A Forward Regridding Method With Minimal Oversampling for Accurate and Efficient Iterative Tomographic Algorithms.
Reconstruction of underconstrained tomographic data sets remains a major challenge. Standard analytical techniques frequently lead to unsatisfactory results due to insufficient information. Several iterative algorithms, which can easily integrate a priori knowledge, have been developed to tackle this problem during the last few decades. Most of these iterative algorithms are based on an implementation of the Radon transform that acts as forward projector. This operator and its adjoint, the backprojector, are typically called few times per iteration and represent the computational bottleneck of the reconstruction process. Here, we present a Fourier-based forward projector, founded on the regridding method with minimal oversampling. We show that this implementation of the Radon transform significantly outperforms in efficiency other state-of-the-art operators with O(N2log2N) complexity. Despite its reduced computational cost, this regridding method provides comparable accuracy to more sophisticated projectors and can, therefore, be exploited in iterative algorithms to substantially decrease the time required for the reconstruction of underconstrained tomographic data sets without loss in the quality of the results.


Structural and kinetic effects of mobile phone microwaves on acetylcholinesterase activity.
The present study provides evidence that "in vitro" simple exposure of an aqueous solution of electric eel acetylcholinesterase (EeAChE; EC 18.104.22.168.) to cellular phone emission alters its enzymatic activity. This paper demonstrates, by combining different experimental techniques, that radio frequency (RF) radiations irreversibly affect the structural and biochemical characteristics of an important CNS enzyme. These results were obtained by using a commercial cellular phone to reproduce the reality of the human exposition. This experimental procedure provided surprising effects collected practically without experimental errors because they were obtained comparing native and irradiated sample of the same enzyme solution. Although these results cannot be used to conclude whether exposure to RF during the use of cellular phone can lead to any hazardous health effect, they may be a significant first step towards further verification of these effects on other "ex vivo" or "in vivo" biological systems.


A novel role for E2F3b in regulating cocaine action in the prefrontal cortex.
Drug abuse is a multifaceted disorder that involves maladaptive decision making. Long-lasting changes in the addicted brain are mediated by a complex circuit of brain reward regions. The prefrontal cortex (PFC) is one region in which chronic drug exposure changes expression and function of upstream transcriptional regulators to alter drug responses and aspects of the addicted phenotype. We reported recently that the transcription factor E2F3a is a critical mediator of cocaine responses in the nucleus accumbens. E2F3a is one of two splice variants of the E2f3 gene; the other is E2F3b. Another recent study predicted E2F3 as an upstream regulator of the transcriptional response to cocaine self-administration (SA) in PFC. Based on previous findings that E2F3a and E2F3b have divergent regulatory roles, we set out to study the putative transcriptional role of these transcripts in PFC in the context of repeated I.P. cocaine exposure. We implemented viral-mediated isoform-specific gene manipulation, RNA-sequencing, advanced bioinformatics analyses, and animal behavior to determine how E2F3a and E2F3b contribute to persistent cocaine-induced transcriptional changes in PFC. We show that E2F3b, but not E2F3a, in PFC is critical for cocaine locomotor and place preference behaviors. Interestingly, RNA-seq of PFC following E2f3b overexpression or I.P. cocaine exposure showed very different effects on expression levels of differentially expressed genes. However, we found that E2F3b drives a similar transcriptomic pattern to that of cocaine SA with overlapping upstream regulators and downstream pathways predicted. These findings reveal a novel transcriptional mechanism in PFC that controls behavioral and molecular responses to cocaine.


Homomorphic sex chromosomes and the intriguing Y chromosome of Ctenomys rodent species (Rodentia, Ctenomyidae).
Unlike the X chromosome, the mammalian Y chromosome undergoes evolutionary decay resulting in small size. This sex chromosomal heteromorphism, observed in most species of the fossorial rodent Ctenomys, contrasts with the medium-sized, homomorphic acrocentric sex chromosomes of closely related C. maulinus and C. sp. To characterize the sequence composition of these chromosomes, fluorescent banding, self-genomic in situ hybridization, and fluorescent in situ hybridization with an X painting probe were performed on mitotic and meiotic plates. High molecular homology between the sex chromosomes was detected on mitotic material as well as on meiotic plates immunodetected with anti-SYCP3 and anti-γH2AX. The Y chromosome is euchromatic, poor in repetitive sequences and differs from the X by the loss of a block of pericentromeric chromatin. Inferred from the G-banding pattern, an inversion and the concomitant prevention of recombination in a large asynaptic region seems to be crucial for meiotic X chromosome inactivation. These peculiar findings together with the homomorphism of Ctenomys sex chromosomes are discussed in the light of the regular purge that counteracts Muller's ratchet and the probable mechanisms accounting for their origin and molecular homology.


Structure and lipid-binding properties of the kindlin-3 pleckstrin homology domain.
Kindlins co-activate integrins alongside talin. They possess, like talin, a FERM domain (4.1-erythrin-radixin-moiesin domain) comprising F0-F3 subdomains, but with a pleckstrin homology (PH) domain inserted in the F2 subdomain that enables membrane association. We present the crystal structure of murine kindlin-3 PH domain determined at a resolution of 2.23 Å and characterise its lipid binding using biophysical and computational approaches. Molecular dynamics simulations suggest flexibility in the PH domain loops connecting β-strands forming the putative phosphatidylinositol phosphate (PtdInsP)-binding site. Simulations with PtdInsP-containing bilayers reveal that the PH domain associates with PtdInsP molecules mainly via the positively charged surface presented by the β1-β2 loop and that it binds with somewhat higher affinity to PtdIns(3,4,5)P3 compared with PtdIns(4,5)P2 Surface plasmon resonance (SPR) with lipid headgroups immobilised and the PH domain as an analyte indicate affinities of 300 µM for PtdIns(3,4,5)P3 and 1 mM for PtdIns(4,5)P2 In contrast, SPR studies with an immobilised PH domain and lipid nanodiscs as the analyte show affinities of 0.40 µM for PtdIns(3,4,5)P3 and no affinity for PtdIns(4,5)P2 when the inositol phosphate constitutes 5% of the total lipids (∼5 molecules per nanodisc). Reducing the PtdIns(3,4,5)P3 composition to 1% abolishes nanodisc binding to the PH domain, as does site-directed mutagenesis of two lysines within the β1-β2 loop. Binding of PtdIns(3,4,5)P3 by a canonical PH domain, Grp1, is not similarly influenced by SPR experimental design. These data suggest a role for PtdIns(3,4,5)P3 clustering in the binding of some PH domains and not others, highlighting the importance of lipid mobility and clustering for the biophysical assessment of protein-membrane interactions.


Breastfeeding duration and cognitive, language and motor development at 18 months of age: Rhea mother-child cohort in Crete, Greece.
Breast feeding duration has been associated with improved cognitive development in children. However, few population-based prospective studies have evaluated dose-response relationships of breastfeeding duration with language and motor development at early ages, and results are discrepant. The study uses data from the prospective mother-child cohort ('Rhea' study) in Crete, Greece. 540 mother-child pairs were included in the present analysis. Information about parental and child characteristics and breastfeeding practices was obtained by interview-administered questionnaires. Trained psychologists assessed cognitive, language and motor development by using the Bayley Scales of Infant Toddler Development (3rd edition) at the age of 18 months. Duration of breast feeding was linearly positively associated with all the Bayley scales, except of gross motor. The association persisted after adjustment for potential confounders with an increase of 0.28 points in the scale of cognitive development (β=0.28; 95% CI 0.01 to 0.55), 0.29 points in the scale of receptive communication (β=0.29; 95% CI 0.04 to 0.54), 0.30 points in the scale of expressive communication (β=0.30; 95% CI 0.04 to 0.57) and 0.29 points in the scale of fine motor development (β=0.29; 95% CI 0.02 to 0.56) per accumulated month of breast feeding. Children who were breast fed longer than 6 months had a 4.44-point increase in the scale of fine motor development (β=4.44; 95% CI 0.06 to 8.82) compared with those never breast fed. Longer duration of breast feeding was associated with increased scores in cognitive, language and motor development at 18 months of age, independently from a wide range of parental and infant characteristics. Additional longitudinal studies and trials are needed to confirm these results.


Solvent effects on coupling yields during rapid solid-phase synthesis of CGRP(8-37) employing in situ neutralization.
The success of solid-phase peptide synthesis is often dependent upon solvation of the resin and the growing resin-bound peptide chain. We investigated the relationship between solvent properties and solvation of the resin and peptide-resin in order to obtain satisfactory coupling yields for the rapid solid-phase peptide synthesis, using butyloxycarbonyl-(Boc)-amino acid derivatives, of human-alpha-calcitonin gene-related peptide(8-37) (CGRP(8-37)). Solvation of (p-methylbenzhydrylamine)copoly(styrene-1% divinylbenzene (DVB) (resin) and resin covalently bound to the fully protected amino acid sequence of CGRP(8-37) (peptide-resin) was correlated to solvent Hildebrand solubility (delta) and hydrogen-bonding (delta(h)) parameters. Contour solvation plots of delta(h) vs. delta revealed maximum solvation regions of resin and peptide-resin. Maximum resin solvation occurred with N-methylpyrrolidinone (NMP), NMP : dimethylsulfoxide (DMSO) (8 : 2) and DMSO. Inefficient solvation of the peptide-resin occurred with these solvents and resulted in poor syntheses with average coupling yields of 78.1, 88.9 and 91.8%, respectively. Superior peptide-resin solvation was obtained using dimethylacetamide (DMA) and dimethylformamide (DMF), resulting in significantly higher average coupling yields of 98.0 and 99.5%, respectively. Thus, the region of maximum peptide-resin solvation shifts to solvents with higher delta(h) values. DMF provided the most effective peptide-resin solvation and was the only solvent from which CGRP(8-37) was obtained as a single major product in the crude cleaved material.


