The relationship between real-time and discrete-generation models of epidemic spread.
Many important results in stochastic epidemic modelling are based on the Reed-Frost model or on other similar models that are characterised by unrealistic temporal dynamics. Nevertheless, they can be extended to many other more realistic models thanks to an argument first provided by Ludwig [Final size distributions for epidemics. Math. Biosci. 23 (1975) 33-46], that states that, for a disease leading to permanent immunity after recovery, under suitable conditions, a continuous-time infectious process has the same final size distribution as another more tractable discrete-generation contact process; in other words, the temporal dynamics of the epidemic can be neglected without affecting the final size distribution. Despite the importance of such an argument, its presence behind many results is often not clearly stated or hidden in references to previous results. In this paper, we reanalyse Ludwig's result, highlighting some of the conditions under which it does not hold and providing a general framework to examine the differences between the continuous-time and the discrete-generation process.


Human Pumilio proteins recruit multiple deadenylases to efficiently repress messenger RNAs.
PUF proteins are a conserved family of eukaryotic RNA-binding proteins that regulate specific mRNAs: they control many processes including stem cell proliferation, fertility, and memory formation. PUFs repress protein expression from their target mRNAs but the mechanism by which they do so remains unclear, especially for humans. Humans possess two PUF proteins, PUM1 and PUM2, which exhibit similar RNA binding specificities. Here we report new insights into their regulatory activities and mechanisms of action. We developed functional assays to measure sequence-specific repression by PUM1 and PUM2. Both robustly inhibit translation and promote mRNA degradation. Purified PUM complexes were found to contain subunits of the CCR4-NOT (CNOT) complex, which contains multiple enzymes that catalyze mRNA deadenylation. PUMs interact with the CNOT deadenylase subunits in vitro. We used three approaches to determine the importance of deadenylases for PUM repression. First, dominant-negative mutants of CNOT7 and CNOT8 reduced PUM repression. Second, RNA interference depletion of the deadenylases alleviated PUM repression. Third, the poly(A) tail was necessary for maximal PUM repression. These findings demonstrate a conserved mechanism of PUF-mediated repression via direct recruitment of the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation. A second, deadenylation independent mechanism was revealed by the finding that PUMs repress an mRNA that lacks a poly(A) tail. Thus, human PUMs are repressors capable of deadenylation-dependent and -independent modes of repression.


SNP array analysis in constitutional and cancer genome diagnostics--copy number variants, genotyping and quality control.
Array-based comparative genomic hybridization analysis of genomic DNA was first applied in postnatal diagnosis for patients with intellectual disability (ID) and/or congenital anomalies (CA). Genome-wide single-nucleotide polymorphism (SNP) array analysis was subsequently implemented as the first line diagnostic test for ID/CA patients in our laboratory in 2009, because its diagnostic yield is significantly higher than that of routine cytogenetic analysis. In addition to the detection of copy number variations, the genotype information obtained with SNP array analysis enables the detection of stretches of homozygosity and thereby the possible identification of recessive disease genes, mosaic aneuploidy, or uniparental disomy. Patient-parent (trio) information analysis is used to screen for the presence of any form of uniparental disomy in the patient and can determine the parental origin of a de novo copy number variation. Moreover, the outcome of a genotype analysis is used as a final quality control by ruling out potential sample mismatches due to non-paternity or sample mix-up. SNP array analysis is now also used in our laboratory for patients with disorders for which locus heterogeneity is known (homozygosity pre-screening), in prenatal diagnosis in case of structural ultrasound anomalies, and for patients with leukemia. In this report, we summarize our array findings and experiences in the various diagnostic applications and demonstrate the power of a SNP-based array platform for molecular karyotyping, because it not only significantly improves the diagnostic yield in both constitutional and cancer genome diagnostics, but it also enhances the quality of the diagnostic laboratory workflow.


A Validation Study of the Web-Based Physical Activity Questionnaire Active-Q Against the GENEA Accelerometer.
Valid physical activity assessment in epidemiological studies is essential to study associations with various health outcomes. To validate the Web-based physical activity questionnaire Active-Q by comparing results of time spent at different physical activity levels with results from the GENEA accelerometer and to assess the reproducibility of Active-Q by comparing two admissions of the questionnaire. A total of 148 men (aged 33 to 86 years) responded to Active-Q twice and wore the accelerometer during seven consecutive days on two occasions. Time spent on six different physical activity levels including sedentary, light (LPA), moderate (MPA), and vigorous (VPA) as well as additional combined categories of sedentary-to-light and moderate-to-vigorous (MVPA) physical activity was assessed. Validity of Active-Q was determined using Spearman correlation coefficients with 95% confidence intervals (CI) and the Bland-Altman method. Reproducibility was assessed using intraclass correlation coefficients (ICCs) comparing two admissions of the questionnaire. The validity correlation coefficients were statistically significant for time spent at all activity levels; sedentary (r=0.19, 95% CI: 0.04-0.34), LPA (r=0.15, 95% CI: 0.00-0.31), sedentary-to-light (r=0.35, 95% CI: 0.19-0.51), MPA (r=0.27, 95% CI: 0.12-0.42), VPA (r=0.54, 95% CI: 0.42-0.67), and MVPA (r=0.35, 95% CI: 0.21-0.48). The Bland-Altman plots showed a negative mean difference for time in LPA and positive mean differences for time spent in MPA, VPA and MVPA. The ICCs of test-retest reliability ranged between r=0.51-0.80 for the different activity levels in Active-Q. More moderate and vigorous activities and less light activities were reported in Active-Q compared to accelerometer measurements. Active-Q shows comparable validity and reproducibility to other physical activity questionnaires used today.


