MicroRNA-665 mediates propofol-induced cell apoptosis in human stem cell-derived neurons.
We aimed to evaluate the neurotoxicity and mechanisms of anesthetics propofol in hESC-derived neurons. Cell apoptosis in hESC-derived neurons' exposure to 4, 10 and 20 μg/mL propofol for 6 h was assessed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling (TUNEL) staining and microRNA-665 (miR-665) expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). miR-665 was overexpressed and knocked down using a miR-665 mimic and anti-665 transfection, respectively. The results showed that hESCs exposed to propofol showed a dose-dependent cell apoptosis, followed by the upregulation of miR-665 expression. Overexpression of miR-665 increased propofol-induced apoptosis in hESC cells. And targeting miR-665 decreased propofol-induced cell apoptosis in hESC cells. These data suggest that propofol induces cell death in hESC-derived neurons and the propofol-induced cell apoptosis may occur via miR-665-dependent mechanism.


X-ray astronomy in the new millennium: a summary.
Recent X-ray observations have had a major impact on topics ranging from proto-stars to cosmology. They have also drawn attention to important and general physical processes that currently limit our understanding of thermal and non-thermal X-ray sources. These include unmeasured atomic astrophysics data (wavelengths, oscillator strengths, etc.), basic hydromagnetic processes (e.g. shock structure, reconnection), plasma processes (such as electron-ion equipartition and heat conduction) and radiative transfer (in discs and accretion columns). Progress on these problems will probably come from integrative studies that draw upon observations, throughout the electromagnetic spectrum, of different classes of source. X-ray observations are also giving a new perspective on astronomical subjects, like the nature of galactic nuclei and the evolution of stellar populations. In addition, they are helping us to address central cosmological questions, including the measurement of the matter content of the Universe, understanding its overall luminosity density, describing its chemical evolution and locating the first luminous objects. X-ray astronomy has a healthy future with several international space missions under construction and in development.


IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes.
Human chromosome 11p15.5 and distal mouse chromosome 7 include a megabase-scale chromosomal domain with multiple genes subject to parental imprinting. Here we describe mouse and human versions of a novel imprinted gene, IMPT1 , which lies between IPL and p57 KIP2 and which encodes a predicted multi-membrane-spanning protein similar to bacterial and eukaryotic polyspecific metabolite transporter and multi-drug resistance pumps. Mouse Impt1 and human IMPT1 mRNAs are highly expressed in tissues with metabolite transport functions, including liver, kidney, intestine, extra-embryonic membranes and placenta, and there is strongly preferential expression of the maternal allele in various mouse tissues at fetal stages. In post-natal tissues there is persistent expression, but the allelic bias attenuates. An allelic expression bias is also observed in human fetal and post-natal tissues, but there is significant interindividual variation and rare somatic allele switching. The fact that Impt1 is relatively repressed on the paternal allele, together with data from other imprinted genes, allows a statistical conclusion that the primary effect of human chromosome 11p15.5/mouse distal chromosome 7 imprinting is domain-wide relative repression of genes on the paternal homolog. Dosage regulation of the metabolite transporter gene(s) by imprinting might regulate placental and fetal growth.


Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants.
Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We therefore analysed the potential of stem cell-derived brain implants and of paracrine adenosine release to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk-/-), and respective wild-type (wt) cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Therapeutic effects of NP-derived brain implants were compared with those of wt baby hamster kidney cells (BHK) and adenosine releasing BHK cell implants (BHK-AK2), which were previously shown to suppress seizures by paracrine adenosine release. Wild-type NP-graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine releasing NPs displayed sustained protection from developing generalized seizures. In contrast, recipients of wt BHK cells failed to display any effects on kindling development, while recipients of BHK-AK2 cells were only moderately protected from seizure development. The therapeutic effect of Adk(-/-)-NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP-implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal location of graft-derived cells expressing mature neuronal markers. In contrast, BHK and BHK-AK2 cell implants only formed cell clusters within the infrahippocampal cleft. We conclude that ES cell-derived adenosine releasing brain implants are superior to paracrine adenosine release from BHK-AK2 cell implants in suppressing seizure progression in the rat kindling-model. These findings may indicate a potential antiepileptogenic function of stem cell-mediated adenosine delivery.


Safe driving and executive functions in healthy middle-aged drivers.
The introduction of the point system driver's license in several European countries could offer a valid framework for evaluating driving skills. This is the first study to use this framework to assess the functional integrity of executive functions in middle-aged drivers with full points, partial points or no points on their driver's license (N = 270). The purpose of this study is to find differences in executive functions that could be determinants in safe driving. Cognitive tests were used to assess attention processes, processing speed, planning, cognitive flexibility, and inhibitory control. Analyses for covariance (ANCOVAS) were used for group comparisons while adjusting for education level. The Bonferroni method was used for correcting for multiple comparisons. Overall, drivers with the full points on their license showed better scores than the other two groups. In particular, significant differences were found in reaction times on Simple and Conditioned Attention tasks (both p-values < 0.001) and in number of type-III errors on the Tower of Hanoi task (p = 0.026). Differences in reaction time on attention tasks could serve as neuropsychological markers for safe driving. Further analysis should be conducted in order to determine the behavioral impact of impaired executive functioning on driving ability.


A field model for human detection and tracking.
The large shape variability and partial occlusions challenge most object detection and tracking methods for nonrigid targets such as pedestrians. This paper presents a new approach based on a two-layer statistical field model that characterizes the prior of the complex shape variations as a Boltzmann distribution and embeds this prior and the complex image likelihood into a Markov field. A probabilistic variational analysis of this model reveals a set of fixed-point equations characterizing the equilibrium of the field. It leads to computationally efficient methods for calculating the image likelihood and for training the model. Based on that, effective algorithms for detecting nonrigid objects are developed. This new approach has several advantages. First, it is intrinsically suitable for capturing local nonrigidity. In addition, due to the distributed likelihood, this approach is robust to partial occlusions. Moreover, the two-layer structure provides large flexibility of modeling the image observations, which makes the new method robust to clutters. Extensive experiments demonstrate its effectiveness.


Competing molecular interactions of aPKC isoforms regulate neuronal polarity.
Atypical protein kinase C (aPKC) isoforms ζ and λ interact with polarity complex protein Par3 and are evolutionarily conserved regulators of cell polarity. Prkcz encodes aPKC-ζ and PKM-ζ, a truncated, neuron-specific alternative transcript, and Prkcl encodes aPKC-λ. Here we show that, in embryonic hippocampal neurons, two aPKC isoforms, aPKC-λ and PKM-ζ, are expressed. The localization of these isoforms is spatially distinct in a polarized neuron. aPKC-λ, as well as Par3, localizes at the presumptive axon, whereas PKM-ζ and Par3 are distributed at non-axon-forming neurites. PKM-ζ competes with aPKC-λ for binding to Par3 and disrupts the aPKC-λ-Par3 complex. Silencing of PKM-ζ or overexpression of aPKC-λ in hippocampal neurons alters neuronal polarity, resulting in neurons with supernumerary axons. In contrast, the overexpression of PKM-ζ prevents axon specification. Our studies suggest a molecular model wherein mutually antagonistic intermolecular competition between aPKC isoforms directs the establishment of neuronal polarity.


Diarrhea reduces the rates of cardiac protein synthesis in myofibrillar protein fractions in rats in vivo.
Although chronic diarrhea affects heart function and morphology, the pathogenic mechanisms are unknown. It was our hypothesis that diarrhea imposes metabolic stress to inhibit the synthesis of new contractile proteins. To test this hypothesis, we investigated the effects of lactose-induced diarrhea in rats. The groups were: 1) freely fed controls, 2) rats with lactose-induced diarrhea or 3) pair-fed rats. After 1 wk, hearts from the rats were subjected to subcellular fractionation techniques to isolate the major protein fractions, including myofibrillar proteins. The rates of protein synthesis were measured with concomitant assay of cardiac composition and plasma analytes. In comparison with the control group, diarrhea induced the following changes (P < 0.05): a decrease in heart weight, reduced RNA and mixed protein contents and a reduction in the fractional rate of mixed protein synthesis. There was a reduction in the content of all protein fractions. The fractional synthesis rate was reduced only for the myofibrillar fraction. Plasma insulin-like growth factor-I, but not corticosterone, was reduced. Plasma cholesterol and triglyceride concentrations were also reduced. In comparison with the pair-fed group, diarrhea induced the following changes (P < 0.05): a reduction in heart weight and fractional rate of mixed protein synthesis, reduced myofibrillar absolute synthesis rate and increased sarcoplasmic/myofibrillar fractional synthesis rate ratio. Plasma bicarbonate, triglyceride and urea concentrations were reduced, with an increase in albumin. Diarrhea impaired cardiac biochemistry, including a reduction in protein content and synthesis. A substantial proportion of these changes is due to anorexia, but the selective reduction in the synthesis of contractile proteins is a feature exclusive to the diarrhea group and may be due to reductions in plasma insulin-like growth factor-I.


