Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics.
Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed. Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis. We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population, we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4+ and CD8+ T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly enriched in lesional macrophages, endothelial, and smooth muscle cells. This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease.


Tuning the excited-state dynamics of GFP-inspired imidazolone derivatives.
The excited-state dynamics of five derivatives of the GFP-chromophore, which differ by the position and nature of their substituents, has been investigated in solvents of various viscosity and polarity and in rigid media using femtosecond-resolved spectroscopy. In polar solvents of low viscosity, like acetonitrile or methanol, the fluorescence decays of all compounds are multiexponential, with average lifetimes of the order of a few picoseconds, whereas in rigid matrices (polymer films and low temperature glasses), they are single exponential with lifetimes of the order of a few nanoseconds and fluorescence quantum yields close to unity. Global analysis of the fluorescence decays recorded at several wavelengths and of the transient absorption spectra reveals the presence of several excited-state populations with slightly different fluorescence and absorption spectra and with distinct lifetimes. These populations are attributed to the existence of multiple ground-state conformers. From the analysis of the dependence of the excited-state dynamics on the solvent and on the nature of the substituents, it follows that the nonradiative deactivation of all these excited chromophores involves an intramolecular coordinate with large amplitude motion. However, depending on the solvent and substituent, additional channels, namely, inter- and intramolecular hydrogen bond assisted nonradiative deactivation, are operative. This allows tuning of the excited-state lifetime of the chromophore. Finally, an ultrafast photoinduced intramolecular charge transfer is observed in polar solvents with one derivative bearing a dimethylaminophenyl substituent.


Raman spectroscopy using a spatial heterodyne spectrometer: proof of concept.
The use of a spatial heterodyne interferometer-based spectrometer (SHS) for Raman spectroscopy is described. The motivation for this work is to develop a small, rugged, high-resolution ultraviolet (UV) Raman spectrometer that is compatible with pulsed laser sources and that is suitable for planetary space missions. UV Raman is a particular technical challenge for space applications because dispersive (grating) approaches require large spectrographs and very narrow slits to achieve the spectral resolution required to maximize the potential of Raman spectroscopy. The heterodyne approach of the SHS has only a weak coupling of resolution and throughput, so a high-resolution UV SHS can both be small and employ a wide slit to maximize throughput. The SHS measures all optical path differences in its interferogram simultaneously with a detector array, so the technique is compatible with gated detection using pulsed lasers, important to reject ambient background and mitigate fluorescence (already low in the UV) that might be encountered on a planetary surface where samples are uncontrolled. The SHS has no moving parts, and as the spectrum is heterodyned around the laser wavelength, it is particularly suitable for Raman measurements. In this preliminary report we demonstrate the ability to measure visible wavelength Raman spectra of liquid and solid materials using an SHS Raman spectrometer and a visible laser. Spectral resolution and bandpass are also discussed. Separation of anti-Stokes and Stokes Raman bands is demonstrated using two different approaches. Finally spectral bandpass doubling is demonstrated by forming an interference pattern in both directions on the ICCD detector followed by analysis using a two-dimensional Fourier transform.


Accurate measurements of dynamics and reproducibility in small genetic networks.
Quantification of gene expression has become a central tool for understanding genetic networks. In many systems, the only viable way to measure protein levels is by immunofluorescence, which is notorious for its limited accuracy. Using the early Drosophila embryo as an example, we show that careful identification and control of experimental error allows for highly accurate gene expression measurements. We generated antibodies in different host species, allowing for simultaneous staining of four Drosophila gap genes in individual embryos. Careful error analysis of hundreds of expression profiles reveals that less than ∼20% of the observed embryo-to-embryo fluctuations stem from experimental error. These measurements make it possible to extract not only very accurate mean gene expression profiles but also their naturally occurring fluctuations of biological origin and corresponding cross-correlations. We use this analysis to extract gap gene profile dynamics with ∼1 min accuracy. The combination of these new measurements and analysis techniques reveals a twofold increase in profile reproducibility owing to a collective network dynamics that relays positional accuracy from the maternal gradients to the pair-rule genes.


Spatial sampling in human visual cortex is modulated by both spatial and feature-based attention.
Spatial attention changes the sampling of visual space. Behavioral studies suggest that feature-based attention modulates this resampling to optimize the attended feature's sampling. We investigate this hypothesis by estimating spatial sampling in visual cortex while independently varying both feature-based and spatial attention. Our results show that spatial and feature-based attention interacted: resampling of visual space depended on both the attended location and feature (color vs. temporal frequency). This interaction occurred similarly throughout visual cortex, regardless of an area's overall feature preference. However, the interaction did depend on spatial sampling properties of voxels that prefer the attended feature. These findings are parsimoniously explained by variations in the precision of an attentional gain field. Our results demonstrate that the deployment of spatial attention is tailored to the spatial sampling properties of units that are sensitive to the attended feature.


Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation.
Invadopodia are actin-rich membrane protrusions of cancer cells that facilitate pericellular proteolysis and invasive behavior. We show here that reactive oxygen species (ROS) generated by the NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) system are necessary for invadopodia formation and function. Knockdown of the invadopodia protein Tks5 [tyrosine kinase substrate with five Src homology 3 (SH3) domains], which is structurally related to the Nox component p47(phox), reduces total ROS abundance in cancer cells. Furthermore, Tks5 and p22(phox) can associate with each other, suggesting that Tks5 is part of the Nox complex. Tyrosine phosphorylation of Tks5 and Tks4, but not other Src substrates, is reduced by Nox inhibition. We propose that Tks5 facilitates the production of ROS necessary for invadopodia formation, and that in turn ROS modulate Tks5 tyrosine phosphorylation in a positive feedback loop.


CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population.
Neural tube defects (NTDs) are among the most common of all human congenital defects. Over the last two decades, accumulating evidence has made it clear that periconceptional intake of folic acid can significantly reduce the risk of NTD affected pregnancies. This beneficial effect may be related to the ability of folates to donate methyl groups for critical physiological reactions. Choline is an essential nutrient and it is also a methyl donor critical for the maintenance of cell membrane integrity and methyl metabolism. Perturbations in choline metabolism in vitro have been shown to induce NTDs in mouse embryos. This study investigated whether single nucleotide polymorphisms (SNPs) in human choline kinase A (CHKA) gene and CTP:phosphocholine cytidylytransferase (PCYT1A) gene were risk factors for spina bifida. Fluorescence-based allelic discrimination analysis was performed for the two CHKA intronic SNPs hCV1562388 (rs7928739) and hCV1562393, and PCYT1A SNP rs939883 and rs3772109. The study population consisted of 103 infants with spina bifida and 338 non-malformed control infants who were born in selected California counties in the period 1989-1991. The CHKA SNP hCV1562388 genotypes with at least one C allele were associated with a reduced risk of spina bifida (odds ratio = 0.60, 95%CI = 0.38-0.94). The PCYT1A SNP rs939883 genotype AA was associated with a twofold increased risk of spina bifida (odds ratio = 1.89, 95% CI = 0.97-3.67). These gene-only effects were not substantially modified by analytic consideration to maternal periconceptional choline intake. Our analyses showed genotype effects of CHKA and PCYT1A genes on spina bifida risk, but did not show evidence of gene-nutrient interactions. The underlying mechanisms are yet to be resolved.


Structural studies of viperin, an antiviral radical SAM enzyme.
Viperin is an IFN-inducible radical S-adenosylmethionine (SAM) enzyme that inhibits viral replication. We determined crystal structures of an anaerobically prepared fragment of mouse viperin (residues 45-362) complexed with S-adenosylhomocysteine (SAH) or 5'-deoxyadenosine (5'-dAdo) and l-methionine (l-Met). Viperin contains a partial (βα)6-barrel fold with a disordered N-terminal extension (residues 45-74) and a partially ordered C-terminal extension (residues 285-362) that bridges the partial barrel to form an overall closed barrel structure. Cys84, Cys88, and Cys91 located after the first β-strand bind a [4Fe-4S] cluster. The active site architecture of viperin with bound SAH (a SAM analog) or 5'-dAdo and l-Met (SAM cleavage products) is consistent with the canonical mechanism of 5'-deoxyadenosyl radical generation. The viperin structure, together with sequence alignments, suggests that vertebrate viperins are highly conserved and that fungi contain a viperin-like ortholog. Many bacteria and archaebacteria also express viperin-like enzymes with conserved active site residues. Structural alignments show that viperin is similar to several other radical SAM enzymes, including the molybdenum cofactor biosynthetic enzyme MoaA and the RNA methyltransferase RlmN, which methylates specific nucleotides in rRNA and tRNA. The viperin putative active site contains several conserved positively charged residues, and a portion of the active site shows structural similarity to the GTP-binding site of MoaA, suggesting that the viperin substrate may be a nucleoside triphosphate of some type.


High-power asynchronous midinfrared optical parametric oscillator frequency combs.
We introduce a new stabilization scheme providing a pair of high-power, carrier-envelope-offset (CEO) frequency-stabilized, broadband, asynchronous frequency combs operating at 3.3 μm. The two channels, each with 100 mW average power and originating from a single synchronously pumped optical parametric oscillator, share all the components for midinfrared generation and CEO-frequency detection, and can be stabilized independently at repetition frequencies up to 5 kHz apart. This unique source is fully compatible with midinfrared dual-comb spectroscopy, and the approach can be readily extended to other wavelengths.


Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis.
Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting. To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data. Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study. Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants. In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.


