and spatial arrangements did not. When all of the luminances of the surrounds changed equally, the upper-limit luminances of the test colors for the surface-color mode appearance changed by the same ratio. This result indicates that the brightness of a target was a determinant for selecting the mode of color appearance and that the brightest surround stimulus acted as a cue for determining the judgment.


Functional specialization within macaque dorsolateral prefrontal cortex for the maintenance of task rules and cognitive control.
The abilities of switching between and maintaining task rules are fundamental aspects of goal-oriented behavior. The PFC is thought to implement the cognitive processes underling such rule-based behavior, but the specific contributions of the several cytoarchitecturally distinct subfields of PFC remain poorly understood. Here, we used bilateral cryogenic deactivation to investigate the relative contributions of two regions of the dorsolateral PFC (dlPFC)--the inferior dlPFC (idlPFC) area, consisting of the cortex lining the caudal principal sulcus, and the dorsally adjacent superior dlPFC (sdlPFC)--to different aspects of rule-based behavior. Macaque monkeys performed two variants of a task that required them to alternate unpredictably between eye movements toward (prosaccade) or away from (antisaccade) a visual stimulus. In one version of the task, the current rule was overtly cued. In the second, the task rule was uncued, and successful performance required the animals to detect rule changes on the basis of reward outcome and subsequently maintain the current task rule within working memory. Deactivation of the idlPFC impaired the monkeys' ability to perform pro- and antisaccades in the uncued task only. In contrast, deactivation of the sdlPFC had no effect on performance in either task. Combined deactivation of idlPFC and sdlPFC impaired performance on antisaccade, but not prosaccade, trials in both task variants. These results suggest that the idlPFC is required for mnemonic processes involved in maintenance of task rules, whereas both idlPFC and sdlPFC together are necessary for the deployment of the cognitive control required to perform antisaccades. Together, these data support the concept of a functional specialization of subregions within the dlPFC for rule-guided behavior.


The effect of exposure of rats during prenatal period to radiation spreading from mobile phones on renal development.
The aim of this study was to investigate the effects of exposure to a 900-MHz electromagnetic field (EMF) produced by mobile phones on the renal development of prenatal rats. Histopathological changes and apoptosis in the kidneys, together with levels of urea, creatinine and electrolyte in serum were determined. A total of 14 Sprague-Dawley rats were studied. Pregnant rats were divided into two equal groups: a control group and an EMF-exposed group. The study group was exposed to 900-MHz of EMF during the first 20 days of pregnancy, while the control group was unexposed to EMF. Sections obtained from paraffin blocks were stained for caspase-3 by immunohistochemistry, hematoxylin-eosin and Masson's trichrome. Mild congestion and tubular defects, and dilatation of Bowman's capsule were observed in the kidney tissues of rats in the exposed group. Apoptosis was evaluated using anti-caspase-3; stronger positive staining was observed in the renal tubular cells in the study group than those of the control group. Although there was a significant difference between the study and control groups in terms of K+ level (p<0.05), no significant difference was observed in the other parameters studied (p>0.05). Our study shows that the electromagnetic waves propagated from mobile phones have harmful effects on the renal development of prenatal rats.


Collective localized surface plasmons for high performance fluorescence biosensing.
Metallic nanostructures supporting collective localized surface plasmons (cLSPs) are investigated for the amplification of signal in fluorescence biosensors. cLSPs modes are supported by diffractive arrays of metallic nanoparticles that are embedded in a refractive index-symmetrical environment. They exhibit lower damping and thus their excitation is associated with higher field intensity enhancement and narrower resonance than that for regular localized surface plasmons. Through finite difference time domain (FDTD) simulations, we designed a novel cLSP structure that exhibit two resonances overlapping with absorption and emission wavelengths of assumed fluorophore (similar to Cy5 or Alexa Fluor 647). The simulations of surface plasmon-enhanced fluorescence (PEF) took into account the cLSP-driven excitation, directional emission, and mediated quantum yield in realistic sandwich immunoassays that utilize fluorophore-labeled detection antibodies. Achieved results indicate that cLSP-based structures holds potential for extraordinarily high fluorescence intensity enhancement that exceeds a value of 10(3).


Does nasal neuroglial heterotopia represent a risk for the newborn during delivery?
Neuroglial heterotopia is a rare developmental abnormality. Most frequently the diagnosis is established at birth or in early childhood by a typical clinical presentation. Neuroglial heterotopia can be intracranial or extracranial. A typical example of extracranial heterotopia is nasal glioma, which can be isolated or can communicate directly with the intracranium. The most sensitive investigation for the confirmation of its site is magnetic resonance imaging. Histological investigation is crucial in establishing the diagnosis. The authors present the case of postnatally assessed nasal glioma. They emphasize the importance of detailed prenatal investigation as most important in preventing birth trauma and consequent complications.


Co-solvent effects on reaction rate and reaction equilibrium of an enzymatic peptide hydrolysis.
This work presents an approach that expresses the Michaelis constant KaM and the equilibrium constant Kth of an enzymatic peptide hydrolysis based on thermodynamic activities instead of concentrations. This provides KaM and Kth values that are independent of any co-solvent. To this end, the hydrolysis reaction of N-succinyl-l-phenylalanine-p-nitroanilide catalysed by the enzyme α-chymotrypsin was studied in pure buffer and in the presence of the co-solvents dimethyl sulfoxide, trimethylamine-N-oxide, urea, and two salts. A strong influence of the co-solvents on the measured Michaelis constant (KM) and equilibrium constant (Kx) was observed, which was found to be caused by molecular interactions expressed as activity coefficients. Substrate and product activity coefficients were used to calculate the activity-based values KaM and Kth for the co-solvent free reaction. Based on these constants, the co-solvent effect on KM and Kx was predicted in almost quantitative agreement with the experimental data. The approach presented here does not only reveal the importance of understanding the thermodynamic non-ideality of reactions taking place in biological solutions and in many technological applications, it also provides a framework for interpreting and quantifying the multifaceted co-solvent effects on enzyme-catalysed reactions that are known and have been observed experimentally for a long time.


DNA-protein cross-linking by 1,2,3,4-diepoxybutane.
1,2,3,4-diepoxybutane (DEB) is a strongly genotoxic diepoxide hypothesized to be the ultimate carcinogenic metabolite of the common industrial chemical and environmental carcinogen 1,3-butadiene. DEB is a bis-electrophile capable of cross-linking cellular biomolecules to form DNA-DNA and DNA-protein cross-links (DPCs), which are thought to play a central role in its biological activity. Previous studies with recombinant proteins have shown that the biological outcomes of DEB-induced DPCs are strongly influenced by protein identities. The present work combines affinity capture methodology with mass spectrometry-based proteomics and immunological detection to identify the proteins that form DPCs in nuclear extracts from human cervical carcinoma (HeLa) cells. We identified 39 human proteins that form covalent DPCs in the presence of DEB. DNA-protein cross-linking efficiency following treatment with 25 mM DEB was 2-12%, depending on protein identity. High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI+-MS/MS) analysis of the total proteolytic digests of cross-linked proteins revealed the presence of 1-(S-cysteinyl)-4-(guan-7-yl)-2,3-butanediol conjugates, suggesting that DEB forms DPCs between cysteine thiols within proteins and the N-7 guanine positions within DNA.


