Spatial and quantitative assessment of wind erosion from adjacent dunes with different surface cover ratios.
Direct measurements, models, and risk maps play significant roles in assessment and monitoring of wind erosion cases. Although active and passive traps allow researchers to measure point sediment transports directly, it is also possible to make geostatistical analysis of wind erosion with grid and random sampling at multiple points. Geostatistical models can be used in multi-sample eolian researches to improve model success and update model parameters. The present study was conducted for case-based geostatistical analysis of sediment transport rates (STRs) over two adjacent dunes (plot A and B) with different vegetation cover rates between 22 May and 15 June 2011. The plot A has a vegetative cover ratio of 30%, while the plot B has a vegetation cover ratio of 2% and sand content of the plots is 88%. Actual mass transports were measured with BEST sediment traps. A total of 19 BEST sediment trap assemblies were placed randomly over the plot A and 21 were placed over the plot B. A climate station was installed over the research site to record climate data throughout the experimental period. There were two wind erosion cases during the research period. U test indicated that differences in sediment transport rates of the plots for each case were significant (p < 0.00). Spatial analyses of STRs (kg m-1 h-1) also exhibited case-based differences. While nugget effect was observed in case 1 of the plot B, the other case in both plots were modeled with spherical model. Maximum likelihood distances in plot A and B were respectively identified as 61 m and 1 m in the first case and as 13 m and 30 m in the second case. Total mass transport was measured as 112 kg m-1 in plot A and as 2162 kg m-1 in plot B. Consequently, it was found that 30% vegetation cover reduced the total mass transport dramatically.


Mitochondrial DNA diversity in Mennonite communities from the midwestern United States.
We examined mitochondrial DNA (mtDNA) variation in six Mennonite communities from Kansas (Goessel, Lone Tree, Garden View, Meridian, and Garden City) and Nebraska (Henderson) to determine their genetic structure and its relationship to population history. Mitochondrial DNA haplogroup and haplotype information were obtained from blood samples from 118 individuals. Molecular genetic variation was analyzed using diversity measures, neutrality test statistics, spatial analysis of molecular variance (SAMOVA), and multidimensional scaling plots. The Mennonite samples exhibited eight western European mtDNA haplogroups: H, HV0, I, J, K, T, U, and X. Comparable to other populations of European descent, haplogroup H was the most frequent in all six communities and ranged from 35% in Lone Tree to 75% in Old Order Mennonites from Garden City. Fifty-eight different mtDNA haplotypes were found in these groups with only one shared among all six populations. Haplotype diversities varied from 0.81 in Goessel to 0.96 in Henderson and Garden View. Multivariate statistical analysis of these populations indicates that these Anabaptist communities formed new congregations by fissioning along familial lines. Population subdivision of these communities into congregations supports previously documented patterns of fission-fusion. These haploid molecular data provide a more accurate reflection of biological relationships between midwestern Mennonite communities than evidence based on classical genetic markers.


High-Temperature Core Flood Investigation of Nanocellulose as a Green Additive for Enhanced Oil Recovery.
Recent studies have discovered a substantial viscosity increase of aqueous cellulose nanocrystal (CNC) dispersions upon heat aging at temperatures above 90 °C. This distinct change in material properties at very low concentrations in water has been proposed as an active mechanism for enhanced oil recovery (EOR), as highly viscous fluid may improve macroscopic sweep efficiencies and mitigate viscous fingering. A high-temperature (120 °C) core flood experiment was carried out with 1 wt. % CNC in low salinity brine on a 60 cm-long sandstone core outcrop initially saturated with crude oil. A flow rate corresponding to 24 h per pore volume was applied to ensure sufficient viscosification time within the porous media. The total oil recovery was 62.2%, including 1.2% oil being produced during CNC flooding. Creation of local log-jams inside the porous media appears to be the dominant mechanism for additional oil recovery during nano flooding. The permeability was reduced by 89.5% during the core flood, and a thin layer of nanocellulose film was observed at the inlet of the core plug. CNC fluid and core flood effluent was analyzed using atomic force microscopy (AFM), particle size analysis, and shear rheology. The effluent was largely unchanged after passing through the core over a time period of 24 h. After the core outcrop was rinsed, a micro computed tomography (micro-CT) was used to examine heterogeneity of the core. The core was found to be homogeneous.


Multiwavelength phase unwrapping and aberration correction using depth filtered digital holography.
In this Letter, we present a new approach to processing data from a standard spectral domain optical coherence tomography (OCT) system using depth filtered digital holography (DFDH). Intensity-based OCT processing has an axial resolution of the order of a few micrometers. When the phase information is used to obtain optical path length differences, subwavelength accuracy can be achieved, but this limits the resolvable step heights to half of the wavelength of the system. Thus there is a metrology gap between phase- and intensity-based methods. Our concept addresses this metrology gap by combining DFHD with multiwavelength phase unwrapping. Additionally, the measurements are corrected for aberrations. Here, we present proof of concept measurements of a structured semiconductor sample.


Half-life extension and non-human primate pharmacokinetic safety studies of i-body AD-114 targeting human CXCR4.
Single domain antibodies that combine antigen specificity with high tissue penetration are an attractive alternative to conventional antibodies. However, rapid clearance from the bloodstream owing to their small size can be a limitation of therapeutic single domain antibodies. Here, we describe and evaluate the conjugation of a single domain i-body, AD-114, which targets CXCR4, to a panel of half-life extension technologies including a human serum albumin-binding peptide, linear and branched PEG, and PASylation (PA600). The conjugates were assessed in murine, rat and cynomolgus monkey pharmacokinetic studies and showed that the branched PEG was most effective at extending circulating half-life in mice; however, manufacturing limitations of PEGylated test material precluded scale-up and assessment in larger animals. PA600, by comparison, was amenable to scale-up and afforded considerable half-life improvements in mice, rats and cynomolgus monkeys. In mice, the circulating half-life of AD-114 was extended from 0.18 h to 7.77 h following conjugation to PA600, and in cynomolgus monkeys, the circulating half-life of AD-114-PA600 was 24.27 h. AD-114-PA600 was well tolerated in cynomolgus monkeys at dose rates up to 100 mg/kg with no mortalities or drug-related clinical signs.


TGF-β type II receptor expression in thymic epithelial cells inhibits the development of Hassall's corpuscles in mice.
Hassall's corpuscles are concentric clusters of keratinized epithelial cells located within the thymic medulla of humans and guinea pigs but are scant in mouse and rat. They are considered to be the terminally differentiated stages of medullary thymic epithelial cells (mTECs) but the mechanisms of their origin are unclear. We have previously deleted the TGF-β type II receptor (TGFβRII) specifically in mouse TECs and reported that these mice have mitigated thymic involution and exhibit earlier reconstitution post-irradiation. In this study, we analyzed the differentiation of mTECs in the TGFβRII-knockout mice. Interestingly, the TGFβRII-knockout mice display enhanced development of Hassall's corpuscles. The expression of Aire, stromal-cell-derived factor 1 and thymic stromal lymphopoietin in the thymi of the TGFβRII-knockout mice was similar to that previously reported for the human thymus. In addition, the putative epithelial progenitor markers MTS20 and MTS24 labeled Hassall's corpuscles in normal mice, but the extent and intensity of this staining were greatly enhanced in Hassall's corpuscles of the TGFβRII-knockout mice. The phosphorylated forms of ERK and JNK were also found in Hassall's corpuscles of the TGFβRII-knockout mice. Taken together, we suggest that TGFβRII-mediated signaling in TECs inhibits their development into Hassall's corpuscles in mice.


Surface proteome analysis and characterization of surface cell antigen (Sca) or autotransporter family of Rickettsia typhi.
Surface proteins of the obligate intracellular bacterium Rickettsia typhi, the agent of murine or endemic typhus fever, comprise an important interface for host-pathogen interactions including adherence, invasion and survival in the host cytoplasm. In this report, we present analyses of the surface exposed proteins of R. typhi based on a suite of predictive algorithms complemented by experimental surface-labeling with thiol-cleavable sulfo-NHS-SS-biotin and identification of labeled peptides by LC MS/MS. Further, we focus on proteins belonging to the surface cell antigen (Sca) autotransporter (AT) family which are known to be involved in rickettsial infection of mammalian cells. Each species of Rickettsia has a different complement of sca genes in various states; R. typhi, has genes sca1 thru sca5. In silico analyses indicate divergence of the Sca paralogs across the four Rickettsia groups and concur with previous evidence of positive selection. Transcripts for each sca were detected during infection of L929 cells and four of the five Sca proteins were detected in the surface proteome analysis. We observed that each R. typhi Sca protein is expressed during in vitro infections and selected Sca proteins were expressed during in vivo infections. Using biotin-affinity pull down assays, negative staining electron microscopy, and flow cytometry, we demonstrate that the Sca proteins in R. typhi are localized to the surface of the bacteria. All Scas were detected during infection of L929 cells by immunogold electron microscopy. Immunofluorescence assays demonstrate that Scas 1-3 and 5 are expressed in the spleens of infected Sprague-Dawley rats and Scas 3, 4 and 5 are expressed in cat fleas (Ctenocephalides felis). Sca proteins may be crucial in the recognition and invasion of different host cell types. In short, continuous expression of all Scas may ensure that rickettsiae are primed i) to infect mammalian cells should the flea bite a host, ii) to remain infectious when extracellular and iii) to infect the flea midgut when ingested with a blood meal. Each Sca protein may be important for survival of R. typhi and the lack of host restricted expression may indicate a strategy of preparedness for infection of a new host.