Nutrient Limitation in Surface Waters of the Oligotrophic Eastern Mediterranean Sea: an Enrichment Microcosm Experiment.
The growth rates of planktonic microbes in the pelagic zone of the Eastern Mediterranean Sea are nutrient limited, but the type of limitation is still uncertain. During this study, we investigated the occurrence of N and P limitation among different groups of the prokaryotic and eukaryotic (pico-, nano-, and micro-) plankton using a microcosm experiment during stratified water column conditions in the Cretan Sea (Eastern Mediterranean). Microcosms were enriched with N and P (either solely or simultaneously), and the PO4 turnover time, prokaryotic heterotrophic activity, primary production, and the abundance of the different microbial components were measured. Flow cytometric and molecular fingerprint analyses showed that different heterotrophic prokaryotic groups were limited by different nutrients; total heterotrophic prokaryotic growth was limited by P, but only when both N and P were added, changes in community structure and cell size were detected. Phytoplankton were N and P co-limited, with autotrophic pico-eukaryotes being the exception as they increased even when only P was added after a 2-day time lag. The populations of Synechococcus and Prochlorococcus were highly competitive with each other; Prochlorococcus abundance increased during the first 2 days of P addition but kept increasing only when both N and P were added, whereas Synechococcus exhibited higher pigment content and increased in abundance 3 days after simultaneous N and P additions. Dinoflagellates also showed opportunistic behavior at simultaneous N and P additions, in contrast to diatoms and coccolithophores, which diminished in all incubations. High DNA content viruses, selective grazing, and the exhaustion of N sources probably controlled the populations of diatoms and coccolithophores.


Anti-VEGF antibody treatment accelerates polycystic kidney disease.
Polycystic kidney growth implies expansion of the vasculature, suggesting that vascular endothelial growth factor (VEGF)-dependent processes play a critical role and that VEGF is a putative therapeutic target. Whether an anti-VEGF antibody improves renal cystic disease has not been determined. We administrated 5 mg/kg B20.4.1, an anti-VEGF-A antibody, or vehicle intraperitoneally twice weekly to 4-wk-old male normal (+/+) and cystic (Cy/+) Han:SPRD rats for 6 wk. Renal function, urinary protein excretion, organ/body weight ratios, cyst volume, tubular epithelial cell (TEC) proliferation, renal VEGF, hypoxia-inducible factor (HIF)-1α and -2α expression, renal histology, and kidney hypoxia visualized by [(18)F]fluoromisonidazole positron emission tomography were assessed. The treated compared with untreated +/+ rats had lower TEC proliferation rates, whereas Cy/+ rats receiving B20.4.1 displayed an increased proximal TEC proliferation rate, causing enhanced cyst and kidney growth. The +/+ and Cy/+ rats receiving B20.4.1 had severe renal failure and extensive glomerular damage. Proteinuria, which was highest in anti-VEGF-treated Cy/+ and lowest in untreated normal littermates, was positively correlated with renal HIF-1α and negatively correlated with VEGF expression. The untreated Cy/+ vs. +/+ rats had higher overall [(18)F]fluoromisonidazole uptake. The +/+ rats receiving B20.4.1 vs. untreated had increased [(18)F]fluoromisonidazole uptake, whereas the uptake was unchanged among treated vs. untreated Cy/+ animals. In conclusion, B20.4.1 caused an exaggerated cystic response of the proximal tubules in cystic rats and severe kidney injury that was associated with low renal VEGF and high HIF-1α levels. Anti-VEGF drug therapy may therefore not be a treatment option for polycystic kidney disease.


Do haplogroups H and U act to increase the penetrance of Alzheimer's disease?
1. Alzheimer's disease (AD) is the most common form of dementia in the elderly in which interplay between genes and the environment is supposed to be involved. Mitochondrial DNA (mtDNA) has the only noncoding regions at the displacement loop (D-loop) region that contains two hypervariable segments (HVS-I and HVS-II) with high polymorphism. mtDNA has already been fully sequenced and many subsequent publications have shown polymorphic sites, haplogroups, and haplotypes. Haplogroups could have important implications to understand the association between mutability of the mitochondrial genome and the disease.2. To assess the relationship between mtDNA haplogroup and AD, we sequenced the mtDNA HVS-I in 30 AD patients and 100 control subjects. We could find that haplogroups H and U are significantly more abundant in AD patients (P = 0.016 for haplogroup H and P = 0.0003 for haplogroup U), Thus, these two haplogroups might act synergistically to increase the penetrance of AD disease.


Randomised Controlled Trial Comparing Daily Versus Depot Vitamin D3 Therapy in 0-16-Year-Old Newly Settled Refugees in Western Australia Over a Period of 40 Weeks.
Vitamin D deficiency is highly prevalent in newly settled refugees in Western Australia (WA). If adherence to daily vitamin D therapy is problematic, depot therapy is a therapeutic alternative. The aim of this study was to compare daily versus depot treatment and factors influencing the therapeutic outcome. Newly settled refugees (n = 151) with 25(OH)D levels less than 78 nmol/L were randomised to receive daily or depot vitamin D therapy with eight weekly interval follow up to 40 weeks. Biochemical and clinical parameters were collected at each visit. Generalized Linear Mixed Models (GLMM) examined the longitudinal changes over time controlling for confounders including age, gender, treatment arm, season, country of refuge/origin and sun exposure score. Participants were aged 5.5 months to 16.0 years (75 males, 83 females). Both treatment groups achieved vitamin D sufficiency. The daily treatment group had significantly higher 25(OH)D levels at each visit post baseline and a higher proportion of participants with levels above 50 nmol/L at all time points. Time, treatment group, calcium and sun exposure score were significant predictors of 25(OH)D serum levels. Depot vitamin D therapy is an alternative to daily treatment in this at-risk group of children and adolescents in whom treatment adherence is problematic.


Hot-Volumes as Uniform and Reproducible SERS-Detection Enhancers in Weakly-Coupled Metallic Nanohelices.
Reproducible and enhanced optical detection of molecules in low concentrations demands simultaneously intense and homogeneous electric fields acting as robust signal amplifiers. To generate such sophisticated optical near-fields, different plasmonic nanostructures were investigated in recent years. These, however, exhibit either high enhancement factor (EF) or spatial homogeneity but not both. Small interparticle gaps or sharp nanostructures show enormous EFs but no near-field homogeneity. Meanwhile, approaches using rounded and separated monomers create uniform near-fields with moderate EFs. Here, guided by numerical simulations, we show how arrays of weakly-coupled Ag nanohelices achieve both homogeneous and strong near-field enhancements, reaching even the limit forreproducible detection of individual molecules. The unique near-field distribution of a single nanohelix consists of broad hot-spots, merging with those from neighbouring nanohelices in specific array configurations and generating a wide and uniform detection zone ("hot-volume"). We experimentally assessed these nanostructures via surface-enhanced Raman spectroscopy, obtaining a corresponding EF of ~107 and a relative standard deviation <10%. These values demonstrate arrays of nanohelices as state-of-the-art substrates for reproducible optical detection as well as compelling nanostructures for related fields such as near-field imaging.


A Compressed Language Model Embedding Dataset of ICD 10 CM Descriptions.
This paper presents novel datasets providing numerical representations of ICD-10-CM codes by generating description embeddings using a large language model followed by a dimension reduction via autoencoder. The embeddings serve as informative input features for machine learning models by capturing relationships among categories and preserving inherent context information. The model generating the data was validated in two ways. First, the dimension reduction was validated using an autoencoder, and secondly, a supervised model was created to estimate the ICD-10-CM hierarchical categories. Results show that the dimension of the data can be reduced to as few as 10 dimensions while maintaining the ability to reproduce the original embeddings, with the fidelity decreasing as the reduced-dimension representation decreases. Multiple compression levels are provided, allowing users to choose as per their requirements. The readily available datasets of ICD-10-CM codes are anticipated to be highly valuable for researchers in biomedical informatics, enabling more advanced analyses in the field. This approach has the potential to significantly improve the utility of ICD-10-CM codes in the biomedical domain.


Generating arbitrary one-dimensional dose profiles using rotational therapy.
Conformal radiation therapy can be delivered using several methods: intensity-modulated radiotherapy (IMRT) at fixed gantry angles, through the continuous gantry rotation of linac (rotational arc therapy), or by a dedicated treatment unit such as tomotherapy. The recently developed volumetric modulated arc therapy (VMAT), a form of rotational arc therapy, has attracted lots of attention from investigators to explore its capability of generating highly conformal dose to the target. The main advanced features of VMAT are the variable dose rate and gantry rotation speed. In this paper, we present a theoretical framework of generating arbitrary one-dimensional dose profiles using rotational arc therapy to further explore the new degree of freedom of the VMAT technique. This framework was applied to design a novel technique for total body irradiation (TBI) treatment, where the desired dose distribution can be simplified by a one-dimensional profile. The technique was validated using simulations and experimental measurements. The preliminary results demonstrated that the new TBI technique using either dynamic MLC only, variable dose rate only, or a combination of dynamic MLC and variable dose rate can achieve arbitrary dose distribution in one dimension, such as uniform dose to target and lower dose to critical organ. This technique does not require the use of customized compensators, nor large treatment rooms as in the conventional extended SSD technique.