Three-dimensional plotted scaffolds with controlled pore size gradients: Effect of scaffold geometry on mechanical performance and cell seeding efficiency.
Scaffolds produced by rapid prototyping (RP) techniques have proved their value for tissue engineering applications, due to their ability to produce predetermined forms and structures featuring fully interconnected pore architectures. Nevertheless, low cell seeding efficiency and non-uniform distribution of cells remain major limitations when using such types of scaffold. This can be mainly attributed to the inadequate pore architecture of scaffolds produced by RP and the limited efficiency of cell seeding techniques normally adopted. In this study we aimed at producing scaffolds with pore size gradients to enhance cell seeding efficiency and control the spatial organization of cells within the scaffold. Scaffolds based on blends of starch with poly(ε-caprolactone) featuring both homogeneously spaced pores (based on pore sizes of 0.75 and 0.1 mm) and pore size gradients (based on pore sizes of 0.1-0.75-0.1 and 0.75-0.1-0.75 mm) were designed and produced by three-dimensional plotting. The mechanical performance of the scaffolds was characterized using dynamic mechanical analysis (DMA) and conventional compression testing under wet conditions and subsequently characterized using scanning electron microscopy and micro-computed tomography. Osteoblast-like cells were seeded onto such scaffolds to investigate cell seeding efficiency and the ability to control the zonal distribution of cells upon seeding. Scaffolds featuring continuous pore size gradients were originally produced. These scaffolds were shown to have intermediate mechanical and morphological properties compared with homogenous pore size scaffolds. The pore size gradient scaffolds improved seeding efficiency from ∼35% in homogeneous scaffolds to ∼70% under static culture conditions. Fluorescence images of cross-sections of the scaffolds revealed that scaffolds with pore size gradients induce a more homogeneous distribution of cells within the scaffold.


A tumor suppressor role for C/EBPα in solid tumors: more than fat and blood.
The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) plays a critical role during embryogenesis and is thereafter required for homeostatic glucose metabolism, adipogenesis and myeloid development. Its ability to regulate the expression of lineage-specific genes and induce growth arrest contributes to the terminal differentiation of several cell types, including hepatocytes, adipocytes and granulocytes. CEBPA loss of-function mutations contribute to the development of ~10% of acute myeloid leukemia (AML), stablishing a tumor suppressor role for C/EBPα. Deregulation of C/EBPα expression has also been reported in a variety of additional human neoplasias, including liver, breast and lung cancer. However, functional CEBPA mutations have not been found in solid tumors, suggesting that abrogation of C/EBPα function in non-hematopoietic tissues is regulated by alternative mechanisms. Here we review the function of C/EBPα in solid tumors and focus on the molecular mechanisms underlying its tumor suppressive role.


A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats.
Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose- and time-dependence) induced by the acute ibogaine and noribogaine administration in rats using the forced swim test (FST, 20 and 40 mg/kg i.p., single injection for each dose). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine's FST effect was short-lived (30 min) and correlated with high brain concentrations (estimated >8 μM of free drug), while the ibogaine's antidepressant-like effect was significant at 3 h. At this time point, both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own (ibogaine ∼0.5 μM, noribogaine ∼2.5 μM). Our data suggests a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.


Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability.
Self-emulsifying drug delivery systems are a vital tool in solving low bioavailability issues of poorly soluble drugs. Hydrophobic drugs can be dissolved in these systems, enabling them to be administered as a unit dosage form for per-oral administration. When such a system is released in the lumen of the gastrointestinal tract, it disperses to form a fine emulsion (micro/nano) with the aid of GI fluid. This leads to in situ solubilization of drug that can subsequently be absorbed by lymphatic pathways, bypassing the hepatic first-pass effect. This article presents an exhaustive account of various literature reports on diverse types of self-emulsifying formulations with emphasis on their formulation, characterization and in vitro analysis, with examples of currently marketed preparations.


Prediction of prognosis after trimodal therapy in patients with locally advanced squamous cell carcinoma of the oesophagus.
Due to the poor prognosis of locally advanced oesophageal cancer, predictive markers are warranted to better select patients who may benefit from multimodal therapy. Patients with oesophageal cancer from two multicentric prospective trials were selected for having received radiochemotherapy followed by macroscopic complete tumour resection. Several pretreatment and treatment related factors were retrospectively analysed for their ability to serve as predictive markers. Overall 107 patients with squamous cell carcinomas stage T3-4 N and M0 were included in the analysis. All of them had complete preoperative radiochemotherapy. Microscopic (n=96) or macroscopic (N=11) complete resection was achieved by transthoracic oesophagectomy. The median follow-up time exceeded 6 years. Local progression free and overall survival were significantly hampered in patients with residual tumour in their resected specimen (n=76) compared with patients who showed a pathohistologic complete tumour remission (n=31) (overall survival rate at 3 years 25.2% versus 65.6%; hazard ratio (HR)=3.50 (95%-confidence interval (CI) 1.91-6.44); p<0.0001). A multivariable analysis proved both resection status and pathohistologic results to be independent acting predictive factors for local progression free and overall survival after preoperative radiochemotherapy with surgery. From our study it appears that the pathohistologic results can be a valuable surrogate marker for predicting long term survival and local tumour control in patients with locally advanced squamous cell carcinoma (SCC) of the oesophagus after preoperative radiochemotherapy and surgery. Moreover, even after intensive preoperative therapy a complete tumour resection seems to be an important precondition for long term survival.


Internet delivered diabetes self-management education: a review.
Diabetes self-management education is a cornerstone of successful diabetes management. Various methods have been used to reach the increasing numbers of patients with diabetes, including Internet-based education. The purpose of this article is to review various delivery methods of Internet diabetes education that have been evaluated, as well as their effectiveness in improving diabetes-related outcomes. Literature was identified in the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Medline, EBSCO, the Cochrane Library, and the Web of Science databases through searches using the following terms: "type 2 diabetes AND internet/web based AND education" and "type 2 diabetes AND diabetes self-management education (DSME) AND web-based/internet OR technology assisted education." The search was limited to English language articles published in the last 10 years. The search yielded 111 articles; of these, 14 met criteria for inclusion in this review. Nine studies were randomized controlled trials, and study lengths varied from 2 weeks to 24 months, for a total of 2,802 participants. DSME delivered via the Internet is effective at improving measures of glycemic control and diabetes knowledge compared with usual care. In addition, results demonstrate that improved eating habits and increased attendance at clinic appointments occur after the online DSME, although engagement and usage of Internet materials waned over time. Interventions that included an element of interaction with healthcare providers were seen as attractive to participants. Internet-delivered diabetes education has the added benefit of easier access for many individuals, and patients can self-pace themselves through materials. More research on the cost-benefits of Internet diabetes education and best methods to maintain patient engagement are needed, along with more studies assessing the long-term impact of Internet-delivered DSME.


Influence of material properties on gloves' bacterial barrier efficacy in the presence of microperforation.
Medical examination gloves and surgical gloves protect the wearer directly and the patient indirectly from the risk of contamination. Because of concerns related to latex allergy, an increasing trend toward the use of synthetic gloves made of materials other than latex is observable. However, currently it is unknown if the physical properties of different materials may influence bacterial passage in case of a glove puncture. We examined 9 different medical examination gloves from various manufacturers made of nitrile (n = 4), latex (n = 3), or neoprene (n = 2). Additionally, 1 latex surgical glove each with and without antibacterial chlorhexidine gluconate coating and 1 synthetic surgical glove made of thermoplastic elastomer were included in the experiments. The studied materials were perforated following a standardized procedure, and direct bacterial passage was measured under dynamic conditions. Glove elasticity at 1 cm up to 2.5 cm elongation was measured following EN 455-2. Nitrile gloves demonstrated higher material stiffness compared with latex gloves. Medical examination gloves made of nitrile and neoprene showed a 10-fold higher bacterial passage through a standardized puncture compared with latex gloves. All surgical gloves showed a lower bacterial passage compared with the tested examination gloves. Bacterial passage through punctures is correlated with the stiffness or elasticity of the glove material. Therefore, gloves made of latex may have an increased protective effect in case of a glove breach. Whenever gloves are purchased and selected, a risk-benefit assessment should be conducted, balancing the risk of allergy against the degree of required protection in case of a glove puncture.