Recent Developments on the Synthesis and Bioactivity of Ilamycins/Rufomycins and Cyclomarins, Marine Cyclopeptides That Demonstrate Anti-Malaria and Anti-Tuberculosis Activity.
Ilamycins/rufomycins and cyclomarins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclomarins are also very potent inhibitors of Plasmodium falciparum. Biosynthetically the cyclopeptides are obtained via a heptamodular nonribosomal peptide synthetase (NRPS) that directly incorporates some of the nonproteinogenic amino acids. A wide range of derivatives can be obtained by fermentation, while bioengineering also allows the mutasynthesis of derivatives, especially cyclomarins. Other derivatives are accessible by semisynthesis or total syntheses, reported for both natural product classes. The anti-tuberculosis (anti-TB) activity results from the binding of the peptides to the N-terminal domain (NTD) of the bacterial protease-associated unfoldase ClpC1, causing cell death by the uncontrolled proteolytic activity of this enzyme. Diadenosine triphosphate hydrolase (PfAp3Aase) was found to be the active target of the cyclomarins in Plasmodia. SAR studies with natural and synthetic derivatives on ilamycins/rufomycins and cyclomarins indicate which parts of the molecules can be simplified or otherwise modified without losing activity for either target. This review examines all aspects of the research conducted in the syntheses of these interesting cyclopeptides.


Microbial Beta Glucosidase Enzymes: Recent Advances in Biomass Conversation for Biofuels Application.
The biomass to biofuels production process is green, sustainable, and an advanced technique to resolve the current environmental issues generated from fossil fuels. The production of biofuels from biomass is an enzyme mediated process, wherein β-glucosidase (BGL) enzymes play a key role in biomass hydrolysis by producing monomeric sugars from cellulose-based oligosaccharides. However, the production and availability of these enzymes realize their major role to increase the overall production cost of biomass to biofuels production technology. Therefore, the present review is focused on evaluating the production and efficiency of β-glucosidase enzymes in the bioconversion of cellulosic biomass for biofuel production at an industrial scale, providing its mechanism and classification. The application of BGL enzymes in the biomass conversion process has been discussed along with the recent developments and existing issues. Moreover, the production and development of microbial BGL enzymes have been explained in detail, along with the recent advancements made in the field. Finally, current hurdles and future suggestions have been provided for the future developments. This review is likely to set a benchmark in the area of cost effective BGL enzyme production, specifically in the biorefinery area.


Micro-spectroscopy on silicon wafers and solar cells.
Micro-Raman (μRS) and micro-photoluminescence spectroscopy (μPLS) are demonstrated as valuable characterization techniques for fundamental research on silicon as well as for technological issues in the photovoltaic production. We measure the quantitative carrier recombination lifetime and the doping density with submicron resolution by μPLS and μRS. μPLS utilizes the carrier diffusion from a point excitation source and μRS the hole density-dependent Fano resonances of the first order Raman peak. This is demonstrated on micro defects in multicrystalline silicon. In comparison with the stress measurement by μRS, these measurements reveal the influence of stress on the recombination activity of metal precipitates. This can be attributed to the strong stress dependence of the carrier mobility (piezoresistance) of silicon. With the aim of evaluating technological process steps, Fano resonances in μRS measurements are analyzed for the determination of the doping density and the carrier lifetime in selective emitters, laser fired doping structures, and back surface fields, while μPLS can show the micron-sized damage induced by the respective processes.


Mechanical forces used for cell fractionation can create hybrid membrane vesicles.
The ability to understand the inner works of the cell requires methods for separation of intracellular membrane-enclosed compartments. Disruption of the plasma membrane (PM) by mechanical forces to investigate the content of the cell is common practice. Whether vesicles or membranes of different sources can fuse as a result is unclear. If such contamination occurs, conclusions based on these techniques should consider these. Utilizing an endoplasmic reticulum (ER) membrane marker and a PM marker, we were able to detect the source of membranes following the breakup of cells using flow cytometry and immuno Electron Microscopy (immuno EM). Fractionation processes produced a small fraction of new membrane entities from two distinctively different origins generated during the initial disruption steps in a temperature independent manner, stressing that defining organelles or intrinsic fusion events based on such procedures and markers are valid when exceeding the small number of vesicles fused during the fractionation process.


Formation of the prebiotic molecule NH2CHO on astronomical amorphous solid water surfaces: accurate tunneling rate calculations.
Investigating how formamide forms in the interstellar medium is a hot topic in astrochemistry, which can contribute to our understanding of the origin of life on Earth. We have constructed a QM/MM model to simulate the hydrogenation of isocyanic acid on amorphous solid water surfaces to form formamide. The binding energy of HNCO on the ASW surface varies significantly between different binding sites, we found values between ∼0 and 100 kJ mol-1. The barrier for the hydrogenation reaction is almost independent of the binding energy, though. We calculated tunneling rate constants of H + HNCO → NH2CO at temperatures down to 103 K combining QM/MM with instanton theory. Tunneling dominates the reaction at such low temperatures. The tunneling reaction is hardly accelerated by the amorphous solid water surface compared to the gas phase for this system, even though the activation energy of the surface reaction is lower than the one of the gas-phase reaction. Both the height and width of the barrier affect the tunneling rate in practice. Strong kinetic isotope effects were observed by comparing to rate constants of D + HNCO → NHDCO. At 103 K we found a KIE of 231 on the surface and 146 in the gas phase. Furthermore, we investigated the gas-phase reaction NH2 + H2CO → NH2CHO + H and found it unlikely to occur at cryogenic temperatures. The data of our tunneling rate constants are expected to significantly influence astrochemical models.


Density functional theory simulation of titanium migration and reaction with oxygen in the early stages of oxidation of equiatomic NiTi alloy.
The biocompatibility of NiTi shape memory alloys (SMA) has made possible applications in self-expandable cardio-vascular stents, stone extraction baskets, catheter guide wires and other invasive and minimally invasive biomedical devices. The NiTi intermetallic alloy spontaneously forms a thin passive layer of TiO(2), which provides its biocompatibility. The oxide layer is thought to form as the Ti in the alloy surface reacts with oxygen, resulting in a depletion of Ti in the subsurface region - experimental evidence indicates formation of a Ni-rich layer below the oxide film. In this paper, we study the initial stages of oxide growth on the (110) surface of the NiTi alloy to understand the formation of alloy/oxide interface. We initially adsorb atomic and molecular oxygen on the (110) surface and then successively add O(2) molecules, up to 2 monolayer of O(2). Oxygen adsorption always results in a large energy gain. With atomic oxygen, Ti is pulled out of the surface layer leaving behind a Ni-rich subsurface region. Molecular O(2), on the other hand adsorbs dissociatively and pulls a Ti atom farther out of the surface layer. The addition of further O(2) up to 1 monolayer is also dissociative and results in complete removal of Ti from the initial surface layer. When further O(2) is added up to 2 monolayer, Ti is pulled even further out of the surface and a single thin layer of composition O-Ti-O is formed. The electronic structure shows that the metallic character of the alloy is unaffected by interaction with oxygen and formation of the oxide layer, consistent with the oxide layer being a passivant.


Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis.
Glioblastoma (GBM) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is associated with intrinsic or acquired apoptosis resistance and the presence of a highly tumourigenic subpopulation of cancer cells called GBM stem cells. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising novel therapy for some treatment-resistant tumours but unfortunately GBM can be completely resistant to TRAIL monotherapy. In this study, we identified Mcl-1, an anti-apoptotic Bcl-2 family member, as a critical player involved in determining the sensitivity of GBM to TRAIL-induced apoptosis. Effective targeting of Mcl-1 in TRAIL resistant GBM cells, either by gene silencing technology or by treatment with R-roscovitine, a cyclin-dependent kinase inhibitor that targets Mcl-1, was demonstrated to augment sensitivity to TRAIL, both within GBM cells grown as monolayers and in a 3D tumour model. Finally, we highlight that two separate pathways are activated during the apoptotic death of GBM cells treated with a combination of TRAIL and R-roscovitine, one which leads to caspase-8 and caspase-3 activation and a second pathway, involving a Mcl-1:Noxa axis. In conclusion, our study demonstrates that R-roscovitine in combination with TRAIL presents a promising novel strategy to trigger cell death pathways in glioblastoma.


The Drosophila GOLPH3 homolog regulates the biosynthesis of heparan sulfate proteoglycans by modulating the retrograde trafficking of exostosins.
The exostosin (EXT) genes encode glycosyltransferases required for glycosaminoglycan chain polymerization in the biosynthesis of heparan sulfate proteoglycans (HSPGs). Mutations in the tumor suppressor genes EXT1 and EXT2 disturb HSPG biosynthesis and cause multiple osteochondroma (MO). How EXT1 and EXT2 traffic within the Golgi complex is not clear. Here, we show that Rotini (Rti), the Drosophila GOLPH3, regulates the retrograde trafficking of EXTs. A reduction in Rti shifts the steady-state distribution of EXTs to the trans-Golgi. These accumulated EXTs tend to be degraded and their re-entrance towards the route for polymerizing GAG chains is disengaged. Conversely, EXTs are mislocalized towards the transitional endoplasmic reticulum/cis-Golgi when Rti is overexpressed. Both loss of function and overexpression of rti result in incomplete HSPGs and perturb Hedgehog signaling. Consistent with Drosophila, GOLPH3 modulates the dynamic retention and protein stability of EXT1/2 in mammalian species. Our data demonstrate that GOLPH3 modulates the activities of EXTs, thus implicating a putative role for GOLPH3 in the formation of MO.