Extrastriate Visual Areas Integrate Form Features over Space and Time to Construct Representations of Stationary and Rigidly Rotating Objects.
When an object moves behind a bush, for example, its visible fragments are revealed at different times and locations across the visual field. Nonetheless, a whole moving object is perceived. Unlike traditional modal and amodal completion mechanisms known to support spatial form integration when all parts of a stimulus are simultaneously visible, relatively little is known about the neural substrates of the spatiotemporal form integration (STFI) processes involved in generating coherent object representations from a succession visible fragments. We used fMRI to identify brain regions involved in two mechanisms supporting the representation of stationary and rigidly rotating objects whose form features are shown in succession: STFI and position updating. STFI allows past and present form cues to be integrated over space and time into a coherent object even when the object is not visible in any given frame. STFI can occur whether or not the object is moving. Position updating allows us to perceive a moving object, whether rigidly rotating or translating, even when its form features are revealed at different times and locations in space. Our results suggest that STFI is mediated by visual regions beyond V1 and V2. Moreover, although widespread cortical activation has been observed for other motion percepts derived solely from form-based analyses [Tse, P. U. Neural correlates of transformational apparent motion. Neuroimage, 31, 766-773, 2006; Krekelberg, B., Vatakis, A., & Kourtzi, Z. Implied motion from form in the human visual cortex. Journal of Neurophysiology, 94, 4373-4386, 2005], increased responses for the position updating that lead to rigidly rotating object representations were only observed in visual areas KO and possibly hMT+, indicating that this is a distinct and highly specialized type of processing.


Obesity and adiposity: the culprit of dietary protein efficacy.
Obesity and increased body adiposity have been alarmingly increasing over the past decades and have been linked to a rise in food intake. Many dietary restrictive approaches aiming at reducing weight have resulted in contradictory results. Additionally, some policies to reduce sugar or fat intake were not able to decrease the surge of obesity. This suggests that food intake is controlled by a physiological mechanism and that any behavioural change only leads to a short-term success. Several hypotheses have been postulated, and many of them have been rejected due to some limitations and exceptions. The present review aims at presenting a new theory behind the regulation of energy intake, therefore providing an eye-opening field for energy balance and a potential strategy for obesity management.


The association of body mass index and prostate-specific antigen in a population-based study.
Recent studies of men with prostate carcinoma suggest that obesity may be associated with more advanced-stage disease and lower overall survival rates. One possible link between body mass index (BMI) and prostate carcinoma prognosis may be disease ascertainment. Prostate-specific antigen (PSA) is widely used to screen for prostate carcinoma. The authors examined the association between BMI and PSA in a population-based study of 2779 men without prostate carcinoma. Between 2001 and 2004, these men were enrolled in a study sponsored by the San Antonio Center of Biomarkers of Risk, a clinical and epidemiologic center of the Early Detection Research Network of the National Cancer Institute. The mean PSA value decreased in a linear fashion with an increase in BMI category, from 1.01 ng/mL in normal weight men to 0.69 ng/mL in obese (Class III) men, after adjusting for race/ethnicity and age. Lower levels of PSA in obese and overweight men could mask biologically consequential prostate carcinoma.


Seasonal influenza vaccination campaigns for health care personnel: systematic review.
In Canada, vaccination coverage for seasonal influenza among health care personnel remains below 50%. The objective of this review was to determine which seasonal influenza vaccination campaign or campaign components in health care settings were significantly associated with increases in influenza vaccination among staff. We identified articles in eight electronic databases and included randomized controlled trials, controlled before-and-after studies and studies with interrupted time series designs in our review. Two reviewers independently abstracted the data and assessed the risk of biases. We calculated risk ratios and 95% confidence intervals for randomized controlled trials and controlled before-and-after studies and described interrupted time series studies. We identified 99 studies evaluating influenza vaccination campaigns for health care workers, but only 12 of the studies were eligible for review. In nonhospital health care settings, including long-term care facilities, campaigns with a greater variety of components (including education or promotion, better access to vaccines, legislation or regulation and/or role models) were associated with higher risk ratios (i.e, favouring the intervention group). Within hospital settings, the results reported for various types of campaigns were mixed. Many of the criteria for assessing risk of bias were not reported. Campaigns involving only education or promotion resulted in minimal changes in vaccination rates. Further studies are needed to determine the appropriate components and combinations of components in influenza vaccination campaigns for health care personnel.


T-cell activation, both pre- and post-HAART levels, correlates with carotid artery stiffness over 6.5 years among HIV-infected women in the WIHS.
T-cell activation is a major pathway driving HIV disease progression. Little is known regarding the impact of T-cell activation on HIV-associated atherosclerosis and cardiovascular disease, a common comorbidity in HIV infection. We hypothesized that T-cell activation will predict vascular stiffness, a measure of subclinical atherosclerosis. Linear regression models evaluated the covariate-adjusted association of T-cell activation with vascular stiffness. CD38 and HLA-DR expression on CD4⁺ and CD8⁺ T cells was assessed by flow cytometry among 59 HIV-negative and 376 HIV-infected (185 hepatitis C coinfected) women in the Women's Interagency HIV Study. T-cell activation was defined by CD8⁺CD38⁺DR+ and CD4⁺CD3⁺8DR+. Multiple activation assessments over 6.5 years were averaged. In 140 women, T-cell activation was measured before and after highly active antiretroviral therapy (HAART) initiation. Carotid artery ultrasounds were completed a median of 6.5 years after last measurement of T-cell activation and carotid artery stiffness including distensibility and elasticity were calculated. Percentages of CD4⁺ and CD8⁺ T-cell activation were significantly higher in HIV- infected compared with HIV-negative women. Among HIV-negative women, T-cell activation was not associated with carotid artery stiffness. Among HIV-infected women, higher CD4⁺ T-cell activation levels significantly predicted increased arterial stiffness independent of CD4⁺ cell count and HIV RNA. The association was stronger among HIV/hepatitis C-coinfected women compared with HIV-monoinfected women; however, the difference was not statistically significant (P for interaction >0.05). Pre- and post-HAART levels of CD4⁺ T-cell activation significantly predicted carotid artery stiffness. Persistent T-cell activation, even after HAART initiation, can contribute to structural and/or functional vascular damage accelerating atherogenesis in HIV infection. These results need to be confirmed in a longitudinal prospective study.


Anti-seizure activity of the aqueous leaf extract of Solanum nigrum linn (solanaceae) in experimental animals.
Solanum nigrum is claimed in traditional medical practice, to be useful in the treatment of epilepsy in some parts of Nigeria. To study the anti-convulsant property of the aqueous extract of the leaves of S. nigrum in chicks, mice and rats. Aqueous extracts were administered intraperitoneally, at a pre-treatment time of 30 minutes, at graded doses and animals were challenged with different types of proconvulsants. The aqueous leaf extract produced a significantly (P<0.05) dose dependent protection against electrically-induced seizure in chicks and rats, pentylenetetrazole-induced seizure in mice and rats and picrotoxin-induced seizure in mice and rats. The anti-seizure property of the extract was potentiated by amphetamine. The result obtained in this study suggests that the leaves of this plant may possess anti-convulsant property in chicks, mice and rats.


Human cytomegalovirus glycoprotein N (gpUL73-gN) genomic variants: identification of a novel subgroup, geographical distribution and evidence of positive selective pressure.
Human cytomegalvirus (HCMV) ORF UL73 is a polymorphic locus, encoding the viral glycoprotein gpUL73-gN, a component of the gC-II envelope complex. The previously identified gN genomic variants, denoted gN-1, gN-2, gN-3 and gN-4, were further investigated in this work by analysing a large panel of HCMV clinical isolates collected from all over the world (223 samples). Sequencing and phylogenetic analysis confirmed the existence of the four gN genotypes, but also allowed the identification of a novel subgroup belonging to the gN-3 genotype, which was designated gN-3b. The number of non-synonymous (d(N)) and synonymous (d(S)) nucleotide substitutions and their ratio (d(N)/d(S)) were estimated among the gN genotypes to evaluate the possibility of positive selection. Results showed that the four variants evolved by neutral (random) selection, but that the gN-3 and gN-4 genotypes are maintained by positive selective pressure. The 223 HCMV clinical isolates were subdivided according to their geographical origin, and four main regions of gN prevalence were identified: Europe, China, Australia and Northern America. The gN variants were found to be widespread and represented within the regions analysed without any significant difference, and no new genotype was detected. Finally, for clinical and epidemiological purposes, a rapid and low-cost method for genetic grouping of the HCMV clinical isolates was developed based on the RFLP revealed by SacI, ScaI and SalI digestion of the PCR-amplified UL73 sequence. This technique enabled us to distinguish all four gN genomic variants and also their subtypes.


Selective and divided attention during visual discriminations of shape, color, and speed: functional anatomy by positron emission tomography.
Positron emission tomography (PET) was used to identify the neural systems involved in discriminating the shape, color, and speed of a visual stimulus under conditions of selective and divided attention. Psychophysical evidence indicated that the sensitivity for discriminating subtle stimulus changes in a same-different matching task was higher when subjects selectively attended to one attribute than when they divided attention among the attributes. PET measurements of brain activity indicated that modulations of extrastriate visual activity were primarily produced by task conditions of selective attention. Attention to speed activated a region in the left inferior parietal lobule. Attention to color activated a region in the collateral sulcus and dorsolateral occipital cortex, while attention to shape activated collateral sulcus (similarly to color), fusiform and parahippocampal gyri, and temporal cortex along the superior temporal sulcus. Outside the visual system, selective and divided attention activated nonoverlapping sets of brain regions. Selective conditions activated globus pallidus, caudate nucleus, lateral orbitofrontal cortex, posterior thalamus/colliculus, and insular-premotor regions, while the divided condition activated the anterior cingulate and dorsolateral prefrontal cortex. The results in the visual system demonstrate that selective attention to different features modulates activity in distinct regions of extrastriate cortex that appear to be specialized for processing the selected feature. The disjoint pattern of activations in extravisual brain regions during selective- and divided-attention conditions also suggests that preceptual judgements involve different neural systems, depending on attentional strategies.


