Hexagonal core-shell and alloy Au/Ag nanodisks on ZnO nanorods and their optical enhancement effect.
Au and Ag hybrid hexagonal nanodisks were synthesized on ZnO nanorods' (0002) surface via a new two-step deposition-annealing method. The structural, compositional, as well as optical investigations were carried out systematically to find out the nanodisks' formation mechanism and optical enhancement effect. It was shown that the core-shell Au/Ag nanodisk can be formed under rapid annealing temperature of 500°C, while Au/Ag alloy nanodisks are formed if higher temperatures (>550°C) are applied. The optical effect from these nanodisks was studied through photoluminescence and absorption spectroscopy. It was found that the carrier-plasmon coupling together and carrier transfer between metal and ZnO contribute to the emission enhancement. Furthermore, the results suggest that the composition of nanodisk on the vicinity of metal/ZnO interface plays an important role in terms of the enhancement factors.


The feasibility and validity of ambulatory self-report of psychotic symptoms using a smartphone software application.
Semi-structured interview scales for psychosis are the gold standard approach to assessing psychotic and other symptoms. However, such assessments have limitations such as recall bias, averaging, insensitivity to change and variable interrater reliability. Ambulant, real-time self-report assessment devices may hold advantages over interview measures, but it needs to be shown that the data thus collected are valid, and the collection method is acceptable, feasible and safe. We report on a monitoring system for the assessment of psychosis using smartphone technology. The primary aims were to: i) assess validity through correlations of item responses with those on widely accepted interview assessments of psychosis, and ii) examine compliance to the procedure in individuals with psychosis of varying severity. A total of 44 participants (acute or remitted DSM-4 schizophrenia and related disorders, and prodromal) completed 14 branching self-report items concerning key psychotic symptoms on a touch-screen mobile phone when prompted by an alarm at six pseudo-random times, each day, for one week. Face to face PANSS and CDS interviews were conducted before and after the assessment period blind to the ambulant data. Compliance as defined by completion of at least 33% of all possible data-points over seven days was 82%. In the 36 compliant participants, 5 items (delusions, hallucinations, suspiciousness, anxiety, hopelessness) showed moderate to strong (rho 0.6-0.8) associations with corresponding items from interview rating scales. Four items showed no significant correlation with rating scales: each was an item based on observable behaviour. Ambulant ratings showed excellent test-retest reliability and sensitivity to change. Ambulatory monitoring of symptoms several times daily using smartphone software applications represents a feasible and valid way of assessing psychotic phenomena for research and clinical management purposes. Further evaluation required over longer assessment periods, in clinical trials and service settings.


Modeling temporal and hormonal regulation of plant transcriptional response to wounding.
Plants respond to wounding stress by changing gene expression patterns and inducing the production of hormones including jasmonic acid. This wounding transcriptional response activates specialized metabolism pathways such as the glucosinolate pathways in Arabidopsis thaliana. While the regulatory factors and sequences controlling a subset of wound-response genes are known, it remains unclear how wound response is regulated globally. Here, we how these responses are regulated by incorporating putative cis-regulatory elements, known transcription factor binding sites, in vitro DNA affinity purification sequencing, and DNase I hypersensitive sites to predict genes with different wound-response patterns using machine learning. We observed that regulatory sites and regions of open chromatin differed between genes upregulated at early and late wounding time-points as well as between genes induced by jasmonic acid and those not induced. Expanding on what we currently know, we identified cis-elements that improved model predictions of expression clusters over known binding sites. Using a combination of genome editing, in vitro DNA-binding assays, and transient expression assays using native and mutated cis-regulatory elements, we experimentally validated four of the predicted elements, three of which were not previously known to function in wound-response regulation. Our study provides a global model predictive of wound response and identifies new regulatory sequences important for wounding without requiring prior knowledge of the transcriptional regulators.


Obesity, cholesterol metabolism, and breast cancer pathogenesis.
Obesity and altered lipid metabolism are risk factors for breast cancer in pre- and post-menopausal women. These pathologic relationships have been attributed in part to the impact of cholesterol on the biophysical properties of cell membranes and to the influence of these changes on signaling events initiated at the membrane. However, more recent studies have indicated that the oxysterol 27-hydroxycholesterol (27HC), and not cholesterol per se, may be the primary biochemical link between lipid metabolism and cancer. The enzyme responsible for production of 27HC from cholesterol, CYP27A1, is expressed primarily in the liver and in macrophages. In addition, significantly elevated expression of this enzyme within breast tumors has also been observed. It is believed that 27HC, acting through the liver X receptor in macrophages and possibly other cells, is involved in maintaining organismal cholesterol homeostasis. It has also been shown recently that 27HC is an estrogen receptor agonist in breast cancer cells and that it stimulates the growth and metastasis of tumors in several models of breast cancer. These findings provide the rationale for the clinical evaluation of pharmaceutical approaches that interfere with cholesterol/27HC synthesis as a means to mitigate the impact of cholesterol on breast cancer pathogenesis. Cancer Res; 74(18); 4976-82. ©2014 AACR.


Increasing endothelial cell specific expression by the use of heterologous hypoxic and cytokine-inducible enhancers.
One of the current challenges in gene therapy is to construct a vector that will target specific tissues. Targeting expression to endothelium is of particular interest in the treatment of several pathologies. We have shown previously that defined regions of the E-selectin and KDR promoters confer endothelial cell specific expression following retroviral delivery. However, the levels of expression were low. In an attempt to increase expression but to preserve the tissue specificity we have examined hypoxic and cytokine-inducible enhancer elements in combination with the KDR and E-selectin promoters. Both enhancers should be active in the tumour environment, boosting expression and giving additional specificity of gene expression in the tumour endothelium. The hypoxia response element (HRE) of the murine phosphoglycerate kinase-1 (PGK-1) promoter was used as a hypoxic enhancer and the tandem-binding site for NFKB from the murine vascular cell adhesion molecule-1 (VCAM-1) promoter as a cytokine-inducible enhancer. The HRE conferred hypoxia inducibility to the KDR and E-selectin promoters. Endothelial specificity of expression was retained with the KDR but not the E-selectin promoter. The NFKB-binding site conferred responsiveness to TNF-alpha to the KDR promoter, however the level of induction was less than that achieved with the HRE. Retrovirus combining both enhancer elements transferred inducibility by hypoxia and TNF-alpha, and reached the highest expression levels upon stimulation. These results confirm that heterologous enhancer elements may operate on a single endothelial cell specific promoter. These findings make the use of inducible enhancers a promising strategy for increasing tissue specific gene expression.


Numerous possible oriented partial differential equations and investigation of their performance for optical interferometry fringes denoising.
Filtering methods based on oriented partial differential equations (OPDEs) have been demonstrated as a powerful tool for denoising while preserving all fringes. In this paper, we first briefly review the existing OPDEs and then derive numerous possible OPDE filtering models based on the variational methods. These models include a class of new single OPDE models, a class of new selective OPDE models, a class of new coupled OPDEs, and a class of new double OPDEs. We also investigate the performance of main OPDE models, including the choices of parameters and the influences of fringe orientation and diffusion control function on filtering results via our extensive experiments. Finally, we summarize the performance of these OPDEs.


Seasonality of absolute humidity explains seasonality of influenza-like illness in Vietnam.
Experimental and ecological studies have shown the role of climatic factors in driving the epidemiology of influenza. In particular, low absolute humidity (AH) has been shown to increase influenza virus transmissibility and has been identified to explain the onset of epidemics in temperate regions. Here, we aim to study the potential climatic drivers of influenza-like illness (ILI) epidemiology in Vietnam, a tropical country characterized by a high diversity of climates. We specifically focus on quantifying and explaining the seasonality of ILI. We used 18 years (1993-2010) of monthly ILI notifications aggregated by province (52) and monthly climatic variables (minimum, mean, maximum temperatures, absolute and relative humidities, rainfall and hours of sunshine) from 67 weather stations across Vietnam. Seasonalities were quantified from global wavelet spectra, using the value of the power at the period of 1 year as a measure of the intensity of seasonality. The 7 climatic time series were characterized by 534 summary statistics which were entered into a regression tree to identify factors associated with the seasonality of AH. Results were extrapolated to the global scale using simulated climatic times series from the NCEP/NCAR project. The intensity of ILI seasonality in Vietnam is best explained by the intensity of AH seasonality. We find that ILI seasonality is weak in provinces experiencing weak seasonal fluctuations in AH (annual power <17.6), whereas ILI seasonality is strongest in provinces with pronounced AH seasonality (power >17.6). In Vietnam, AH and ILI are positively correlated. Our results identify a role for AH in driving the epidemiology of ILI in a tropical setting. However, in contrast to temperate regions, high rather than low AH is associated with increased ILI activity. Fluctuation in AH may be the climate factor that underlies and unifies the seasonality of ILI in both temperate and tropical regions. Alternatively, the mechanism of action of AH on disease transmission may be different in cold-dry versus hot-humid settings.


