Apolipoprotein M modulates erythrocyte efflux and tubular reabsorption of sphingosine-1-phosphate.
Sphingosine-1-phosphate (S1P) mediates several cytoprotective functions of HDL. apoM acts as a S1P binding protein in HDL. Erythrocytes are the major source of S1P in plasma. After glomerular filtration, apoM is endocytosed in the proximal renal tubules. Human or murine HDL elicited time- and dose-dependent S1P efflux from erythrocytes. Compared with HDL of wild-type (wt) mice, S1P efflux was enhanced in the presence of HDL from apoM transgenic mice, but not diminished in the presence of HDL from apoM knockout (Apom(-/-)) mice. Artificially reconstituted and apoM-free HDL also effectively induced S1P efflux from erythrocytes. S1P and apoM were not measurable in the urine of wt mice. Apom(-/-) mice excreted significant amounts of S1P. apoM was detected in the urine of mice with defective tubular endocytosis because of knockout of the LDL receptor-related protein, chloride-proton exchanger ClC-5 (Clcn5(-/-)), or the cysteine transporter cystinosin. Urinary levels of S1P were significantly elevated in Clcn5(-/-) mice. In contrast to Apom(-/-) mice, these mice showed normal plasma concentrations for apoM and S1P. In conclusion, HDL facilitates S1P efflux from erythrocytes by both apoM-dependent and apoM-independent mechanisms. Moreover, apoM facilitates tubular reabsorption of S1P from the urine, however, with no impact on S1P plasma concentrations.


Honey: Single food stuff comprises many drugs.
Honey is a natural food item produced by honey bees. Ancient civilizations considered honey as a God gifted prestigious product. Therefore, a huge literature is available regarding honey importance in almost all religions. Physically, honey is a viscous and jelly material having no specific color. Chemically, honey is a complex blend of many organic and inorganic compounds such as sugars, proteins, organic acids, pigments, minerals, and many other elements. Honey use as a therapeutic agent is as old as human civilization itself. Prior to the appearance of present day drugs, honey was conventionally used for treating many diseases. At this instant, the modern research has proven the medicinal importance of honey. It has broad spectrum anti-biotic, anti-viral and anti-fungal activities. Honey prevents and kills microbes through different mechanism such as elevated pH and enzyme activities. Till now, no synthetic compound that works as anti-bacterial, anti-viral and anti-fungal drugs has been reported in honey yet it works against bacteria, viruses and fungi while no anti-protozoal activity has been reported. Potent anti-oxidant, anti-inflammatory and anti-cancerous activities of honey have been reported. Honey is not only significant as anti-inflammatory drug that relieve inflammation but also protect liver by degenerative effects of synthetic anti-inflammatory drugs. This article reviews physico-chemical properties, traditional use of honey as medicine and mechanism of action of honey in the light of modern scientific medicinal knowledge.


Differential mobility and local variation in infection attack rate.
Infectious disease transmission is an inherently spatial process in which a host's home location and their social mixing patterns are important, with the mixing of infectious individuals often different to that of susceptible individuals. Although incidence data for humans have traditionally been aggregated into low-resolution data sets, modern representative surveillance systems such as electronic hospital records generate high volume case data with precise home locations. Here, we use a gridded spatial transmission model of arbitrary resolution to investigate the theoretical relationship between population density, differential population movement and local variability in incidence. We show analytically that a uniform local attack rate is typically only possible for individual pixels in the grid if susceptible and infectious individuals move in the same way. Using a population in Guangdong, China, for which a robust quantitative description of movement is available (a travel kernel), and a natural history consistent with pandemic influenza; we show that local cumulative incidence is positively correlated with population density when susceptible individuals are more connected in space than infectious individuals. Conversely, under the less intuitively likely scenario, when infectious individuals are more connected, local cumulative incidence is negatively correlated with population density. The strength and direction of correlation changes sign for other kernel parameter values. We show that simulation models in which it is assumed implicitly that only infectious individuals move are assuming a slightly unusual specific correlation between population density and attack rate. However, we also show that this potential structural bias can be corrected by using the appropriate non-isotropic kernel that maps infectious-only code onto the isotropic dual-mobility kernel. These results describe a precise relationship between the spatio-social mixing of infectious and susceptible individuals and local variability in attack rates. More generally, these results suggest a genuine risk that mechanistic models of high-resolution attack rate data may reach spurious conclusions if the precise implications of spatial force-of-infection assumptions are not first fully characterized, prior to models being fit to data.


Sanitation safety planning as a tool for achieving safely managed sanitation systems and safe use of wastewater.
Increasing water stress and growing urbanization force a greater number of people to use wastewater as an alternative water supply, especially for irrigation. Although wastewater irrigation in agriculture has a long history and substantial benefits, without adequate treatment and protective measures on farms and in markets, use of wastewater poses risks to human health and the environment. Against this background, the World Health Organization (WHO) published Guidelines for the safe use of wastewater, excreta and greywater in agriculture and aquaculture, in 2006. The Sanitation safety planning: manual for safe use and disposal of wastewater, greywater and excreta - a step-by-step risk-based management tool for sanitation systems - was published by WHO in 2016 to put these guidelines into practice. Sanitation safety planning (SSP) can be applied to all sanitation systems, to ensure the systems are managed to meet health objectives. This paper summarizes the pilot-testing of the SSP manual in India, Peru, Portugal, Philippines, Uganda and Viet Nam. Also reviewed are some of the key components of the manual and training, and an overview of SSP training and dissemination efforts and opportunities for implementation in the WHO South-East Asia Region. Lessons learnt during the piloting phase show how reducing health risks can be surprisingly easy, even in a low-income setting, especially when combining many smaller measures. The SSP approach can make an important contribution towards Sustainable Development Goal target 6.3, by reducing pollution, eliminating dumping and minimizing the release of hazardous chemicals and materials, thereby halving the proportion of untreated wastewater and substantially increasing recycling and safe reuse globally.


A randomized controlled trial of concept based indexing of Web page content.
Medical information is increasingly being presented in a web-enabled format. Medical journals, guidelines, and textbooks are all accessible in a web-based format. It would be desirable to link these reference sources to the electronic medical record to provide education, to facilitate guideline implementation and usage and for decision support. In order for these rich information sources to be accessed via the medical record they will need to be indexed by a single comparable underlying reference terminology. We took a random sample of 100 web pages out of the 6,000 web pages on the Mayo Clinic's Health Oasis web site. The web pages were divided into four datasets each containing 25 pages. These were humanly reviewed by four clinicians to identify all of the health concepts present (R1DA, R2DB, R3DC, R4DD). The web pages were simultaneously indexed using the SNOMED-RT beta release. The indexing engine has been previously described and validated. A new clinician reviewed the indexed web pages to determine the accuracy of the automated mappings as compared with the human identified concepts (R4DA, R3DB, R2DC, R1DD). This review found 13,220 health concepts. Of these 10,383 concepts were identified by the initial human review (78.5% +/- 3.6%). The automated process identified 10,083 concepts correctly (76.3% +/- 4.0%) from within this corpus. The computer identified 2,420 concepts, which were not identified by the clinician's review but were upon further consideration important to include as health concepts. There was on average a 17.1% +/- 3.5% variability in the human reviewers ability to identify the important health concepts within web page content. Concept Based Indexing provided a positive predictive value (PPV) of finding a health concept of 79.3% as compared with keyword indexing which only has a PPV of 33.7% (p < 0.001). SNOMED-RT is a reasonable ontology for web page indexing. Concept based indexing provides a significantly greater accuracy in identifying health concepts when compared with keyword indexing.


Clinical and Microbiologic Assessment of Cases of Pediatric Community-associated Clostridium difficile Infection Reveals Opportunities for Improved Testing Decisions.
Most children with Clostridium difficile infection (CDI) experience community onset of CDI symptoms. We retrospectively compared hospital-onset healthcare facility-associated CDI cases to community-associated (CA) CDI cases diagnosed by Cepheid Xpert tcdB polymerase chain reaction (PCR) at an academic children's hospital over a 1-year period. Saved stools from CDI cases additionally underwent anaerobic stool culture and multiplex gastrointestinal pathogen PCR testing. Compared with 25 hospital-onset healthcare facility-associated CDI cases, the 74 CA-CDI cases were more frequently <2 years old (18% vs. 0%, P = 0.034) and less frequently had antibiotic exposure in the past 30 days (26% vs. 88%, P < 0.0001), proton pump inhibitor exposure (16% vs. 36%, P = 0.036) or a gastrostomy tube (11% vs. 32%, P = 0.013). Among children diagnosed with CA-CDI, 19 (26%) had no identified CDI risk factors (immunocompromised; gastrostomy tube; recent antibiotic, proton pump inhibitor or inpatient/outpatient healthcare exposures). Clinical testing for viral pathogens was uncommon among children thought to have CA-CDI. Multiplex PCR testing of saved stool samples failed to identify C. difficile among 23% of cases diagnosed with CA-CDI by the Cepheid Xpert tcdB PCR assay. CDI antibiotic therapy was provided to nearly all patients testing positive by tcdB PCR irrespective of CDI risk factors. Many children diagnosed with CA-CDI by PCR lack CDI risk factors and have discordant results when additional CDI testing methods are performed, suggesting overdiagnosis of CDI in children with community-onset diarrhea. More selective CDI testing of low-risk pediatric patients is needed to more accurately diagnose CDI and limit unnecessary CDI antibiotic treatment in children.


Alterations in Mitochondrial and Endoplasmic Reticulum Signaling by p53 Mutants.
The p53 protein is probably the most important tumor suppressor, acting as a nuclear transcription factor primarily through the modulation of cell death. However, currently, it is well accepted that p53 can also exert important transcription-independent pro-cell death actions. Indeed, cytosolic localization of endogenous wild-type or transactivation-deficient p53 is necessary and sufficient for the induction of apoptosis and autophagy. Here, we present the extra-nuclear activities of p53 associated with the mitochondria and the endoplasmic reticulum, highlighting the activities of the p53 mutants on these compartments. These two intracellular organelles play crucial roles in the regulation of cell death, and it is now well established that they also represent sites where p53 can accumulate.


