Enhancement of Exercise Performance by 48 Hours, and 15-Day Supplementation with Mangiferin and Luteolin in Men.
The natural polyphenols mangiferin and luteolin have free radical-scavenging properties, induce the antioxidant gene program and down-regulate the expression of superoxide-producing enzymes. However, the effects of these two polyphenols on exercise capacity remains mostly unknown. To determine whether a combination of luteolin (peanut husk extract containing 95% luteolin, PHE) and mangiferin (mango leave extract (MLE), Zynamite®) at low (PHE: 50 mg/day; and 140 mg/day of MLE containing 100 mg of mangiferin; L) and high doses (PHE: 100 mg/day; MLE: 420 mg/day; H) may enhance exercise performance, twelve physically active men performed incremental exercise to exhaustion, followed by sprint and endurance exercise after 48 h (acute effects) and 15 days of supplementation (prolonged effects) with polyphenols or placebo, following a double-blind crossover design. During sprint exercise, mangiferin + luteolin supplementation enhanced exercise performance, facilitated muscle oxygen extraction, and improved brain oxygenation, without increasing the VO₂. Compared to placebo, mangiferin + luteolin increased muscle O₂ extraction during post-exercise ischemia, and improved sprint performance after ischemia-reperfusion likely by increasing glycolytic energy production, as reflected by higher blood lactate concentrations after the sprints. Similar responses were elicited by the two doses tested. In conclusion, acute and prolonged supplementation with mangiferin combined with luteolin enhances performance, muscle O₂ extraction, and brain oxygenation during sprint exercise, at high and low doses.


Investigation of the possibility of human-beta defensin 2 (hBD2) as a molecular marker of gastric mucosal inflammation.
It has previously been reported that human-beta defensin 2 (hBD2) has a physiological role as a proinflammatory mediator in gastric mucosal inflammation as well as an antimicrobial peptide for Helicobacter pylori (Hp). The present study was conducted to evaluate the possibility of hBD2 as a molecular marker of gastric mucosal inflammation. The subjects were 40 A1 to S2 gastric ulcer patients, with or without Hp infection. Biopsy specimens of the mucosa were obtained endoscopically before and after the administration of lansoprazole (LPZ) (15mg/day) or famotidine (FAM) (40 mg/day or 20 mg/day), consecutively, and each set of samples was divided into two groups; one group was subjected to RT-PCR to assess the expression of hBD2, and the other was subjected to immunohistochemical analysis for evaluating the expression of CD68. The expression of hBD2 was observed through the stage of gastric ulcer, from A1 to S1, regardless of the presence or absence of Hp infection, both before and after LPZ or FAM administration, and its intensity of expression decreasing as the number of CD68-positive cells decreased. The number of CD68-positive cells deceased as the severity of the ulcer increased from stage A1 to S2, regardless of the presence/absence of Hp infection. CD68-positive cells could hardly be observed in stage S2 gastric ulcers, in which hBD2 expression was also only scarcely noted. These results suggested the possibility that hBD2 may be a molecular marker of gastric mucosal inflammation, irrespective of the presence/absence of Hp infection.


Data transmission by hypergeometric modes through a hyperbolic-index medium.
We study the existence of a novel complete family of exact and orthogonal solutions of the paraxial wave equation. The complex amplitude of these beams is proportional to the confluent hypergeometric function, which we name hypergeometric modes of type-II (HyG-II). It is formally demonstrated that hyperbolic-index medium can generate and support the propagation of such a class of beams. Since these modes are eigenfunctions of the photon orbital angular momentum, we conclude that an optical fiber with hyperbolic-index profile could take advantage over other graded-index fibers by the capacity of data transmission.


A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.
Myocardial infarction (MI) and ischemic stroke are thought to be caused by matrix digestion by metalloproteinases (MMPs) leading to rupture of atherosclerotic plaques. Production of macrophage MMP-2 and MMP-9 is induced by cyclooxygenase 2 (COX-2) and prostaglandin E(2) synthesis. Although COX-2 expression may be genetically determined, the relation between COX-2 polymorphisms and the risk of MI and stroke is unclear. To investigate the relationship between the -765G-->C polymorphism of the COX-2 gene and clinically evident plaque rupture. Prospective, matched case-control study conducted between March 2002 and October 2003 among 864 patients with first MI or atherothrombotic ischemic stroke and 864 hospitalized controls. The groups were matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The -765G-->C variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products. Presence of the -765G-->C polymorphism of the COX-2 gene; COX-2, MMP-2, and MMP-9 expression and activity in plaques and in peripheral monocytes; urinary 6-keto PGF1alpha (marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation. The prevalence of -765GC was 2.41 times higher among controls than among cases (43.3% vs 17.9%; P<.001). The prevalence of -765CC homozygosity was 5.81 times higher (6.4% vs 1.1%; P =.04). Among participants carrying the -765GC and -765CC genotypes, the prevalence ratios for MI or stroke were 0.48 (95% CI, 0.36-0.68) and 0.33 (95% CI, 0.24-0.55), respectively. Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the -765C allele, while the -765G-->C polymorphism did not affect endothelial prostacyclin biosynthesis or endothelium-dependent vasodilation in vivo. In subgroup analyses (n = 224 cases), serum high-sensitivity C-reactive protein was significantly lower in patients carrying the -765C allele (mean [SD], 0.78 [0.1] vs 2.56 [0.4] mg/L; P =.04). We found that the -765G-->C polymorphism of the COX-2 gene is associated with a decreased risk of MI and stroke. Detection of this genotype may be useful for predicting genetic risk of MI and stroke.


Harmine suppresses the proliferation and migration of human ovarian cancer cells through inhibiting ERK/CREB pathway.
Ovarian cancer is the most lethal gynaecological cancer and the sixth most common cause of cancer related death among Western women. Recent studies show that harmine, a small-molecular β-carboline alkaloid present in medicinal plants, displayed obvious anticancer effects in several cancer cells. However, the effect of harmine on ovarian cancer is not well understood. In the present study, the effect of harmine on the cell proliferation and migration of ovarian cancer SKOV-3 cells and the underlying mechanism were investigated. Our results indicated that harmine significantly suppressed the proliferation of SKOV-3 cells in a dose-dependent manner. Interestingly, it also inhibited the epidermal growth factor (EGF)-induced proliferation of SKOV-3 cells. Moreover, the migration of SKOV-3 cells was markedly inhibited by harmine treatment. Further study showed that harmine inhibited not only the basal phosphorylation level of extra-cellular signal-regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) but also EGF-induced ERK1/2 and CREB phosphorylation. Finally, harmine significantly suppressed the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) family MMP-2, and MMP-9. In conclusion, our data revealed that harmine inhibited the proliferation and migration of SKOV-3 cells, which might be mediated by ERK/CREB pathway. These findings elucidate that harmine may act as a potential therapeutic drug for ovarian cancer treatment.


Risk management in inpatient units in the Czech Republic from the point of view of nurses in leadership positions.
The goal of this study was to assess specific features of risk management from the point of view of nurses in leadership positions in inpatient units in Czech hospitals. The study was performed using a quantitative research strategy, i.e., a questionnaire. The data sample was analyzed using SPSS v. 23.0. Pearson's chi-square and analysis of adjusted residues were used for identifying the existence associations of nominal and/or ordinal quantities. 315 nurses in leadership positions working in inpatient units of Czech hospitals were included in the sample. The sample was created using random selection by means of quotas. Based on the study results, statistically significant relations between the respondents' education and the utilization of methods to identify risks were identified. Furthermore, statistically significant relationships were found between a nurse's functional role within the system and regular analysis and evaluation of risks and between the type of the healthcare facility and the degree of patient involvement in risk management. The study found statistically significant correlations that can be used to increase the effectiveness of risk management in inpatient units of Czech hospitals. From this perspective, the fact that patient involvement in risk management was only reported by 37.8% of respondents seems to be the most notable problem.


Isolation and characterization of a serine protease, Ba III-4, from Peruvian Bothrops atrox venom.
A serine protease from Bothrops atrox (Peruvian specimen's venom) was isolated in two chromatographic steps in LC molecular exclusion and reverse phase-HPLC. This protein was denominated Ba III-4 (33,080.265 Da determinated by MALDI-TOF mass spectrometry) and showed pI of 5.06, Km 0.2 x 10(-1 ) M and the V (máx) 4.1 x 10(-1 )nmoles p-NA/lt/min on the synthetic substrate BapNA. Ba III-4 also showed ability to coagulate bovine fibrinogen. The serine protease was inhibited by soyben trypsin inhibitor and DA2II, which is an anti-hemorrhagic factor isolated from the opossum specie Didelphis albiventris. The primary structure of Ba III-4 showed the presence of His(44), Asp(94) and Ser(193) residues in the corresponding positions to the catalytic triad established in the serine proteases and Ser(193) are inhibited by phenylmethylsulfonylfluoride (PMSF). Amino acid analysis showed a high content of Asp, Glu, Gly, Ser, Ala and Pro, as well as 12 half-cysteine residues. Ba III-4 contained 293 amino acid residues and the primary structure of VIGGDECDIN EHPFLAFMYY SPRYFCGMTL INQEWVLTAA HCRYFCGMTL IHLGVHRESE KANYDEVRRF PKEKYFIFCD NNFTDDEVDK DIMLIRLDKP VSNSEHIAPL SLPSNPPSVG SVCRIMGWGQ TTTSPIDVLS PDEPHCANIN LFDNTVCHTA HPQVANTRTS TDTLCAGDLQ GGRDTCNGDS GGPLICNEQL HGILSWGGDP CAQPNKPAFY TKVYYFDHPW IKSIIAGNKK TVNFTCPPLR SDAKDDSTTY INQEWDWVLT AEHCDRTHMR NSFYDYSSIN SDS. Titration experiments did not show the presence of free sulfhydryl groups after 4 h incubation, nor were differences found in relation to titration kinetics in the presence of nondenaturating buffer. The isolation of this protein, Ba III-4, is of potential interest for the understanding of the pathomechanism of the snake venom action and for the identification of new blood coagulation enzymes of natural sources.