Stability of graph theoretical measures in structural brain networks in Alzheimer's disease.
Graph analysis has become a popular approach to study structural brain networks in neurodegenerative disorders such as Alzheimer's disease (AD). However, reported results across similar studies are often not consistent. In this paper we investigated the stability of the graph analysis measures clustering, path length, global efficiency and transitivity in a cohort of AD (N = 293) and control subjects (N = 293). More specifically, we studied the effect that group size and composition, choice of neuroanatomical atlas, and choice of cortical measure (thickness or volume) have on binary and weighted network properties and relate them to the magnitude of the differences between groups of AD and control subjects. Our results showed that specific group composition heavily influenced the network properties, particularly for groups with less than 150 subjects. Weighted measures generally required fewer subjects to stabilize and all assessed measures showed robust significant differences, consistent across atlases and cortical measures. However, all these measures were driven by the average correlation strength, which implies a limitation of capturing more complex features in weighted networks. In binary graphs, significant differences were only found in the global efficiency and transitivity measures when using cortical thickness measures to define edges. The findings were consistent across the two atlases, but no differences were found when using cortical volumes. Our findings merits future investigations of weighted brain networks and suggest that cortical thickness measures should be preferred in future AD studies if using binary networks. Further, studying cortical networks in small cohorts should be complemented by analyzing smaller, subsampled groups to reduce the risk that findings are spurious.


A Systematic Review of Electromyography Studies in Normal Shoulders to Inform Postoperative Rehabilitation Following Rotator Cuff Repair.
Study Design Systematic review. Background Electromyography (EMG) has previously been used to guide postoperative rehabilitation progression following rotator cuff repair to prevent deleterious loading of early surgical repair. Objective To review the current literature investigating EMG during rehabilitation exercises in normal shoulders, and to identify exercises that meet a cut point of 15% maximal voluntary isometric contraction (MVIC) or less and are unlikely to result in excessive loading in the early postoperative stages. Methods An electronic search of MEDLINE via Ovid, Embase, CINAHL, SPORTDiscus, PubMed, and the Cochrane Library for all years up to June 2016 was performed. Studies were selected in relation to predefined selection criteria. Pooled mean MVICs were reported and classified as low (0%-15% MVIC), low to moderate (16%-20% MVIC), moderate (21%-40% MVIC), high (41%-60% MVIC), and very high (greater than 60% MVIC). Results A search identified 2159 studies. After applying the selection criteria, 20 studies were included for quality assessment, data extraction, and data synthesis. In total, 43 exercises spanning passive range of motion, active-assisted range of motion, and strengthening exercises were evaluated. Out of 13 active-assisted exercises, 9 were identified as suitable (15% MVIC or less) to load the supraspinatus and 10 as suitable to load the infraspinatus early after surgery. All exercises were placed in a theoretical-continuum model, by which general recommendations could be made for prescription in patients post rotator cuff repair. Conclusion This review identified passive and active-assisted exercises that may be appropriate in the early stages after rotator cuff repair. J Orthop Sports Phys Ther 2017;47(12):931-944. Epub 13 Jul 2017. doi:10.2519/jospt.2017.7271.


Interaction potential and hopping dynamics governing sliding friction.
The friction force on a nanometer-sized tip sliding on a surface is related to the thermally activated hopping of the contact atoms on an effective atomic interaction potential. A general analytical expression relates the height of this potential and the hopping attempt frequency to measurements of the velocity dependence of the friction force performed with an atomic force microscope. While the height of the potential is roughly proportional to the normal load, the attempt frequency falls in the range of mechanical eigenfrequencies of the probing tip in contact with the surface.


Cerebello-basal ganglia connectivity fingerprints related to motor/cognitive performance in Parkinson's disease.
The role of the cerebellum in Parkinson's disease (PD) has attracted increasing attention; however, the role of functional connectivity (FC) between the basal ganglia and particular cerebellar subregions remains to be elucidated. We aimed to clarify the FC and its contribution to motor and cognitive performances in patients with PD. We included 99 patients with PD and 99 age- and sex-matched healthy controls in this study. We created a cerebellar functional parcellation by performing cerebellum-only independent component analysis. Using the functional parcellation map, we performed seed-based connectivity analysis using each region as a seed and extracted the mean correlation coefficients within the thalamus and basal ganglia, including the caudate, pallidum, putamen and subthalamic nucleus. We examined the group differences and correlations with the motor and general cognitive scores. In addition, we conducted a mediation analysis to clarify the relationship among FC, motor severity, and cognition. The PD group showed decreased FC between a wide range of cerebellar subregions and the basal ganglia. Motor severity was correlated with FC between the subthalamic nucleus and posterior Crus I/II, and general cognitive performance scores correlated with FC between the caudate nucleus and medial-posterior part of the Crus I/II (p < 0.05, corrected for multiple comparisons). The cerebello-caudate network had a direct effect on cognitive performance (p = 9.0 × 10-3), although partially mediated by motor performance (p = 8.2 × 10-3). FC between cerebellar Crus I/II and divergent basal ganglia related to motor and cognitive performance in PD.


Poster Session I: Vernier thresholds of a Poisson-noise-limited computational observer with and without fixational eye movements.
Vernier acuity is a fundamental measure of spatial vision. We modeled how stimulus encoding by the cones limits Vernier acuity. We determined Vernier thresholds for a computational observer that had access to the Poisson-distributed cone photopigment excitations. The observer also had access to the cone mosaic layout and the stimulus possibilities on each trial. We varied stimulus contrast (100%, 50%, 22%, 11% Michelson contrast) and duration (2, 4, 9, 18 stimulus frames; frame duration 8.33 ms) while fixing other stimulus properties (foveal viewing; two achromatic vertical bars; length 6.2 arcmin; width 1 arcmin; vertical gap 0.1 arcmin). When the retinal image is stationary, Vernier thresholds depend jointly on contrast and duration through contrast energy: squared contrast times duration. Introducing fixational drift eye movements impairs performance, when the information about eye path is not accounted for by the computational observer. When the path of fixational drift is made available and used ideally, there is no noticeable difference with the stationary case. The lack of improvement when the path of fixational drift is known exactly may reflect the high-density of foveal cones relative to the optical point spread function and the fact that we did not introduce temporal filtering by the visual system. Our results suggest the possibility of a rich interaction between optics, cone sampling, fixational eye movements, post-receptoral filtering and visual performance.