Dissecting the Salmonella response to copper.
Intracellular copper homeostasis in bacteria is maintained as the result of a complex ensemble of cellular processes that in Escherichia coli involve the coordinated action of two systems, cue and cus. In contrast, the pathogenic bacterium Salmonella harbours only the cue regulon, including copA, which is shown here to be transcriptionally controlled by CueR. Mutant strains in the CueR-regulated genes were constructed to characterize the response of Salmonella enterica serovar Typhimurium to high concentrations of extracellular copper under both aerobic and anaerobic conditions. Unlike its counterpart in E. coli, inactivation of cuiD displays the most severe phenotype and is also required for copper tolerance under anaerobic conditions. Deletion of copA has a mild effect in aerobiosis, but strongly impairs survival in the absence of oxygen. In a DeltacopA strain, a second Salmonella-specific P-type ATPase, GolT, can substitute the copper transporter, diminishing the effect of its deletion. The overall results highlight the importance of the cue system for controlling intracellular copper stress. The observed differences between Salmonella and E. coli in handling copper excess may contribute to our understanding of the distinct capability of these related pathogenic bacteria to survive outside the host.


An Ex Vivo Tissue Culture Model of Cartilage Remodeling in Bovine Knee Explants.
Ex vivo culture systems cover a broad range of experiments dedicated to studying tissue and cellular function in a native setting. Cartilage is a unique tissue important for proper function of the synovial joint and is constituted by a dense extracellular matrix (ECM), rich in proteoglycan and type II collagen. Chondrocytes are the only cell type present within cartilage and are widespread and relatively low in number. Altered external stimuli and cellular signalling can lead to changes in ECM composition and deterioration, which are important pathological hallmarks in diseases such as osteoarthritis (OA) and rheumatoid arthritis. Ex vivo cartilage models allow 1) profiling of chondrocyte mediated alterations of cartilage tissue turnover, 2) visualizing the cartilage ECM composition, and 3) chondrocyte rearrangement directly in the tissue. Profiling these alterations in response to stimuli or treatments are of high importance in various aspects of cartilage biology, and complement in vitro experiments in isolated chondrocytes, or more complex models in live animals where experimental conditions are more difficult to control. Cartilage explants present a translational and easily accessible method for assessing tissue remodeling in the cartilage ECM in controllable settings. Here, we describe a protocol for isolating and culturing live bovine cartilage explants. The method uses tissue from the bovine knee, which is easily accessible from the local butchery. Both explants and conditioned culture medium can be analyzed to investigate tissue turnover, ECM composition, and chondrocyte function, thus profiling ECM modulation.


TAP1-independent loading of class I molecules by exogenous viral proteins.
Presentation of peptides derived from endogenous proteins on class I molecules needs functional TAP peptide transporters. To reveal whether class I-associated presentation of exogenous proteins also required the presence of TAP transporters, we assessed in vitro the ability of spleen cells and macrophages from TAP1-deficient mice (TAP1-/-) to present peptides derived from exogenous recombinant viral proteins on their class I molecules. We found that recombinant glyco- and nucleoprotein from lymphocytic choriomeningitis virus and nucleoprotein of vesicular stomatitis virus were presented as efficiently by TAP1-/- cells as by control cells. Peptide regurgitation was not involved. Since particulate, non-replicating antigens can efficiently prime anti-viral cytotoxic T cells in vivo, this new, TAP-independent pathway of class I-associated antigen presentation may be applicable for vaccine strategies.


E-N-cadherin heterodimers define novel adherens junctions connecting endoderm-derived cells.
Intercellular junctions play a pivotal role in tissue development and function and also in tumorigenesis. In epithelial cells, decrease or loss of E-cadherin, the hallmark molecule of adherens junctions (AJs), and increase of N-cadherin are widely thought to promote carcinoma progression and metastasis. In this paper, we show that this "cadherin switch" hypothesis does not hold for diverse endoderm-derived cells and cells of tumors derived from them. We show that the cadherins in a major portion of AJs in these cells can be chemically cross-linked in E-N heterodimers. We also show that cells possessing E-N heterodimer AJs can form semistable hemihomotypic AJs with purely N-cadherin-based AJs of mesenchymally derived cells, including stroma cells. We conclude that these heterodimers are the major AJ constituents of several endoderm-derived tissues and tumors and that the prevailing concept of antagonistic roles of these two cadherins in developmental and tumor biology has to be reconsidered.


Predictors of cervical cancer screening adherence in the United States: a systematic review.
Cervical cancer incidence rates have decreased dramatically since the implementation of the Papanicolaou (Pap) smear. Nevertheless, the American Cancer Society (ACS) estimates for 2013 predicted more than 12,000 new cases of cervical cancer in the United States. Given that some subpopulations in the United States are at a higher risk for cervical cancer than others, efforts to increase screening adherence are warranted. Many studies have explored the demographics of underscreened women, but no systematic reviews of screening demographics in adult US women were identified in the past 10 years, after release of the 2002 ACS cervical cancer screening guidelines. Knowledge of adherence to these guidelines becomes important as new guidelines were developed and released in 2012. The purpose of this systematic review of relevant studies was to identify factors that predict the use of cervical cancer screening in US women. Variables found to be significantly associated with adherence to screening included education, financial status, acculturation, psychosocial issues, and marital status. Using this information, nurse practitioners and other providers can target specific at-risk populations to increase screening by educating women about the need for cervical cancer screening and ensuring access to methods for prevention and early detection of the disease.


Accessing targeted therapies for cancer: self and collective advocacy alongside and beyond mainstream cancer charities.
As precision oncology has evolved, patients and their families have become more involved in efforts to access these treatments via fundraising and campaigning that take place outside of the larger cancer charities. In this paper, we explore the solidarities, networks, and emotional work of the UK-based access advocates, drawing on the stories of nine advocates, which included interviews and content analyses of their social media posts and coverage of their case in news, commentary, and fundraising websites. We consider the emotional and knowledge work of building networks that spanned consumerist and activist agendas, forged individual and collective goals, and orientations toward the public, private, and third sectors as part of securing support and access. Through these various practices, the actors we have studied cultivated personal advantage and solidarities with other patients and advocates, and in so doing engaged in self and collective advocacy alongside and beyond mainstream cancer charities.


Analysis of genetic diversity and sites of recombination in human rhinovirus species C.
Human rhinoviruses (HRVs) are a highly prevalent and diverse group of respiratory viruses. Although HRV-A and HRV-B are traditionally detected by virus isolation, a series of unculturable HRV variants have recently been described and assigned as a new species (HRV-C) within the picornavirus Enterovirus genus. To investigate their genetic diversity and occurrence of recombination, we have performed comprehensive phylogenetic analysis of sequences from the 5' untranslated region (5' UTR), VP4/VP2, VP1, and 3Dpol regions amplified from 89 HRV-C-positive respiratory samples and available published sequences. Branching orders of VP4/VP2, VP1, and 3Dpol trees were identical, consistent with the absence of intraspecies recombination in the coding regions. However, numerous tree topology changes were apparent in the 5' UTR, where >60% of analyzed HRV-C variants showed recombination with species A sequences. Two recombination hot spots in stem-loop 5 and the polypyrimidine tract in the 5' UTR were mapped using the program GroupingScan. Available HRV-C sequences showed evidence for additional interspecies recombination with HRV-A in the 2A gene, with breakpoints mapping precisely to the boundaries of the C-terminal domain of the encoded proteinase. Pairwise distances between HRV-C variants in VP1 and VP4/VP2 regions fell into two separate distributions, resembling inter- and intraserotype distances of species A and B. These observations suggest that, without serological cross-neutralization data, HRV-C genetic groups may be equivalently classified into types using divergence thresholds derived from distance distributions. The extensive sequence data from multiple genome regions of HRV-C and analyses of recombination in the current study will assist future formulation of consensus criteria for HRV-C type assignment and identification.


Crystallization dynamics on curved surfaces.
We study the evolution from a liquid to a crystal phase in two-dimensional curved space. At early times, while crystal seeds grow preferentially in regions of low curvature, the lattice frustration produced in regions with high curvature is rapidly relaxed through isolated defects. Further relaxation involves a mechanism of crystal growth and defect annihilation where regions with high curvature act as sinks for the diffusion of domain walls. The pinning of grain boundaries at regions of low curvature leads to the formation of a metastable structure of defects, characterized by asymptotically slow dynamics of ordering and activation energies dictated by the largest curvatures of the system. These glassylike ordering dynamics may completely inhibit the appearance of the ground-state structures.


An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors.
SHP is an orphan member of the nuclear hormone receptor superfamily that contains the dimerization and ligand-binding domain found in other family members but lacks the conserved DNA binding domain. In the yeast two-hybrid system, SHP interacted with several conventional and orphan members of the receptor superfamily, including retinoid receptors, the thyroid hormone receptor, and the orphan receptor MB67. SHP also interacted directly with these receptors in vitro. In mammalian cells, SHP specifically inhibited transactivation by the superfamily members with which it interacted. These results suggest that SHP functions as a negative regulator of receptor-dependent signaling pathways.


Efficacy of gradual pressure-decline compressing stockings in Asian patients with lower leg varicose veins: analysis by general measurements and magnetic resonance image.
Most applications of gradual pressure-decline compressing stockings (GPDCS) are used in the United States and Western European countries, with over a decade of clinical experiments. Up to know, there is no standard establishment of gradual pressure-decline compressing stockings for Asian patients with venous insufficiency and varicose vein formations. We collected data on volunteer candidates of varicose vein for general measurements and assessments and magnetic resonance imaging (MRI) by non-contrast enhanced MRV techniques, and for post processing data analysis. Clinical use of GPCDS provide a mild to moderate improvement in the varicose vein conditions of patients with deep venous insufficiency by improving their deep vein circulation, by general measurements; recording major symptoms and complaint; comfort and stretching/flexibility to the candidates after using GPDCS; and area changes/flow velocity changes/available hemoglobin changes in deep veins monitored by MRI. The benefits and data collected in these results may help in developing compression stockings standards in Taiwanese and Asian countries, and to establishing criterias for product sizes, compression levels, and related parameters.


