Combination treatment of berberine and solid lipid curcumin particles increased cell death and inhibited PI3K/Akt/mTOR pathway of human cultured glioblastoma cells more effectively than did individual treatments.
The treatment of glioblastoma is challenging for the clinician, due to its chemotherapeutic resistance. Recent findings suggest that targeting glioblastoma using anti-cancer natural polyphenols is a promising strategy. In this context, curcumin and berberine have been shown to have potent anti-cancer and anti-inflammatory effects against several malignancies. Due to the poor solubility and limited bioavailability, these compounds have limited efficacy for treating cancer. However, use of a formulation of curcumin with higher bioavailability or combining it with berberine as a co-treatment may be proving to be more efficacious against cancer. Recently, we demonstrated that solid lipid curcumin particles (SLCPs) provided more bioavailability and anti-cancer effects in cultured glioblastoma cells than did natural curcumin. Interestingly, a combination of curcumin and berberine has proven to be more effective in inhibiting growth and proliferation of cancer in the liver, breast, lung, bone and blood. However, the effect of combining these drugs for treating glioblastoma, especially with respect to its effect on activating the PI3K/Akt/mTOR pathways has not been studied. Therefore, we decided to assess the co-treatment effects of these drugs on two different glioblastoma cell lines (U-87MG and U-251MG) and neuroblastoma cell lines (SH-SY5Y) derived from human tissue. In this study, we compared single and combination (1:5) treatment of SLCP (20 μM) and berberine (100 μM) on measures of cell viability, cell death markers, levels of c-Myc and p53, along with biomarkers of the PI3K/Akt/mTOR pathways after 24-48 h of incubation. We found that co-treatment of SLCP and berberine produced more glioblastoma cell death, more DNA fragmentation, and significantly decreased ATP levels and reduced mitochondrial membrane potential than did single treatments in both glioblastoma cells lines. In addition, we observed that co-treatment inhibited the PI3K/Akt/mTOR pathway more efficiently than their single treatments. Our study suggests that combination treatments of SLCP and berberine may be a promising strategy to reduce or prevent glioblastoma growth in comparison to individual treatments using either compound.


Antidepressants for anorexia nervosa.
Anorexia Nervosa (AN) is an illness characterised by extreme concern about body weight and shape, severe self-imposed weight loss, and endocrine dysfunction. In spite of its high mortality, morbidity and chronicity, there are few intervention studies on the subject. The aim of this review was to evaluate the efficacy and acceptability of antidepressant drugs in the treatment of acute AN. The strategy comprised of database searches of the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register, MEDLINE (1966 to April 28th, 2005), EMBASE (1980 to week 36, 2004), PsycINFO (1969 to August week 5, 2004), handsearching the International Journal of Eating Disorders and searching the reference lists of all papers selected. Personal letters were sent to researchers in the field requesting information on unpublished or in-progress trials. All randomised controlled trials of antidepressant treatment for AN patients, as defined by the Diagnostic and Statistical Manual, fourth edition (DSM-IV) or similar international criteria, were selected. Quality ratings were made giving consideration to the strong relationship between allocation concealment and potential for bias in the results; studies meeting criteria A and B were included. Trials were excluded if non-completion rates were above 50%. The standardised mean difference and relative risk were used for continuous data and dichotomous data comparisons, respectively. Whenever possible, analyses were performed according to intention-to-treat principles. Heterogeneity was tested with the I-squared statistic. Weight change was the primary outcome. Secondary outcomes were severity of eating disorder, depression and anxiety symptoms, and global clinical state. Acceptability of treatment was evaluated by considering non-completion rates. Only seven studies were included. Major methodological limitations such as small trial size and large confidence intervals decreased the power of the studies to detect differences between treatments, and meta-analysis of data was not possible for the majority of outcomes. Four placebo-controlled trials did not find evidence that antidepressants improved weight gain, eating disorder or associated psychopathology. Isolated findings, favouring amineptine and nortriptyline, emerged from the antidepressant versus antidepressant comparisons, but cannot be conceived as evidence of efficacy of a specific drug or class of antidepressant in light of the findings from the placebo comparisons. Non-completion rates were similar between the compared groups. A lack of quality information precludes us from drawing definite conclusions or recommendations on the use of antidepressants in acute AN. Future studies testing safer and more tolerable antidepressants in larger, well designed trials are needed to provide guidance for clinical practice.


Drinking resumption: problematic alcohol use relapse after rehabilitation. A phenomenological hermeneutical perspective.
The majority of patients being treated for alcohol abuse disorders experience one or more relapses after treatment. The fact that people use this inebriant in a way leading to so much harm and suffering might seem a conundrum. Therapists, family and others might find the person's relapse to be dramatic and upsetting, and one might question whether the person has the sufficient will or motivation to change. However, few previous studies have explored relapse from the patient's perspective. The aim of this study was to illuminate the patient's lived experience of relapse and to develop a deeper understanding of this phenomenon. The study consisted of qualitative interviews using a phenomenological hermeneutical approach. Three main themes emerged from the analyses: 'craving', 'self-image' and 'time'. The findings were discussed in the context of phenomenological literature. Cravings could occur unpredictably; nevertheless, craving was a common experience for the patients and signified a risk of relapse. Bodily experiences of craving were frequently mentioned, and alcohol addiction could be understood as to be a disease or a learned habit. Self-image was, at times, adversely affected by relapse episodes. Therefore, feelings of shame, self-respect and recognition were significant concepts. This study found that the perception of time as past, present and future greatly influenced the participants' experiences of relapse and rehabilitation. Thus, relapse was an upsetting and dramatic experience that could cause great discomfort and sometimes life-threatening situations. However, relapse could also be viewed as a planned event. This study highlights important truth and reality about alcoholism and relapse grounded in people's lived experience.


Decade-long changes in the use of combination evidence-based medical therapy at discharge for patients surviving acute myocardial infarction.
Current practice guidelines suggest routine use of several effective cardiac medications in hospital survivors of acute myocardial infarction (AMI). The objectives of our population-based study were to describe decade-long trends (1990-2001) in the use of aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, lipid-lowering agents, and combinations thereof, in patients discharged from all metropolitan Worcester (Mass) hospitals after AMI. The study sample consisted of 5965 adult men and women of all ages discharged after AMI from all greater Worcester hospitals in 7 annual periods between 1990 and 2001. Although consistent increases in the use of each of the effective cardiac medications examined were observed over time, particularly marked relative increases in the use of angiotensin-converting enzyme inhibitors (168% relative increase) and lipid-lowering agents (1086% relative increase) were noted. Use of combinations of effective cardiac medications also increased substantially over time. Between 1990 and 2001, the percentage of hospital survivors treated with > or =3 cardiac medications increased from 12.9% to 74.0%. Advancing age, female sex, history of angina, hypertension, or heart failure during hospitalization, presence of an initial non-Q wave MI, and development of atrial fibrillation during the index hospitalization were independently associated with underuse of combination medical therapy. The present results suggest considerable improvements over the last decade in the medical management of patients hospitalized with AMI. Educational efforts, however, aimed at clinicians and designed to improve use of these therapies, as well as efforts to simplify medication regimens and enhance rates of adherence, remain warranted.


Rapid creation of BAC-based human artificial chromosome vectors by transposition with synthetic alpha-satellite arrays.
Efficient construction of BAC-based human artificial chromosomes (HACs) requires optimization of each key functional unit as well as development of techniques for the rapid and reliable manipulation of high-molecular weight BAC vectors. Here, we have created synthetic chromosome 17-derived alpha-satellite arrays, based on the 16-monomer repeat length typical of natural D17Z1 arrays, in which the consensus CENP-B box elements are either completely absent (0/16 monomers) or increased in density (16/16 monomers) compared to D17Z1 alpha-satellite (5/16 monomers). Using these vectors, we show that the presence of CENP-B box elements is a requirement for efficient de novo centromere formation and that increasing the density of CENP-B box elements may enhance the efficiency of de novo centromere formation. Furthermore, we have developed a novel, high-throughput methodology that permits the rapid conversion of any genomic BAC target into a HAC vector by transposon-mediated modification with synthetic alpha-satellite arrays and other key functional units. Taken together, these approaches offer the potential to significantly advance the utility of BAC-based HACs for functional annotation of the genome and for applications in gene transfer.


Negotiating the Edge: The Rationalization of Sexual Risk Taking Among Western Male Sex Tourists to Thailand.
Every year thousands of Western men travel to Thailand as sex tourists to participate in paid-for sex. Although many of these men will use condoms to protect themselves against sexually transmitted infections (STIs), others will not, despite the risks. By applying Steven Lyng's (1990) concept of edgework to data collected from 14 face-to-face interviews with male sex tourists in Pattaya, Thailand, and 1,237 online discussion board posts, this article explores the ways in which these men understood and sought to rationalize the sexual risks they took. We argue that notions of likelihood of infection and significance of consequence underpin these behaviors, and we identify the existence of understandings of sexual risk that reject mainstream safer-sex messages and frame condomless sex as a broadly safe activity for heterosexual men. The article concludes by summarizing the difficulties inherent in driving behavior change among this group of men, for whom sexual risks appear to be easily rationalized away as either inconsequential or irrelevant.