Impact of polyphenol-rich sources on acute postprandial glycaemia: a systematic review.
Increasingly, evidence suggests a role for polyphenols in blood glucose control. The objective of this systematic review was to evaluate the effect of polyphenol-rich sources in combination with carbohydrate sources on resulting postprandial glycaemic and insulin responses. A literature search was conducted using Medline, CINHAL and Web of Science databases. Selected studies included randomised controlled trials in which the association of polyphenol-containing food or beverage consumption with a carbohydrate source and effect on acute postprandial glycaemia and/or insulin was reported. A total of thirteen full articles were included in the review. Polyphenol sources included coffee, black tea, fruit juice, plant extracts, berries and different rye breads, and carbohydrate sources included bread, pancakes and simple sugars such as sucrose, glucose and fructose. Although glycaemic and insulin responses differed depending on the polyphenol-carbohydrate combination, overall, polyphenol sources were shown to reduce the peak and early-phase glycaemic response and maintain the glycaemic response in the later stages of digestion. To a lesser extent, polyphenol sources were also shown to reduce peak insulin response and sustain the insulin response, especially when consumed with bread. This review supports epidemiological data suggesting that polyphenols in foods and beverages may have a beneficial effect on reducing the risk of type 2 diabetes. However, the extent of this effect is variable depending on the polyphenol and carbohydrate source.


The physics of blood flood in capillaries. II. The capillary resistance to flow.
A previous communication described the peculiar motion of the plasma trapped between erythrocytes in a capillary (bolus flow). In this paper the effect of this motion on capillary resistance to flow, as well as on dissipative effects associated directly with the cells, are described. The resistance that would be associated with plasma in bolus flow at high Reynolds numbers (relative to a capillary value of 0.01) was studied in a model, in which air bubbles, separated by short segments of water, passed along a glass tube. The resistance to flow, especially with short boluses, was at least ten times greater than that associated with Poiseuille flow. In a second series of experiments at lower Reynolds numbers, a single bolus of liquid was forced by air pressure along a glass tube. In these latter experiments, which more closely simulate biological conditions, the mean resistance to flow was only 30 per cent greater than that associated with Poiseuille flow. In the final series of experiments human blood and plasma, diluted in acid-citrate dextrose (A.C.D.) in varying degrees, were forced through glass micropipettes of capillary dimensions. The mean apparent viscosity of whole blood was found to exceed that of plasma by only about 5 per cent, thus verifying a conjecture to this effect made by Fahraeus and Lindqvist in 1931.


Protein Preferential Solvation in Water:Glycerol Mixtures.
For proteins in solvent mixtures, the relative abundances of each solvent in their solvation shell have a critical impact on their properties. Preferential solvation of a series of proteins in water-glycerol mixtures is studied here over a broad range of solvent compositions via classical molecular dynamics simulations. Our simulation results reveal that the differences between shell and bulk compositions exhibit dramatic changes with solvent composition, temperature, and protein nature. In contrast with the simple and widely used picture where glycerol is completely excluded from the protein interface, we show that for aqueous solutions with less than 50% glycerol in volume, protein solvation shells have approximately the same composition as the bulk solvent and proteins are in direct contact with glycerol. We further demonstrate that at high glycerol concentration, glycerol depletion from the solvation shell is due to an entropic factor arising from the reduced accessibility of bulky glycerol molecules in protein cavities. The resulting molecular picture is important to understand protein activity and cryopreservation in mixed aqueous solvents.


Volumetric trends of progressive in-field recurrences after stereotactic radiosurgery of metastatic intracranial tumors.
Local recurrence after stereotactic radiosurgery for brain metastasis is a well-known problem. We analyzed volumetric trends from the time of radiosurgery to time of treatment to understand progression behavior. A retrospective review of patients who underwent treatment for post-radiation progressive lesions was performed. Volumetric trends were obtained by plotting individual lesion volumes from the post-radiation nadir volume to volume at treatment and then fitted to exponential decay or linear regressions. Twenty-eight post-radiation recurrences demonstrated exponential growth and thirteen followed a linear pattern. For lesions exhibiting exponential growth, the average nadir volume was 0.26cm3 (SEM=0.06) at an average of 298 days before treatment and mean volume at treatment was 2.39cm3 (SEM=0.33). The average adjusted R2 was 0.94 (SEM=0.013) and doubling factor was 68.60days (SEM=12.55). In the linear growth cohort, the mean nadir volume was 1.43cm3 (SEM=0.25) at an average of 158 days before treatment and average volume at treatment was 6.90cm3 (SEM=1.43). The mean R2 was 0.92 (SEM=0.02) and average growth rate was 0.034cm3/day. Majority of lesions from primary non-small cell lung cancer (81%) and breast cancer (63%) followed exponential growth. Exponential and linear regressions are accurate representations of post-radiation progression behavior and may be valuable in understanding the growth patterns for recurrences ultimately requiring treatment.


Nitric oxide generation in children with malaria and the NOS2G-954C promoter polymorphism.
Previous epidemiological studies have demonstrated a protective association between the NOS2G-954C (NOS2(Lambaréné)) polymorphism in inducible nitric oxide synthase and severe malaria. The polymorphism is commoner in children with uncomplicated compared with severe malaria. We now show that the likely mechanism for such protection is increased flux of nitrogen from arginine to nitric oxide (NO) during episodes of malaria. Forty-seven boys with uncomplicated malaria received an infusion of (15)N-arginine to measure directly whole body in vivo NO production. The NOS2G-954C genotype previously associated with reduced risk of severe malaria in Gabon was also assessed. Evaluable data were obtained from 40 boys, of whom 6 were NOS2G-954C heterozygotes. Heterozygotes had higher urinary (15)N nitrate enrichments, 2.3 ± 0.6 vs. 1.4 ± 0.5 atoms percent excess (P = 0.001) and higher ratios of (15)N between urine nitrate and plasma arginine (87 ± 11 vs. 57 ± 18%, P = 0.001) consistent with accelerated NO production. We also derived total NO production rates, combining data with total urine production rate and nitrate concentration; these showed no difference by genotype (0.62 ± 0.36, n = 6 vs. 0.83 ± 0.50 μmol/kg·h, n = 16; P = 0.36), but data were confounded by very high variability in measurements of urine output and nitrate concentrations. This study supports the idea that NOS2 genotype protects against severe malaria by increasing NO production during episodes of uncomplicated malaria.


The origins of commitment for substance abuse in the United States.
Policymakers in the United States have long been perplexed by how to deal with substance abuse. As attitudes shifted in the 19th century toward viewing substance abuse as a medical problem akin to insanity rather than as a moral failing, greater emphasis was given to the potential for treatment. Thus, by the middle of the 19th century, states began developing substance abuse commitment codes and institutions to which substance abusers could be committed. Public ambivalence over whether substance abusers should be seen as having an illness or a weakness of will, however, was reflected in the lack of sustained support for these efforts, in contrast to support accorded systems for commitment of the mentally ill. Contemporary policymakers are faced with the same ambivalence, as they struggle with the extent to which substance abusers ought to be subjected to involuntary treatment. The legacy of the early years of substance abuse commitment lives on.


Barriers to treatment and culturally endorsed coping strategies among depressed African-American older adults.
Older adults are particularly vulnerable to the effects of depression, however, they are less likely to seek and engage in mental health treatment. African-American older adults are even less likely than their White counterparts to seek and engage in mental health treatment. This qualitative study examined the experience of being depressed among African-American elders and their perceptions of barriers confronted when contemplating seeking mental health services. In addition, we examined how coping strategies are utilized by African-American elders who choose not to seek professional mental health services. A total of 37 interviews were conducted with African-American elders endorsing at least mild symptoms of depression. Interviews were audiotaped and subsequently transcribed. Content analysis was utilized to analyze the qualitative data. Thematic analysis of the interviews with African-American older adults is presented within three areas: (1) Beliefs about Depression Among Older African-Americans; (2) Barriers to Seeking Treatment for Older African-Americans; and (3) Cultural Coping Strategies for Depressed African-American Older Adults. Older African-Americans in this study identified a number of experiences living in the Black community that impacted their treatment seeking attitudes and behaviors, which led to identification and utilization of more culturally endorsed coping strategies to deal with their depression. Findings from this study provide a greater understanding of the stigma associated with having a mental illness and its influence on attitudes toward mental health services.


Initial flux of sediment-associated radiocesium to the ocean from the largest river impacted by Fukushima Daiichi Nuclear Power Plant.
This study aimed to quantify the flux of radiocesium in the Abukuma Basin (5,172 km(2)), the largest river system affected by fallout from the Fukushima Daiichi Nuclear Power Plant (FDNPP) event. In the period from 10 August 2011 to 11 May 2012 an estimated 84 to 92% of the total radiocesium transported in the basin's fluvial system was carried in particulate form. During this monitoring period Typhoon Roke (September 2011) was observed to induce a significant and temporally punctuated redistribution of radiocesium. The storm-mobilised radiocesium was an estimated 6.18 Terabecquerels corresponding to 61.4% of the total load delivered to the coastal zone during the observation period. The total flux of radiocesium into the Pacific Ocean estimated at the outlet station (basin area 5,172 km(2)) was 5.34 TBq for (137)Cs, and 4.74 TBq for (134)Cs, corresponding to 1.13% of the total estimated radiocesium fallout over the basin catchment (890 TBq). This was equivalent to the estimated amount of direct leakage from FDNPP to the ocean during June 2011 to September 2012 of 17 TBq and the Level 3 Scale Leakage on 21 August 2013 (24 TBq).