Diamond-metal contacts: interface barriers and real-time characterization.
A review of diamond-metal contacts is presented with reference to reported values of interfacial potential (Schottky) barriers and their dependence on macroscopic and microscopic properties of the diamond surface, the interface and the metal. No simple model can account for the overall spread of p-diamond barriers, although there are, for certain metals, correlations with metal electronegativity, interface chemistry and diamond surface preparation. Detailed studies are presented for a selected contact (Al-p-diamond) using real-time monitoring during metal growth from sub-nanometre to bulk films and subsequent in situ heating to 1000 °C. This contact, prepared in a clean vacuum environment on characterized single-crystal substrates, provides a case study for a combined in situ electrical and spectroscopic investigation using IV measurements for macroscopic diodes and real-time photoelectron spectroscopy for nanoscale metal films. Band bending during growth leads to a rectifying contact with a measured IV barrier height of 1.05 V and an ideality factor of 1.4. A transition from layered to clustered growth of the metal film is revealed in the real-time measurements and this is confirmed by AFM. For the annealed contact, a direct correlation is revealed by real-time photoemission between the onset of interfacial carbide formation and the change from a rectifying to an ohmic contact at 482 °C.


Patterns and drivers of intraspecific variation in avian life history along elevational gradients: a meta-analysis.
Elevational gradients provide powerful natural systems for testing hypotheses regarding the role of environmental variation in the evolution of life-history strategies. Case studies have revealed shifts towards slower life histories in organisms living at high elevations yet no synthetic analyses exist of elevational variation in life-history traits for major vertebrate clades. We examined (i) how life-history traits change with elevation in paired populations of bird species worldwide, and (ii) which biotic and abiotic factors drive elevational shifts in life history. Using three analytical methods, we found that fecundity declined at higher elevations due to smaller clutches and fewer reproductive attempts per year. By contrast, elevational differences in traits associated with parental investment or survival varied among studies. High-elevation populations had shorter and later breeding seasons, but longer developmental periods implying that temporal constraints contribute to reduced fecundity. Analyses of clutch size data, the trait for which we had the largest number of population comparisons, indicated no evidence that phylogenetic history constrained species-level plasticity in trait variation associated with elevational gradients. The magnitude of elevational shifts in life-history traits were largely unrelated to geographic (altitude, latitude), intrinsic (body mass, migratory status), or habitat covariates. Meta-population structure, methodological issues associated with estimating survival, or processes shaping range boundaries could potentially explain the nature of elevational shifts in life-history traits evident in this data set. We identify a new risk factor for montane populations in changing climates: low fecundity will result in lower reproductive potential to recover from perturbations, especially as fewer than half of the species experienced higher survival at higher elevations.


Alterations in free radical tissue-defense mechanisms in streptozocin-induced diabetes in rat. Effects of insulin treatment.
We investigated the possible involvement of reactive oxygen radical-related processes in chronic (12-wk) diabetes induced in rats by streptozocin (STZ). Diabetes was associated with significantly increased activities of catalase (CAT), glutathione reductase (GSSG-RD), and CuZn-superoxide dismutase (SOD) in the pancreas and of CAT and GSSG-RD in the heart. On the other hand, the liver of diabetic rats showed a generalized decrease in CAT, glutathione peroxidase (GSH-PX), and SOD as well as in the levels of reduced glutathione (GSH). Diabetic kidney also showed decreases in CAT and SOD, but the activities of GSH-PX were increased. Insulin treatment (9-12 U/kg body wt) that was started after 8 wk of diabetes and continued for 4 wk reversed all of the foregoing alterations in tissue antioxidant status. Our results suggest the presence of increased oxidative stress in uncontrolled diabetes as manifested by the marked alterations in tissue antioxidant enzyme activities, the magnitude of which increased with the degree of emaciation. The complex patterns of changes observed in the various tissues examined are believed to be the result of compensatory increases in enzyme activities (usually involving enzymes whose activity in control tissues is low) and direct inhibitory effects, possibly resulting from an increased tissue-oxidant activity. Our findings support the view that tissue antioxidant status may be an important factor in the etiology of diabetes and its complications.


CREB trans-activation of disruptor of telomeric silencing-1 mediates forskolin inhibition of CTGF transcription in mesangial cells.
Connective tissue growth factor (CTGF) participates in diverse fibrotic processes including glomerulosclerosis. The adenylyl cyclase agonist forskolin inhibits CTGF expression in mesangial cells by unclear mechanisms. We recently reported that the histone H3K79 methyltransferase disruptor of telomeric silencing-1 (Dot1) suppresses CTGF gene expression in collecting duct cells (J Clin Invest 117: 773-783, 2007) and HEK 293 cells (J Biol Chem In press). In the present study, we characterized the involvement of Dot1 in mediating the inhibitory effect of forskolin on CTGF transcription in mouse mesangial cells. Overexpression of Dot1 or treatment with forskolin dramatically suppressed basal CTGF mRNA levels and CTGF promoter-luciferase activity, while hypermethylating H3K79 in chromatin associated with the CTGF promoter. siRNA knockdown of Dot1 abrogated the inhibitory effect of forskolin on CTGF mRNA expression. Analysis of the Dot1 promoter sequence identified a CREB response element (CRE) at -384/-380. Overexpression of CREB enhanced forskolin-stimulated Dot1 promoter activity. A constitutively active CREB mutant (CREB-VP16) strongly induced Dot1 promoter-luciferase activity, whereas overexpression of CREBdLZ-VP16, which lacks the CREB DNA-binding domain, abolished this activation. Mutation of the -384/-380 CRE resulted in 70% lower levels of Dot1 promoter activity. ChIP assays confirmed CREB binding to the Dot1 promoter in chromatin. We conclude that forskolin stimulates CREB-mediated trans-activation of the Dot1 gene, which leads to hypermethylation of histone H3K79 at the CTGF promoter, and inhibition of CTGF transcription. These data are the first to describe regulation of the Dot1 gene, and disclose a complex network of genetic and epigenetic controls on CTGF transcription.


Lateral trunk lean and medializing the knee as gait strategies for knee osteoarthritis.
To determine (1) if Medial Thrust or Trunk Lean reduces the knee adduction moment (EKAM) the most during gait in patients with medial knee osteoarthritis, (2) if the best overall strategy is the most effective for each patient and (3) if these strategies affect ankle and hip kinetics. Thirty patients with symptomatic medial knee osteoarthritis underwent 3-dimensional gait analysis. Participants received verbal instructions on two gait strategies (Trunk Lean and Medial Thrust) in randomized order after comfortable walking was recorded. The peaks and impulse of the EKAM and strategy-specific kinematic and kinetic variables were calculated for all conditions. Early stance EKAM peak was significantly reduced during Medial Thrust (-29%). During Trunk Lean, early and late stance EKAM peak and EKAM impulse reduced significantly (38%, 21% and -25%, respectively). In 79% of the subjects, the Trunk Lean condition was significantly more effective in reducing EKAM peak than Medial Thrust. Peak ankle dorsi and plantar flexion, knee flexion and hip extension and adduction moments were not significantly increased. Medial Thrust and Trunk Lean reduced the EKAM during gait in patients with knee osteoarthritis. Individual selection of the most effective gait modification strategy seems vital to optimally reduce dynamic knee loading during gait. No detrimental effects on external ankle and hip moments or knee flexion moments were found for these conditions.


Launching the C-HPP neXt-CP50 Pilot Project for Functional Characterization of Identified Proteins with No Known Function.
An important goal of the Human Proteome Organization (HUPO) Chromosome-centric Human Proteome Project (C-HPP) is to correctly define the number of canonical proteins encoded by their cognate open reading frames on each chromosome in the human genome. When identified with high confidence of protein evidence (PE), such proteins are termed PE1 proteins in the online database resource, neXtProt. However, proteins that have not been identified unequivocally at the protein level but that have other evidence suggestive of their existence (PE2-4) are termed missing proteins (MPs). The number of MPs has been reduced from 5511 in 2012 to 2186 in 2018 (neXtProt 2018-01-17 release). Although the annotation of the human proteome has made significant progress, the "parts list" alone does not inform function. Indeed, 1937 proteins representing ∼10% of the human proteome have no function either annotated from experimental characterization or predicted by homology to other proteins. Specifically, these 1937 "dark proteins" of the so-called dark proteome are composed of 1260 functionally uncharacterized but identified PE1 proteins, designated as uPE1, plus 677 MPs from categories PE2-PE4, which also have no known or predicted function and are termed uMPs. At the HUPO-2017 Annual Meeting, the C-HPP officially adopted the uPE1 pilot initiative, with 14 participating international teams later committing to demonstrate the feasibility of the functional characterization of large numbers of dark proteins (CP), starting first with 50 uPE1 proteins, in a stepwise chromosome-centric organizational manner. The second aim of the feasibility phase to characterize protein (CP) functions of 50 uPE1 proteins, termed the neXt-CP50 initiative, is to utilize a variety of approaches and workflows according to individual team expertise, interest, and resources so as to enable the C-HPP to recommend experimentally proven workflows to the proteome community within 3 years. The results from this pilot will not only be the cornerstone of a larger characterization initiative but also enhance understanding of the human proteome and integrated cellular networks for the discovery of new mechanisms of pathology, mechanistically informative biomarkers, and rational drug targets.


Risk factors for development of lower limb osteoarthritis in physically demanding occupations: A narrative umbrella review.
Osteoarthritis (OA) is a common disorder which affects the joints. As relationships between occupational factors and lower limb OA have been widely studied in systematic reviews, the aim of this umbrella review was to synthesize their key findings in the risk factors for development of lower limb OA. A systematic search was conducted using the databases PUBMED, Cumulative Index of Nursing and Allied Health Literature, and Elton B Stevens Company to identify reviews examining associations between lower limb OA and occupational tasks. These reviews were rated for their methodological quality before key data were extracted and synthesized. Sixteen reviews were found, seven pertained to the knee, four to the hip, two to a variety of joints, and three to both the hip and knee. One was deemed to be of high methodological quality, one of critically low methodological quality, and the others of moderate methodological quality. The reviews found moderate to good evidence for heavy occupational lifting to be associated with an increased risk of OA at the knee and the hip. Kneeling, squatting, and climbing, previous injuries to joints, being overweight and obese were also predictive of lower limb OA. Occupations which involve heavy physical workloads increase the risk of developing lower limb OA. Heavy lifting, squatting, knee bending, kneeling, and climbing may all increase the risk of developing OA in both the knees and hips. Efforts to reduce exposure to these tasks, reducing joint injuries, optimizing bodyweight may reduce the risks of lower limb OA for occupations which are physically demanding.