Effects of symmetry, methyl groups and serendipity on intramolecular vibrational energy dispersal.
We consider two key parameters that have been proposed to be important for vibrational energy delocalization, closely related to intramolecular vibrational redistribution (IVR), in molecules. These parameters are the symmetry of the molecule, and the presence of torsional (internal rotor) modes of a methyl group. We consider four para-disubstituted benzene molecules and examine their vibrational character. The molecules selected are para-difluorobenzene, para-chlorofluorobenzene, para-fluorotoluene, and para-xylene. This set of molecules allows the above parameters to be assessed in a systematic way. The probe we use is zero-electron-kinetic-energy (ZEKE) spectroscopy, which is employed in a resonant scheme, where the intermediate levels are selected vibrational levels of the S1 excited electronic state, with wavenumbers up to 1300 cm-1. We conclude that symmetry, and the presence of a methyl groups, do indeed have a profound effect on "restricted" IVR at low energies. This is underpinned by serendipitous coincidences in the energies of the levels, owing to small shifts in vibrational wavenumbers between molecules, so bringing levels into resonance. Additionally, methyl groups play an important role in opening up new routes for coupling between vibrations of different symmetry, and this is critical in the transition to "statistical" IVR at lower energies for molecules that contain them. Further, the presence of two methyl groups in the symmetrically-substituted p-xylene causes more widespread IVR than does the single methyl group in the asymmetrically-substituted p-fluorotoluene.


Characteristics of dr1790 disruptant and its functional analysis in Deinococcus radiodurans.
Deinococcus radiodurans (DR) is an extremophile that is well known for its resistance to radiation, oxidants and desiccation. The gene dr1790 of D. radiodurans was predicted to encode a yellow-related protein. The primary objective of the present study was to characterize the biological function of the DR1790 protein, which is a member of the ancient yellow/major royal jelly (MRJ) protein family, in prokaryotes. Fluorescence labeling demonstrated that the yellow-related protein encoded by dr1790 is a membrane protein. The deletion of the dr1790 gene decreased the cell growth rate and sensitivity to hydrogen peroxide and radiation and increased the membrane permeability of D. radiodurans. Transcript profiling by microarray and RT-PCR analyses of the dr1790 deletion mutant suggested that some genes that are involved in protein secretion and transport were strongly suppressed, while other genes that are involved in protein quality control, such as chaperones and proteases, were induced. In addition, the expression of genes with predicted functions that are involved in antioxidant systems, electron transport, and energy metabolism was significantly altered through the disruption of dr1790. Moreover, the results of proteomic analyses using 2-DE and MS also demonstrated that DR1790 contributed to D. radiodurans survival. Taken together, these results indicate that the DR1790 protein from the ancient yellow protein family plays a pleiotropic role in the survival of prokaryotic cells and contributes to the extraordinary resistance of D. radiodurans against oxidative and radiation stresses.


The physiology and psychology of selective attention to touch.
In this chapter we review psychological and physiological experiments on selective attention to touch stimuli. We explore the role of selective attention in tactile target detection and search, determining those tasks that benefit from attention and those which can be effectively performed pre-attentively. We also try to determine the stage at which attentional selection occurs. We review electrophysiological and human brain imaging (PET, fMRI, MEG, SEP) studies to assess how early in the somatosensory processing pathway attentional modulation occurs. There is some evidence that the primary somatosensory cortex (S1) can show attentional effects. However, a number of studies have suggested that there is a hierarchy to attentional modulation in the somatosensory system, with the greatest effects being observed in secondary and association areas.


DNA barcoding and surveillance sampling strategies for Culicoides biting midges (Diptera: Ceratopogonidae) in southern India.
Culicoides spp. biting midges transmit bluetongue virus (BTV), the aetiological agent of bluetongue (BT), an economically important disease of ruminants. In southern India, hyperendemic outbreaks of BT exert high cost to subsistence farmers in the region, impacting on sheep production. Effective Culicoides spp. monitoring methods coupled with accurate species identification can accelerate responses for minimising BT outbreaks. Here, we assessed the utility of sampling methods and DNA barcoding for detection and identification of Culicoides spp. in southern India, in order to provide an informed basis for future monitoring of their populations in the region. Culicoides spp. collected from Tamil Nadu and Karnataka were used to construct a framework for future morphological identification in surveillance, based on sequence comparison of the DNA barcode region of the mitochondrial cytochrome c oxidase I (COI) gene and achieving quality standards defined by the Barcode of Life initiative. Pairwise catches of Culicoides spp. were compared in diversity and abundance between green (570 nm) and ultraviolet (UV) (390 nm) light emitting diode (LED) suction traps at a single site in Chennai, Tamil Nadu over 20 nights of sampling in November 2013. DNA barcode sequences of Culicoides spp. were mostly congruent both with existing DNA barcode data from other countries and with morphological identification of major vector species. However, sequence differences symptomatic of cryptic species diversity were present in some groups which require further investigation. While the diversity of species collected by the UV LED Center for Disease Control (CDC) trap did not significantly vary from that collected by the green LED CDC trap, the UV CDC significantly outperformed the green LED CDC trap with regard to the number of Culicoides individuals collected. Morphological identification of the majority of potential vector species of Culicoides spp. samples within southern India appears relatively robust; however, potential cryptic species diversity was present in some groups requiring further investigation. The UV LED CDC trap is recommended for surveillance of Culicoides in southern India.


Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling.
Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4+ T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4+ T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3+ regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4+ T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4+ T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3+ Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4+ T cell subsets by altering their TCR downstream signaling.


Pindolol occupancy of 5-HT(1A) receptors measured in vivo using small animal positron emission tomography with carbon-11 labeled WAY 100635.
Positron emission tomography (PET), following an intravenous injection of [carbonyl-(11)C]WAY 100635, was used to image central 5-HT(1A) receptors in rat following pretreatment with graded doses of (-)-pindolol (0.001-3 mg/kg, i.v.). The use of PET had advantages over ex vivo radioligand binding methods in that it produced parametric image volumes and reduced errors due to inter-rat variability. Time-radioactivity curves from regions of interest (ROI) acquired from individual rats enabled the estimation of specific binding of the radioligand using a compartmental model with reference tissue input. Binding potential (BP) of [(11)C]WAY 100635 was estimated for frontal cortex and hippocampus (postsynaptic), and midbrain raphe nuclei (presynaptic). In the latter ROI, pindolol dose-dependently decreased BP. The saturation curve could be fitted to a single-site model up to the lowest dose of pindolol used, giving an ED(50) (dose to cause 50% occupancy) value of 0.26 +/- 0. 05 mg/kg, and inclusion of control (nonpindolol-treated) rats did not affect the fit. In contrast, in cortex and hippocampus ROI, low doses of pindolol caused an increase in BP compared with controls. Pindolol doses greater than approximately 0.1 mg/kg, resulted in a dose-dependent decrease in BP, and ED(50) values in cortex and hippocampus were estimated as 0.44 +/- 0.13 and 0.48 +/- 0.12 mg/kg, respectively. The increase in [(11)C]WAY 100635 binding at low pindolol doses is feasibly related to a decrease in basal receptor occupancy following reduced release of endogenous 5-HT. Considering the apparently greater potency of pindolol at the midbrain raphe ROI, this effect could be mediated via agonist activity at the autoreceptor.


Supercritical Grüneisen parameter and its universality at the Frenkel line.
We study the thermomechanical properties of matter under extreme conditions deep in the supercritical state, at temperatures exceeding the critical one by up to four orders of magnitude. We calculate the Grüneisen parameter γ and find that on isochores it decreases with temperature from 3 to 1, depending on the density. Our results indicate that from the perspective of thermomechanical properties, the supercritical state is characterized by a wide range of γ's which includes solidlike values-an interesting finding in view of the common perception of the supercritical state as being an intermediate state between gases and liquids. We rationalize this result by considering the relative weights of oscillatory and diffusive components of the supercritical system below the Frenkel line. We also find that γ is nearly constant at the Frenkel line above the critical point and explain this universality in terms of the pressure and temperature scaling of system properties along the lines where particle dynamics changes qualitatively.


A Multi-modal Approach to Understanding Degradation of Organic Photovoltaic Materials.
State-of-the-art organic photovoltaic (OPV) materials are composed of complex, chemically diverse polymeric and molecular structures that form highly intricate solid-state interactions, collectively yielding exceptional tunability in performance and aesthetics. These properties are especially attractive for semitransparent power-generating windows or shades in living environments, greenhouses, or other architectural integrations. However, before such a future is realized, a broader and deeper understanding of property stability must be acquired. Stability during operating and environmental conditions is critical, namely, material color steadfastness, optoelectronic performance retention, morphological rigidity, and chemical robustness. To date, no single investigation encompasses all four distinct, yet interconnected, metrics. Here, we present a multimodal strategy that captures a dynamic and interconnected evolution of each property during the course of an accelerated photobleaching experiment. We demonstrate this approach across relevant length scales (from molecular to visual macroscale) using X-ray photoelectron spectroscopy, grazing-incidence X-ray scattering, microwave conductivity, and time-dependent photobleaching spectroscopies for two high-performance semitransparent OPV blends-PDPP4T:PC60BM and PDPP4T:IEICO-4F, with comparisons to the stabilities of the individual components. We present direct evidence that specific molecular acceptor (fullerene vs nonfullerene) designs and the resulting donor-acceptor interactions lead to distinctly different mechanistic routes that ultimately arrive at what is termed "OPV degradation." We directly observe a chemical oxidation of the cyano endcaps of the IEICO-4F that coincides with a morphological change and large loss in photoconductivity while the fullerene acceptor-containing blend demonstrates a significantly greater fraction of oxygen uptake but retains 55% of the photoconductivity. This experimental roadmap provides meaningful guidance for future high-throughput, multimodal studies, benchmarking the sensitivity of the different analytical techniques for assessing stability in printable active layers, independent of complete device architectures.


Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data.
Questions concerning the safety of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression in children led us to compare and contrast published and unpublished data on the risks and benefits of these drugs. We did a meta-analysis of data from randomised controlled trials that evaluated an SSRI versus placebo in participants aged 5-18 years and that were published in a peer-reviewed journal or were unpublished and included in a review by the Committee on Safety of Medicines. The following outcomes were included: remission, response to treatment, depressive symptom scores, serious adverse events, suicide-related behaviours, and discontinuation of treatment because of adverse events. Data for two published trials suggest that fluoxetine has a favourable risk-benefit profile, and unpublished data lend support to this finding. Published results from one trial of paroxetine and two trials of sertraline suggest equivocal or weak positive risk-benefit profiles. However, in both cases, addition of unpublished data indicates that risks outweigh benefits. Data from unpublished trials of citalopram and venlafaxine show unfavourable risk-benefit profiles. Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people. Clinical guideline development and clinical decisions about treatment are largely dependent on an evidence base published in peer-reviewed journals. Non-publication of trials, for whatever reason, or the omission of important data from published trials, can lead to erroneous recommendations for treatment. Greater openness and transparency with respect to all intervention studies is needed.


The heterologous expression of the cytochromes P450: a new approach for the study of enzyme activities and regulation.
The superfamily of cytochrome P450s encompasses a vast arena of biologically important reactions. The ever-increasing numbers of P450s and the diversity of their enzymatic properties dictate the need to develop new approaches for studying their chemical, physical and catalytic properties. The heterologous expression of P450s in various cell systems (e.g., COS cells, yeast, E. coli, etc.) now provides a means of producing recombinant proteins for such studies. The example is presented of the expression of P450(17)alpha in COS cells and the use of this technique for the comparison of the enzymatic properties of the rat, bovine and human enzymes. Further, studies are described whereby cotransfection results in the simultaneous expression of more than one P450 permitting the construction of 'designer membranes' for assessing protein-protein interactions and the reconstruction of complex pathways of metabolism. Recent advances with genetically engineered systems point to the power of the transfection technique for the study of structure-function relationships with this class of important hemoproteins.


A Unique Multifunctional Nanoenzyme Tailored for Triggering Tumor Microenvironment Activated NIR-II Photoacoustic Imaging and Chemodynamic/Photothermal Combined Therapy.
The accurate diagnosis and targeted therapy of malignant tumors face significant challenges. To address these, an oxidized molybdenum polyoxometalate-copper nanocomposite (Ox-POM@Cu) is designed and synthesized here. The doping with Cu determines the formation of oxygen vacancies, which can increase the carrier concentration in Ox-POM@Cu, accelerate electron transfer, and enhance the redox activity, thus playing an efficient catalytic role. The nanocomposite presents unique enzymatic functions characterized by a multielement catalytic activity in the tumor microenvironment (TME). In addition, it can be employed as an NIR-II photoacoustic imaging (PAI) probe and cancer therapy agent. First, it participates in a redox reaction with glutathione (GSH) in tumor tissues, activates the PAI and photothermal therapy functions via NIR-II irradiation, and depletes the GSH supply in cancerous cells. Subsequently, it catalyzes a Fenton-like reaction with H2 O2 in tumor tissues to form hydroxyl radicals, thereby performing a chemodynamic therapy function. The findings show that the developed nanoenzyme is very efficient in the diagnosis and treatment of malignant tumors. This work not only provides a new strategy for the design of TME-induced NIR-II PAI but also presents new insights into enhanced cancer therapy.


Deep phosphoproteome analysis of Schistosoma mansoni leads development of a kinomic array that highlights sex-biased differences in adult worm protein phosphorylation.
Although helminth parasites cause enormous suffering worldwide we know little of how protein phosphorylation, one of the most important post-translational modifications used for molecular signalling, regulates their homeostasis and function. This is particularly the case for schistosomes. Herein, we report a deep phosphoproteome exploration of adult Schistosoma mansoni, providing one of the richest phosphoprotein resources for any parasite so far, and employ the data to build the first parasite-specific kinomic array. Complementary phosphopeptide enrichment strategies were used to detect 15,844 unique phosphopeptides mapping to 3,176 proteins. The phosphoproteins were predicted to be involved in a wide range of biological processes and phosphoprotein interactome analysis revealed 55 highly interconnected clusters including those enriched with ribosome, proteasome, phagosome, spliceosome, glycolysis, and signalling proteins. 93 distinct phosphorylation motifs were identified, with 67 providing a 'footprint' of protein kinase activity; CaMKII, PKA and CK1/2 were highly represented supporting their central importance to schistosome function. Within the kinome, 808 phosphorylation sites were matched to 136 protein kinases, and 68 sites within 37 activation loops were discovered. Analysis of putative protein kinase-phosphoprotein interactions revealed canonical networks but also novel interactions between signalling partners. Kinomic array analysis of male and female adult worm extracts revealed high phosphorylation of transformation:transcription domain associated protein by both sexes, and CDK and AMPK peptides by females. Moreover, eight peptides including protein phosphatase 2C gamma, Akt, Rho2 GTPase, SmTK4, and the insulin receptor were more highly phosphorylated by female extracts, highlighting their possible importance to female worm function. We envision that these findings, tools and methodology will help drive new research into the functional biology of schistosomes and other helminth parasites, and support efforts to develop new therapeutics for their control.


Non-destructive pollution exposure assessment by means of wood mice hair.
Concentrations of cadmium, copper, lead and zinc were measured in hair, kidney, liver, lung and muscle tissue of wood mice captured along a pollution gradient. We found positive relationships between cadmium concentrations in hair and all internal tissues. Hair lead concentrations were positively correlated with lead contents in kidney and liver. Age had a significant effect on cadmium accumulation in all tissues and hair. Apart from a very weak relationship between zinc concentrations in hair and liver, no significant relation between copper or zinc content in hair and any of the internal organs was observed. In summary, our observations suggest that hair of wood mice can be used for monitoring exposure to non-essential metals like cadmium and lead, but not to homeostatically regulated metals such as copper or zinc.


Twenty-five year results of the national cancer institute randomized breast conservation trial.
Breast conservation therapy (BCT) consisting of lumpectomy and postoperative radiation has become an accepted alternative to mastectomy (MRM) for the treatment of early stage breast cancer. We currently report the 25 year outcomes of a single institution, prospective, randomized clinical trial at the National Cancer Institute. 237 women with pathologically confirmed invasive breast tumors 5 cm or less were accrued between 1979 and 1987 and randomized to receive either BCT or MRM. Overall survival was the primary endpoint. Patients with node positive disease were included and treated with doxorubicin and cyclophosphamide. Both arms received axillary dissection. BCT patients had radiation to the whole breast followed by a boost. At a median follow-up of 25.7 years, overall survival was 43.8% for the MRM group and 37.9% for BCT (P = 0.38). Although the cumulative incidence of a disease-free survival event was higher in BCT patients (29.0% MRM vs. 56.4% BCT, P = 0.0017), the additional treatment failures were primarily isolated ipsilateral breast tumor recurrences (IBTR's) requiring salvage mastectomy. 22.3% of BCT patients experienced an IBTR. Distant disease and second cancers were similar in both arms. After 25 years, long term survival between BCT and MRM continues to be similar in patients treated for early stage breast cancer. Patients receiving BCT may be at risk for additional treatment-related morbidity, which may occur as a late event. Further studies are required to delineate patients at higher risk for these events, and prolonged follow up should be encouraged after treatment for all women.


Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study.
Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]). MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.


Shear-induced rigidity of frictional particles: Analysis of emergent order in stress space.
Solids are distinguished from fluids by their ability to resist shear. In equilibrium systems, the resistance to shear is associated with the emergence of broken translational symmetry as exhibited by a nonuniform density pattern that is persistent, which in turn results from minimizing the free energy. In this work, we focus on a class of systems where this paradigm is challenged. We show that shear-driven jamming in dry granular materials is a collective process controlled by the constraints of mechanical equilibrium. We argue that these constraints can lead to a persistent pattern in a dual space that encodes the statistics of contact forces and the topology of the contact network. The shear-jamming transition is marked by the appearance of this persistent pattern. We investigate the structure and behavior of patterns both in real space and the dual space as the system evolves through the rigidity transition for a range of packing fractions and in two different shear protocols. We show that, in the protocol that creates homogeneous jammed states without shear bands, measures of shear jamming do not depend on strain and packing fraction independently but obey a scaling form with a packing-fraction-dependent characteristic strain that goes to zero at the isotropic jamming point ϕ_{J}. We demonstrate that it is possible to define a protocol-independent order parameter in this dual space, which provides a quantitative measure of the rigidity of shear-jammed states.