Using geographic information systems (GIS) to identify communities in need of health insurance outreach: An OCHIN practice-based research network (PBRN) report.
Our practice-based research network (PBRN) is conducting an outreach intervention to increase health insurance coverage for patients seen in the network. To assist with outreach site selection, we sought an understandable way to use electronic health record (EHR) data to locate uninsured patients. Health insurance information was displayed within a web-based mapping platform to demonstrate the feasibility of using geographic information systems (GIS) to visualize EHR data. This study used EHR data from 52 clinics in the OCHIN PBRN. We included cross-sectional coverage data for patients aged 0 to 64 years with at least 1 visit to a study clinic during 2011 (n = 228,284). Our PBRN was successful in using GIS to identify intervention sites. Through use of the maps, we found geographic variation in insurance rates of patients seeking care in OCHIN PBRN clinics. Insurance rates also varied by age: The percentage of adults without insurance ranged from 13.2% to 86.8%; rates of children lacking insurance ranged from 1.1% to 71.7%. GIS also showed some areas of households with median incomes that had low insurance rates. EHR data can be imported into a web-based GIS mapping tool to visualize patient information. Using EHR data, we were able to observe smaller areas than could be seen using only publicly available data. Using this information, we identified appropriate OCHIN PBRN clinics for dissemination of an EHR-based insurance outreach intervention. GIS could also be used by clinics to visualize other patient-level characteristics to target clinic outreach efforts or interventions.


Stress Alters the Neural Context for Building New Memories.
Stressful events affect mnemonic processing, in particular for emotionally arousing events. Previous research on the mechanisms underlying stress effects on human memory focused on stress-induced changes in the neural activity elicited by a stimulus. We tested an alternative mechanism and hypothesized that stress may already alter the neural context for successful memory formation, reflected in the neural activity preceding a stimulus. Therefore, 69 participants underwent a stress or control procedure before encoding neutral and negative pictures. During encoding, we recorded high-density EEG and analyzed-based on multivariate searchlight analyses-oscillatory activity and cross-frequency coupling patterns before stimulus onset that were predictive of memory tested 24 hr later. Prestimulus theta predicted subsequent memory in controls but not in stressed participants. Instead, prestimulus gamma predicted successful memory formation after stress, specifically for emotional material. Likewise, stress altered the patterns of prestimulus theta-beta and theta-gamma phase-amplitude coupling predictive of subsequent memory, again depending on the emotionality of the presented material. Our data suggest that stress changes the neural context for building new memories, tuning this neural context specifically to the encoding of emotionally salient events. These findings point to a yet unknown mechanism through which stressful events may change (emotional) memory formation.


The importance of early carotid endarterectomy in symptomatic patients.
Early carotid endarterectomy (CEA) in symptomatic patients may prevent repeat cerebral events. This study investigates the relationship between waiting time for CEA and the incidence of repeat cerebral events prior to surgery in symptomatic patients. A prospective database of consecutive patients undergoing CEA between January 2002 and December 2006 was reviewed. Repeat event rates prior to surgery were calculated using Kaplan-Meier analysis and predictive factors identified using Cox regression analysis. A total of 118 patients underwent CEA for non-disabling stroke, TIA and amaurosis fugax. Repeat cerebral events occurred in 34 of 118 (29%) patients at a median 51 days (range, 2-360 days) after the first event. The estimated risk of repeat events was 2% at 7 days and 9% at 1 month after first event (Kaplan-Meier survival analysis). Age (HR 1.059; 95% CI 1.014-1.106; P = 0.009] was identified as a predictor of repeat events. Patients underwent surgery at median 97 days (range, 7-621 days) after the first event. Eleven of 60 (18%) patients waiting < or = 97 days for surgery and 23 of 58 (40%) patients waiting > 97 days had repeat events. (P = 0.011, chi-squared test). Delays in surgery should be reduced in order to minimise repeat cerebral events in patients with symptomatic carotid stenosis, particularly in the elderly population.


Familias 3 - Extensions and new functionality.
In relationship testing the aim is to determine the most probable pedigree structure given genetic marker data for a set of persons. Disaster Victim Identification (DVI) based on DNA data from presumed relatives of the missing persons can be considered to be a collection of relationship problems. Forensic calculations in investigative mode address questions like "How many markers and reference persons are needed?" Such questions can be answered by simulations. Mutations, deviations from Hardy-Weinberg Equilibrium (or more generally, accounting for population substructure) and silent alleles cannot be ignored when evaluating forensic evidence in case work. With the advent of new markers, so called microvariants have become more common. Previous mutation models are no longer appropriate and a new model is proposed. This paper describes methods designed to deal with DVI problems and a new simulation model to study distribution of likelihoods. There are softwares available, addressing similar problems. However, for some problems including DVI, we are not aware of freely available validated software. The Familias software has long been widely used by forensic laboratories worldwide to compute likelihoods in relationship scenarios, though previous versions have lacked desired functionality, such as the above mentioned. The extensions as well as some other novel features have been implemented in the new version, freely available at www.familias.no. The implementation and validation are briefly mentioned leaving complete details to Supplementary sections.


Structure, conformation and biological activity of a novel lipodepsipeptide from Pseudomonas corrugata: cormycin A.
Cationic lipodepsipeptides from Pseudomonas spp. have been characterized for their structural and antimicrobial properties. In the present study, the structure of a novel lipodepsipeptide, cormycin A, produced in culture by the tomato pathogen Pseudomonas corrugata was elucidated by combined protein chemistry, mass spectrometry and two-dimensional NMR procedures. Its peptide moiety corresponds to L-Ser-D-Orn-L-Asn-D-Hse-L-His-L-aThr-Z-Dhb-L-Asp(3-OH)-L-Thr(4-Cl) [where Orn represents ornithine, Hse is homoserine, aThr is allo-threonine, Z-Dhb is 2,3-dehydro-2-aminobutanoic acid, Asp(3-OH) is 3-hydroxyaspartic acid and Thr(4-Cl) is 4-chlorothreonine], with the terminal carboxy group closing a macrocyclic ring with the hydroxy group of the N-terminal serine residue. This is, in turn, N-acylated by 3,4-dihydroxy-esadecanoate. In aqueous solution, cormycin A showed a rather compact structure, being derived from an inward orientation of some amino acid side chains and from the 'hairpin-bent' conformation of the lipid, due to inter-residue interactions involving its terminal part. Cormycin was significantly more active than the other lipodepsipeptides from Pseudomonas spp., as demonstrated by phytotoxicity and antibiosis assays, as well as by red-blood-cell lysis. Differences in biological activity were putatively ascribed to its weak positive net charge at neutral pH. Planar lipid membrane experiments showed step-like current transitions, suggesting that cormycin is able to form pores. This ability was strongly influenced by the phospholipid composition of the membrane and, in particular, by the presence of sterols. All of these findings suggest that cormycin derivatives could find promising applications, either as antifungal compounds for topical use or as post-harvest biocontrol agents.


Does atrioventricular ring motion always distinguish constriction from restriction? A Doppler myocardial imaging study.
Constrictive pericarditis and restrictive cardiomyopathy can be difficult to differentiate on clinical examination. Cardiac ultrasonography is increasingly being used as the noninvasive method of choice for confirming the specific morphologic and hemodynamic abnormalities associated with either condition. Interrogation of atrioventricular valve plane motion by Doppler myocardial imaging (DMI) has been suggested as a valuable new approach that can help differentiate one from the other. We report the color DMI, pulsed DMI, and strain rate findings in 2 cases of constrictive pericarditis in which consideration of the annular motion pattern alone would not have allowed such differentiation.


Noise in ecosystems: a short review.
Noise, through its interaction with the nonlinearity of the living systems, can give rise to counter-intuitive phenomena such as stochastic resonance, noise-delayed extinction, temporal oscillations, and spatial patterns. In this paper we briefly review the noise-induced effects in three different ecosystems: (i) two competing species; (ii) three interacting species, one predator and two preys, and (iii) N-interacting species. The transient dynamics of these ecosystems are analyzed through generalized Lotka-Volterra equations in the presence of multiplicative noise, which models the interaction between the species and the environment. The interaction parameter between the species is random in cases (i) and (iii), and a periodical function, which accounts for the environmental temperature, in case (ii). We find noise-induced phenomena such as quasi-deterministic oscillations, stochastic resonance, noise-delayed extinction, and noise-induced pattern formation with nonmonotonic behaviors of patterns areas and of the density correlation as a function of the multiplicative noise intensity. The asymptotic behavior of the time average of the i(th) population when the ecosystem is composed of a great number of interacting species is obtained and the effect of the noise on the asymptotic probability distributions of the populations is discussed.


How to Get the Most from Methotrexate (MTX) Treatment for Your Rheumatoid Arthritis Patient?-MTX in the Treat-to-Target Strategy.
Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis (RA) at every stage of its evolution. Its attributes include good overall efficacy for signs and symptoms, inhibition of structural damage and preservation of function with acceptable and manageable safety, a large dose-titratable range, options for either an oral or parenteral route of administration, and currently unrivalled cost-effectiveness. It has a place as a monotherapy and also as an anchor drug that can be safely used in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or used concomitantly with biological DMARDs or targeted synthetic DMARDs. MTX is not without potential issues regarding toxicity, notably hepatotoxicity and bone marrow toxicity, as well as tolerability problems for some, but not all, patients. But many of these issues can be mitigated or managed. In the face of a welcome expansion in available targeted therapies for the treatment of RA, MTX looks set to remain at the foundation of pharmacotherapy for the majority of people living with RA and other inflammatory rheumatic diseases. In this article, we provide an evidence-based discussion as to how to achieve the best outcomes with this versatile drug in the context of a treat-to-target strategy for the management of RA.


The National Cambodian American Town Hall Meeting: a community dialogue on "eat, walk, sleep" for health.
The 2009 National Cambodian American Town Hall Meeting was a public-private partnership convened to address long-term health issues related the Cambodian holocaust. Goals for participants were to dispel myths about diabetes; goals for the partnership were to build research capacity and to strengthen relationships. Partners collaborated on all aspects of the meeting which was held in Khmer by bridged videoconferencing in 10 sites and webinar at 5 sites across the United States over a 3-hour period. EAT, WALK, SLEEP for Health (EWS), the National Cambodian American Diabetes Project program, provided the framework for the meeting. Pre and post surveys were completed by 323 participants. Modest improvements were seen in participants' belief that they could improve their own and their community's health, although significant barriers remained. Participants and community partners evaluated the meeting positively. The meeting is a model for other populations, and results inform future work.