The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics.
Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype. In different cell lines, either ABCG2 or ABCB1 was found to be responsible for this effect. Purified SP cells featured virtually all characteristics of bona fide CSC, including clonogenicity, asymmetric division and high tumorigenicity in vivo. Using in-depth phenotyping by multicolor flow cytometry, we found that among the investigated ovarian cancer cell lines the SP compartment exhibits tremendous heterogeneity and is composed of multiple phenotypically distinct subpopulations. Thus, our study confirms previous results showing that CSC are contained within the SP. However, the exact identity of the CSC is still disguised by the high complexity of the CSC-containing compartment. Further functional studies are needed to determine whether a single cellular subset can unambiguously be defined as CSC or whether multiple stem cell-like cells with different properties coexist. Moreover, the observed heterogeneity may reflect a high level of plasticity and likely influences tumor progression, escape from immune-surveillance and development of resistance to anticancer therapies and should therefore be considered in the development of new treatment strategies.


Expression is computed separately from facial identity, and it is computed separately for moving and static faces: neuropsychological evidence.
We report data contrasting the processing of facial identity from static photographs, and facial expression from static and moving images, in two patients with face processing impairments. One patient is markedly impaired at perceiving facial identity and he is poor at discriminating facial expression and gender from static photographs of faces. In contrast, he performs normally when required to make judgements of facial expression and gender to faces depicted by sets of moving light dots. The second patient is relatively good at perceiving facial identity, but poor at judging emotional expression from both static and moving faces. The data are consistent with the existence of separate processes for encoding face identity and facial expression, and, furthermore, indicate the separate encoding of expression from moving and static images.


Inferring pathobiology from structural MRI in schizophrenia and bipolar disorder: Modeling head motion and neuroanatomical specificity.
Despite over 400 peer-reviewed structural MRI publications documenting neuroanatomic abnormalities in bipolar disorder and schizophrenia, the confounding effects of head motion and the regional specificity of these defects are unclear. Using a large cohort of individuals scanned on the same research dedicated MRI with broadly similar protocols, we observe reduced cortical thickness indices in both illnesses, though less pronounced in bipolar disorder. While schizophrenia (n = 226) was associated with wide-spread surface area reductions, bipolar disorder (n = 227) and healthy comparison subjects (n = 370) did not differ. We replicate earlier reports that head motion (estimated from time-series data) influences surface area and cortical thickness measurements and demonstrate that motion influences a portion, but not all, of the observed between-group structural differences. Although the effect sizes for these differences were small to medium, when global indices were covaried during vertex-level analyses, between-group effects became nonsignificant. This analysis raises doubts about the regional specificity of structural brain changes, possible in contrast to functional changes, in affective and psychotic illnesses as measured with current imaging technology. Given that both schizophrenia and bipolar disorder showed cortical thickness reductions, but only schizophrenia showed surface area changes, and assuming these measures are influenced by at least partially unique sets of biological factors, then our results could indicate some degree of specificity between bipolar disorder and schizophrenia. Hum Brain Mapp 38:3757-3770, 2017. © 2017 Wiley Periodicals, Inc.


Development and evaluation of a health education intervention against Taenia solium in a rural community in Mexico.
A comprehensive study was undertaken in a rural community in the state of Morelos, Mexico to evaluate health education as an intervention measure against Taenia solium. An educational program was developed to promote recognition and knowledge of the transmission of the parasite and to improve hygienic behavior and sanitary conditions that foster transmission. The effects of educational intervention were evaluated by measuring changes in knowledge and practices and prevalence of human taeniasis and swine cysticercosis before and after the campaign. The health education strategy was implemented with the active participation of the population based on the information obtained from a sociologic study. A questionnaire was designed and used before, immediately after the intervention, and six months later. Statistically significant improvements occurred in knowledge of the parasite, its life cycle, and how it is acquired by humans; however, changes in behavior related to transmission were less dramatic and persistent. The prevalences of cysticercosis in pigs at the start of the education intervention were 2.6% and 5.2% by lingual examination and antibody detection (immunoblot assay), respectively, and approximately one year after the intervention they were 0% and 1.2% (P < 0.05). These changes were accompanied by significant reductions in the reported access of pigs to sources of infection and freedom to roam. We conclude that health education, developed along with community involvement, reduced opportunities for transmission of T. solium in the human-pig cycle.


Illicit drug use, early age at first use and risk of premenstrual syndrome: A longitudinal study.
Premenstrual syndrome (PMS) is common among women of reproductive age. Limited studies have investigated the long-term association between illicit drug use and PMS. The 1973-1978 cohort from the Australian Longitudinal Study on Women's Health, a prospective cohort study, was followed up for 13-year from 2000 to 2012. Data were collected through self-reported questionnaires on all variables, including PMS, illicit drug use and a range of sociodemographic, lifestyle, reproductive and psychological factors. When the women were 22-27 years of age, over 40% use illicit drug in the last 12 months, 9% first used drug before age 15 years and approximately 35% reported PMS. Over the study period, the prevalence of drug use in the last 12 months declined whereas that of PMS remained fairly stable except an increase when they were 34-39 years old. Generalised estimating equations analysis showed that, compared to never drug users, significantly higher odds of reporting PMS were detected for illicit drug use in the last 12 months: multiple drugs (odds ratio (OR) 1.31, 95% confidence interval (CI) 1.21, 1.43), exclusive marijuana (OR 1.23, 95% CI 1.08, 1.40). A higher odds of PMS was identified for age at first drug use before 15 years (OR 1.20, 95% CI 1.03, 1.40). Illicit drug use in the last 12 months, especially early age at first use and multiple drug use, is associated with increased risk of PMS. However current study is unable to prove causality.


Genomic changes associated with the evolutionary transition of an insect gut symbiont into a blood-borne pathogen.
The genus Bartonella comprises facultative intracellular bacteria with a unique lifestyle. After transmission by blood-sucking arthropods they colonize the erythrocytes of mammalian hosts causing acute and chronic infectious diseases. Although the pathogen-host interaction is well understood, little is known about the evolutionary origin of the infection strategy manifested by Bartonella species. Here we analyzed six genomes of Bartonella apis, a honey bee gut symbiont that to date represents the closest relative of pathogenic Bartonella species. Comparative genomics revealed that B. apis encodes a large set of vertically inherited genes for amino acid and cofactor biosynthesis and nitrogen metabolism. Most pathogenic bartonellae have lost these ancestral functions, but acquired specific virulence factors and expanded a vertically inherited gene family for harvesting cofactors from the blood. However, the deeply rooted pathogen Bartonella tamiae has retained many of the ancestral genome characteristics reflecting an evolutionary intermediate state toward a host-restricted intraerythrocytic lifestyle. Our findings suggest that the ancestor of the pathogen Bartonella was a gut symbiont of insects and that the adaptation to blood-feeding insects facilitated colonization of the mammalian bloodstream. This study highlights the importance of comparative genomics among pathogens and non-pathogenic relatives to understand disease emergence within an evolutionary-ecological framework.


Irreversible depletion of intestinal CD4+ T cells is associated with T cell activation during chronic HIV infection.
HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within Westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4+ T cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on antiretroviral treatment (ART) or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal antiretroviral (ARV) drugs revealed no differences in drug penetration between the duodenum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T cell activation was inversely correlated with loss of gut CD4+ T cells in PLWH alone. T cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4+ T cells is a key event in the HIV pathogenesis of PLWH in South Africa, yet the underlying mechanisms remain unknown.


Use of abatacept in rheumatoid arthritis.
Abatacept (CTLA-Ig), a modulator of T-lymphocyte activation, has been approved by the Swiss health regulatory agency Swissmedic for the treatment of active rheumatoid arthritis (RA). This article summarises the key trial findings for this biologic agent in RA in different situations such as early erosive rheumatoid arthritis (RA), biologic-naïve RA, RA before and after the use of methotrexate or TNF-inhibitors and includes safety information from these trials. Based on these data, recommendations for clinical practice in Switzerland are made by a panel of experts.


Hyposensitization with Dermatophagoides pteronyssinus antigen: trial in asthma induced by house dust.
A double-blind clinical trial of hyposensitization with aqueous extracts of Dermatophagoides pteronyssinus (the house-dust mite) and human skin scales showed a substantial improvement in symptoms in 11 asthmatics allergic to house dust treated with the D. pteronyssinus extract and a reduction in their need for other therapy. Five patients were well for a year but six relapsed. These results contrasted with the generally unfavourable course of the patients treated with the extract of human skin scales. Asthma due to house-dust allergy may be substantially improved by hyposensitization with D. pteronyssinus extract.


Older adults' attitudes about continuing cancer screening later in life: a pilot study interviewing residents of two continuing care communities.
Individualized decision making has been recommended for cancer screening decisions in older adults. Because older adults' preferences are central to individualized decisions, we assessed older adults' perspectives about continuing cancer screening later in life. Face to face interviews with 116 residents age 70 or over from two long-term care retirement communities. Interview content included questions about whether participants had discussed cancer screening with their physicians since turning age 70, their attitudes about information important for individualized decisions, and their attitudes about continuing cancer screening later in life. Forty-nine percent of participants reported that they had an opportunity to discuss cancer screening with their physician since turning age 70; 89% would have preferred to have had these discussions. Sixty-two percent believed their own life expectancy was not important for decision making, and 48% preferred not to discuss life expectancy. Attitudes about continuing cancer screening were favorable. Most participants reported that they would continue screening throughout their lives and 43% would consider getting screened even if their doctors recommended against it. Only 13% thought that they would not live long enough to benefit from cancer screening tests. Factors important to consider stopping include: age, deteriorating or poor health, concerns about the effectiveness of the tests, and doctors recommendations. This select group of older adults held positive attitudes about continuing cancer screening later in life, and many may have had unrealistic expectations. Individualized decision making could help clarify how life expectancy affects the potential survival benefits of cancer screening. Future research is needed to determine whether educating older adults about the importance of longevity in screening decisions would be acceptable, affect older adults' attitudes about screening, or change their screening behavior.