Neurofeedback training induces changes in white and gray matter.
The main objective of this structural magnetic resonance imaging (MRI) study was to investigate, using diffusion tensor imaging, whether a neurofeedback training (NFT) protocol designed to improve sustained attention might induce structural changes in white matter (WM) pathways, purportedly implicated in this cognitive ability. Another goal was to examine whether gray matter (GM) volume (GMV) might be altered following NFT in frontal and parietal cortical areas connected by these WM fiber pathways. Healthy university students were randomly assigned to an experimental group (EXP), a sham group, or a control group. Participants in the EXP group were trained to enhance the amplitude of their β1 waves at F4 and P4. Measures of attentional performance and MRI data were acquired one week before (Time 1) and one week after (Time 2) NFT. Higher scores on visual and auditory sustained attention were noted in the EXP group at Time 2 (relative to Time 1). As for structural MRI data, increased fractional anisotropy was measured in WM pathways implicated in sustained attention, and GMV increases were detected in cerebral structures involved in this type of attention. After 50 years of research in the field of neurofeedback, our study constitutes the first empirical demonstration that NFT can lead to microstructural changes in white and gray matter.


Chronic epinephrine treatment fails to alter prejunctional adrenoceptor modulation of sympathetic neurotransmission in the rat mesentery.
Rats were treated chronically with epinephrine (EPI-T; 100 micrograms/kg/hr, s.c.) for 6 days. On day 6 of treatment, the rats were anesthetized and the mesenteric vascular bed was isolated and perfused with Krebs' bicarbonate buffer containing cocaine (10 microM) and corticosterone (40 microM). Stimulus-induced (2 Hz, 120 pulses) overflow of neurotransmitter and its modulation by prejunctional adrenoceptors was studied. After chronic exposure to EPI, 50% of the mesenteric catecholamine stores consisted of EPI with no increase in total catecholamine content as compared to the control group (C). Absolute and fractional overflows of catecholamines upon periarterial nerve stimulation (2 Hz, 1 min) were not significantly different in the two groups. Beta adrenoceptor blockade by propranolol (10(-10) to 10(-6) M) did not alter the overflow of catecholamines. Alpha adrenoceptor blockade by phentolamine (10(-5) M) increased neurotransmitter overflow in both EPI-T and C groups. However, there was no significant difference in total catecholamine overflows between the two groups. Moreover, in the presence of phentolamine, propranolol (10(-6) M) remained without effect on overflow in both groups. These data suggest that EPI-T did not significantly increase the stimulus-induced overflow of catecholamines in the rat mesentery, nor did EPI-T result in prejunctional beta adrenoceptor modulation of neurotransmitter release in the mesenteric vascular bed.


[Exclusive breastfeeding at the point of discharge of high-risk newborns at a Neonatal Intensive Care Unit and the factors associated with this practice].
To study the rate of exclusive breastfeeding at the moment of hospital discharge of newborns admitted to a neonatal Intensive Care Unit and to analyze potential risk factors. Four hundred and ninety-five medical records were studied, pertaining to neonates born between 1998 and 1999, admitted to a neonatal intensive care unit, before and after the implementation of the Baby Friendly Hospital Initiative policies. Babies born during the Baby Friendly Hospital Initiative transition period and outside the Maternity ward were excluded from the study, as were children or mothers who were transferred from the institution, abandoned children and also mothers unfit to breastfeed. Risk factors for non-exclusive breast-feeding at discharge were studied. Odds ratio and 95% confidence intervals were calculated using multivariate logistic regression. The exclusive breastfeeding rate increased from 36% at discharge (before the Baby Friendly Hospital Initiative) to 54.7% (after BFHI). The independent risk factors associated with non-exclusive breastfeeding were the use of enteral feeding (OR = 3.01), ante-natal consultations < 6 (OR = 2.75), relactation use (OR = 2.66), birth weight < 2,500 g (OR = 2.64) and being born during the period before Baby Friendly policies were implemented (OR = 2.75). This research shows the potential efficiency of adopting Baby Friendly policies to increase the chance of successful breastfeeding at the point of discharge for high-risk newborns.


Identifying orthologs with OMA: A primer.
The Orthologous Matrix (OMA) is a method and database that allows users to identify orthologs among many genomes. OMA provides three different types of orthologs: pairwise orthologs, OMA Groups and Hierarchical Orthologous Groups (HOGs). This Primer is organized in two parts. In the first part, we provide all the necessary background information to understand the concepts of orthology, how we infer them and the different subtypes of orthology in OMA, as well as what types of analyses they should be used for. In the second part, we describe protocols for using the OMA browser to find a specific gene and its various types of orthologs. By the end of the Primer, readers should be able to (i) understand homology and the different types of orthologs reported in OMA, (ii) understand the best type of orthologs to use for a particular analysis; (iii) find particular genes of interest in the OMA browser; and (iv) identify orthologs for a given gene. The data can be freely accessed from the OMA browser at https://omabrowser.org.


Callyspongisines A-D: bromopyrrole alkaloids from an Australian marine sponge, Callyspongia sp.
An extract of the Great Australian Bight marine sponge Callyspongia sp. (CMB-01152) displayed inhibitory activity against the neurodegenerative disease kinase targets casein kinase 1 (CK1), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3β). Chemical investigation, employing HPLC-DAD-MS single ion extraction protocols, facilitated identification of the new bromopyrrole alkaloids, callyspongisines A-D (1-4), and two known co-metabolites, hymenialdisine (5) and 2-bromoaldisine (6). Structure elucidation of 1-6 was supported by detailed spectroscopic analysis and chemical interconversion, as well as biosynthetic and synthetic considerations. Callyspongisine A (1) is only the second reported example of a natural imino-oxazoline, and the first to feature a spiro heterocyclic framework, while callyspongisines B-D (2-4) were speculated to be storage and handling artefacts of 1. The kinase inhibitory activity detected in Callyspongia sp. (CMB-01152) was attributed to 5.


Gene expression signatures that predict radiation exposure in mice and humans.
The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.


Assessing consumer health vocabulary familiarity: an exploratory study.
Accurate assessment of the difficulty of consumer health texts is a prerequisite for improving readability. General purpose readability formulas based primarily on word length are not well suited for the health domain, where short technical terms may be unfamiliar to consumers. To address this need, we previously developed a regression model for predicting "average familiarity" with consumer health vocabulary (CHV) terms. The primary goal was to evaluate the ability of the CHV term familiarity model to predict (1) surface-level familiarity of health-related terms and (2) understanding of the underlying meaning (concept familiarity) among actual consumers. Secondary goals involved exploring the effect of demographic factors (eg, health literacy) on surface-level and concept-level familiarity and describing the relationship between the two levels of familiarity. Survey instruments for assessing surface-level familiarity (45 items) and concept-level familiarity (15 items) were developed. All participants also completed a demographic survey and a standardized health literacy assessment, S-TOFHLA. Based on surveys completed by 52 consumers, linear regression suggests that predicted CHV term familiarity is a statistically significantly predictor (P < .001) of participants' surface-level and concept-level familiarity performance. Health literacy was a statistically significant predictor of surface-level familiarity scores (P < .001); its effect on concept-level familiarity scores warrants further investigation (P = 0.06). Educational level was not a significant predictor of either type of familiarity. Participant scores indicated that conceptualization lagged behind recognition, especially for terms predicted as "likely to be familiar" (P = .006). This exploratory study suggests that the CHV term familiarity model is predictive of consumer recognition and understanding of terms in the health domain. Potential uses of such a model include readability formulas tailored to the consumer health domain and tools to "translate" professional medical documents into text that is more accessible to consumers. The study also highlights the usefulness of distinguishing between surface-level term familiarity and deeper concept understanding and presents one method for assessing familiarity at each level.


Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants.
Organisms must respond to hypoxia to preserve oxygen homeostasis. We identify a thiol oxidase, previously assigned as cysteamine (2-aminoethanethiol) dioxygenase (ADO), as a low oxygen affinity (high-K mO2) amino-terminal cysteine dioxygenase that transduces the oxygen-regulated stability of proteins by the N-degron pathway in human cells. ADO catalyzes the conversion of amino-terminal cysteine to cysteine sulfinic acid and is related to the plant cysteine oxidases that mediate responses to hypoxia by an identical posttranslational modification. We show in human cells that ADO regulates RGS4/5 (regulator of G protein signaling) N-degron substrates, modulates G protein-coupled calcium ion signals and mitogen-activated protein kinase activity, and that its activity extends to other N-cysteine proteins including the angiogenic cytokine interleukin-32. Identification of a conserved enzymatic oxygen sensor in multicellular eukaryotes opens routes to better understanding and therapeutic targeting of adaptive responses to hypoxia.