Reducing backward masking through action game training.
Action video game play enhances basic visual skills such as crowding acuity and contrast sensitivity (C. S. Green & D. Bavelier, 2007; R. Li, U. Polat, W. Makous, & D. Bavelier, 2009). Here, we ask whether the dynamics of perception may also be altered as a result of playing action games. A backward masking paradigm was used to test the hypothesis that action video game play also alters the temporal dynamics of vision. As predicted, action gamers showed reduced backward masking and an accompanying training study established the causal role of action game play in this enhancement. Implications of this result are discussed in the context of the faster reaction times and enhanced sensitivity also documented after action game play.


Do we need gastric acid?
Evidence from comparative anatomy and physiology studies indicates that gastric acid secretion developed during the evolution of vertebrates approximately 350 million years ago. The cellular mechanisms that produce gastric acid have been conserved over the millennia and therefore proton pump inhibitors have pharmacological effects in almost all relevant species. These observations suggest that gastric acid provides an important selective advantage; however, in modern-day humans the need for gastric acid can be questioned in light of the widespread use of safe and effective pharmacologic acid suppression. The Kandahar Working Group addressed questions concerning the need, production and effects of gastric acid, specifically: (1) motility in the upper gastrointestinal (GI) tract; (2) neuroendocrine factors; (3) digestive and mucosal processes; (4) microbiology, and (5) central processes and psychological involvement. We addressed each topic with the individual models available to answer our questions including animal versus human studies, pharmacologic, surgical as well as pathophysiologic states of acid suppression.


Nurses' views and experiences of caring for malnourished patients in surgical settings in Saudi Arabia - a qualitative study.
Although the occurrence of malnutrition in hospitals is a growing concern, little is known about how hospital staff understand the care that nurses provide to patients with malnutrition. The purpose of this study was to explore nurses' views and experiences of caring for malnourished patients in Saudi Arabia (KSA). Using a qualitative explorative design, fifteen nurses were interviewed as part of a purposive sample hospital staff. The transcripts were analyzed using latent content analysis. The nurses spontaneously and consistently linked malnutrition with physical inactivity. The two main categories, which emerged, were: 'Potentials for nurses to provide good nutrition and physical activity', and 'Having the ability but not the power to promote proper nutrition and physical activity'. These arose from the subcategories: Good nursing implies providing appropriate health education; Acknowledging the Mourafiq (sitter) as a potential resource for the nursing, but also as a burden; Inadequate control and lack of influence; Cultural diversity and lack of dialog; and Views of women's weight gain in KSA society. The nurses felt they have the capacity and passion to further improve the nutrition and activity of their patients, but obstacles in the health care system are impeding these ambitions. The implications for nursing practice could be acknowledgement of the nurses' views in the clinical practice; culturally adjusted care, improved communication and enhanced language skills.


Recognizing an index case of tuberous sclerosis.
Tuberous sclerosis is the most common neurocutaneous syndrome after neurofibromatosis. Dermatologic manifestations may be the only clues the family physician has to the diagnosis of the disorder, which is also marked by childhood seizures and mental retardation. Characteristic signs of tuberous sclerosis vary widely in severity and can include hypopigmented "ash-leaf spots," fibrous plaques on the forehead, angiofibromas on the face (adenoma sebaceum), a shagreen patch on the lower back and fibromas of the nails. Computed tomographic scanning or magnetic resonance imaging reveal subependymal nodules or cortical "tubers" in the brain. Associated cardiac, retinal, renal and pulmonary pathology can increase morbidity and mortality. Genetic counseling is helpful but has limited use because of the variation in genetic expression and the frequency of new gene mutations that cause this disorder.


Theoretical investigation of silicide Schottky barrier detector integrated in horizontal metal-insulator-silicon-insulator-metal nanoplasmonic slot waveguide.
An ultracompact integrated silicide Schottky barrier detector (SBD) is designed and theoretically investigated to electrically detect the surface plasmon polariton (SPP) propagating along horizontal metal-insulator-silicon-insulator-metal nanoplasmonic slot waveguides at the telecommunication wavelength of 1550 nm. An ultrathin silicide layer inserted between the silicon core and the insulator, which can be fabricated precisely using the well-developed self-aligned silicide process, absorbs the SPP power effectively if a suitable silicide is chosen. Moreover, the Schottky barrier height in the silicide-silicon-silicide configuration can be tuned substantially by the external voltage through the Schottky effect owing to the very narrow silicon core. For a TaSi(2) detector with optimized dimensions, numerical simulation predicts responsivity of ~0.07 A/W, speed of ~60 GHz, dark current of ~66 nA at room temperature, and minimum detectable power of ~-29 dBm. The design also suggests that the device's size can be reduced and the overall performances will be further improved if a silicide with smaller permittivity is used.


Inflammatory breast cancer: high risk of contralateral breast cancer compared to comparably staged non-inflammatory breast cancer.
Inflammatory breast cancer (IBC), the most lethal form of breast cancer, has characteristics linked to higher risk of contralateral breast cancer. However, no large studies have examined risk of contralateral breast cancer following IBC. We calculated absolute risk of invasive contralateral breast cancer among 5,631 IBC and 174,634 comparably staged non-IBC first breast cancer cases who survived at least 2 months following diagnosis and were reported to 13 Surveillance, Epidemiology, and End Results (SEER) registries between January 1, 1973 and December 31, 2006. We considered that contralateral cancers occurring within 2-23 months of first cancer diagnosis may more likely be metastatic/recurrent disease and those occurring 2 or more years after diagnosis independent primaries. Absolute risk of contralateral breast cancer was generally greater following IBC than regional/distant non-IBC, regardless of age and hormone receptor status of first cancer diagnosis. Much of the increase in absolute risk following IBC occurred within 2-23 months of first cancer diagnosis, while the risk for non-IBC occurred more gradually over time since diagnosis. For instance, among women first diagnosed before age 50, absolute risks following IBC and non-IBC were 4.9 vs. 1.1% at 2 years, 6.0 vs. 2.2% at 5 years, and 7.7 vs. 6.1% at 20 years after diagnosis. However, patterns of higher risk following IBC than non-IBC were also evident for at least 10-15 years in the subcohort of women who survived at least 24 months without a contralateral cancer. In conclusion, our results suggest that IBC has higher risk of cancer in the contralateral breast than comparably staged non-IBC, possibly due to both metastatic/recurrent disease and independent primaries.


Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.
USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also demonstrated that a targeted NGS approach is a valuable tool for the genetic diagnosis of USH2 and RP.


Health effects of trans-fatty acids: experimental and observational evidence.
Growing evidence indicates that trans-fatty acids (TFA) adversely affect cardiovascular health. As part of the World Health Organization (WHO) Scientific Update on TFA, we reviewed the evidence for effects of TFA consumption on coronary heart disease (CHD). We searched Medline publications examining TFA consumption and CHD risk factors or outcomes, emphasizing results of studies in humans. We evaluated and synthesized evidence from both controlled feeding trials evaluating risk factors and long-term observational studies evaluating risk factors or clinical outcomes, each of which have complementary strengths and limitations, to enable the most robust and reliable inferences of effects. The effects of TFA consumption on risk factors most consistently seen in both controlled trials and observational studies included adverse lipid effects (for example [upward arrow] low-density lipoprotein cholesterol, [downward arrow] high-density lipoprotein cholesterol (HDL-C), [upward arrow] total/HDL-C ratio), proinflammatory effects (for example [upward arrow] tumor necrosis factor-alpha activity, [upward arrow] interleukin-6, [upward arrow] C-reactive protein) and endothelial dysfunction. These effects were most prominent in comparison with cis unsaturated fats; adverse effects on total/HDL-C and endothelial function were also seen in comparison with saturated fatty acids (SFA). TFA may also worsen insulin sensitivity, particularly among individuals predisposed to insulin resistance; possible effects on weight gain and diabetes incidence require further confirmation. Five retrospective case-control studies and four prospective cohort studies demonstrated positive associations between TFA consumption and CHD events. A meta-analysis of prospective studies indicated 24, 20, 27 and 32% higher risk of myocardial infarction (MI) or CHD death for every 2% energy of TFA consumption isocalorically replacing carbohydrate, SFA, cis monounsaturated fatty acids and cis polyunsaturated fatty acids, respectively. The differential effects of specific TFA isomers may be important but are less well established. The available evidence indicates that trans-18:1 and particularly trans-18:2 isomers have stronger CHD effects than trans-16:1 isomers. The limited data suggest that the experimental effects of ruminant and industrial TFA are similar when consumed in similar quantities, but very few persons consume such high levels of ruminant TFA, and observational studies do not support adverse CHD effects of ruminant TFA in amounts actually consumed. Controlled trials and observational studies provide concordant evidence that consumption of TFA from partially hydrogenated oils adversely affects multiple cardiovascular risk factors and contributes significantly to increased risk of CHD events. The public health implications of ruminant TFA consumption appear much more limited. The effects of specific TFA isomers require further investigation.