The language of birth.
Our language both reflects and influences our attitudes and behavior. This Roundtable Discussion explores the language used in obstetrics and in the interactions between caregivers and women or their families: What do practitioners say to mothers and families during labor? At birth? In consultations? To describe what is happening? To encourage a woman's efforts? To lighten the atmosphere? When advising about possible interventions? Medical terminology in perinatal care can often be deceptive or confusing, not only for mothers but for caregivers. The authors of this Roundtable, representing health professionals from different specialties and interests in the field, have examined some examples of such language use, misuse, and abuse in perinatal care. (BIRTH 39:2 June 2012).


Active colonization dynamics and diversity patterns are influenced by dendritic network connectivity and species interactions.
Habitat network connectivity influences colonization dynamics, species invasions, and biodiversity patterns. Recent theoretical work suggests dendritic networks, such as those found in rivers, alter expectations regarding colonization and dispersal dynamics compared with other network types. As many native and non-native species are spreading along river networks, this may have important ecological implications. However, experimental studies testing the effects of network structure on colonization and diversity patterns are scarce. Up to now, experimental studies have only considered networks where sites are connected with small corridors, or dispersal was experimentally controlled, which eliminates possible effects of species interactions on colonization dynamics. Here, we tested the effect of network connectivity and species interactions on colonization dynamics using continuous linear and dendritic (i.e., river-like) networks, which allow for active dispersal. We used a set of six protist species and one rotifer species in linear and dendritic microcosm networks. At the start of the experiment, we introduced species, either singularly or as a community within the networks. Species subsequently actively colonized the networks. We periodically measured densities of species throughout the networks over 2 weeks to track community dynamics, colonization, and diversity patterns. We found that colonization of dendritic networks was faster compared with colonization of linear networks, which resulted in higher local mean species richness in dendritic networks. Initially, community similarity was also greater in dendritic networks compared with linear networks, but this effect vanished over time. The presence of species interactions increased community evenness over time, compared with extrapolations from single-species setups. Our experimental findings confirm previous theoretical work and show that network connectivity, species-specific dispersal ability, and species interactions greatly influence the dispersal and colonization of dendritic networks. We argue that these factors need to be considered in empirical studies, where effects of network connectivity on colonization patterns have been largely underestimated.


Preventing the oral cavity cancer epidemic.
Bhurgri Y (2005) have studied the time trends in the site specific oral cancer incidence in the Karachi South, a sample population of Pakistan with a representation of all ethnic and socio-economic groups of the country. Oral cancer ranks 6th world-wide. However, 58% of the cases are concentrated in South and Southeast Asia (Nair et al; 2004). In Karachi, it ranks 2nd in all malignancies among both males and females, with the highest reported incidence in the world. In the absence of alcohol use, chewing of products of betel, areca and tobacco remain the main etiological risk factors. These products include paan, chaalia, gutka and naswar. Because of the ancient history of these products, their use is socially acceptable in all sections of South Asian society.


Trigeminal neuralgia without neurovascular compression presents earlier than trigeminal neuralgia with neurovascular compression.
Trigeminal neuralgia (TN) occurs and recurs in the absence of neurovascular compression (NVC). To characterize what may be distinct patient populations, the authors examined age at onset in patients with TN with and without NVC. A retrospective review of patients undergoing posterior fossa surgery for Type I TN at Oregon Health & Science University from 2009 to 2013 was undertaken. Charts were reviewed, and imaging and operative data were collected for patients with and without NVC. Mean, median, and the empirical cumulative distribution of onset age were determined. Statistical analysis was performed using Student t-test, Wilcoxon and Kolmogorov-Smirnoff tests, and Kaplan-Meier analysis. Multivariate analysis was performed using a Cox proportional hazards model. The charts of 219 patients with TN were reviewed. There were 156 patients who underwent posterior fossa exploration and microvascular decompression or internal neurolysis: 129 patients with NVC and 27 without NVC. Mean age at symptoms onset for patients with and without NVC was 51.1 and 42.6 years, respectively. This difference (8.4 years) was significant (t-test: p = 0.007), with sufficient power to detect an effect size of 8.2 years. Median age between groups with and without NVC was 53.25 and 41.2 years, respectively (p = 0.003). Histogram analysis revealed a bimodal age at onset in patients without NVC, and cumulative distribution of age at onset revealed an earlier presentation of symptoms (p = 0.003) in patients without NVC. Chi-square analysis revealed a trend toward female predominance in patients without NVC, which was not significant (p = 0.08). Multivariate analysis revealed that age at onset was related to NVC but not sex, symptom side or distribution, or patient response to medical treatment. NVC is neither sufficient nor necessary for the development of TN. Patients with TN without NVC may represent a distinct population of younger, predominantly female patients. Further research into the pathophysiology underlying this debilitating disease is needed.


The persistence of multiple strains of avian influenza in live bird markets.
Multiple subtypes of avian influenza (AI) and novel reassortants are frequently isolated from live bird markets (LBMs). However, our understanding of the drivers of persistence of multiple AI subtypes is limited. We propose a stochastic model of AI transmission within an LBM that incorporates market size, turnover rate and the balance of direct versus environmental transmissibility. We investigate the relationship between these factors and the critical community size (CCS) for the persistence of single and multiple AI strains within an LBM. We fit different models of seeding from farms to two-strain surveillance data collected from Shantou, China. For a single strain and plausible estimates for continuous turnover rates and transmissibility, the CCS was approximately 11 800 birds, only a 4.2% increase in this estimate was needed to ensure persistence of the co-infecting strains (two strains in a single host). Precise values of CCS estimates were sensitive to changes in market turnover rate and duration of the latent period. Assuming a gradual daily sell rate of birds the estimated CCS was higher than when an instantaneous selling rate was assumed. We were able to reproduce prevalence dynamics similar to observations from a single market in China with infection seeded every 5-15 days, and a maximum non-seeding duration of 80 days. Our findings suggest that persistence of co-infections is more likely to be owing to sequential infection of single strains rather than ongoing transmission of both strains concurrently. In any given system for a fixed set of ecological and epidemiological conditions, there is an LBM size below which the risk of sustained co-circulation is low and which may suggest a clear policy opportunity to reduce the frequency of influenza co-infection in poultry.


The iron regulatory proteins are defective in repressing translation via exogenous 5' iron responsive elements despite their relative abundance in leukemic cellular models.
In animal cells the specific translational control of proteins contributing to iron homeostasis is mediated by the interaction between the Iron Regulatory Proteins (IRP1 and IRP2) and the Iron Responsive Elements (IRE) located in the untranslated regions (UTR) of regulated messengers, such as those encoding ferritin or the transferrin receptor. The absolute concentrations of the components of this regulatory system in hematopoietic cells and the ability of the endogenous IRP to regulate exogenous IRE have been measured. The IRP concentration is in the low μM (10-6 M) range, whereas the most abundant IRE-containing messenger RNA (mRNA), i.e. those of the ferritin subunits, do not exceed 100 nM (10-7 M). Most other IRP mRNA targets are around or below 1 nM. The distribution of the mRNA belonging to the cellular iron network is similar in human leukemic cell lines and in normal cord blood progenitors, with differences among the cellular models only associated with their different propensities to synthesize hemoglobin. Thus, the IRP regulator is in large excess over its presently identified regulated mRNA targets. Yet, despite this excess, endogenous IRP poorly represses translation of transfected luciferase cDNA engineered with a series of IRE sequences in the 5' UTR. The cellular concentrations of the central hubs of the mammalian translational iron network will have to be included in the description of the proliferative phenotype of leukemic cells and in assessing any therapeutic action targeting iron provision.


Disease outcomes in a cohort of women in Ireland infected by hepatitis C-contaminated anti-D immunoglobulin during 1970s.
In the mid-1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotype 1b infection, following administration of contaminated anti-D immunoglobulin in 1977-79. We aimed to describe their disease history and estimate the effect of selected host and treatment factors on disease progression. We conducted a cohort study on the women infected with HCV. Information was collected from records at seven HCV treatment centres on demographics, treatment and health outcomes up to the 31st December 2013. We calculated cumulative incidence, case fatality, and sub hazard ratios (SHR) for disease progression using competing risks regression. Six hundred and eighty-two patients were included in the study. Among the chronically infected patients (n=374), 35% completed interferon-based antiviral treatment; 42% of whom had a sustained virological response. At the end of 2013, 19%, 1.9%, and 4.9% of chronically infected patients had developed cirrhosis, hepatocellular carcinoma, and liver-related death, respectively, compared with 10%, 0.8%, and 2.4% at the end of 2008. At the end of 2013, 321 (86%) of the chronically infected patients remained alive, 247 (77%) of whom were still chronically infected. Factors associated with increased cirrhosis rates included high alcohol intake (aSHR=4.9 [2.5-9.5]) and diabetes mellitus (aSHR=5.0 [2.9-8.8]). Development of liver-related outcomes accelerated with time, with the risk of cirrhosis, hepatocellular carcinoma, and liver-related death doubling in the last five years of follow-up, particularly in women with high alcohol consumption and diabetes mellitus. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of alcohol, and that data be collected on this cohort after a further five years to analyse the effect of subsequent antiviral treatment during this rapidly evolving period in HCV treatment history. In the mid-1990s, a group of women were diagnosed with chronic hepatitis C virus (HCV) infection following receipt of contaminated anti-D immunoglobulin between 1977 and 1979 in Ireland. Seventy-two (19%) developed cirrhosis and 18 had died from liver-related causes (5%) after 36years of infection. Disease progression accelerated in the last five years of follow-up, particularly in women with diabetes mellitus and high alcohol consumption. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of high alcohol consumption.