Policies for reduced deforestation and their impact on agricultural production.
Policies to effectively reduce deforestation are discussed within a land rent (von Thünen) framework. The first set of policies attempts to reduce the rent of extensive agriculture, either by neglecting extension, marketing, and infrastructure, generating alternative income opportunities, stimulating intensive agricultural production or by reforming land tenure. The second set aims to increase either extractive or protective forest rent and--more importantly--create institutions (community forest management) or markets (payment for environmental services) that enable land users to capture a larger share of the protective forest rent. The third set aims to limit forest conversion directly by establishing protected areas. Many of these policy options present local win-lose scenarios between forest conservation and agricultural production. Local yield increases tend to stimulate agricultural encroachment, contrary to the logic of the global food equation that suggests yield increases take pressure off forests. At national and global scales, however, policy makers are presented with a more pleasant scenario. Agricultural production in developing countries has increased by 3.3-3.4% annually over the last 2 decades, whereas gross deforestation has increased agricultural area by only 0.3%, suggesting a minor role of forest conversion in overall agricultural production. A spatial delinking of remaining forests and intensive production areas should also help reconcile conservation and production goals in the future.


Fertility-Preserving Treatment in Young Women With Grade 1 Presumed Stage IA Endometrial Adenocarcinoma: A Meta-Analysis.
The aim of this study was to investigate the different efficacies of various fertility-preserving therapies for grade 1 presumed stage IA endometrial cancer. We searched the major online databases (PubMed, MEDLINE, Cochrane Library, Web of Science, and Ovid) and retrieved all the research on fertility-preserving treatment for young, grade 1 presumed stage IA endometrial adenocarcinoma patients since January 2000. We used the systemic evaluation of the Cochrane Collaboration to select the literature and merge the data we collected using R3.2.2 software (R Development Core Team, Auckland, New Zealand). By comparing the remission, recurrence, and pregnancy rates, we evaluated the efficiency of 3 existing fertility-preserving treatments indirectly: a) taking oral progestin only therapy, b) hysteroscopic resection followed by progestin therapy, and c) intrauterine progestin therapy: levonorgestrel-releasing intrauterine system combined with gonadotropin-releasing hormone agonist/progestin therapy. Twenty-eight studies met the selection criteria. A total of 619 cases were included in this study. The group that took oral progestin only (456 patients) achieved a complete remission rate (CRR), recurrence rate (ReR), and pregnancy rate (PregR) of 76.3%, (95% confidence interval [CI], 70.7%-81.1%); 30.7% (95% CI, 21.0%-42.4%); and 52.1% (95% CI, 41.2%-66.0%), respectively. The hysteroscopic resection followed by progestin therapy group (73 patients) achieved a CRR, ReR, and PregR of 95.3% (95% CI, 87.8%-100%); 14.1% (95% CI, 7.1%-26.1%); and 47.8% (95% CI, 33.0%-69.5%), respectively. The intrauterine progestin therapy group (90 patients) achieved a CRR, ReR, and PregR of 72.9% (95% CI, 60.4%-82.5%); 11.0% (95% CI, 5.1%-22.0%); and 56.0% (95% CI, 37.3%-73.1%), respectively. The existing results show that patients who received hysteroscopic resection followed by progestin therapy achieved the highest CRR. Patients who received oral progestin only might be more likely to recur and have more systemic adverse effects. Recent intrauterine progestin therapy such as levonorgestrel-releasing intrauterine system combined with gonadotropin-release hormone receptor agonist/progestin have a satisfactory PregR and low ReR rate. Considering the inherent limitations of the studies we included, further well-designed, randomized controlled trials are necessary to confirm and update this analysis.


The Function of SPARC as a Mediator of Fibrosis.
Fibrosis is a common end-point of a number of different diseases such as hypertension, diabetes, liver cirrhosis, and those associated with chronic inflammation. Fibrosis is characterized by excessive deposition of extracellular matrix that interferes with normal tissue architecture and function. Increased expression of secreted protein acidic and rich in cysteine (SPARC) in fibrotic tissues has been reported in numerous studies. SPARC is a 43 kDa collagen-binding protein secreted from several different cell types into the extracellular matrix and has been shown to be anti-proliferative and counter-adhesive in vitro. SPARC is a matricellular protein; meaning SPARC is secreted into the extracellular space but does not serve a structural function. Instead, SPARC modulates interactions between cells and the surrounding extracellular matrix. In animal models of fibrotic disease and in human fibrotic tissues, elevated expression of SPARC has been reported in many tissues including heart, lungs, kidneys, liver, dermis, intestine, and eyes. In this review, we will summarize current studies that have examined the expression and functional importance of SPARC in various animal models of fibrosis and in human tissues. Although cellular mechanisms of SPARC in fibrosis remain to be fully elucidated, the studies summarized here provide impetus to further explore the efficacy of SPARC as a potential target for reducing fibrosis.


Syncope in childhood.
The records of 108 children, ages 2 to 19 years (mean age 11.3 years), who were referred to the pediatric neurology and pediatric cardiology clinics for syncope, were reviewed. Sixty-six cases were identified retrospectively, and 42 prospectively. Syncope was defined as transient and complete loss of consciousness with no etiology determined at the time of presentation. The mean follow-up was 2.0 years. In 27 cases (25%), an etiology for syncope was found, including migraines in 12 cases (11%), seizures in 9 cases (8%), and cardiac arrhythmias in 6 cases (6%). All other cases were classified as vasovagal (neurocardiogenic). The past medical history, family history, clinical features of each syncopal episode, and diagnostic tests of each subject were correlated to final diagnosis. No clinical or historical features reliably distinguished children with vasovagal syncope from those with other etiologies. Children referred for the evaluation of syncope have a significant incidence of serious but treatable disorders, which should be actively sought.


Comparison of arsenic(V) and arsenic(III) sorption onto iron oxide minerals: implications for arsenic mobility.
Arsenic derived from natural sources occurs in groundwater in many countries, affecting the health of millions of people. The combined effects of As(V) reduction and diagenesis of iron oxide minerals on arsenic mobility are investigated in this study by comparing As(V) and As(III) sorption onto amorphous iron oxide (HFO), goethite, and magnetite at varying solution compositions. Experimental data are modeled with a diffuse double layer surface complexation model, and the extracted model parameters are used to examine the consistency of our results with those previously reported. Sorption of As(V) onto HFO and goethite is more favorable than that of As(III) below pH 5-6, whereas, above pH 7-8, As(II) has a higher affinity for the solids. The pH at which As(V) and As(III) are equally sorbed depends on the solid-to-solution ratio and type and specific surface area of the minerals and is shifted to lower pH values in the presence of phosphate, which competes for sorption sites. The sorption data indicate that, under most of the chemical conditions investigated in this study, reduction of As(V) in the presence of HFO or goethite would have only minor effects on or even decrease its mobility in the environment at near-neutral pH conditions. As(V) and As(III) sorption isotherms indicate similar surface site densities on the three oxides. Intrinsic surface complexation constants for As(V) are higher for goethite than HFO, whereas As(III) binding is similar for both of these oxides and also for magnetite. However, decrease in specific surface area and hence sorption site density that accompanies transformation of amorphous iron oxides to more crystalline phases could increase arsenic mobility.


Food and Drug Administration (FDA) postmarket reported side effects and adverse events associated with pulmonary hypertension therapy in pediatric patients.
Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.