Pathology of fatal lineage 1 and 2 West Nile virus infections in horses in South Africa.
Since 2007, West Nile virus (WNV) has been reported in South African horses, causing severe neurological signs. All cases were of lineage 2, except for one case that clustered with lineage 1 viruses. In the present study, gross and microscopic lesions of six South African lineage 2-infected horses and the one lineage 1 case are described. Diagnoses were confirmed by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) of central nervous system (CNS) tissue and one by RT-PCR of a brain virus isolate. The CNS of all cases was negative by RT-PCR or immunohistochemistry (IHC) for African horse sickness (AHS), equine encephalosis virus, equine herpes viruses 1 and 4, other zoonotic flaviviruses, alphaviruses, and shunivirus, and either by immunofluorescence or IHC for rabies. Gross visceral lesions were nonspecific but often mimicked those of AHS. The CNS histopathology of WNV lineage 2 cases resembled the nonsuppurative polioencephalomyelitis reported in the Northern Hemisphere lineage 1 and recent Hungarian lineage 2 cases. Occasional meningitis, focal spinal ventral horn poliomalacia, dorsal and lateral horn poliomyelitis, leucomyelitis, asymmetrical ventral motor spinal neuritis and frequent olfactory region involvement were also seen. Lineage 2 cases displayed marked variations in CNS lesion severity, type and distribution, and suggested various viral entry routes into the CNS, based on findings in experimental mice and hamsters. Lineage 1 lesions were comparable to the milder lineage 2 cases. West Nile virus IHC on CNS sections with marked lesions from all cases elicited only two antigen-positive cells in the olfactory cortex of one case. The presence in the CNS of T-lymphocytes, B-lymphocytes, plasma cells and macrophage-monocytes was confirmed by cluster of differentiation (CD) 3, CD20, multiple myeloma oncogene 1 (MUM1) and macrophage (MAC) 387 IHC.


A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene.
We purified the oncoprotein SnoN and found that it functions as a corepressor of the tumor suppressor p53 in the regulation of the hepatic alpha-fetoprotein (AFP) tumor marker gene. p53 promotes SnoN and histone deacetylase interaction at an overlapping Smad binding, p53 regulatory element (SBE/p53RE) in AFP. Comparison of wild-type and p53-null mouse liver tissue by using chromatin immunoprecipitation (ChIP) reveals that the absence of p53 protein correlates with the disappearance of SnoN at the SBE/p53RE and loss of AFP developmental repression. Treatment of AFP-expressing hepatoma cells with transforming growth factor-beta1 (TGF-beta1) induced SnoN transcription and Smad2 activation, concomitant with AFP repression. ChIP assays show that TGF-beta1 stimulates p53, Smad4, P-Smad2 binding, and histone H3K9 deacetylation and methylation, at the SBE/p53RE. Depletion, by small interfering RNA, of SnoN and/or p53 in hepatoma cells disrupted repression of AFP transcription. These findings support a model of cooperativity between p53 and TGF-beta effectors in chromatin modification and transcription repression of an oncodevelopmental tumor marker gene.


Binocular Goggle Augmented Imaging and Navigation System provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping.
The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence, and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery, and improve the accuracy of cancer staging.


Role of the long form leptin receptor and of the STAT3 signaling pathway in colorectal cancer progression.
Although a number of recent studies have reported the involvement of leptin in colorectal carcinogenesis, findings are contradictory and difficult to interpret. Our group has previously reported that leptin signaling might have an important role in the development of colorectal adenomas. In this study, we investigated leptin signaling in colorectal carcino-genesis focusing in particular on the differences in leptin signaling between colorectal adenoma and cancer. Whereas no significant differences in the serum leptin levels were observed among normal control subjects and adenoma/cancer patients, increased expression and activation of the long form leptin receptor (ObRL) was observed in colorectal adenoma and cancer tissues compared with the normal colorectal tissues. However, no significant differences were observed between the colorectal adenoma and cancer tissues. Significant increases in the phosphorylation levels of important molecules of the JAK/STAT signaling pathway, located downstream of leptin signaling, and transcriptional regulation of STAT3-downstream target molecules were observed in colorectal adenoma tissue compared with the findings in normal colorectal tissues. Furthermore, these changes were significantly more pronounced in colorectal cancer compared to colorectal adenoma tissues. This is the first analysis of leptin and JAK/STAT signaling in a human colorectal adenoma-carcinoma sequence. These results suggest that the STAT3-mediated leptin signaling through the activation of ObRL may be involved in colorectal carcinogenesis, both in adenoma formation and in the progression to cancer. STAT3 signaling in colorectal cancer may be mediated not only by leptin but by other factors.


Malondialdehyde-acetaldehyde adduct is the dominant epitope after MDA modification of proteins in atherosclerosis.
Antibodies to malondialdehyde (MDA)-modified macromolecules (adducts) have been detected in the serum of patients with atherosclerosis and correlate with the progression of this disease. However, the epitope and its formation have not been characterized. Studies have shown that excess MDA can be degraded to acetaldehyde, which combines with proteins to from a stable dihydropyridine adduct. To investigate, mice were immunized with MDA adducts in the absence of adjuvant and showed an increase in antibodies to MDA adducts and the carrier protein as the concentration of MDA was increased. In fact, a number of the commercially available antibodies to MDA-modified proteins were able to be inhibited by a chemical analogue, hexyl-MAA. Also, MDA-MAA adducts were detected in the serum and aortic tissue of JCR diabetic/atherosclerotic rats. These studies determined that commercially available antibodies to MDA predominantly react with the MAA adduct and are present in the JCR model of atherosclerosis in both the serum and the aortic tissue. Therefore, the immune response to MDA-modified proteins is most probably to the dihydropyridine structure (predominant epitope in MAA), which suggests that MAA adducts may play a role in the development and/or progression of atherosclerosis.


The Effect of Propulsion Style on Wrist Movement Variability During the Push Phase After a Bout of Fatiguing Propulsion.
Wheelchair propulsion has been linked to overuse injuries regardless of propulsion style. Many aspects of the arcing (ARC) and semicircular (SEMI) propulsion styles have been compared, but differences in intracycle movement variability, which have been linked to overuse injuries, have not been examined. To explore how ARC and SEMI affect changes in intracycle wrist movement variability after a fatiguing bout of propulsion. Repeated measures crossover design. Wheelchair rollers and wheelchair fatigue course in a research laboratory. Twenty healthy, nondisabled adult men without previous wheelchair experience. Participants learned ARC and SEMI and used each to perform a wheelchair fatigue protocol. Thirty seconds of propulsion on rollers were recorded by motion-capture cameras before and after a fatigue protocol for each propulsion style on 2 testing days. Angular wrist orientations (flexion/extension and radial/ulnar deviation) and linear wrist trajectories (mediolateral direction) were computed, and intracycle movement variability was calculated as standard deviations of the detrended and filtered values during the push phase beginning and end. Paired samples t tests were used to compare ARC and SEMI based on the percent changes from pre- to postfatigue protocol. Both propulsion styles resulted in increased intracycle wrist movement variability postfatigue, but observed increases did not significantly differ between ARC and SEMI. This study evinces that intersubject variability exceeded average changes in intracycle wrist movement variability for both propulsion styles. Neither propulsion style resulting in a greater change in intracycle movement variability may suggest that no single propulsion style is ideal for everyone. The large intersubject variability may indicate that the propulsion style resulting in the smallest increase in intracycle movement variability after a fatiguing bout of propulsion may differ for each person and may help explain why wheelchair users self-select to use different propulsion styles.


Attitudes of Croatian psychiatrists towards long-acting injectable antipsychotics.
Despite many advantages of long-acting injectable antipsychotics (LAIA), this type of therapy is still underused in routine practice. Since psychiatrists' attitudes play an important role in prescription rate of LAIA, we found it valuable to examine their attitudes because, according to our knowledge, there hasn't been similar research in Croatia so far. In this research, we included the total of 48 psychiatrists. For research purposes, we created a questionnaire modeled on standardized questionnaire. Results are described with descriptive statistics and Likert scale was used to measure respondents' attitudes to statements. The number of years of their experience in practice is expressed with median of 13.50 years with minimal value of 1.00 and maximum value of 36.00 years. Most of psychiatrists find that LAIA play an important role in treatment of schizophrenia (n=44, 93.62%) and that they tend to prescribe that type of therapy (n=39, 81.25%). Almost all of psychiatrists (n=45, 93.75%) agree or strongly agree that it is easier to control patients' disease if they are treated with LAIA rather than with oral therapy and 32 of them (68.08%) think that doctor-patient relationship is more successful when patients are treated with LAIA than with oral antipsychotics. According to their experience (n=32, 68.08%) patients prefer to be treated with oral antipsychotics instead of LAIA. We expressed approximate percentage of their patients treated with LAIA with median of 20%, with minimum value of 0.00% and maximum value of 70.00%. According to the results of our research, attitudes of psychiatrists towards LAIA are mostly positive, but considering the fact that there is a small number of their patients who are treated with them, we emphasize that psychiatrists still prescribe oral antipsychotics much more often than LAIA. Despite positive attitudes of patients towards LAIA, majority of psychiatrists think that patients would rather choose oral therapy.


Breastfeeding Challenges: ACOG Committee Opinion Summary, Number 820.
Breastfeeding is associated with a decrease in a woman's risk of breast cancer, ovarian cancer, diabetes mellitus, and hypertensive heart disease. Breastfeeding initiation rates in the United States are increasing, and many women are aware of the maternal and infant health benefits of breastfeeding. However, problems may arise that can keep women from achieving their breastfeeding goals, and only 25% of women in the United States are breastfeeding exclusively at 6 months. Many women experience early and undesired weaning because of persistent pain or nipple injury. A focused history and physical examination are essential to help obstetrician-gynecologists and other obstetric care professionals distinguish the specific cause of their patients' pain and determine appropriate treatment. Studies have shown that pain with breastfeeding may be associated with postpartum depression; therefore, postpartum depression screening is an important part of the medical history when caring for these patients. Some women choose not to initiate breastfeeding, stop breastfeeding sooner than intended, or are unable to complete treatment with prescribed medications because they may have concerns regarding medication use during lactation. Health care professionals prescribing medications during lactation should base their counseling on accurate, current information from resources such as the National Center for Biotechnology Information's Drugs and Lactation database (known as LactMed). Causes of early weaning also may be attributed to societal factors, such as limited access to paid maternity leave and barriers to breastfeeding in the workplace. Obstetrician-gynecologists and other obstetric care professionals are uniquely positioned to support women in these situations.