Ultrastructural analysis of the cellular response to Schistosoma mansoni: initial and challenge infections in the rat.
Morphological examination of both the lung and liver stages of Schistosoma mansoni infection in the CDF rat was conducted to further define the interactions of host cells with developing schistosomula. Examination of the developing schistosomula in the lungs revealed that all worms observed were in the vasculature, usually wedged in a vessel just large enough to accommodate the worms and a few erythrocytes. No concentrations of granulocytes or mononuclear cells were seen in direct contact with worms. Examination of livers 17-19 days postinfection showed a similar intravascular location for the worms. There was a striking perivascular response in the livers of infected rats, consisting of numerous eosinophils, frequent mast cells and macrophages, as well as mononuclear cells. No cells from this response were observed in direct contact with the schistosomula. In challenge exposures, the portal venules containing schistosomula were surrounded by an intense perivascular accumulation of eosinophils, macrophages, mast cells, and plasma cells. Fibroblasts and intercellular deposition of collagen in the inflammatory focus were also evident. Granulocytes, primarily eosinophils, were observed in the blood spaces near the schistosomula. This secondary cellular response differed from the initial hepatic lesion in containing increased numbers of mast cells and plasma cells, and in the presence of perivascular fibrosis.


E-cadherin is a specific marker for erythroid differentiation and has utility, in combination with CD117 and CD34, for enumerating myeloblasts in hematopoietic neoplasms.
E-cadherin, epithelial calcium-dependent cell adhesion protein, has been identified as a marker of immature erythroid precursors in recent years. However, the specificity of E-cadherin in bone marrow specimens for erythroblasts vs myeloblasts or other early hematopoietic precursors in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has not been fully elucidated. We analyzed 105 cases of AML and MDS to evaluate the specificity of E-cadherin. Of 84 cases of AML, including cases with megakaryocytic, erythroid, monocytic, and granulocytic differentiation, all five acute erythroleukemia cases were positive, as well as one case of megakaryoblastic leukemia that showed coexpression of glycophorin A. In addition, we demonstrate that a panel of three markers, E-cadherin, CD117, and CD34, is effective in identifying lineage-specific myeloblasts in cases of MDS where left-shifted erythroid hyperplasia may complicate morphologic assessment of myeloblasts. In marrow specimens, E-cadherin is a useful marker for erythroid differentation.


Influence of CMO pharmaceutical care model-based intervention on readmission rate in high risk HIV patients: the INFARDAR study.
Many studies have indicated that hospitalization and readmissions occur frequently, especially among people living with HIV. The aim of the study was to determine the effectiveness of a programmed and structured pharmaceutical intervention, based on "CMO PC model" to reduce the readmission rate in high-risk HIV patients. This was a single-center, prospective study based on a structured health intervention conducted between March-2017 and March-2018 with 12 months of follow-up at outpatient pharmacy services. At discharge, HIV patients included were classified according to the risk of readmission as low or high risk patients, being the latter proposed to participate. The selected patients were randomly assigned to a control group (usual care) or intervention group (including stratification-motivational interview and new technologies: CMO pharmaceutical care). The primary endpoint was readmission rate at one year of follow-up in each group. A total of 39 patients were included. As regards the main variable, in the intervention group, 21,4% (n=3) of patients were readmitted in the first year after discharge vs. 66,7% (n=6) in the control group (p=0,042). Tailored pharmaceutical care based on risk stratification, motivational interviewing, and new technologies has a positive influence to reduce the percentage of readmission in high risk HIV patients.


Self-Assembled Metal Nanohole Arrays with Tunable Plasmonic Properties for SERS Single-Molecule Detection.
Arrays of metal nano-holes have proved to be among of the most promising structures for applications in the field of nano-photonics and optoelectronics. Supporting both localized and propagating surface plasmons resonances, they are characterized by very high versatility thanks to the tunability of these modes, by means of the change of their periodicity, the size of the holes and metal composition. The interaction between different optical features can be exploited to modulate electromagnetic field distribution leading various hot-spots excitations on the metal surfaces. In this work, long range ordered arrays of nano-holes in thin gold films, with different geometrical characteristics, were fabricated by a modified nano-sphere lithography protocol, which allows precise control on holes' dimensions together with the preservation of the order and of the pristine periodicity of the array. An in-depth analysis of the correlation between surface plasmon modes interference and its effect on electromagnetic field distribution is proposed, both by numerical simulations and experimentally. Finally, metal nano-holes arrays are exploited for surface enhanced Raman experiments, evaluating and comparing their performances by the estimation of the enhancement factor. Values close to the single molecule detection are obtained for most of the samples, proving their potentialities in surface enhanced spectroscopy applications.


A multicenter multinational registry for assessing ventriculoperitoneal shunt infections for hydrocephalus.
Reported infection rates after ventriculoperitoneal shunt surgery vary from 1 to 25%. Antibiotic-impregnated (AI) catheters may reduce shunt infection rates, but this is uncertain. To establish a prospective shunt registry to evaluate short-term (3-month) infection rates associated with ventriculoperitoneal shunts and standard or AI catheters during surgical treatment of hydrocephalus. A prospective, multicenter, noncontrolled, open-label registry investigated patients with de novo catheter implantation or catheter replacement of an existing ventriculoperitoneal shunt. The primary outcome was shunt infection. A total of 440 patients were entered into the registry at 10 sites: 3 in North America, 2 in Singapore, 4 in China and 1 in India. Seven patients were excluded. Of the 433 remaining patients, 314 had new shunts and 119 were revisions. Shunt infections occurred in 14 of 433 patients (3.2%) overall and in 2 of 37 infants (5.2%) younger than 1 year. AI catheters were used in 46 of 433 patients at 7 centers. The shunt infection rate was 0 of 46 for shunts with AI catheters and 14 of 387 (3.6%) without AI catheters. Infection rates were similar with AI catheters, adjusting for age and catheter type. The overall shunt infection rate was lower than in previous multicentered studies. The low infection rate and low rate of AI catheter use precludes any meaningful statement regarding the value of AI catheters in reducing the infection rate. Consideration should be given to performing a well designed, adequately powered, prospective randomized controlled trial to determine whether AI catheters reduce shunt infection rates.


Viral warts (Human Papilloma Virus) as a potential risk for breast cancer among younger females.
There have been several reports on the role of human papillomavirus (HPV) in the etiology of breast cancer. To our knowledge, this is first study to use disease-disease association data-mining approach to analyzing viral warts and breast cancer to be conducted in Taiwanese population. We analyzed the Taiwan's National Health Insurance database (NHIDM data comprising of 23 million patient data) to examine the association between viral warts and female breast carcinoma. The patients were categorized into three groups: breast cancer only, viral warts only, and those with both breast cancer and viral warts. The Cox proportion hazard regression analysis was used to measure the effect of HPV on the time to breast cancer diagnosis. Multivariable analyzes and stratified analyzes using hazard ratios (HRs) were presented with 95% confidence intervals (CIs) after adjusting for age, and CCI. Among 807,578 HPV population, we identified 6014 breast cancer cases. The HPV group was associated with a significantly higher risk of developing breast cancer (HR, 1.18; 95% CI, 1.15-1.21; p< 0.001) compared with the non-HPV group. HPV patients with age group 18-39 was slightly higher risk of breast cancer occurrence (HR, 1.07; 95% CI, 1.01-1.13; p<.05). The risk of breast cancer in 10-year incidence was 7% higher for females less than 40 years and 23% for over 40 year's patients when compared with non-HPV patients of the same age group. Our study indicates that women who develop viral warts are at a significantly higher risk of developing breast cancer than women who have not diagnosed with viral warts. Thus, the presence of viral warts is a potential risk to breast cancer. Therefore, we suggest patients diagnosed with viral warts may get early screening for breast cancer.


Faculty Perceptions of Online Teaching Effectiveness and Indicators of Quality.
Online education programs in nursing are increasing rapidly. Faculty need to be competent in their role and possess the skills necessary to positively impact student outcomes. Existing research offers effective teaching strategies for online education; however, there may be some disconnect in the application of these strategies and faculty perceptions of associated outcomes. Focus groups were formed to uncover how nursing faculty in an online program define and describe teaching effectiveness and quality indicators in an asynchronous online environment. A semistructured interview format guided group discussion. Participants (n = 11) included nurse educators from an online university with an average of 15 years of experience teaching in nursing academia and 6 years in an online environment. Teaching effectiveness, indicators of quality, and student success were three categories that emerged from the analysis of data. What materialized from the analysis was an overarching concept of a "dance" that occurs in the online environment. Effective online teachers facilitate, connect, lead, and work in synchrony with students to obtain indicators of quality such as student success, student improvement over time, and student application of knowledge to the professional role.


Injury morbidity in an urban and a rural area in Tanzania: an epidemiological survey.
Injuries are becoming a major health problem in developing countries. Few population based studies have been carried out in African countries. We examined the pattern of nonfatal injuries and associated risk factors in an urban and rural setting of Tanzania. A population-based household survey was conducted in 2002. Participants were selected by cluster sampling. A total of 8,188 urban and 7,035 rural residents of all ages participated in the survey. All injuries reported among all household members in the year preceding the interview and resulting in one or more days of restricted activity were included in the analysis. A total of 206 (2.5%) and 303 (4.3%) persons reported to have been injured in the urban and rural area respectively. Although the overall incidence was higher in the rural area, the incidence of major injuries (> or = 30 disability days) was similar in both areas. Males were at a higher risk of having an injury than females. Rural residents were more likely to experience injuries due to falls (OR = 1.6; 95% CI = 1.1 - 2.3) and cuts (OR = 4.3; 95% CI = 3.0 - 6.2) but had a lower risk of transport injuries. The most common causes of injury in the urban area were transport injuries and falls. In the rural area, cuts and stabs, of which two thirds were related to agriculture, formed the most common cause. Age was an important risk factor for certain types of injuries. Poverty levels were not significantly associated with experiencing a nonfatal injury. The patterns of injury differ in urban and rural areas partly as a reflection of livelihoods and infrastructure. Rural residents are at a higher overall injury risk than urban residents. This may be important in the development of injury prevention strategies.