An internet-based intervention with brief nurse support to manage obesity in primary care (POWeR+): a pragmatic, parallel-group, randomised controlled trial.
The obesity epidemic has major public health consequences. Expert dietetic and behavioural counselling with intensive follow-up is effective, but resource requirements severely restrict widespread implementation in primary care, where most patients are managed. We aimed to estimate the effectiveness and cost-effectiveness of an internet-based behavioural intervention (POWeR+) combined with brief practice nurse support in primary care. We did this pragmatic, parallel-group, randomised controlled trial at 56 primary care practices in central and south England. Eligible adults aged 18 years or older with a BMI of 30 kg/m(2) or more (or ≥28 kg/m(2) with hypertension, hypercholesterolaemia, or diabetes) registered online with POWeR+-a 24 session, web-based, weight management intervention lasting 6 months. After registration, the website automatically randomly assigned patients (1:1:1), via computer-generated random numbers, to receive evidence-based dietetic advice to swap foods for similar, but healthier, choices and increase fruit and vegetable intake, in addition to 6 monthly nurse follow-up (control group); web-based intervention and face-to-face nurse support (POWeR+Face-to-face [POWeR+F]; up to seven nurse contacts over 6 months); or web-based intervention and remote nurse support (POWeR+Remote [POWeR+R]; up to five emails or brief phone calls over 6 months). Participants and investigators were masked to group allocation at the point of randomisation; masking of participants was not possible after randomisation. The primary outcome was weight loss averaged over 12 months. We did a secondary analysis of weight to measure maintenance of 5% weight loss at months 6 and 12. We modelled the cost-effectiveness of each intervention. We did analysis by intention to treat, with multiple imputation for missing data. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN21244703. Between Jan 30, 2013, and March 20, 2014, 818 participants were randomly assigned to the control group (n=279), the POWeR+F group (n=269), or the POWeR+R group (n=270). Weight loss averaged over 12 months was recorded in 666 (81%) participants. The control group lost almost 3 kg over 12 months (crude mean weight: baseline 104·38 kg [SD 21·11; n=279], 6 months 101·91 kg [19·35; n=136], 12 months 101·74 kg [19·57; n=227]). The primary imputed analysis showed that compared with the control group, patients in the POWeR+F group achieved an additional weight reduction of 1·5 kg (95% CI 0·6-2·4; p=0·001) averaged over 12 months, and patients in the POWeR+R group achieved an additional 1·3 kg (0·34-2·2; p=0·007). 21% of patients in the control group had maintained a clinically important 5% weight reduction at month 12, compared with 29% of patients in the POWeR+F group (risk ratio 1·56, 0·96-2·51; p=0·070) and 32% of patients in the POWeR+R group (1·82, 1·31-2·74; p=0·004). The incremental overall cost to the health service per kg weight lost with the POWeR+ interventions versus the control strategy was £18 (95% CI -129 to 195) for POWeR+F and -£25 (-268 to 157) for POWeR+R; the probability of being cost-effective at a threshold of £100 per kg lost was 88% and 98%, respectively. No adverse events were reported. Weight loss can be maintained in some individuals by use of novel written material with occasional brief nurse follow-up. However, more people can maintain clinically important weight reductions with a web-based behavioural program and brief remote follow-up, with no increase in health service costs. Future research should assess the extent to which clinically important weight loss can be maintained beyond 1 year. Health Technology Assessment Programme of the National Institute for Health Research.


A decontamination process to remove metals and stabilise Montreal sewage sludge.
The Montreal Urban Community (MUC) treatment plant produces approximately 270 tons of dry sludge daily (tds/day) during physicochemical wastewater treatment. The sludges are burned and contribute to the greenhouse effect by producing atmospheric CO2. Moreover, the sludge emanates a nauseating odour during its thermal stabilisation and retains unpleasant odours for the part (25%) that is dried and granulated. To solve this particular problem, the treatment plant authorities are currently evaluating an acidic chemical leaching (sulfuric or hydrochloric acid) process at a pH between 2 and 3, using an oxidizing agent such as ferric chloride or hydrogen peroxide (METIX-AC technology, patent pending; [20]). They could integrate it to a 70 tds/day granulated sludge production process. Verification of the application of METIX-AC technology was carried out in a pilot plant set up near the sludge production plant of the MUC. The tests showed that METIX-AC technology can be advantageously integrated to the process used at the MUC. The residual copper (274 +/- 58 mg/kg) and cadmium (5.6 +/- 2.9 mg/kg) concentrations in the treated sludge meet legislation standards. The results have also shown that odours have been significantly eliminated for the dewatered, decontaminated, and stabilized biosolids (> 97%) compared to the non-decontaminated biosolids. A high rate of odour elimination also was obtained for the liquid leached biosolids (> 93%), compared to the untreated liquid biosolids. The fertilising value (N and P) is well preserved by the METIX-AC process. Dissolved organic carbon measurements have showed that little organic matter is brought in solution during the treatment. In fact, the average concentration of dissolved organic carbon measured in the treated liquid phase is 966 +/- 352 mg/l, whereas it is 1190 +/- 325 mg/l in untreated sludge. The treated sludge was first conditioned with an organic polymer and a coagulant aid. It was successfully dewatered with various dehydration equipments (filter press, rotary press, centrifuge).


A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage.
Cu,Zn-superoxide dismutase (SOD1) is an abundant, largely cytosolic enzyme that scavenges superoxide anions. The biological role of SOD1 is somewhat controversial because superoxide is thought to arise largely from the mitochondria where a second SOD (manganese SOD) already resides. Using bakers' yeast as a model, we demonstrate that Cu,Zn-SOD1 helps protect mitochondria from oxidative damage, as sod1Delta mutants show elevated protein carbonyls in this organelle. In accordance with this connection to mitochondria, a fraction of active SOD1 localizes within the intermembrane space (IMS) of mitochondria together with its copper chaperone, CCS. Neither CCS nor SOD1 contains typical N-terminal presequences for mitochondrial uptake; however, the mitochondrial accumulation of SOD1 is strongly influenced by CCS. When CCS synthesis is repressed, mitochondrial SOD1 is of low abundance, and conversely IMS SOD1 is very high when CCS is largely mitochondrial. The mitochondrial form of SOD1 is indeed protective against oxidative damage because yeast cells enriched for IMS SOD1 exhibit prolonged survival in the stationary phase, an established marker of mitochondrial oxidative stress. Cu,Zn-SOD1 in the mitochondria appears important for reactive oxygen physiology and may have critical implications for SOD1 mutations linked to the fatal neurodegenerative disorder, amyotrophic lateral sclerosis.


Non-invasive fibrosis tests to predict complications in compensated post-hepatitis C cirrhosis.
Markers predicting complications of post-hepatitis C cirrhosis are needed. We asked whether changes in noninvasive markers of fibrosis can predict liver-related complications. This was a case-controlled study using a prospective national cohort (ANRS-CO12-CIRVIR) of 1323 HCV-infected patients with compensated cirrhosis: 97 patients who developed liver-related complications such as hepatocellular carcinoma or hepatic decompensation (cases) matched in age, sex and follow-up duration were compared with 257 patients without complications (controls). Actitest/Fibrotest™, Inflameter/Fibrometer™, ELF™ and Fibroscan™ were performed at baseline and yearly. Samples based on Propensity score matching were built and mixed linear models performed. Outcomes in a sustained virological response (SVR) negative population and a SVR-positive population were also described. At baseline, all characteristics of patients were similar between the groups. All fibrosis tests were statistically higher for cases compared to controls, Fibroscan™ excepted: Fibrotest™: 0.83±0.13 vs. 0.77±0.16; Fibrometer™: 0.93±0.07 vs. 0.90±0.11; ELF™: 11.4±1.0 vs. 11.0±1.2 (P<0.02). The mean follow-up was 5.7±1.9 years. Over a 3-year period, the significant difference in fibrosis marker values between cases and controls remained constant; with a trend toward a decrease in inflammation markers in controls, independent of SVR status. Baseline noninvasive serum fibrosis and inflammation markers were significantly higher in patients developing a complication than in controls. During the follow-up only inflammatory markers decreased in controls, but not in cases, and thus could potentially be used to predict the occurrence of complications in cirrhotic patients.