Tailoring a Plasmodium vivax Vaccine To Enhance Efficacy through a Combination of a CSP Virus-Like Particle and TRAP Viral Vectors.
Vivax malaria remains one of the most serious and neglected tropical diseases, with 132 to 391 million clinical cases per year and 2.5 billion people at risk of infection. A vaccine against Plasmodium vivax could have more impact than any other intervention, and the use of a vaccine targeting multiple antigens may result in higher efficacy against sporozoite infection than targeting a single antigen. Here, two leading P. vivax preerythrocytic vaccine candidate antigens, the P. vivax circumsporozoite protein (PvCSP) and the thrombospondin-related adhesion protein (PvTRAP) were delivered as a combined vaccine. This strategy provided a dose-sparing effect, with 100% sterile protection in mice using doses that individually conferred low or no protection, as with the unadjuvanted antigens PvTRAP (0%) and PvCSP (50%), and reached protection similar to that of adjuvanted components. Efficacy against malaria infection was assessed using a new mouse challenge model consisting of a double-transgenic Plasmodium berghei parasite simultaneously expressing PvCSP and PvTRAP used in mice immunized with the virus-like particle (VLP) Rv21 previously reported to induce high efficacy in mice using Matrix-M adjuvant, while PvTRAP was concomitantly administered in chimpanzee adenovirus and modified vaccinia virus Ankara (MVA) vectors (viral-vectored TRAP, or vvTRAP) to support effective induction of T cells. We examined immunity elicited by these vaccines in the context of two adjuvants approved for human use (AddaVax and Matrix-M). Matrix-M supported the highest anti-PvCSP antibody titers when combined with Rv21, and, interestingly, mixing PvCSP Rv21 and PvTRAP viral vectors enhanced immunity to malaria over levels provided by single vaccines.


Paraneoplastic stiff-person syndrome, heterotopic soft tissue ossification and gonarthritis in a HLA B27-positive woman preceding the diagnosis of Hodgkin's lymphoma.
Paraneoplastic neurologic syndromes associated with Hodgkin's lymphoma include the stiff-person syndrome. A case of stiff-person syndrome is reported who first presented with muscular hyperactivity and acute respiratory failure followed by heterotopic soft tissue ossification and acute seronegative gonarthitis. Initial improvement of a tetanus-like clinical picture was achieved with benzodiazepam given by continuous infusion for analgo-sedation to mechanically ventilate the patient followed by baclofen after successful weaning. The patient was HLA B27 positive and on conventional testing no autoantibodies were detected including anti-glutamic acid decarboxylase antibodies (anti-GAD). Months later in the absence of signs of stiff-person syndrome, mediastinal lymphadenopathy and pleural effusions developed which were diagnosed as classical Hodgkin's lymphoma that was successfully treated with polychemotherapy. No relapse of paraneoplastic neurologic syndromes was seen after two years of lymphoma remission. The case illustrates that stiff-person syndrome may precede the clinical appearance of symptomatic Hodgkin's lymphoma.


Errant life, molecular biology, and biopower: Canguilhem, Jacob, and Foucault.
This paper considers the theoretical circumstances that urged Michel Foucault to analyse modern societies in terms of biopower. Georges Canguilhem's account of the relations between science and the living forms an essential starting point for Foucault's own later explorations, though the challenges posed by the molecular revolution in biology and François Jacob's history of it allowed Foucault to extend and transform Canguilhem's philosophy of error. Using archival research into his 1955-1956 course on "Science and Error," I show that, for Canguilhem, it is inauthentic to treat a living being as an error, even if living things are capable of making errors in the domain of knowledge. The emergent molecular biology in the 1960s posed a grave challenge, however, since it suggested that individuals could indeed be errors of genetic reproduction. The paper discusses how Canguilhem and Foucault each responded to this by examining, among other texts, their respective reviews of Jacob's The Logic of the Living. For Canguilhem this was an opportunity to reaffirm the creativity of life in the living individual, which is not a thing to be evaluated, but the source of values. For Foucault, drawing on Jacob's work, this was the opportunity to develop a transformed account of valuation by posing biopower as the DNA of society. Despite their disagreements, the paper examines these three authors as different iterations of a historical epistemology attuned to errancy, error, and experimentation.


Clinical complexity in middle-aged and older adults with diabetes: the Health and Retirement Study.
Some patients with diabetes may have health status characteristics that could make diabetes self-management (DSM) difficult and lead to inadequate glycemic control, or limit the benefit of some diabetes management interventions. To investigate how many older and middle-aged adults with diabetes have such health status characteristics. Secondary data analysis of a nationally representative health interview survey, the Health and Retirement Study, and its diabetes mail-out survey. Americans aged 51 and older with diabetes (n = 3506 representing 13.6 million people); aged 56 and older in diabetes survey (n = 1132, representing 9.9 million). Number of adults with diabetes and (a) relatively good health; (b) health status that could make DSM difficult (eg, comorbidities, impaired instrumental activities of daily living; and (c) characteristics like advanced dementia and activities of daily living dependency that could limit benefit of some diabetes management. Health and Retirement Study measures included demographics. Diabetes Survey included self-measured HbA1c. Nearly 22% of adults > or =51 with diabetes (about 3 million people) have health characteristics that could make DSM difficult. Another 10% (1.4 million) may receive limited benefit from some diabetes management. Mail-out respondents with health characteristics that could make DSM difficult had significantly higher mean HbA1c compared with people with relatively good health (7.6% vs. 7.3%, P < 0.04.). Some middle-aged as well as older adults with diabetes have health status characteristics that might make DSM difficult or of limited benefit. Current diabetes quality measures, including measures of glycemic control, may not reflect what is possible or optimal for all patient groups.


Carbamoylation of azorhizobial Nod factors is mediated by NodU.
Lipochitooligosaccharides (LCOs) synthesized by Azorhizobium caulinodans ORS571 are substituted at the nonreducing-terminal residue with a 6-O-carbamoyl group. LCO biosynthesis in A. caulinodans is dependent on the nodABCSUIJZnoeC operon. Until now, the role of the nodulation protein NodU in the synthesis of azorhizobial LCOs remained unclear. Based on sequence similarities and structural analysis of LCOs produced by a nodU mutant, a complemented nodU mutant, and Escherichia coli DH5 alpha expressing the nodABCSU genes, NodU was shown to be involved in the carbamoylation step.


Tumor cells positive and negative for the common cancer stem cell markers are capable of initiating tumor growth and generating both progenies.
The cancer stem cell (CSC) model depicts that tumors are hierarchically organized and maintained by CSCs lying at the apex. CSCs have been "identified" in a variety of tumors through the tumor-forming assay, in which tumor cells distinguished by a certain cell surface marker (known as a CSC marker) were separately transplanted into immunodeficient mice. In such assays, tumor cells positive but not negative for the CSC marker (hereby defined as CSC(+) and CSC(-) cells, respectively) have the ability of tumor-forming and generating both progenies. However, here we show that CSC(+) and CSC(-) cells exhibit similar proliferation in the native states. Using a cell tracing method, we demonstrate that CSC(-) cells exhibit similar tumorigenesis and proliferation as CSC(+) cells when they were co-transplanted into immunodeficient mice. Through serial single-cell derived subline construction, we further demonstrated that CSC(+) and CSC(-) cells from CSC marker expressing tumors could invariably generate both progenies, and their characteristics are maintained among different generations irrespective of the origins (CSC(+)-derived or CSC(-)-derived). These findings demonstrate that tumorigenic cells cannot be distinguished by common CSC markers alone and we propose that cautions should be taken when using these markers independently to identify cancer stem cells due to the phenotypic plasticity of tumor cells.


Assessment of exposure to electromagnetic fields from wireless computer networks (wi-fi) in schools; results of laboratory measurements.
Laboratory measurements have been carried out with examples of Wi-Fi devices used in UK schools to evaluate the radiofrequency power densities around them and the total emitted powers. Unlike previous studies, a 20 MHz bandwidth signal analyzer was used, enabling the whole Wi-Fi signal to be captured and monitored. The radiation patterns of the laptops had certain similarities, including a minimum toward the torso of the user and two maxima symmetrically opposed across a vertical plane bisecting the screen and keyboard. The maxima would have resulted from separate antennas mounted behind the top left and right corners of the laptop screens. The patterns for access points were more symmetrical with generally higher power densities at a given distance. The spherically-integrated radiated power (IRP) ranged from 5 to 17 mW for 15 laptops in the 2.45 GHz band and from 1 to 16 mW for eight laptops in the 5 GHz band. For practical reasons and because access points are generally wall-mounted with beams directed into the rooms, their powers were integrated over a hemisphere. These ranged from 3 to 28 mW for 12 access points at 2.4 GHz and from 3 to 29 mW for six access points at 5 GHz. In addition to the spherical measurements of IRP, power densities were measured at distances of 0.5 m and greater from the devices, and consistent with the low radiated powers, these were all much lower than the ICNIRP reference level.


Musculoskeletal injuries related to yoga: imaging observations.
The purpose of this article is to describe the imaging appearances of musculoskeletal injuries related to yoga. We performed an automated search in the database of a large tertiary care center and conducted a retrospective analysis of the imaging findings in 38 patients over a 9-year period. The most frequently encountered musculoskeletal injuries were tendinous lesions, including tears of the supraspinatus, Achilles, and peroneus brevis tendons and fibrocartilaginous tears involving the medial meniscus, acetabular labrum, glenoid labrum, and lumbar disk with extrusion.