Health equity monitoring for healthcare quality assurance.
Population-wide health equity monitoring remains isolated from mainstream healthcare quality assurance. As a result, healthcare organizations remain ill-informed about the health equity impacts of their decisions - despite becoming increasingly well-informed about quality of care for the average patient. We present a new and improved analytical approach to integrating health equity into mainstream healthcare quality assurance, illustrate how this approach has been applied in the English National Health Service, and discuss how it could be applied in other countries. We illustrate the approach using a key quality indicator that is widely used to assess how well healthcare is co-ordinated between primary, community and acute settings: emergency inpatient hospital admissions for ambulatory care sensitive chronic conditions ("potentially avoidable emergency admissions", for short). Whole-population data for 2015 on potentially avoidable emergency admissions in England were linked with neighborhood deprivation indices. Inequality within the populations served by 209 clinical commissioning groups (CCGs: care purchasing organizations with mean population 272,000) was compared against two benchmarks - national inequality and inequality within ten similar populations - using neighborhood-level models to simulate the gap in indirectly standardized admissions between most and least deprived neighborhoods. The modelled inequality gap for England was 927 potentially avoidable emergency admissions per 100,000 people, implying 263,894 excess hospitalizations associated with inequality. Against this national benchmark, 17% of CCGs had significantly worse-than-benchmark equity, and 23% significantly better. The corresponding figures were 11% and 12% respectively against the similar populations benchmark. Deprivation-related inequality in potentially avoidable emergency admissions varies substantially between English CCGs serving similar populations, beyond expected statistical variation. Administrative data on inequality in healthcare quality within similar populations served by different healthcare organizations can provide useful information for healthcare quality assurance.


Prevalence of Dirofilaria immitis antigen and antibodies to Leishmania infantum in cats from southern Portugal.
Vector-borne diseases (VBD) are caused by a range of pathogens transmitted by arthropods and have emerged in recent years, showing a wider geographic distribution and increased global prevalence. In addition to their veterinary medical importance, cats play a central role in the transmission cycles of some VBD agents by acting as reservoirs, amplifying hosts or sentinels. The aim of this study was to determine the prevalence of Dirofilaria immitis antigen and of antibodies to Leishmania infantum in a sample of 271 cats from southern Portugal. Thirteen (4.8%) cats were positive to D. immitis, while antibodies to L. infantum were detected in 10 (3.7%) animals. The prevalence of D. immitis and L. infantum in the feline population from southern Portugal should alert for the need to implement control measures to protect animals and people from these zoonotic parasites. Furthermore, both parasitoses must be included in the differential diagnosis in feline clinical practice.


Improving rates of herpes zoster vaccination with a clinical decision support system in a primary care practice.
Herpes zoster (shingles) is a localized neurocutaneous eruption of blisters caused by reactivation of the varicella zoster virus. The cost of care for herpes zoster and its complications is estimated at $1.1 billion. The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends a one-time dose of the vaccine for adults aged 60 years or older. Despite that recommendation, utilization of the vaccine is very low. One way to boost the delivery of preventive services such as vaccinations is with a computerized clinical decision support system. Our study found that the herpes zoster vaccination rate increased significantly after the implementation of such a system. To study utilization of herpes zoster vaccine before and after the implementation of a web-based clinical decision support software solution in a primary care practice. Billing data was utilized to determine number of herpes zoster vaccination administered to patients for a 12-month period during the implementation of the software solution. The utilization of vaccinations improved from 63 to 117 (53.8% increase) for one primary care practice and from 54 to 127 (42.5% increase) in the other primary care practice. Herpes zoster vaccination rate significantly improved with implementation of a web-based clinical decision support system.


DNA melting in small-molecule-DNA-hybrid dimer structures: experimental characterization and coarse-grained molecular dynamics simulations.
When DNA hybridization is used to link together nanoparticles or molecules, the melting transition of the resulting DNA-linked material often is very sharp. In this paper, we study a particularly simple version of this class of material based on a small-molecule-DNA-hybrid (SMDH) structure that has three DNA strands per 1,3,5-tris(phenylethynyl)benzene core. By varying the concentration of the SMDHs, it is possible to produce either SMDH dimers or bulk aggregates, with the former having highly packed duplex DNA while the latter has an extended network. Melting measurements that we present show that the dimers exhibit sharp melting while the extended aggregates show broad melting. To interpret these results, we have performed coarse-grained molecular dynamics (CGMD) studies of the dimer melting and also of isolated duplex melting using CGMD potentials that have either implicit or explicit ions. Details of the melting simulation technology demonstrate that the simulations properly describe equilibrium transitions in isolated duplexes. The results show that the SMDH dimer has much sharper melting than the isolated duplex. Both implicit and explicit ion calculations show this effect, but the explicit ion results are sharper. An analytical model of the melting thermodynamics is developed which shows that the sharp melting is entropically driven and can be understood primarily in terms of the differences between the effective concentrations of the DNA strands for intracomplex hybridization events compared to intermolecular hybridization.


Facile photoimmobilization of proteins onto low-binding PEG-coated polymer surfaces.
Immobilization of proteins onto polymer surfaces usually requires specific reactive functional groups. Here, we show an easy one-step method to conjugate protein covalently onto almost any polymer surface, including low protein-binding poly(ethylene glycol) (PEG), without the requirement for the presence of specific functional groups. Several types of proteins, including alkaline phosphatase, bovine serum albumin, and polyclonal antibodies, were photoimmobilized onto a PEG-coated polymer surface using a water-soluble benzophenone as photosensitizer. Protein functionality after immobilization was verified for both enzymes and antibodies, and their presence on the surface was confirmed by X-ray photoelectron spectroscopy (XPS) and confocal fluorescence microscopy. Conjugation of capture antibody onto the PEG coating was employed for a simplified ELISA protocol without the need for blocking uncoated surface areas, showing ng/mL sensitivity to a cytokine antigen target. Moreover, spatially patterned attachment of fluorescently labeled protein onto the low-binding PEG-coated surface was achieved with a projection lithography system that enabled the creation of micrometer-sized protein features.


Application of the ICRP respiratory tract model to estimate pulmonary retention of industrially sampled indium-containing dusts.
Inhalation of indium-containing dusts is associated with the development of indium lung disease. Workers may be exposed to several different chemical forms of indium; however, their lung dosimetry is not fully understood. We characterized the physicochemical properties and measured the lung dissolution kinetics of eight indium-containing dusts. Indium dissolution rates in artificial lung fluids spanned two orders of magnitude. We used the International Commission on Radiological Protection (ICRP) human respiratory model (HRTM) to estimate pulmonary indium deposition, retention and biokinetic clearance to blood. For a two-year (median workforce tenure at facility) exposure to respirable-sized particles of the indium materials, modeled indium clearance (>99.99% removed) from the alveolar-interstitial compartment was slow for all dusts; salts would clear in 4 years, sintered indium-tin oxide (ITO) would clear in 9 years, and indium oxide would require 48 years. For this scenario, the ICRP HRTM predicted that indium translocated to blood would be present in that compartment for 3.5-18 years after cessation of exposure, depending on the chemical form. For a 40-year exposure (working lifetime), clearance from the alveolar-interstitial compartment would require 5, 10 and 60 years for indium salts, sintered ITO and indium oxide, respectively and indium would be present in blood for 5-53 years after exposure. Consideration of differences in chemical forms of indium, dissolution rates, alveolar clearance and residence time in blood should be included in exposure assessment and epidemiological studies that rely on measures of total indium in air or blood to derive risk estimates.


Estimation of heritability and breeding values for early egg production in laying hens from pooled data.
Under commercial conditions, data on egg production in laying hens are usually collected per cage rather than individually. In current breeding programs, genetic evaluations are, however, based on individually recorded egg production. Because commercial flocks are not maintained in single cages, this environmental difference between the breeding and commercial setting may result in a genotype x environment interaction. This study was aimed at estimating genetic parameters and predicting estimated breeding values for early egg production of laying hens by using pooled data (i.e., data from multiple bird cages) from pedigree birds housed in 4-bird cages. Using cage records, we compared 2 different methods of handling pooled data: cage sums and the assignment of cage means to individual birds, referred to as the approximate method. The 2 methods were compared by using cross-validation. Data from 3 purebred White Leghorn layer lines were used. Estimated heritability for early egg production was 0.36 when cage sums were used and 0.30 with the approximate method. The correlation of estimated breeding values between the cage sums method and the approximate method was 0.88. Cross-validation showed that the use of cage sums led to better predictions of missing phenotypes compared with the approximate method. The results of the research demonstrate that pooled data can be used in the genetic evaluation of laying hens and show that using directly pooled records (e.g., cage sums) gives better results than assigning group means to the birds of the group, thus simulating individual records.


Managing breast cancer in the renal transplant patient: a unique dilemma.
Improvements in immunosuppression have increased patient and graft survival in transplant recipients. As a result, there is greater risk of neoplastic processes such as breast cancer. Treatment in this population is complicated by the necessary immunosuppression, vascular accesses, and transplant grafts. General surgeons may expect to encounter more of these complex patients in the community setting. We sought to evaluate the surgical treatment of breast cancer in patients with renal transplants. Hospital and private physician records were queried to identify patients who developed breast cancer after a renal or pancreatic/renal transplantation. These charts were reviewed for demographics, type of breast cancer and treatment, location of dialysis access, and complications. From June 1, 1994, to May 31, 2004, 14 patients were identified. Eight patients had functioning transplants. All patients underwent operative interventions. Ten patients underwent adjuvant treatment. Three had functioning transplants and chose not to risk the graft with cessation of immunotherapy. However, no patient with functioning transplants who underwent chemotherapy developed organ failure. Breast cancer after transplantation poses a unique dilemma. The threat of transplanted organ failure is a major concern to these patients and often supersedes adjuvant therapies.