Orienting proteins by nanostructured surfaces: evidence of a curvature-driven geometrical resonance.
Experimental and theoretical reports have shown that nanostructured surfaces have a dramatic effect on the amount of protein adsorbed and the conformational state and, in turn, on the performances of the related devices in tissue engineering strategies. Here we report an innovative method to prepare silica-based nanostructured surfaces with a reproducible, well-defined local curvature, consisting of ordered hexagonally packed arrays of curved hemispheres, from nanoparticles of different diameters (respectively 147 nm, 235 nm and 403 nm). The nanostructured surfaces have been made chemically homogeneous by partially embedding silica nanoparticles in poly(hydroxymethylsiloxane) films, further modified by means of UV-O3 treatments. This paper has been focused on the experimental and theoretical study of laminin, taken as a model protein, to study the nanocurvature effects on the protein configuration at nanostructured surfaces. A simple model, based on the interplay of electrostatic interactions between the charged terminal domains of laminin and the nanocurved charged surfaces, closely reproduces the experimental findings. In particular, the model suggests that nanocurvature drives the orientation of rigid proteins by means of a "geometrical resonance" effect, involving the matching of dimensions, charge distribution and spatial arrangement of both adsorbed molecules and adsorbent nanostructures. Overall, the results pave the way to unravel the nanostructured surface effects on the intra- and inter-molecular organization processes of proteins.


Fixation-related Brain Potentials during Semantic Integration of Object-Scene Information.
In vision science, a particularly controversial topic is whether and how quickly the semantic information about objects is available outside foveal vision. Here, we aimed at contributing to this debate by coregistering eye movements and EEG while participants viewed photographs of indoor scenes that contained a semantically consistent or inconsistent target object. Linear deconvolution modeling was used to analyze the ERPs evoked by scene onset as well as the fixation-related potentials (FRPs) elicited by the fixation on the target object (t) and by the preceding fixation (t - 1). Object-scene consistency did not influence the probability of immediate target fixation or the ERP evoked by scene onset, which suggests that object-scene semantics was not accessed immediately. However, during the subsequent scene exploration, inconsistent objects were prioritized over consistent objects in extrafoveal vision (i.e., looked at earlier) and were more effortful to process in foveal vision (i.e., looked at longer). In FRPs, we demonstrate a fixation-related N300/N400 effect, whereby inconsistent objects elicit a larger frontocentral negativity than consistent objects. In line with the behavioral findings, this effect was already seen in FRPs aligned to the pretarget fixation t - 1 and persisted throughout fixation t, indicating that the extraction of object semantics can already begin in extrafoveal vision. Taken together, the results emphasize the usefulness of combined EEG/eye movement recordings for understanding the mechanisms of object-scene integration during natural viewing.


Phylogenetic utility of the nuclear gene dopa decarboxylase in noctuoid moths (Insecta: Lepidoptera: noctuoidea).
Phylogenetic utility for the nuclear gene encoding dopa decarboxylase (DDC), little used in systematics, was recently demonstrated within the noctuid moth subfamily Heliothinae. Here we extend the test of the utility of a 709-bp DDC fragment to deeper levels, analyzing 49 species representing major groups across the superfamily Noctuoidea. Parsimony, distance, and maximum-likelihood analyses recover all or nearly all of a set of "test clades" supported by clear morphological synapomorphies, spanning a wide range of taxonomic levels. DDC also upholds a recent proposal that the Noctuidae are paraphyletic. Nt3 contributes a majority of the signal and recovers the basal split between Notodontidae and all other noctuoids, despite a plateau of nt3 divergence at this level. However, nonsynonymous changes also support groups at all levels, and in contrast to nt3, amino acid divergence shows no plateau. The utility of DDC promises to extend back to the early Tertiary and Cretaceous, a time span for which few suitable genes have been identified.


Studies on primary cultures of differentiated fetal liver cells.
A method for culturing non- or slowly growing, differentiated fetal rat liver cells is described. It involves the use of collagenase as a digesting agent and of a selective medium deficient in arginine which suppresses the growth of nonparenchymal liver cells. Evidence is presented that surviving cells (a) retain liver-specific urea cycle functions measured by their capacity to transform ornithine into arginine, (b) synthesize DNA in glucose-deficient medium, and (c) synthesize and secrete albumin. This primary cell culture responds to partially hepatectomized rat serum and may be an appropriate assay system for the study of mechanisms which regulate liver regeneration.


mago nashi mediates the posterior follicle cell-to-oocyte signal to organize axis formation in Drosophila.
Establishment of the anteroposterior and dorsoventral axes in the Drosophila egg chamber requires reciprocal signaling between the germ line and soma. Upon activation of the Drosophila EGF receptor in the posterior follicle cells, these cells signal back to the oocyte, resulting in a reorganization of the oocyte cytoplasm and anterodorsal migration of the oocyte nucleus. We demonstrate that the gene mago nashi (mago) encodes an evolutionarily conserved protein that must be localized within the posterior pole plasm for germ-plasm assembly and Caenorhabditis elegans mago is a functional homologue of Drosophila mago. In the absence of mago+ function during oogenesis, the anteroposterior and dorsoventral coordinates of the oocyte are not specified and the germ plasm fails to assemble.