A Summer Nutrition Benefit Pilot Program and Low-income Children's Food Security.
Federal summer meals programs serve less than one-sixth of children that receive free or reduced-price meals during the school year. To address this gap in food assistance for school-aged children, the Summer Electronic Benefits Transfer for Children (SEBTC) Demonstrations provided summer food assistance in the form of electronic benefits transfer cards to households with school-aged children certified for free or reduced-price meals during the school year. Over 2011-2013, the SEBTC demonstrations were evaluated by using a random assignment design. Households were randomly assigned a monthly $60-per-child benefit, a monthly $30-per-child benefit, or no benefit, depending on the study year. Key outcomes included children's food security and consumption of foods and food groups related to a healthful diet (diet quality). At baseline (in the spring) and again in the summer, the evaluation surveyed ∼52 000 households over the course of the 3 years of the impact study. SEBTC reduced the prevalence of very low food security among children by one-third. It also had positive impacts on 6 of the 8 child nutrition outcomes measured (amounts of fruits and vegetables; whole grains; dairy foods; and added sugars). SEBTC is a promising model to improve food security and the dietary quality of low-income school-aged children in the summer months.


Risk factors for ovarian cancer: a case-control study.
A hospital-based case-control study of ovarian cancer was conducted in London and Oxford between October 1978 and February 1983. Menstrual characteristics, reproductive and contraceptive history and history of exposure to various environmental factors were compared between 235 women with histologically diagnosed epithelial ovarian cancer and 451 controls. High gravidity, hysterectomy, female sterilisation and oral contraceptive use were associated with a reduced risk of ovarian cancer. Infertility and late age at menopause were associated with an increase in risk. While these factors were related, they were each found to be independently associated with ovarian cancer risk after adjusting for the effect of the other factors.


Factors associated with self-reported pain scores among ED patients.
Pain is a common presenting complaint among emergency department (ED) patients. The verbal numeric pain scale is commonly used in the ED to assess self-reported pain. This study was undertaken to describe and compare pain scores in a variety of painful conditions and identify factors associated with self-reported pain scores. The study was a prospective, observational, descriptive survey study conducted at an urban university hospital ED. Eligible participants included consenting adults 18 years and older, with an acute painful condition, who spoke English, and were not in severe distress. Through a structured interview, collected data included pain score; diagnosis; medical history; previous painful experiences; and demographic information including age, insurance status, and highest level of education completed. Among 268 eligible participants, 263 (98%) consented and completed the study protocol. Seventy-one percent of participants were 50 years old or younger; 55%, women; and 68%, white. Fifty-four percent had private insurance, and 81%, high school education or higher. The most common chief complaints were soft tissue injury (33%), abdominal pain (18%), and chest pain (13%). The median self-reported pain score was 7/10 (mean, 6.7; interquartile range, 6-9; range, 0-10). The most common previous painful experiences were childbirth (21%), major trauma (18%), and surgery (14%). Participants cited reasons for self-reported pain scores, including current feeling of pain (62%), comparison to previous pain (31%), and comparison to hypothetical pain (12%). The number of previous ED visits was positively correlated with current pain score (Spearman correlation R = 0.28; P < .001). The chief complaints associated with the highest pain scores included dental pain (mean pain score, 8.5) and back pain (mean pain score, 7.6). Chief complaints associated with the lowest pain scores included chest pain (mean pain score, 5.2) and other medical conditions (mean pain score, 5.3). Factors associated with higher pain scores included younger age (P < .001, Kruskal-Wallis), Medicaid insurance (P = .02), and lower educational status (P = .01). There was not a statistically significant association between current pain score and sex, race, previous painful experiences, or number of hospital admissions. Emergency department patients with acute painful conditions report a wide range of self-reported pain scores. Participants rated pain based on current feeling of pain or comparison to previous or hypothetical pain. Chief complaints with highest pain scores included dental pain and back pain. Factors associated with higher pain scores included younger age, Medicaid insurance, lower educational status, and higher number of previous ED visits.


Gamma glutamyl transferase and oxidative stress in obstructive sleep apnea: a study in 1744 patients.
We analyze a large population of patients to determine whether gamma glutamyl transferase (GGT) levels are increased in sleep apnea-hypopnea syndrome (OSA) and whether these levels are related to clinical characteristics or polygraphic indexes. A cross-sectional study in a population of 1744 patients referred for OSA suspicion was conducted. The following variables were determined: glucose, cholesterol, triglycerides, aspartate aminotransferase (GOT), alanine aminotransferase (GPT), GGT, body mass index, waist-hip ratio (WHR), and overnight sleep study. The 483 patients with GGT ≥40 IU/l were younger and more obese, and had a pattern of more centrally distributed fat than the 1261 with GGT <40 IU/l. Patients with high levels of GGT also consumed more alcohol, had a poorer biochemical profile, and had more respiratory and oximetric alterations during sleep. GGT levels were significantly correlated with AHI, DI, and CT90. In the binary regression test, WHR, glucose, cholesterol, triglycerides, and grams of alcohol consumed per day predicted GGT levels ≥40 IU/l, while none of the polygraphic variables had predictive value. High GGT levels were associated with the severity of OSA. However, this relationship seems to be due to the coexistence of other associated factors, mainly central obesity, rather than to the respiratory disorders found in this disease.


The repeatability of measurement of the ocular components.
Studies of the ocular components of refraction typically neglect issues of repeatability of measurement methods or analyze method comparison/repeatability data inappropriately using correlation. The authors have examined the repeatability of refractive error measures (retinoscopy, subjective refraction, and Canon R-1 autorefraction, noncycloplegic and cycloplegic), axial dimension measures (Allergan-Humphrey A-scan ultrasound), and corneoscopy (keratometry and KERA photokeratoscopy), and the agreement between different refractive error and corneal measurement methods on 40 pre-presbyopic normal adults. The authors plotted the difference versus the mean of two different measurement occasions (repeatability), or two different methods (agreement), to determine the bias (mean of the differences relative to zero) and 95% limits of agreement of each technique. The most reliable measure of refractive error was autorefraction with cycloplegia, with 95% limits of agreement of +/- 0.32 diopters. Cycloplegic autorefraction had no statistically significant bias compared to cycloplegic subjective refraction. Cycloplegic retinoscopy was the least reliable refractive error measure, with repeat measures on two separate occasions extending over 95% limits of agreement of +/- 0.95 D. Anterior chamber depth was reliable to +/- 0.29 mm, lens thickness to +/- 0.20 mm, and vitreous chamber depth to +/- 0.37 mm. Corneal curvature measures show keratometry to be more reliable (to +/- 0.87 D) than photokeratoscopy (+/- 2.02 D) with a statistically significant bias (paired t-test, P less than 0.0001) of 0.57 D flatter for photokeratoscopy.


Laminin and cathepsin B as prognostic factors in stage I non-small cell lung cancer: are they useful?
Laminin, a glycoprotein component of basement membrane, and cathepsin B, a lysosome-derived proteinase, are thought to play a role in the complex process of tumor invasion and metastasis. This study evaluates the possible prognostic significance of laminin degradation and cathepsin B expression in Stage I (T1NO, T2NO) human non-small cell lung cancer. Archival, formalin-fixed, paraffin-embedded lung tissue from patients with documented Stage I non-small cell cancer was studied in a series of 31 patients (14 men, 17 women; ages 40-82 yr; mean age, 67 yr) by using polyclonal antibodies against laminin and cathepsin B. The immunoexpression of laminin was assessed with respect to a continuous versus discontinuous pattern, whereas that of cathepsin B was semiquantitated according to a four-tiered grading scale: 0, 0% positive cells; 1, 1 to 9%; 2, 10 to 49%; and 3, more than 50% positive cells. Cox proportional hazards models and Kaplan-Meler survival analysis were used to evaluate the association of possible risk factors, including laminin and cathepsin B, with survival. Univariate analysis looking at possible associations of survival with age, sex, histologic type, degree of tumor differentiation, and tumoral stage (T1NO, T2NO) did not show significant association. Likewise, degradation of laminin and immunoexpression of cathepsin B did not show significant association with survival. Although previous studies suggested improved survival with increased laminin expression and decreased survival with high expression of cathepsin B, the results applying to intrastage (Stage I) non-small cell cancer suggest that the expression of laminin and cathepsin B has little prognostic significance.


Signs of abdominal pain caused by disruption of the small intestinal mesentery in three postparturient cows.
Three Holstein cows were admitted on postpartum day 3 with signs of abdominal pain, inappetence, and decreased milk production. All 3 were depressed, tachycardic, and dehydrated. Right paralumbar fossa laparotomy was performed on each cow. At surgery, a rent in the proximal portion of the jejunal mesentery, with perforation of the jejunum adjacent to the mesenteric rent, was found in all 3 cows. All had evidence of severe peritonitis and gross contamination of the abdomen with digesta. Because of severe peritonitis and inability to exteriorize the affected segment of jejunum, all 3 cows were euthanatized. We postulate that the mesenteric rent occurred at the time of parturition, resulting in ischemia and jejunal perforation in the segment of jejunum adjacent to the rent.