Robust diffraction-limited near-infrared-to-near-ultraviolet wide-field imaging from stratospheric balloon-borne platforms-Super-pressure Balloon-borne Imaging Telescope performance.
At a fraction of the total cost of an equivalent orbital mission, scientific balloon-borne platforms, operating above 99.7% of the Earth's atmosphere, offer attractive, competitive, and effective observational capabilities-namely, space-like seeing, transmission, and backgrounds-which are well suited for modern astronomy and cosmology. The Super-pressure Balloon-borne Imaging Telescope (SUPERBIT) is a diffraction-limited, wide-field, 0.5 m telescope capable of exploiting these observing conditions in order to provide exquisite imaging throughout the near-infrared to near-ultraviolet. It utilizes a robust active stabilization system that has consistently demonstrated a 48 mas 1σ sky-fixed pointing stability over multiple 1 h observations at float. This is achieved by actively tracking compound pendulations via a three-axis gimballed platform, which provides sky-fixed telescope stability at < 500 mas and corrects for field rotation, while employing high-bandwidth tip/tilt optics to remove residual disturbances across the science imaging focal plane. SUPERBIT's performance during the 2019 commissioning flight benefited from a customized high-fidelity science-capable telescope designed with an exceptional thermo- and opto-mechanical stability as well as a tightly constrained static and dynamic coupling between high-rate sensors and telescope optics. At the currently demonstrated level of flight performance, SUPERBIT capabilities now surpass the science requirements for a wide variety of experiments in cosmology, astrophysics, and stellar dynamics.


Performance Plateau in Prelingually and Postlingually Deafened Adult Cochlear Implant Recipients.
To characterize the performance plateau after unilateral cochlear implantation (CI) in prelingually and postlingually deafened adults and to compare their relative progress. Retrospective chart review. Tertiary referral center. Prelingually and postlingually deaf adults who received a unilateral CI and completed a minimum of 2 years of follow-up at our center. Unilateral CI. Standard speech perception testing (consonant-nucleus-consonant [CNC] monosyllabic word test and hearing in noise test [HINT] or AzBio sentence test) were performed preoperatively and 3 and 12 months postoperatively, and annually thereafter. In postlingually deaf patients (n = 102), there was a significant improvement in word scores for 3 years postimplantation (p < 0.01). Beyond the 3 years postoperative time point, word scores continued to improve, albeit at a flatter rate. In prelingually deaf patients (n = 16) word scores improved significantly for 5 years postimplantation (p = 0.03). Adults with postlingual deafness undergoing unilateral CI show significant improvement in speech perception for 3 years postimplantation, at which point their performance continues to improve, albeit at a flatter rate. The performance of adults with prelingual deafness improves significantly as late as 5 years postimplantation. These time intervals reflect a change to the currently reported 6 to 12 months period and should impact on counseling, especially in the prelingual CI candidate.


Evaluation of Cynanchum otophyllum glucan sulfate against human immunodeficiency virus and herpes simplex virus as a microbicide agent.
The root of Cynanchum otophyllum-also known as Qing Yang Sheng-is a traditional ethnical Chinese medicine. The objective of this study was to evaluate in vitro activities and safety of C. otophyllum glucan sulfate (PS20) against Human Immunodeficiency Virus (HIV) and Herpes Simplex Virus (HSV). Anti-HIV activity was detected with syncytial formation assay and quantitative P24 Enzyme-Linked Immunosorbent Assay (ELISA). Anti-HSV activity was detected with plaque reduction assay; cytotoxicity was tested with MTT colorimetric assay; and anti-bacterial activity was tested with microdilution method. Anti-HIV mechanism was investigated with fusion inhibition, time of addition, and pretreatment. The 50% Inhibition Concentration (IC(50)) of PS20 for HIV-1(IIIB), HIV-(Ada-M), HIV-1(Bal), HSV-I, and -II were 0.26 ± 0.02 mM, 0.46 ± 0.02 mM, 0.90 ± 0.04 mM, 3.45 ± 0.85 μM, and 0.70 ± 0.22 mM, respectively. Selectivity Indices (SI) were 653, 50, 39, 85, and 362, respectively. Studies on anti-HIV mechanism of PS20 showed that the target molecule should be the envelope protein. The 50% Cytotoxicity Concentrations (CC(50)) of PS20 for HeLa and ME-180 cell lines and human foreskin fibroblast cells was more than 70 μM. The Minimum Inhibitory Concentration (MIC) for vaginal lactobacilli was more than 1000 μM. PS20 possesses anti-HIV and HSV effect and low cytotoxicity to epithelium cells and vaginal lactobacilli. It may be considered as a potential microbicide agent for further investigation.


An Ultrastructural and Immunohistochemical Analysis of the Outer Plexiform Layer of the Retina of the European Silver Eel (Anguilla anguilla L).
Here we studied the ultrastructural organization of the outer retina of the European silver eel, a highly valued commercial fish species. The retina of the European eel has an organization very similar to most vertebrates. It contains both rod and cone photoreceptors. Rods are abundantly present and immunoreactive for rhodopsin. Cones are sparsely present and only show immunoreactivity for M-opsin and not for L-, S- or UV-cone opsins. As in all other vertebrate retinas, Müller cells span the width of the retina. OFF-bipolar cells express the ionotropic glutamate receptor GluR4 and ON-bipolar cells, as identified by their PKCα immunoreactivity, express the metabotropic receptor mGluR6. Both the ON- and the OFF-bipolar cell dendrites innervate the cone pedicle and rod spherule. Horizontal cells are surrounded by punctate Cx53.8 immunoreactivity indicating that the horizontal cells are strongly electrically coupled by gap-junctions. Connexin-hemichannels were found at the tips of the horizontal cell dendrites invaginating the photoreceptor synapse. Such hemichannels are implicated in the feedback pathway from horizontal cells to cones. Finally, horizontal cells are surrounded by tyrosine hydroxylase immunoreactivity, illustrating a strong dopaminergic input from interplexiform cells.


The assessment of pain quality: an item response theory analysis.
Item Response Theory (IRT) is being increasingly used to develop and evaluate outcome measures. However, many pain measures, including those that assess pain quality, have yet to be evaluated from the IRT perspective. The current study evaluated the scales of a commonly used measure of pain quality (the Pain Quality Assessment Scale, or PQAS) using IRT analyses in 3 samples of patients with chronic pain. The findings indicated variability in the precision of the scales, suggesting that all 3 of the PQAS scales are precise when pain is severe and that the Paroxysmal and Deep scales but not necessarily the Surface scale are precise when pain is of moderate or lower severity. In addition, 2 potential problems with the 11 (ie, 0 to 10) response levels used for the PQAS items were identified: (1) a high degree of overlap between adjacent response levels and (2) a lack of interval scaling. Research is needed to determine the extent to which these problems do, or do not, threaten the validity of the PQAS items and scales as outcome measures in pain clinical trials. IRT analyses provide important information about the psychometric and practical qualities of pain measures that is not provided by standard (classical test theory) analyses. IRT analyses of the PQAS subscales indicate that some of the scales are more precise than others at different levels of pain severity and provide important directions for further research to better understand the PQAS. IRT analyses would probably similarly provide important information concerning the utility of other measures commonly used in pain research.


Information theory and robotics meet to study predator-prey interactions.
Transfer entropy holds promise to advance our understanding of animal behavior, by affording the identification of causal relationships that underlie animal interactions. A critical step toward the reliable implementation of this powerful information-theoretic concept entails the design of experiments in which causal relationships could be systematically controlled. Here, we put forward a robotics-based experimental approach to test the validity of transfer entropy in the study of predator-prey interactions. We investigate the behavioral response of zebrafish to a fear-evoking robotic stimulus, designed after the morpho-physiology of the red tiger oscar and actuated along preprogrammed trajectories. From the time series of the positions of the zebrafish and the robotic stimulus, we demonstrate that transfer entropy correctly identifies the influence of the stimulus on the focal subject. Building on this evidence, we apply transfer entropy to study the interactions between zebrafish and a live red tiger oscar. The analysis of transfer entropy reveals a change in the direction of the information flow, suggesting a mutual influence between the predator and the prey, where the predator adapts its strategy as a function of the movement of the prey, which, in turn, adjusts its escape as a function of the predator motion. Through the integration of information theory and robotics, this study posits a new approach to study predator-prey interactions in freshwater fish.


Exposure and Tumor Fn14 Expression as Determinants of Pharmacodynamics of the Anti-TWEAK Monoclonal Antibody RG7212 in Patients with Fn14-Positive Solid Tumors.
The TWEAK-Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors. Patients with Fn14-positive tumors (IHC ≥ 1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK-Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK-Fn14 signaling and clinical outcome were explored. Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥ 300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure. RG7212 reduced tumor TWEAK-Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies.


Combined Targeted DNA Sequencing in Non-Small Cell Lung Cancer (NSCLC) Using UNCseq and NGScopy, and RNA Sequencing Using UNCqeR for the Detection of Genetic Aberrations in NSCLC.
The recent FDA approval of the MiSeqDx platform provides a unique opportunity to develop targeted next generation sequencing (NGS) panels for human disease, including cancer. We have developed a scalable, targeted panel-based assay termed UNCseq, which involves a NGS panel of over 200 cancer-associated genes and a standardized downstream bioinformatics pipeline for detection of single nucleotide variations (SNV) as well as small insertions and deletions (indel). In addition, we developed a novel algorithm, NGScopy, designed for samples with sparse sequencing coverage to detect large-scale copy number variations (CNV), similar to human SNP Array 6.0 as well as small-scale intragenic CNV. Overall, we applied this assay to 100 snap-frozen lung cancer specimens lacking same-patient germline DNA (07-0120 tissue cohort) and validated our results against Sanger sequencing, SNP Array, and our recently published integrated DNA-seq/RNA-seq assay, UNCqeR, where RNA-seq of same-patient tumor specimens confirmed SNV detected by DNA-seq, if RNA-seq coverage depth was adequate. In addition, we applied the UNCseq assay on an independent lung cancer tumor tissue collection with available same-patient germline DNA (11-1115 tissue cohort) and confirmed mutations using assays performed in a CLIA-certified laboratory. We conclude that UNCseq can identify SNV, indel, and CNV in tumor specimens lacking germline DNA in a cost-efficient fashion.