Allicin Protects against Cisplatin-Induced Stria Vascularis Damage: Possible Relation to Inhibition of Caspase-3 and PARP-1-AIF-Mediated Apoptotic Pathways.
Cisplatin is an anti-cancer drug that causes oxotoxic side effects such as impairment of inner ear function and hearing loss. We aimed to investigate the effects of allicin against cisplatin-induced stria vascularis damage in mice, and to clarify the mechanism underlying the protective effects of allicin against ototoxicity. Stria vascularis injury was induced in mice by intraperitoneal injection of cisplatin, which was significantly prevented by pretreatment with allicin. Allicin not only reduced cisplatin-activated expression of cleaved caspase-3 in marginal cells, PVM/Ms (perivascular resident macrophage-like melanocytes), and basal cells of the stria vascularis, but also decreased the expression of poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF) nuclear translocation in the stria vascularis cells. Our results demonstrate that allicin plays an effective role in protecting stria vascularis injury induced by cisplatin by inhibiting caspase-dependent, as well as caspase-independent PARP-1-AIF-mediated apoptotic pathways. Therefore, allicin may be useful in preventing cisplatin-induced ototoxicity.


Why regenerative medicine needs an extracellular matrix.
Regenerative medicine is now coming of age. Many attempts at cell therapy have failed to show significant efficacy, and the umbrella term 'stem cell therapy' is perceived in some quarters as hype or just expensive and unnecessary medical tourism. Here we present a short editorial in three parts. First, we examine the importance of using a semisynthetic extracellular matrix (ECM) mimetic, or sECM, to deliver and retain therapeutic cells at the site of administration. Second, we describe one approach in which biophysical and biochemical properties are tailored to each tissue type, which we call "design for optimal functionality." Third, we describe an alternative approach to sECM design and implementation, called "design for simplicity," in which a deconstructed, minimalist sECM is employed and biology is allowed to perform the customization in situ. We opine that an sECM, whether minimal or instructive, is an essential contributor to improve the outcomes of cell-based therapies.


Sounds Healthy: Modelling sound-evoked consumer food choice through visual attention.
Food choice is a multifaceted construct that is not solely guided by our internal incentives. In fact, sensory scientist, consumer psychologists, and marketers have demonstrated that external ambient cues, including background music, can influence myriads of subconscious consumer behaviors, effectively leading to increased sales of food and beverages. However, the vast majority of literature in on this topic has thus far been confined to monocultural field studies in which the underlying mechanisms of food choice are unexplored. We therefore studied the explicit and implicit effects of custom-composed soundtracks on food choices and eye-movements in consumers from both 'East' and 'West'. Firstly, based on the results from a pre-study (N = 396), we composed a 'healthy' and 'unhealthy' soundtrack. Subsequently, we recruited 215 participants from China (n = 114) and Denmark (n = 101) respectively for in an in-laboratory eye-tracking food choice paradigm. For each culture, half of the participants listened to the 'healthy' soundtrack and the other half to the 'unhealthy' soundtrack during the experiment. Chi-square tests of independence revealed that across cultures, the healthy (vs. unhealthy) soundtrack led to more healthy food choices. Similarly, the generalized linear mixed models showed that the healthy soundtrack induced more and longer fixations on healthy (vs. unhealthy) food. Finally, a multiple mediation analysis signified a partial mediation effect of sound on food choice through the mediators of fixation duration, fixation count, and revisit count. Our results indicate that, with strategically chosen soundscapes, it is possible to influence consumers' decision-making processes and guide their attention towards healthier foods, providing valuable knowledge for local as well as global food business.


High Extratumoral Mast Cell Counts Are Associated with a Higher Risk of Adverse Prostate Cancer Outcomes.
Given our previous findings that low intratumoral and high extratumoral mast cell numbers are associated with higher risk of biochemical recurrence after radical prostatectomy, we now assessed this relationship with race and the development of metastases. We stained for mast cell tryptase via IHC and fluorescent immunolabeling in 885 men across multiple tissue microarray sets designed to assess biomarkers in association with race and prostate cancer outcomes (median follow-up, 7.0 years). Intratumoral and extratumoral mast cell counts were significantly lower in tissues from African-American compared with European-American men, but not within strata of cancer grade. There was no association between mast cell counts and ERG positivity, PTEN loss, or TP53 missense mutation. Higher minimum extratumoral mast cells were associated with an increased risk of biochemical recurrence [comparing highest with lowest tertiles: HR, 1.61; 95% confidence interval (CI), 1.12-2.29; P trend = 0.01]; this pattern was similar among European-American and African-American men and by grade of disease. There was no significant association between minimum intratumoral mast cell count and biochemical recurrence, overall or within strata of race and grade. Finally, high minimum number of extratumoral mast cells was associated with prostate cancer metastases (comparing highest with lowest tertiles: HR, 2.12; 95% CI, 1.24-3.63; P trend = 0.01). High extratumoral mast cell numbers are associated with biochemical recurrence and the development of metastases after radical prostatectomy. Higher numbers of benign tissue mast cells are associated with a higher risk of adverse outcomes after radical prostatectomy, including metastatic prostate cancer.


Placental calcium transporter (PMCA3) gene expression predicts intrauterine bone mineral accrual.
Evidence is accruing that environmental exposures during critical periods of early development induce persisting changes in skeletal growth, and alter fracture risk in later life. We have previously demonstrated that placental calcium transport, partly determined by maternal 25-(OH) vitamin D status, may underlie this phenomenon. However, the precise relationship between expression of calcium transport proteins in the human placenta, and neonatal bone mineral accrual in the offspring, remains unknown. Tissue samples from 70 human placentae were fast frozen in liquid nitrogen and stored at -70 degrees C. A quantitative real time reverse transcriptase polymerase chain reaction was used to measure the mRNA expression of PMCA isoforms 1-4, using beta-actin as a control gene. Neonatal whole body bone area, mineral content and areal density (BA, BMC, BMD) were measured within 2 weeks of birth using DXA. PMCA3 mRNA expression predicted BA (r=0.28, p=0.02), BMC (r=0.25, p=0.04), placental weight (r=0.26, p=0.04) and birth weight (r=0.33, p=0.006) of the neonate. In a multivariate model, the relationship between placental PMCA3 expression and neonatal BMC was independent of maternal height, pre-pregnant fat stores, parity, physical activity, smoking, and calcium intake (p<0.05). Expression of the placental calcium transporter PMCA3 mRNA predicts neonatal whole body bone mineral content. This association may explain, in part, the mechanism whereby a mother's 25(OH)-vitamin D stores influence her offspring's bone mass.


Macromolecular crowding tunes 3D collagen architecture and cell morphogenesis.
Collagen I is the primary extracellular matrix component of most solid tumors and influences metastatic progression. Collagen matrix engineering techniques are useful for understanding how this complex biomaterial regulates cancer cell behavior and for improving in vitro cancer models. Here, we establish an approach to tune collagen fibril architecture using PEG as an inert molecular crowding agent during gelation and cell embedding. We find that crowding produces matrices with tighter fibril networks that are less susceptible to proteinase mediated degradation, but does not significantly alter matrix stiffness. The resulting matrices have the effect of preventing cell spreading, confining cells, and reducing cell contractility. Matrix degradability and fibril length are identified as strong predictors of cell confinement. Further, the degree of confinement predicts whether breast cancer cells will ultimately undergo individual or collective behaviors. Highly confined breast cancer cells undergo morphogenesis to form either invasive networks reminiscent of aggressive tumors or gland and lobule structures reminiscent of normal breast epithelia. This morphological transition is accompanied by expression of cell-cell adhesion genes, including PECAM1 and ICAM1. Our study suggests that cell confinement, mediated by matrix architecture, is a design feature that tunes the transcriptional and morphogenic state of breast cancer cells.


G protein-linked signaling pathways in bipolar and major depressive disorders.
The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, "activated" cAMP signaling activity in BPD and "blunted" cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.


Representation of change: separate electrophysiological markers of attention, awareness, and implicit processing.
Awareness of change within a visual scene only occurs in the presence of focused attention. When two versions of a complex scene are presented in alternating sequence separated by a blank mask, unattended changes usually remain undetected, although they may be represented implicitly. To test whether awareness of change and focused attention had the same or separable neurophysiological substrates, and to search for the neural substrates of implicit representation of change, we recorded event-related brain potentials (ERPs) during a change blindness task. Relative to active search, focusing attention in the absence of a change enhanced an ERP component over frontal sites around 100-300 msec after stimulus onset, and in posterior sites at the 150-300 msec window. Focusing attention to the location of a change that subjects were aware of, replicated those attentional effects, but also produced a unique positive deflection in the 350-600 msec window, broadly distributed with its epicenter in mediocentral areas. The unique topography and time course of this latter modulation, together with its dependence on the aware perception of change, distinguishes this "awareness of change" electrophysiological response from the electrophysiological effects of focused attention. Finally, implicit representation of change elicited a distinct electrophysiological event: Unaware changes triggered a positive deflection at the 240-300 msec window, relative to trials with no change. Overall, the present data suggest that attention, awareness of change, and implicit representation of change may be mediated by separate underlying systems.