Formation of a primary care pharmacist practice-based research network.
The results of a survey conducted to characterize participating practice sites, patient populations, and collaborative physician-pharmacist services provided through an emerging practice-based research network (PBRN) in the primary care setting are presented. A targeted sample of faculty pharmacist investigators practicing in primary care settings were selected for participation in this PBRN based on several factors, including past research activities, their interest in soliciting additional clinics within their state to participate in a research network, the potential for regional collaboration, geographic location, and the patient population served. A baseline survey to characterize the PBRN was distributed to members of the PBRN in June 2006. Data were analyzed using descriptive statistics. A total of 81 pharmacists in 48 practice sites were recruited to join the PBRN. Most practice sites were located within family medicine residency programs, and the majority were affiliated with a community hospital or health system. Half of participating practices had 300-599 ambulatory care visits per week. Pharmacists in the PBRN spent their time performing direct patient management and had collaborative practice agreements with physicians. Patient revenue was used to cover pharmacist salaries in about one fifth of the practice sites. Pharmacists in the PBRN reported participation in diverse educational activities, such as point-of-care resident education and curbside consultation in the clinic hallways or their office. Eighty-one pharmacists from 48 primary care practice sites in 11 states were recruited to join a PBRN. These pharmacists provided descriptive data regarding their practice site, characteristics of patients served, and clinical services provided as a first step in collaborative research efforts.


Three-scale analysis of the permeability of a natural shale.
The macroscopic permeability of a natural shale is determined by using structural measurements on three different scales. Transmission electron microscopy yields two-dimensional (2D) images with pixels smaller than 1 nm; these images are used to reconstruct 3D nanostructures. Three-dimensional focused ion beam-scanning electron microscopy (5.95- to 8.48-nm voxel size) provides 3D mesoscale pores of limited relative volume (1.71-5.9%). Micro-computed tomography (700-nm voxel size) provides information on the mineralogy of the shale, including the pores on this scale which do not percolate; synthetic 3D media are derived on the macroscopic scale by a training image technique. Permeability of the nanoscale, of the mesoscale structures and of their superposition is determined by solving the Stokes equation and this enables us to estimate the permeabilities of the 700-nm voxels located within the clay matrix. Finally, the Darcy equation is solved on synthetic 3D macroscale media to obtain the macroscopic permeability which is found in good agreement with experimental results obtained on the centimetric scale.


Clonal variants of hybridoma cells that switch isotype at a high frequency.
As B cells differentiate under the influence of antigen and T cells, they frequently switch from the expression of IgM antibody to the expression of other isotypes. This is accomplished by rearranging the expressed variable region gene to downstream constant region genes and deleting the intervening sequences. Some B-cell lines that represent early stages in development switch constitutively in culture at frequencies that approach those of lipopolysaccharide- or lymphokine-stimulated normal B cells. Hybridoma cells represent a later stage of development and rarely switch in culture. In contrast to early B-cell lines, hybridomas produce large amounts of immunoglobulin, and single cells can be assayed easily for the expression of new isotypes. We have used the ELISA spot assay and fluctuation analysis to determine the rate of switching of two hybridoma cell lines. By identifying subclones that switched more frequently, we have progressively enriched for cells that switch spontaneously at higher rates. These cells, like normal cells, switch by rearrangement and deletion, and the frequency of switched cells in some of the clones is comparable to that which has been observed in less differentiated B-cell lines and in normal B cells.


Adult bacteremic Haemophilus parainfluenzae infections. Seven reports of cases and a review of the literature.
Seven cases of adult Haemophilus parainfluenzae infections diagnosed by positive blood cultures are compared with cases previously reported in the English literature. Three patients had pneumonia, while the others had epiglottitis with meningitis, pharyngitis, arthritis, and endocarditis, respectively. Nonendocarditic manifestations of adult H parainfluenzae infection were reported in four other cases. In addition to the diseases of our patients, H parainfluenzae also has been isolated from cerebral abscesses. Patients did well with antibiotic therapy and there were no deaths. Patients did well with antibiotic therapy and there were no deaths. Report of antibiotic sensitivity testing of 50 strains disclosed 6% of isolates resistant to ampicillin sodium, with all sensitive to chloramphenicol. If the antibiotic sensitivity of the organism is unknown, then chloramphenicol therapy should be instituted until adequate susceptibility studies have been performed. If the organism is sensitive to ampicillin, then this is the drug of choice.


Suboccipital dermatomyotomic stimulation and digital blood flow.
The effect of gentle, soft tissue manipulation in the suboccipital region on digital blood flow, as a measure of sympathetic nervous system activity, was studied. Digital strain gauge plethysmography was used to measure the changes in pulse contour during (1) a normative test period with the subject in the supine position, (2) after a control interval (placebo) during which the investigator placed his hands under the suboccipital region, and (3) after an interval during which the investigator's fingers applied slow, steady, circular kneading in the suboccipital triangle region. Twenty-five studies were performed in a crossover design with the patient as his or her own control. Total pulse amplitude (Y) and the height from the dicrotic notch to the peak (X) were measured. Examination of the total data of all subjects revealed the occurrence of a significant change in X and Y with simply touching the suboccipital region with the hands. An even more favorable response ensued when suboccipital manipulation was applied. Those subjects reporting comfort or neutral responses had larger significant changes with manipulation when compared with the group reporting the experience as uncomfortable. The response within each group suggests that favorable autonomic changes (sympathetic dampening) occur with specific suboccipital manipulation as well as, indeed, the simple touching of the suboccipital triangle.