Muscle and Myotendinous Tissue Properties at the Distal Tibia as Assessed by High-Resolution Peripheral Quantitative Computed Tomography.
High-resolution peripheral quantitative computed tomography (HR-pQCT) quantifies bone microstructure and density at the distal tibia where there is also a sizable amount of myotendinous (muscle and tendon) tissue (MT); however, there is no method for the quantification of MT. This study aimed (1) to assess the feasibility of using HR-pQCT distal tibia scans to estimate MT properties using a custom algorithm, and (2) to determine the relationship between MT properties at the distal tibia and mid-leg muscle density (MD) obtained from pQCT. Postmenopausal women from the Hamilton cohort of the Canadian Multicenter Osteoporosis Study had a single-slice (2.3 ± 0.5 mm) 66% site pQCT scan measuring muscle cross-sectional area (MCSA) and MD. A standard HR-pQCT scan was acquired at the distal tibia. HR-pQCT-derived MT cross-sectional area (MTCSA) and MT density (MTD) were calculated using a custom algorithm in which thresholds (34.22-194.32 mg HA/cm3) identified muscle seed volumes and were iteratively expanded. Pearson and Bland-Altman plots were used to assess correlations and systematic differences between pQCT- and HR-pQCT-derived muscle properties. Among 45 women (mean age: 74.6 ± 8.5 years, body mass index: 25.9 ± 4.3 kg/m2), MTD was moderately correlated with mid-leg MD across the 2 modalities (r = 0.69-0.70, p < 0.01). Bland-Altman analyses revealed no evidence of directional bias for MTD-MD. HR-pQCT and pQCT measures of MTCSA and MCSA were moderately correlated (r = 0.44, p < 0.01). Bland-Altman plots for MTCSA revealed that larger MCSAs related to larger discrepancy between the distal and the mid-leg locations. This is the first study to assess the ability of HR-pQCT to measure MT size, density, and morphometry. HR-pQCT-derived MTD was moderately correlated with mid-leg MD from pQCT. This relationship suggests that distal MT may share common properties with muscle throughout the length of the leg. Future studies will assess the value of HR-pQCT-derived MT properties in the context of falls, mobility, and balance.


The Role of Magnesium in Pathophysiology and Migraine Treatment.
Migraine is one of the most common recurrent types of headache and is the seventh cause of disability. This neurological disorder is characterized by having pain in head and other various symptoms such as nausea, emesis, photophobia, phonophobia, and sometimes visual sensory disorders. Magnesium (Mg) is a necessary ion for human body and has a crucial role in health and life maintenance. One of the main roles of Mg is to conserve neurons electric potential. Therefore, magnesium deficiency can cause neurological complications. Migraine is usually related to low amounts of Mg in serum and cerebrospinal fluid (CSF). Deficits in magnesium have significant role in the pathogenesis of migraine. Mg has been extensively used in migraine prophylaxis and treatment. This review summarizes the role of Mg in migraine pathogenesis and the potential utilizations of Mg in the prevention and treatment of migraine with the emphasis on transdermal magnesium delivery.


Bacterial community structure in simultaneous nitrification, denitrification and organic matter removal process treating saline mustard tuber wastewater as revealed by 16S rRNA sequencing.
A simultaneous nitrification, denitrification and organic matter removal (SNDOR) process in sequencing batch biofilm reactor (SBBR) was established to treat saline mustard tuber wastewater (MTWW) in this study. An average COD removal efficiency of 86.48% and total nitrogen removal efficiency of 86.48% were achieved at 30gNaClL-1 during 100days' operation. The underlying mechanisms were investigated by PacBio SMRT DNA sequencing (V1-V9) to analyze the microbial community structures and its variation from low salinity at 10gNaClL-1 to high salinity at 30gNaClL-1. Results showed elevated salinity did not affect biological performance but reduced microbial diversity in SBBR, and halophilic bacteria gradually predominated by succession. Despite of high C/N, autotrophic ammonia-oxidizing bacteria (AOB) Nitrosomonas and ammonia-oxidizing archaea (AOA) Candidatus Nitrososphaera both contributed to ammonium oxidation. As salinity increasing, nitrite-oxidizing bacteria (NOB) were significantly inhibited, partial nitrification and denitrification (PND) process gradually contributed to nitrogen removal.


Vulnerable learners in the age of COVID-19: A scoping review.
This scoping review provides an overview of COVID-19 approaches to managing unanticipated school closures and available literature related to young people learning outside-of-school. A range of material has been drawn upon to highlight educational issues of this learning context, including psychosocial and emotional repercussions. Globally, while some countries opted for a mass school shut-down, many schools remained open for students from disadvantaged backgrounds. This partial closure not only enabled learning in smaller targeted groups but also offered a safe sanctuary for those who needed a regulated and secure environment. In Australia, if full school closures were to be enforced over a long period, a significant proportion of students from more vulnerable backgrounds would likely experience persistent disadvantage through a range of barriers: long-term educational disengagement, digital exclusion, poor technology management, and increased psychosocial challenges. This scoping review combines research on technology availability and learning, with analysis of the long-term educational impacts of navigating the COVID-19 disruption.


The 'problem' of Asian women's sexuality: public discourses in Aotearoa/New Zealand.
Public health research in New Zealand views Asian health - particularly, Asian women's sexual health issues - as a priority problem. In recent years, high rates of abortion and the growing incidence of unsafe sex among younger age Asian migrants have been publicized as a health concern. Public health research implicates migrant experiences and cultural factors as responsible for these trends. Loneliness and isolation among international students, inability to communicate effectively in English and lack of knowledge of available services are highlighted as reasons for the growing sexual ill-health in the Asian population in New Zealand. Extending from these, public health measures aim at improving culture-sensitive services, including targeted education. The present paper offers a critical commentary on these accepted public health perceptions that inform policy in New Zealand. It takes a Third World feminist approach to critique dominant public health discourses on Asian women's sexuality and questions the construction of knowledges about what are 'normal' and 'pathological' sexual practices. The paper revisits the data used to describe the 'problem' of Asian sexuality and argues that in order to understand sexual practices, it is important to query the cultural lenses that are used to describe and define them.


The Early Mother-to-Child Bond and Its Unique Prospective Contribution to Child Behavior Evaluated by Mothers and Teachers.
Maternal bonding has been described as the quality of the affective tie from a mother to her infant. This early bond's mental components and its longitudinal impact on child outcome have been markedly understudied. Although most researchers assume impaired maternal bonding to have a negative impact on child development, there is a lack of prospective studies evaluating this hypothesis. Since maternal mental health problems may negatively affect both bonding quality and child development, it is still to be determined whether there is a unique contribution of bonding quality to child behavior problems over and above maternal psychopathology. We examined a community sample of 101 mother-child dyads at the child's age of 2 weeks (t1) and 6 weeks (t2), 4 months (t3), 14 months (t4), and 5.5 years (t5). Maternal bonding and psychopathology were assessed at time points t1-t4 using the Postpartum Bonding Questionnaire (PBQ-16) and the Symptom Checklist Revised (SCL 90-R). Child behavior problems were rated in a multi-informant design by mothers and teachers at t5 using the Strengths and Difficulties Questionnaire (SDQ). In the case of maternal judgment of child behavior problems, bonding at 14 months (t4) proved to be a significant predictor (β = 0.30; p = 0.011). Teacher-rated child behavior problems were significantly predicted by maternal bonding at 2 weeks (t1; β = 0.48; p = 0.025). Our results indicate a prospective influence of the early mother-infant bond on child development and underline the unique contribution of bonding quality to child behavior problems over and above the impact of maternal psychopathology in a community sample.


MrDNA: a multi-resolution model for predicting the structure and dynamics of DNA systems.
Although the field of structural DNA nanotechnology has been advancing with an astonishing pace, de novo design of complex 3D nanostructures and functional devices remains a laborious and time-consuming process. One reason for that is the need for multiple cycles of experimental characterization to elucidate the effect of design choices on the actual shape and function of the self-assembled objects. Here, we demonstrate a multi-resolution simulation framework, mrdna, that, in 30 min or less, can produce an atomistic-resolution structure of a self-assembled DNA nanosystem. We demonstrate fidelity of our mrdna framework through direct comparison of the simulation results with the results of cryo-electron microscopy (cryo-EM) reconstruction of multiple 3D DNA origami objects. Furthermore, we show that our approach can characterize an ensemble of conformations adopted by dynamic DNA nanostructures, the equilibrium structure and dynamics of DNA objects constructed using off-lattice self-assembly principles, i.e. wireframe DNA objects, and to study the properties of DNA objects under a variety of environmental conditions, such as applied electric field. Implemented as an open source Python package, our framework can be extended by the community and integrated with DNA design and molecular graphics tools.


ACR Appropriateness Criteria® rectal cancer: metastatic disease at presentation.
The management of rectal cancer in patients with metastatic disease at presentation is highly variable. There are no phase III trials addressing therapeutic approaches, and the optimal sequencing of chemotherapy, radiation therapy, and surgery remains unresolved. Although chemoradiation is standard for patients with stage II/III rectal cancer, its role in the metastatic setting is controversial. Omitting chemoradiation may not be appropriate in all stage IV patients, particularly those with symptomatic primary tumors. Moreover, outcomes in this setting are vastly different, as some treatments carry the potential for cure in selected patients, while others are purely palliative. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (Modified Delphi) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.