Deconvolution method for specific and nonspecific binding of ligand to multiprotein complex by native mass spectrometry.
In native mass spectrometry, it has been difficult to discriminate between specific bindings of a ligand to a multiprotein complex target from the nonspecific interactions. Here, we present a deconvolution model that consists of two levels of data reduction. At the first level, the apparent association binding constants are extracted from the measured intensities of the target/ligand complexes by varying ligand concentration. At the second level, two functional forms representing the specific and nonspecific binding events are fit to the apparent binding constants obtained from the first level of modeling. Using this approach, we found that a power-law distribution described nonspecific binding of α-amanitin to yeast RNA polymerase II. Moreover, treating the concentration of the multiprotein complex as a fitting parameter reduced the impact of inaccuracies in this experimental measurement on the apparent association constants. This model improves upon current methods for separating specific and nonspecific binding to large, multiprotein complexes in native mass spectrometry, by modeling nonspecific binding with a power-law function.


Genotype-phenotype association studies of chromosome 8p inverted duplication deletion syndrome.
Individuals diagnosed with chromosome 8p inverted duplication deletion (invdupdel(8p)) manifest a wide range of clinical features and cognitive impairment. The purpose of this study is to employ array CGH technology to define more precisely the cytogenetic breakpoints and regions of copy number variation found in several individuals with invdupdel(8p), and compare these results with their neuropsychological characteristics. We examined the cognitive-behavioral features of two male and two female children, ages 3-15 years, with invdupdel(8p). We noted cognitive deficits that ranged from mild to severe, and adaptive behavior composites that ranged from significantly to substantially lower than adequate levels. CARS scores, a measure of autistic behavior, identified three children with autism or autistic-like features. Three of the four children exhibited attention deficits and hyperactivity consistent with a DSM-IV-TR diagnosis of ADHD. One child showed extreme emotional lability. Interestingly, intellectual disability was not correlated with deletion size, nor was the deletion location associated with the autistic phenotype. On the other hand, the duplication length in 8p21.1/8p22 was associated with cognitive deficit. In addition, a small locus of over-expression in 8p21.3 was common for all three participants diagnosed as autistic. A limitation of the study is its small sample size. Further analyses of the deleted and over-expressed regions are needed to ascertain the genes involved in cognitive function and, possibly, autism.


Effect of strain on stripe phases in the quantum Hall regime.
Preferential orientation of the stripe phases in the quantum Hall (QH) regime has remained a puzzle since its discovery. We show experimentally and theoretically that the direction of high and low resistance of the two-dimensional (2D) hole gas in the QH regime can be controlled by an external strain. Depending on the sign of the in-plane shear strain, the Hartree-Fock energy of holes or electrons is minimized when the charge density wave (CDW) is oriented along the [110] or [110] directions. We suggest that shear strains due to internal electric fields in the growth direction are responsible for the observed orientation of CDW in pristine electron and hole samples.


Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges.
The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia-US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research between the two countries. In this article, we discuss the methodology and related challenges associated with the implementation of the Ebola vaccines clinical trial, based on a double-blinded randomized controlled trial, in Liberia.


Role of cyclic AMP in hydrogen peroxide-induced potentiation of sympathetic neurotransmission in the bovine iris.
Hydrogen peroxide (H2O2) has been shown to enhance electrically-evoked norepinephrine (NE) release from isolated, superfused bovine irides. Since stimulation of presynaptic adenylyl cyclase can potentiate sympathetic neurotransmission in several tissues, the present study considered the possibility that cyclic AMP may mediate the effects of H2O2 in the iris. Isolated bovine irides were prepared for analysis of field stimulation-induced [3H]NE release using the superfusion method. Both the diterpene activator of adenylyl cyclase, forskolin and the cyclic AMP-specific phosphodiesterase inhibitor, RO-201724 enhanced evoked [3H]NE overflow by 32%. On the other hand, inhibition of cyclic AMP-dependent protein kinase I/II by Rp-cAMPS attenuated field-stimulated [3H]NE release by 20%. Interestingly, both RO-201724 and Rp-cAMPS did not alter the enhancement of electrically-evoked [3H]NE overflow caused by submaximal concentrations of H2O2. We conclude that cyclic AMP may be involved in the pathway leading to NE release from sympathetic nerves in the bovine isolated iris. However, cyclic AMP may not be a mediator of H2O2-induced potentiation of sympathetic neurotransmission in this tissue.


Bioprospecting the Bibleome: Adding Evidence to Support the Inflammatory Basis of Cancer.
BioProspecting is a novel approach that enabled our team to mine genetic marker related data from the New England Journal of Medicine (NEJM) utilizing Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) and the Human Gene Ontology (HUGO). Genes associated with disorders using the Multi-threaded Clinical Vocabulary Server (MCVS) Natural Language Processing (NLP) engine, whose output was represented as an ontology-network incorporating the semantic encodings of the literature. Metabolic functions were used to identify potentially novel relationships between (genes or proteins) and (diseases or drugs). In an effort to identify genes important to transformation of normal tissue into a malignancy, we went on to identify the genes linked to multiple cancers and then mapped those genes to metabolic and signaling pathways. Ten Genes were related to 30 or more cancers, 72 genes were related to 20 or more cancers and 191 genes were related to 10 or more cancers. The three pathways most often associated with the top 200 novel cancer markers were the Acute Phase Response Signaling, the Glucocorticoid Receptor Signaling and the Hepatic Fibrosis/Hepatic Stellate Cell Activation pathway. This association highlights the role of inflammation in the induction and perhaps transformation of mortal cells into cancers. BioProspecting can speed our identification and understanding of synergies between articles in the biomedical literature. In this case we found considerable synergy between the Oncology literature and the Sepsis literature. By mapping these associations to known metabolic, regulatory and signaling pathways we were able to identify further evidence for the inflammatory basis of cancer.


Population pharmacokinetics of intravenous pantoprazole in paediatric intensive care patients.
The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit. Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce. Our population approach has determined the pharmacokinetic parameters of intravenous pantoprazole in paediatric intensive care patients and the relative importance of factors influencing its disposition. Pantoprazole clearance was significantly influenced by developmental changes and by the presence of systemic inflammatory syndrome, hepatic dysfunction and CYP2C19 inhibitors. To characterize the pharmacokinetics of intravenous pantoprazole in a paediatric intensive care population and to determine the influence of demographic factors, systemic inflammatory response syndrome (SIRS), hepatic dysfunction and concomitantly used CYP2C19 inducers and inhibitors on the drug's pharmacokinetics. A total of 156 pantoprazole concentration measurements from 20 patients (10 days to 16.4 years of age) at risk for or with upper gastrointestinal bleeding, who received pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m(2)/day, were analysed using a population pharmacokinetic approach (nonmem program). The best structural model for pantoprazole was a two-compartment model with zero order infusion and first-order elimination. Body weight, SIRS, age, hepatic dysfunction and presence of CYP2C19 inhibitors were significant covariates affecting clearance (CL), accounting for 75% of interindividual variability. Only body weight significantly influenced central volume of distribution (V(c)). In the final population model, the estimated CL and V(c) were 5.28 l h(-1) and 2.22 l, respectively, for a typical 5-year-old child weighing 20 kg. Pantoprazole CL increased with weight and age, whereas the presence of SIRS, CYP2C19 inhibitors and hepatic dysfunction, when present separately, significantly decreased pantoprazole CL by 62.3, 65.8 and 50.5%, respectively. For patients aged between 6 months and 5 years without SIRS, CYP2C19 inhibitor or hepatic dysfunction, the predicted pantoprazole CL is faster than that reported in adults. These results provide important information for physicians regarding selection of a starting dose and dosing regimens of pantoprazole for paediatric intensive care patients based on factors frequently encountered in this population.


Imaging of congenital heart disease in adults.
Imaging is fundamental to the lifelong care of adult congenital heart disease (ACHD) patients. Echocardiography remains the first line imaging for inpatient, outpatient, or perioperative care. Cross-sectional imaging with cardiovascular magnetic resonance (CMR) or computed tomography (CT) provides complementary and invaluable information on cardiac and vascular anatomy and other intra-thoracic structures. Furthermore, CMR provides quantification of cardiac function and vascular flow. Cardiac catheterization is mostly reserved for assessment of pulmonary vascular resistance, ventricular end-diastolic pressure, and percutaneous interventions. There have been further advances in non-invasive imaging for ACHD including the application of advanced echocardiographic techniques, faster automated CMR imaging, and radiation dose reduction in CT. As a result ACHD, a heterogeneous population, benefit from appropriate application of multiple imaging modalities matched with tertiary ACHD expertise.


Improving data quality and supervision of antiretroviral therapy sites in Malawi: an application of Lot Quality Assurance Sampling.
High quality program data is critical for managing, monitoring, and evaluating national HIV treatment programs. By 2009, the Malawi Ministry of Health had initiated more than 270,000 patients on HIV treatment at 377 sites. Quarterly supervision of these antiretroviral therapy (ART) sites ensures high quality care, but the time currently dedicated to exhaustive record review and data cleaning detracts from other critical components. The exhaustive record review is unlikely to be sustainable long term because of the resources required and increasing number of patients on ART. This study quantifies the current levels of data quality and evaluates Lot Quality Assurance Sampling (LQAS) as a tool to prioritize sites with low data quality, thus lowering costs while maintaining sufficient quality for program monitoring and patient care. In January 2010, a study team joined supervision teams at 19 sites purposely selected to reflect the variety of ART sites. During the exhaustive data review, the time allocated to data cleaning and data discrepancies were documented. The team then randomly sampled 76 records from each site, recording secondary outcomes and the time required for sampling. At the 19 sites, only 1.2% of records had discrepancies in patient outcomes and 0.4% in treatment regimen. However, data cleaning took 28.5 hours in total, suggesting that data cleaning for all 377 ART sites would require over 350 supervision-hours quarterly. The LQAS tool accurately identified the sites with the low data quality, reduced the time for data cleaning by 70%, and allowed for reporting on secondary outcomes. Most sites maintained high quality records. In spite of this, data cleaning required significant amounts of time with little effect on program estimates of patient outcomes. LQAS conserves resources while maintaining sufficient data quality for program assessment and management to allow for quality patient care.