Occupational radiation procedures and doses in South Korean dentists.
Dentistry is among the occupations involving chronic exposure to ionizing radiation. Although several cohort studies on medical radiation workers have been conducted in some countries, only a few epidemiological studies on dentists have been performed to examine occupational radiation exposure worldwide. The aim of this study was to investigate occupational characteristics and radiation exposures in South Korean dentists. A total of 658 dentists were surveyed from April 2012 to May 2013, and survey data were linked with dosimetry data from the National Dose Registry. Multiple linear regression analysis was used to identify the relationship between demographic or occupational factors and individual radiation doses. Of the dentists sampled, 78% were men, 51% were younger than age 40, and 61% began employment after 2000. The most frequent procedures performed by dentists were panoramic radiography, followed by intraoral and portable dental radiography. Male dentists were more frequently involved in radiation procedures, and a higher proportion of male than female dentists wore a lead apron for diagnostic radiology. The average annual effective dose was 0.18 mSv for male and 0.13 mSv for female dentists. Female dentists working in provincial areas had significantly higher average annual and cumulative effective doses than those in metropolitan areas. The cumulative effective doses were significantly greater for older dentists, those who entered the field in the 1990s, and those with longer employment duration. Our findings provided detailed information on work practices, number of procedures performed on a weekly basis, and occupational radiation doses, which enabled in-depth evaluation of occupational radiation exposure and work status among dentists.


Correlates of physical activity in young adult survivors of childhood cancers.
To examine correlates of participation in regular physical activities among young adult survivors of childhood cancers. Descriptive, correlational. Web-based survey. 117 well-educated, predominately Caucasian survivors of various types of childhood cancers (-X age = 24 years). Participants completed four rating scales, a stages of change measure, and background questions. Logistic regression and graphical methods were used to examine relationships among physical activity correlates and physical activity. Physical activity stages of change, autonomous motivation, physical activity pros and cons, self-efficacy, and self-reported worries. More than 80% of participants reported that they were physically active. Survivors who were autonomously motivated and who perceived fewer cons to being physically active were more likely to report being active than survivors with lower autonomous motivation scores and higher physical activity cons scores. Worries about the present and future moderated the effect of physical activity cons on physical activity. The estimated probabilities of reporting being active for women and men changed as the collective contribution of autonomous motivation, physical activity cons, and worries varied from low to high values. Engaging in physical activity willingly and without a sense of pressure (autonomous motivation), perceiving fewer cons to physical activity participation (cognitive appraisal), and worrying about the present and future (affective response) were important correlates of self-reported physical activity beyond the influence of gender. Interventions that promote autonomous motivation, decrease physical activity cons, and address present and future worries may increase physical activity in young adult cancer survivors and may have a greater impact on women than men.


Attendance at pulmonary rehabilitation classes: an exploration of demographic, physiological and psychological factors that predict completion of treatment.
Pulmonary rehabilitation (PR) is an effective treatment for people with chronic obstructive pulmonary disease (COPD). However, uptake and adherence to rehabilitation is poor and non-adherence is associated with poorer clinical outcomes. This study investigated the factors that might predict an individual completing his/her PR programme. Demographic, physiological and psychological data were collected from routine assessment information. Non-completers (N = 213) who dropped out after initial assessment were compared with completers (N = 438) who attended all 6 weeks of PR programme. Regression analysis indicated that smoking status was the strongest predictor for completing PR programme, that is, ex-smokers were 2.6 times (95% confidence interval (CI) = 1.7-3.9) and those who had never smoked were 2.5 times (95% confidence interval (CI) = 1.1-5.7) more likely to complete in comparison with those who were current smokers. Scoring better on psychological well-being measures (odds ratio = 1.6; 95% CI = 1.2-1.9) was also a strong predictor. The findings suggest the areas that could be addressed to enhance adherence to rehabilitation, for example, targeted interventions for clients who continue to smoke and for those who require support for psychological distress.


Sleepiness and health in midlife women: results of the National Sleep Foundation's 2007 Sleep in America poll.
The 2007 Sleep in America poll, a random-sample telephone survey, provided data for this study of sleep in community-dwelling women aged 40 to 60 years. The majority of the respondents were post- or perimenopausal, overweight, married or living with someone, and reported good health. A subsample (20%) reported sleepiness that consistently interfered with daily life; the sleepy subsample reported more symptoms of insomnia, restless legs syndrome, obstructive sleep apnea, depression and anxiety, as well as more problems with health-promoting behaviors, drowsy driving, job performance, household duties, and personal relationships. Hierarchical regression showed that sleepiness along with depressive symptoms, medical comorbidities, obesity, and lower education were associated with poor self-rated health, whereas menopause status (pre-, peri- or post-) was not. These results suggest that sleep disruptions and daytime sleepiness negatively affect the daily life of midlife women.


A case of irritant contact dermatitis with leech.
Medicinal leeches are invertebrated parasites that have been used for medical purposes for centuries as one of the traditional treatment methods. Medicinal leeches are used for wound and flap healing in the plastic and reconstructive surgery, in the treatment of venous insufficiency, varicosities, hemorrhoids, and in many other diseases. However, due to medicinal leech therapy (hirudotherapy) complications such as anaphylaxis, local allergic reactions, anemia, and mucosal synechiae can occur. In this article, we report a case of an irritant contact dermatitis in a patient who experienced severe redness and itching after applying leeches for the relief of head and neck pain. Leeches are being used widely in some regions in the world and if people are informed about the leeches, it may be helpful in preventing complications that may occur.