Effects of curcumin on the skeletal system in rats.
There is increasing interest in the discovery of natural compounds that could favorably affect the skeletal system. Curcumin is a constituent of turmeric, a plant which has been used for centuries as a dietary spice and a traditional Indian medicine. Curcumin has been reported to affect differentiation, activity and the lifespan of osteoblasts and osteoclasts in vitro. The aim of the present study was to investigate the effects of curcumin on the skeletal system of rats in vivo. Curcumin (10 mg/kg, po daily) was administered for four weeks to normal (non-ovariectomized) and bilaterally ovariectomized (estrogen-deficient) three-month-old female Wistar Cmd:(WI)WU rats. Ovariectomy was performed seven days before the start of curcumin administration. Bone mass, mineral and calcium content, macrometric and histomorphometric parameters, as well as the mechanical properties of the bone, were examined. Serum total cholesterol and estradiol levels were also determined. In rats with normal estrogen levels, curcumin decreased serum estradiol level and slightly increased cancellous bone formation, along with decreased mineralization. Estrogen deficiency induced osteoporotic changes in the skeletal system of the ovariectomized control rats. In ovariectomized rats, curcumin decreased body mass gain and serum total cholesterol level, slightly improved some bone histomorphometric parameters impaired by estrogen deficiency, but did not improve bone mineralization or mechanical properties. In conclusion, the results of the present in vivo study in rats did not support the hypothesis that curcumin, at doses that are readily achievable through dietary intake, could be useful for the prevention or treatment of osteoporosis.


The specificity of prospective memory costs.
A current issue in the field of prospective memory (i.e., memory for intentions) is the extent to which intentions interfere with ongoing activities. A question of interest is whether this interference is specific to stimuli that are relevant to the intention or whether interference is more general in its influence. Participants performed a lexical decision task (LDT) with an embedded prospective memory (PM) task in which they had to remember to press a computer key if a pre-specified target appeared (e.g., GIRL). Results demonstrated a consistent pattern of results. Increased reaction time costs were observed on trials where there was a match between PM targets and non-target ongoing stimuli. That is, when a prospective memory target was a word, then reaction time costs were observed on non-target word LDT trials and there were no costs on non-target nonword trials. Similarly, if a PM target was a nonword (e.g., UEBL) then costs were observed on non-target nonword LDT trials relative to non-target word trials. Evidence from three experiments suggests that task interference is specific to the type of stimulus (word or nonword) that is relevant to the intention. We refer to this finding as a Stimulus Specific Interference Effect (SSIE).


Suppression of AKT anti-apoptotic signaling by a novel drug candidate results in growth arrest and apoptosis of hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer fatalities worldwide, with limited treatment options and five year survival rates of between <5 and 15%. To address this medical need, we conducted a screen of a drug-like small molecule library for HCC-selective cytotoxins. We report here the identification of a disubstituted aminothiazole termed HBF-0079, with remarkable selective toxicity for HCC-derived cell lines versus non-HCC liver lines and most other cancer lines. HBF-0079 caused irreversible growth arrest and apoptosis of the HCC lines Huh7, Hep3B, HepaRG as well as the hepatoblastoma line HepG2, with CC₅₀ values from ∼0.7-7.7 µM, while more than 45 µM was needed to achieve CC₅₀ values for the immortalized normal hepatocyte lines THLE-2 and PH5CH. Of the sixty cancer lines from the National Cancer Institute panel, only five exhibited >50% growth inhibition by HBF-0079. In Huh7 cells, HBF-0079 induced cell cycle arrest in G1 and concomitant apoptosis, and its effects were irreversible after removal of the compound. These observations corroborate a loss of AKT phosphorylation at the mTORC2-targeted residue S473, with concurrent loss of phosphorylation of the mTORC1 targets SK6 and 4EBP1 in Huh7 but not PH5CH cells. Finally, growth of Hep3B-derived tumors in a murine xenograft model was significantly repressed by the compound through either systemic or intratumoral administration of formulated HBF-0079. The potential for development of this drug candidate is discussed.


Classification and rates of adverse events in a Malawi male circumcision program: impact of quality improvement training.
Assessing safety outcomes is critical to inform optimal scale-up of voluntary medical male circumcision (VMMC) programs. Clinical trials demonstrated adverse event (AE) rates from 1.5 to 8 %, but we have limited data on AEs from VMMC programs. A group problem-solving, quality improvement (QI) project involving retrospective chart audits, case-conference AE classification, and provider training was conducted at a VMMC clinic in Malawi. For each identified potential AE, the timing, assessment, treatment, and resolution was recorded, then a clinical team classified each event for type and severity. During group discussions, VMMC providers were queried regarding lessons learned and challenges in providing care. After baseline evaluation, clinicians and managers initiated a QI plan to improve AE assessment and management. A repeat audit 6 months later used similar methods to assess the proportions and severity of AEs after the QI intervention. Baseline audits of 3000 charts identified 418 possible AEs (13.9 %), including 152 (5.1 %) excluded after determination of provider misclassification. Of the 266 remaining AEs, the team concluded that 257 were procedure-related (8.6 AEs per 100 VMMC procedures), including 6 (0.2 %) classified as mild, 218 (7.3 %) moderate, and 33 (1.1 %) severe. Structural factors found to contribute to AE rates and misclassification included: provider management of post-operative inflammation was consistent with national guidelines for urethral discharge; available antibiotics were from the STI formulary; providers felt well-trained in surgical skills but insecure in post-operative assessment and care. After implementation of the QI plan, a repeat process evaluating 2540 cases identified 115 procedure-related AEs (4.5 AEs per 100 VMMC procedures), including 67 (2.6 %) classified as mild, 28 (1.1 %) moderate, and 20 (0.8 %) severe. Reports of AEs decreased by 48 % (from 8.6 to 4.5 per 100 VMMC procedures, p < 0.001). Reports of moderate-plus-severe (program-reportable) AEs decreased by 75 % (from 8.4 to 1.9 per 100 VMMC procedures, p < 0.001). AE rates from our VMMC program implementation site were within the range of clinical trial experiences. A group problem-solving QI intervention improved post-operative assessment, clinical management, and AE reporting. Our QI process significantly improved clinical outcomes and led to more accurate reporting of overall and program-reportable AEs.


Mortality and cholesterol metabolism in familial hypercholesterolemia. Long-term follow-up of 96 patients.
The aim of this prospective study was to explore the association of different prognostic factors including parameters of cholesterol metabolism with coronary morbidity and mortality in a study group of 96 patients who were heterozygous for familial hypercholesterolemia. During a 15-year follow-up period, 27% of the patients (44% of the men and 10% of the women, p less than 0.01) died from coronary disease, and an additional 4% died of noncoronary causes. Of the baseline characteristics, male gender, previous myocardial infarction, and smoking were the classical risk factors significantly associated with poor cardiac prognosis. In addition, a low bile acid synthesis predicted enhanced coronary mortality both in univariate and multivariate analysis, and in men bile acid synthesis was significantly correlated with cardiac mortality. Further analysis indicated that also in subjects without baseline myocardial infarction, low bile acid, cholesterol synthesis, or both predicted increased risk of coronary events. In multivariate analysis, male gender, previous myocardial infarction, and low bile acid synthesis at baseline explained 5%, 15%, and 5% (25%), respectively, of the variability of survival. Age, serum total cholesterol, and triglyceride values were unrelated to survival.


Phase 1 safety and immunogenicity evaluation of ADVAX, a multigenic, DNA-based clade C/B' HIV-1 candidate vaccine.
We conducted a Phase I dose escalation trial of ADVAX, a DNA-based candidate HIV-1 vaccine expressing Clade C/B' env, gag, pol, nef, and tat genes. Sequences were derived from a prevalent circulating recombinant form in Yunnan, China, an area of high HIV-1 incidence. The objective was to evaluate the safety and immunogenicity of ADVAX in human volunteers. ADVAX or placebo was administered intramuscularly at months 0, 1 and 3 to 45 healthy volunteers not at high risk for HIV-1. Three dosage levels [0.2 mg (low), 1.0 mg (mid), and 4.0 mg (high)] were tested. Twelve volunteers in each dosage group were assigned to receive ADVAX and three to receive placebo in a double-blind design. Subjects were followed for local and systemic reactogenicity, adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. ADVAX was safe and well-tolerated, with no vaccine-related serious adverse events. Local and systemic reactogenicity events were reported by 64% and 42% of vaccine recipients, respectively. The majority of events were mild. The IFNgamma ELISpot response rates to any HIV antigen were 0/9 (0%) in the placebo group, 3/12 (25%) in the low-dosage group, 4/12 (33%) in the mid-dosage group, and 2/12 (17%) in the high-dosage group. Overall, responses were generally transient and occurred to each gene product, although volunteers responded to single antigens only. Binding antibodies to gp120 were not detected in any volunteers, and HIV seroconversion did not occur. ADVAX delivered intramuscularly is safe, well-tolerated, and elicits modest but transient cellular immune responses. Clinicaltrials.gov NCT00249106.


Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy.
Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown. To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice. A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice. Patients were randomized to receive six instillations of BCG Connaught or Tice. For experimental studies, BCG strains were compared in C57Bl/6 mice. Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG. BCG genomic DNA was sequenced and compared with reference genomes. Recurrence-free survival was the primary end point of the clinical study. The Kaplan-Meier estimator was used for estimating survival and time-to-event end points. Nonparametric tests served for the analysis of the in vivo results. Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice (p=0.0108). Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group (p=0.09). In mice, BCG Connaught induced stronger T-helper cell 1-biased responses, greater priming of BCG-specific CD8(+) T cells, and more robust T-cell recruitment to the bladder than BCG Tice. Genome sequencing of the BCG strains revealed candidate genes potentially involved in the differential clinical responses. BCG strain may have an impact on treatment outcome in NMIBC immunotherapy. We compared the efficacy of two commonly used bacillus Calmette-Guérin (BCG) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught. We also identified genetic differences that may explain the differential efficacy of the Connaught and Tice BCG strains. NCT00003779.


Consequences of mild stroke in persons <75 years -- a 1-year follow-up.
Mild strokes can be neglected regarding subtle sequels as fatigue, and cognitive and emotional changes. We have addressed this topic by exploring late consequences of an initially mild stroke (Barthel score >or=50). Accordingly, we assayed impairment, disability and handicap data 1 year after the first-ever stroke in persons <75 years, focusing on symptoms as fatigue, concentration difficulties, memory disturbances, emotional lability, stress resistance, anxiety and uneasiness, symptoms comprised in the astheno-emotional disorder (AED), and its relation to life satisfaction. The mean value of the Barthel Index was 99.5 (SD 0.5) and 25% scored 0-1 on the Oxford Handicap Scale. AED was diagnosed in 71% of the patients, and fatigue was experienced by 72%. AED correlated significantly with life satisfaction, handicap and depression. Life satisfaction was significantly below that of norm values according to satisfaction with life as a whole, sex life and ability to manage selfcare. Our findings emphasize that 'hidden dysfunctions' not so easily discovered within the hospital context are common consequences of mild stroke. The concept of mild stroke as principally founded in motor function or ability in P-ADL therefore seems to be insufficient with respect to the patient long-term perspective.


Life events and adolescent depressive symptoms: Protective factors associated with resilience.
Depression is a public health concern among youth, and it is pertinent to identify factors that can help prevent development of depressive symptoms in adolescence. This study aimed to investigate the association between negative life events and depressive symptoms among adolescents, and to examine the influence and relative contributions of personal, social and family protective factors related to resilience. Data stem from the cross-sectional youth@hordaland-survey, conducted in Hordaland, Norway. In all, 9,546 adolescents, aged 16-19 years old (52.8% girls) provided self-report information on depressive symptoms, negative life events and protective factors related to resilience. Experiencing a higher number of negative life events was related to increases in depressive symptoms, while the potential protective factors goal orientation, self-confidence, social competence, social support, and family cohesion individually were associated with fewer symptoms. Although there were small moderating effects of goal orientation and self-confidence, the results mainly supported a compensatory resilience model. When considering the potential protective factors jointly, only self-confidence and family cohesion were significantly associated with fewer depressive symptoms for both genders, with the addition of social support for girls. There were significant interactions between all the potential protective factors and gender, indicating a greater reduction of depressive symptoms with higher levels of protective factors among girls. Interventions aimed at fostering self-confidence and family cohesion could be effective in preventing depressive symptoms for adolescent boys and girls, regardless of their exposure to negative events. Results further indicate that preventive interventions targeting these potential protective factors could be especially beneficial for adolescent girls.


Circadian clocks are resounding in peripheral tissues.
Circadian rhythms are prevalent in most organisms. Even the smallest disturbances in the orchestration of circadian gene expression patterns among different tissues can result in functional asynchrony, at the organism level, and may to contribute to a wide range of physiologic disorders. It has been reported that as many as 5%-10% of transcribed genes in peripheral tissues follow a circadian expression pattern. We have conducted a comprehensive study of circadian gene expression on a large dataset representing three different peripheral tissues. The data have been produced in a large-scale microarray experiment covering replicate daily cycles in murine white and brown adipose tissues as well as in liver. We have applied three alternative algorithmic approaches to identify circadian oscillation in time series expression profiles. Analyses of our own data indicate that the expression of at least 7% to 21% of active genes in mouse liver, and in white and brown adipose tissues follow a daily oscillatory pattern. Indeed, analysis of data from other laboratories suggests that the percentage of genes with an oscillatory pattern may approach 50% in the liver. For the rest of the genes, oscillation appears to be obscured by stochastic noise. Our phase classification and computer simulation studies based on multiple datasets indicate no detectable boundary between oscillating and non-oscillating fractions of genes. We conclude that greater attention should be given to the potential influence of circadian mechanisms on any biological pathway related to metabolism and obesity.


The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma.
Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.


Bioengineering murine mastocytoma cells to produce anticoagulant heparin.
Heparin (HP), an important anticoagulant polysaccharide, is produced in a complex biosynthetic pathway in connective tissue-type mast cells. Both the structure and size of HP are critical factors determining the anticoagulation activity. A murine mastocytoma (MST) cell line was used as a model system to gain insight into this pathway. As reported, MST cells produce a highly sulfated HP-like polysaccharide that lacks anticoagulant activity (Montgomery RI, Lidholt K, Flay NW, Liang J, Vertel B, Lindahl U, Esko JD. 1992. Stable heparin-producing cell lines derived from the Furth murine mastocytoma. Proc Natl Acad Sci USA 89:11327-11331). Here, we show that transfection of MST cells with a retroviral vector containing heparan sulfate 3-O-sulfotransferase-1 (Hs3st1) restores anticoagulant activity. The MST lines express N-acetylglucosamine N-deacetylase/N-sulfotransferase-1, uronosyl 2-O-sulfotransferase and glucosaminyl 6-O-sulfotransferase-1, which are sufficient to make the highly sulfated HP. Overexpression of Hs3st1 in MST-10H cells resulted in a change in the composition of heparan sulfate (HS)/HP and CS/dermatan sulfate (DS) glycosaminoglycans. The cell-associated HS/HP closely resembles HP with 3-O-sulfo group-containing glucosamine residues and shows anticoagulant activity. This study contributes toward a better understanding of the HP biosynthetic pathway with the goal of providing tools to better control the biosynthesis of HP chains with different structures and activities.


Hyaluronic acid and platelet-rich plasma, a new therapeutic alternative for scleroderma patients: a prospective open-label study.
Systemic sclerosis is a systemic connective tissue disease characterized by endothelium damage, fibrosis, and subsequent atrophy of the skin. Perioral fibrosis produces a characteristic microstomia together with microcheilia, both of which cause severe difficulties and affects patients' daily life, such as eating and oral hygiene. Since there are no effective and specific therapies, we have aimed at evaluating the response to filler injections of hyaluronic acid together with platelet-rich plasma. Ten female patients aged between 18 and 70 were included in this study. Each patient was treated with three filler injections of hyaluronic acid and platelet-rich plasma at an interval of 15 to 20 days. Follow-up check-ups were recorded 1, 3, and 24 months after the end of the treatment. During the therapy and the subsequent follow-up, we evaluated the mouth's opening, freedom of movement of the lips, and skin elasticity. After the treatment, patients had achieved good results already after the first injection and the improvement was maintained in the following months, up to 2 years. In particular, 8 (80%) patients showed a greater mouth's opening and increased upper lip's thickness during 1-month follow-up and maintained these results after 2 years (maximum mouth's opening T0 47.61; T3 49.23; T4 48.60 p < 0.0001. Upper lip's thickness T0 4.20; T3 4.75; T4 4.45 p < 0.0001). Moreover, distance between upper and lower incisors (T0 27.05; T3 29.03; T4 28.14 p < 0.0001), inter-commissural distance (T0 49.12; T3 51.44; T4 50.31: p < 0.0001), and lower lip's thickness (T0 3.80; T3 4.85, 5.10; T4 4.25; p < 0.0001) were increased in all of patients in 1-month follow-up, keeping these benefits after 24 months and having a significant increase of skin elasticity 1 month after the end of therapy. Our study demonstrates that filler injections of hyaluronic acid and platelet-rich plasma represent an efficient local therapeutic alternative for patients affected by scleroderma. The treatment has significantly improved patients' quality of living.