Utilizing a Wristband Sensor to Measure the Stress Level for People with Dementia.
Stress is a common problem that affects most people with dementia and their caregivers. Stress symptoms for people with dementia are often measured by answering a checklist of questions by the clinical staff who work closely with the person with the dementia. This process requires a lot of effort with continuous observation of the person with dementia over the long term. This article investigates the effectiveness of using a straightforward method, based on a single wristband sensor to classify events of "Stressed" and "Not stressed" for people with dementia. The presented system calculates the stress level as an integer value from zero to five, providing clinical information of behavioral patterns to the clinical staff. Thirty staff members participated in this experiment, together with six residents suffering from dementia, from two nursing homes. The residents were equipped with the wristband sensor during the day, and the staff were writing observation notes during the experiment to serve as ground truth. Experimental evaluation showed relationships between staff observations and sensor analysis, while stress level thresholds adjusted to each individual can serve different scenarios.


In vitro micro-physiological models for translational immunology.
The immune system is a source of regulation of the human body and is key for its stable functioning. Animal models have been successfully used for many years to study human immunity and diseases and provided significant contributions to the development of powerful new therapies. However, such models inevitably display differences from the human metabolism and disease state and therefore may correlate poorly with the human conditions. This explains the interest for the use of in vitro models of human cells, which have better potential to assist in understanding the physiological events that characterize the immune response in humans. Microfluidic technologies offer great capabilities to create miniaturized in vivo-like physiological models that mimic tissue-tissue interactions and simulate the body metabolism in both the healthy and diseased states. The micro-scale features of these microfluidic systems allow positioning heterogeneous cellular cultures in close proximity to each other in a dynamic fluidic environment, thereby allowing efficient cell-cell interactions and effectively narrowing the gap between in vivo and in vitro conditions. Due to the relative simplicity of these systems, compared to animal models, it becomes possible to investigate cell signaling by monitoring the metabolites transported from one tissue to another in real time. This allows studying detailed physiological events and in consequence understanding the influence of metabolites on a specific tissue/organ function as well as on the healthy/diseased state modulation. Numerous in vitro models of human organs have been developed during the last few years, aiming to mimic as closely as possible the in vivo characteristics of such organs. This technology is still in its infancy, but is promised a bright future in industrial and medical applications. Here we review the recent literature, in which functional microphysiological models have been developed to mimic tissues and to explore multi-tissue interactions, focusing in particular on the study of immune reactions, inflammation and the development of diseases. Also, an outlook on the opportunities and issues for further translational development of functional in vitro models in immunology will be presented.


Modulation of methylenedioxymethamphetamine-induced striatal dopamine release by the interaction between serotonin and gamma-aminobutyric acid in the substantia nigra.
The effects of the amphetamine analog, 3,4-methylenedioxymethamphetamine (MDMA) were compared to the effects of d-amphetamine on the in vivo release of dopamine and gamma-aminobutyric acid (GABA) in the striatum and substantia nigra. The brain region-dependent role of the 5-HT2 receptors in the striatum and substantia nigra in regulating MDMA-induced dopamine and GABA release also was studied. Changes in the extracellular concentration of dopamine, 5-HT and GABA were measured simultaneously in the awake rat by in vivo microdialysis. The increase in striatal dopamine produced by systemic administration of MDMA was attenuated by infusion of TTX into the striatum. Infusion of the 5-HT2A/2C antagonist ritanserin into the striatum or the ipsilateral substantia nigra also significantly attenuated MDMA-induced dopamine release in the striatum. At the doses used in this study, MDMA but not d-amphetamine increased the extracellular concentrations of 5-HT and decreased GABA efflux in the substantia nigra. The ability of MDMA to decrease nigral GABA efflux also was blocked by the local infusion of ritanserin into either the substantia nigra or the striatum. Overall, these data provide evidence that MDMA increases dopamine release partly through an impulse-mediated mechanism. Furthermore, this increase in striatal dopamine efflux produced by MDMA is regulated, in part, by 5-HT2A/2C receptors in the striatum and the substantia nigra and ultimately by GABAergic input into the substantia nigra.


The effect of acute fenitrothion exposure on a variety of physiological indices, including avian aerobic metabolism during exercise and cold exposure.
The effect of fenitrothion exposure on birds was examined by measuring aerobic metabolism, blood hemoglobin content, plasma cholinesterases, and body weight for up to 21 d postdose. Peak metabolic rate was measured in a flight chamber in three-dose groups of house sparrows (Passer domesticus; 100 mg/kg = high, 60 mg/kg = medium, 30 mg/kg = low) and one-dose groups of zebra finches (Taeniopygia guttata; 3 mg/kg) and king quails (Coturnix chinensis; 26 mg/kg). Aerobic metabolism was measured during 1 h of exposure to subfreezing thermal conditions in low-dose house sparrows and king quails (26 mg/kg). Fenitrothion had no effect on metabolic rate during cold exposure or on blood hemoglobin at any time. By contrast, aerobic performance during exercise in sparrows was reduced by 58% (high), 18% (medium), and 20% (low), respectively, 2 d postdose. House sparrows (high) had the longest recovery period for peak metabolic rate (21 d) and plasma cholinesterase activity (14 d). House sparrows (high) and treated king quails had significantly lower myoglobin at 48 h postdose, whereas myoglobin was invariant in zebra finches and house sparrows (medium and low). Cholinesterase was maximally inhibited at 6 h postdose, and had recovered within 24 h, in house sparrows (low), king quails, and zebra finches. Exercise peak metabolic rate in zebra finches and king quails was reduced by 23% at 2 d and 3 d, respectively, despite these birds being asymptomatic in both behavior and plasma cholinesterase activities.


Constraints on the pMSSM, AMSB model and on other models from the search for long-lived charged particles in proton-proton collisions at [Formula: see text].
Stringent limits are set on the long-lived lepton-like sector of the phenomenological minimal supersymmetric standard model (pMSSM) and the anomaly-mediated supersymmetry breaking (AMSB) model. The limits are derived from the results presented in a recent search for long-lived charged particles in proton-proton collisions, based on data collected by the CMS detector at a centre-of-mass energy of 8 TeV at the Large Hadron Collider. In the pMSSM parameter sub-space considered, 95.9 % of the points predicting charginos with a lifetime of at least 10 ns are excluded. These constraints on the pMSSM are the first obtained at the LHC. Charginos with a lifetime greater than 100 ns and masses up to about 800 GeV in the AMSB model are also excluded. The method described can also be used to set constraints on other models.


The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific.
Disruption of CB(1) receptor signaling through the use of CB(1) (-/-) mice or the CB(1) receptor antagonist rimonabant (SR141716) has been demonstrated to impair extinction of learned responses in conditioned fear and Morris water maze tasks. In contrast, CB(1) (-/-) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task. The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks. Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement. After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session. Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions. Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task. These results support the hypothesis that the CB(1) receptor plays a vital role in the extinction of aversive memories but is not essential for extinction of learned responses in appetitively motivated tasks.


Rapid detection of colicin E9-induced DNA damage using Escherichia coli cells carrying SOS promoter-lux fusions.
ColE9 is a plasmid-encoded protein antibiotic produced by Escherichia coli and closely related species that kills E. coli cells expressing the BtuB receptor. The 15-kDa cytotoxic DNase domain of colicin E9 preferentially nicks double-stranded DNA at thymine bases and shares a common active-site structural motif with a variety of other nucleases, including the H-N-H homing endonucleases and the apoptotic CAD proteins of eukaryotes. Studies of the mechanism by which the DNase domain of ColE9 reaches the cytoplasm of E. coli cells are limited by the lack of a rapid, sensitive assay for the DNA damage that results. Here, we report the development of an SOS promoter-lux fusion reporter system for monitoring DNA damage in colicin-treated cells and illustrate the value of this reporter system in experiments that probe the mechanism and time required for the DNase domain of colicin E9 to reach the cytoplasm.


A 12-Week Exercise Program for Pregnant Women with Obesity to Improve Physical Activity Levels: An Open Randomised Preliminary Study.
To evaluate whether a 12-week supervised exercise program promotes an active lifestyle throughout pregnancy in pregnant women with obesity. In this preliminary randomised trial, pregnant women (body mass index ≥ 30 kg/m2) were allocated to either standard care or supervised training, from 15 to 27 weeks of gestation. Physical activity was measured by accelerometry at 14, 28 and 36 weeks, while fitness (oxygen consumption (VO2) at the anaerobic threshold), nutrition (caloric intake and macronutrients percentage) and anthropometry were assessed at 14 and 28 weeks of gestation. Analyses were performed using repeated measures ANOVA. A total of fifty (50) women were randomised, 25 in each group. There was no time-group interaction for time spent at moderate and vigorous activity (pinteraction = 0.064), but the exercise group's levels were higher than controls' at all times (pgroup effect = 0.014). A significant time-group interaction was found for daily physical activity (p = 0.023); similar at baseline ((22.0 ± 6.7 vs 21.8 ± 7.3) x 10(4) counts/day) the exercise group had higher levels than the control group following the intervention ((22.8 ± 8.3 vs 19.2 ± 4.5) x 10(4) counts/day, p = 0.020) and at 36 weeks of gestation ((19.2 ± 1.5 vs 14.9 ± 1.5) x 10(4) counts/day, p = 0.034). Exercisers also gained less weight than controls during the intervention period despite similar nutritional intakes (difference in weight change = -0.1 kg/week, 95% CI -0.2; -0.02, p = 0.016) and improved cardiorespiratory fitness (difference in fitness change = 8.1%, 95% CI 0.7; 9.5, p = 0.041). Compared with standard care, a supervised exercise program allows pregnant women with obesity to maintain fitness, limit weight gain and attenuate the decrease in physical activity levels observed in late pregnancy. ClinicalTrials.gov NCT01610323.