The effect of ischaemia-reperfusion on [3H]inositol phosphates and ins(1,4,5)P3 levels in cardiac atria and ventricles--a comparative study.
In this study incorporation of [3H]inositol into inositol phosphates and phosphoinositides as well as tissue Ins(1,4,5)P3 levels of the atria and ventricles of isolated, perfused rat hearts were compared. Although the incorporation of [3H]inositol into the phosphoinositides of atria and ventricles was similar, significantly higher (2-3 fold) incorporation rates into inositol phosphates were observed in atrial tissue. Using a D-myo-[3H]Ins(1,4,5)P3 assay system, the Ins(1,4,5)P3 levels observed in atria from perfused rat hearts were also significantly higher than those obtained under the same experimental circumstances in the ventricles. Since previous studies on whole hearts showed inhibition of the phosphatidylinositol (PI) pathway during ischaemia with an immediate significant stimulation upon reperfusion [12, 20], the effects of ischaemia and 1 min postischaemic reperfusion were also examined separately in atria and ventricles. The results showed that 20 min of global ischaemia significantly depressed Ins(1,4,5)P3 levels as well as incorporation of [3H]inositol into ventricular InsP2 and InsP3. Reperfusion caused an immediate (within 1 min) increase in Ins(1,4,5)P3 levels and also [3H]inositol incorporation into all three cytosolic inositol phosphates in the ventricles. However, the effect of ischaemia and reperfusion on Ins(1,4,5)P3 levels as well as the incorporation of [3H]inositol into the inositol phosphates were less prominent in the atria. It therefore appears that the differential responses of the atria and the ventricles to an oxygen deficiency [41] are also reflected in the differences in PI metabolism during ischaemia-reperfusion.


Effect of gastric pH on urease-dependent colonization of gnotobiotic piglets by Helicobacter pylori.
Thirty-seven gnotobiotic piglets from seven litters were infected with either Helicobacter pylori N6 or urease-negative H. pylori N6ureG::Km which contains an insertion in the ureG gene and produces inactive urease. To produce achlorhydria, piglets were treated throughout the experiment with omeprazole (5 mg intravenously every 12 h) and ranitidine (75 mg orally every 6 h). Treatment resulted in elevation of gastric pH to 7.0 +/- 1.1 throughout the experiment. Control piglets were not treated and remained normochlorhydric. Strain N6 colonized well in both normal and achlorhydric piglets. All 10 piglets were colonized, and colonization ranged from 4.4 +/- 1.5 log10 CFU/g of gastric mucosa in normochlorhydric piglets sacrificed after 2 days to 6.9 +/- 0.5 log10 CFU/g in normochlorhydric piglets sacrificed after 5 days. Strain N6ureG::Km did not colonize any of seven normochlorhydric piglets and was recovered only in low numbers (< 100 CFU/g) from four of nine achlorhydric piglets. In the second experiment, piglets were coinoculated with both strains N6 and N6ureG::Km. Coinoculation did not affect colonization by urease-positive N6. Urease-deficient N6ureG::Km was unable to colonize even in the presence of urease-positive bacteria. These results confirm that urease enzymatic activity (and not urease protein) is essential for colonization, that this effect is independent of diffusible products of urea metabolism, and that gastric pH protection is not a major role of urease in promoting colonization by H. pylori.


Time for a re-evaluation of mammography in the young? Results of an audit of mammography in women younger than 40 in a resource restricted environment.
Mammography in younger women is considered to be of limited value. In a resource restricted environment without access to magnetic resonance imaging (MRI) and with a high incidence of breast cancer in the young, mammography remains an important diagnostic tool. Recent technical advances and better regulation of mammography make a reassessment of its value in these conditions necessary. Data of all the mammograms performed at a tertiary hospital and private breast clinic between January 2003 and July 2009 in women less than 40 years of age were collected. Indications were the presence of a mass, follow-up after primary cancer therapy, and screening for patients perceived at high risk due to a family history or the presence of atypical hyperplasia. Data acquired were as follows: Demographics, prior breast surgery, indication for mammography, outcome of mammography, diagnostic procedures, and their results. Of 2,167 mammograms, 393 were performed for a palpable mass, diagnostic mammography. In these, the overall cancer detection rate was 40%. If the mammography was reported as breast imaging reporting and data system (BIRADS(®)) 5 versus BIRADS(®) 3 and 4 versus BIRADS(®) 1 and 2, a final diagnosis of malignancy was established in 96, 48, and 5%, respectively. Of 367 mammograms done for the follow-up after primary treatment of breast cancer, seven cancers were diagnosed for a detection rate of 1.9%. Of 1,312 mammograms performed for screening, the recall rate was 4%; the biopsy rate 2%, and the cancer diagnosis rate 3/1,000 examinations. In contrast to past series, this series has shown that recent advances in mammography have made it a useful tool in the management of breast problems in young women, notably in a resource-restricted environment. Women for screening should be selected carefully.