Sequences and diversity of human T cell receptor beta chain variable region genes.
The nucleotide sequences of 22 human T cell antigen receptor (TcR) beta chain variable region genes isolated from various T lymphocytes have been analyzed. Of the 19 variable gene segment (V beta)-containing sequences, 17 were unique. The V beta gene segments were grouped into 11 families. Comparisons were made with the data of Concannon et al. to unify the nomenclature. The data is consistent with a total V beta gene segment repertoire with a most probable value of 38 members and an upper bound of 104 members at the 95% confidence level. Southern blot data of germline DNA using selected TcR V beta cDNAs as probes support this estimate. The human repertoire is approximately three to four times greater than that reported for the mouse. Explanations for this discrepancy are proposed.


Cannabinoid interactions with ion channels and receptors.
Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. One such protein is the voltage-gated sodium channel (Nav). CBD shows a lack of specificity for sodium channels; however, the method of interaction is still unknown. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Nav. Nav are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Nav potential targets for CBD interaction since it has been reported to reduce pain and seizures. One potential method of interaction that is of interest in this review is whether CBD affects channel function by altering lipid bilayer properties, independent of any possible direct interaction with membrane channels. CBD's ability to interact with its targets is a novel and important discovery. This discovery will not only prompt further research towards CBD's characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.


Tunneling nanotube formation is essential for the regulation of osteoclastogenesis.
Osteoclasts are the multinucleated giant cells formed by cell fusion of mononuclear osteoclast precursors. Despite the finding of several membrane proteins involving DC-STAMP as regulatory proteins required for fusion among osteoclast precursors, cellular and molecular events concerning this process are still ambiguous. Here we identified Tunneling Nanotubes (TNTs), long intercellular bridges with small diameters, as the essential cellular structure for intercellular communication among osteoclast precursors in prior to cell fusion. Formation of TNTs was highly associated with osteoclastogenesis and it was accompanied with the significant induction of the M-Sec gene, an essential gene for TNT formation. M-Sec gene expression was significantly upregulated by RANKL-treatment in osteoclast precursor cell line. Blockage of TNT formation by Latrunclin B or by M-Sec siRNA significantly suppressed osteoclastogenesis. We have detected the rapid intercellular transport of not only the membrane phospholipids labeled with DiI but also the DC-STAMP-GFP fusion protein through TNTs formed among osteoclast precursors during osteoclastogenesis. Transportation of such regulatory molecules through TNTs would be essential for the process of the specific cell fusion among osteoclast precursors.


Soft and central mode behaviour in PbMg(1/3)Nb(2/3)O(3) relaxor ferroelectric.
The relaxor ferroelectric PbMg(1/3)Nb(2/3)O(3) (PMN) is investigated by means of dielectric and Fourier transform far infrared transmission spectroscopy in the frequency range from 10 kHz to 15 THz at temperatures between 20 and 900 K using mostly thin films on infrared transparent sapphire substrates. While the thin film relaxors display reduced dielectric permittivity at low frequencies, their high frequency lattice response is shown to be the same as for single-crystal/ceramic specimens. In contrast to the results of inelastic neutron scattering, the optic soft mode is found to be underdamped at all temperatures. On heating, the TO1 soft phonon follows the Cochran law with an extrapolated critical temperature of 670 K near to the Burns temperature. Above 450 K the soft mode frequency levels off near 50 cm(-1) and above the Burns temperature it slightly hardens. Central-mode-type dispersion assigned to the dynamics of polar nanoclusters appears below the Burns temperature at frequencies near to but below the soft mode and slows down and broadens dramatically on cooling, finally, below the freezing temperature of 200 K, giving rise to frequency independent losses from the microwave range down. A new explanation of the phonon 'waterfall' effect in inelastic neutron scattering spectra is proposed.


Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia.
The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph(+)ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph(+)ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ~30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph(+)ALL as compared to just 4.8% of Ph(-)ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph(+)ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.


Deciphering the enigma of undetected species, phylogenetic, and functional diversity based on Good-Turing theory.
Estimating the species, phylogenetic, and functional diversity of a community is challenging because rare species are often undetected, even with intensive sampling. The Good-Turing frequency formula, originally developed for cryptography, estimates in an ecological context the true frequencies of rare species in a single assemblage based on an incomplete sample of individuals. Until now, this formula has never been used to estimate undetected species, phylogenetic, and functional diversity. Here, we first generalize the Good-Turing formula to incomplete sampling of two assemblages. The original formula and its two-assemblage generalization provide a novel and unified approach to notation, terminology, and estimation of undetected biological diversity. For species richness, the Good-Turing framework offers an intuitive way to derive the non-parametric estimators of the undetected species richness in a single assemblage, and of the undetected species shared between two assemblages. For phylogenetic diversity, the unified approach leads to an estimator of the undetected Faith's phylogenetic diversity (PD, the total length of undetected branches of a phylogenetic tree connecting all species), as well as a new estimator of undetected PD shared between two phylogenetic trees. For functional diversity based on species traits, the unified approach yields a new estimator of undetected Walker et al.'s functional attribute diversity (FAD, the total species-pairwise functional distance) in a single assemblage, as well as a new estimator of undetected FAD shared between two assemblages. Although some of the resulting estimators have been previously published (but derived with traditional mathematical inequalities), all taxonomic, phylogenetic, and functional diversity estimators are now derived under the same framework. All the derived estimators are theoretically lower bounds of the corresponding undetected diversities; our approach reveals the sufficient conditions under which the estimators are nearly unbiased, thus offering new insights. Simulation results are reported to numerically verify the performance of the derived estimators. We illustrate all estimators and assess their sampling uncertainty with an empirical dataset for Brazilian rain forest trees. These estimators should be widely applicable to many current problems in ecology, such as the effects of climate change on spatial and temporal beta diversity and the contribution of trait diversity to ecosystem multi-functionality.


Intermonomer electron transfer between the low-potential b hemes of cytochrome bc₁.
Cytochrome (cyt) bc(1) is a structural dimer with its monomers consisting of the Fe-S protein, cyt b, and cyt c(1) subunits. Its three-dimensional architecture depicts it as a symmetrical homodimer, but the mobility of the head domain of the Fe-S protein indicates that the functional enzyme exists in asymmetrical heterodimeric conformations. Here, we report a new genetic system for studying intra- and intermonomer interactions within the cyt bc(1) using the facultative phototrophic bacterium Rhodobacter capsulatus. The system involves two different sets of independently expressed cyt bc(1) structural genes carried by two plasmids that are coharbored by a cell without its endogenous enzyme. Our results indicate that coexpressed cyt bc(1) subunits were matured, assorted, and assembled in vivo into homo- and heterodimeric enzymes that can bear different mutations in each monomer. Using the system, the occurrence of intermonomer electron transfer between the low-potential b hemes of cyt bc(1) was probed by choosing mutations that perturb electron transfer at the hydroquinone oxidation (Q(o)) and quinone reduction (Q(i)) sites of the enzyme. The data demonstrate that active heterodimeric variants, formed of monomers carrying mutations that abolish only one of the two (Q(o) or Q(i)) active sites of each monomer, are produced, and they support photosynthetic growth of R. capsulatus. Detailed analyses of the physicochemical properties of membranes of these mutants, as well as purified homo- and heterodimeric cyt bc(1) preparations, demonstrated that efficient and productive electron transfer occurs between the low-potential b(L) hemes of the monomers in a heterodimeric enzyme. Overall findings are discussed with respect to intra- and intermonomer interactions that take place during the catalytic turnover of cyt bc(1).


Coordinators for health science libraries in the Midwest Health Science Library Network.
In the summer of 1973 one resource library in each of the six states of the Midwest Health Science Library Network received funding from the National Library of Medicine to hire a coordinator for health science libraries. The development of the role of coordinator is examined and evaluated. The coordinators have proved valuable in the areas of consortium formation, basic unit development, communication facilitation, and program initiation. The function of the coordinators in the extensive planning effort now being undertaken by the network and the future need for the coordinator positions are discussed.


Plant sterols as selective DNA polymerase beta lyase inhibitors and potentiators of bleomycin cytotoxicity.
In a survey of crude plant extracts for DNA polymerase beta lyase inhibitors, the hexanes extracts of Cladogynus orientalis, Hymenache donacifolia, and Heteropsis integerrima, and the methyl ethyl ketone extract of Acacia pilispina were found to exhibit good inhibition of the dRP lyase activity of DNA polymerase beta. Bioassay-guided fractionation of these extracts led to the isolation of three DNA polymerase beta lyase inhibitory phytosterols, namely stigmasterol (1) and beta-sitosterol (2), isolated from the hexanes extracts, and beta-sitosterol-beta-d-glucoside (3), isolated from the methyl ethyl ketone extract. Compounds 1-3 inhibited the DNA polymerase beta lyase activity with IC(50) values of 43.6, 43.3, and 72.4 microM, respectively. Compounds 1 and 2 were found capable of potentiating the action of bleomycin in cultured human tumor cells, consistent with the possibility that lyase inhibitors may find utility in vivo.