Large-Scale Targeted Proteomics Using Internal Standard Triggered-Parallel Reaction Monitoring (IS-PRM).
Targeted high-resolution and accurate mass analyses performed on fast sequencing mass spectrometers have opened new avenues for quantitative proteomics. More specifically, parallel reaction monitoring (PRM) implemented on quadrupole-orbitrap instruments exhibits exquisite selectivity to discriminate interferences from analytes. Furthermore, the instrument trapping capability enhances the sensitivity of the measurements. The PRM technique, applied to the analysis of limited peptide sets (typically 50 peptides or less) in a complex matrix, resulted in an improved detection and quantification performance as compared with the reference method of selected reaction monitoring performed on triple quadrupole instruments. However, the implementation of PRM for the analysis of large peptide numbers requires the adjustment of mass spectrometry acquisition parameters, which affects dramatically the quality of the generated data, and thus the overall output of an experiment. A newly designed data acquisition scheme enabled the analysis of moderate-to-large peptide numbers while retaining a high performance level. This new method, called internal standard triggered-parallel reaction monitoring (IS-PRM), relies on added internal standards and the on-the-fly adjustment of acquisition parameters to drive in real-time measurement of endogenous peptides. The acquisition time management was designed to maximize the effective time devoted to measure the analytes in a time-scheduled targeted experiment. The data acquisition scheme alternates between two PRM modes: a fast low-resolution "watch mode" and a "quantitative mode" using optimized parameters ensuring data quality. The IS-PRM method exhibited a highly effective use of the instrument time. Applied to the analysis of large peptide sets (up to 600) in complex samples, the method showed an unprecedented combination of scale and analytical performance, with limits of quantification in the low amol range. The successful analysis of various types of biological samples augurs a broad applicability of the method, which is likely to benefit a wide range of proteomics experiments.


Compartmentalized control of skin immunity by resident commensals.
Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease.


An Assessment of Patient Comfort and Morbidity After Robot-Assisted Radical Prostatectomy with Suprapubic Tube Versus Urethral Catheter Drainage.
Robot-assisted laparoscopic prostatectomy (RALP) with suprapubic tube (SPT), compared to urethral catheter (UC) drainage, has been proposed to improve patient comfort and recovery. We sought to compare short-term outcomes for pain and morbidity after RALP with SPT vs UC drainage. Between August 2012 and 2014, 159 men underwent a RALP and prospectively completed a questionnaire addressing postoperative pain and satisfaction. Group 1 (n = 94) underwent a RALP by one surgeon who placed a UC and removed it between postoperative day (POD) 7 and 10. Group 2 (n = 65) underwent a RALP by a different surgeon who placed an SPT and UC. On POD 1, the UC was removed. On POD 9, the SPT was capped and removed on POD 11 if the patient was voiding adequately. Preoperative and intraoperative data, complications, questionnaires, and patient-reported morbidity, including unplanned telephone calls and emergency department (ED) visits, were compared between groups. Patient characteristics were similar between groups. One week after surgery, the penile pain score was statistically significantly lower in Group 2 compared to Group 1 (56.9% and 79.8%, respectively, reported minimal-to-moderate pain, p = 0.003). Bladder spasms and overall pain were not significantly higher for Group 1 compared to Group 2 (p > 0.05). When asked "How big a problem has your urine storage device been?," 20.2% of patients in Group 1 reported it as a "moderate-to-big" problem compared to 10.8% in Group 2 (p > 0.05). The number of catheter-related unplanned telephone encounters did not differ between the two groups (p = 0.7), however, although not statistically significant, 4.6% of patients in Group 2 presented to the ED with catheter-related issues (p = 0.07). SPT after RALP was associated with less penile pain compared to UC drainage, and modestly better patient satisfaction. There were no significant differences in bladder spasms, overall pain, and patient-reported morbidity between groups.


Visual search, singleton capture, and the control of attentional set in ADHD.
We report the data on effects on visual search of (1) preview displays and (2) singleton targets and distractors in IQ-matched ADHD and control children. All children showed interference from singleton distractors even when targets never carried singleton values. This interference from singleton distractors increased under preview conditions, indicating that the children then had fewer resources available to control attention. There was also one selective deficit for ADHD children; they showed marked problems in responding to singleton targets following preview displays. This suggests that, in ADHD, there is either a selective delay or an impairment in switching attentional sets (from a negative set to the preview to a positive set to a singleton target). We discuss the implications for understanding both ADHD and the development of selective attention.


Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys.
Polycystic ovary syndrome (PCOS) is prevalent in reproductive-aged women and confounded by metabolic morbidities, including insulin resistance and type 2 diabetes. Although the etiology of PCOS is undefined, contribution of prenatal androgen (PA) exposure has been proposed in a rhesus monkey model as premenopausal PA female adults have PCOS-like phenotypes in addition to insulin resistance and decreased glucose tolerance. PA female infants exhibit relative hyperinsulinemia, suggesting prenatal sequelae of androgen excess on glucose metabolism and an antecedent to future metabolic disease. We assessed consequences of PA exposure on pancreatic islet morphology to identify evidence of programming on islet development. Islet counts and size were quantified and correlated with data from intravenous glucose tolerance tests (ivGTT) obtained from dams and their offspring. Average islet size was decreased in PA female infants along with corresponding increases in islet number, while islet fractional area was preserved. Infants also demonstrated an increase in both the proliferation marker Ki67 within islets and the beta to alpha cell ratio suggestive of enhanced beta cell expansion. PA adult females have reduced proportion of small islets without changes in proliferative or apoptotic markers, or in beta to alpha cell ratios. Together, these data suggest in utero androgen excess combined with mild maternal glucose intolerance alter infant and adult islet morphology, implicating deviant islet development. Marked infant, but subtle adult, morphological differences provide evidence of islet post-natal plasticity in adapting to changing physiologic demands: from insulin sensitivity and relative hypersecretion to insulin resistance and diminished insulin response to glucose in the mature PCOS-like phenotype.


Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy.
In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8a(V929F)). Here, we confirmed the prior suggestion that Scn8a(V929F) exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when Scn8a(V929F) is fully placed onto the C57BL/6J strain compared with C3H. Examination of sequence differences in NaV subunits between these two inbred strains suggested NaV1.2(V752F) as a potential source of this modifier effect. Recognising that the spatial co-localisation of the NaV channels at the axon initial segment (AIS) provides a plausible mechanism for functional interaction, we tested this idea by undertaking biophysical characterisation of the variant NaV channels and by computer modelling. NaV1.2(V752F) functional analysis revealed an overall gain-of-function and for NaV1.6(V929F) revealed an overall loss-of-function. A biophysically realistic computer model was used to test the idea that interaction between these variant channels at the AIS contributes to the strain background effect. Surprisingly this modelling showed that neuronal excitability is dominated by the properties of NaV1.2(V752F) due to "functional silencing" of NaV1.6(V929F) suggesting that these variants do not directly interact. Consequent genetic mapping of the major strain modifier to Chr 7, and not Chr 2 where Scn2a maps, supported this biophysical prediction. While a NaV1.6(V929F) loss of function clearly underlies absence seizures in this mouse model, the strain background effect is apparently not due to an otherwise tempting Scn2a variant, highlighting the value of combining physiology and genetics to inform and direct each other when interrogating genetic complex traits such as absence epilepsy.


Olfactory deficits and amyloid-β burden in Alzheimer's disease, mild cognitive impairment, and healthy aging: a PiB PET study.
Olfactory deficits and increased amyloid-β (Aβ) burden are observed in people with amnestic mild cognitive impairment (aMCI); both factors may be predictive of Alzheimer's disease (AD). We explored whether olfactory identification is related to in vivo measures of Aβ burden using Pittsburgh Compound B (PiB) PET. Nineteen control, 24 aMCI, and 20 AD participants completed an olfactory identification task and underwent PiB PET scanning. Control participants performed better on olfactory identification and showed lower PiB binding than aMCI patients. There was a significant correlation between both factors when pooling all groups together but not when considering each group separately. In addition, the olfactory identification score did not differ between aMCI participants who were PiB-positive and those who were PiB-negative. We conclude that AD-related olfactory identification deficits are not directly related to Aβ burden.


Anthocyanins Promote Learning through Modulation of Synaptic Plasticity Related Proteins in an Animal Model of Ageing.
Anthocyanin-rich foods, such as berries, reportedly ameliorate age-related cognitive deficits in both animals and humans. Despite this, investigation into the mechanisms which underpin anthocyanin-mediated learning and memory benefits remains relatively limited. The present study investigates the effects of anthocyanin intake on a spatial working memory paradigm, assessed via the cross-maze apparatus, and relates behavioural test performance to underlying molecular mechanisms. Six-week supplementation with pure anthocyanins (2% w/w), administered throughout the learning phase of the task, improved both spatial and psychomotor performances in aged rats. Behavioural outputs were accompanied by changes in the expression profile of key proteins integral to synaptic function/maintenance, with upregulation of dystrophin, protein kinase B (PKB/Akt) and tyrosine hydroxylase, and downregulation of apoptotic proteins B-cell lymphoma-extra-large (Bcl-xL) and the phosphorylated rapidly accelerated fibrosarcoma (p-Raf). Separate immunoblot analysis supported these observations, indicating increased activation of extracellular signal-related kinase (ERK1), Akt Ser473, mammalian target of rapamycin (mTOR) Ser2448, activity-regulated cytoskeleton-associated protein (Arc/Arg 3.1) and brain-derived neurotrophic factor (BDNF) in response to anthocyanin treatment, whilst α-E-catenin, c-Jun N-terminal kinase (JNK1) and p38 protein levels decreased. Together, these findings suggest that purified anthocyanin consumption enhances spatial learning and motor coordination in aged animals and can be attributed to the modulation of key synaptic proteins, which support integrity and maintenance of synaptic function.