Sex-dependent hepatic transcripts and metabolites in the development of glucose intolerance and insulin resistance in Zucker diabetic fatty rats.
Male Zucker diabetic fatty (mZDF) rats spontaneously develop type 2 diabetes, whereas females only become diabetic when fed a diabetogenic high-fat diet (high-fat-fed female ZDF rat, HF-fZDF). The aim of this study was to investigate if differences in liver functions could provide clues to this sex difference. Non-diabetic obese fZDF rats were compared with either mZDF or HF-fZDF regarding hepatic molecular profiles, to single out those components that might be protective in the females. High-fat feeding in fZDF led to enhanced weight gain, increased blood glucose and insulin levels, reduced insulin sensitivity and a trend towards reduced glucose tolerance, indicative of a prediabetic state. mZDF rats were diabetic, with low levels of insulin, high levels of glucose, reduced insulin sensitivity and impaired glucose tolerance. Transcript profiling and capillary electrophoresis time-of-flight mass spectrometry were used to indentify hepatic transcripts and metabolites that might be related to this. Many diet-induced alterations in transcript and metabolite levels in female rats were towards a 'male-like' phenotype, including reduced lipogenesis, increased fatty acid (FA) oxidation and increased oxidative stress responses. Alterations detected at the level of hepatic metabolites, indicated lower capacity for glutathione (GSH) production in male rats, and higher GSH turnover in females. Taken together, this could be interpreted as if anabolic pathways involving lipogenesis and lipid output might limit the degree of FA oxidation and oxidative stress in female rats. Together with a greater capacity to produce GSH, these hepatic sex differences might contribute to the sex-different development of diabetes in ZDF rats.


Progress towards identifying inflammatory bowel disease susceptibility genes.
Genomewide searches have identified about a dozen genomic regions potentially containing inflammatory bowel disease (IBD) susceptibility loci. Although some were observed in more than one genome scan or in replication studies, no one locus has been identified in all studies. This apparent lack of consistency is explained by the modest effect of most genetic loci in complex traits and by the modest power and the sampling variance of individual family-based studies. Despite these challenges, the field of IBD genetics found convincing evidence of linkage and, more recently, of genetic sequence variants that are strongly associated with disease. The first example was that of the IBD1 locus on chromosome 16, a linkage region confirmed by a large multicentre study, for which the CARD 15 gene was identified--using independent association strategies-as being a gene contributing to Crohn's disease susceptibility. Despite these advances, a number of questions still remain: (1) What is the best approach to identify the remaining IBD susceptibility loci? (2) How do we prove causality for any given gene or genetic variant? (3) How can we best use this information to obtain an understanding of the biological mechanisms underlying disease susceptibility and to identify useful markers of disease progression and response to therapy?


A cellular automata model for expanding turbulent flames.
Cellular automata models based on population dynamics, introduced by Von Neumann in the 1950s, has been successfully used to describe pattern development and front propagation in many applications, such as crystal growth, forest fires, fractal growth in biological media, etc. We, herein, explore the possibility of using a cellular automaton, based on the population dynamics of flamelets, as a low-order model to describe the dynamics of an expanding flame propagating in a turbulent environment. A turbulent flame is constituted by numerous flamelets, each of which interacts with their neighborhood composed of other flamelets, as well as unburned and burnt fluid particles. This local interaction leads to global flame dynamics. The effect of turbulence is simulated by introducing stochasticity in the local interaction and hence in the temporal evolution of the flamefront. Our results show that the model preserves various multifractal characteristics of the expanding turbulent flame and captures several characteristics of expanding turbulent flames observed in experiments. For example, at low turbulence levels, an increase in global burning rate leads to an increase in the turbulence level, while beyond a critical turbulence level, the expanding flame becomes increasingly fragmented, and consequently, the total burning rate decreases with increasing turbulence. Furthermore, at an extremely high turbulence level, the ignition kernel quenches at its nascent state and consequently loses its ability to propagate as an expanding flame.


Circulating influenza virus, climatic factors, and acute myocardial infarction: a time series study in England and Wales and Hong Kong.
Previous studies identifying associations between influenza and acute cardiac events may have been confounded by climatic factors. Differing seasonal patterns of influenza activity in Hong Kong and England and Wales provide a natural experiment to examine associations with myocardial infarction (MI) independent of cold weather effects. Weekly clinical and laboratory influenza surveillance data, environmental temperature and humidity data, and counts of MI-associated hospitalizations and deaths were obtained for England and Wales and for Hong Kong for the period 1998-2008. We used Poisson regression models that included environmental and seasonal variables to investigate the relationship between influenza and MI. There were ≥1.2 million MI-associated hospitalizations and 410,204 MI-associated deaths in England and Wales, with a marked peak in the winter season. In Hong Kong, the incidence of MI, on the basis of 65,108 hospitalizations and 18,780 deaths, had a large winter and smaller summer peak, mirroring patterns of influenza activity. There was strong evidence for a link between influenza and MI both in England and Wales, where 3.1%-3.4% of MI-associated deaths (P < .001) and 0.7%-1.2% of MI-associated hospitalizations (P < .001) were attributable to influenza, and in Hong Kong, where the corresponding figures were 3.9%-5.6% (P = .018) and 3.0%-3.3% (P = .002). Influenza was associated with an increase in MI-associated deaths and hospitalizations in 2 contrasting settings.


Improving treatment success rates for type 2 diabetes: recommendations for a changing environment.
As demonstrated by suboptimal levels of therapeutic goal achievement, there exists significant room for improvement in type 2 diabetes management. Despite widespread disease awareness and high rates of risk-factor testing in managed care, effective metabolic control in patients with type 2 diabetes is lacking and points toward a phenomenon known as clinical inertia. Clinical inertia, defined as a failure to initiate or advance therapy in a patient who is not at the evidence-based goal, is a key contributing factor in the suboptimal rates of therapeutic target achievement for type 2 diabetes. The causes of clinical inertia are multifactorial and interactive, arising among patients, providers, and health systems and from specific characteristics of available treatments. Therapeutic nonadherence is perhaps the most significant factor contributing to clinical inertia, with recent analyses demonstrating that providers are more likely to prescribe a dose escalation in patients who are adherent to therapy compared with those who are not. While the concept may be counterintuitive, antihyperglycemic agents also have the potential to cause or contribute to the phenomenon of clinical inertia. This often occurs via factors inherent to the drugs themselves, such as treatment-related adverse effects (eg, hypoglycemia, weight gain, edema, gastrointestinal symptoms), perception of long-term safety profiles, and the complexity of the treatment regimen. Often not considered, but equally important, is the durability of an antihyperglycemic agent to maintain glycosylated hemoglobin (A1C) level goals. Because no monotherapy exists to arrest the pancreatic beta-cell failure of type 2 diabetes, early combination therapy with thiazolidinediones and glucagon-like protein-1 agonists that is associated with sustained A1C level reduction is the only hope to change the progressive nature of type 2 diabetes mellitus.


Antagonism of p66shc by melanoma inhibitory activity.
The p66shc protein governs oxidant stress and mammalian lifespan. Here, we identify melanoma inhibitory activity (MIA), a protein secreted by melanoma cells, as a novel binding partner and antagonist of p66shc. The N-terminal collagen homology-2 (CH2) domain of p66shc binds to the Src Homology-3 (SH3)-like domain of MIA in vitro. In cells, ectopically expressed MIA and p66shc colocalize and co-precipitate. MIA also co-precipitates with the CH2 domain of p66shc in vivo. MIA expression in vivo suppresses p66shc-stimulated increase in endogenous hydrogen peroxide (H(2)O(2)), and inhibits basal and H(2)O(2)-induced phosphorylation of p66shc on serine 36 and H(2)O(2)-induced death. In human melanoma cells expressing MIA, endogenous MIA and p66shc co-precipitate. Downregulation of MIA in melanoma cells increases basal and ultraviolet radiation (UVR)-induced phosphorylation of p66shc on serine 36, augments endogenous H(2)O(2) levels, and increases their susceptibility to UVR-induced death. These findings show that MIA binds to p66shc, and suggest that this interaction antagonizes phosphorylation and function of p66shc.


Doubly distributional population codes: simultaneous representation of uncertainty and multiplicity.
Perceptual inference fundamentally involves uncertainty, arising from noise in sensation and the ill-posed nature of many perceptual problems. Accurate perception requires that this uncertainty be correctly represented, manipulated, and learned about. The choices subjects make in various psychophysical experiments suggest that they do indeed take such uncertainty into account when making perceptual inferences, posing the question as to how uncertainty is represented in the activities of neuronal populations. Most theoretical investigations of population coding have ignored this issue altogether; the few existing proposals that address it do so in such a way that it is fatally conflated with another facet of perceptual problems that also needs correct handling: multiplicity (that is, the simultaneous presence of multiple distinct stimuli). We present and validate a more powerful proposal for the way that population activity may encode uncertainty, both distinctly from and simultaneously with multiplicity.


Allocation of work activities in a comprehensive cancer genetics program
Hereditary cancer programs that provide risk assessment, genetic education, and counseling services are becoming increasingly common. This article describes one possible approach to providing comprehensive cancer genetics care by a credentialed genetics advanced practice nurse. In addition to the description of the program, data from a recently conducted time study are included to provide insight into work allocation of different program components. Findings from the study indicate that about 41% of the time is spent in direct clinical time with patients and families, including initial visit counseling, phone consultation, and follow-up visits. The rest of the time is spent in other indirect care activities, including previsit activities, risk calculation, clinical trials enrollment, correspondence, teaching, and administrative duties. For those developing or expanding a cancer genetics program, considering all activities that will occur and the time allocated to each activity is important.