Bi- to tetravalent glycoclusters: synthesis, structure-activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity.
The emerging functional versatility of cellular glycans makes research on the design of synthetic inhibitors a timely topic. In detail, the combination of ligand (or headgroup or contact site) structure with spatial parameters that depend on topological and geometrical factors underlies the physiological selectivity of glycan-protein (lectin) recognition. We herein tested a panel of bi-, tri- and tetravalent compounds against two plant agglutinins and adhesion/growth-regulatory lectins (galectins). In addition, we examined the impact of headgroup tailoring (converting lactose to 2'-fucosyllactose) in combination with valency increase in two assay types of increasing biorelevance (from solid-phase binding to cell binding). Compounds were prepared using copper-catalysed azide alkyne cycloaddition from peracetylated lactosyl or 2'-fucosyllactosyl azides. Significant inhibition was achieved for the plant toxin with a tetravalent compound. Different levels of sensitivity were noted for the three groups of the galectin family. The headgroup extension to 2'-fucosyllactose led to a selectivity gain, especially for the chimera-type galectin-3. Valency increase established discrimination against the homodimeric proteins, whereas the combination of valency with the headgroup extension led to discrimination against the tandem-repeat-type galectin-8 for chicken galectins but not human galectins-3 and -4. Thus, detailed structure-activity profiling of glycoclusters combined with suitably modifying the contact site for the targeted lectin will help minimize cross-reactivity among this class of closely related proteins.


Neural correlates of four broad temperament dimensions: testing predictions for a novel construct of personality.
Four suites of behavioral traits have been associated with four broad neural systems: the 1) dopamine and related norepinephrine system; 2) serotonin; 3) testosterone; 4) and estrogen and oxytocin system. A 56-item questionnaire, the Fisher Temperament Inventory (FTI), was developed to define four temperament dimensions associated with these behavioral traits and neural systems. The questionnaire has been used to suggest romantic partner compatibility. The dimensions were named: Curious/Energetic; Cautious/Social Norm Compliant; Analytical/Tough-minded; and Prosocial/Empathetic. For the present study, the FTI was administered to participants in two functional magnetic resonance imaging studies that elicited feelings of love and attachment, near-universal human experiences. Scores for the Curious/Energetic dimension co-varied with activation in a region of the substantia nigra, consistent with the prediction that this dimension reflects activity in the dopamine system. Scores for the Cautious/Social Norm Compliant dimension correlated with activation in the ventrolateral prefrontal cortex in regions associated with social norm compliance, a trait linked with the serotonin system. Scores on the Analytical/Tough-minded scale co-varied with activity in regions of the occipital and parietal cortices associated with visual acuity and mathematical thinking, traits linked with testosterone. Also, testosterone contributes to brain architecture in these areas. Scores on the Prosocial/Empathetic scale correlated with activity in regions of the inferior frontal gyrus, anterior insula and fusiform gyrus. These are regions associated with mirror neurons or empathy, a trait linked with the estrogen/oxytocin system, and where estrogen contributes to brain architecture. These findings, replicated across two studies, suggest that the FTI measures influences of four broad neural systems, and that these temperament dimensions and neural systems could constitute foundational mechanisms in personality structure and play a role in romantic partnerships.


Aldosterone suppression with dopamine infusion in low-renin hypertension.
A dopaminergic mechanism has been proposed to suppress aldosterone secretion. To assess the possibility that a defect in the dopaminergic mechanism might enhance aldosterone secretion in hypertensive patients, we determined basal and adrenocorticotropic hormone (ACTH)-stimulated plasma aldosterone (PA), cortisol, renin activity, and potassium concentrations before and during dopamine receptor stimulation with dopamine infusion and bromocriptine administration and dopamine receptor blockade with metoclopramide. The patient study groups included: (a) seven patients with low-renin hypertension and abnormal aldosterone suppression with sodium loading and presumed bilateral zona glomerulosa hyperplasia (ZGHP); (b) two patients with aldosterone-producing adenoma; (c) five patients with low-renin hypertension but normal aldosterone suppression with sodium loading; and (d) six patients with normal-renin hypertension. Dopamine infusion in patients with ZGHP caused PA to fall (P less than 0.01) into the normal range, but did not block the enhanced (P less than 0.05) aldosterone response to ACTH that is characteristic of these patients. Dopamine infusion in patients with low-renin hypertension but normal aldosterone suppression also suppressed PA (P less than 0.01), whereas it had no effect upon PA in patients with normal-renin hypertension or aldosterone-producing adenoma and did not blunt the PA response to ACTH in either group. Bromocriptine administration had no effect upon basal or ACTH-stimulated PA. Dopamine infusion in patients with ZGHP also enhanced (P less than 0.05) diuresis and natriuresis in comparison with normal-renin patients. Metoclopramide administration increased (P less than 0.01) PA in all patients. Thus, a dopaminergic mechanism appears to be important in the regulation of aldosterone secretion in patients with ZGHP and in other low-renin hypertensives with normal aldosterone suppression with sodium loading. In contrast, this latter group does not exhibit an enhanced aldosterone response to ACTH. Both of these groups differ from normal-renin hypertensives, who have no PA suppression with dopamine infusion.


Focus issue: networking cancer treatment strategies.
Receptor tyrosine kinases and the signaling networks that they control contribute to cancer and resistance to therapies. Therefore, understanding these networks, how they vary within and among tumors and how they adapt to enable cancer cells to circumvent treatment, should lead to more effective therapeutic strategies in treating the diverse disease that is cancer. As Science Signaling highlights in this week's issue, systems biology and computational biology are shining light on these complex networks and enabling integration of diverse information about genetics, proteomics, and network activity to effectively predict therapeutic response and identify key components to target for intervention.


The vulnerability to freezing-induced xylem cavitation of Larrea tridentata (Zygophyllaceae) in the Chihuahuan desert.
The temperature dependence of freezing-induced xylem cavitation was studied in a Chihuahuan desert population of Larrea tridentata (Zygophyllaceae). Field measurements of wood temperature and xylem embolism were combined with anatomical studies and laboratory measurements of embolism in stem and root samples frozen under controlled conditions. Our laboratory experiments corroborated the previously observed relationship between minimum freezing temperature and embolism. The area of the low-temperature exotherms produced during the freezing treatments was correlated with the resulting embolism, suggesting that the freezing of water inside parenchyma cells is associated with the occurrence of xylem embolism. In the laboratory experiments, embolism in stems increased only at temperatures below -14°C. Although this meant that the studied population was more resistant to freezing-induced xylem embolism than a previously studied population from the Sonoran desert, the impact of freezing was nevertheless greater because of much lower environmental temperatures. This result suggests that dieback associated with periodic extreme freezes may contribute to limiting the present distribution of L. tridentata in central New Mexico. Although laboratory experiments showed that root xylem embolism increased after freezing to less negative minimum temperatures than stems (significant effects at T = -7°C), root embolism in the field was lower than shoot embolism in accordance with measured soil temperatures throughout the study.