Do respiratory limitations affect metabolism of insect larvae before moulting? An empirical test at the individual level.
Recent data suggest that oxygen limitation may induce moulting in larval insects. This oxygen-dependent induction of moulting (ODIM) hypothesis stems from the fact that the tracheal respiratory system of insects grows primarily at moults, whereas tissue mass increases massively between moults. This may result in a mismatch between oxygen supply and demand at the end of each larval instar because oxygen demand of growing tissues exceeds the relatively fixed supply capacity of the respiratory system. The ODIM hypothesis predicts that, within larval instars, respiration and metabolic rates of an individual larva first increase with increasing body mass but eventually level off once the supply capacity of the tracheal system starts to constrain metabolism. Here, we provide the first individual-level test of this key prediction of the ODIM hypothesis. We use a novel methodology where we repeatedly measure respiration and metabolic rates throughout the penultimate- and final-instar larvae in the butterfly Pieris napi In the penultimate instar, respiration and metabolic rates gradually decelerated along with growth, supporting the ODIM hypothesis. However, respiration and metabolic rates increased linearly during growth in the final instar, contradicting the prediction. Moreover, our data suggest considerable variation among individuals in the association between respiration rate and mass in the final instar. Overall, the results provide partial support for the ODIM hypothesis and suggest that oxygen limitation may emerge gradually within a larval instar. The results also suggest that there may be different moult induction mechanisms in larva-to-larva moults compared with the final metamorphic moult.


Efficacy, safety, and tolerability of doravirine/lamivudine/tenofovir disoproxil fumarate fixed dose combination tablets in adolescents living with HIV: results through week 96 from IMPAACT 2014.
IMPAACT 2014 study is a phase I/II, multicenter, open-label, non-randomized study of doravirine (DOR) co-formulated with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) as fixed dose combination (DOR FDC) in adolescents with HIV-1. We report the efficacy, safety, and tolerability of DOR FDC through 96 weeks. Participants were adolescents aged 12 to <18 years who weighed at least 45 kg and who were either antiretroviral (ARV)-naïve or virologically suppressed without documented resistance mutations to DOR/3TC/TDF. The efficacy endpoint was the proportion of participants with HIV-1 RNA <40 copies/mL assessed at week 48 and 96 using the observed failure approach. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. A total of 45 adolescents, median age 15 (range, 12 - 17) years, 58% females, were enrolled, 2 (4.4%) participants were ARV-naïve. Of the 45 participants, 42 (93.3%) completed the study and 41 (91.1%) completed study treatment. At week 48, 41/42 (97.6%; 95% confidence interval [CI], 87.4 - 99.9) and week 96, 37/40 (92.5%; 95% CI, 79.6 - 98.4) participants had achieved or maintained HIV-1 RNA <40 copies/mL. There were no treatment-related discontinuations due to adverse events and no drug-related adverse events ≥ grade 3 or deaths. We found once daily dosing of DOR FDC to be safe and well tolerated for maintaining viral suppression through 96 weeks in adolescents living with HIV-1.


Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study.
Genetic predisposition as a cause of inflammatory bowel disease (IBD) has been proven by both family and twin studies and genetic variants associated with the disease have been identified. The aim of our study was to determine the concordance rates for IBD in German twin pairs and to evaluate clinical characteristics of concordant and discordant twin pairs. Patients with IBD were asked to participate and complete a questionnaire that contained questions about zygosity, demographic data, and medical history. A total of 189 twin pairs in which at least 1 member had IBD were recruited (68 monozygotic and 121 dizygotic pairs). Within monozygotic pairs, 11 out of 31 (35%) were concordant for Crohn's disease (CD) and 6 out of 37 (16%) for ulcerative colitis (UC). Two of the 58 (3%) dizygotic pairs with CD and 1 out of 63 (2%) dizygotic pairs with UC were concordant for the disease. In 14 out of 20 (70%) discordant monozygotic CD pairs and 25 out of 31 (81%) discordant monozygotic pairs with UC, the first-born was affected by IBD. For discordant dizygotic twins, the first in birth order had IBD in 33 out of 56 (59%) pairs with CD and 40 out of 62 (64.5%) pairs with UC. This study confirms a stronger genetic influence in CD than in UC. The high preponderance in being affected of the first-born twin and the fact that concordance was only 35% for CD and 16% for UC monozygotic twins highlight the important role of environmental trigger factors.


Differential requirement for the N-terminal catalytic domain of the DNA polymerase ε p255 subunit in the mitotic cell cycle and the endocycle.
In Drosophila, the 255kDa catalytic subunit (dpolεp255) and the 58kDa subunit of DNA polymerase ε (dpolεp58) have been identified. The N-terminus of dpolεp255 carries well-conserved six DNA polymerase subdomains and five 3'→5' exonuclease motifs as observed with Polε in other species. We here examined roles of dpolεp255 during Drosophila development using transgenic fly lines expressing double stranded RNA (dsRNA). Expression of dpolεp255 dsRNA in eye discs induced a small eye phenotype and inhibited DNA synthesis, indicating a role in the G1-S transition and/or S-phase progression of the mitotic cycle. Similarly, expression of dpolεp255 dsRNA in the salivary glands resulted in small size and endoreplication defects, demonstrating a critical role in endocycle progression. In the eye disc, defects induced by knockdown of dpolεp255 were rescued by overexpression of the C-terminal region of dpolεp255, indicating that the function of this non-catalytic domain is conserved between yeast and Drosophila. However, this was not the case for the salivary gland, suggesting that the catalytic N-terminal region is crucial for endoreplication and its defect cannot be complemented by other DNA polymerases. In addition, several genetic interactants with dpolεp255 including genes related to DNA replication such as RFC, DNA primase, DNA polη, Mcm10 and Psf2 and chromatin remodeling such as Iswi were also identified.


Characterization of contractile properties of porcine mesenteric and tracheobronchial lymphatic smooth muscle.
We performed morphometric and length-tension analyses comparing mesenteric and tracheobronchial lymph vessel segments to determine the potential of the latter tissue to regulate pulmonary and mediastinal lymph flow via alterations in smooth muscle tone. Fresh porcine lymph vessel rings were prepared for 1) in vitro assessment of length-tension relationships and 2) histologic preparation and measurement of smooth muscle cross-sectional area (SMA). Mesenteric and tracheobronchial optimal vessel ring lengths were 3.1 +/- 0.2 and 3.5 +/- 0.2 mm, and maximum active tensions were 1518 +/- 25 and 1703 +/- 162 mg. Smooth muscle formed indistinct layers in each tissue, and only 30% of the smooth muscle was oriented circumferentially. Stress generated by the circular smooth muscle was similar to that generated by other types of vascular smooth muscle. In 75% of mesenteric vessel rings spontaneous contractions were observed that had a mean contraction frequency of 1.7 +/- 0.2 min-1 and a mean contraction amplitude of 349 +/- 35 mg, while only 40% of tracheobronchial vessels exhibited spontaneous contractions (p < 0.001) that had a mean frequency of 0.6 +/- 0.2 min-1 (p = 0.0021) and a mean contraction amplitude of 118 +/- 10 mg (p < 0.0001). We conclude that tracheobronchial lymphatic vascular smooth muscle is capable of developing stress similar to that generated by mesenteric lymph vessels, and that spontaneous rhythmic contractile activity is qualitatively and quantitatively different in tracheobronchial than in mesenteric porcine lymph vessels. The data suggest that tracheobronchial lymph vessels are capable of regulating pulmonary and mediastinal lymph flow through intrinsic mechanisms. Such regulation may occur by alterations in vascular resistance rather than via spontaneous pumping activity.


Bringing sexual and reproductive health in the urban contexts to the forefront of the development agenda: the case for prioritizing the urban poor.
Estimates suggest that over 90 % of population increase in the least developed countries over the next four decades will occur in urban areas. These increases will be driven both by natural population growth and rural-urban migration. Moreover, despite its status as the world's least urbanized region, the urban population in the sub-Saharan Africa region is projected to increase from under 40 % currently to over 60 % by 2050. Currently, approximately 70 % of all urban residents in the region live in slums or slum-like conditions. Sexual and reproductive health (SRH) risks for the urban poor are severe and include high rates of unwanted pregnancies, sexually transmitted infections, and poor maternal and child health outcomes. However, the links between poverty, urbanization, and reproductive health priorities are still not a major focus in the broader development agenda. Building on theoretical and empirical data, we show that SRH in urban contexts is critical to the development of healthy productive urban populations and, ultimately, the improvement of quality of life. We posit that a strategic focus on the sexual and reproductive health of urban residents will enable developing country governments achieve international goals and national targets by reducing health risks among a large and rapidly growing segment of the population. To that end, we identify key research, policy and program recommendations and strategies required for bringing sexual and reproductive health in urban contexts to the forefront of the development agenda.


Introduction of hypermodified nucleotides in RNA.
The anticodon domain of lysine transfer ribonucleic acid (tRNA) is a model system for investigation of the structural and biochemical effects of nucleoside posttranscriptional modification. To enable detailed study of the biophysical and structural effects of hypermodified nucleosides, methods have been developed to synthesize RNA oligonucleotides containing the modified nucleosides found in lysine tRNA. We describe in detail the synthesis of protected phosphoramidites of the nucleosides methylaminomethyl-2-thiouridine (mnm5s2U), methylcarboxymethyl-2-thiouridine (mcm5s2U), and 2-thiomethyl-N-6-carbamoylthreonyl-adenosine (ms2t6A). We also describe methods for using these nucleoside phosphoramidite reagents to synthesize RNA oligonucleotides with modified nucleosides incorporated at the specific sequence locations corresponding to their positions in the native lysine tRNAs.