[Heart auscultatory assessment of pulmonary artery systolic pressure].
The clinical assessment of pulmonary artery systolic pressure (PASP) by means of heart auscultation may be comparable to the measures obtained by Doppler echocardiography. To compare PASP estimated by heart auscultation and echocardiography. Thirty consecutive patients aged 70 ± 16 years (68% women) were evaluated prospectively, all of whom had an echocardiogram requested by their attending physician. Echocardiographic evaluation of PASP was made by tricuspid regurgitation velocity plus right a trial pressure estimate. Two trained clinicians, blinded for the clinical history and rest of physical examination, auscultated the patients. PASP was estimated from the auscultatory intensity of the pulmonary component in comparison to the aortic component of the second heart sound and its propagation towards the apex, in accordance to a pre-established algorithm. Correlation between auscultatory and echocardiographic measures of PASP was made by Pearson test. Variability between both methods and among observers was evaluated with Bland-Altman analysis. Fifty two per cent of patients were hypertensive and 20% diabetic. Admission diagnoses were heart failure in 50% of cases, exacerbation of chronic obstructive pulmonary disease in 20%, pulmonary thromboembolism in 10% and other clinical entities in 20%. A significant correlation was found between auscultatory and echocardiographic estimation of PASP (r = 0.64, p = 0, 01). Bland-Altman analysis showed a mean difference between both determinations of 7.6 ± 7.6 mmHg. Bland-Altman analysis between both operators showed an average difference of 5.4 ± 8.4 mm Hg. Heart auscultatory evaluation allows a precise and reproducible estimation of PASP and compares favorably with echocardiographic assessment.


Neuromuscular blocking agents in the critically ill patient: neither sedating nor pain relieving.
Although neuromuscular blocking agents (NMBAs), such as pancuronium bromide and succinylcholine, are widely used in the management of critically ill patients, many misconceptions regarding the agents' clinical effects and indications persist. This article will discuss these misconceptions and review the indications for the use of NMBAs in the critically ill patient, how these potent agents work, and strategies to effectively manage critically ill patients who are receiving NMBAs as a part of their treatment regimen.


Physical fitness and thermoregulatory reactions in a cold environment in men.
The relationship between the physical fitness level (maximal O2 consumption, VO2max) and thermoregulatory reactions was studied in 17 adult males submitted to an acute cold exposure. Standard cold tests were performed in nude subjects, lying for 2 h in a climatic chamber at three ambient air temperatures (10, 5, and 1 degrees C). The level of physical fitness conditioned the intensity of thermoregulatory reactions to cold. For all subjects, there was a direct relationship between physical fitness and 1) metabolic heat production, 2) level of mean skin temperature (Tsk), 3) level of skin conductance, and 4) level of Tsk at the onset of shivering. The predominance of thermogenic or insulative reactions depended on the intensity of the cold stress: insulative reactions were preferential at 10 degrees C, or even at 5 degrees C, whereas colder ambient temperature (1 degree C) triggered metabolic heat production abilities, which were closely related to the subject's physical fitness level. Fit subjects have more efficient thermoregulatory abilities against cold stress than unfit subjects, certainly because of an improved sensitivity of the thermoregulatory system.


Interactions of CcdB with DNA gyrase. Inactivation of Gyra, poisoning of the gyrase-DNA complex, and the antidote action of CcdA.
The F plasmid-carried bacterial toxin, the CcdB protein, is known to act on DNA gyrase in two different ways. CcdB poisons the gyrase-DNA complex, blocking the passage of polymerases and leading to double-strand breakage of the DNA. Alternatively, in cells that overexpress CcdB, the A subunit of DNA gyrase (GyrA) has been found as an inactive complex with CcdB. We have reconstituted the inactive GyrA-CcdB complex by denaturation and renaturation of the purified GyrA dimer in the presence of CcdB. This inactivating interaction involves the N-terminal domain of GyrA, because similar inactive complexes were formed by denaturing and renaturing N-terminal fragments of the GyrA protein in the presence of CcdB. Single amino acid mutations, both in GyrA and in CcdB, that prevent CcdB-induced DNA cleavage also prevent formation of the inactive complexes, indicating that some essential interaction sites of GyrA and of CcdB are common to both the poisoning and the inactivation processes. Whereas the lethal effect of CcdB is most probably due to poisoning of the gyrase-DNA complex, the inactivation pathway may prevent cell death through formation of a toxin-antitoxin-like complex between CcdB and newly translated GyrA subunits. Both poisoning and inactivation can be prevented and reversed in the presence of the F plasmid-encoded antidote, the CcdA protein. The products of treating the inactive GyrA-CcdB complex with CcdA are free GyrA and a CcdB-CcdA complex of approximately 44 kDa, which may correspond to a (CcdB)2(CcdA)2 heterotetramer.


Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death.
The role of extracellular α-synuclein (α-syn) in the initiation and the spreading of neurodegeneration in Parkinson's disease (PD) has been studied extensively over the past 10 years. However, the nature of the α-syn toxic species and the molecular mechanisms by which they may contribute to neuronal cell loss remain controversial. In this study, we show that fully characterized recombinant monomeric, fibrillar or stabilized forms of oligomeric α-syn do not trigger significant cell death when added individually to neuroblastoma cell lines. However, a mixture of preformed fibrils (PFFs) with monomeric α-syn becomes toxic under conditions that promote their growth and amyloid formation. In hippocampal primary neurons and ex vivo hippocampal slice cultures, α-syn PFFs are capable of inducing a moderate toxicity over time that is greatly exacerbated upon promoting fibril growth by addition of monomeric α-syn. The causal relationship between α-syn aggregation and cellular toxicity was further investigated by assessing the effect of inhibiting fibrillization on α-syn-induced cell death. Remarkably, our data show that blocking fibril growth by treatment with known pharmacological inhibitor of α-syn fibrillization (Tolcapone) or replacing monomeric α-syn by monomeric β-synuclein in α-syn mixture composition prevent α-syn-induced toxicity in both neuroblastoma cell lines and hippocampal primary neurons. We demonstrate that exogenously added α-syn fibrils bind to the plasma membrane and serve as nucleation sites for the formation of α-syn fibrils and promote the accumulation and internalization of these aggregates that in turn activate both the extrinsic and intrinsic apoptotic cell death pathways in our cellular models. Our results support the hypothesis that ongoing aggregation and fibrillization of extracellular α-syn play central roles in α-syn extracellular toxicity, and suggest that inhibiting fibril growth and seeding capacity constitute a viable strategy for protecting against α-syn-induced toxicity and slowing the progression of neurodegeneration in PD and other synucleinopathies.


Performance of the PEdiatric Logistic Organ Dysfunction-2 score in critically ill children requiring plasma transfusions.
Organ dysfunction scores, based on physiological parameters, have been created to describe organ failure. In a general pediatric intensive care unit (PICU) population, the PEdiatric Logistic Organ Dysfunction-2 score (PELOD-2) score had both a good discrimination and calibration, allowing to describe the clinical outcome of critically ill children throughout their stay. This score is increasingly used in clinical trials in specific subpopulation. Our objective was to assess the performance of the PELOD-2 score in a subpopulation of critically ill children requiring plasma transfusions. This was an ancillary study of a prospective observational study on plasma transfusions over a 6-week period, in 101 PICUs in 21 countries. All critically ill children who received at least one plasma transfusion during the observation period were included. PELOD-2 scores were measured on days 1, 2, 5, 8, and 12 after plasma transfusion. Performance of the score was assessed by the determination of the discrimination (area under the ROC curve: AUC) and the calibration (Hosmer-Lemeshow test). Four hundred and forty-three patients were enrolled in the study (median age and weight: 1 year and 9.1 kg, respectively). Observed mortality rate was 26.9 % (119/443). For PELOD-2 on day 1, the AUC was 0.76 (95 % CI 0.71-0.81) and the Hosmer-Lemeshow test was p = 0.76. The serial evaluation of the changes in the daily PELOD-2 scores from day 1 demonstrated a significant association with death, adjusted for the PELOD-2 score on day 1. In a subpopulation of critically ill children requiring plasma transfusion, the PELOD-2 score has a lower but acceptable discrimination than in an entire population. This score should therefore be used cautiously in this specific subpopulation.


The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease.
A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.


Mutation accumulation in space and the maintenance of sexual reproduction.
The maintenance of sexual reproduction remains one of the major puzzles of evolutionary biology, since, all else being equal, an asexual mutant should have a twofold fitness advantage over the sexual wildtype. Most theories suggest that sex helps either to purge deleterious mutations, or to adapt to changing environments. Both mechanisms have their limitations if they act in isolation because they require either high genomic mutation rates or very virulent pathogens, and it is therefore often thought that they must act together to maintain sex. Typically, however, these theories have in common that they are not based on spatial processes. Here, we show that local dispersal and local competition can explain the maintenance of sexual reproduction as a means of purging deleterious mutations. Using a spatially explicit individual-based model, we find that even with reasonably low genomic mutation rates and large total population sizes, asexual clones cannot invade a sexual population. Our results demonstrate how spatial processes affect mutation accumulation such that it can fully erode the twofold benefit of asexuality faster than an asexual clone can take over a sexual population. Thus, the cost of sex is generally overestimated in models that ignore the effects of space on mutation accumulation.