Firearm Ownership and Capability for Suicide in Post-Deployment National Guard Service Members.
National Guard service members demonstrate increased suicide risk relative to the civilian population. One potential mechanism for this increased risk may be familiarity with and access to firearms following deployment. This study examined the association between firearm ownership, reasons for ownership, and firearm familiarity with a widely studied suicide risk factor-capability for suicide-among National Guard service members. Data were drawn from a cross-sectional survey of National Guard service members conducted immediately post-deployment in 2010. Service members (n = 2,292) completed measures of firearm ownership, firearm familiarity, and capability for suicide. Firearm ownership and increased firearm familiarity were associated with capability for suicide (d = 0.47 and r = .25, for firearm ownership and familiarity, respectively). When examined separately based on reason for ownership, owning a firearm for self-protection (d = 0.33) or owning a military weapon (d = 0.27) remained significantly associated with capability for suicide. In contrast, owning a firearm for hobby purposes did not (d = -0.07). Our findings support theories emphasizing practical aspects of suicide (e.g., three-step theory) and suggest that owning firearms, in particular for self-protection, along with familiarity using firearms may be associated with greater capability for suicide.


Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis.
Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors. We used data from EPIC-CVD, a case-cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders. After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01-1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10-1.42, p < 0.001), but this attenuated after additional adjustment for age at menopause and intermediates (HR = 1.12, 95% CI = 0.96-1.29, p = 0.15). A proportion of the association was explained by cardiovascular risk factors. Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.


Validation of three mental health scales among pregnant women in Qatar.
The objective of this study is to validate three mental health scales in a targeted sample of pregnant Arab women living in Qatar: the Kuwait University Anxiety Scale, the Perceived Stress Scale, and the Edinburgh Postnatal Depression Scale. Random split-half exploratory factor analysis and confirmatory factor analyses (n = 336; n = 331), conducted separately, were used to evaluate scale dimensionality, factor loadings, and factor structure of the KUAS, the PSS, and the EPDS. Fit statistics for the three scales suggested adequate fit to the data and estimated factor loadings were positive, similar in magnitude, and were significant. The final CFA model for the KUAS supported a 19-item, two factor structure. CFA models also confirmed 8- and 10-item, single-factor structures for the PSS and EPDS, respectively. The validation of scales for these aspects of mental health in Arab pregnant women is critical to ensure appropriate screening, identification, and treatment to reduce the risk of sequelae in women and their children. Findings offer a useful comparison to mental-health scale validations in other Arab contexts.


Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice.
The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.


Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study.
The World Health Organization (WHO) recommendation of treating uncomplicated malaria during the second and third trimester of pregnancy with an artemisinin-based combination therapy (ACT) has already been implemented by all sub-Saharan African countries. However, there is limited knowledge on the effect of ACT on pregnancy outcomes, and on newborn and infant's health. Pregnant women with malaria in four countries (Burkina Faso, Ghana, Malawi and Zambia) were treated with either artemether-lumefantrine (AL), amodiaquine-artesunate (ASAQ), mefloquine-artesunate (MQAS), or dihydroartemisinin-piperaquine (DHA-PQ); 3127 live new-borns (822 in the AL, 775 in the ASAQ, 765 in the MQAS and 765 in the DHAPQ arms) were followed-up until their first birthday. Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no significant differences between treatment arms. No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and infant mortality (p = 0.96) were found. Outcome of pregnancy and infant survival were similar between treatment arms indicating that any of the four artemisinin-based combinations could be safely used during the second and third trimester of pregnancy without any adverse effect on the baby. Nevertheless, smaller safety differences between artemisinin-based combinations cannot be excluded; country-wide post-marketing surveillance would be very helpful to confirm such findings. Trial registration ClinicalTrials.gov, NCT00852423, Registered on 27 February 2009, https://clinicaltrials.gov/ct2/show/NCT00852423.


Clinical and immunologic features of selective IgA deficiency.
Selective absence of serum and secretory IgA is probably the most common form of human immunodeficiency. High frequencies of recurrent sinusitis, otitis media, pneumonia, and atopy were noted among a group of 75 such patients, all but 4 of whom were Caucasian. Seven instances of familial absence of IgA were detected among 106 relatives of 34 of the group; in 1 family 1 member from each of 3 successive generations was affected. Two IgA-deficient children were later found to have normal amounts of serum IgA. Despite their humoral deficit, B lymphocytes bearing surface IgA were detected in 9/9 IgA-deficient patients in immunofluorescence studies of their peripheral blood lymphocytes. Although in vitro lymphocyte responses to 2 putative T-cell mitogens and to allogenic cells were normal, results of spontaneous rosette formation studies with sheep erythrocytes raise the possibility of a lymphocyte subpopulation deficit in this condition.


Cost-effectiveness of adding a birth dose of hepatitis B vaccine in the Dafra district of the Hauts-Bassins Region in Burkina Faso (NéoVac Study).
The World Health Organization (WHO) recommends a first hepatitis B vaccine dose within 24 h of birth (HepB-BD) to prevent mother-to-child transmission. Evidence for this strategy's economic value in Africa is limited. We assessed the costs and cost-effectiveness of adding HepB-BD to the current three-dose pentavalent schedule (HepB3) in the Dafra district of the Hauts-Bassins Region in Burkina Faso. Using a decision tree combined with a Markov model, we estimated the expected number of life-years (LY) and disability-adjusted life-years (DALYs) saved, incremental costs, and incremental cost-effectiveness ratios (ICER) of HepB-BD + HepB3 versus HepB3 alone in Dafra's 2017 birth cohort (n = 11,462). Institutional delivery rates, vaccine coverage, and vaccination costs from a health system perspective were estimated from field-collected data. We estimated the effectiveness of HepB-BD, age-specific transition probabilities, and horizontal transmission risks using data from previous African studies. Costs and health outcomes were discounted at an annual rate of 3%. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty. In the base-case analysis without discounting, HepB-BD + HepB3 yielded a net cost saving of US$18,979 and saved 163 DALYs compared with HepB3 alone. With discounting, HepB-BD + HepB3 compared with HepB3 resulted in an incremental cost of US$554 and 31 DALYs averted, translating into an ICER of US$18/DALY averted. In one-way sensitivity analyses, HepB-BD + HepB3 remained cost-effective (at the cost-effectiveness threshold of US$671 i.e. the Burkina Faso per-capita gross domestic product) for all parameter changes. However, results were very sensitive to variations in HepB-BD unit cost per vaccinated neonate and perinatal transmission risk in mothers carrying the hepatitis B e antigen. The probabilities of HepB-BD + HepB3 being cost-effective were 71.7% and 86.7%, at the cost-effectiveness thresholds of US$335 and US$671, respectively. Introducing HepB-BD in Burkina Faso is likely to be cost-effective.


[Acupuncture resources in Cochrane Library].
To identify acupuncture resources in six databases of Cochrane Library (CL) with computer retrieve. Seventy-two literatures were identified in Cochrane Database of Systematic Reviews (CDSR). Among them, 12 Cochrane systematic review (CSR) verified the effectiveness of acupuncture, 29 concerning the indeterminacy of the efficacy of acupuncture with 1 didn't support acupuncture for epilepsy and 31 remained as protocols; 121 literatures were found in Database of Abstracts of Reviews of Effects (DARE) with more types of diseases or symptoms and rich modality comparing to CSR; 4218 randomized controlled trials and clinical controlled trials were identified in Cochrane Central Register of Controlled Trials (CCRCT); 43 literatures in Cochrane Methodology Register Database (CMRD) which focused on blindness study, quality assessment of methodology of research and publication bias and so on; 25 literatures in Health Technology Assessment Database (HTAD) and 18 in NHS Economic Evaluation Database (NHS EED) which were centered on acupuncture analgesia. Consequently, acupuncture literatures in 6 databases of CL do provide good resources for acupuncture researchers due to its abundant content, concrete classification and high quality evidence.


Neuropathologic Associations of Learning and Memory in Primary Progressive Aphasia.
The dementia syndrome of primary progressive aphasia (PPA) can be caused by 1 of several neuropathologic entities, including forms of frontotemporal lobar degeneration (FTLD) or Alzheimer disease (AD). Although episodic memory is initially spared in this syndrome, the subtle learning and memory features of PPA and their neuropathologic associations have not been characterized. To detect subtle memory differences on the basis of autopsy-confirmed neuropathologic diagnoses in PPA. Retrospective analysis was conducted at the Northwestern Cognitive Neurology and Alzheimer's Disease Center in August 2015 using clinical and postmortem autopsy data that had been collected between August 1983 and June 2012. Thirteen patients who had the primary clinical diagnosis of PPA and an autopsy-confirmed diagnosis of either AD (PPA-AD) or a tau variant of FTLD (PPA-FTLD) and 6 patients who had the clinical diagnosis of amnestic dementia and autopsy-confirmed AD (AMN-AD) were included. Scores on the effortless learning, delayed retrieval, and retention conditions of the Three Words Three Shapes test, a specialized measure of verbal and nonverbal episodic memory. The PPA-FTLD (n = 6), PPA-AD (n = 7), and AMN-AD (n = 6) groups did not differ by demographic composition (all P > .05). The sample mean (SD) age was 64.1 (10.3) years at symptom onset and 67.9 (9.9) years at Three Words Three Shapes test administration. The PPA-FTLD group had normal (ie, near-ceiling) scores on all verbal and nonverbal test conditions. Both the PPA-AD and AMN-AD groups had deficits in verbal effortless learning (mean [SD] number of errors, 9.9 [4.6] and 14.2 [2.0], respectively) and verbal delayed retrieval (mean [SD] number of errors, 6.1 [5.9] and 12.0 [4.4], respectively). The AMN-AD group had additional deficits in nonverbal effortless learning (mean [SD] number of errors, 10.3 [4.0]) and verbal retention (mean [SD] number of errors, 8.33 [5.2]), which were not observed in the PPA-FTLD or PPA-AD groups (all P < .005). This study identified neuropathologic associations of learning and memory in autopsy-confirmed cases of PPA. Among patients with clinical PPA syndrome, AD neuropathology appeared to interfere with effortless learning and delayed retrieval of verbal information, whereas FTLD-tau pathology did not. The results provide directions for future research on the interactions between limbic and language networks.