Janus Kinase-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis.
Background Novel coronavirus (SARS-CoV-2) has infected over 17 million. Novel therapies are urgently needed. Janus-kinase (JAK) inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and by their ability to promote viral clearance in past coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate role of these therapies in COVID-19 patients. Methods MEDLINE and MedRxiv were searched until July 30th, 2020, including studies that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clear risk estimates or those that permitted back-calculation. Results We searched 733 studies, ultimately including four randomized and eleven non-randomized clinical trials. JAK-inhibitor recipients had significantly reduced odds of mortality (OR, 0.12; 95%CI, 0.03-0.39, p=0.0005) and ICU admission (OR, 0.05; 95%CI, 0.01-0.26, p=0.0005), and had significantly increased odds of hospital discharge (OR, 22.76; 95%CI, 10.68-48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95%CI, 0.04-0.85, p=0.03), and increased odds of discharge bordering significance (OR, 1.89; 95%CI, 1.00-3.59, p=0.05). Conclusions JAK-inhibitor treatment is significantly associated with positive clinical outcomes regarding mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes regarding mortality and discharge. While these data show promise, additional randomized clinical trials are needed to further elucidate the efficacy of JAK-inhibitors and Type I interferons and clinical outcomes in COVID-19.


Discovery of candidate KEN-box motifs using cell cycle keyword enrichment combined with native disorder prediction and motif conservation.
KEN-box-mediated target selection is one of the mechanisms used in the proteasomal destruction of mitotic cell cycle proteins via the APC/C complex. While annotating the Eukaryotic Linear Motif resource (ELM, http://elm.eu.org/), we found that KEN motifs were significantly enriched in human protein entries with cell cycle keywords in the UniProt/Swiss-Prot database-implying that KEN-boxes might be more common than reported. Matches to short linear motifs in protein database searches are not, per se, significant. KEN-box enrichment with cell cycle Gene Ontology terms suggests that collectively these motifs are functional but does not prove that any given instance is so. Candidates were surveyed for native disorder prediction using GlobPlot and IUPred and for motif conservation in homologues. Among >25 strong new candidates, the most notable are human HIPK2, CHFR, CDC27, Dab2, Upf2, kinesin Eg5, DNA Topoisomerase 1 and yeast Cdc5 and Swi5. A similar number of weaker candidates were present. These proteins have yet to be tested for APC/C targeted destruction, providing potential new avenues of research.


Gut environment-induced intraepithelial autoreactive CD4(+) T cells suppress central nervous system autoimmunity via LAG-3.
The gut environment has been found to significantly influence autoimmune diseases such as multiple sclerosis; however, immune cell mechanisms are unclear. Here we show that the gut epithelium of myelin oligodendrocyte glycoprotein(35-55)-specific T-cell receptor transgenic mice contains environmental stimuli-induced intraepithelial lymphocytes (IELs) that inhibit experimental autoimmune encephalomyelitis on transfer. These cells express surface markers phenotypical of 'induced' IELs, have a TH17-like profile and infiltrate the central nervous system (CNS). They constitutively express Ctla4 and Tgfb1 and markedly upregulate Lag3 expression in the CNS, thereby inhibiting inflammation. We also demonstrate the suppressive capability of CD4(+) IELs with alternative antigen specificities, their proliferation in response to gut-derived antigens and contribution of the microbiota and dietary aryl hydrocarbon receptor ligands to their induction. Thus, the gut environment favours the generation of autoreactive CD4(+) T cells with unique regulatory functions, potentially important for preventing CNS autoimmunity.


Uniform magnetic properties for an ultrahigh-density lattice of noninteracting co nanostructures.
We report on the magnetic properties of two-dimensional Co nanoparticles arranged in macroscopically phase-coherent superlattices created by self-assembly on Au(788). Our particles have a density of 26 Tera/in2 (1 Tera=10(12)), are monodomain, and have uniaxial out-of-plane anisotropy. The distribution of the magnetic anisotropy energies has a half width at half maximum of 17%, a factor of 2 more narrow than the best results reported for superlattices of three-dimensional nanoparticles. Our data show the absence of magnetic interactions between the particles. Co/Au(788) thus constitutes an ideal model system to explore the ultimate density limit of magnetic recording.


A meta-analysis of acupuncture techniques for smoking cessation.
To determine the effectiveness of acupuncture for smoking cessation and to examine whether any individual aspect of trials is associated with an effect. All randomised controlled trials of acupuncture for smoking cessation that were listed in computerised databases or reference lists of relevant articles. All randomised single-blind studies that compared acupuncture with sham acupuncture. Methodological data were extracted for quality assessment. Outcome data were extracted for rates of total smoking cessation at three intervals: early after treatment and after six and 12 months follow up. Results were expressed as odds ratios of success over failure in intervention over control groups. The combined odds ratio for all studies was calculated. Repeated meta-analyses were subsequently performed on subsets of studies combined according to defined characteristics: acupuncture technique, number of attendances, country of origin, status of journal, and control procedure. The overall quality of studies was poor. The combined odds ratio for smoking cessation calculated for the earliest results after the end of treatment was 1.20 (95% confidence intervals (95% CIs) = 0.98 to 1.48). The combined odds ratio for smoking cessation after six months was 1.29 (95% CI = 0.82 to 2.01), and after 12 months was 1.03 (95% CI = 0.73 to 1.46). There were no significant effects of relevance among subsets of studies grouped according to defined characteristics. Acupuncture was not superior to sham acupuncture for smoking cessation; no particular aspect of acupuncture technique was associated with a positive effect. The conclusions are limited by methodological inadequacies of studies and by the absence of testable hypotheses; design of future trials should avoid these deficiencies.


UV light-induced autofluorescence of full-length Abeta-protein deposits in the human brain.
The formation of amyloid plaques is a hallmark of Alzheimer's disease (AD). Amyloid plaques and vascular amyloid deposits in cerebral amyloid angiopathy (CAA) consist of the beta-amyloid protein (Abeta) in association with other proteins. These Abeta-deposits can be visualized by thioflavin S, Congo red staining, silver staining methods and immunohistochemistry. Senile plaques also have been shown to exhibit blue autofluorescence. Here we report that UV light-induced autofluorescence is restricted to full-length Abeta-containing amyloid plaques and is also seen in blood vessels affected by CAA. Different types of samples from AD and control cortices were examined: native samples, formalin-fixed paraffin and polyethylene glycol-embedded tissue sections. These samples were viewed with a fluorescence microscope under UV light excitation (360 - 370 nm). By emitting blue fluorescence (>420 nm), amyloid plaques and blood vessels affected by CAA were detected in AD and CAA samples. Combination with immunofluorescence against anti-Abeta1-42, anti-Abeta17-24, and anti-Abeta8-17 demonstrated co-localization of the autofluorescent deposits with full-length Abeta containing Abeta-deposits. N-terminal truncated Abeta-deposits, such as the fleecy amyloid, do not exhibit autofluorescence. In doing so, Abeta-autofluorescence is a suitable method for screening native tissue samples for full-length Abeta-deposits. In contradistinction to conventional and immunohistochemical procedures, detection of plaques and CAA by autofluorescence enables the recognition of full-length Abeta-deposits in the human brain without any chemical interaction whatsoever on the part of Abeta.


Development of a multisystem surveillance database for transfusion-transmitted infections among blood donors in the United States.
The frequency of positive test results for transfusion-transmitted infections (TTIs) among blood donors is an important index of safety; thus, appropriate monitoring is critical, particularly when there are changes in policies affecting donor suitability. Testing algorithms from three large blood systems were reviewed and consensus definitions for a surveillance-positive result for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and human T-cell lymphotropic virus (HTLV) established. In addition, information on each donation, including donor demographics and location, was collected. Combined data were analyzed to characterize the epidemiology of TTIs by person, place, and time. Data from 14.8 million donations were collected for 2011 to 2012, representing more than 50% of the US blood supply. Surveillance-positive rates per 10,000 donations were as follows: HBV, 0.76; HCV, 2.0; HIV, 0.28; and HTLV 0.34. Rates did not vary between the 2 years, although there was variation within a year. With the exception of HTLV, rates were higher among males, and all rates were higher among first-time donations. Window-period donations (those positive only in nucleic acid tests) were infrequent (HBV, 13; HCV, 60; HIV, 14) during the 2-year period. Frequencies of surveillance-positive results varied by donor age and residence location. We demonstrated that standardized data from multiple major US blood systems can be combined and analyzed for change. However, TTI frequencies are low, impacting their sensitivity to change. Furthermore, observed fluctuations in TTI frequencies may be secondary to changes in blood donor demographics rather than necessarily reflecting the immediate impact of policy modification.


Assessing urology and nephrology research activity in Arab countries using ISI web of science bibliometric database.
Bibliometric analysis is increasingly being used for research assessment. The main objective of this study was to assess research output in Urology and Nephrology subject from the Arab countries. Original scientific articles or reviews published from the 21 Arab countries in "Urology and Nephrology" subject were screened using the ISI Web of Science database. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analyzing the annual productivity, names of journals, citations; top 10 active institution and authors as well as country contribution to Urology and Nephrology research. Three thousand and seventy six documents in "urology and nephrology" subject category were retrieved from 104 journals. This represents 1.4% of the global research output in "urology and nephrology". Four hundred and two documents (12.66%) were published in Annales D Urologie Journal. The h-index of the retrieved documents was 57. The total number of citations, at the time of data analysis, was 30401 with an average citation of 9.57 per document. Egypt, with a total publication of 1284 (40.43%) ranked first among the Arab countries in "urology and nephrology" subject category. Mansoura University in Egypt was the most productive institution with a total of 561 (15.33%) documents. Arab researchers collaborated most with researchers from the United States of America (226; 7.12%) in urology and nephrology research. The present data reveals a good contribution of some Arab countries to the field of "urology and nephrology". More efforts are needed by some other Arab countries to bridge the gap in urology and nephrology research. Overall, the quality of urology/nephrology research is considered relatively high as measured by h-index. Cooperation in urology/nephrology research should be encouraged in the Arab world to bridge the gap with that from developed countries.