Renaturation of guanidine-unfolded tryptophan synthase by multi-mixing stopped-flow dilution in D2O.
Guanidine hydrochloride (GdnHCl) at high concentrations, e.g. 4 to 8 M, has been used extensively to promote reversible denaturation of several proteins. The refolding is induced by removal of the denaturing agent by diluting the denatured protein at least 50-100-fold in a 'renaturation buffer'. Fast kinetic studies, using a stopped-flow apparatus to achieve such dilutions, are difficult for two reasons: firstly, injecting widely different volumes of the two reagents does not afford a proper mixing. Secondly, the density differences existing between the concentrated GdnHCl solution and the renaturation buffer often causes important mixing and redistribution artefacts particularly in vertical stopped-flows. Here, it is shown that these difficulties can be overcome by using a multi-mixing stopped-flow to achieve 2 successive 7-fold dilutions and by using heavy water (D2O) to adjust the density of the renaturation buffer. This enabled us to study the appearance of a short-lived intermediate during the folding of the beta 2-subunit of Escherichia coli tryptophan synthase.


Carcinoid heart disease.
The patient, C.P., is a 59-year-old woman who was diagnosed with metastatic carcinoid of the terminal ileum in May 2003. In June 2003, she underwent an extensive resection including hemicolectomy, cholecystectomy, distal pancreatectomy, and splenectomy with metastatic disease in her pancreas, mesentery, and liver. She had been treated with octreotide, everolimus, oxaliplatin, and multiple hepatic artery embolizations in the past eight years and, most recently, capecitabine and bevacizumab with monthly octreotide. She has had intermittent pleural effusions not requiring intervention and a trace pericardial effusion. Her tumor is functional, meaning it demonstrates hormonal hypersecretion which causes flushing, diarrhea, bronchospasm, and abdominal pain.


Culture confirmation of Escherichia coli serotype O157:H7 by direct immunofluorescence.
An evaluation of a fluorescein-labeled, polyclonal, affinity-purified goat antibody to Escherichia coli serotype O157:H7 (Kirkegaard & Perry Laboratories Inc., Gaithersburg, Md.) was conducted to determine the efficacy of this research reagent for the rapid direct immunofluorescence identification of E. coli O157:H7 isolated from fecal specimens cultured on sorbitol-MacConkey (SMAC) agar. The E. coli O157:H7 fluorescent-antibody conjugate proved to be 100% sensitive and specific for the rapid identification of non-sorbitol-fermenting E. coli O157:H7 from SMAC agar inoculated with fecal specimens. The addition of SMAC agar to the battery of primary isolation media routinely used for fecal specimens resulted in the identification of 16 patients with E. coli O157:H7 disease from a total of 799 fecal specimens cultured during 1988.


Acute Exercise Modulates Feature-selective Responses in Human Cortex.
An organism's current behavioral state influences ongoing brain activity. Nonhuman mammalian and invertebrate brains exhibit large increases in the gain of feature-selective neural responses in sensory cortex during locomotion, suggesting that the visual system becomes more sensitive when actively exploring the environment. This raises the possibility that human vision is also more sensitive during active movement. To investigate this possibility, we used an inverted encoding model technique to estimate feature-selective neural response profiles from EEG data acquired from participants performing an orientation discrimination task. Participants (n = 18) fixated at the center of a flickering (15 Hz) circular grating presented at one of nine different orientations and monitored for a brief shift in orientation that occurred on every trial. Participants completed the task while seated on a stationary exercise bike at rest and during low- and high-intensity cycling. We found evidence for inverted-U effects; such that the peak of the reconstructed feature-selective tuning profiles was highest during low-intensity exercise compared with those estimated during rest and high-intensity exercise. When modeled, these effects were driven by changes in the gain of the tuning curve and in the profile bandwidth during low-intensity exercise relative to rest. Thus, despite profound differences in visual pathways across species, these data show that sensitivity in human visual cortex is also enhanced during locomotive behavior. Our results reveal the nature of exercise-induced gain on feature-selective coding in human sensory cortex and provide valuable evidence linking the neural mechanisms of behavior state across species.


Bacteremia shortly after placental separation during cesarean delivery.
To assess frequency, risk factors, and microbiology of bacteremia within 15 minutes of placental separation during cesarean delivery. Ninety-three women undergoing cesarean delivery after a minimum of 4 hours of labor or ruptured membranes were compared with 26 women not in labor undergoing cesarean. Blood cultures for aerobic and anaerobic bacteria were obtained within 15 minutes of delivery of the placenta and before prophylactic antibiotic administration. Chorioamnionic membranes were also cultured. Demographic, labor, delivery, and postpartum characteristics were abstracted from the medical record. Bacteremia was detected in 13 (11%) of 119 women. Bacteremia occurred in 13 (14%) of 93 women after labor or rupture of membranes compared with zero of 26 women not in labor (P = .02). Isolates included group B streptococcus (n = 5), Gardnerella vaginalis (n = 5), Streptococcus pneumoniae (n = 1), Peptostreptococcus sp (n = 1), and mixed flora of Prevotella bivia, G vaginalis, and viridans streptococci (n = 1). Bacteremia was associated with earlier median gestational age, lower median birth weight, and a positive chorioamnionic membrane culture. After adjustment for gestational age, intrauterine monitoring was also significantly associated with bacteremia. Bacteremia was common after labor in this population, especially in preterm deliveries and those with positive chorioamnionic-placental culture. Many of the isolates are capable of causing endocarditis. Appraisal of the risk of bacteremia and the risk of bacterial endocarditis should be made in individual patients to assess the need for antibiotic prophylaxis.


Food elimination, food substitution, and nutrient supplementation among ARV-exposed HIV-positive persons in southern Ghana.
Optimal nutrition is a determinant of health in all persons. In persons living with HIV (PLHIV), nutrition is particularly important. Various factors, including dietary practices, play a role in guaranteeing nutritional health. We investigated multiple non-prescription drugs use among HIV-positive persons receiving antiretroviral therapy (ART) from four treatment centers in southern Ghana. This paper, however, focuses on nutrient supplement use, food elimination, and food substitution practices by the PLHIV. Using quantitative and qualitative methods, we collected data from 540 HIV-positive persons at the health facility level. This paper focuses on only the quantitative data. Individual study participants were selected using a systematic random sampling procedure. Participants were interviewed after informed consent. We used univariate analysis to generate descriptive tabulations for key variables. Multivariable logistic regression modeling identified predictors of three practices (nutrient supplementation, food elimination, and food substitution). P value less than 0.05 or 95% confidence intervals facilitated determination of statistical significance. All analyses were performed using IBM SPSS Statistics for Windows, version 20.0. The use of nutrient supplements was a popular practice; 72% of the PLHIV used various kinds. The primary motive for the practice was to boost appetite and to gain weight. A little over 20% of the participants reportedly eliminated certain foods and beverages, while 17% introduced new foods since their initial HIV diagnosis. All the three practices were largely driven by the quest for improved health status. We determined predictors of nutrient supplementation to be ART clinic location and having an ART adherence monitor. Having an ART adherence monitor was significantly associated with reduced odds of nutrient supplementation (AOR = 0.34; 95% CI 0.12-0.95). The only predictor for food elimination was education level (AOR = 0.29; 95% CI 0.30-0.92); predictors of food substitution were ART clinic location (AOR = 0.11; 95% CI 0.02-0.69) and anemia (defined as hemoglobin concentration less than 11.0 g/dl) (AOR = 0.21; 95% CI 0.12-0.85). The practice of supplementation is popular among this group of PLHIV. Food elimination and substitution are practiced, albeit in moderation. The predictors identified may prove helpful in provider-client encounters as well as local HIV programming.


Anesthetic Care During Posterior Spinal Fusion in an Adolescent With Ebstein's Anomaly.
Ebstein's anomaly is a rare form of cyanotic congenital heart disease (CHD) that involves malformation and dysfunction of the tricuspid valve and right ventricle (RV). The severity of the defect impacts clinical presentation, survival, and treatment options. Presentation during the neonatal period with hypoxemia and cyanosis is noted in patients with severe tricuspid valve malformation, a hypoplastic RV, or RV outflow tract obstruction. However, presentation later in infancy is more common when there is a moderate tricuspid valve malformation and no associated RV outflow tract obstruction. Although Ebstein's anomaly is not generally associated with other congenital defects, patients may occasionally require surgery for other comorbid conditions. We describe the perioperative anesthetic management of an adolescent with Ebstein's anomaly for posterior spinal fusion. Previous reports of anesthetic care in this clinical scenario are reviewed, anesthetic considerations discussed, and options for intraoperative monitoring and anesthetic care presented.


Education reduces the effects of genetic susceptibilities to poor physical health.
Greater education is associated with better physical health. This has been of great concern to public health officials. Most demonstrations show that education influences mean levels of health. Little is known about the influence of education on variance in health status, or about how this influence may impact the underlying genetic and environmental sources of health problems. This study explored these influences. In a 2002 postal questionnaire, 21 522 members of same-sex pairs in the Danish Twin Registry born between 1931 and 1982 reported physical health in the 12-item Short Form Health Survey. We used quantitative genetic models to examine how genetic and environmental variance in physical health differed with level of education, adjusting for birth-year effects. and Conclusions As expected, greater education was associated with better physical health. Greater education was also associated with smaller variance in health status. In both sexes, 2 standard deviations (SDs) above mean educational level, variance in physical health was only about half that among those 2 SDs below. This was because fewer highly educated people reported poor health. There was less total variance in health primarily because there was less genetic variance. Education apparently reduced expression of genetic susceptibilities to poor health. The patterns of genetic and environmental correlations suggested that this might take place because more educated people manage their environments to protect their health. If so, fostering the personal charactieristics associated with educational attainment could be important in reducing the education-health gradient.