In vivo phosphorylation site mapping in mouse cardiac troponin I by high resolution top-down electron capture dissociation mass spectrometry: Ser22/23 are the only sites basally phosphorylated.
Cardiac troponin I (cTnI) is the inhibitory subunit of cardiac troponin, a key myofilament regulatory protein complex located on the thin filaments of the contractile apparatus. cTnI is uniquely specific for the heart and is widely used in clinics as a serum biomarker for cardiac injury. Phosphorylation of cTnI plays a critical role in modulating cardiac function. cTnI is known to be regulated by protein kinase A and protein kinase C at five sites, Ser22/Ser23, Ser42/44, and Thr143, primarily based on results from in vitro phosphorylation assays by the specific kinase(s). However, a comprehensive characterization of phosphorylation of mouse cTnI occurring in vivo has been lacking. Herein, we have employed top-down mass spectrometry (MS) methodology with electron capture dissociation for precise mapping of in vivo phosphorylation sites of cTnI affinity purified from wild-type and transgenic mouse hearts. As demonstrated, top-down MS (analysis of intact proteins) is an extremely valuable technology for global characterization of labile phosphorylation occurring in vivo without a priori knowledge. Our top-down MS data unambiguously identified Ser22/23 as the only two sites basally phosphorylated in wild-type mouse cTnI with full sequence coverage, which was confirmed by the lack of phosphorylation in cTnI-Ala(2) transgenic mice where Ser22/23 in cTnI have been rendered nonphosphorylatable by mutation to alanine.


Contribution of sleep research to the development of new antidepressants.
Several sleep anomalies are known to accompany depression and other psychiatric disorders, and to be partially modified by drugs efficient on clinical symptoms. Many puzzling theoretical questions remain, even after 30 years of research, because these drugs do not act in a uniform way: some reduce slow-wave sleep while others increase it some prolong rapid-eye movement sleep latency, while others do not. The relationship between insomnia and depression is likely to be a close one, since a large majority of patients with depression suffer insomnia, and that insomnia can predate depression by a few years. However, questions remain here, too, since sleep deprivation is also an effective means to combat depression, and some patients present with hypersomnia rather than insomnia. This review details the action of all current classes of antidepressants on sleep. It examines the predictive value of baseline electronencephalographic sleep symptoms or early modifications due to treatment for eventual clinical efficiency. We will also discuss the two main theories on the relationship between sleep and depression. The action on sleep of all new drugs-and antidepressants in particular-is carefully examined during development, for insomnia is currently considered to be a major health con-insomnia is currently considered to be a major health concern in industrialized countries.


Determination of cardiac volumes and mass with FLASH and SSFP cine sequences at 1.5 vs. 3 Tesla: a validation study.
To compare cardiac cine MR imaging using steady state free precession (SSFP) and fast low angle shot (FLASH) techniques at 1.5 and 3 T, and to establish their variabilities and reproducibilities for cardiac volume and mass determination in volunteers. To assess the feasibility of SSFP imaging in patients at 3 T and to determine comparability to volume data acquired at 1.5 T. Ten healthy volunteers underwent cardiac magnetic resonance imaging using SSFP and segmented gradient-echo FLASH, using both a 1.5 and a 3 T MR system on the same day. Ten patients with impaired left ventricular (LV) function were also studied at both field strengths with SSFP. For both SSFP and FLASH, field strength had no effect on the quantification of LV and right ventricular (RV) volumes, mass, or function (P > or = 0.05 for field strength for all parameters). At both 1.5 and 3 T, SSFP yielded smaller LV mass (e.g., at 3 T 109 +/- 30 g vs. 142 +/- 37 g; P = 0.011) and larger LV volume (e.g., at 3 T end-diastolic volume 149 +/- 37 mL vs. 133 +/- 31 mL at 5 T; P = 0.041) measurements than FLASH. In patients with reduced LV function, all volume and mass measurements were again similar for SSFP sequences at 1.5 vs. 3 T. In volunteers and patients, measurement variabilities for LV parameters were small for both field strength and sequences, ranging between 3.7% and 10.7% for mass. Compared to 1.5 T, cardiac cine MR imaging at 3 T, using either FLASH or SSFP sequences, is feasible and highly reproducible. Field strength does not have an influence on quantification of cardiac volume or mass, but the systematic overestimation of LV mass and underestimation of LV volume by FLASH compared to SSFP is present at both 1.5 and 3 T. Normal values for cardiac volumes and mass established at 1.5 T can be applied to scans obtained at 3 T.


Critical analysis and validation of lymph node density as prognostic variable in urothelial carcinoma of bladder.
To validate the prognostic relevance of lymph node density (LND) and identify its optimal cut-points in a large international multicenter series of patients treated with radical cystectomy (RC) for invasive bladder cancer. From 1993 to 2005, 4,430 bladder cancer patients who underwent RC without neoadjuvant chemotherapy were reviewed; of these, 1,038 were pN+M0 disease and form the basis of this report. Median age of patients was 67 years with median follow-up in survivors of 33 months. Overall, 5-year DSS estimate was 36%. Median number of lymph nodes removed was 18 (IQR, 11-32), median number of positive lymph nodes was 2 (IQR, 1-5), and median LND was 14.3% (IQR, 6.67-33.3%). LND as continuous variable was a stronger prognostic factor for DSS in patients that underwent a more extensive PLND (P < 0.001). HR for inverse association of LND with DSS increased incrementally with increasing LND cut-points. Categorizing LND into quintiles revealed strong tertiary distribution of risk based on LND <6%, 6%-41%, or >41% with cumulative 5-year DSS of 47%, 36%, and 21%, respectively (P < 0.001). When patients were stratified by adjuvant chemotherapy, LND remains independently prognostic in patients who received adjuvant chemotherapy as well as those who did not. Lymph node density is prognostic in bladder cancer patients who undergo a more extensive PLND and remains prognostic even when adjuvant chemotherapy is used. Prognostic value of LND is best represented as a continuum of risk and LND <6% represents the best possible outcome in patients with nodal disease.