CCR7 Receptor Expression in Mono-MAC-1 Cells: Modulation by Liver X Receptor α Activation and Prostaglandin E 2.
Cell migration via chemokine receptor CCR7 expression is an essential function of the immune system. We previously showed that prostaglandin E2 (PGE2), an important immunomodulatory molecule, increases CCR7 expression and function in monocytes. Here, we explore the role of the liver X receptor α (LXRα) activation on CCR7 expression in Mono-Mac-1 (MM-1) cells in the presence of PGE2. To do this, MM-1 cells were stimulated with the LXRα synthetic agonist T0901317 in the presence or absence of PGE2. CCR7 mRNA transcription was measured using quantitative RT-PCR and protein expression was examined using flow cytometry. CCR7 function was analyzed using migration assays in response to CCL19/CCL21, which are natural ligands for CCR7. Our results show that agonist-mediated activation of LXRα in the presence of PGE2 increases CCR7 mRNA transcription and MM-1 cell migratory capacity in response to CCL19/21. In addition, our results demonstrate that engagement of the E-prostanoids 2 and 4 (EP2/EP4) receptors present on MM-1 cells is responsible for the observed increase in CCR7 mRNA expression and function during LXRα activation. Examination of monocyte migration in response to lipid derivatives such as PGE2 and oxysterols that are produced at sites of chronic inflammation would contribute to understanding the excessive monocyte migration that characterizes atherosclerosis.


The potential of fosfomycin for multi-drug resistant sepsis: an analysis of in vitro activity against invasive paediatric Gram-negative bacteria.
Antimicrobial resistance (AMR) is of increasing global concern, threatening to undermine recent progress in reducing child and neonatal mortality. Repurposing older antimicrobials is a prominent strategy to combat multidrug-resistant sepsis. A potential agent is fosfomycin, however, there is scarce data regarding its in vitro activity and pharmacokinetics in the paediatric population. We analysed a contemporary, systematically collected archive of community-acquired (CA) and hospital-acquired (HA) paediatric Gram-negative bacteraemia isolates for their susceptibility to fosfomcyin. MICs were determined using agar serial dilution methods and validated by disk diffusion testing where breakpoints are available. Disk diffusion antimicrobial susceptibility testing was also conducted for current empirical therapies (ampicillin, gentamicin, ceftriaxone) and amikacin (proposed in the literature as a new combination empirical therapeutic option). Fosfomycin was highly active against invasive Gram-negative isolates, including 90 % (202/224) of Enterobacteriaceae and 96 % (22/23) of Pseudomonas spp. Fosfomycin showed high sensitivity against both CA isolates (94 %, 142/151) and HA isolates (81 %, 78/96; P =0.0015). CA isolates were significantly more likely to be susceptible to fosfomycin than the current first-line empirical therapy (96 % vs 59 %, P <0.0001). Extended spectrum β-lactamases (ESBL) production was detected in 34 % (85/247) of isolates with no significant difference in fosfomycin susceptibility between ESBL-positive or -negative isolates [73/85 (86 %) vs 147/162 (91 %) respectively, P =0.245]. All isolates were susceptible to a fosfomycin-amikacin combination. Gram-negative paediatric bacteraemia isolates are highly susceptible to fosfomycin, which could be combined with aminoglycosides as a new, carbapenem-sparing regimen to achieve excellent coverage to treat antimicrobial-resistant neonatal and paediatric sepsis.


Chemical composition of three polysaccharides from Gynostemma pentaphyllum and their antioxidant activity in skeletal muscle of exercised mice.
To investigate the effects of polysaccharide from Gynostemma pentaphyllum on antioxidant activity in skeletal muscle of mice exercised to exhaustion. Three polysaccharide fractions were obtained from G. pentaphyllum polysaccharide (GPP) and termed GPP1-a, GPP2-b, and GPP3-a. Gas chromatography (GC) and infrared spectrum of the polysaccharides were determined. The fractions were orally administrated to mice once daily for 1 wk. The exercise time to exhaustion was assessed using a forced swim test of mice after a week. The glucose, creatine phosphokinase, and lactic dehydrogenase in serum; the activity of superoxide dismutase and glutathione peroxidase; and the levels of malondialdehyde (MDA) and glycogen in muscle were determined. The results of GC demonstrated that GPP1-a, GPP2-b, and GPP3-a were composed of different monosaccharides with distinct molar ratios. Infrared spectrum showed that the main typicals of GPP1-a and GPP2-b were β-configuration and the main typical of GPP3-a was α-configuration. Among the 3 fractions of GPP, GPP1-a administration significantly prolonged exercise time to exhaustion of mice, increased glycogen level and some of antioxidant enzyme activities, and decreased MDA level in muscle. The mechanism by which GPP1-a prolonged exercise time to exhaustion in mice may be associated with scavenging reactive oxygen species excessively produced and further increasing glycogen levels in skeletal muscle.


Prevalence and determining factors related to depression among adult women in Korea.
Korean women are likely to experience symptoms of depression, possibly due to socially fixed limitations on the roles that Korean women are expected to perform. Also if a Korean woman experiences negative relationship problem or stress in her family, she would feel responsible, which will worsen her depression. Nonetheless, much of the research on depression among Korean women has focused on menopausal women. This study aims to understand the depression of Korean women to provide fundamental data to develop nursing intervention method for promoting women's health. The present investigation assessed the prevalence and correlates of depression in a large sample of Korean women, aged 18 or older, from the general population. With a probability sample of 3312 women drawn from two areas in Korea, a survey, which contains the Center for Epidemiological Studies Depression Scale (CES-D) and background, was completed. According to CES-D classification criteria, 36.5% of the women in the sample displayed either no depression or mild depression, 55.6% exhibited moderate depression, and 7.8% manifested severe depression. Significant bivariate relationships were observed between depression and each measured background variable except alcohol use. Logistic regression analysis indicated that the strongest combination of predictors of depression included income, menopausal, and marital status. The data support the premise that Korean women disproportionately experience elevated levels of depression. Consistent with the theory, depression may be related to social pressures to conform to the traditional roles. The study suggests the need for further research, primary prevention activities, and increased access to treatment.


Defensins and other antimicrobial peptides at the ocular surface.
Although constantly exposed to the environment and "foreign bodies" such as contact lenses and unwashed fingertips, the ocular surface succumbs to infection relatively infrequently. This is, in large part, due to a very active and robust innate immune response mounted at the ocular surface. Studies over the past 20 years have revealed that small peptides with antimicrobial activity are a major component of the human innate immune response system. The ocular surface is no exception, with peptides of the defensin and cathelicidin families being detected in the tear film and secreted by corneal and conjunctival epithelial cells. There is also much evidence to suggest that the role of some antimicrobial peptides is not restricted to direct killing of pathogens, but, rather, that they function in various aspects of the immune response, including recruitment of immune cells, and through actions on dendritic cells provide a link to adaptive immunity. A role in wound healing is also supported. In this article, the properties, mechanisms of actions and functional roles of antimicrobial peptides are reviewed, with particular emphasis on the potential multifunctional roles of defensins and LL-37 (the only known human cathelicidin) at the ocular surface.


Differentiated baroreflex modulation of sympathetic nerve activity during deep brain stimulation in humans.
Targeted electric deep brain stimulation in midbrain nuclei in humans alters cardiovascular parameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at 2 distinct brain locations. The aim of this study was to evaluate sympathetic outflow in humans with deep brain stimulating electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Multiunit muscle sympathetic nerve activity was recorded in 17 patients undergoing deep brain stimulation for treatment of chronic neuropathic pain (n=7) and Parkinson disease (n=10). Sympathetic outflow was recorded during ON and OFF stimulation. Arterial blood pressure, heart rate, and respiratory frequency were monitored during the recording session, and spontaneous vasomotor and cardiac baroreflex sensitivity were assessed. Head-up tilt testing was performed separately in the patients with Parkinson disease postoperatively. Stimulation of the dorsal most part of the subthalamic nucleus and ventrolateral periaqueductal gray resulted in improved vasomotor baroreflex sensitivity, decreased burst frequency and blood pressure, unchanged burst amplitude distribution, and a reduced fall in blood pressure after tilt. Stimulation of the dorsolateral periaqueductal gray resulted in a shift in burst amplitude distribution toward larger amplitudes, decreased spontaneous beat-to-beat blood pressure variability, and unchanged burst frequency, baroreflex sensitivity, and blood pressure. Our results indicate that a differentiated regulation of sympathetic outflow occurs in the subthalamic nucleus and periaqueductal gray. These results may have implications in our understanding of abnormal sympathetic discharge in cardiovascular disease and provide an opportunity for therapeutic targeting.