Neisseria arctica sp. nov., isolated from nonviable eggs of greater white-fronted geese (Anser albifrons) in Arctic Alaska.
During the summers of 2013 and 2014, isolates of a novel Gram-stain-negative coccus in the genus Neisseriawere obtained from the contents of nonviable greater white-fronted goose (Anseralbifrons) eggs on the Arctic Coastal Plain of Alaska. We used a polyphasic approach to determine whether these isolates represent a novel species. 16S rRNA gene sequences, 23S rRNA gene sequences, and chaperonin 60 gene sequences suggested that these Alaskan isolates are members of a distinct species that is most closely related to Neisseria canis, Neisseriaanimaloris and Neisseriashayeganii. Analysis of the rplF gene additionally showed that the isolates are unique and most closely related to Neisseriaweaveri. Average nucleotide identity of the whole genome sequence of the type strain was between 71.5 and 74.6 % compared to close relatives, further supporting designation as a novel species. Fatty acid methyl ester analysis showed a predominance of C14 : 0, C16 : 0 and C16 : 1ω7c fatty acids. Finally, biochemical characteristics distinguished the isolates from other species of the genus Neisseria. On the basis of these combined data, the isolates are proposed to represent a novel species of the genus Neisseria, with the name Neisseria arctica sp. nov. The type strain is KH1503T (=ATCC TSD-57T=DSM 103136T).


The Effects of Home Exercise in Older Women With Vertebral Fractures: A Pilot Randomized Controlled Trial.
Regular exercise is advocated in osteoporosis guidelines to prevent fractures. Few studies have evaluated the effect of exercise on functional performance, posture, and other outcomes that are important to patients after vertebral fractures. This pilot study will explore the effect of home exercise versus control on functional performance, posture, and patient-reported outcome measures. This study was a parallel 2-arm pilot feasibility trial with 1:1 randomization to exercise or attentional control groups. This study took place in 5 Canadian and 2 Australian academic or community hospitals/centers. This study included 141 women ≥65 years of age with radiographically confirmed vertebral fractures. A physical therapist delivered exercise and behavioral counseling in 6 home visits over 8 months and monthly calls. Participants were to exercise ≥3 times weekly. Controls received equal attention. Functional performance, posture, quality of life, pain, and behavior-change outcomes were assessed at baseline and after 6 (questionnaires only) and 12 months. Adherence to exercise was assessed by calendar diary. All t tests examined between-group mean differences (MD) in change from baseline in intention-to-treat and per-protocol analyses. There was a small effect of exercise on 5 times sit-to-stand test versus control (MD = -1.58 [95% CI = -3.09 to -0.07], intention-to-treat; MD = -1.49 [95% CI = -3.12 to 0.16], per-protocol). There were no other major or statistically significant MDs for any other measured outcomes after follow-up. Adherence declined over time. Treatment effects on variables may have been underestimated due to multiple comparisons and underpowered analyses. Our exploratory estimate of the effect of exercise on functional leg muscle strength was consistent in direction and magnitude with other trials in individuals with vertebral fractures. Declining adherence to home exercise suggests that strategies to enhance long-term adherence might be important in future confirmatory trials.


Cognitive function in people with and without freezing of gait in Parkinson's disease.
Freezing of gait (FOG) is common in people with Parkinson's disease (PD) which is extremely debilitating. One hypothesis for the cause of FOG episodes is impaired cognitive control, however, this is still in debate in the literature. We aimed to assess a comprehensive range of cognitive tests in older adults and people with Parkinson's with and without FOG and associate FOG severity with cognitive performance. A total of 227 participants took part in the study which included 80 healthy older adults, 81 people with PD who did not have FOG and 66 people with PD and FOG. A comprehensive battery of neuropsychological assessments tested cognitive domains of global cognition, executive function/attention, working memory, and visuospatial function. The severity of FOG was assessed using the new FOG questionnaire and an objective FOG severity score. Cognitive performance was compared between groups using an ANCOVA adjusting for age, gender, years of education and disease severity. Correlations between cognitive performance and FOG severity were analyzed using partial correlations. Cognitive differences were observed between older adults and PD for domains of global cognition, executive function/attention, and working memory. Between those with and without FOG, there were differences for global cognition and executive function/attention, but these differences disappeared when adjusting for covariates. There were no associations between FOG severity and cognitive performance. This study identified no significant difference in cognition between those with and without FOG when adjusting for covariates, particularly disease severity. This may demonstrate that complex rehabilitation programs may be undertaken in those with FOG.


Opinion on the re-evaluation of ascorbyl palmitate (E 304i) as a food additive in foods for infants below 16 weeks of age and the follow-up of its re-evaluation as a food additive for uses in foods for all population groups.
Ascorbyl palmitate (E 304(i)) was re-evaluated in 2015 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow-up to this assessment, the Panel on Food Additives and Flavourings (FAF) was requested to assess the safety of ascorbyl palmitate (E 304(i)) for its uses as food additive in food for infants below 16 weeks of age belonging to food categories 13.1.1 (Infant formulae) and 188.8.131.52 (Dietary foods for infants for special medical purposes and special formulae for infants) and as carry over in line with Annex III, Part 5 Section B to Regulation (EC) No 1333/2008. In addition, the FAF Panel was requested to address the issues already identified during the re-evaluation of the food additive when used in food for the general population. The process involved the publication of a call for data to allow the interested business operators to provide the requested information to complete the risk assessment. On the basis of the data submitted by interested business operators and the considerations from the Panel, a revision of the existing EU specifications for ascorbyl palmitate (E 304 (i)) has been recommended. Based on in vitro data, the FAF Panel assumed that ascorbyl palmitate fully hydrolyses pre-systemically to ascorbic acid and palmitate. The Panel concluded that the intake of both metabolites, at the MPLs for ascorbyl palmitate as a food additive in infant formula belonging to FC 13.1.1 or in food for special medical purposes belonging to FC 126.96.36.199, does not raise health concerns.


The immunogenic privilege of corneal allografts.
Corneal grafts enjoy the highest success rate of any form of organ transplantation. The low incidence of graft rejection is particularly impressive considering that human leukocyte antigen matching of donor and recipient is not normally performed. Although corticosteroids are applied topically, systemic immunosuppressive drugs are not routinely implemented for keratoplasty. The most widely accepted explanation to account for corneal allograft success suggests that the avascularity of the graft bed prevents corneal alloantigens from reaching the regional lymphoid tissues and therefore results in an "afferent blockade" of the immune response. However, recent findings suggest that the unique immunologic characteristics of the corneal graft itself may play a crucial role in determining the fate of the transplant. In particular, the presence and distribution of donor-derived Ia+ Langerhans cells can have a profound impact on graft immunogenicity and thus, graft survival even if the graft bed is initially free of lymphatic and blood vascular drainage channels. Thus, the immunologically unique characteristics of the corneal graft conspire with the avascular graft bed to produce an "immunologically privileged" environment that promotes graft survival.


Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant.
Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.


Near patient testing in general practice: attitudes of general practitioners and practice nurses, and quality assurance procedures carried out.
The evaluation of near patient testing in British general practice has largely been confined to studies examining individual tests or comparing equipment. This study set out to determine the attitudes of practice staff to near patient testing, and the extent to which staff undertook quality assessment. Four types of near patient testing machines were introduced into 12 general practices in two regions of England, south west Thames and west Midlands. General practitioner and practice nurse attitudes to near patient testing were assessed by semi-structured interview before and six months after the introduction of the machines. The extent to which routine quality assurance procedures were carried out within the surgery and as part of local and national schemes was examined. Although 80% of general practitioners anticipated changing patient management with near patient testing, only two fifths reported having done so after six months. Nurses generally were enthusiastic at the outset, although one third were unhappy about incorporating near patient testing into their work schedules. Time pressure was the most important factor restricting uptake of near patient testing. Nurses performed quality control regularly but complete local external quality assurance procedures were established in only half the practices. All the practices participated in a national scheme for cholesterol assays. General practitioners in this study did not find near patient testing a very useful addition to their resources. Pressure on nurses' time was the most frequently reported limitation.


Central region of talin has a unique fold that binds vinculin and actin.
Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.


HPLC determination of catechins and caffeine in tea. Differentiation of green, black and instant teas.
A simple and fast high performance liquid chromatographic method for five catechins and caffeine using an ODS column and a water-acetonitrile-formic acid mobile phase system was developed. The catechins (epicatechin, catechin, epigallocatechin, epigallocatechin gallate, epicatechin gallate) and caffeine were separated by an acetonitrile gradient within 20 min. The detection limit of the method was approximately 10 ng for all the compounds (by injecting 10 microL). Several green, black and instant teas were analysed using this method. By using the studied compounds as chemical descriptors, linear discriminant analysis was performed and complete differentiation of the green, black and instant teas was achieved.


A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images.
There is a growing interest in the use of 18F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs. We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case. Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.


Characterization of herpes simplex virus 1 alpha proteins 0, 4, and 27 with monoclonal antibodies.
Analyses of the reactivity and patterns of synthesis of infected cell polypeptides (ICPs) specified by herpes simplex virus (HSV) 1 and 2 and by HSV-1 X HSV-2 recombinants indicated that monoclonal antibody H1183 reacted with HSV-1 alpha ICP0, whereas monoclonal antibody H1113 reacted with both HSV-1 and HSV-2 alpha ICP27. H1083 and H1113 and a monoclonal antibody to ICP4 (H640) similar to one previously described (D. K. Braun et al., J. Virol. 46:103-112.) were then used to study the properties of these alpha proteins. The results were as follows: alpha ICP0, ICP4, and ICP27 accumulated primarily in the nuclei of infected cells. ICP4 and ICP27 were poorly soluble in nondenaturing buffer solutions. ICP0 was considerably more soluble than ICP4 and ICP27. ICP0, ICP4, and ICP27 were readily partially purified by immunoaffinity chromatography from lysates of infected cells solubilized with denaturing agents such as sodium dodecyl sulfate. ICP0 and ICP27 were phosphorylated in cells overlaid with medium containing 32P early (1 to 3 h) or late (18 to 20 h) postinfection. A fraction, but not all, 32P that was incorporated early was chased in the presence of unlabeled phosphate. ICP0, ICP4, and ICP27 labeled with either 32P or [35S]methionine yielded multiple spots upon two-dimensional separations. However, ICP4 quantitatively precipitated at the origin when the migration in the first dimension was from acid to base, and both ICP4 and ICP27 partially precipitated at the origin when the direction of migration was reversed.