What is Health and What is Important for its Achievement? A Qualitative Study on Adolescent Boys' Perceptions and Experiences of Health.
Few qualitative studies have explored adolescent boys' perceptions of health. The aim of this study was therefore to explore how adolescent boys understand the concept of health and what they find important for its achievement. Grounded theory was used as a method to analyse interviews with 33 adolescent boys aged 16 to 17 years attending three upper secondary schools in a relatively small town in Sweden. There was a complexity in how health was perceived, experienced, dealt with, and valued. Although health on a conceptual level was described as 'holistic', health was experienced and dealt with in a more dualistic manner, one in which the boys were prone to differentiate between mind and body. Health was experienced as mainly emotional and relational, whereas the body had a subordinate value. The presence of positive emotions, experiencing self-esteem, balance in life, trustful relationships, and having a sense of belonging were important factors for health while the body was experienced as a tool to achieve health, as energy, and as a condition. Our findings indicate that young, masculine health is largely experienced through emotions and relationships and thus support theories on health as a social construction of interconnected processes.


The Drosophila Accessory Gland as a Model for Prostate Cancer and Other Pathologies.
The human prostate is a gland of the male reproductive tract, which together with the seminal vesicles, is responsible for most seminal fluid production. It is a common site of cancer, and unlike other glands, it typically enlarges in aging men. In flies, the male accessory glands make many major seminal fluid components. Like their human equivalents, they secrete proteins from several conserved families, including proteases, lectins, and cysteine-rich secretory proteins, some of which interact with sperm and affect fertility. A key protein, sex peptide, is not conserved in vertebrates but plays a central role in mediating long-term effects on females after mating. Although postmitotic, one epithelial cell type in the accessory glands, the secondary cell, continues to grow in adults. It secretes microvesicles called exosomes from the endosomal multivesicular body, which, after mating, fuse with sperm. They also appear to affect female postmating behavior. Remarkably, the human prostate epithelium also secretes exosomes, which fuse to sperm in vitro to modulate their activity. Exosomes from prostate and other cancer cells are increasingly proposed to play fundamental roles in modulating the tumor microenvironment and in metastasis. Here we review a diverse accessory gland literature, which highlights functional analogies between the male reproductive glands of flies and humans, and a critical role for extracellular vesicles in allowing seminal fluid to promote male interests within the female. We postulate that secondary cells and prostate epithelial cells use common mechanisms to control growth, secretion, and signaling, which are relevant to prostate and other cancers, and can be genetically dissected in the uniquely tractable fly model.


Effect of tumor load on energy expenditure in patients with pancreatic cancer.
Increased metabolic rate may play a role in cancer cachexia, especially when caloric intake is significantly reduced. We studied the effect of tumor load on resting energy expenditure (REE) in patients with pancreatic cancer after normalizing for their daily caloric intake and body composition. The cross-sectional study included 45 patients with pancreatic cancer (15 postoperation) and 75 controls. Resting energy expenditure was measured by indirect calorimetry, body composition was measured by dual-energy x-ray absorptiometry, and energy intake was measured by 3-day food records. There were no differences between pancreatic cancer patients who underwent surgery and those who did not in any of the anthropometric or metabolic parameters tested. Body mass index, lean body mass, body fat percentage, and energy intake were significantly lower in patients with pancreatic cancer (P < 0.0001) compared with healthy controls. Resting energy expenditure and the respiratory quotient were significantly lower in patients (P < 0.0001 and P < 0.025, respectively). There were no differences in REE between patients and controls when normalized by lean body mass. Respiratory quotients were significantly lower in patients who underwent surgery and in those who did not compared with controls. Pancreatic cancer does not increase REE above the normal levels nor does tumor burden contribute to increasing REE. Decreased daily energy intake of our patients may have reduced measured REE.


Prediction of chemical respiratory sensitizers using GARD, a novel in vitro assay based on a genomic biomarker signature.
Repeated exposure to certain low molecular weight (LMW) chemical compounds may result in development of allergic reactions in the skin or in the respiratory tract. In most cases, a certain LMW compound selectively sensitize the skin, giving rise to allergic contact dermatitis (ACD), or the respiratory tract, giving rise to occupational asthma (OA). To limit occurrence of allergic diseases, efforts are currently being made to develop predictive assays that accurately identify chemicals capable of inducing such reactions. However, while a few promising methods for prediction of skin sensitization have been described, to date no validated method, in vitro or in vivo, exists that is able to accurately classify chemicals as respiratory sensitizers. Recently, we presented the in vitro based Genomic Allergen Rapid Detection (GARD) assay as a novel testing strategy for classification of skin sensitizing chemicals based on measurement of a genomic biomarker signature. We have expanded the applicability domain of the GARD assay to classify also respiratory sensitizers by identifying a separate biomarker signature containing 389 differentially regulated genes for respiratory sensitizers in comparison to non-respiratory sensitizers. By using an independent data set in combination with supervised machine learning, we validated the assay, showing that the identified genomic biomarker is able to accurately classify respiratory sensitizers. We have identified a genomic biomarker signature for classification of respiratory sensitizers. Combining this newly identified biomarker signature with our previously identified biomarker signature for classification of skin sensitizers, we have developed a novel in vitro testing strategy with a potent ability to predict both skin and respiratory sensitization in the same sample.


Exposure to Environmental Arsenic and Emerging Risk of Alzheimer's Disease: Perspective Mechanisms, Management Strategy, and Future Directions.
Alzheimer's disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth's crust, and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition, although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not yet clear. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed.


Endocytic pathways in polarized Caco-2 cells: identification of an endosomal compartment accessible from both apical and basolateral surfaces.
The enterocyte-like cell line Caco-2 forms a polarized epithelium when grown on filters. We have investigated the interaction of endocytic pathways from the apical and basolateral surfaces. The transferrin receptor was an appropriate marker for the basolateral route; uptake of radiolabeled transferrin was highly polarized, and recycling of this ligand back to the basolateral surface occurred with an efficiency of 95%, even after prolonged incubations with transferrin. Using a transferrin-peroxidase conjugate to delineate the morphological pathway, we have identified an early endocytic compartment in the basolateral cytoplasm of the cells. Longer incubations revealed a deeper endocytic compartment in the apical cytoplasm. Concanavalin A complexed to gold was used to simultaneously label the apical endocytic route. After 60 min, extensive mixing of the two labels was seen in endocytic elements throughout the apical cytoplasm, including in the Golgi area, but never in the basal cytoplasm. Using a second double labeling procedure in which antitransferrin receptor antibody complexed to gold was applied to the basolateral surface for up to 2 h and free peroxidase applied to the apical surface for shorter periods, we demonstrated that this apical marker rapidly (within 5 min) reached endosomes containing antibody-gold. Our results indicate that, in Caco-2 cells, the endocytic pathways from the apical and basolateral surfaces meet in an endosomal compartment from which transferrin can still be recycled.


High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35.
Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs demonstrated evidence of linkage to chromosomes 7 and 10. This screen included 44 multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7. To investigate this family more thoroughly, a high-density single nucleotide polymorphism (SNP) screen was performed. Two-point and multipoint linkage analyses were performed using both parametric and nonparametric methods. For both the microsatellite and SNP markers, linkage analysis suggested the involvement of a locus or loci proximal to the telomeric regions of chromosomes 2q and 7p, with both regions generating a LOD* score of 3.0 using a nonparametric identity by descent relative sharing method. The regions with the strongest evidence for linkage map proximal to the telomeres on these two chromosomes. In addition to mutations and/or variants in a major gene, these loci may harbor a microdeletion and/or translocation; potentially, polygenic factors may also be involved. This single family may be promising for narrowing the search for NTD susceptibility genes.


Serologic evidence of natural togavirus infections in Panamanian sloths and other vertebrates.
Plasmas of sloths and other Central Panamanian wild vertebrates were tested for plaque-reduction neutralizing (PRN) antibodies against four flaviviruses and one alpha-virus. Forty percent of 97 two-toed sloths, Choloepus hoffmanni, and 8% of 168 three-toed sloths, Bradypus variegatus, were specifically positive against St. Louis encephalitis (SLE) virus. The prevalence of antibody against SLE virus was considerably higher in sloths than in any other group of wild vertebrates tested, including birds, and was found mainly in adult sloths. Specific PRN antibody against yellow fever (YF) virus was found only in monkeys. A high prevalence of PRN antibody against Ilheus and Mayaro viruses was detected in agoutis, Dasyprocta punctata, and against Mayaro virus in howler monkeys, Alouatta villosa. No plasma was specifically positive against Bussuquara virus. The results are interpreted as evidence that sloths are probably not important hosts in jungle YF cycles, but may be significant amplifying hosts in tropical SLE virus cycles.


The prevalence of SDQ-measured mental health problems at age 5-7 years and identification of predictors from birth to preschool age in a Danish birth cohort: the Copenhagen Child Cohort 2000.
The objective of the study is to investigate the prevalence, distribution and predictors of mental health problems in 5-7-year-old Danish children in the general population. This study is a 5-7-year follow-up study of a birth cohort of 6,090 children, the Copenhagen Child Cohort 2000. The extended version of the Strengths and Difficulties Questionnaire (SDQ) was answered by parents and pre-school teachers. Data from Danish national registers included perinatal data, socioeconomic data and data on child mental illness diagnosed at hospital in preschool age. Register data from the first year of life was obtained from 99.7% of the children in the cohort. Of 5,898 eligible children, 3,501 participated in the SDQ assessment (59%). The overall estimated 6-month prevalence of mental health problems was 4.8% (95% CI 4.1-5.6). Conduct problems were found in 3.0% (95% CI 2.4-3.6), problems of hyperactivity/inattention in 0.7% (95% CI 0.4-1.0) and emotional problems in 1.5% (95% CI 1.1-1.9). Boys showed a higher risk of having mental health problems as compared to girls: risk ratio 2.0 (95% CI 1.5-2.8). Several markers of socioeconomic disadvantages were associated with mental health problems at 5-7 years of age. In conclusion, the 6-month prevalence of SDQ-measured mental health problems was relatively low in Danish children when compared with findings from several European countries, but was in line with findings from other studies in Nordic countries. The lower prevalence might reflect differences in psychosocial risk load and environmental stress given the social and cultural context.