Nutritional factors and osteoarthritis: recent developments.
The role of nutrition and nutritional supplements in the development and progression of osteoarthritis is now a topic of considerable public, industry, and academic interest. This review focuses on how the evidence for a role of nutritional factors or nutritional supplements in the management of knee osteoarthritis has been changed by recent research. Recent studies include clinical trials of weight loss and exercise as interventions for osteoarthritis of the knee, the elucidation of mechanisms of oxidative stress on the chondrocyte genome, further study of vitamin C supplementation in an animal with spontaneous osteoarthritis, and further clinical and pharmacodynamic evaluations of glucosamine and chondroitin sulfate. Perplexing findings among these studies include the deleterious effects of vitamin C on osteoarthritis in the Hartley guinea pig, the low levels of glucosamine achieved in serum after an oral dose, recent negative clinical studies of glucosamine, and the heterogeneity of results among glucosamine trials. With an intensification of research in this field come new clinical and basic science data, sometimes with surprising results. These confirm the considerable potential for a role of nutritional interventions for osteoarthritis, but they emphasize the need for systematic scientific evaluation of the claims made for such products.


Trichurid nematodes in ring-necked pheasants from backyard flocks of the State of Rio de Janeiro, Brazil: frequency and pathology.
The present investigation is related to the frequency of infection and to the gross and microscopic lesions associated to the presence of trichurid worms in 50 ring-necked pheasants (Phasianus colchicus) from backyard flocks in the state of Rio de Janeiro, Brazil. In the investigated birds, the overall infection rate was of 74%, with the presence of Eucoleus perforans with 72% of prevalence and 21.2 of mean intensity, in the esophageal and crop mucosa and rarely in the junction of the proventriculus and esophagus, E. annulatus with 2% and 3 in the crop mucosa, Capillaria phasianina, with 12% and 4.3 in the cecum and small intestine and Baruscapillaria obsignata, for the first time referred in this host, with 2% and 1 in the small intestine. Clinical signs were absent. The gross lesions observed in the crop and esophagus of 14 (38.9%) pheasants parasitized with E. perforans were thickening, small nodules, congestion, and petechial haemorrhages in the mucosa. These birds presented a mean infection of 37.5 and a range of infection of 10-82. The microscopic lesions revealed chronic esophagitis with diffuse inflammatory process in the lamina propria characterized mostly by a mononuclear cell infiltrate and also with the presence of granulocytes. In the case of the parasitism of pheasants with C. phasianina, the gross lesions were absent; microscopic lesions were characterized by chronic typhlitis with mononuclear infiltrate. Gross and microscopic lesions were absent in the pheasants parasitized with E. annulatus and B. obsignata.


Multi-targeted directed ligands for Alzheimer's disease: design of novel lead coumarin conjugates.
Alzheimer's Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin-morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin-piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 μM and 1 μM, respectively. Molecular modelling studies were conducted with Accelrys® Discovery Studio® V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.


Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma.
Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.


Mode-locked pulse generation from an all-fiberized, Tm-Ho-codoped fiber laser incorporating a graphene oxide-deposited side-polished fiber.
An in-depth experimental investigation was conducted into the use of a graphene oxide-based saturable absorber implemented on a side-polished fiber platform for femtosecond pulse generation in the 2 μm region. First, it was experimentally shown that an all-fiberized thulium-holmium (Tm-Ho)-codoped fiber ring laser with reduced cavity length can produce stable femtosecond pulses by incorporating a graphene oxide-deposited side-polished fiber. Second, the measurement accuracy issue in obtaining a precise pulse-width value by use of an autocorrelator together with a silica fiber-based 2 μm-band amplifier was investigated. It showed that the higher-order soliton compression effect caused by the combination of anomalous dispersion and Kerr nonlinearity can provide incorrect pulse-width information. Third, an experimental investigation into the precise role of the graphene oxide-deposited side-polished fiber was carried out to determine whether its polarization-dependent loss (PDL) can be a substantial contributor to mode-locking through nonlinear polarization rotation. By comparing its performance with that of a gold-deposited side-polished fiber, the PDL contribution to mode-locking was found to be insignificant, and the dominant mode-locking mechanism was shown to be saturable absorption due to mutual interaction between the evanescent field of the oscillated beam and the deposited graphene oxide particles.


Cardiovascular risk factors among people living with HIV in rural Kenya: a clinic-based study.
To determine the prevalence of cardiovascular risk factors and their association with antiretroviral therapy (ART) among HIV-infected adults in a rural sub-county hospital in Kenya. This was a descriptive survey of patient charts characterising cardiovascular risk among adult patients (> 18 years) at Ukwala sub-county hospital between June 2013 and January 2015. Post-stratification survey weights were applied to obtain prevalence levels. Adjusted odds ratios (AOR) for each variable related to cardiovascular risk factors were calculated using logistic regression models. Overall, the prevalence of diabetes mellitus was 0.4%, 0.3% of patients had had a previous cardiovascular event (heart attack or stroke), 40.4% had pre-hypertension, while 10.4% had stage 1 and 2.9% stage 2 hypertension. Up to 14% of patients had elevated non-fasting total cholesterol levels. Factors associated with hypertension were male gender (AOR 1.59, p = 0.0001), being over 40 years of age (AOR 1.78, p = 0.0001) and having an increased waist circumference (OR 2.56, p = 0.0014). Raised total cholesterol was more likely in those on tenofovir disoproxil fumarate (TDF) (AOR 2.2, p = 0.0042), azidothymidine (AZT) (AOR 2.5, p = 0.0004) and stavudine (D4T) -containing regimens (AOR 3.13, p = 0.0002). An elevated prevalence of undiagnosed cardiovascular risk factors such as hypertension and raised total cholesterol levels was found among people living with HIV. There was an association between raised total cholesterol and nucleoside reverse-transcriptase inhibitor (NRTI) -based ART regimens. Our findings provide further rationale for integrating routine cardiovascular risk-factor screening into HIV-care services.


Integrating phenotypic and expression profiles to map arsenic-response networks.
Arsenic is a nonmutagenic carcinogen affecting millions of people. The cellular impact of this metalloid in Saccharomyces cerevisiae was determined by profiling global gene expression and sensitivity phenotypes. These data were then mapped to a metabolic network composed of all known biochemical reactions in yeast, as well as the yeast network of 20,985 protein-protein/protein-DNA interactions. While the expression data unveiled no significant nodes in the metabolic network, the regulatory network revealed several important nodes as centers of arsenic-induced activity. The highest-scoring proteins included Fhl1, Msn2, Msn4, Yap1, Cad1 (Yap2), Pre1, Hsf1 and Met31. Contrary to the gene-expression analyses, the phenotypic-profiling data mapped to the metabolic network. The two significant metabolic networks unveiled were shikimate, and serine, threonine and glutamate biosynthesis. We also carried out transcriptional profiling of specific deletion strains, confirming that the transcription factors Yap1, Arr1 (Yap8), and Rpn4 strongly mediate the cell's adaptation to arsenic-induced stress but that Cad1 has negligible impact. By integrating phenotypic and transcriptional profiling and mapping the data onto the metabolic and regulatory networks, we have shown that arsenic is likely to channel sulfur into glutathione for detoxification, leads to indirect oxidative stress by depleting glutathione pools, and alters protein turnover via arsenation of sulfhydryl groups on proteins. Furthermore, we show that phenotypically sensitive pathways are upstream of differentially expressed ones, indicating that transcriptional and phenotypic profiling implicate distinct, but related, pathways.


The search for DAF-16/FOXO transcriptional targets: approaches and discoveries.
The insulin/IGF-1 receptor (IIR)/FOXO pathway is remarkably conserved in worms, flies, and mammals, and downregulation of signaling in this pathway has been shown to extend lifespan in all of these animals. FOXO-mediated transcription is required for the long lifespan of IIR mutants; thus, there is great interest in identifying FOXO target genes, as they may carry out the biochemical activities that extend longevity. A number of approaches have been used to identify the transcriptional targets of FOXO. Thus far, the best data available on the components downstream of this pathway are from experiments involving the Caenorhabditis elegans FOXO transcription factor, DAF-16; some of these targets have been tested for their contributions to longevity, dauer formation, and fat storage. Here, I examine and compare the approaches used to identify DAF-16/FOXO targets, review the genes regulated by DAF-16, and discuss the processes that may be at work to extend lifespan in IIR mutants. Rather than upregulating every possible beneficial gene, DAF-16 appears to selectively upregulate genes that contribute to specific protective mechanisms, while simultaneously downregulating potentially deleterious genes. In addition to genes that carry out expected roles in stress protection, many previously unknown targets have been identified in these studies, suggesting that some mechanisms of lifespan extension still await discovery. These mechanisms may act cooperatively or cumulatively to increase longevity, and are likely to be at least partially conserved in higher organisms.