Pre-Synaptic Inhibition of Afferent Feedback in the Macaque Spinal Cord Does Not Modulate with Cycles of Peripheral Oscillations Around 10 Hz.
Spinal interneurons are partially phase-locked to physiological tremor around 10 Hz. The phase of spinal interneuron activity is approximately opposite to descending drive to motoneurons, leading to partial phase cancellation and tremor reduction. Pre-synaptic inhibition of afferent feedback modulates during voluntary movements, but it is not known whether it tracks more rapid fluctuations in motor output such as during tremor. In this study, dorsal root potentials (DRPs) were recorded from the C8 and T1 roots in two macaque monkeys following intra-spinal micro-stimulation (random inter-stimulus interval 1.5-2.5 s, 30-100 μA), whilst the animals performed an index finger flexion task which elicited peripheral oscillations around 10 Hz. Forty one responses were identified with latency < 5 ms; these were narrow (mean width 0.59 ms), and likely resulted from antidromic activation of afferents following stimulation near terminals. Significant modulation during task performance occurred in 16/41 responses, reflecting terminal excitability changes generated by pre-synaptic inhibition (Wall's excitability test). Stimuli falling during large-amplitude 8-12 Hz oscillations in finger acceleration were extracted, and sub-averages of DRPs constructed for stimuli delivered at different oscillation phases. Although some apparent phase-dependent modulation was seen, this was not above the level expected by chance. We conclude that, although terminal excitability reflecting pre-synaptic inhibition of afferents modulates over the timescale of a voluntary movement, it does not follow more rapid changes in motor output. This suggests that pre-synaptic inhibition is not part of the spinal systems for tremor reduction described previously, and that it plays a role in overall-but not moment-by-moment-regulation of feedback gain.


Prevalence, clinical associations, and impact of intimate partner violence among HIV-infected gay and bisexual men: a population-based study.
Intimate partner violence (IPV) is a risk factor for HIV infection. Little is known, however, about the prevalence, clinical associations, and impact of IPV among patients living with HIV. HIV-infected gay and bisexual men in Southern Alberta, Canada were screened for IPV between May 2009 and December 2011. The associations with IPV of sociodemographic factors, psychological factors, clinical status, and HIV-related and HIV-unrelated hospitalizations, data for which were obtained from a regional database, were evaluated using Poisson regression. Of 687 gay and bisexual patients, 22.4% had experienced one or several types of IPV. Patients disclosing IPV were more likely to be Aboriginal [adjusted prevalence ratio (APR) = 2.48; 95% confidence interval (CI) 1.18-5.20], to be younger (APR/year = 0.97; 95% CI 0.95-0.99), to be victims of childhood abuse (APR = 4.27; 95% CI 2.84-6.41), to be smokers (APR = 2.53; 95% CI 1.59-4.00), to have had depression prior to HIV diagnosis (APR = 1.87; 95% CI 1.10-3.16), to use ongoing psychiatric resources (APR = 3.53; 95% CI 2.05-6.10), to have recently participated in unprotected sex (APR = 2.29; 95% CI 1.10-4.77), and to have poor or fair vs. very good or excellent health-related quality of life (APR = 2.91; 95% CI 1.57-5.39). IPV was also associated with a higher rate of clinically relevant interruptions in care (APR = 1.95; 95% CI 1.23-3.08), a higher incidence of AIDS among patients presenting early to care (CD4 count ≥ 200 cells/μL; APR = 2.06; 95% CI 1.15-3.69), and an increased rate of HIV-related hospitalizations [relative risk (RR) = 1.55; 95% CI 0.99-2.33], especially after HIV diagnosis was established (RR = 2.46; 95% CI 1.51-3.99). The prevalence of IPV is high among HIV-infected gay and bisexual men and is associated with poor social, psychiatric, and medical outcomes. IPV is an under-recognized social determinant of health in this community that may be amenable to meaningful clinical interventions.


Functional divergence of duplicated genes results in a novel blast resistance gene Pi50 at the Pi2/9 locus.
We characterized a novel blast resistance gene Pi50 at the Pi2/9 locus; Pi50 is derived from functional divergence of duplicated genes. The unique features of Pi50 should facilitate its use in rice breeding and improve our understanding of the evolution of resistance specificities. Rice blast disease, caused by the fungal pathogen Magnaporthe oryzae, poses constant, major threats to stable rice production worldwide. The deployment of broad-spectrum resistance (R) genes provides the most effective and economical means for disease control. In this study, we characterize the broad-spectrum R gene Pi50 at the Pi2/9 locus, which is embedded within a tandem cluster of 12 genes encoding proteins with nucleotide-binding site and leucine-rich repeat (NBS-LRR) domains. In contrast with other Pi2/9 locus, the Pi50 cluster contains four duplicated genes (Pi50_NBS4_1 to 4) with extremely high nucleotide sequence similarity. Moreover, these duplicated genes encode two kinds of proteins (Pi50_NBS4_1/2 and Pi50_NBS4_3/4) that differ by four amino acids. Complementation tests and resistance spectrum analyses revealed that Pi50_NBS4_1/2, not Pi50_NBS4_3/4, control the novel resistance specificity as observed in the Pi50 near isogenic line, NIL-e1. Pi50 shares greater than 96 % amino acid sequence identity with each of three other R proteins, i.e., Pi9, Piz-t, and Pi2, and has amino acid changes predominantly within the LRR region. The identification of Pi50 with its novel resistance specificity will facilitate the dissection of mechanisms behind the divergence and evolution of different resistance specificities at the Pi2/9 locus.


Influence of different cut-off values on the diagnosis of mild cognitive impairment in Parkinson's disease.
Comparable to Alzheimer's disease, mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with an increased risk for dementia. However different definitions of PD-MCI may have varying predictive accuracy for dementia. In a cohort of 101 nondemented Parkinson patients who underwent neuropsychological testing, the frequency of PD-MCI subjects and PD-MCI subtypes (i.e., amnestic/nonamnestic) was determined by use of varying healthy population-based cut-off values. We also investigated the association between defined PD-MCI groups and ADL scales. Varying cut-off values for the definition of PD-MCI were found to affect frequency of PD-MCI subjects (9.9%-92.1%) and, maybe more important, lead to a "shift" of proportion of detected PD-MCI subtypes especially within the amnestic single-domain subtype. Models using a strict cut-off value were significantly associated with lower ADL scores. Thus, the use of defined cut-off values for the definition of PD-MCI is highly relevant for comparison purposes. Strict cut-off values may have a higher predictive value for dementia.


Matrix enrichment by black phosphorus improves ionization and reproducibility of mass spectrometry of intact cells, peptides, and amino acids.
Intact (whole) cell matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) is an established method for biotyping in clinical microbiology as well as for revealing phenotypic shifts in cultured eukaryotic cells. Intact cell MALDI-TOF MS has recently been introduced as a quality control tool for long-term cultures of pluripotent stem cells. Despite the potential this method holds for revealing minute changes in cells, there is still a need for improving the ionization efficiency or peak reproducibility. Here we report for the first time that supplementation by fine particles of black phosphorus to the standard MALDI matrices, such as sinapinic and α-cyano-4-hydroxycinnamic acids enhance intensities of mass spectra of particular amino acids and peptides, presumably by interactions with aromatic groups within the molecules. In addition, the particles of black phosphorus induce the formation of small and regularly dispersed crystals of sinapinic acid and α-cyano-4-hydroxycinnamic acid with the analyte on a steel MALDI target plate. Patterns of mass spectra recorded from intact cells using black phosphorus-enriched matrix were more reproducible and contained peaks of higher intensities when compared to matrix without black phosphorus supplementation. In summary, enrichment of common organic matrices by black phosphorus can improve discrimination data analysis by enhancing peak intensity and reproducibility of mass spectra acquired from intact cells.


Comparison of ribosomal ITS regions among Androctonus spp. sorpions (Scorpionida: Buthidae) from Tunisia.
Three species of scorpions have been reported from Tunisia: Androctonus amoreuxi Audoin, A. aeneas Koch, and A. australis L. The latest has been divided in two subspecies: A. australis garzonii Goyffon & Lamy and A. australis hector Koch. Despite the public health importance of these animals, which cause several cases of poisoning each year, nothing is know about the genetic diversity of the group. To gain a better understanding of the group, we studied the variation of rDNA sequences of the ITS1, 5.8S, and ITS2 region of 14 representatives of the four taxa in Tunisia. The main result is the high polymorphism of the ITS regions. In some instances in both intra- and interspecific comparisons, it was difficult to unambiguously align the sequences. However, some representatives of different species were relatively similar, so that it appeared difficult to recognize the species on the basis of these sequences. A phylogenetic analysis was conducted that inquires the validity of the subspecies status of A. australis garzonii and A. australis hector. Moreover, the taxonomic status of A. aeneas is also questioned. Our studies highlighted the need of a revision of the taxonomy of the scorpions in Tunisia; however, the use of other genetic markers will be necessary to solve this question.