Movement and site selection for priming by the primosome in phage phi X174 DNA replication.
The Escherichia coli priming system used for initiation of DNA chains on phage phi X174 single-stranded DNA is a multiprotein unit called the primosome [Arai, K. & Kornberg. A. (1981) Proc. Natl. Acad. Sci. USA 78, 69-73]. Assembled with participation of seven prepriming proteins and primase at a unique place on the phi X174 DNA template, the primosome is bound tightly to the DNA, yet moves rapidly and unidirectionally opposite to primer and DNA chain synthesis. Contributions of protein n' and dnaB protein, two components of the primosome, to movement and site selection for priming are considered in this report. Figuratively, the primosome can be likened to a locomotive that depends on protein n' as its engine and dnaB protein as the engineer. Protein n', a DNA-dependent ATPase (dATPase) appears to use the energy of hydrolysis of the nucleoside triphosphate for processive translocation of the primosome. dnaB protein, A DNA-dependent ribonucleosidetriphosphatase, depends on allosteric effects of a nucleoside triphosphate to induce changes in the structure of the single-stranded DNA at preferred sequences that enable primase to synthesize a short primer for initiation of DNA synthesis (unpublished data). These primosome properties have important implications for the progress of the replication fork of the E. coli chromosome.


Measurement of time delay for a prospectively gated CT simulator.
For the management of mobile tumors, respiratory gating is the ideal option, both during imaging and during therapy. The major advantage of respiratory gating during imaging is that it is possible to create a single artifact-free CT data-set during a selected phase of the patient's breathing cycle. The purpose of the present work is to present a simple technique to measure the time delay during acquisition of a prospectively gated CT. The time delay of a Philips Brilliance BigBore (Philips Medical Systems, Madison, WI) scanner attached to a Varian Real-Time Position Management (RPM) system (Varian Medical Systems, Palo Alto, CA) was measured. Two methods were used to measure the CT time delay: using a motion phantom and using a recorded data file from the RPM system. In the first technique, a rotating wheel phantom was altered by placing two plastic balls on its axis and rim, respectively. For a desired gate, the relative positions of the balls were measured from the acquired CT data and converted into corresponding phases. Phase difference was calculated between the measured phases and the desired phases. Using period of motion, the phase difference was converted into time delay. The Varian RPM system provides an external breathing signal; it also records transistor-transistor logic (TTL) 'X-Ray ON' status signal from the CT scanner in a text file. The TTL 'X-Ray ON' indicates the start of CT image acquisition. Thus, knowledge of the start time of CT acquisition, combined with the real-time phase and amplitude data from the external respiratory signal, provides time-stamping of all images in an axial CT scan. The TTL signal with time-stamp was used to calculate when (during the breathing cycle) a slice was recorded. Using the two approaches, the time delay between the prospective gating signal and CT simulator has been determined to be 367 +/- 40 ms. The delay requires corrections both at image acquisition and while setting gates for the treatment delivery; otherwise the simulation and treatment may not be correlated with the patient's breathing.


Phase-field study of spacing evolution during transient growth.
The primary spacing of a dendritic array grown under transient growth conditions displays a distribution of wavelengths. The average primary spacing is shown, both experimentally and numerically, to evolve between characteristic incubation periods during which the distribution of wavelengths remains essentially stable. Our primary spacing results display a gradual transition period from one spacing range to another, consistent with the fact that the abrupt doubling of spacing predicted by Warren and Langer for an idealized periodic array affects different wavelengths of the distribution at different times. This transition is shown to depend on the rate of change in growth speed using phase-field simulations of directional solidification where the pulling speed is ramped at different rates. In particular, for high rates of change of the pulling speed we observe temporary marginally stable array configurations separated by relatively short lived transitions, while for lower rates of change of the pulling speed the distinction between incubation and transition periods disappears.


Mutations in dynein link motor neuron degeneration to defects in retrograde transport.
Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.


Crenosoma brasiliense sp. n. (Nematoda: Metastrongyloidea) parasitic in lesser grison, Galictis cuja (Molina, 1782) (Carnivora, Mustelidae) from Brazil, with a key to species of Crenosoma Molin, 1861.
This study describes Crenosoma brasiliense (Nematoda, Metastrongyloidea), a new species parasitic in bronchi and bronchioles of Galictis cuja (Molina) (Carnivora, Mustelidae) from Brazil. This species differs from other 11 species of Crenosoma by having a cuticular projection at the distal end of the spicules, forming a prominent blade at the tip of the spicule, a vulval cuticular appendage with a triangular shape and prominent vulval lips. There are no previous records of species of Metastrongyloidea in G. cuja or species of Crenosoma in South America. Therefore, the new species represents the first host record and first geographical record of species of Crenosoma in South America.


Characteristics of vomiting as a predictor of intracranial injury in pediatric minor head injury.
Vomiting is common in children after minor head injury. In previous research, isolated vomiting was not a significant predictor of intracranial injury after minor head injury; however, the significance of recurrent vomiting is unclear. This study aimed to determine the value of recurrent vomiting in predicting intracranial injury after pediatric minor head injury. This secondary analysis of the CATCH2 prospective multicenter cohort study included participants (0-16 years) who presented to a pediatric emergency department (ED) within 24 hours of a minor head injury. ED physicians completed standardized clinical assessments. Recurrent vomiting was defined as ≥ four episodes. Intracranial injury was defined as acute intracranial injury on computed tomography scan. Predictors were examined using chi-squared tests and logistic regression models. A total of 855 (21.1%) of the 4,054 CATCH2 participants had recurrent vomiting, 197 (4.9%) had intracranial injury, and 23 (0.6%) required neurosurgical intervention. Children with recurrent vomiting were significantly more likely to have intracranial injury (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.7-3.1), and require neurosurgical intervention (OR, 3.5; 95% CI, 1.5-7.9). Recurrent vomiting remained a significant predictor of intracranial injury (OR, 2.8; 95% CI, 1.9-3.9) when controlling for other CATCH2 criteria. The probability of intracranial injury increased with number of vomiting episodes, especially when accompanied by other high-risk factors, including signs of a skull fracture, or irritability and Glasgow Coma Scale score < 15 at 2 hours postinjury. Timing of first vomiting episode, and age were not significant predictors. Recurrent vomiting (≥ four episodes) was a significant risk factor for intracranial injury in children after minor head injury. The probability of intracranial injury increased with the number of vomiting episodes and if accompanied by other high-risk factors, such as signs of a skull fracture or altered level of consciousness.


[6]-Shogaol attenuates inflammation, cell proliferation via modulate NF-κB and AP-1 oncogenic signaling in 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis.
Nuclear factor-kappaB (NF-κB) and activator protein 1 (AP-1) is a major transcription factor which regulates many biological and pathological processes such as inflammation and cell proliferation, which are major implicates in cancer progression. [6]-Shogaol ([6]-SHO) is a major constituent of ginger, exhibits various biological properties such as anti-oxidants, anti-inflammation and anti-tumor. Recently, we proven that [6]-SHO prevents oral squamous cell carcinoma by activating proapoptotic factors in in vitro and in vivo experimental model. However, the preventive efficacy of [6]-SHO in 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis (HBP) has not been fully elucidated, so far. Hence, we aimed to investigate the effect of [6]-SHO on inflammation and cell proliferation by inhibiting the translocation of NF-κB and AP-1 in DMBA induced HBP carcinogenesis. In this study, we observed upregulation of inflammatory markers (COX-2, iNOS, TNF-α, interleukin-1 and -6), cell proliferative markers (Cyclin D1, PCNA and Ki-67) and aberrant activation of NF-κB, AP-1, IKKβ, c-jun, c-fos and decreased IκB-α in DMBA induced hamsters. Conversely, oral administration of [6]-SHO strongly inhibited constitutive phosphorylation and degradation of IκB and inhibit phosphorylation of c-jun, c-fos, resulting in inhibition of nuclear translocation of NF-κBp65 and AP-1. Thus, inhibition of NF-κB and AP-1 activation by [6]-SHO attenuates inflammation and cell proliferative response in DMBA induced hamsters. Our finding suggested that [6]-SHO is a novel functional agent capable of preventing DMBA induced inflammation and cell proliferation associated tumorigenesis by modulating multiple signalling molecules.


Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia.
Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34(+) umbilical cord blood (CB) and bone marrow (BM) cells with 3 lentiviral vectors expressing small interfering RNA (siRNA) against RPS19 and 1 scrambled control vector. All vectors also express green fluorescent protein (GFP). Transduction with the siRNA vectors reduced RPS19 mRNA levels to various degrees, which resulted in erythroid defects, correlating to the degree of RPS19 down-regulation, and was rescued by expression of an siRNA-resistant RPS19 transcript. Erythroid colony formation capacity conjointly decreased with RPS19 levels in CD34(+) CB and BM cells. In liquid culture supporting erythroid differentiation, RPS19-silenced as well as DBA patient CD34(+) cells exhibited reduced proliferative capacity and impaired erythroid differentiation resulting in fewer erythroid colony-forming units (CFU-Es). When assaying myeloid development, a less pronounced influence on proliferation was seen. This study shows for the first time that RPS19 silencing decreases the proliferative capacity of hematopoietic progenitors and leads to a defect in erythroid development.