Radon-222 from the island of hawaii: deep soils are more important than lava fields or volcanoes.
The mean flux of radon-222 atoms from the island of Hawaii is 0.45 atom per square centimeter per second. Lava fields occupy 50 percent of the land area, but their radon flux is only 1 percent of that from deep volcanic soils. The island yields approximately 10 curies of radon-222 per hour to the air surrounding it. The radon-222 contribuition of volcanoes is negligible.


Medication reconciliation at hospital discharge: evaluating discrepancies.
Hospital discharge is an interface of care when patients are at a high risk of medication discrepancies as they transition from hospital to home. These discrepancies are important, as they may contribute to drug-related problems, medication errors, and adverse drug events. To identify, characterize, and assess the clinical impact of unintentional medication discrepancies at hospital discharge. All consecutive general internal medicine patients admitted for at least 72 hours to a tertiary care teaching hospital were prospectively assessed. Patients were excluded if they were discharged with verbal prescriptions; died during hospitalization; or transferred from or to a nursing home, another institution, or another unit within the same hospital. The primary endpoint was to determine the number of patients with at least one unintended medication discrepancy on hospital discharge. Medication discrepancies were assessed through comparison of a best possible medication discharge list with the actual discharge prescriptions. Secondary objectives were to characterize and assess the potential clinical impact of the unintentional discrepancies. From March 14, 2006, to June 2, 2006, 430 patients were screened for eligibility; 150 patients were included in the study. Overall, 106 (70.7%) patients had at least one actual or potential unintentional discrepancy. Sixty-two patients (41.3%) had at least one actual unintentional medication discrepancy at hospital discharge and 83 patients (55.3%) had at least one potential unintentional discrepancy. The most common unintentional discrepancies were an incomplete prescription requiring clarification, which could result in a patient delay in obtaining medications (49.5%), and the omission of medications (22.9%). Of the 105 unintentional discrepancies, 31(29.5%) had the potential to cause possible or probable patient discomfort and/or clinical deterioration. Medication discrepancies occur commonly on hospital discharge. Understanding the type and frequency of discrepancies can help clinicians better understand ways to prevent them. Structured medication reconciliation may help to prevent discharge medication discrepancies.


Mapping EQ-5D utility scores from the PedsQL™ generic core scales.
The Pediatric Quality of Life Inventory™ (PedsQL™) General Core Scales (GCS) were designed to provide a modular approach to measuring health-related quality of life in healthy children, as well as those with acute and chronic health conditions, across the broadest, empirically feasible, age groups (2-18 years). Currently, it is not possible to estimate health utilities based on the PedsQL™ GCS, either directly or indirectly. This paper assesses different mapping methods for estimating EQ-5D health utilities from PedsQL™ GCS responses. This study is based on data from a cross-sectional survey conducted in four secondary schools in England amongst children aged 11-15 years. We estimate models using both direct and response mapping approaches to predict EQ-5D health utilities and responses. The mean squared error (MSE) and mean absolute error (MAE) were used to assess the predictive accuracy of the models. The models were internally validated on an estimation dataset that included complete PedsQL™ GCS and EQ-5D scores for 559 respondents. Validation was also performed making use of separate data for 337 respondents. Ordinary least squares (OLS) models that used the PedsQL™ GCS subscale scores, their squared terms and interactions (with and without age and gender) to predict EQ-5D health utilities had the best prediction accuracy. In the external validation sample, the OLS model with age and gender had a MSE (MAE) of 0.036 (0.115) compared with a MSE (MAE) of 0.036 (0.114) for the OLS model without age and gender. However, both models generated higher prediction errors for children in poorer health states (EQ-5D utility score <0.6). The response mapping models encountered some estimation problems because of insufficient data for some of the response levels. Our mapping algorithms provide an empirical basis for estimating health utilities in childhood when EQ-5D data are not available; they can be used to inform future economic evaluations of paediatric interventions. They are likely to be robust for populations comparable to our own (children aged 11-15 years in attendance at secondary school). The performance of these algorithms in childhood populations, which differ according to age or clinical characteristics to our own, remains to be evaluated.


Bioinspired assembly of small molecules in cell milieu.
Self-assembly, the autonomous organization of components to form patterns or structures, is a prevalent process in nature at all scales. Particularly, biological systems offer remarkable examples of diverse structures (as well as building blocks) and processes resulting from self-assembly. The exploration of bioinspired assemblies not only allows for mimicking the structures of living systems, but it also leads to functions for applications in different fields that benefit humans. In the last several decades, efforts on understanding and controlling self-assembly of small molecules have produced a large library of candidates for developing the biomedical applications of assemblies of small molecules. Moreover, recent findings in biology have provided new insights on the assemblies of small molecules to modulate essential cellular processes (such as apoptosis). These observations indicate that the self-assembly of small molecules, as multifaceted entities and processes to interact with multiple proteins, can have profound biological impacts on cells. In this review, we illustrate that the generation of assemblies of small molecules in cell milieu with their interactions with multiple cellular proteins for regulating cellular processes can result in primary phenotypes, thus providing a fundamentally new molecular approach for controlling cell behavior. By discussing the correlation between molecular assemblies in nature and the assemblies of small molecules in cell milieu, illustrating the functions of the assemblies of small molecules, and summarizing some guiding principles, we hope this review will stimulate more molecular scientists to explore the bioinspired self-assembly of small molecules in cell milieu.


Pregnancy and Motherhood During Surgical Training.
Although family priorities influence specialty selection and resident attrition, few studies describe resident perspectives on pregnancy during surgical training. To directly assess the resident experience of childbearing during training. A self-administered 74-question survey was electronically distributed in January 2017 to members of the Association of Women Surgeons, to members of the Association of Program Directors in Surgery listserv, and through targeted social media platforms. Surgeons who had 1 or more pregnancies during an Accreditation Council for Graduate Medical Education-accredited US general surgery residency program and completed training in 2007 or later were included. Important themes were identified using focus groups of surgeons who had undergone pregnancy during training in the past 7 years. Additional topics were identified through MEDLINE searches performed from January 2000 to July 2016 combining the keywords pregnancy, resident, attrition, and parenting in any specialty. Descriptive data on perceptions of work schedule during pregnancy, maternity leave policies, lactation and childcare support, and career satisfaction after childbirth. This study included 347 female surgeons (mean [SD] age, 30.5 [2.7] years) with 452 pregnancies. A total of 297 women (85.6%) worked an unmodified schedule until birth, and 220 (63.6%) were concerned that their work schedule adversely affected their health or the health of their unborn child. Residency program maternity leave policies were reported by 121 participants (34.9%). A total of 251 women (78.4%) received maternity leave of 6 weeks or less, and 250 (72.0%) perceived the duration of leave to be inadequate. The American Board of Surgery leave policy was cited as a major barrier to the desired length of leave by 268 of 326 respondents (82.2%). Breastfeeding was important to 329 (95.6%), but 200 (58.1%) stopped earlier than they wished because of poor access to lactation facilities and challenges leaving the operating room to express milk. Sixty-four women (18.4%) had institutional support for childcare, and 231 (66.8%) reported a desire for greater mentorship on integrating a surgical career with motherhood and pregnancy. A total of 135 (39.0%) strongly considered leaving surgical residency, and 102 (29.5%) would discourage female medical students from a surgical career, specifically because of the difficulties of balancing pregnancy and motherhood with training. The challenges of having children during surgical residency may have significant workforce implications. A deeper understanding is critical to prevent attrition and to continue recruiting talented students. This survey characterizes these issues to help design interventions to support childbearing residents.


Role of esophageal function tests in diagnosis of gastroesophageal reflux disease.
Clinicians typically make the diagnosis of gastroesophageal reflux disease (GERD) from the clinical findings and then prescribe acid-suppressing drugs. Endoscopy is usually done for persistent or severe symptoms. Esophageal function tests (EFTs: esophageal manometry and 24-hr pH monitoring) are generally reserved for patients who have the most severe disease, including those being considered for surgery. We hypothesized that EFTs are more accurate than symptoms and endoscopy in the diagnosis of GERD. This was a retrospective study undertaken in a university tertiary care center. Between October 1989 and November 1998, 822 patients with a clinical diagnosis of GERD (based on symptoms and endoscopic findings) were referred for EFTs. The patients were divided into two groups depending on whether the 24-hr pH monitoring score showed GERD (group A, GERD-; group B, GERD+). The groups were compared with respect to the incidence and severity of symptoms, presence of a hiatal hernia on barium x-rays, presence and severity of esophagitis on endoscopy, and esophageal motility. In all, 247 patients (30%) had normal reflux scores (group A, GERD-), and 575 patients (70%) had abnormal scores (Group B, GERD+). Eighty percent of group A and 88% of group B had been treated with acid-suppressing medications. The incidence of heartburn and regurgitation was similar in the two groups. Grade I-II esophagitis was diagnosed by endoscopy in 25% of group A and 35% of group B, and grade III esophagitis in 4% of group A and 11% of group B. Esophageal manometry showed that group B more often had esophageal dysmotility, consisting of a hypotensive lower esophageal sphincter and abnormal esophageal peristalsis. These data show that: (1) symptoms were unreliable for diagnosing GERD; (2) endoscopic evidence of grade I-II esophagitis was diagnostically nonspecific, and grade III was much less certain than claimed in other reports; and (3) pH monitoring identified patients with GERD and stratified them according to the severity of the disease. We conclude that esophageal manometry and pH monitoring are important in diagnosing GERD accurately. More liberal use of these tests early in patient management would avoid much improper and costly medical therapy and would help single out for special attention the patients with GERD who have the most severe disease.