Evaluation of a tuberculosis education video among immigrants and refugees at an adult education center: a community-based participatory approach.
Tuberculosis disproportionately affects immigrants and refugees to the United States. Upon arrival to the United States, many of these individuals attend adult education centers, but little is known about how to deliver tuberculosis health information at these venues. Therefore, the authors used a participatory approach to design and evaluate a tuberculosis education video in this setting. The authors used focus group data to inform the content of the video that was produced and delivered by adult learners and their teachers. The video was evaluated by learners for acceptability through 3 items with a 3-point Likert scale. Knowledge (4 items) and self-efficacy (2 items) about tuberculosis were evaluated before and after viewing the video. A total of 159 learners (94%) rated the video as highly acceptable. Knowledge about tuberculosis improved after viewing the video (56% correct vs. 82% correct; p <.001), as did tuberculosis-related self-efficacy (77% vs. 90%; p <.001). Adult education centers that serve large immigrant and refugee populations may be excellent venues for health education, and a video may be an effective tool to educate these populations. Furthermore, a participatory approach in designing health education materials may enhance the efficacy of these tools.


Analysis of virC, an operon involved in the secretion of Yop proteins by Yersinia enterocolitica.
Upon incubation at 37 degrees C in the absence of Ca2+ ions, pathogenic yersiniae release large amounts of pYV plasmid-encoded proteins called Yops that are involved in pathogenesis. Yersinia enterocolitica also expresses an outer membrane protein that is considered an adhesin and called YadA (previously called P1 or YopA). The production of Yops is coordinately regulated by a 20-kb region of the plasmid referred to as the Ca2+ dependence region and containing at least four loci called virA, virB, virC, and virF. The virF gene encodes a key transcriptional activator of yop genes. We have shown here that virF is also required for transcription of yadA and that virB is necessary for full transcription of the yop and yadA genes. In contrast, mutations in genes virA and virC had only a weak influence on the transcription of yop and yadA genes. These mutations did not affect the production of YadA but they completely inhibited the translocation of Yops from the intracellular compartment to the extracellular milieu. We inferred from these data that virA and virC are involved in the specific transport of Yops. We analyzed the 8.5-kb virC region and showed that it is most probably a single operon containing 13 open reading frames called yscA to yscM (for Yop secretion). Protein YscC has a putative signal sequence and shares significant homology with outer membrane proteins involved in the secretion of pullulanase by Klebsiella pneumoniae (PulD) or in the assembly of filamentous bacteriophages (gene IV product). At least the putative products of yscD, yscJ, and yscL were shown to be required for the export of Yops. YscJ turned out to be YlpB, a lipoprotein that we had detected previously. The yscM gene shares homology with yopH, the adjacent gene on the pYV plasmid. Its product does not appear to be necessary for the production of Yops. Transcription of the virC operon was subjected to the same regulation as the yop genes.


Neurological and physiological disorders in Artemia harboring manipulative cestodes.
There are many impressive examples of host manipulation by parasites, but mechanisms underlying these ethological changes, as well as their physiological consequences, are not well characterized. Here, we analyzed part of the cerebral proteome of brine shrimp Artemia infected by manipulative cestodes, using for the first time the ProteinChip Surface-Enhanced Laser Desorption Ionization and Time of Fly Mass Spectrometry (SELDI-TOF MS) system, which has been proposed as an excellent way to analyze the host genome during the host-parasite interaction processes. We found 2 peptides downregulated in individuals infected by the dilepidid, Anomotaenia tringae (4.5 kDa), and by the 2 hymenolepidids, Flamingolepis liguloides and Confluaria podicipina (3.9 kDa), which are potential candidates for involvement with the manipulation process. The identification of 2 head peptides (4.1 and 4.2 kDa) overexpressed in all the categories in brine shrimp living at the surface (both infected individuals and uninfected controls) suggests its association with the different environmental conditions experienced at the water surface. In parallel, brine shrimp infected by C. podicipina showed significant values of triglycerides, potentially augmenting their profitability and attractiveness for the predaceous definitive host (grebes). We discuss our findings in relationship with current ideas on the complexity of parasitically modified organisms.


Amino acid substitutions in the H5N1 avian influenza haemagglutinin alter pH of fusion and receptor binding to promote a highly pathogenic phenotype in chickens.
Highly pathogenic H5N1 avian influenza viruses cause devastating outbreaks in farmed poultry with serious consequences for animal welfare and economic losses. Zoonotic infection of humans through close contact with H5N1 infected birds is often severe and fatal. England experienced an outbreak of H5N1 in turkeys in 1991 that led to thousands of farmed bird mortalities. Isolation of clonal populations of one such virus from this outbreak uncovered amino acid differences in the virus haemagglutinin (HA) gene whereby the different genotypes could be associated with distinct pathogenic outcomes in chickens; both low pathogenic (LP) and high pathogenic (HP) phenotypes could be observed despite all containing a multi-basic cleavage site (MBCS) in the HA gene. Using reverse genetics, three amino acid substitutions in HA were examined for their ability to affect pathogenesis in the chicken. Restoration of amino acid polymorphisms close to the receptor binding site that are commonly found in H5 viruses only partially improved viral fitness in vitro and in vivo. A third novel substitution in the fusion peptide, HA2G4R, enabled the HP phenotype. HA2G4R decreased the pH stability of HA and increased the pH of HA fusion. The substitutions close to the receptor binding site optimised receptor binding while modulating the pH of HA fusion. Importantly, this study revealed pathogenic determinants beyond the MBCS.