A systematic review of evidence for the added benefits to health of exposure to natural environments.
There is increasing interest in the potential role of the natural environment in human health and well-being. However, the evidence-base for specific and direct health or well-being benefits of activity within natural compared to more synthetic environments has not been systematically assessed. We conducted a systematic review to collate and synthesise the findings of studies that compare measurements of health or well-being in natural and synthetic environments. Effect sizes of the differences between environments were calculated and meta-analysis used to synthesise data from studies measuring similar outcomes. Twenty-five studies met the review inclusion criteria. Most of these studies were crossover or controlled trials that investigated the effects of short-term exposure to each environment during a walk or run. This included 'natural' environments, such as public parks and green university campuses, and synthetic environments, such as indoor and outdoor built environments. The most common outcome measures were scores of different self-reported emotions. Based on these data, a meta-analysis provided some evidence of a positive benefit of a walk or run in a natural environment in comparison to a synthetic environment. There was also some support for greater attention after exposure to a natural environment but not after adjusting effect sizes for pretest differences. Meta-analysis of data on blood pressure and cortisol concentrations found less evidence of a consistent difference between environments across studies. Overall, the studies are suggestive that natural environments may have direct and positive impacts on well-being, but support the need for investment in further research on this question to understand the general significance for public health.


The importance of genome sequence quality to microbial comparative genomics.
The quality of microbial genome sequences has been a concern ever since the emergence of genome sequencing. The quality of the genome assemblies is dependent on the sequencing technology used and the aims for which the sequence was generated. Novel sequencing and bioinformatics technologies are not intrinsically better than the older technologies, although they are generally more efficient. In this correspondence, the importance for comparative genomics of additional manual assembly efforts over autoassembly and careful annotation is emphasized.


Correctness of belief propagation in Gaussian graphical models of arbitrary topology.
Graphical models, such as Bayesian networks and Markov random fields, represent statistical dependencies of variables by a graph. Local "belief propagation" rules of the sort proposed by Pearl (1988) are guaranteed to converge to the correct posterior probabilities in singly connected graphs. Recently, good performance has been obtained by using these same rules on graphs with loops, a method we refer to as loopy belief propagation. Perhaps the most dramatic instance is the near Shannon-limit performance of "Turbo codes," whose decoding algorithm is equivalent to loopy propagation. Except for the case of graphs with a single loop, there has been little theoretical understanding of loopy propagation. Here we analyze belief propagation in networks with arbitrary topologies when the nodes in the graph describe jointly gaussian random variables. We give an analytical formula relating the true posterior probabilities with those calculated using loopy propagation. We give sufficient conditions for convergence and show that when belief propagation converges, it gives the correct posterior means for all graph topologies, not just networks with a single loop. These results motivate using the powerful belief propagation algorithm in a broader class of networks and help clarify the empirical performance results.


Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumors.
A high percentage of transgenic mice developing from eggs microinjected with plasmids containing the SV40 early region genes and a metallothionein fusion gene develop tumors within the choroid plexus. A line of mice has been established in which nearly every affected animal succumbs to this brain tumor. Thymic hypertrophy and kidney pathology are also observed in some mice. SV40 T-antigen mRNA and protein are readily detected in affected tissues; however, SV40 T-antigen gene expression is barely detectable in unaffected tissues or in susceptible tissues prior to overt pathology, suggesting that tumorigenesis depends upon activation of the SV40 genes. Comparison of DNA from tumor tissue (or cell lines derived from tumors) with DNA from unaffected tissues reveals structural rearrangements as well as changes in DNA methylation of the foreign DNA. The SV40 genes are frequently amplified in tumor tissue, which further indicates that their expression is intimately involved in tumorigenesis in transgenic mice.


PLC-based LP₁₁ mode rotator for mode-division multiplexing transmission.
A PLC-based LP11 mode rotator is proposed. The proposed mode rotator is composed of a waveguide with a trench that provides asymmetry of the waveguide. Numerical simulations show that converting LP11a (LP11b) mode to LP11b (LP11a) mode can be achieved with high conversion efficiency (more than 90%) and little polarization dependence over a wide wavelength range from 1450 nm to 1650 nm. In addition, we fabricate the proposed LP11 mode rotator using silica-based PLC. It is confirmed that the fabricated mode rotator can convert LP11a mode to LP11b mode over a wide wavelength range.


Drinking before going to licensed premises: an event-level analysis of predrinking, alcohol consumption, and adverse outcomes.
Research in the United States and the United Kingdom indicates that drinking before going out (commonly called "predrinking") is common among young people and associated with increased harm. On the basis of Swiss data, this study investigates differences in alcohol consumption and adverse or risky outcomes for evenings when persons consumed alcohol before going to a licensed premise (i.e., predrinking), drank on-premise only, or drank off-premise only. Using the recently developed Internet-based cell phone-optimized assessment technique (ICAT), alcohol consumption and drinking location were assessed at 6 time points (5 pm to the next morning) on Thursdays, Fridays, and Saturdays over 5 consecutive weeks by means of participants' cell phones. Overall, 7,828 assessments provided by 183 young adults (53.0% women, mean age [SD] = 23.1 [3.1]) on 1,441 evenings were analyzed by means of cluster-adjusted means and proportion tests and of multilevel structural equation models. The extent to which alcohol consumption mediated the association between predrinking and adverse outcomes was also examined. Higher alcohol consumption occurred on evenings with predrinking (7.1 drinks on average) compared with on-premise only (4.2 drinks) and off-premise only (4.3 drinks) evenings. Adverse outcomes occurred more often on evenings with predrinking (with 23.8% of predrinking nights involving at least 1 outcome) than on evenings with on-premise drinking only (13.9%) and off-premise drinking only (12.0%). Predrinking was indirectly associated with adverse outcomes, mediated by larger amounts of alcohol consumed in the evening. Because of its association with heavier consumption and related adverse outcomes, predrinking, especially combined with on-premise drinking, represents a major target for prevention. Educational interventions as well as structural measures, such as reduction in late-night off-sale opening hours, and staff training in responsible beverage service, are needed to prevent high total consumption and related adverse consequences among young people.


A spectroscopic measurement of the coronal density of procyon.
One of the open key issues in the astrophysics of stellar coronae is the determination of their spatial structure and density. From almost all previous measurements, one can infer merely the presence of a corona, which for the most energetic stellar coronae may exceed the solar x-ray output by as much as five orders of magnitude, but no information can be obtained on the densities and hence volumes and sizes of the hot x-ray emitting material. A direct spectroscopic measurement of the coronal density was obtained for the star Procyon with the spectrometer on board the Extreme Ultraviolet Explorer satellite; the ratio of two Fe XIV lines at 211.32 and 264.79 angstroms was used to determine a density of approximately 4 x 10(9) to 7 x 10(9) electrons per cubic centimeter, which is a factor of 2 to 3 higher than typical solar active region densities. From this value, we estimate that approximately 6 percent of the stellar surface is covered with approximately 7 x 10(4) coronal loops.


Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast.
The silent mating loci and chromosomal regions adjacent to telomeres of S. cerevisiae have features similar to heterochromatin of more complex eukaryotes. Transcriptional repression at these sites depends on the silent information regulators SIR3 and SIR4 as well as histones H3 and H4. We show here that the SIR3 and SIR4 proteins interact with specific silencing domains of the H3 and H4 N-termini in vitro. Certain mutations in these factors, which affect their silencing functions in vivo, also disrupt their interactions in vitro. Immunofluorescence studies with antibodies against RAP1 and SIR3 demonstrate that the H3 and H4 N-termini are required for the association of SIR3 with telomeric chromatin and the perinuclear positioning of yeast telomeres. Based on these interactions, we propose a model for heterochromatin-mediated transcriptional silencing in yeast, which may serve as a paradigm for other eukaryotic organisms as well.


Clinical characteristics of peripheral venous catheter-associated gram-negative bloodstream infection among patients with malignancy.
Previous studies have suggested that peripheral venous catheter is a significant source of gram-negative bacteraemia in patients with malignancy. We aimed to identify risk factors and develop a clinical prediction rule for the involvement of gram-negative organisms in peripheral venous catheter-associated bloodstream infections (PVC-BSIs) among patients with malignancy. This retrospective cohort study was conducted at a 700-bed cancer hospital in Japan. Consecutive patients diagnosed with PVC-BSI based on clinical and microbiological criteria were included in this study. Based on clinical and microbiological characteristics of PVC-BSIs in cancer patients, a logistic regression model for predicting gram-negative organisms as causative organisms in PVC-BSIs was then developed. Of the 99 patients included in our cohort, 60 patients (60.6%) had gram-negative PVC-BSIs. The median age of patients with PVC-BSIs was 67 years (interquartile range [IQR], 59-74 years), and the median Pitt bactearemia score was 1 (IQR, 0-3). The median duration of catherization was 5 days (IQR, 4-7 days) and 70 patients (70.7%) received peripheral parenteral nutrition that contained amino acids. On multivariable analysis, age ≥65 years (odds ratio [OR], 3.07; 95% confidence interval [CI], 1.10-8.62), showering (OR, 3.15; 95% CI, 1.07-9.26), Pitt bacteraemia score ≥2 points (OR, 6.96; 95% CI, 2.52-19.2), and use of peripheral parenteral nutrition (OR, 0.31; 95% CI, 0.10-0.98) were independent predictors for gram-negative PVC-BSIs among all PVC-BSIs. The simplified PVC-GN scores established to predict gram-negative PVC-BSIs had a optimism-corrected c-index of 0.775. Gram-negative bacteria were more commonly responsible for PVC-BSI than Gram-positive bacteria among cancer patients in this cohort. Involvement of Gram-negative bacteria in PVC-BSIs could be predicted with readily available clinical variables.