GABA uptake into astrocytes is not associated with significant metabolic cost: implications for brain imaging of inhibitory transmission.
Synaptically released glutamate has been identified as a signal coupling excitatory neuronal activity to increased glucose utilization. The proposed mechanism of this coupling involves glutamate uptake into astrocytes resulting in increased intracellular Na+ (Nai+) and activation of the Na+/K+-ATPase. Increased metabolic demand linked to disruption of Nai+ homeostasis activates glucose uptake and glycolysis in astrocytes. Here, we have examined whether a similar neurometabolic coupling could operate for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), also taken up by Na+-dependent transporters into astrocytes. Thus, we have compared the Nai+ response to GABA and glutamate in mouse astrocytes by microspectrofluorimetry. The Nai+ response to GABA consisted of a rapid rise of 4-6 mM followed by a plateau that did not, however, significantly activate the pump. Indeed, the GABA transporter-evoked Na+ influxes are transient in nature, almost totally shutting off within approximately 30 sec of GABA application. The metabolic consequences of the GABA-induced Nai+ response were evaluated by monitoring cellular ATP changes indirectly in single cells and measuring 2-deoxyglucose uptake in astrocyte populations. Both approaches showed that, whereas glutamate induced a robust metabolic response in astrocytes (decreased ATP levels and glucose uptake stimulation), GABA did not cause any measurable metabolic response, consistent with the Nai+ measurements. Results indicate that GABA does not couple inhibitory neuronal activity with glucose utilization, as does glutamate for excitatory neurotransmission, and suggest that GABA-mediated synaptic transmission does not contribute directly to brain imaging signals based on deoxyglucose.


Cost-effective innovation of locally assembled mannequins for undergraduate skill development in parenteral drug administration.
The new competencybased curriculum for undergraduate medical education by the Medical Council of India mandates simulation using mannequins for teaching parenteral drug administration. Traditional education tends to focus on textbook learning, whereas competencybased education concentrates on the outcomes that directly guide the assessment of learners. To introduce a module for the development of the core competency of parenteral drug administration using costeffective locally assembled mannequins for handson skill development in administering injections to be assessed using objective structured practical examination (OSPE). Costeffective and durable fiberglass arms from mannequins used for fashion display were prepared for parenteral drug administration. The padding is easily done with wadding and gauze/crepe bandages, and the assembling requires only 15 minutes per arm. The training can be conducted in the department, giving students adequate opportunity for handson learning on individual arms during the practical sessions. As initial investment and recurring costs are low, it is possible for the department to obtain enough number of mannequins for each student to practice individually on an injection arm. Students practice injection technique freely, without fear of damaging the mannequin or having to do it on a patient. This helps them to assimilate the steps and sub-steps of doing the task in a much more realistic way and builds their confidence. Assessment of the performance of injection technique, infection control practices, and drug delivery are possible. We have observed a greater trend toward selflearning and selfefficacy and better adherence to the protocol of injection technique because of the handson training the students receive.


VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer.
Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis.


A High-Performance 2.5 μm Charge Domain Global Shutter Pixel and Near Infrared Enhancement with Light Pipe Technology.
We developed a new 2.5 μm global shutter (GS) pixel using a 65 nm process with an advanced light pipe (LP) structure. This is the world's smallest charge domain GS pixel reported so far. This new developed pixel platform is a key enabler for ultra-high resolution sensors, industrial cameras with wide aperture lenses, and low form factors optical modules for mobile applications. The 2.5 μm GS pixel showed excellent optical performances: 68% quantum efficiency (QE) at 530 nm, ±12.5 degrees angular response (AR), and quite low parasitic light sensitivity (PLS)-10,400 1/PLS with the F#2.8 lens. In addition, we achieved an extremely low memory node (MN) dark current 13 e-/s at 60 °C by fully pinned MN. Furthermore, we studied how the LP technology contributes to the improvement of the modulation transfer function (MTF) in near infrared (NIR) enhanced GS pixel. The 2.8 μm GS pixel using a p-substrate showed 109 lp/mm MTF@50% at 940 nm, which is 1.6 times better than that without an LP. The MTF can be more enhanced by the combination of the LP and the deep photodiode (PD) electrically isolated from the substrate. We demonstrated the advantage of using LP technology and our advanced stacked deep photodiode (SDP) technology together. This unique combination showed an improvement of more than 100% in NIR QE while maintaining an MTF that is close to the theoretical Nyquist limit (MTF @50% = 156 lp/mm).


In situ ellipsometric study of optical properties of ultrathin films.
A method has been developed for analysis of a series of ellipsometric data taken in situ during deposition. With this method the optical constants n and k and thickness d of growing ion-beam-sputtered films of C, Si, Ni, Nb, Mo, Ru, Rh, Pd, Ag, W, Re, and Au have been determined as a function of deposition time t. The minimum critical thickness d(i) needed for a film to become optically isotropic has been determined from the n, k, d-versus-t curves. Anomalous behavior of these curves appears in the region d less, similar d(c) resulting from a breakdown of the isotropic film model employed. This is shown, by transmission electron micrographs, to have a correlation with a transition region from island/anisotropic to continuous/isotropic.


Acute and Post-acute Neuromodulation Induces Stroke Recovery by Promoting Survival Signaling, Neurogenesis, and Pyramidal Tract Plasticity.
Repetitive transcranial magnetic stimulation (rTMS) has gained interest as a non-invasive treatment for stroke based on the data promoting its effects on functional recovery. However, the exact action mechanisms by which the rTMS exert beneficial effects in cellular and molecular aspect are largely unknown. To elucidate the effects of high- and low-frequency rTMS in the acute-ischemic brain, we examined how rTMS influences injury development, cerebral blood flow (CBF), DNA fragmentation, neuronal survival, pro- and anti-apoptotic protein activations after 30 and 90 min of focal cerebral ischemia. In addition, inflammation, angiogenesis, growth factors and axonal outgrowth related gene expressions, were analyzed. Furthermore, we have investigated the effects of rTMS on post-acute ischemic brain, particularly on spontaneous locomotor activity, perilesional tissue remodeling, axonal sprouting of corticobulbar tracts, glial scar formation and cell proliferation, in which rTMS was applied starting 3 days after the stroke onset for 28 days. In the high-frequency rTMS received animals reduced DNA fragmentation, infarct volume and improved CBF were observed, which were associated with increased Bcl-xL activity and reduced Bax, caspase-1, and caspase-3 activations. Moreover, increased angiogenesis, growth factors; and reduced inflammation and axonal sprouting related gene expressions were observed. These results correlated with reduced microglial activation, neuronal degeneration, glial scar formation and improved functional recovery, tissue remodeling, contralesional pyramidal tract plasticity and neurogenesis in the subacute rTMS treated animals. Overall, we propose that high-frequency rTMS in stroke patients can be used to promote functional recovery by inducing the endogenous repair and recovery mechanisms of the brain.


Macrophages unlock progression of breast cancer cells experiencing matrigel-segregation in transplantation models.
Basement membrane matrix proteins, such as matrigel, are able to improve the efficiency of tumour transplantation. This assay represents the gold standard to measure tumour initiation potential in vivo of a limited number of cancer cells. However, in culture conditions, matrigel directly signals to cancer cells altering their phenotype. We here investigate how matrigel influences the tumour reconstitution dynamics of breast cancer cells in vivo. This is particularly relevant in the setting of limiting dilution assay where cells are transplanted in a relatively high amount of Matrigel. We show that matrigel initially induces a normalized growth of transplanted MMTV-PyMT breast tumours cells. This occurs in the context of a matrigel-segregation effect where cancer cells are transiently isolated from host tissue. We identify macrophages as gatekeepers of the cancer-host cell interaction: depriving transplants from macrophages locked cancer cells in this isolated environment where they fail to form tumours despite retaining their intrinsic tumorigenic potential. This is a decisive proof of concept that cancer cells' malignant behaviour can be dominated by their microenvironment. Moreover, considering that diverse breast cancer cells are differently subjected to a segregation effect, this needs to be considered when comparing tumour initiation potential of different cancer cells.


Database analysis of children and adolescents with bipolar disorder consuming a micronutrient formula.
Eleven previous reports have shown potential benefit of a 36-ingredient micronutrient formula (known as EMPowerplus) for the treatment of psychiatric symptoms. The current study asked whether children (7-18 years) with pediatric bipolar disorder (PBD) benefited from this same micronutrient formula; the impact of Attention-Deficit/Hyperactivity Disorder (ADHD) on their response was also evaluated. Data were available from an existing database for 120 children whose parents reported a diagnosis of PBD; 79% were taking psychiatric medications that are used to treat mood disorders; 24% were also reported as ADHD. Using Last Observation Carried Forward (LOCF), data were analyzed from 3 to 6 months of micronutrient use. At LOCF, mean symptom severity of bipolar symptoms was 46% lower than baseline (effect size (ES) = 0.78) (p < 0.001). In terms of responder status, 46% experienced >50% improvement at LOCF, with 38% still taking psychiatric medication (52% drop from baseline) but at much lower levels (74% reduction in number of medications being used from baseline). The results were similar for those with both ADHD and PBD: a 43% decline in PBD symptoms (ES = 0.72) and 40% in ADHD symptoms (ES = 0.62). An alternative sample of children with just ADHD symptoms (n = 41) showed a 47% reduction in symptoms from baseline to LOCF (ES = 1.04). The duration of reductions in symptom severity suggests that benefits were not attributable to placebo/expectancy effects. Similar findings were found for younger and older children and for both sexes. The data are limited by the open label nature of the study, the lack of a control group, and the inherent self-selection bias. While these data cannot establish efficacy, the results are consistent with a growing body of research suggesting that micronutrients appear to have therapeutic benefit for children with PBD with or without ADHD in the absence of significant side effects and may allow for a reduction in psychiatric medications while improving symptoms. The consistent reporting of positive changes across multiple sites and countries are substantial enough to warrant a call for randomized clinical trials using micronutrients.