Pore-scale simulation of fluid flow and solute dispersion in three-dimensional porous media.
In the present work fluid flow and solute transport through porous media are described by solving the governing equations at the pore scale with finite-volume discretization. Instead of solving the simplified Stokes equation (very often employed in this context) the full Navier-Stokes equation is used here. The realistic three-dimensional porous medium is created in this work by packing together, with standard ballistic physics, irregular and polydisperse objects. Emphasis is placed on numerical issues related to mesh generation and spatial discretization, which play an important role in determining the final accuracy of the finite-volume scheme and are often overlooked. The simulations performed are then analyzed in terms of velocity distributions and dispersion rates in a wider range of operating conditions, when compared with other works carried out by solving the Stokes equation. Results show that dispersion within the analyzed porous medium is adequately described by classical power laws obtained by analytic homogenization. Eventually the validity of Fickian diffusion to treat dispersion in porous media is also assessed.


Cytotoxicity, mutagenicity, and tumorigenicity of mainstream smoke from three reference cigarettes machine-smoked to the same yields of total particulate matter per cigarette.
The particle phase of mainstream smoke from three types of cigarettes was investigated in vitro in the Neutral Red cytotoxicity assay and the Salmonella typhimurium Reverse Mutation Assay (Ames Assay) and in vivo in the two-stage dermal tumorigenicity assay (Skin Painting Assay) in SENCAR mice. The cigarettes used were the Reference Cigarettes 1R5F, 2R4F, and 2R1F from the University of Kentucky, USA, which, when smoked according to the smoking regimen defined by the International Standards Organization (ISO), produce a yield of approximately 2, 12, and 26 mg total particulate matter (TPM)/cigarette, respectively. All cigarettes were machine smoked according to ISO and then again in such a way that the TPM yields per cigarette equaled the ISO TPM yields of the other two cigarette types. The TPM from cigarettes with inherently different smoke yields showed similar in vitro toxicity and in vivo toxicity when, with different smoking regimens, these cigarettes were smoked to the same TPM yield. More intensive smoking conditions were associated with lower in vitro and in vivo activity per gram of TPM. The strongest decrease, and the tightest correlation, in this regard was observed for dermal tumorigenicity (tumor incidence).


Arithmetic inside the universal genetic code.
The first information system emerged on the earth as primordial version of the genetic code and genetic texts. The natural appearance of arithmetic power in such a linguistic milieu is theoretically possible and practical for producing information systems of extremely high efficiency. In this case, the arithmetic symbols should be incorporated into an alphabet, i.e. the genetic code. A number is the fundamental arithmetic symbol produced by the system of numeration. If the system of numeration were detected inside the genetic code, it would be natural to expect that its purpose is arithmetic calculation e.g., for the sake of control, safety, and precise alteration of the genetic texts. The nucleons of amino acids and the bases of nucleic acids seem most suitable for embodiments of digits. These assumptions were used for the analyzing the genetic code. The compressed, life-size, and split representation of the Escherichia coli and Euplotes octocarinatus code versions were considered simultaneously. An exact equilibration of the nucleon sums of the amino acid standard blocks and/or side chains was found repeatedly within specified sets of the genetic code. Moreover, the digital notations of the balanced sums acquired, in decimal representation, the unique form 111, 222...., 999. This form is a consequence of the criterion of divisibility by 037. The criterion could simplify some computing mechanism of a cell if any and facilitate its computational procedure. The cooperative symmetry of the genetic code demonstrates that possibly a zero was invented and used by this mechanism. Such organization of the genetic code could be explained by activities of some hypothetical molecular organelles working as natural biocomputers of digital genetic texts. It is well known that if mutation replaces an amino acid, the change of hydrophobicity is generally weak, while that of size is strong. The antisymmetrical correlation between the amino acid size and the degeneracy number is known as well. It is shown that these and some other familiar properties may be a physicochemical effect of arithmetic inside the genetic code. The "frozen accident" model, giving unlimited freedom to the mapping function, could optimally support the appearance of both arithmetic symbols and physicochemical protection inside the genetic code.


The outcome to axitinib or everolimus after sunitinib in metastatic renal cell carcinoma.
We aimed to investigate the different outcomes in patients with metastatic renal cell carcinoma treated with second-line axitinib or everolimus after sunitinib. Patients treated in 16 oncological centres in Italy were included, and those receiving axitinib or everolimus from January 2013 onwards were analysed for outcomes. Descriptive statistical tests were used to highlight differences between groups. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Data on 634 patients with metastatic renal cell carcinoma treated with first-line sunitinib have been obtained. A total of 182 patients received a second-line therapy with everolimus (79 patients, 43%) or axitinib (103 patients, 57%), respectively. The median PFS was 4.6 [95% confidence (CI): 2.6-6.5] months for patients treated with everolimus and 5.5 (95% CI: 4.3-6.7) months for patients treated with axitinib (P=0.7). The median OS was 13.9 (95% CI: 10.4-17.4) months for patients treated with everolimus and 12.0 (95% CI: 7.9-16.2) months for patients treated with axitinib (P=0.3). No differences were found based on length of first-line treatment. Major limitations are the retrospective nature of the study and the lack of a prospective evaluation of the progression. This study reports no significantly differences between everolimus and axitinib in terms of both PFS and OS. Furthermore, the length of first-line treatment cannot be used as such a predictive factor and cannot suggest the use of a molecule compared with another.


Revisiting the F + HCl → HF + Cl reaction using a multireference coupled-cluster method.
We have constructed a new potential energy surface for the title reaction, based on the internally contracted multireference coupled-cluster method. The calculated barrier height is 1.59 ± 0.08 kcal mol-1. This value is much lower than that obtained in previous ab initio calculations and it is close to the experimentally suggested value. Other features of the [F,H,Cl] system are also analysed, such as van der Waals minima and conical intersections. The rate constant and the vibrational and rotational distributions of the products were calculated using a fully converged time independent quantum mechanical approach. The calculated rate constant agrees well with the experimental values. Qualitative agreement for the vibrational distribution is obtained and it is shown that it is strongly influenced by the initial rotational state distribution.


A receptor-like kinase mutant with absent endodermal diffusion barrier displays selective nutrient homeostasis defects.
The endodermis represents the main barrier to extracellular diffusion in plant roots, and it is central to current models of plant nutrient uptake. Despite this, little is known about the genes setting up this endodermal barrier. In this study, we report the identification and characterization of a strong barrier mutant, schengen3 (sgn3). We observe a surprising ability of the mutant to maintain nutrient homeostasis, but demonstrate a major defect in maintaining sufficient levels of the macronutrient potassium. We show that SGN3/GASSHO1 is a receptor-like kinase that is necessary for localizing CASPARIAN STRIP DOMAIN PROTEINS (CASPs)--major players of endodermal differentiation--into an uninterrupted, ring-like domain. SGN3 appears to localize into a broader band, embedding growing CASP microdomains. The discovery of SGN3 strongly advances our ability to interrogate mechanisms of plant nutrient homeostasis and provides a novel actor for localized microdomain formation at the endodermal plasma membrane.


Food Safety Practices in the Egg Products Industry.
We conducted a national census survey of egg product plants (n = 57) to obtain information on the technological and food safety practices of the egg products industry and to assess changes in these practices from 2004 to 2014. The questionnaire asked about operational and sanitation practices, microbiological testing practices, food safety training for employees, other food safety issues, and plant characteristics. The findings suggest that improvements were made in the industry's use of food safety technologies and practices between 2004 and 2014. The percentage of plants using advanced pasteurization technology and an integrated, computerized processing system increased by almost 30 percentage points. Over 90% of plants voluntarily use a written hazard analysis and critical control point (HACCP) plan to address food safety for at least one production step. Further, 90% of plants have management employees who are trained in a written HACCP plan. Most plants (93%) conduct voluntary microbiological testing. The percentage of plants conducting this testing on egg products before pasteurization has increased by almost 30 percentage points since 2004. The survey findings identify strengths and weaknesses in egg product plants' food safety practices and can be used to guide regulatory policymaking and to conduct required regulatory impact analysis of potential regulations.


Quantum Dot and Polymer Composite Cross-Reactive Array for Chemical Vapor Detection.
A cross-reactive chemical sensing array was made from CdSe Quantum Dots (QDs) and five different organic polymers by inkjet printing to create segmented fluorescent composite regions on quartz substrates. The sensor array was challenged with exposures from two sets of analytes, including one set of 14 different functionalized benzenes and one set of 14 compounds related to security concerns, including the explosives trinitrotoluene (TNT) and ammonium nitrate. The array was broadly responsive to analytes with different chemical functionalities due to the multiple sensing mechanisms that altered the QDs' fluorescence. The sensor array displayed excellent discrimination between members within both sets. Classification accuracy of more than 93% was achieved, including the complete discrimination of very similar dinitrobenzene isomers and three halogenated, substituted benzene compounds. The simple fabrication, broad responsivity, and high discrimination capacity of this type of cross-reactive array are ideal qualities for the development of sensors with excellent sensitivity to chemical and explosive threats while maintaining low false alarm rates.