Non-small cell lung cancer patient with a rare UGP2-ALK fusion protein responded well to alectinib: a case report.
Several rare anaplastic lymphoma kinase (ALK) fusions have been identified in patients with non-small cell lung cancer (NSCLC); however, their treatment is not currently uniform. alectinib has been commonly used to treat rare ALK fusions in patients with NSCLC. This is the first study to report the occurrence of a uridine diphosphate-glucose pyrophosphorylase 2 (UGP2)-ALK fusion in a patient with NSCLC. The patient, who was hospitalized because of shortness of breath lasting 20 days, showed hydrothorax of the left lung under a computerized tomography chest scan. Pathological histology revealed lung adenocarcinoma in the patient. The UGP2-ALK mutation was found by next-generation sequencing. Subsequently, the patient was administered alectinib, and thereafter, the tumor lesion was observed to gradually shrink over the follow-up period. Progression-free survival reached 10 months as of the follow-up date, with no adverse events detected. This case report provides valuable insights into the clinical management of NSCLC patients with UGP2-ALK fusions. Moreover, alectinib is confirmed to be an appropriate therapeutic agent for such patients.


Resident participation in neighbourhood audit tools - a scoping review.
Healthy urban environments require careful planning and a testing of environmental quality that goes beyond statutory requirements. Moreover, it requires the inclusion of resident views, perceptions and experiences that help deepen the understanding of local (public health) problems. To facilitate this, neighbourhoods should be mapped in a way that is relevant to them. One way to do this is participative neighbourhood auditing. This paper provides an insight into availability and characteristics of participatory neighbourhood audit instruments. A scoping review in scientific and grey literature, consisting of the following steps: literature search, identification and selection of relevant audit instruments, data extraction and data charting (including a work meeting to discuss outputs), reporting. In total, 13 participatory instruments were identified. The role of residents in most instruments was as 'data collectors'; only few instruments included residents in other audit activities like problem definition or analysis of data. The instruments identified focus mainly on physical, not social, neighbourhood characteristics. Paper forms containing closed-ended questions or scales were the most often applied registration method. The results show that neighbourhood auditing could be improved by including social aspects in the audit tools. They also show that the role of residents in neighbourhood auditing is limited; however, little is known about how their engagement takes place in practice. Developers of new instruments need to balance not only social and physical aspects, but also resident engagement and scientific robustness. Technologies like mobile applications pose new opportunities for participative approaches in neighbourhood auditing.


Failure of nimodipine to prevent ischemic neuronal damage in rats.
The efficacy of nimodipine in preventing ischemic brain injury was tested in rats subjected to a 20-minute period of high-grade forebrain ischemia by 4-vessel occlusion. Three minutes after restoration of circulation to the brain, an intravenous bolus of 5 micrograms/kg nimodipine or an equivalent amount of vehicle or saline was given, followed by continuous intravenous infusion of the respective solution at 1 microgram/kg/min for 2 hours. In a second series, a larger bolus (20 micrograms/kg of nimodipine) and longer infusion period (6 hours) were employed. Histopathology of the brain was evaluated blindly 72 hours later and graded on a conventional 3-point scale. There was no significant effect of treatment in either series. In the 6-hour series, the percent of cerebral hemispheres showing damage of Grades 2 or 3 in zone CA1 of the hippocampus and in the striatum, respectively, was 100 and 40% for the nimodipine-treated rats, 100 and 42% for rats receiving vehicle, and 75 and 25% for animals receiving saline. Thus, this study revealed no beneficial effect of nimodipine when given following a 20-minute period of severe forebrain ischemia.


Comparative skull analysis suggests species-specific captivity-related malformation in lions (Panthera leo).
Lion (Panthera leo) populations have dramatically decreased worldwide with a surviving population estimated at 32,000 across the African savannah. Lions have been kept in captivity for centuries and, although they reproduce well, high rates of stillbirths as well as morbidity and mortality of neonate and young lions are reported. Many of these cases are associated with bone malformations, including foramen magnum (FM) stenosis and thickened tentorium cerebelli. The precise causes of these malformations and whether they are unique to captive lions remain unclear. To test whether captivity is associated with FM stenosis, we evaluated 575 lion skulls of wild (N = 512) and captive (N = 63) origin. Tiger skulls (N = 276; 56 captive, 220 wild) were measured for comparison. While no differences were found between males and females or between subadults and adults in FM height (FMH), FMH of captive lions (17.36±3.20 mm) was significantly smaller and with greater variability when compared to that in wild lions (19.77±2.11 mm). There was no difference between wild (18.47±1.26 mm) and captive (18.56±1.64 mm) tigers in FMH. Birth origin (wild vs. captive) as a factor for FMH remained significant in lions even after controlling for age and sex. Whereas only 20/473 wild lions (4.2%) had FMH equal to or smaller than the 5th percentile of the wild population (16.60 mm), this was evident in 40.4% (23/57) of captive lion skulls. Similar comparison for tigers found no differences between the captive and wild populations. Lions with FMH equal to or smaller than the 5th percentile had wider skulls with smaller cranial volume. Cranial volume remained smaller in both male and female captive lions when controlled for skull size. These findings suggest species- and captivity-related predisposition for the pathology in lions.


Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy.
The links among the extent of hippocampal neurodegeneration, the frequency of spontaneous recurrent motor seizures (SRMS), and the degree of aberrant mossy fiber sprouting (MFS) in temporal lobe epilepsy (TLE) are a subject of contention because of variable findings in different animal models and human studies. To understand these issues further, we quantified these parameters at 3-5 months after graded injections of low doses of kainic acid (KA) in adult F344 rats. KA was administered every 1 hr for 4 hr, for a cumulative dose of 10.5 mg/kg bw, to induce continuous stages III-V motor seizures for >3 hr. At 4 days post-KA, the majority of rats (77%) exhibited moderate bilateral neurodegeneration in different regions of the hippocampus; however, 23% of rats exhibited massive neurodegeneration in all hippocampal regions. All KA-treated rats displayed robust SRMS at 3 months post-KA, and the severity of SRMS increased over time. Analyses of surviving neurons at 5 months post-KA revealed two subgroups of rats, one with moderate hippocampal injury (HI; 55% of rats) and another with widespread HI (45%). Rats with widespread HI exhibited greater loss of CA3 pyramidal neurons and robust aberrant MFS than rats with moderate HI. However, the frequency of SRMS (approximately 3/hr) was comparable between rats with moderate and widespread HI. Thus, in comparison with TLE model using Sprague-Dawley rats (Hellier et al. [1998] Epilepsy Res. 31:73-84), a much lower cumulative dose of KA leads to robust chronic epilepsy in F344 rats. Furthermore, the occurrence of SRMS in this model is always associated with considerable bilateral hippocampal neurodegeneration and aberrant MFS. However, more extensive hippocampal CA3 cell loss and aberrant MFS do not appear to increase the frequency of SRMS. Because most of the features are consistent with mesial TLE in humans, the F344 model appears ideal for testing the efficacy of potential treatment strategies for mesial TLE.


Neural correlates of deficient response inhibition in mentally disordered violent individuals.
In this study, response inhibition and associated neural activation during a motor inhibition paradigm were investigated in (i) men with antisocial personality disorder (APD) with a history of violence (n = 14), (ii) men with schizophrenia with a history of violence (n = 12), (iii) men with schizophrenia without a history of violence (n = 12), and (iv) healthy control subjects (n = 14) using functional magnetic resonance imaging (fMRI). At the behavioural level, individuals with schizophrenia showed impaired performance across all conditions, whereas an increased error rate was seen in the APD group only during the conditions requiring inhibition. At the neural level, both violent groups showed reduced thalamic activity, compared with controls, in association with modulation of inhibition by task demands. In addition, the violent schizophrenia group, compared with controls, showed reduced activity in the caudate nucleus during the condition requiring inhibition. It is concluded that violence may not be specifically associated with impaired voluntary inhibition in schizophrenia but this is likely in APD. Reduced thalamic function, perhaps due to its known association with sensorimotor disturbances, is implicated in violent behaviour across both disorders. In addition, caudate dysfunction may contribute, given its role in timing and temporal processing as well as suppression of motor actions, to deficient inhibition and violent behaviour in schizophrenia.


Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.


Dose-response curve and time course of the antihypertensive effect of SKF 92 657, a beta-receptor-blocking and vasodilating compound.
1. The antihypertensive effect of the new drug, SKF 92 657, a hydrazinopyridazine derivative, possessing both beta-adrenoreceptor-blocking and vasodilating properties, was investigated in essential hypertension. 2. Single oral doses of 1.0 or 2.0 mg/kg did not produce any consistent decrease in blood pressure; 4.0 mg/kg was the threshold dose for a mild but not significant blood pressure reduction, whereas 8.0 mg/kg caused a significant and marked blood pressure decrease without clinically relevant changes in heart rate. 3. Continued administration of the drug for 7 days induced a significant and uniform reduction in blood pressure without tachycardia. The increase in systolic blood pressure and in heart rate caused by dynamic exercise was left unaffected by the drug.