Rare earth doped ring-shaped luminescent micro-composites on patterned ferroelectrics.
Ferroelectric domain patterns are used as templates on which rare earth doped high refractive index nanoparticles activated with trivalent rare earth ions (RE(3+)) are selectively assembled on domain surfaces with a specific polarization. Two-dimensional luminescent heterostructures, with sizes and geometries defined by the ferroelectric patterning are achieved. The process of incorporation and consolidation of the optically active nanoparticles into the alternate domain structures leads to luminescent ring-shaped arrangements with innovative geometries and to a micrometer spatial control of the trivalent rare earth ion emitters. Multicolor emission systems and the possibility of chromatic switching at the micrometer scale among the three different compounds forming the two dimensional structure is demonstrated.


A tRNA modifying enzyme as a tunable regulatory nexus for bacterial stress responses and virulence.
Post-transcriptional modifications can impact the stability and functionality of many different classes of RNA molecules and are an especially important aspect of tRNA regulation. It is hypothesized that cells can orchestrate rapid responses to changing environmental conditions by adjusting the specific types and levels of tRNA modifications. We uncovered strong evidence in support of this tRNA global regulation hypothesis by examining effects of the well-conserved tRNA modifying enzyme MiaA in extraintestinal pathogenic Escherichia coli (ExPEC), a major cause of urinary tract and bloodstream infections. MiaA mediates the prenylation of adenosine-37 within tRNAs that decode UNN codons, and we found it to be crucial to the fitness and virulence of ExPEC. MiaA levels shifted in response to stress via a post-transcriptional mechanism, resulting in marked changes in the amounts of fully modified MiaA substrates. Both ablation and forced overproduction of MiaA stimulated translational frameshifting and profoundly altered the ExPEC proteome, with variable effects attributable to UNN content, changes in the catalytic activity of MiaA, or availability of metabolic precursors. Cumulatively, these data indicate that balanced input from MiaA is critical for optimizing cellular responses, with MiaA acting much like a rheostat that can be used to realign global protein expression patterns.


The heterogeneous distribution of acid hydrolases within a homogeneous population of cultured mammalian cells.
1. Chinese-hamster ovary fibroblasts were cultured to provide a homogeneous cell population. Homogenates obtained from these cells were fractionated by centrifugation techniques and the resulting fractions were analysed for protein and for enzymes representative of certain subcellular particles. 2. Unlike those in rat liver homogenates, the mitochondrial and lysosomal populations proved impossible to separate by differential centrifugation owing to the similarity of their sedimentation properties. Their resolution was possible by using isopycnic centrifugation in a continuous sucrose density gradient. 3. The mitochondrial population equilibrated at a density of 1.17g.cm(-3) as in rat liver homogenates. However, the lysosomal population equilibrated at a lower rather than a higher density position than the mitochondria and the probable reasons for this are discussed. 4. The lysosomal population subdivided into two groups characterized by differences in acid hydrolase content and equilibrium densities. The fraction with a density of 1.15g.cm(-3) contained the majority of arylsulphatases A and B, of cathepsin and of beta-acetylglucosaminidase activities, whereas that with a density of 1.09g.cm(-3) contained the majority of the acid phosphatase and acid ribonuclease activities. The probable division of the lysosomal population of a single cell into a number of distinguishable subgroups is suggested.


Delayed-type hypersensitivity and chronic fatigue syndrome: the usefulness of assessing T-cell activation by flow cytometry--preliminary study.
Chronic fatigue syndrome or benign myalgic encephalomyelitis has been extensively described and investigated. Although numerous immunological abnormalities have been linked with the syndrome, none have been found to be specific. This article describes the detection of delayed-type hypersensitive responses to certain common environmental antigens in almost fifty per cent of patients with this syndrome. Such hypersensitivity can be detected by the intradermal administration of antigens derived from commensal organisms like the yeast Candida albicans albicans, and then monitoring for a systemic reaction over the following six to forty-eight hours. This approach can be consolidated by performing lymphocyte activation tests in parallel and measuring in vitro T-cell activation by Candida albicans albicans antigens by three-colour flow cytometry based on CD3, CD4 and either CD69 or CD25. Another useful parameter is the kinetics of neopterin excretion in the urine over the course of the skin test. The results showed that the intensity of the DTH response correlated with the number of T-cells activated in vitro. Various factors have been implicated in the fatigue of many patients, notably lack of sleep. However, it remains difficult to establish causality in either one direction or the other. This work is in the spirit of a multifactorial approach to the group of conditions referred to as "chronic fatigue syndrome".


Utilizing the Wikidata system to improve the quality of medical content in Wikipedia in diverse languages: a pilot study.
Wikipedia is an important source of medical information for both patients and medical professionals. Given its wide reach, improving the quality, completeness, and accessibility of medical information on Wikipedia could have a positive impact on global health. We created a prototypical implementation of an automated system for keeping drug-drug interaction (DDI) information in Wikipedia up to date with current evidence about clinically significant drug interactions. Our work is based on Wikidata, a novel, graph-based database backend of Wikipedia currently in development. We set up an automated process for integrating data from the Office of the National Coordinator for Health Information Technology (ONC) high priority DDI list into Wikidata. We set up exemplary implementations demonstrating how the DDI data we introduced into Wikidata could be displayed in Wikipedia articles in diverse languages. Finally, we conducted a pilot analysis to explore if adding the ONC high priority data would substantially enhance the information currently available on Wikipedia. We derived 1150 unique interactions from the ONC high priority list. Integration of the potential DDI data from Wikidata into Wikipedia articles proved to be straightforward and yielded useful results. We found that even though the majority of current English Wikipedia articles about pharmaceuticals contained sections detailing contraindications, only a small fraction of articles explicitly mentioned interaction partners from the ONC high priority list. For 91.30% (1050/1150) of the interaction pairs we tested, none of the 2 articles corresponding to the interacting substances explicitly mentioned the interaction partner. For 7.21% (83/1150) of the pairs, only 1 of the 2 associated Wikipedia articles mentioned the interaction partner; for only 1.48% (17/1150) of the pairs, both articles contained explicit mentions of the interaction partner. Our prototype demonstrated that automated updating of medical content in Wikipedia through Wikidata is a viable option, albeit further refinements and community-wide consensus building are required before integration into public Wikipedia is possible. A long-term endeavor to improve the medical information in Wikipedia through structured data representation and automated workflows might lead to a significant improvement of the quality of medical information in one of the world's most popular Web resources.


The prion protein knockout mouse: a phenotype under challenge.
The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP?


Emissions pathways, climate change, and impacts on California.
The magnitude of future climate change depends substantially on the greenhouse gas emission pathways we choose. Here we explore the implications of the highest and lowest Intergovernmental Panel on Climate Change emissions pathways for climate change and associated impacts in California. Based on climate projections from two state-of-the-art climate models with low and medium sensitivity (Parallel Climate Model and Hadley Centre Climate Model, version 3, respectively), we find that annual temperature increases nearly double from the lower B1 to the higher A1fi emissions scenario before 2100. Three of four simulations also show greater increases in summer temperatures as compared with winter. Extreme heat and the associated impacts on a range of temperature-sensitive sectors are substantially greater under the higher emissions scenario, with some interscenario differences apparent before midcentury. By the end of the century under the B1 scenario, heatwaves and extreme heat in Los Angeles quadruple in frequency while heat-related mortality increases two to three times; alpine/subalpine forests are reduced by 50-75%; and Sierra snowpack is reduced 30-70%. Under A1fi, heatwaves in Los Angeles are six to eight times more frequent, with heat-related excess mortality increasing five to seven times; alpine/subalpine forests are reduced by 75-90%; and snowpack declines 73-90%, with cascading impacts on runoff and streamflow that, combined with projected modest declines in winter precipitation, could fundamentally disrupt California's water rights system. Although interscenario differences in climate impacts and costs of adaptation emerge mainly in the second half of the century, they are strongly dependent on emissions from preceding decades.