Anomalies of dielectric-coated gratings.
Experimental results at millimeter wavelengths on dielectric-coated gratings are reported that show sharp anomalous dips in the transmission intensity for both P and S polarizations (i.e., incident electric field parallel and perpendicular to the slits, respectively). These dips almost disappear when either the dielectric is removed or the slits are randomly spaced. Next, a theory is developed for the gratings of finite extent and nonuniform spacings. Theoretical results, although approximate, agree remarkably well with the experiment.


The fate of revised uncemented acetabular components in patients with rheumatoid arthritis.
The results of patients with rheumatoid arthritis who had revision hip arthroplasty have been studied infrequently. The purpose of this study was to review the authors' clinical and radiographic experiences and outcomes with revision hip arthroplasty. Revision total hip arthroplasties were done on 28 patients (30 hips). All hips had morselized bone grafting and four hips had bulk allografts for segmental defects. The mean age of the patients at the time of surgery was 50 years (range, 20-74 years). Patients were followed up for 4 to 15 years (mean, 7 years). At the latest followup, 14 hips (13 patients) of the 30 hips (47%) had good and excellent Harris hip score ratings. Mechanical failures included six hips (five patients) that had revision arthroplasty and two hips (two patients) that had resection arthroplasty. Six other hips (five patients) had poor Harris hip score ratings. The Kaplan-Meier survivorship curve for failure of the acetabular component revealed an 89% chance of survivorship curve for failure of the acetabular component revealed an 89% chance of survival at 60 months and a 44% chance of survival at 108 months. Based on the results of this study, revision hip arthroplasty for acetabular loosening with a cementless acetabular prosthesis has a low rate of success in patients with rheumatoid arthritis.


Effect of insulin on spatial memory in aluminum chloride-induced dementia in rats.
Latest reports suggest the involvement of insulin in modulating memory. A few published in-vitro studies favor the antidementia effect of insulin. Thus, the present study aimed to evaluate the prophylactic role of insulin and its combination with glucose and its possible mechanism(s) in an aluminum chloride (AlCl3)-induced cognitive dysfunction model in rodents, with a special focus on memory centers namely, the hippocampus and the frontal cortex. Male Wistar rats were exposed to AlCl3 (175 mg/kg orally) for 60 days. Insulin (0.5 IU/kg), Insulin (0.5 IU/kg) in combination with glucose (200 mg/kg), and rivastigmine (1 mg/kg) were administered intraperitoneally 45 min before the administration of AlCl3 for 60 days. Spatial memory was assessed using the Morris water-maze test. After 60 days of treatment, animals were killed, and the hippocampus and frontal cortex were collected and analyzed for acetylcholinesterase activity and antioxidant enzyme level. Blood glucose levels were also analyzed. Treatment with the standard drug, rivastigmine (1 mg/kg), produced a significant reduction in escape latency and increased the time spent in the target quadrant compared with the AlCl3-treated group. Insulin and its combination with glucose could not inhibit the behavioral impairments in aluminum-exposed rats. Treatment with insulin alone and its combination with glucose reversed the increased glucose levels. Insulin alone and its combination with glucose could not inhibit aluminum-induced oxidative stress and impaired cholinergic transmission in the hippocampus and frontal cortex regions. The study suggests the inability of prophylactic insulin administration against cognitive dysfunction induced by environmental toxin (AlCl3) in the hippocampus and the frontal cortex.


PLK1 down-regulates parainfluenza virus 5 gene expression.
The paramyxoviruses are a family of negative-sense RNA viruses that includes many important human and animal pathogens. Paramyxovirus RNA synthesis requires the viral phosphoprotein (P) and the large (L) protein. Phosphorylation of P is thought to regulate viral gene expression, though direct proof remains elusive. Recently, we reported that phosphorylation of a specific residue (Ser157) of the P protein of parainfluenza virus 5 (PIV5), a prototypical paramyxovirus, correlates with decreased viral gene expression and cytokine expression in infected cells. Here, we show that: Polo-like kinase 1 (PLK1), a serine/theronine kinase that plays a critical role in regulating the cell cycle, interacts with PIV5 P through the S157 residue; PLK1 inhibition increases viral gene expression; PLK1 over-expression inhibits viral gene expression; and PLK1 directly phosphorylates P in vitro, indicating that PLK1 down-regulates viral gene expression by phosphorylating P. Furthermore, we have determined the PLK1 phosphorylation site on P and found that mutant recombinant PIV5 whose P proteins cannot either bind to or be phosphorylated by PLK1 have similar phenotypes. Increased viral gene expression in PIV5 with mutations in the PLK1 binding/phosphorylation sites correlates with increased induction of cell death and cytokine expression, suggesting that PIV5 limits its viral gene expression to avoid these host effects. It is possible that targeting PLK1 will enhance host innate immune responses, leading to a novel strategy of clearing paramyxovirus infections quickly.


Effects of topical anti-inflammatory agents in a botulinum toxin B-induced mouse model of keratoconjunctivitis sicca.
The aim of this study was to compare the effects of topical nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid, doxycycline, and artificial tears for the treatment of ocular surface damage in the Botulinum toxin B (BTX-B)-induced mouse model of dry eye. CBA/J mice were randomized into 2 experimental groups of 35 animals each. The control group received a transconjunctival injection of 0.05 mL of saline into the left lacrimal gland, and another group was injected with 0.05 mL of 20 milliunits BTX-B solution (SPSS, Inc., Chicago, IL). Three (3) days after intralacrimal gland injections, each group was equally randomized into 7 subgroups (n=5 each) to receive treatment unilaterally into their left eyes with topical artificial tears (0.5% carboxymethylcellulose sodium), 0.1% fluorometholone, 0.1% nepafenac, 0.4% ketorolac, 0.09% bromfenac, 0.1% diclofenac, or 0.025% doxycycline. Tear volume, ocular surface changes, and spontaneous blink rate were evaluated in each of the 14 experimental subgroups. Topical fluorometholone, nepafenac, and doxycycline significantly improved corneal surface staining in the BTX-B-injected mice within 2 weeks of treatment. Topical ketorolac, diclofenac, and bromfenac, applied twice-daily, partially reduce corneal staining, and did so more slowly by the 4-week time point. In comparison, topical artificial tear-treated mice did not demonstrate significant improvement of the corneal surface at any time point. Aqueous tear production in the BTX-B-injected fluorometholone-treated group started to return to baseline level within 2 weeks, although not significantly. Meanwhile, BTX-B-injected mice treated with artificial tears, topical NSAIDs, and doxycycline still exhibited a reduction in tear production up to 4 weeks. No significant differences in blink rate between the control and study groups undergoing the various treatments were noted at all time points. This study suggests the potential usefulness of topical NSAIDs, corticosteroid, and doxycycline for the clinical treatment of ocular surface epithelial disorders associated with dry eye.


A novel approach towards development of real time chemical dosimetry using pulsating sensor-based instrumentation.
The paper presents an innovative approach towards development of real time dosimetry using a chemical dosimeter for measurement of absorbed radiation dose in the range between 1 and 400 Gy. Saturated chloroform solution in water, a well known chemical dosimeter, is used to demonstrate the concept of online measurement of radiation dose. The measurement approach involves online monitoring of increase in conductivity of saturated chloroform solution due to progressive build up of traces of highly conducting HCl during exposure to gamma irradiation. A high performance pulsating sensor-based conductivity monitoring instrument has been used to monitor such real time change in conductivity of solution. A relation between conductivity shift and radiation dose has been established using radiochemical yield value (G value) of HCl. The G value of HCl in saturated chloroform dosimeter has been determined using laboratory developed pulsating sensor-based devices. In this connection dose rate of Co-60 gamma chamber was determined using Fricke dosimeter following a simple potentiometric measurement approach developed in-house besides conventional spectrophotometry. Results obtained from both measurement approaches agreed well. Complete instrumentation package has also been developed to measure real time radiation dose. The proposed real time radiation dosimeter is successfully tested in several measurement campaigns in order to assure its performance prior to its deployment in field.


Three-dimensional extracellular matrix-directed cardioprogenitor differentiation: systematic modulation of a synthetic cell-responsive PEG-hydrogel.
We show that synthetic three-dimensional (3D) matrix metalloproteinase (MMP)-sensitive poly(ethylene glycol) (PEG)-based hydrogels can direct differentiation of pluripotent cardioprogenitors, using P19 embryonal carcinoma (EC) cells as a model, along a cardiac lineage in vitro. In order to systematically probe 3D matrix effects on P19 EC differentiation, matrix elasticity, MMP-sensitivity and the concentration of a matrix-bound RGDSP peptide were modulated. Soft matrices (E=322+/-64.2 Pa, stoichiometric ratio: 0.8), mimicking the elasticity of embryonic cardiac tissue, increased the fraction of cells expressing the early cardiac transcription factor Nkx2.5 around 2-fold compared to embryoid bodies (EB) in suspension. In contrast, stiffer matrices (E=4,036+/-419.6 Pa, stoichiometric ratio: 1.2) decreased the number of Nkx2.5-positive cells significantly. Further indicators of cardiac maturation were promoted by ligation of integrins relevant in early cardiac development (alpha(5)beta(1,) alpha(v)beta(3)) by the RGDSP ligand in combination with the MMP-sensitivity of the matrix, with a 6-fold increased amount of myosin heavy chain (MHC)-positive cells as compared to EB in suspension. This precisely controlled 3D culture system thus may serve as a potential alternative to natural matrices for engineering cardiac tissue structures for cell culture and potentially therapeutic applications.