Mindfulness meditation training effects on CD4+ T lymphocytes in HIV-1 infected adults: a small randomized controlled trial.
Mindfulness meditation training has stress reduction benefits in various patient populations, but its effects on biological markers of HIV-1 progression are unknown. The present study tested the efficacy of an 8-week Mindfulness-based stress reduction (MBSR) meditation program compared to a 1-day control seminar on CD4+ T lymphocyte counts in stressed HIV infected adults. A single-blind randomized controlled trial was conducted with enrollment and follow-up occurring between November 2005 and December 2007. A diverse community sample of 48 HIV-1 infected adults was randomized and entered treatment in either an 8-week MBSR or a 1-day control stress reduction education seminar. The primary outcome was circulating counts of CD4+ T lymphocytes. Participants in the 1-day control seminar showed declines in CD4+ T lymphocyte counts whereas counts among participants in the 8-week MBSR program were unchanged from baseline to post-intervention (time x treatment condition interaction, p=.02). This effect was independent of antiretroviral (ARV) medication use. Additional analyses indicated that treatment adherence to the mindfulness meditation program, as measured by class attendance, mediated the effects of mindfulness meditation training on buffering CD4+ T lymphocyte declines. These findings provide an initial indication that mindfulness meditation training can buffer CD4+ T lymphocyte declines in HIV-1 infected adults. clinicaltrials.gov, Identifier: NCT00600561.


Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway.
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and has a poor prognosis. We, here, report a potent antitumor effect of berberine, an isoquinoline alkaloid, on GBM. Berberine was found to have an IC50 that is much lower than temozolomide in vitro in U87, U251, and U118 glioblastoma cells. Although previous studies showed that berberine primarily exerts its anticancer effect by inducing cell-cycle arrest, apoptosis, and autophagy, we observed that the antitumor effect of berberine on glioblastoma cells was primarily achieved through induction of cellular senescence. In glioblastoma cells treated with berberine, the level of epidermal growth factor receptor (EGFR) was greatly reduced. Examination of the activities of the kinases downstream of EGFR revealed that the RAF-MEK-ERK signaling pathway was remarkably inhibited, whereas AKT phosphorylation was not altered. Pharmacologic inhibition or RNA interference of EGFR similarly induced cellular senescence of glioblastoma cells. Furthermore, the cellular senescence induced by berberine could be rescued by introduction of a constitutive active MKK. Berberine also potently inhibited the growth of tumor xenografts, which was accompanied by downregulation of EGFR and induction of senescence. Our findings thus revealed a new route by which berberine exerts its anticancer activity. Because EGFR is commonly upregulated in glioblastoma, the demonstration of effective inhibition of EGFR by berberine points to the possibility of using berberine in the treatment of patients with glioblastoma.


Coercion in Outpatients under Community Treatment Orders: A Matched Comparison Study.
Since the deinstitutionalization of psychiatric services around the world, the scope of outpatient psychiatric care has also increased to better support treatment access and adherence. For those with serious mental illness who may lack insight into their own illness, available interventions include coercive community practices such as mandated community treatment orders (CTOs). This paper examines the perceptions of coercion among service users treated with a CTO. We used a cross-sectional comparative design where service users treated under a CTO were matched to a comparison group of voluntary psychiatric outpatients. Both groups were receiving intensive community mental health services (n = 69 in each group). Participants were interviewed using a series of questionnaires aimed at evaluating their perceptions of coercion and other aspects of the psychiatric treatment. The level of coercion reported by service users treated under a CTO was significantly higher than that in the comparison group. However, in adjusted analyses, service users' perception of coercion, irrespective of their CTO status, was directly correlated with their previous experience with probation and inversely correlated with the sense of procedural justice in their treatment. Evaluation of psychiatric service users' experiences of coercion should consider their past and current involvement with other types of coercive measures, particularly history of probation. Clinicians may be able to minimize these experiences of coercion by incorporating procedural justice principles into their practice.


Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD.
Vascular stiffening occurs in normal ageing and is accelerated in chronic kidney disease (CKD). Vascular calcification contributes to this stiffening and to the high incidence of vascular morbidity and mortality in this population. A network of inhibitors work in concert to reduce mineralization risk in extra-osseous tissue. Fetuin-A is an important systemic inhibitor of ectopic calcification. A fraction of the total circulating fetuin-A interacts with mineral ions to form stable colloidal complexes, calciprotein particles (CPP), preventing deposition. We sought to assess whether CPP fetuin-A levels were associated with procalcific factors and aortic stiffness in a cohort of patients with Stages 3 and 4 CKD. We measured fetuin-A CPP levels, serum inflammatory markers [C-reactive protein (CRP), interleukin-6, tumour necrosis factor-α], oxidized low-density lipoprotein (oxLDL), bone morphogenetic protein-2 (BMP-2) and -7 (BMP-7) and aortic pulse wave velocity (APWV) in a cohort of 200 CKD patients. Serum measurements were also made in 78 healthy controls. CPP fetuin-A phosphorylation was characterized by phosphate-affinity gel chromatography. Fetuin-A-containing CPPs were only detectable in the serum of CKD patients. Inflammatory markers, oxLDL and BMP-2 levels were all significantly higher in the CKD than control subjects. CPP fetuin-A levels were independently associated with serum phosphate, high-sensitivity C-reactive protein, oxLDL, BMP-2/7 ratio and inversely with estimated glomerular filtration rate (model R(2) = 0.51). After adjusting for confounders, CPP fetuin-A levels were independently associated with APWV. Only phosphorylated fetuin-A was present in serum CPP. Increased CPP fetuin-A levels reflect an increasingly procalcific milieu and are associated with increased aortic stiffness in patients with pre-dialysis CKD.


Identification and characterization of the first endogenous phospholipase A2 inhibitor from a non-venomous tropical snake, Boa constrictor (Serpentes: Boidae).
Endogenous phospholipase A2 inhibitors from snake blood (sbPLIs) have been isolated from several species around the world, with the primary function of self-protection against the action of toxic phospholipases A2. In American snakes, sbPLIs were solely described in pit vipers, in which the natural protection role is justified. In this study, we described a sbPLI in Boa constrictor (popularly known as jiboia), a non-venomous snake species from America. PLA2 inhibitory activity was tested in the blood plasma of B. constrictor using C. d. terrificus venom as the enzyme source. Antibodies developed against CNF, a sbγPLI from Crotalus durissus terrificus, were used to investigate the presence of homologues in the blood plasma of B. constrictor. A CNF-like molecule with a PLA2 inhibitory activity was purified by column chromatography. The encoding gene for the inhibitor was cloned from B. constrictor liver tissue. The DNA fragment was cloned, purified and sequenced. The deduced primary sequence of interest was aligned with known sbγPLIs from the literature. The blood plasma of B. constrictor displayed PLA2 inhibitory activity. A CNF-like molecule (named BcNF) was identified and purified from the blood plasma of B. constrictor. Basic properties such as molecular mass, composing amino acids, and pI were comparable, but BcNF displayed reduced specific activity in PLA2 inhibition. BcNF showed highest identity scores (ISs) with sbγPLIs from pit vipers from Latin America (90-100%), followed by gamma inhibitors from Asian viperid (80-90%). ISs below 70% were obtained for BcNF and non-venomous species from Asia. A functional sbγPLI (BcNF) was described in the blood plasma of B. constrictor. BcNF displayed higher primary identity with sbγPLIs from Viperidae than to sbγPLIs from non-venomous species from Asia. The physiological role played by sbγPLIs in non-venomous snake species remains to be understood. Further investigation is needed.


Impact of post-ejaculatory pain in men with category III chronic prostatitis/chronic pelvic pain syndrome.
Chronic Pelvic Pain Syndrome (CPPS) is a common debilitating condition in which ejaculation relieves symptoms for some but exacerbates them in others. We studied ejaculatory pain in a cohort with CPPS to investigate associations with symptoms, quality of life and risk factors. The 486 men in the National Institutes of Health Chronic Prostatitis Cohort study were stratified into 4 subgroups according to the presence of ejaculatory pain at baseline visit and at each of 3 monthly followup contacts. Subgroups were based on answers and labeled NO (always "no"), Nvar ("no" at baseline but "yes" or missing at least once), Yvar ("yes" at baseline but "no" or missing at least once) and YES (always "yes"). Demographic and quality of life data were obtained at baseline, together with medical and sexual history, symptoms, and cultures and microscopy of urine and seminal fluids. Associations among selected baseline risk factors, symptoms and post-ejaculatory pain were analyzed. Overall 128 men were classified as NO, 106 as Nvar, 137 as Yvar and 115 as YES. There was a progressive increase in baseline National Institutes of Health-Chronic Prostatitis Symptom Index total score (modified to exclude post-ejaculatory pain) from 18.5 for the NO subgroup to 25.5 for the YES subgroup (p <0.0001). Mental and physical quality of life were also progressively lower from the NO to the YES subgroup (p <0.001). There were no significant differences in white blood cell count or bacterial growth in urine, prostate fluid or semen among subgroups. Men in the YES subgroup were younger, more likely to live alone, had lower income and a greater variety of sexual practices than those without ejaculatory pain (NO subgroup). Patients with CPPS and persistent ejaculatory pain have more severe symptoms, are less likely to improve with time, and have differences in demographic and sexual history compared to other patients with CPPS.