A polycomb repression signature in metastatic prostate cancer predicts cancer outcome.
The Polycomb Group (PcG) protein EZH2 is a critical component of a multiprotein complex that methylates Lys(27) of histone 3 (H3K27), which consequently leads to the repression of target gene expression. We have previously reported that EZH2 is overexpressed in metastatic prostate cancer and is a marker of aggressive diseases in clinically localized solid tumors. However, the global set of genes directly regulated by PcG in tumors is largely unknown, and thus how PcG mediates tumor progression remains unclear. Herein we mapped genome-wide H3K27 methylation in aggressive, disseminated human prostate cancer tissues. Integrative analysis revealed that a significant subset of these genes are also targets of PcG in embryonic stem cells, and their repression in tumors is associated with poor prognosis. By stepwise cross-validation, we developed a "Polycomb repression signature" composed of 14 direct targets of PcG in metastatic tumors. Notably, solid tumor subtypes in which this gene signature is repressed show poor clinical outcome in multiple microarray data sets of tumors including breast and prostate cancer. Taken together, our results show a fingerprint of PcG-mediated transcriptional repression in metastatic prostate cancer that is reminiscent of stem cells and associated with cancer progression. Therefore, PcG proteins play a central role in the epigenetic silencing of target genes and functionally link stem cells, metastasis, and cancer survival.


HTLV-I infection: a dynamic struggle between viral persistence and host immunity.
Human T-lymphotropic virus type I (HTLV-I) causes chronic infection for which there is no cure or neutralising vaccine. HTLV-I has been clinically linked to the development of adult T-cell leukaemia/lymphoma (ATL), an aggressive blood cancer, and HAM/TSP, a progressive neurological and inflammatory disease. Infected individuals typically mount a large, persistently activated CD8(+) cytotoxic T-lymphocyte (CTL) response against HTLV-I-infected cells, but ultimately fail to effectively eliminate the virus. Moreover, the identification of determinants to disease manifestation has thus far been elusive. A key issue in current HTLV-I research is to better understand the dynamic interaction between persistent infection by HTLV-I and virus-specific host immunity. Recent experimental hypotheses for the persistence of HTLV-I in vivo have led to the development of mathematical models illuminating the balance between proviral latency and activation in the target cell population. We investigate the role of a constantly changing anti-viral immune environment acting in response to the effects of infected T-cell activation and subsequent viral expression. The resulting model is a four-dimensional, non-linear system of ordinary differential equations that describes the dynamic interactions among viral expression, infected target cell activation, and the HTLV-I-specific CTL response. The global dynamics of the model is established through the construction of appropriate Lyapunov functions. Examining the particular roles of viral expression and host immunity during the chronic phase of HTLV-I infection offers important insights regarding the evolution of viral persistence and proposes a hypothesis for pathogenesis.


Influence of tilt on collinear calibration of a laser interferometer.
Collinear calibration is a typical and common method for a laser (heterodyne) interferometer, but it usually suffers from the influence of the tilt of the target retroreflectors and the dissymmetry of the optical paths during the calibration. This paper mainly analyzes and models the calibration error caused by the tilt error of the target retroreflectors and reveals the error source that is the disturbance from the rotary error of the guideway slider pair. Experimental results prove the validity of the analysis and model of the calibration error. The calibration error is up to 0.5 μm when the tilt error is 0.36°, which is large enough to equal the maximum tolerance of laser interferometer (0.5 μm) in use.


The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors.
DNA methylation in mammals is required for embryonic development, X chromosome inactivation and imprinting. Previous studies have shown that methylation patterns become abnormal in malignant cells and may contribute to tumorigenesis by improper de novo methylation and silencing of the promoters for growth-regulatory genes. RNA and protein levels of the DNA methyltransferase DNMT1 have been shown to be elevated in tumors, however murine stem cells lacking Dnmt1 are still able to de novo methylate viral DNA. The recent cloning of a new family of DNA methyltransferases (Dnmt3a and Dnmt3b) in mouse which methylate hemimethylated and unmethylated templates with equal efficiencies make them candidates for the long sought de novo methyltransferases. We have investigated the expression of human DNMT1, 3a and 3b and found widespread, coordinate expression of all three transcripts in most normal tissues. Chromosomal mapping placed DNMT3a on chromosome 2p23 and DNMT3b on chromosome 20q11.2. Significant overexpression of DNMT3b was seen in tumors while DNMT1 and DNMT3a were only modestly over-expressed and with lower frequency. Lastly, several novel alternatively spliced forms of DNMT3b, which may have altered enzymatic activity, were found to be expressed in a tissue-specific manner.


Non-ulcerative cutaneous leishmaniasis in Honduras fails to respond to topical paromomycin.
A double-'blind', placebo-controlled trial of topical therapy with 15% paromomycin (aminosidine) and 10% urea in white paraffin was carried out on 53 patients with non-ulcerating cutaneous leishmaniasis in Honduras. Although the treatment was not effective, several unexpected findings emerged from the trial. Leishmania mexicana was found to be the cause of many of the skin lesions in one of the 2 study sites. These lesions were clinically indistinguishable from those caused by L. chagasi, the aetiologic agent previously found for this form of leishmaniasis. This is the first documented report of L. mexicana in Honduras.


Effect of maternal confidence on breastfeeding duration: an application of breastfeeding self-efficacy theory.
Although much research has focused on identifying factors that influence breastfeeding initiation and duration, many high-risk factors are nonmodifiable demographic variables. Predisposing factors for low breastfeeding duration rates that are amenable to supportive interventions should be identified. The purpose of this study was to assess the effect of maternal confidence (breastfeeding self-efficacy) on breastfeeding duration. A prospective survey was conducted with 300 women in the last trimester of pregnancy recruited from the antenatal clinic of a large metropolitan hospital in Brisbane, Australia. Telephone interviews were conducted at 1 week and 4 months postpartum to assess infant feeding methods and breastfeeding confidence using the Breastfeeding Self-Efficacy Scale. Although 92 percent of participants initiated breastfeeding, by 4 months postpartum almost 40 percent discontinued and only 28.6 percent were breastfeeding exclusively; the most common reason for discontinuation was insufficient milk supply. Antenatal and 1-week Breastfeeding Self-Efficacy Scale scores were significantly related to breastfeeding outcomes at 1 week and 4 months. Mothers with high breastfeeding self-efficacy were significantly more likely to be breastfeeding, and doing so exclusively, at 1 week and 4 months postpartum than mothers with low breastfeeding self-efficacy. Maternal breastfeeding self-efficacy is a significant predictor of breastfeeding duration and level. Integrating self-efficacy enhancing strategies may improve the quality of healthcare that healthcare professionals deliver and may increase a new mother's confidence in her ability to breastfeed, and to persevere if she does encounter difficulties.


Condition responsive nanoparticles for managing infection and inflammation in keratitis.
Keratitis is a major cause of avoidable visual impairment. About 30% of patients with fungal keratitis eventually become permanently blind in the developing world. Proteases, secreted by the pathogen and the host, damage the cornea before the infection is resolved. Treating keratitis is a challenge because both infection and inflammation need to be addressed. An additional challenge is to maintain a therapeutic dose at the corneal surface as blinking and tear film wash away the drugs, administered as eye drops. We have developed a nanoparticle-based drug delivery system that enhances the drug residence time by anchoring to the cornea, down-regulates inflammation and releases the antifungal drug: all in a condition-responsive manner. The expression of Toll-Like Receptors (TLR4) on the corneal epithelial cells increases in response to infection. We have conjugated anti-TLR4 antibodies on the surface of ketoconazole-encapsulated gelatin nanoparticles. The anti-TLR4 antibody not only facilitates binding of nanoparticles to the cornea, enhancing their residence time, but also reduces the levels of inflammatory cytokines. Host and fungal proteases degrade the gelatin nanoparticle, an alternative substrate for proteases, thereby reducing corneal damage and releasing the encapsulated drug, ketoconazole, proportional to the severity of infection. After testing the efficacy of the system with human corneal epithelial cells, we have extended our studies to a rat model of keratitis. The results show a significantly increased corneal retention, suppressed inflammation and resolution of infection in the infected eyes. We believe that this will be an excellent approach to manage keratitis as well as other topical ocular infections.


Collaborative interactions between type 2 innate lymphoid cells and antigen-specific CD4+ Th2 cells exacerbate murine allergic airway diseases with prominent eosinophilia.
Type-2 innate lymphoid cells (ILC2s) and the acquired CD4(+) Th2 and Th17 cells contribute to the pathogenesis of experimental asthma; however, their roles in Ag-driven exacerbation of chronic murine allergic airway diseases remain elusive. In this study, we report that repeated intranasal rechallenges with only OVA Ag were sufficient to trigger airway hyperresponsiveness, prominent eosinophilic inflammation, and significantly increased serum OVA-specific IgG1 and IgE in rested mice that previously developed murine allergic airway diseases. The recall response to repeated OVA inoculation preferentially triggered a further increase of lung OVA-specific CD4(+) Th2 cells, whereas CD4(+) Th17 and ILC2 cell numbers remained constant. Furthermore, the acquired CD4(+) Th17 cells in Stat6(-/-)/IL-17-GFP mice, or innate ILC2s in CD4(+) T cell-ablated mice, failed to mount an allergic recall response to OVA Ag. After repeated OVA rechallenge or CD4(+) T cell ablation, the increase or loss of CD4(+) Th2 cells resulted in an enhanced or reduced IL-13 production by lung ILC2s in response to IL-25 and IL-33 stimulation, respectively. In return, ILC2s enhanced Ag-mediated proliferation of cocultured CD4(+) Th2 cells and their cytokine production, and promoted eosinophilic airway inflammation and goblet cell hyperplasia driven by adoptively transferred Ag-specific CD4(+) Th2 cells. Thus, these results suggest that an allergic recall response to recurring Ag exposures preferentially triggers an increase of Ag-specific CD4(+) Th2 cells, which facilitates the collaborative interactions between acquired CD4(+) Th2 cells and innate ILC2s to drive the exacerbation of a murine allergic airway diseases with an eosinophilic phenotype.