Coercive sex in rural Uganda: prevalence and associated risk factors.
Despite growing recognition of the problem, relatively little is known about the issue of coercive sex in developing countries. This study presents findings from a community-based survey of 4279 reproductive-aged women in current partnerships in the Rakai District of Uganda carried out in 1998-99. One in four women in our study report having experienced coercive sex with their current male partner, with most women reporting its occasional occurrence. In a regression analysis of risk factors for coercive sex, conventional socio-demographic characteristics emerged as largely unpredictive of the risk of coercive sex. Behavioral risk factors-most notably, younger age of women at first intercourse and alcohol consumption before sex by the male partner-were strongly and positively related to the risk of coercive sex. Coercive sex was also strongly related to perceptions of the male partner's HIV risk, with women who perceived their partner to be at highest risk experiencing almost three times the risk of coercive sex relative to low risk partnerships. Supplemental analysis of 1-year longitudinal data provides additional support for the hypothesis that coercive sex may frequently be a consequence of women's perceptions of increased HIV risk for their male partner. The findings of this study are discussed in terms of the need for sexual violence prevention programs more generally in settings such as Uganda, and in terms of the possible importance of incorporating issues of sexual and physical violence within current HIV prevention programs.


Toward the training of feed-forward neural networks with the D-optimum input sequence.
The problem under consideration is to obtain a measurement schedule for training neural networks. This task is perceived as an experimental design in a given design space that is obtained in such a way as to minimize the difference between the neural network and the system being considered. This difference can be expressed in many different ways and one of them, namely, the D-optimality criterion is used in this paper. In particular, the paper presents a unified and comprehensive treatment of this problem by discussing the existing and previously unpublished properties of the optimum experimental design (OED) for neural networks. The consequences of the above properties are discussed as well. A hybrid algorithm that can be used for both the training and data development of neural networks is another important contribution of this paper. A careful analysis of the algorithm is presented and its comprehensive convergence analysis with the help of the Lyapunov method are given. The paper contains a number of numerical examples that justify the application of the OED theory for neural networks. Moreover, an industrial application example is given that deals with the valve actuator.


The variability of transfusion practice in coronary artery bypass surgery. Transfusion Medicine Academic Award Group.
We audited 540 patients undergoing elective first-time coronary artery bypass grafts at 18 institutions. The purposes of the study were to describe the variability in transfusions among institutions and to determine factors that may account for variability. Mean homologous red blood cell use per patient was 2.9(+/- 0.1) U (institutional range, 0.4 to 6.3 U). One hundred seventy-seven patients (32%) received plasma (institutional range, 0% to 97%), and 119 (22%) received platelets (institutional range, 0% to 80%). After controlling for patient and surgical practice variables, transfusion practice factors still accounted for variation in red blood cell transfusions. Variation in patients receiving plasma and platelet transfusions among institutions was determined in part by prophylactic transfusions. We conclude that blood component usage for coronary artery bypass grafts differs widely among institutions. The variability in use of these components is accounted for in part by unnecessary transfusions in otherwise routine, uncomplicated coronary artery bypass graft procedures.


EB1 and EB3 promote cilia biogenesis by several centrosome-related mechanisms.
The microtubule (MT) plus-end-tracking protein EB1 is required for assembly of primary cilia in mouse fibroblasts, but the mechanisms involved and the roles of the related proteins EB2 and EB3 in ciliogenesis are unknown. Using protein depletion experiments and expression of dominant-negative constructs we show here that EB1 and EB3, but not EB2, are required for assembly of primary cilia in cultured cells. Electron microscopy and live imaging showed that cells lacking EB1 or EB3 are defective in MT minus-end anchoring at the centrosome and/or basal body, and possess abnormally short cilia stumps surrounded by vesicles. Further, GST pull-down assays, mass spectrometry and immunoprecipitation indicated that EB1 and EB3 interact with proteins implicated in MT minus-end anchoring or vesicular trafficking to the cilia base, suggesting that EB1 and EB3 promote ciliogenesis by facilitating such trafficking. In addition, we show that EB3 is localized to the tip of motile cilia in bronchial epithelial cells and affects the formation of centriole-associated rootlet filaments. Collectively, our findings indicate that EBs affect biogenesis of cilia by several centrosome-related mechanisms and support the idea that different EB1-EB3 dimer species have distinct functions within cells.


Assessment of Duration and Effects of 3 vs 6 Months of Adjuvant Chemotherapy in High-Risk Stage II Colorectal Cancer: A Subgroup Analysis of the TOSCA Randomized Clinical Trial.
The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage III colon cancer. The utility remains unknown. To assess the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer enrolled in the TOSCA trial. The TOSCA study was a noninferiority phase 3 randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian centers. Included patients had resected colorectal cancer located 12 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. In this preplanned study assessing the per-protocol population, 5-year relapse-free survival was evaluated in 1254 patients with high-risk stage II resected colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Patients were originally randomized (1:1) in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. A hazard ratio of at least 1.2 between the 3-month and 6-month chemotherapy groups was set to reject the null hypothesis of noninferiority. Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women [45.1%]) with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients (76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 1.41 (95% CI, 1.05-1.89; P = .86 for noninferiority). For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm; 95% CI, -6.28% to 7.80%), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). Nevertheless, the test for an interaction between duration and regimen was not statistically significant. Neurotoxicity was approximately 5 times lower in the shorter duration arm than in the longer duration arm. In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. ClinicalTrials.gov Identifier: NCT0064660.


Age-related functional and structural retinal modifications in the Igf1-/- null mouse.
Mutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic neurosensorial deafness. To understand the precise role of IGF-I in retinal physiology, we have studied the morphology and electrophysiology of the retina of the Igf1(-/-) mice in comparison with that of the Igf1(+/-) and Igf1(+/+) animals during aging. Serological concentrations of IGF-I, glycemia and body weight were determined in Igf1(+/+), Igf1(+/-) and Igf1(-/-) mice at different times up to 360days of age. We have analyzed hearing by recording the auditory brainstem responses (ABR), the retinal function by electroretinographic (ERG) responses and the retinal morphology by immunohistochemical labeling on retinal preparations at different ages. IGF-I levels are gradually reduced with aging in the mouse. Deaf Igf1(-/-) mice had an almost flat scotopic ERG response and a photopic ERG response of very small amplitude at postnatal age 360days (P360). At the same age, Igf1(+/-) mice still showed both scotopic and photopic ERG responses, but a significant decrease in the ERG wave amplitudes was observed when compared with those of Igf1(+/+) mice. Immunohistochemical analysis showed that P360 Igf1(-/-) mice suffered important structural modifications in the first synapse of the retinal pathway, that affected mainly the postsynaptic processes from horizontal and bipolar cells. A decrease in bassoon and synaptophysin staining in both rod and cone synaptic terminals suggested a reduced photoreceptor output to the inner retina. Retinal morphology of the P360 Igf1(+/-) mice showed only small alterations in the horizontal and bipolar cell processes, when compared with Igf1(+/+) mice of matched age. In the mouse, IGF-I deficit causes an age-related visual loss, besides a congenital deafness. The present results support the use of the Igf1(-/-) mouse as a new model for the study of human syndromic deaf-blindness.


Small bowel absorption of sulfasalazine and its hepatic metabolism in human beings, cats, and rats.
To elucidate the role of the small bowel and liver in sulfasalazine (SASP) metabolism, we performed studies in patients, cats, and rats. The role of the small bowel in absorption and metabolism of SASP was determined by the amount of administered SASP excreted in ileostomy effluents, and the concentration of serum and urinary SASP and its metabolites, sulfapyridine and 5-amino salicylic acid. Seventy-five to ninety percent of the drug was excreted in ileostomy effluents of 6 patients as SASP, and only 5% of the dose was sulfapyridine. In cats, ileostomy and portal venous cannulations revealed that 20--30% of administered SASP is absorbed from the small bowel without being metabolized. The role of the liver in SASP metabolism was established in vivo and in vitro. SASP metabolites were measured in bile, serum, and urine of 2 patients with a choledochal T-tube and in serum and bile in six cats and four rats. Twenty to fifty percent of the absorbed drug was excreted in bile as SASP and no detectable sulfapyridine appeared in the bile. SASP concentration in peripheral blood and urine ranged between 3 and 12 microgram/ml, and no significant amount of sulfapyridine metabolites were detected in the bile, serum, or urine of animals with an ileostomy. In vitro experiments with liver from cats and rats showed nearly complete reduction of SASP into metabolites. These studies reveal that SASP is not metabolized by the liver in vivo, and after absorption from the small bowel, 25--50% of the SASP is excreted unchanged in the bile, and the rest enters the circulation. Implications of these results in the treatment of patients with Crohn's disease of the small intestine are discussed.