Self-organization of control circuits for invariant fiber projections.
Assuming that patterns in memory are represented as two-dimensional arrays of local features, just as they are in primary visual cortices, pattern recognition can take the form of elastic graph matching (Lades et al., 1993 ). Neural implementation of this may be based on preorganized fiber projections that can be activated rapidly with the help of control units (Wolfrum, Wolff, Lücke, & von der Malsburg, 2008 ). Each control unit governs a set of projection fibers that form part of a coherent mapping. We describe a mathematical model for the ontogenesis of the underlying connectivity based on a principle of network self-organization as described by the Häussler system (Häussler & von der Malsburg, 1983 ), modified to be sensitive to pattern similarity and to support formation of multiple mappings, each under the command of a control unit. The process takes the form of a soft-winner-take-all, where units compete for the representation of maps. We show simulations for invariant point-to-point and feature-to-feature mappings.


Spins, electromagnetic moments, and isomers of (107-129)Cd.
The neutron-rich isotopes of cadmium up to the N=82 shell closure have been investigated by high-resolution laser spectroscopy. Deep-uv excitation at 214.5 nm and radioactive-beam bunching provided the required experimental sensitivity. Long-lived isomers are observed in (127)Cd and (129)Cd for the first time. One essential feature of the spherical shell model is unambiguously confirmed by a linear increase of the 11/2(-) quadrupole moments. Remarkably, this mechanism is found to act well beyond the h(11/2) shell.


Identification of GIT1/Cat-1 as a substrate molecule of protein tyrosine phosphatase zeta /beta by the yeast substrate-trapping system.
We used a genetic method, the yeast substrate-trapping system, to identify substrates for protein tyrosine phosphatases zeta (PTPzeta/RPTPbeta). This method is based on the yeast two-hybrid system, with two essential modifications: conditional expression of protein tyrosine kinase v-src (active src) to tyrosine-phosphorylate the prey proteins and screening by using a substrate-trap mutant of PTPzeta (PTPzeta-D1902A) as bait. By using this system, several substrate candidates for PTPzeta were isolated. Among them, GIT1/Cat-1 (G protein-coupled receptor kinase-interactor 1/Cool-associated, tyrosine-phosphorylated 1) was examined further. GIT1/Cat-1 bound to PTPzeta-D1902A dependent on the substrate tyrosine phosphorylation. Tyrosine-phosphorylated GIT1/Cat-1 was dephosphorylated by PTPzeta in vitro. Immunoprecipitation experiments indicated that PTPzeta-D1902A and GIT1/Cat-1 form a stable complex also in mammalian cells. Immunohistochemical analyses revealed that PTPzeta and GIT1/Cat-1 were colocalized in the processes of pyramidal cells in the hippocampus and neocortex in rat brain. Subcellular colocalization was further verified in the growth cones of mossy fibers from pontine explants and in the ruffling membranes and processes of B103 neuroblastoma cells. Moreover, pleiotrophin, a ligand for PTPzeta, increased tyrosine phosphorylation of GIT1/Cat-1 in B103 cells. All these results indicate that GIT1/Cat-1 is a substrate molecule of PTPzeta.


Dismal Outcomes and High Societal Burden of Mitral Valve Regurgitation in France in the Recent Era: A Nationwide Perspective.
Background Although US recent data suggest that mitral regurgitation (MR) is severely undertreated and carries a poor outcome, population-based views on outcome and management are limited. We aimed to define the current treatment standards, clinical outcomes, and costs related to MR at the nationwide level. Methods and Results In total, 107 412 patients with MR were admitted in France in 2014 to 2015. Within 1 year, 8% were operated and 92% were conservatively managed and constituted our study population (68% primary MR and 32% secondary MR). The mean age was 77±15 years; most patients presented with comorbidities. In-hospital and 1-year mortality rates were 4.1% and 14.3%, respectively. Readmissions were common (63% at least once and 37% readmitted ≥2 times). Rates of 1-year mortality or all-cause readmission and 1-year mortality or heart failure readmission were 67% and 34%, respectively, and increased with age, Charlson index, heart failure at admission, and secondary MR etiology; however, the event rate remained notably high in the primary MR subset (64% and 28%, respectively). The mean costs of hospital admissions and of readmissions were 5345±6432 and 10 080±10 847 euros, respectively. Conclusions At the nationwide level, MR was a common reason for admission and affected an elderly population with frequent comorbidities. Less than 10% of patients underwent a valve intervention. All subsets of patients who were conservatively managed incurred high mortality and readmissions rates, and MR represented a major societal burden with an extrapolated annual cost of 350 to 550 million euros (390-615 million US dollars). New strategies to improve the management and outcomes of patients with both primary and secondary MR are critical and warranted.


Impact of remote biometric monitoring on cost and hospitalization outcomes in peritoneal dialysis.
Peritoneal dialysis is a home-based therapy for individuals with end-stage renal disease. Telehealth, and in particular - remote monitoring, is making inroads in managing this cohort. We examined whether daily remote biometric monitoring (RBM) of blood pressure and weight among peritoneal dialysis patients was associated with changes in hospitalization rate and hospital length of stay, as well as outpatient, inpatient and overall cost of care. Outpatient visit claim payment amounts (in US dollars derived from CMS data) decreased post-intervention relative to pre-intervention for those at age 18-54 years. For certain subgroups, non- or nearly-significant changes were found among female and Black participants. There was no change in inpatient costs post-intervention relative to pre-intervention for females and while the overall visit claim payment amounts increased in the outpatient setting slightly (US$511.41 (1990.30) vs. US$652.61 (2319.02), p = 0.0783) and decreased in the inpatient setting (US$10,835.30 (6488.66) vs. US$10,678.88 (15,308.17), p = 0.4588), these differences were not statistically significant. Overall cost was lower if RBM was used for assessment of blood pressure and/or weight (US$-734.51, p < 0.05). Use of RBM collected weight was associated with fewer hospitalizations (adjusted odds ratio 0.54, 95% confidence interval 0.33-0.89) and fewer days hospitalized (adjusted odds ratio 0.46, 95% confidence interval 0.26-0.81). Use of RBM collected blood pressure was associated with increased days of hospitalization and increased odds of hospitalization. RBM offers a powerful opportunity to provide care to those receiving home therapies such as peritoneal dialysis. RBM may be associated with reduction in both inpatient and outpatient costs for specific sub-groups receiving peritoneal dialysis.


Quantifying how smokers value attributes of electronic cigarettes.
Rates of electronic cigarette (e-cigarette) use have increased quickly among US adults (3.3% in 2010 to 8.5% in 2013) and youth (4.5% in 2013 to 13.4% in 2014). As state and local governments consider regulatory policies, understanding what smokers believe about e-cigarettes and how they value e-cigarettes is important. Using data from a convenience sample of Florida adult smokers (N=765), we investigated the value smokers place on specific attributes of e-cigarettes (availability of flavours, effectiveness of e-cigarettes as a cessation aid, healthier alternative to regular cigarettes, ability to use e-cigarettes in public places) by asking smokers how much they would be willing to pay for e-cigarettes with and without each of these attributes. For cigarette-only and dual users, losing the ability to use an e-cigarette as a quit aid and losing the harm reduction of an e-cigarette significantly reduced the price respondents were willing to pay for an e-cigarette. For cigarette-only users, not being able to use an e-cigarette indoors and losing flavours also significantly reduced the price respondents were willing to pay for an e-cigarette. Our results suggest that smokers value multiple attributes of e-cigarettes. Our valuation measures also appear to align with smokers' beliefs about e-cigarettes.


Rye cover crop and gamagrass strip effects on NO3 concentration and load in tile drainage.
A significant portion of the NO3 from agricultural fields that contaminates surface waters in the Midwest Corn Belt is transported to streams or rivers by subsurface drainage systems or "tiles." Previous research has shown that N fertilizer management alone is not sufficient for reducing NO3 concentrations in subsurface drainage to acceptable levels; therefore, additional approaches need to be devised. We compared two cropping system modifications for NO3 concentration and load in subsurface drainage water for a no-till corn (Zea mays L.)-soybean (Glycine max [L.] Merr.) management system. In one treatment, eastern gamagrass (Tripsacum dactyloides L.) was grown in permanent 3.05-m-wide strips above the tiles. For the second treatment, a rye (Secale cereale L.) winter cover crop was seeded over the entire plot area each year near harvest and chemically killed before planting the following spring. Twelve 30.5x42.7-m subsurface-drained field plots were established in 1999 with an automated system for measuring tile flow and collecting flow-weighted samples. Both treatments and a control were initiated in 2000 and replicated four times. Full establishment of both treatments did not occur until fall 2001 because of dry conditions. Treatment comparisons were conducted from 2002 through 2005. The rye cover crop treatment significantly reduced subsurface drainage water flow-weighted NO3 concentrations and NO3 loads in all 4 yr. The rye cover crop treatment did not significantly reduce cumulative annual drainage. Averaged over 4 yr, the rye cover crop reduced flow-weighted NO3 concentrations by 59% and loads by 61%. The gamagrass strips did not significantly reduce cumulative drainage, the average annual flow-weighted NO3 concentrations, or cumulative NO3 loads averaged over the 4 yr. Rye winter cover crops grown after corn and soybean have the potential to reduce the NO3 concentrations and loads delivered to surface waters by subsurface drainage systems.