Comment on 'A new method for fusion, denoising and enhancement of x-ray images retrieved from Talbot-Lau grating interferometry'.
In a recent paper (Scholkamm et al 2014 Phys. Med. Biol. 59 1425-40) we presented a new image denoising, fusion and enhancement framework for combining and optimal visualization of x-ray attenuation contrast, differential phase contrast and dark-field contrast images retrieved from x-ray Talbot-Lau grating interferometry. In this comment we give additional information and report about the application of our framework to breast cancer tissue which we presented in our paper as an example. The applied procedure is suitable for a qualitative comparison of different algorithms. For a quantitative juxtaposition original data would however be needed as an input.


Cognitive and affective empathy among adolescent siblings of children with a physical disability.
This study is a continuation of research on possible psychosocial benefits resulting from exposure to sibling with disability present in the family system. The issue seems to be especially important in Poland because of growing number of children with a disability and inconsistent results of previously performed studies. The main aim of this study was to examine the differences in the intensity of cognitive and affective empathy in adolescents who either have or do not have siblings with physical disability. The authors hypothesized that the increased exposure to individual with disability should result in positive attitude towards such people and this tendency should be manifested in elevated empathy and compassion. The study was carried out between September and November 2016. To meet the goals set to the study, a sample of 292 students from public middle and high schools were assessed using self-report demographic questionnaire and measure of empathy (IRI). The participants were between 13 and 19 years old. Among them 128 had a disabled sibling (Group T) and 164 constituted a comparative group (Group C). Interpretation of results is based on descriptive statistics. Participants having a disabled sibling showed significantly higher scores related both to cognitive and affective empathy. Some significant differences were also noted in relation to participants' gender and age. Exposure to individuals with physical disability in family context may facilitate development of positive psychosocial traits including elevated empathy and compassion in nondisabled siblings. Data analysis also showed significantly greater empathic and altruistic tendencies in females that in males.


Topical Biafine and Lipiderm for the prevention of radiation dermatitis: a randomized prospective trial.
We evaluated the effects of Biafine and Lipiderm ointments in preventing radiation dermatitis. The study population included 74 patients after conservative surgery for early breast carcinoma who were referred for adjuvant external beam irradiation. Patients were randomized to receive Biafine or Lipiderm or no treatment. Both study preparations were applied twice daily, starting 10 days before onset of radiotherapy and continuing until 10 days after its completion. The skin treatment was upgraded, if clinically necessary, to steroids (grade 3), antibiotics (grade 4), or pause in therapy (grade 5). Success of treatment was evaluated according to the maximal level of skin treatment, the number of gaps in radiation therapy, the impression of the patients and the subjective skin reaction, and scores of the study nurse and radiotherapist. The three groups were comparable for all clinical features, except for a lower mean age of the Biafine group. Comparative analysis of the results showed no advantage for either preparation compared to the control arm other than maximal treatment level required for a skin reaction (mean 1.7 and 1.6 vs. 2.2), which did not reach statistical significance (p=0.145). Nevertheless, 86% of the patients in both the Biafine and Lipiderm arms expressed satisfaction with the respective ointments. In conclusion, neither Biafine nor Lipiderm seems to have a radioprotective effect.


Impact of stirred suspension bioreactor culture on the differentiation of murine embryonic stem cells into cardiomyocytes.
Embryonic stem cells (ESCs) can proliferate endlessly and are able to differentiate into all cell lineages that make up the adult organism. Under particular in vitro culture conditions, ESCs can be expanded and induced to differentiate into cardiomyocytes in stirred suspension bioreactors (SSBs). However, in using these systems we must be cognizant of the mechanical forces acting upon the cells. The effect of mechanical forces and shear stress on ESC pluripotency and differentiation has yet to be clarified. The purpose of this study was to investigate the impact of the suspension culture environment on ESC pluripotency during cardiomyocyte differentiation. Murine D3-MHC-neo(r) ESCs formed embyroid bodies (EBs) and differentiated into cardiomyocytes over 25 days in static culture and suspension bioreactors. G418 (Geneticin) was used in both systems from day 10 to enrich for cardiomyocytes by eliminating non-resistant, undifferentiated cells. Treatment of EBs with 1 mM ascorbic acid and 0.5% dimethyl sulfoxide from day 3 markedly increased the number of beating EBs, which displayed spontaneous and cadenced contractile beating on day 11 in the bioreactor. Our results showed that the bioreactor differentiated cells displayed the characteristics of fully functional cardiomyocytes. Remarkably, however, our results demonstrated that the bioreactor differentiated ESCs retained their ability to express pluripotency markers, to form ESC-like colonies, and to generate teratomas upon transplantation, whereas the cells differentiated in adherent culture lost these characteristics. This study demonstrates that although cardiomyocyte differentiation can be achieved in stirred suspension bioreactors, the addition of medium enhancers is not adequate to force complete differentiation as fluid shear forces appear to maintain a subpopulation of cells in a transient pluripotent state. The development of successful ESC differentiation protocols within suspension bioreactors demands a more complete understanding of the impacts of shear forces on the regulation of pluripotency and differentiation in pluripotent stem cells.


GTP avoidance in Tetrahymena thermophila requires tyrosine kinase activity, intracellular calcium, NOS, and guanylyl cyclase.
Guanosine 5'-triphosphate (GTP) is a chemorepellent in Tetrahymena thermophila that has been shown to stimulate cell division as well as ciliary reversal. Previous studies have proposed that GTP avoidance is linked to a receptor-mediated, calcium-based depolarization. However, the intracellular mechanisms involved in GTP avoidance have not been previously documented. In this study, we examine the hypothesis that GTP signals through a tyrosine kinase pathway in T. thermophila. Using behavioral assays, enzyme immunosorbent assays, Western blotting, and immunofluorescence, we present data that implicate a tyrosine kinase, phospholipase C, intracellular calcium, nitric oxide synthase (NOS) and guanylyl cyclase in GTP signaling. The tyrosine kinase inhibitor genistein eliminates GTP avoidance in Tetrahymena in behavioral assays. Similarly, pharmacological inhibitors of phospholipase C, NOS, and guanylyl cyclase all eliminated Tetrahymena avoidance to GTP. Immunofluorescence data shows evidence of tyrosine kinase activity in the cilia, suggesting that this enzyme activity could be directly involved in ciliary reversal.


What do health literacy and cultural competence have in common? Calling for a collaborative health professional pedagogy.
Limited health literacy is recognized as contributing to racial/ethnic and other health disparities through mechanisms of poor understanding and adherence, as well as to limited access to health care. Recent studies have focused on interventions to address literacy gaps between patients and health care providers, focusing on communication techniques and redefining the responsibility for closing gaps. Cultural differences between patient and provider, if left unaddressed, have been shown to contribute to poor health outcomes through misunderstanding, value conflicts, and disparate concepts of health and illness. The dual challenges of limited health literacy and cultural differences are likely to increase with an expanding, increasingly diverse, and older population. There is evidence that training providers to attend to both issues can reduce medical errors, improve adherence, patient-provider-family communication, and outcomes of care at both individual and population levels. The two fields continue to have separate trajectories, vocabularies, and research agendas, competing for limited curricular resources. This article presents a conceptual framework for health professions education that attends simultaneously to limited health literacy and cultural differences as a coherent way forward in training culturally competent providers with a common skill-set to deliver patient-centered care that focuses on health disparities reduction.


The quality of diagnostic guidelines for children in primary care: A meta-epidemiological study.
To determine the quality of paediatric guidelines relevant to diagnosis of three of the most common conditions in primary care: fever, gastroenteritis and constipation. We undertook a meta-epidemiological study of paediatric guidelines for fever, gastroenteritis and gastroenteritis. We systematically searched MEDLINE, Embase, Trip Database, Guidelines International Network, the National Guideline Clearinghouse and WHO from February 2011 to September 2022 for guidelines from high-income settings containing diagnostic recommendations. We assessed the quality of guideline reporting for included guidelines using the AGREE II tool. We included 16 guidelines: fever (n = 7); constipation (n = 4) and gastroenteritis (n = 5). The overall quality across the three conditions was graded moderate (median AGREE II score 4.5/7, range 2.5-6.5) with constipation guidelines rated the highest (median 6/7), and fever rated the lowest (median 3.8/7). Major methodological weaknesses included consideration of guideline applicability. Half of the guidelines did not report involving parent representatives, and 56% did not adequately declare or address their competing interests. Substantial variations exist in the quality of paediatric guidelines related to the diagnosis of primary care presentations. Better quality guidance is needed for general practitioners to improve diagnosis for children in primary care.