Sensitivity of fluid detection in patients with neovascular amd using spectral domain optical coherence tomography high-definition line scans.
To determine the sensitivity of the Cirrus high-definition (HD) 5-line raster scans for detecting retinal fluid in neovascular age-related macular degeneration when using the spectral domain optical coherence tomography macular cubes as a gold standard. Patients were retrospectively identified from their initial follow-up visit after being newly diagnosed with neovascular age-related macular degeneration in at least one eye. Patients were imaged with Cirrus spectral domain optical coherence tomography using the 512 × 128 macular cube scan and HD 5-line raster scan settings. Patients with other diseases that cause subretinal or intraretinal fluid, or who had an epiretinal membrane causing macular traction were excluded from the analysis. We recorded the presence or absence of subretinal or intraretinal fluid in the macular cube and on the HD 5-line raster scans. Seventy-nine patients met the study requirements. Of the 63 patients who had fluid present on the macular cube, 1 did not seem to have fluid on the HD 5-line raster scans. Taking the macular cube as a gold standard, the sensitivity of the HD 5-line raster scans for detecting retinal fluid in this cohort was 98.4%. The Cirrus HD 5-line raster scans have a high sensitivity for detecting fluid in the macular cube in patients with neovascular age-related macular degeneration.


Control mechanism of lymphocyte traffic. Altered migration of 51Cr-labeled mouse lymph node cells pretreated in vitro with phospholipases.
Glycoproteins have so far been the only surface components thought to be of importance in the process of recognition between circulating lymphocytes and endothelial cells of the lymph node post-capillary venules and thus in the control of lymphocyte traffic. In this paper the effect of in vitro treatment of 51Cr-labeled mouse lymph node cells with phospholipases (PL) (A and C) on their migration into syngeneic recipients was investigated. PL-A and PL-C treated cells migrated differently from control (untreated) cells. Diminished numbers of PL-A-treated lymphocytes were found in the lymph nodes at 1, 6 and 24 h after cell transfer with a simultaneous increase in the lungs at 1 h, and spleen at 6 h after transfer. PL-C-treated cells remained in the blood longer than untreated cells. We conclude that factors other than the integrity of surface glycoproteins are involved in the control of lymphocyte traffic. The roles played by cell adhesion, in particular cell-to-cell interactions in regulating the rate of cell migration, are discussed.


Towards the identification of type II secretion signals in a nonacylated variant of pullulanase from Klebsiella oxytoca.
Pullulanase (PulA) from the gram-negative bacterium Klebsiella oxytoca is a 116-kDa surface-anchored lipoprotein of the isoamylase family that allows growth on branched maltodextrin polymers. PulA is specifically secreted via a type II secretion system. PelBsp-PulA, a nonacylated variant of PulA made by replacing the lipoprotein signal peptide (sp) with the signal peptide of pectate lyase PelB from Erwinia chrysanthemi, was efficiently secreted into the medium. Two 80-amino-acid regions of PulA, designated A and B, were previously shown to promote secretion of beta-lactamase (BlaM) and endoglucanase CelZ fused to the C terminus. We show that A and B fused to the PelB signal peptide can also promote secretion of BlaM and CelZ but not that of nuclease NucB or several other reporter proteins. However, the deletion of most of region A or all of region B, either individually or together, had only a minor effect on PelBsp-PulA secretion. Four independent linker insertions between amino acids 234 and 324 in PelBsp-PulA abolished secretion. This part of PulA, region C, could contain part of the PulA secretion signal or be important for its correct presentation. Deletion of region C abolished PelBsp-PulA secretion without dramatically affecting its stability. PelBsp-PulA-NucB chimeras were secreted only if the PulA-NucB fusion point was located downstream from region C. The data show that at least three regions of PulA contain information that influences its secretion, depending on their context, and that some reporter proteins might contribute to the secretion of chimeras of which they are a part.


National Institutes of Health Pathways to Prevention Workshop: Advancing Research to Prevent Youth Suicide.
The National Institutes of Health (NIH) Pathways to Prevention Workshop "Advancing Research to Prevent Youth Suicide" was cosponsored by the NIH Office of Disease Prevention, National Institute of Mental Health, National Institute on Drug Abuse, and National Center for Complementary and Integrative Health. A multidisciplinary working group developed the agenda, and an evidence-based practice center prepared an evidence report that addressed data systems relevant to suicide prevention efforts through a contract with the Agency for Healthcare Research and Quality. During the workshop, experts discussed the evidence and participants commented during open forums. After considering the data from the evidence report, expert presentations, and public comments, an independent panel prepared a draft report that was posted on the NIH Office of Disease Prevention Web site for 5 weeks for public comment. This abridged version of the final report provides a road map for optimizing youth suicide prevention efforts by highlighting strategies for guiding the next decade of research in this area. These strategies include recommendations for improving data systems, enhancing data collection and analysis methods, and strengthening the research and practice community.


PCR Based Fecal Pathogen Panel Testing Should Be Interpreted with Caution at Diagnosis of Pediatric Inflammatory Bowel Diseases.
Pediatric inflammatory bowel disease (IBD) is in the differential diagnosis for children presenting with chronic diarrhea. During evaluation, stool studies are typically obtained to evaluate for an infectious source, and stool culture has been the conventional testing modality for bacterial pathogens. Recently, there has been increased utilization of molecular testing for enteric pathogens, including multiplex PCR. While these tests are highly sensitive for the detection of diverse pathogens, the clinical significance of positive results may not always be clear. We report two pediatric cases presenting with diarrhea and positive enteric pathogen (Biofire FilmArray GI Panel) PCR panels, but ultimately diagnosed with IBD. In one case, the PCR test results delayed diagnosis; in the other, they were ignored without any clinical consequence. In children with symptoms concerning for IBD, endoscopic evaluation should not be delayed based on positive molecular testing alone, especially when parallel culture for the same organism is negative.


Comparative transcriptome sequencing of germline and somatic tissues of the Ascaris suum gonad.
Ascaris suum (large roundworm of pigs) is a parasitic nematode that causes substantial losses to the meat industry. This nematode is suitable for biochemical studies because, unlike C. elegans, homogeneous tissue samples can be obtained by dissection. It has large sperm, produced in great numbers that permit biochemical studies of sperm motility. Widespread study of A. suum would be facilitated by more comprehensive genome resources and, to this end, we have produced a gonad transcriptome of A. suum. Two 454 pyrosequencing runs generated 572,982 and 588,651 reads for germline (TES) and somatic (VAS) tissues of the A. suum gonad, respectively. 86% of the high-quality (HQ) reads were assembled into 9,955 contigs and 69,791 HQ reads remained as singletons. 2.4 million bp of unique sequences were obtained with a coverage that reached 16.1-fold. 4,877 contigs and 14,339 singletons were annotated according to the C. elegans protein and the Kyoto Encyclopedia of Genes and Genomes (KEGG) protein databases. Comparison of TES and VAS transcriptomes demonstrated that genes participating in DNA replication, RNA transcription and ubiquitin-proteasome pathways are expressed at significantly higher levels in TES tissues than in VAS tissues. Comparison of the A. suum TES transcriptome with the C. elegans microarray dataset identified 165 A. suum germline-enriched genes (83% are spermatogenesis-enriched). Many of these genes encode serine/threonine kinases and phosphatases (KPs) as well as tyrosine KPs. Immunoblot analysis further suggested a critical role of phosphorylation in both testis development and spermatogenesis. A total of 2,681 A. suum genes were identified to have associated RNAi phenotypes in C. elegans, the majority of which display embryonic lethality, slow growth, larval arrest or sterility. Using deep sequencing technology, this study has produced a gonad transcriptome of A. suum. By comparison with C. elegans datasets, we identified sets of genes associated with spermatogenesis and gonad development in A. suum. The newly identified genes encoding KPs may help determine signaling pathways that operate during spermatogenesis. A large portion of A. suum gonadal genes have related RNAi phenotypes in C. elegans and, thus, might be RNAi targets for parasite control.


Disability status differentials across fifteen Asian and Pacific Islander groups and the effect of nativity and duration of residence in the U.S.
This study examines disparities in disability status across 15 Asian and Pacific Islander American (API) subpopulations and how nativity and duration in the U.S. influence these differences. Employing three disability questions (work limitations, mobility limitations, and self-care limitations) from the 1990 PUMS, the authors find substantial heterogeneity in disability status across API subgroups: while Japanese American adults have the most favorable outcomes, Other Southeast Asian adults (Laotians, Hmong, and Cambodians), followed by Vietnamese and Pacific Islander adults, suffer from a high risk of disabilities. Many of the disparities in disability status across API subpopulation adults are attributable to differentials in demographic characteristics and SES. The inclusion of an interaction term of age and nativity/duration of residence in the U.S. in multivariate regression analyses demonstrates that the effect of nativity/duration plays a different role across age, net of demographic, and SES risk factors. The overall findings are also consistent with previous studies on the relationship between immigrant health and nativity/duration. That is, immigrants with short duration in the U.S. have superior health status, measured by risk of disability, than longer-term immigrants and their U.S.-born counterparts.