The Genome-Wide Influence on Human BMI Depends on Physical Activity, Life Course, and Historical Period.
In this analysis, guided by an evolutionary framework, we investigate how the human genome as a whole interacts with historical period, age, and physical activity to influence body mass index (BMI). The genomic influence is estimated by (1) heritability or the proportion of variance in BMI explained by genome-wide genotype data, and (2) the random effects or the best linear unbiased predictors (BLUPs) of genome-wide association studies (GWAS) data on BMI. Data were used from the Framingham Heart Study (FHS) in the United States. The study was initiated in 1948, and the obesity data were collected repeatedly over the subsequent decades. The analyses draw analysis samples from a pool of >8,000 individuals in the FHS. The hypothesis testing based on Pitman test, permutation Pitman test, F test, and permutation F test produces three sets of significant findings. First, the genomic influence on BMI is substantially larger after the mid-1980s than in the few decades before the mid-1980s within each age group of 21-40, 41-50, 51-60, and >60. Second, the genomic influence on BMI weakens as one ages across the life course, or the genomic influence on BMI tends to be more important during reproductive ages than after reproductive ages within each of the two historical periods. Third, within the age group of 21-50 and not in the age group of >50, the genomic influence on BMI among physically active individuals is substantially smaller than the influence on those who are not physically active. In summary, this study provides evidence that the influence of human genome as a whole on obesity depends on historical period, age, and level of physical activity.


Routine interim disease assessment in patients undergoing induction chemotherapy for acute myeloid leukemia: Can we do better?
The presence of >5% blasts at "day 14" (D14), in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) is problematic. It is unclear if a second course of chemotherapy for early persistent disease will alter outcome in these patients. We conducted a retrospective study of AML patients undergoing induction chemotherapy where diagnostic, interim (around day 14), and recovery (days 21-42) bone marrow (BM) evaluations were available for review. Of the 113 patients included in the final analysis, 99 (87.6%) achieved CR at hematologic recovery. At D14, 90 patients (79.6%) had <5% blasts and of these, 87 (96.7%) ultimately achieved CR. At D14, Twenty-three (20.4%) patients had residual leukemia (>5% blasts). Of these, 11 (47.8%) received a second course of chemotherapy (double induction [DI]) and 12 (52.2%) were observed until count recovery (single induction [SI]). No significant difference in CR rates was observed between these two groups (58.3% DI group vs. 45.5% SI group, P value = 0.684). In our analysis, D14 BM evaluation did not uniformly identify patients with primary induction failure. To unequivocally determine the value of a D14 marrow assessment in AML, prospective studies in the context of large cooperative group trials are required. Considering our findings and similar reports from others, we propose that D14 marrow assessment should be individualized, and that other factors, such as cytogenetics and early peripheral blood blast clearance should be considered, to identify patients most likely to benefit from interim disease assessment during AML induction therapy.


Alcohol and tobacco use in relation to gastric cancer: a prospective study of men in Shanghai, China.
Epidemiologic findings of tobacco and alcohol use in relation to gastric cancer are inconsistent. Well-designed prospective studies examining their relationship are sparse. The association between cigarette smoking/alcohol intake and gastric cancer risk was examined in a population-based prospective cohort of 18,244 middle-aged and older men in Shanghai, China, who were enrolled in the study during 1986-1989. After up to 20 years of follow-up, 391 incident gastric cancer cases were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Ever smokers experienced a statistically significant increased risk of gastric cancer (HR, 1.59; 95% CI, 1.27-1.99) compared with nonsmokers after adjustment for alcohol intake and other confounders. Among nondrinkers, smokers experienced 80% increased risk of gastric cancer (HR, 1.81; 95% CI,1.36, 2.41). Conversely, heavy drinkers experienced a statistically significant increase in risk of gastric cancer (HR, 1.46; 95% CI, 1.05-2.04) among all subjects and a statistically nonsignificant 80% increased risk among never smokers. Further adjustment for Helicobacter pylori serology, serum levels of beta-carotene and vitamin C, and urinary level of total isothiocyanates in combination with glutathione S-transferase (GST) M1 and GSTT1 genotypes did not materially change the associations between smoking/alcohol consumption and gastric cancer risk. These results suggest that cigarette smoking and alcohol consumption may exert independent effects on the development of gastric cancer in this high-risk population. Modification of these lifestyle choices may reduce the incidence of gastric cancer.


Prevalence of and risk factors for hepatitis C virus antibody among people who inject drugs in Cambodia: a national biological and behavioral survey.
Hepatitis C virus (HCV) is a significant global health concern. Despite evidence of the relationship between injecting drug use and HCV, studies on HCV among people who inject drugs in developing countries remain scarce. To address this need, we conducted this study to explore the prevalence of and factors associated with HCV antibody positivity among people who inject drugs in Cambodia. Data used for this study were collected as part of the National Integrated Biological and Behavioral Survey among people who use and inject drugs conducted in 2017. We used the respondent-driven sampling method to recruit participants in 12 provinces for face-to-face interviews and HIV and HCV antibody testing. Weighted multivariable logistic regression analysis was conducted to identify risk factors associated with HCV antibody positivity. This study included 286 people who inject drugs with a mean age of 31.6 (SD = 7.5) years. The prevalence of HCV antibody among participants in this study was 30.4%, of whom 31.0% were co-infected with HIV. After adjustment for other covariates, the odds of HCV antibody positivity was significantly higher among participants who were in the older age group of 25 to 34 (AOR = 1.85, 95% CI = 1.06-7.92) and ≥ 35 (AOR = 2.67, 95% CI = 1.24-5.71), were in Vietnamese ethnic group (AOR = 5.44, 95% CI = 2.25-13.14), were living on the streets (AOR = 3.01, 95% CI = 1.29-704), had been sent to a drug rehabilitation center in the past 12 months (AOR = 2.67, 95% CI = 1.21-5.90), had received methadone maintenance therapy in the past 12 months (AOR = 3.02, 95% CI = 1.32-6.92), and were tested positive for HIV (AOR = 3.80, 95% CI = 1.58-9.12) compared to their respective reference group. The prevalence of HCV antibody among people who inject drugs in Cambodia is high, particularly in older and more vulnerable subgroups. Tailor-made interventions are required to increase access to culturally sensitive harm reduction interventions to prevent primary HCV infection and reinfection. In addition, there is an opportunity to expand screening, diagnosis, and treatment with new directly acting antiviral agents.


The marine algae Sargassum spp. (Sargassaceae) as feed for sheep in tropical and subtropical regions.
The objective of this study was to evaluate Sargassum meal as feed for sheep through the measures of in vivo digestibility, dry matter degradability, pH, ammonia and volatile fatty acids in rumen. The Sargassum algae used in this experiment were collected at the end of spring, when they are more abundant, bigger, and have completed their reproductive cycle. Four tons (wet weigth) were collected manually from the intertidal zone of La Paz bay, Baja California Sur, Mexico. These algae were sun-dried and ground in a hammer mill to obtain the Sargassum meal. Four fistulated Pelibuey sheep, were fed daily with diets containing the marine algae (MA) at different levels (0, 10, 20 and 30 %), using a 4 x 4 Latin-square design experiment. Feed intake was not affected (p>0.05). Water consumption and urine excretion increased with MA (p<0.05; r2=0.54 and r2=0.74, respectively). In all treatments dry matter digestibility was of 74%-79%, and crude protein digestibility was of 85%-88%. Acid detergent fiber (59%-65%) and neutral detergent fiber (55%-66%) digestibility were greater in all treatments with MA. Ruminal pH was greater in all groups fed with MA (p<0.05). Ammonium concentration was not influenced (p>0.05) by MA. Ruminal volatile fatty acids decreased in all MA groups (p<0.05). The marine algae Sargassum spp. can be used as a feed supplement for sheep, especially in tropical and subtropical regions where these marine algae are available.


Divergent evolution of a bifunctional de novo protein.
Primordial proteins, the evolutionary ancestors of modern sequences, are presumed to have been minimally active and nonspecific. Following eons of selective pressure, these early progenitors evolved into highly active and specific proteins. While evolutionary trajectories from poorly active and multifunctional generalists toward highly active specialists likely occurred many times in evolutionary history, such pathways are difficult to reconstruct in natural systems, where primordial sequences are lost to time. To test the hypothesis that selection for enhanced activity leads to a loss of promiscuity, we evolved a de novo designed bifunctional protein. The parental protein, denoted Syn-IF, was chosen from a library of binary patterned 4-helix bundles. Syn-IF was shown previously to rescue two different auxotrophic strains of E. coli: ΔilvA and Δfes. These two strains contain deletions for proteins with very different biochemical functions; IlvA is involved in isoleucine biosynthesis, while Fes is involved in iron assimilation. In two separate experiments, Syn-IF, was evolved for faster rescue of either ΔilvA or Δfes. Following multiple rounds of mutagenesis, two new proteins were selected, each capable of rescuing the selected function significantly faster than the parental protein. In each case, the evolved protein also lost the ability to rescue the unselected function. In both evolutionary trajectories, the original bifunctional generalist was evolved into a monofunctional specialist with enhanced activity.


Atmospheric transmission spectroscopy using the sun as the source.
A method is presented to obtain normalized high resolution slant path transmittance spectra of the atmosphere. Sample spectra are presented. The spectra are of use in remote sensing applications for various types of atmospheric physics and atmospheric photochemistry research, for validating line parameter compilations, and for modeling slant path radiative transfer. The sample spectra are used to demonstrate improved accuracy of line-by-line transmission models when recently reported water vapor line parameters are substituted for those in the 1986 AFGL line parameter compilation in the region near 1 microm.