Central venous access in children: indications, devices, and risks.
Central venous catheters (CVCs) have a prominent role in the diagnostic and therapy of neonates and children. Herein, we describe the multiple indications for CVC use and the different devices available for central venous access. Given the prevalent use of CVCs, healthcare systems are focused on reducing complications from their use, particularly central line-associated bloodstream infections (CLABSIs). The most up-to-date information available sheds light on best practices and future areas of investigation. Large systematic reviews of randomized trials suggest that ultrasound guidance for placement of CVCs in children is safer than using blind technique, at least for internal jugular vein access. Appropriate catheter tip placement is associated with decreased complications. Furthermore, the prophylactic use of ethanol lock between cycles of parenteral nutrition administration has reduced the rates of CLABSI. A recent randomized trial in pediatric CVCs showed a benefit with antibiotic-coated CVCs. Based on the available evidence, multiple techniques for CVC placement are still valid, including the landmark technique based on practitioner experience, but ultrasound guidance has been shown to decrease complications from line placement. Adherence to CVC care protocols is essential in reducing infectious complications.


Parallel changes in intracellular water volume and pH induced by NH(3)/NH(4)(+) exposure in single neuroblastoma cells.
Increased blood levels of ammonia (NH3) and ammonium (NH4(+)), i.e. hyperammonemia, leads to cellular brain edema in humans with acute liver failure. The pathophysiology of this edema is poorly understood. This is partly due to incomplete understanding of the osmotic effects of the pair NH3/NH4(+) at the cellular and molecular levels. Cell exposure to solutions containing NH3/NH4(+) elicits changes in intracellular pH (pHi), which can in turn affect cell water volume (CWV) by activating transport mechanisms that produce net gain or loss of solutes and water. The occurrence of CWV changes caused by NH3/NH4(+) has long been suspected, but the mechanisms, magnitude and kinetics of these changes remain unknown. Using fluorescence imaging microscopy we measured, in real time, parallel changes in pHi and CWV caused by brief exposure to NH3/NH4(+) of single cells (N1E-115 neuroblastoma or NG-108 neuroblastoma X glioma ) loaded with the fluorescent indicator BCECF. Changes in CWV were measured by exciting BCECF at its intracellular isosbestic wavelength (∼438 nm), and pHi was measured ratiometrically. Brief exposure to isosmotic solutions (i.e. having the same osmolality as that of control solutions) containing NH4Cl (0.5- 30 mM) resulted in a rapid, dose-dependent swelling, followed by isosmotic regulatory volume decrease (iRVD). NH4Cl solutions in which either extracellular [NH3] or [NH4(+)] was kept constant while the other was changed by varying the pH of the solution, demonstrated that [NH3]o rather than [NH4(+)]o is the main determinant of the NH4Cl-induced swelling. The iRVD response was sensitive to the anion channel blocker NPPB, and partly dependent on external Ca(2+). Upon removal of NH4Cl, cells shrank and displayed isosmotic regulatory volume increase (iRVI). Regulatory volume responses could not be activated by comparable CWV changes produced by anisosmotic solutions, suggesting that membrane stretch or contraction by themselves are not sufficient to trigger these responses. Inhibition of glutamine synthetase partially blocked the NH4Cl-induced swelling. A quantitative description of the osmotic changes produced by exposure to NH3/NH4(+) in single neurons and glial cells shows that ∼35 to 45% of the initial cell swelling can be explained by intracellular accumulation of NH4(+) due to rapid permeation and protonation of NH3. Another∼23% of the swelling can be accounted for by rapid glutamine accumulation. The results are discussed in terms of basic cell physiology and their potential relevance to the pathophysiology of hyperammonemic cellular brain edema.


Functional impairment of human resident cardiac stem cells by the cardiotoxic antineoplastic agent trastuzumab.
Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells, in addition to previously reported direct adverse effects on cardiomyocytes. To test this idea, we exposed human cardiosphere-derived cells (hCDCs), a natural mixture of cardiac stem cells and supporting cells that has been shown to exert potent regenerative effects, to TZM and tested the effects in vitro and in vivo. We found that ERBB2 mRNA and protein are expressed in hCDCs at levels comparable to those in human myocardium. Although clinically relevant concentrations of TZM had no effect on proliferation, apoptosis, or size of the c-kit-positive hCDC subpopulation, in vitro assays demonstrated diminished potential for cardiogenic differentiation and impaired ability to form microvascular networks in TZM-treated cells. The functional benefit of hCDCs injected into the border zone of acutely infarcted mouse hearts was abrogated by TZM: infarcted animals treated with TZM + hCDCs had a lower ejection fraction, thinner infarct scar, and reduced capillary density in the infarct border zone compared with animals that received hCDCs alone (n = 12 per group). Collectively, these results indicate that TZM inhibits the cardiomyogenic and angiogenic capacities of hCDCs in vitro and abrogates the morphological and functional benefits of hCDC transplantation in vivo. Thus, TZM impairs the function of human resident cardiac stem cells, potentially contributing to TZM cardiotoxicity.


Randomized clinical trial of biodegradeable intraluminal sheath to prevent anastomotic leak after stapled colorectal anastomosis.
Anastomotic leakage is a potential major complication after colorectal surgery. The C-seal was developed to help reduce the clinical leakage rate. It is an intraluminal sheath that is stapled proximal to a colorectal anastomosis, covering it intraluminally and thus preventing intestinal leakage in case of anastomotic dehiscence. The C-seal trial was initiated to evaluate the efficacy of the C-seal in reducing anastomotic leakage in stapled colorectal anastomoses. This RCT was performed in 41 hospitals in the Netherlands, Germany, France, Hungary and Spain. Patients undergoing elective surgery with a stapled colorectal anastomosis less than 15 cm from the anal verge were eligible. Included patients were randomized to the C-seal and control groups, stratified for centre, anastomotic height and intention to create a defunctioning stoma. Primary outcome was anastomotic leakage requiring invasive treatment. Between December 2011 and December 2013, 402 patients were included in the trial, 202 in the C-seal group and 200 in the control group. Anastomotic leakage was diagnosed in 31 patients (7·7 per cent), with a 10·4 per cent leak rate in the C-seal group and 5·0 per cent in the control group (P = 0·060). Male sex showed a trend towards a higher leak rate (P = 0·055). Construction of a defunctioning stoma led to a lower leakage rate, although this was not significant (P = 0·095). C-seal application in stapled colorectal anastomoses does not reduce anastomotic leakage. Registration number: NTR3080 (http://www.trialregister.nl/trialreg/index.asp).


Fourier transform mass spectrometry.
Fourier transform mass spectrometry will play an important role in the future because of its unique combination of high mass resolution, high upper mass limit, and multichannel advantage. These features have already found application in gas chromatography-mass spectrometry, multiphoton ionization, laser desorption, and secondary ion mass spectrometry. However, its most notable feature is the ability to store ions. This characteristic, when combined with the others, will allow expeditious study of the interaction of gas-phase ions with both photons (photodissociation) and neutral molecules, and the convenient application of this fundamental information for chemical analysis.