Platelet-rich plasma-loaded chitosan scaffolds: preparation and growth factor release kinetics.
The aim of this study is to compare the effects of different platelet-rich plasma (PRP) preparation methods on platelet activity and to investigate the growth factor (GF) release kinetics from PRP-loaded chitosan scaffolds for tissue engineering applications. Flow cytometry analysis showed that centrifugation processes used for PRP preparation did not cause significant effect on platelet activation levels by means of markers investigated. Two different methods were used to prepare PRP-loaded chitosan scaffolds: (i) PRP was added to chitosan gel before freeze-drying to prepare scaffolds called as "GEL" and (ii) PRP was embedded to freeze-dried chitosan scaffolds to prepare scaffolds called as "SPONGE." In addition, nonactivated PRP and PRP activated with type-I collagen were used as control groups. Scanning electron microscopy images demonstrated that, in GEL group, there is no deterioration on the scaffolds porous, 3D, and interconnected structure. GF release kinetics was determined by enzyme-linked immunosorbent assay for platelet-derived GF-BB, transforming GF-β1, and insulin-like GF-1. A sustained release of GFs was achieved in GEL group while a sharp burst release was observed for all the GFs from the SPONGE groups. Moreover, platelet-derived GF-BB, insulin-like GF-1, and transforming GF-β1 releases were prolonged to 20 days in GEL groups, and the biological activities of all GFs released from GEL and SPONGE scaffolds were preserved. This study demonstrated that chitosan scaffold that was called GEL could be an appropriate carrier for PRP applications by providing sustained release of GFs.


Oxytocin and emotion processing.
Since the observation that oxytocin has key effects on social decision making, research on this exciting neuropeptide has doubled in volume: hundreds of studies have pursued the promise of a specific oxytocin action on high-level cognition and social function with wide potential translational implications (from autism to social anxiety to dementia). Here we review the evidence on whether the complex behavioural effects observed in humans after exogenous oxytocin administration build on changes in basic emotional information processing, in particular emotional facial expressions recognition, and attention and memory for emotionally-valenced stimuli.We observe that recent studies confirm a facilitatory effect of oxytocin to more accurate emotion processing, irrespective of emotion type. However, it remains unclear whether this action precedes, is independent of or even secondary to the neuropeptide promoting a greater salience of social stimuli. Overall, this growing research area has shown that oxytocin produces behavioural and neurofunctional outcomes that are highly dependent on the experimental context and on individual differences (gender, personality, life experiences). This poses an exciting challenge for future experimental medicine designs to address and unpack complex interactions between individual and context characteristic, which is needed for the development of more precise clinical applications.


Methionine sulfoxide reductases protect against oxidative stress in Staphylococcus aureus encountering exogenous oxidants and human neutrophils.
To establish infection successfully, Staphylococcus aureus must evade clearance by polymorphonuclear neutrophils (PMN). We studied the expression and regulation of the methionine sulfoxide reductases (Msr) that are involved in the repair of oxidized staphylococcal proteins and investigated their influence on the fate of S. aureus exposed to oxidants or PMN. We evaluated a mutant deficient in msrA1 and msrB for susceptibility to hydrogen peroxide, hypochlorous acid and PMN. The expression of msrA1 in wild-type bacteria ingested by human PMN was assessed by real-time PCR. The regulation of msr was studied by screening a library of two-component regulatory system (TCS) mutants for altered msr responses. Relative to the wild-type bacteria, bacteria deficient in Msr were more susceptible to oxidants and PMN. Upregulation of staphylococcal msrA1 occurred within the phagosomes of normal PMN and PMN deficient in NADPH oxidase activity. Furthermore, PMN granule-rich extract stimulated the upregulation of msrA1. Modulation of msrA1 within PMN was shown to be partly dependent on the VraSR TCS. Msr contributes to staphylococcal responses to oxidative attack and PMN. Our study highlights a novel interaction between the oxidative protein repair pathway and the VraSR TCS that is involved in cell wall homeostasis.


Hyperphosphorylation of intrinsically disordered tau protein induces an amyloidogenic shift in its conformational ensemble.
Tau is an intrinsically disordered protein (IDP) whose primary physiological role is to stabilize microtubules in neuronal axons at all stages of development. In Alzheimer's and other tauopathies, tau forms intracellular insoluble amyloid aggregates known as neurofibrillary tangles, a process that appears in many cases to be preceded by hyperphosphorylation of tau monomers. Understanding the shift in conformational bias induced by hyperphosphorylation is key to elucidating the structural factors that drive tau pathology, however, as an IDP, tau is not amenable to conventional structural characterization. In this work, we employ a straightforward technique based on Time-Resolved ElectroSpray Ionization Mass Spectrometry (TRESI-MS) and Hydrogen/Deuterium Exchange (HDX) to provide a detailed picture of residual structure in tau, and the shifts in conformational bias induced by hyperphosphorylation. By comparing the native and hyperphosphorylated ensembles, we are able to define specific conformational biases that can easily be rationalized as enhancing amyloidogenic propensity. Representative structures for the native and hyperphosphorylated tau ensembles were generated by refinement of a broad sample of conformations generated by low-computational complexity modeling, based on agreement with the TRESI-HDX profiles.


The 1985 health promotion and disease prevention survey.
The National Center for Health Statistics, in collaboration with the Office of the Assistant Secretary for Health and other Federal Agencies, developed a questionnaire on health promotion and disease prevention for the 1985 National Health Interview Survey. The answers to the questionnaire, obtained from a probability sample of the civilian noninstitutionalized population of the United States, provide trend and baseline data to track progress toward the 1990 national health objectives. The questions concerned topics related to the objectives in the following areas: general health (including nutrition), injury control, high blood pressure, stress, exercise, smoking, alcohol use, oral health, occupational safety and health, and maternal health. Data from that survey have been used by Public Health Service authors to prepare a series of 11 articles. Five are presented in this issue of Public Health Reports; the remaining six will be published in the January-February 1987 issue of Public Health Reports. This paper, which introduces the series, provides a description of the objectives of the study, the survey methods employed, and the availability of public use data tapes.


Numerical analysis of field-modulated electroosmotic flows in microchannels with arbitrary numbers and configurations of discrete electrodes.
The formation of an electric double layer and electroosmosis are important theoretic foundations associated with microfluidic systems. Field-modulated electroosmotic flows in microchannels can be obtained by applying modulating electric fields in a direction perpendicular to a channel wall. This paper presents a systematic numerical analysis of modulated electroosmotic flows in a microchannel with discrete electrodes on the basis of the Poisson equation of electric fields in a liquid-solid coupled domain, the Navier-Stokes equation of liquid flow, and the Nernst-Planck equation of ion transport. These equations are nonlinearly coupled and are simultaneously solved numerically for the electroosmotic flow velocity, electric potential, and ion concentrations in the microchannel. A number of numerical examples of modulated electroosmotic flows in microchannels with discrete electrodes are presented, including single electrodes, symmetric/asymmetric double electrodes, and triple electrodes. Numerical results indicate that chaotic circulation flows, micro-vortices, and effective fluid mixing can be realized in microchannels by applying modulating electric fields with various electrode configurations. The interaction of a modulating field with an applied field along the channel is also discussed.


Prognostic significance of the morning blood pressure surge in clinical practice: a systematic review.
An exaggerated morning blood pressure surge (MBPS) may be associated with stroke and other cardiovascular events, but the threshold at which an MBPS becomes pathological is unclear. This study aimed to systematically review the existing literature and establish the most appropriate definition of pathological MBPS. A MEDLINE search strategy was adapted for a range of literature databases to identify all prospective studies relating an exaggerated MBPS to cardiovascular endpoints. Hazard ratios (HRs) were extracted and synthesized using random-effects meta-analysis. The search strategy identified 2,964 unique articles, of which 17 were eligible for the study. Seven different definitions of MBPS were identified; the most common was a prewaking surge (mean blood pressure for 2 hours after wake-up minus mean blood pressure for 2 hours before wake-up; n = 6 studies). Summary meta-analysis gave no clear evidence that prewaking MBPS (defined by a predetermined threshold: >25-55 mm Hg) was associated with all cardiovascular events (n = 2 studies; HR = 0.94, 95% confidence interval (CI) = 0.39-2.28) or stroke (n = 2 studies; HR = 1.26, 95% CI = 0.92-1.71). However, using a continuous scale, which has more power to detect an association, there was evidence that a 10 mm Hg increase in MBPS was related to an increased risk of stroke (n = 3 studies; HR = 1.11, 95% CI = 1.03-1.20). These findings suggest that when measured and analyzed as a continuous variable, increasing levels of MBPS may be associated with increased risk of stroke. Large, protocol-driven individual patient data analyses are needed to accurately define this relationship further.


Independent role of arterial O2 tension in local control of coronary blood flow.
The aim of this study of a blood-perfused isolated rabbit heart preparation was to differentiate the effects on coronary resistance of large changes in arterial O2 tension (arterial PO2 = 45-400 Torr) from the effects of variations in arterial O2 content or myocardial O2 delivery. Standard stored human blood was resuspended in Krebs-Henseleit buffer and was oxygenated to obtain normal PO2, high PO2, and low PO2. Hemoglobin concentrations were adjusted to obtain the same arterial O2 content (CaO2) for the three PO2s. In a first set of experiments, in which coronary blood flow (CBF) was free and adapted to a constant perfusion pressure, switching from control [138 +/- 17 (SE) Torr] to high PO2 blood (380 +/- 27 Torr) induced a significant decrease in CBF and myocardial O2 consumption (MVO2). Switching from control (125 +/- 3 Torr) to low PO2 blood (49 +/- 5 Torr) induced a significant increase in CBF and MVO2. In a second set of experiments, the switch from control (159 +/- 5 Torr) to high PO2 (389 +/- 32 Torr) was performed in a preparation in which CBF and consequently O2 delivery were constant. Under these conditions, the increase in perfusion pressure demonstrated that PO2 affected coronary resistance, even though the O2 delivery was constant. No significant change in myocardial performance was observed in any of these experimental procedures. These results show that arterial PO2 may affect coronary blood flow regulation independently of any mediation by the autonomic nervous system and of any associated changes in O2 content or O2 delivery.