Extensive pollen dispersal in a bird-pollinated shrub, Calothamnus quadrifidus, in a fragmented landscape.
Pollen dispersal was investigated in six populations of Calothamnus quadrifidus, a bird-pollinated shrub in the fragmented agricultural region of southern Western Australia. Paternity analysis using six microsatellite loci identified a pollen source within populations for 67% of seedlings, and the remainder were assumed to have arisen from pollen sources outside the populations. Outcrossing was variable, ranging from 5% to 82%, and long-distance pollen dispersal was observed in all populations with up to 43% of pollen sourced from outside the populations over distances of up to 5 km. This extensive pollen immigration was positively associated with population size but not isolation. Comparison of two populations of similar size but different density showed greater internal pollination and less selfing in the denser population, suggesting an influence of density on pollinator behaviour. The study revealed extensive long-distance pollen dispersal for C. quadrifidus within this fragmented agricultural landscape and highlighted the interaction between reserve populations and isolated road verge remnants in maintaining genetic connectivity at the landscape scale.


No genetic evidence for involvement of Deltaretroviruses in adult patients with precursor and mature T-cell neoplasms.
The Deltaretrovirus genus comprises viruses that infect humans (HTLV), various simian species (STLV) and cattle (BLV). HTLV-I is the main causative agent in adult T-cell leukemia in endemic areas and some of the simian T-cell lymphotropic viruses have been implicated in the induction of malignant lymphomas in their hosts. BLV causes enzootic bovine leukosis in infected cattle or sheep. During the past few years several new Deltaretrovirus isolates have been described in various primate species. Two new HTLV-like viruses in humans have recently been identified and provisionally termed HTLV-III and HTLV-IV. In order to identify a broad spectrum of Deltaretroviruses by a single PCR approach we have established a novel consensus PCR based on nucleotide sequence data obtained from 42 complete virus isolates (HTLV-I/-II, STLV-I/-II/-III, BLV). The primer sequences were based on highly interspecies-conserved virus genome regions. We used this PCR to detect Deltaretroviruses in samples from adult patients with a variety of rare T-cell neoplasms in Germany. The sensitivity of the consensus PCR was at least between 10-2 and 10-3 with 100% specificity as demonstrated by serial dilutions of cell lines infected with either HTLV-I, HTLV-II or BLV. Fifty acute T-cell lymphoblastic leukemia (T-ALL) samples and 33 samples from patients with various rare mature T-cell neoplasms (T-PLL, Sézary syndrome and other T-NHL) were subsequently investigated. There were no cases with HTLV-I, HTLV-II or any other Deltaretroviruses. The results rule out a significant involvement of HTLV-I or HTLV-II in these disease entities and show that other related Deltaretroviruses are not likely to be involved. The newly established Deltaretrovirus PCR may be a useful tool for identifying new Deltaretroviruses.


Nephroprotective potential of Bacopa monniera on hypercholesterolemia induced nephropathy via the NO signaling pathway.
Bacopa monniera L. (Scrophulariaceae) is used as a traditional medicine in India for various ailments such as epilepsy, mental disorders, and also as a cardio-tonic. However, its nephroprotective role is still unknown. The present study assesses the modulatory impact of the alcoholic (ethanol) extract of Bacopa monniera (AEBM) on renal oxido-lipidemic stress in hypercholesterolemic rats. B. monniera (1 kg) was extracted with 90% ethanol, filtered, and dried (52 g). Group-I rats as control, Group-II rats fed with a hypercholesterolemic diet (HCD) for 45 d [4% cholesterol and 1% cholic acid], Group-III rats fed with HCD for 45 d + AEBM (40 mg/kg, body weight) for last 30 d, and Group-IV AEBM alone rats. Blood and kidney were removed to analyze lipid, antioxidant status, and histological analysis. The levels of total cholesterol (TC), triacylglycerol (TG), phospholipids (PLs), renal functional parameters (urea, creatinine, and uric acid), and lipid peroxidation (LPO) products were significantly attenuated (p < 0.01) in AEBM-treated hypercholesterolemic rats. Activities of both enzymic (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR)) and non-enzymic antioxidant (GSH, Vit-C, and Vit-E) were significantly increased (p < 0.01), on supplementation with AEBM. Administration with AEBM the mRNA levels of eNOS and iNOS genes was significantly up-regulated and down-regulated (p < 0.01). Histomorphological observations also evidenced that AEBM effectively protects the kidney from hypercholesterolemia-mediated oxido-lipidemic damage. From this study, we hypothesized that AEBM can act as renoprotective agent by attenuating the renal oxido-lipidemic stress via regulating NOS level and thereby protects the nephron in hypercholesterolemic rats.


Multiple-image encryption and authentication with sparse representation by space multiplexing.
A multiple-image encryption and authentication approach by space multiplexing has been proposed. The redundant spaces in the previous security systems employing sparse representation strategy are optimized. With the proposal the information of multiple images can be integrated into a synthesized ciphertext that is convenient for storage and transmission. Only when all the keys are correct can the information of the primary images be authenticated. Computer simulation results have demonstrated that the proposed method is feasible and effective. Moreover, the proposal is also proved to be robust against occlusion and noise attacks.


Melting transition in lipid vesicles functionalised by mobile DNA linkers.
We study phase behaviour of lipid-bilayer vesicles functionalised by ligand-receptor complexes made of synthetic DNA by introducing a modelling framework and a dedicated experimental platform. In particular, we perform Monte Carlo simulations that combine a coarse grained description of the lipid bilayer with state of art analytical models for multivalent ligand-receptor interactions. Using density of state calculations, we derive the partition function in pairs of vesicles and compute the number of ligand-receptor bonds as a function of temperature. Numerical results are compared to microscopy and fluorimetry experiments on large unilamellar vesicles decorated by DNA linkers carrying complementary overhangs. We find that vesicle aggregation is suppressed when the total number of linkers falls below a threshold value. Within the model proposed here, this is due to the higher configurational costs required to form inter-vesicle bridges as compared to intra-vesicle loops, which are in turn related to membrane deformability. Our findings and our numerical/experimental methodologies are applicable to the rational design of liposomes used as functional materials and drug delivery applications, as well as to study inter-membrane interactions in living systems, such as cell adhesion.


Hybrid methods combining atmospheric reanalysis data and a parametric typhoon model to hindcast storm surges in Tokyo Bay.
Reanalysis data and a parametric typhoon model formula are often used to prepare wind and pressure fields for storm surge hindcasting. However, their optimum selection and usage have not been well established. To enhance the accuracy of wind and pressure fields, two hybrid methods were proposed by applying a parametric typhoon model of Mitsuta-Fujii's formula, which is determined from the typhoon center to a certain radius of Rb, and then switching to the reanalysis data of ERA-Interim in the outer region through the interpolated transition bandwidth of Wb. In hybrid model I, Rb and Wb were fixed because the time-varying radius of the maximum wind speed was determined by the typhoon formula. In hybrid model II, these parameters were determined to minimize the mean difference between the reanalysis data and the fields obtained by typhoon formula in the transition band at each time step of the typhoon track. The hindcasting of eight significant typhoon events approaching Tokyo Bay was performed. This validated the proposed methods in comparison with the observed storm surge anomalies. Both models performed satisfactorily. Hybrid model II was found to be superior in terms of the balance of accuracy and preparation cost.


Associations between family income and children's physical fitness and obesity in California, 2010-2012.
Socioeconomic status may influence childhood obesity prevalence and children's fitness level. The purpose of this study was to assess the association between family income and children's physical fitness level and obesity prevalence for 8 racial/ethnic groups. Data for 1,617,400 fifth-, seventh-, and ninth-grade children who took a physical fitness test from 2010 through 2012 in California were used in this cross-sectional study. Multiple linear and log-binomial regressions were used to test whether low family income (as indicated by eligibility for National School Lunch Program) was associated with physical fitness level or obesity prevalence. Differences were tested by race/ethnicity while adjusting for age and sex. Fitness score was measured on a scale from 0 (least healthy) to 6 (most healthy). Average fitness score was 4.45 (standard deviation, 1.47). Prevalence of obesity was 20.3%, and 56% of children were classified as having lower family income. Lower family income (vs higher) was associated with lower fitness score (coefficient = -0.57; 95% confidence interval [CI], -0.62 to -0.53). Lower-income children had higher prevalence of obesity (relative risk = 1.81; 95% CI, 1.72-1.89) compared with higher-income children. These inverse associations were seen among American Indian, Asian, Pacific Islander, Filipino, Hispanic/Latino, African American, and white children and among children who were identified as being of 2 or more races/ethnicities. Children with lower family incomes tend to have less healthy physical fitness status and have higher risk of obesity than children with higher family incomes. This information can be used to help set policies and provide programs aimed at improving fitness and decreasing obesity risk among low-income children.