Step-like band alignment and stacking-dependent band splitting in trilayer TMD heterostructures.
We propose for the first time a kind of van der Waals (vdW) heterostructure composed of three distinct transition-metal dichalcogenide (TMD) monolayers, where step-like band alignment could be realized. In this case, excitons can be spatially separated into constituent top and bottom layers segregated by the middle layer. In light of the reduced binding energy and long lifetime of the interlayer excitons, trilayer TMD heterostructures hold great promise in applications such as solar cells and light-harvesting. In addition, heterostructures with different constituents and stacking orders give rise to distinct band offsets between neighboring layers. Other factors, like strain and SOC, also have apparent effects on the band offset. Our results reveal that 2H stacking can enhance valence band splitting, while 3R stacking has a significant influence on conduction band splitting. On account of the proper step-like band alignment and stacking-dependent band splitting, these trilayer TMD heterostructures also have great potential for applications in spintronics.


Cervical Myeloradiculopathy due to Ossification of the Posterior Longitudinal Ligament with versus without Diffuse Idiopathic Spinal Hyperostosis.
Study Design Retrospective study. Objectives Assess demographics, ossification characteristics, surgical outcomes, and complications in patients with both diffuse idiopathic spinal hyperostosis (DISH) and ossification of the posterior longitudinal ligament (OPLL) compared with patients who only have OPLL. Methods Clinical charts and radiographs of all patients treated surgically from February 2004 to July 2012 for cervical myeloradiculopathy due to DISH with OPLL or OPLL alone were reviewed retrospectively. All patients were observed for a minimum of 1 year. Pre- and postoperative Nurick grades were assessed for all patients. Results Forty-nine patients underwent surgical treatment for cervical myeloradiculopathy due to OPLL, and 8 also had DISH (average 58.9 years, range 37 to 70). The DISH with OPLL group had a significantly higher proportion of subjects with diabetes mellitus (50 versus 9.8% in the OPLL-only group). Everyone in the DISH with OPLL group had continuous or mixed-type OPLL, whereas 78% of patients in the OPLL-only group had primarily segmental type. Operative treatments for patients in the DISH with OPLL group included laminoplasty, anterior decompression and fusion, and posterior laminectomy with fusion. By Nurick grade, 5 patients improved and 3 showed no change. Conclusion Patients with both DISH and OPLL had a higher prevalence of diabetes mellitus and either continuous or mixed-type OPLL classifications. Surgical outcomes were mostly satisfactory; there was no aggravation of symptoms after surgery during the follow up period.


Tuberculosis: what we don't know can, and does, hurt us.
Mycobacterium tuberculosis has a penetrance of its host population that would be the envy of most human pathogens. About one-third of the human population would have a positive skin test for the infection and is thus thought to harbor the bacterium. Globally, 22 "high-burden" countries account for more than 80% of the active tuberculosis cases in the world, which shows the inequitable distribution of the disease. There is no effective vaccine against infection, and current drug therapies are fraught with problems, predominantly because of the protracted nature of the treatment and the increasing occurrence of drug resistance. Here we focus on the biology of the host-pathogen interaction and discuss new and evolving strategies for intervention.


Monomer-polymer equilibria in the axon: direct measurement of tubulin and actin as polymer and monomer in axoplasm.
The monomer-polymer equilibria for tubulin and actin were analyzed for the cytoskeleton of the squid giant axon. Two methods were evaluated for measuring the concentrations of monomer, soluble (equilibrium) polymer, and stable polymer in extruded axoplasm. One method, the Kinetic Equilibration Paradigm ( KEP ), employs the basic principles of diffusion to distinguish freely diffusible monomer from proteins that are present in the form of polymer. The other method is pharmacological and employs either taxol or phalloidin to stabilize the microtubules and microfilaments, respectively. The results of the two methods agree and demonstrate that 22-36% of the tubulin and 41-47% of the actin are monomeric. The in vivo concentration of monomeric actin and tubulin were two to three times higher than the concentration required to polymerize these proteins in vitro, suggesting that assembly of these proteins is regulated by additional mechanisms in the axon. A significant fraction of the polymerized actin and tubulin in the axoplasm was stable microtubules and microfilaments, which suggests that the dissociation reaction is blocked at both ends of these polymers. These results are discussed in relationship to the axonal transport of the cytoskeleton and with regard to the ability of axons to change their shape in response to environmental stimuli.


Risk factors for esophageal cancer in Shanghai, China. I. Role of cigarette smoking and alcohol drinking.
A population-based case-control study of esophageal cancer was conducted in urban Shanghai involving interviews with 902 cases and 1,552 controls. Risk of esophageal cancer was increased among tobacco smokers and alcohol drinkers. Odds ratios (OR) for smoking were 2.1 and 1.6 for men and women, respectively, and increased with number of cigarettes smoked per day, duration of smoking, number of pack-years and decreasing age at start of smoking. For men who were current alcohol drinkers OR was 1.4, with the excess risk primarily among heavy drinkers. Few women drank alcoholic beverages. The combined effect of heavy smoking and drinking among men was pronounced: OR was 12.0 for those who smoked more than 1 pack per day and drank more than 750 g of ethanol per week. The relation with smoking appeared stronger for cancers of the middle and lower thirds of the esophagus than for the upper third, while patterns of risk for squamous cell carcinoma and adenocarcinoma were similar. Heavy drinking affected all 3 subsites, with increased risks mainly limited to squamous cell carcinoma. Cigarette smoking and alcohol drinking combined accounted for almost 50% of all esophageal cancers among men in Shanghai; among women, 14% of cases were attributed to smoking. Our study confirms that smoking and drinking are important risk factors for esophageal cancer in China, thereby paralleling findings from developed countries.


Mediation of hippocampal mossy fiber long-term potentiation by presynaptic Ih channels.
Hippocampal mossy fiber long-term potentiation (LTP) is expressed presynaptically, but the exact mechanisms remain unknown. Here, we demonstrate the involvement of the hyperpolarization-activated cation channel (Ih) in the expression of mossy fiber LTP. Established LTP was blocked and reversed by Ih channel antagonists. Whole-cell recording from granule cells revealed that repetitive stimulation causes a calcium- and Ih-dependent long-lasting depolarization mediated by protein kinase A. Depolarization at the terminals would be expected to enhance transmitter release, whereas somatic depolarization would enhance the responsiveness of granule cells to afferent input. Thus, Ih channels play an important role in the long-lasting control of transmitter release and neuronal excitability.


A probabilistic approach to obtaining limiting estimates of radionuclide concentration in biota.
The US Department of Energy has developed a graded approach for evaluating radiation doses to biota. Limiting concentrations of radionuclides in water, soil, and sediment were derived for twenty-three radionuclides. Four organism types (aquatic animals, riparian animals, terrestrial animals, and terrestrial plants) were selected as the basis for method development. While environmental transfer data needed for deriving biota tissue concentrations are available for aquatic animals and terrestrial plants, less information is available for terrestrial and riparian organisms. Two methods were applied and examined for their ability to provide estimates of organism:soil or organism:water concentration factors in lieu of measured data. The kinetic/allometric approach combined with a parameter uncertainty analysis provides a needed method to estimate concentration factors across multiple species with limited input data.


Engineering of the passband function of a generalized spectrometer.
To our knowledge, we demonstrate a new scheme for passband engineering of a grating spectrometer. Through spatial masking of the input beam and translation of the optical components we present shaping, shifting, and scaling of the passband in optical frequency. Specifically, we demonstrate the relationship between the applied spatial masking function and the spectrometer passband may be tuned from an exact Fourier transform to a direct scaling through longitudinal displacement of the spectrometer lens and sampling slit and that this operation is independent of the choice of spectrometer center frequency.


D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor.
Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although D-serine is a more potent agonist. Localizations of D-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely than glycine. We now show that selective degradation of d-serine with D-amino acid oxidase greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are fully reversed by exogenously applied D-serine, which by itself did not potentiate NMDA receptor-mediated synaptic responses. Thus, D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses.


Correlation between percutaneous transhepatic portography and clinical findings in 56 patients with portal hypertension.
56 consecutive patients with portal hypertension were studied with percutaneous transhepatic portography and the results were correlated to clinical findings and the number of upper gastrointestinal haemorrhages and the size of the individual bleeding. An abundance of collateral paths was noted in most patients. No regularity in development of these collaterals was found. It was not correlated to liver disease etiology, sex or liver function parameters. Portal pressure was not correlated to the size or amount of collaterals. In four patients with liver cirrhosis hepato-fugal flow in one segment of the liver was noted proving that portal flow through the liver is not uniform in this disease. The size of the haemorrhages was only correlated to presence of hepato-fugal flow in the main stem of the portal vein. It was not correlated to the estimated size of the oesophageal varices or to portal pressure. Percutaneous transhepatic portography seems to be of little help in selecting "high risk bleeders" in portal hypertension. Other factors may be of greater help in this task as indicated by the findings in this investigation that patients with alcohol cirrhosis had larger haemorrhages than those with cirrhosis of another etiology and that patients with none or few bleeding episodes had higher thrombocyte count than those with several haemorrhages.


Why science education is more important than most scientists think.
The COVID-19 pandemic has revealed that a shockingly large fraction of the public is willing to ignore scientific judgements on issues such a vaccines and mask wearing. For far too many, scientific findings are viewed as what scientists believe, rather than as the product of an elaborate community process that produces reliable knowledge. This widespread misunderstanding should serve as a wake-up call for scientists, clearly demonstrating that the standard way that we teach science - as a large collection of "facts" that scientists have discovered about the world - needs major change. Three more ambitious and important goals for science education at all levels are outlined. In order of increasing difficulty, these are: (1) to provide all adults with an ability to investigate scientific problems as scientists do, using logic, experiment, and evidence; (2) to provide all adults with an understanding of how the scientific enterprise works - and why they should therefore trust the consensus judgements of science on issues like smoking, vaccination, and climate change; and (3) to provide all adults with the habit of solving their everyday problems as scientists do, using logic, experiment, and evidence. Although examples exist for attaining all of these goals, extensive education research will be needed to discover how best to teach the last two. I argue that such an effort is urgent, and that it can best begin by focusing on the introductory courses in biology and other science disciplines at the university level.