Single-molecule analysis of ligand efficacy in β2AR-G-protein activation.
G-protein-coupled receptor (GPCR)-mediated signal transduction is central to human physiology and disease intervention, yet the molecular mechanisms responsible for ligand-dependent signalling responses remain poorly understood. In class A GPCRs, receptor activation and G-protein coupling entail outward movements of transmembrane helix 6 (TM6). Here, using single-molecule fluorescence resonance energy transfer imaging, we examine TM6 movements in the β2 adrenergic receptor (β2AR) upon exposure to orthosteric ligands with different efficacies, in the absence and presence of the Gs heterotrimer. We show that partial and full agonists differentially affect TM6 motions to regulate the rate at which GDP-bound β2AR-Gs complexes are formed and the efficiency of nucleotide exchange leading to Gs activation. These data also reveal transient nucleotide-bound β2AR-Gs species that are distinct from known structures, and provide single-molecule perspectives on the allosteric link between ligand- and nucleotide-binding pockets that shed new light on the G-protein activation mechanism.


Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization.
The Covid-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Two monoclonal antibody (mAb) therapeutics have received emergency use authorization, and more are in the pipeline. Furthermore, multiple vaccine constructs have shown promise, including two with ~95% protective efficacy against Covid-19. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. Considerable viral evolution has occurred since, including variants with a D614G mutation that have become dominant. Viruses with this mutation alone do not appear to be antigenically distinct, however. Recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK and B.1.351 in South Africa is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a number of mAbs to the receptor-binding domain (RBD). It is modestly more resistant to convalescent plasma (~3 fold) and vaccinee sera (~2 fold). Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple potent mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (~11-33 fold) and vaccinee sera (~6.5-8.6 fold). B.1.351 and emergent variants with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.


Fetal ECG extraction from single-channel maternal ECG using singular value decomposition.
The extraction of fetal electrocardiogram (ECG) from the composite maternal ECG signal obtained from the abdominal lead is discussed. The proposed method employs singular value decomposition (SVD) and analysis based on the singular value ratio (SVR) spectrum. The maternal ECG (M-ECG) and the fetal ECG (F-ECG) components are identified in terms of the SV-decomposed modes of the appropriately configured data matrices, and elimination of the M-ECG and determination of F-ECG are achieved through selective separation of the SV-decomposed components. The unique feature of the method is that only one composite maternal ECG signal is required to determine the F-ECG component. The method is numerically robust and computationally efficient.


Immune Reconstitution Kinetics following Intentionally Induced Mixed Chimerism by Nonmyeloablative Transplantation.
Establishing mixed chimerism is a promising approach for inducing donor-specific transplant tolerance. The establishment and maintenance of mixed chimerism may enable long-term engraftment of organ transplants while minimizing the use of immunosuppressants. Several protocols for inducing mixed chimerism have been reported; however, the exact mechanism underlying the development of immune tolerance remains to be elucidated. Therefore, understanding the kinetics of engraftment during early post-transplant period may provide insight into establishing long-term mixed chimerism and permanent transplant tolerance. In this study, we intentionally induced allogeneic mixed chimerism using a nonmyeloablative regimen by host natural killer (NK) cell depletion and T cell-depleted bone marrow (BM) grafts in a major histocompatibility complex (MHC)-mismatched murine model and analyzed the kinetics of donor (C57BL/6) and recipient (BALB/c) engraftment in the weeks following transplantation. Donor BM cells were well engrafted and stabilized without graft-versus-host disease (GVHD) as early as one week post-bone marrow transplantation (BMT). Donor-derived thymic T cells were reconstituted four weeks after BMT; however, the emergence of newly developed T cells was more obvious at the periphery as early as two weeks after BMT. Also, the emergence and changes in ratio of recipient- and donor-derived NKT cells and antigen presenting cells (APCs) including dendritic cells (DCs) and B cells were noted after BMT. Here, we report a longitudinal analysis of the development of donor- and recipient-originated hematopoietic cells in various lymphatic tissues of intentionally induced mixed chimerism mouse model during early post-transplant period. Through the understanding of immune reconstitution at early time points after nonmyeloablative BMT, we suggest guidelines on intentionally inducing durable mixed chimerism.


Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1.
To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and evidence of antitumor activity of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1 (IGF-1R). Patients with advanced solid malignancies or non-Hodgkin's lymphoma received escalating doses of AMG 479 intravenously (IV) every 2 weeks (Q2W). Blood samples were assayed to determine pharmacokinetic parameters and IGF-1R occupancy on neutrophils; fluorodeoxyglucose-positron emission tomography scans were used to assess tumor metabolic effects. Fifty-three patients received 312 infusions of AMG 479 Q2W. Overall, the most common grades 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. One dose-limiting toxicity (ie, grade 3 thrombocytopenia) occurred in a patient at 20 mg/kg during course 1; grade 3 thrombocytopenia (n = 8) and grade 3 transaminitis elevations (n = 1) also were reported but not in the escalation phase. The maximum-planned dose of 20 mg/kg was safely administered; thus, an MTD was not reached. High levels of neutrophil IGF-1R binding and increases from baseline in serum IGF-1 levels were observed in the 12- and 20-mg/kg cohorts. Tumor responses included one durable complete response (CR) and one unconfirmed partial response (PR) in two patients with Ewing/primitive neuroectodermal tumors and included one PR and one minor response in two patients with neuroendocrine tumors. The patients with Ewing/PNET who had a CR have remained disease free on therapy after 28 months. AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent.


High pH sensing with water-soluble porpholactone derivatives and their incorporation into a Nafion® optode membrane.
The known optical high pH sensing chromophores, free base and metal complexes (M = 2H, Zn(ii), Pt(ii)) of meso-tetrakis(pentafluorophenyl)porpholactone, and the as yet untested Ga(iii) complex, were made freely water-soluble by derivatization at the aryl group with PEG chains. Their halochromic response profiles were determined and found to be surprisingly shifted toward greater base sensitivity when compared to the parent sensors in aqueous solution in the presence of a surfactant. Select PEG-derivatized chromophores were also incorporated into Nafion®-based membranes. The immobilized sensor was shown to be suitable for a moderately rapid (response time in minutes) sensing of high concentrations of hydroxides (pH 11 and above, up to 5 M NaOH concentrations). The lesser sensitivity of the indicators in the membrane is rationalized by the anionic nature of the membrane material. The membrane shows a perfectly reversible response and remains transparent and stable even under extended times of exposure to very caustic environments, and no leaching of the chromophore is observed. The membrane might find use in fiber optics-based optodes suitable for the monitoring of high hydroxide environments inside chemical reactors or fuel cells.


Seasonal variation in TP53 R249S-mutated serum DNA with aflatoxin exposure and hepatitis B virus infection.
Chronic hepatitis B virus (HBV) infection and dietary aflatoxin B1 (AFB1) exposure are etiological factors for hepatocellular carcinoma (HCC) in countries with hot, humid climates. HCC often harbors a TP53 (tumor protein p53) mutation at codon 249 (R249S). In chronic carriers, 1762T/1764A mutations in the HBV X gene are associated with increased HCC risk. Both mutations have been detected in circulating cell-free DNA (CFDNA) from asymptomatic HBV carriers. We evaluated seasonal variation in R249S and HBV in relation to AFB1 exposure. R249S was quantitated by mass spectrometry in CFDNA in a cross-sectional survey of 473 asymptomatic subjects (237 HBV carriers and 236 noncarriers) recruited in three villages in the Gambia over a 10-month period. 1762T/1764A HBV mutations were detected by quantitative polymerase chain reaction. In addition, the HBV S gene was sequenced in 99 subjects positive for HBV surface antigen (HBsAg). We observed a seasonal variation of serum R249S levels. Positivity for R249S and average concentration were significantly higher in HBsAg-positive subjects surveyed during April-July (61%; 5,690 ± 11,300 R249S copies/mL serum) than in those surveyed October-March [32% and 480 ± 1,030 copies/mL serum (odds ratio = 3.59; 95% confidence interval: 2.05, 6.30; p < 0.001)]. Positivity for HBV e antigen (HBeAg) (a marker of HBV replication) and viral DNA load also varied seasonally, with 15-30% of subjects surveyed between April and June HBeAg positive, compared with < 10% surveyed during other months. We detected 1762T/1764A mutations in 8% of carriers, half of whom were positive for R249S. We found HBV genotype E in 95 of 99 HBsAg-positive subjects. R249S is detectable in CFDNA of asymptomatic subjects. Evidence of temporal and quantitative variations suggests an interaction among AFB1 exposure, HBV positivity, and replication on TP53 mutation formation or persistence.


On the interference of two Gaussian beams and their ABCD matrix representation.
Gaussian beam propagation is well described by the q-parameter and the ABCD matrices. A variety of ABCD matrices are available that represent commonly occurring scenarios/components in optics. One important phenomenon that has not been studied in detail is the interference of two optical beams with different q-parameters undergoing interference. In this paper, we describe the effect of interference of two Gaussian beams. We derive an ABCD matrix for the addition of two beams that takes into account both the amplitude and phase difference between two beams. This ABCD matrix will help greatly in determining the propagation of beams inside complex interferometers and finding the solutions for the coupled cavity Eigenmodes.