A perspective on ecologically relevant plant-UV research and its practical application.
Plants perceive ultraviolet-B (UV-B) radiation through the UV-B photoreceptor UV RESISTANCE LOCUS 8 (UVR8), and initiate regulatory responses via associated signalling networks, gene expression and metabolic pathways. Various regulatory adaptations to UV-B radiation enable plants to harvest information about fluctuations in UV-B irradiance and spectral composition in natural environments, and to defend themselves against UV-B exposure. Given that UVR8 is present across plant organs and tissues, knowledge of the systemic signalling involved in its activation and function throughout the plant is important for understanding the context of specific responses. Fine-scale understanding of both UV-B irradiance and perception within tissues and cells requires improved application of knowledge about UV-attenuation in leaves and canopies, warranting greater consideration when designing experiments. In this context, reciprocal crosstalk among photoreceptor-induced pathways also needs to be considered, as this appears to produce particularly complex patterns of physiological and morphological response. Through crosstalk, plant responses to UV-B radiation go beyond simply UV-protection or amelioration of damage, but may give cross-protection over a suite of environmental stressors. Overall, there is emerging knowledge showing how information captured by UVR8 is used to regulate molecular and physiological processes, although understanding of upscaling to higher levels of organisation, i.e. organisms, canopies and communities remains poor. Achieving this will require further studies using model plant species beyond Arabidopsis, and that represent a broad range of functional types. More attention should also be given to plants in natural environments in all their complexity, as such studies are needed to acquire an improved understanding of the impact of climate change in the context of plant-UV responses. Furthermore, broadening the scope of experiments into the regulation of plant-UV responses will facilitate the application of UV radiation in commercial plant production. By considering the progress made in plant-UV research, this perspective highlights prescient topics in plant-UV photobiology where future research efforts can profitably be focussed. This perspective also emphasises burgeoning interdisciplinary links that will assist in understanding of UV-B effects across organisational scales and gaps in knowledge that need to be filled so as to achieve an integrated vision of plant responses to UV-radiation.


Tailored Composite Polymer-Metal Nanoparticles by Miniemulsion Polymerization and Thiol-ene Functionalization.
A simple and modular synthetic approach, based on miniemulsion polymerization, has been developed for the fabrication of composite polymer-metal nanoparticle materials. The procedure produces well-defined composite structures consisting of gold, silver or MnFe(2)O(4) nanoparticles (∼10 nm in diameter) encapsulated within larger spherical nanoparticles of poly(divinylbenzene) (∼100 nm in diameter). This methodology readily permits the incorporation of multiple metal domains into a single polymeric particle, while still preserving the useful optical and magnetic properties of the metal nanoparticles. The morphology of the composite particles is retained upon increasing the inorganic content, and also upon redispersion in organic solvents. Finally, the ability to tailor the surface chemistry of the composite nanoparticles and incorporate steric stabilizing groups using simple thiol-ene chemistry is demonstrated.


Dopamine modulates egalitarian behavior in humans.
Egalitarian motives form a powerful force in promoting prosocial behavior and enabling large-scale cooperation in the human species [1]. At the neural level, there is substantial, albeit correlational, evidence suggesting a link between dopamine and such behavior [2, 3]. However, important questions remain about the specific role of dopamine in setting or modulating behavioral sensitivity to prosocial concerns. Here, using a combination of pharmacological tools and economic games, we provide critical evidence for a causal involvement of dopamine in human egalitarian tendencies. Specifically, using the brain penetrant catechol-O-methyl transferase (COMT) inhibitor tolcapone [4, 5], we investigated the causal relationship between dopaminergic mechanisms and two prosocial concerns at the core of a number of widely used economic games: (1) the extent to which individuals directly value the material payoffs of others, i.e., generosity, and (2) the extent to which they are averse to differences between their own payoffs and those of others, i.e., inequity. We found that dopaminergic augmentation via COMT inhibition increased egalitarian tendencies in participants who played an extended version of the dictator game [6]. Strikingly, computational modeling of choice behavior [7] revealed that tolcapone exerted selective effects on inequity aversion, and not on other computational components such as the extent to which individuals directly value the material payoffs of others. Together, these data shed light on the causal relationship between neurochemical systems and human prosocial behavior and have potential implications for our understanding of the complex array of social impairments accompanying neuropsychiatric disorders involving dopaminergic dysregulation.


Hydrogenase-based electrode for hydrogen sensing in a fermentation bioreactor.
The hydrogen-based economy will require not only sustainable hydrogen production but also sensitive and cheap hydrogen sensors. Commercially available H2 sensors are limited by either use of noble metals or elevated temperatures. In nature, hydrogenase enzymes present high affinity and selectivity for hydrogen, while being able to operate in mild conditions. This study aims at evaluating the performance of an electrochemical sensor based on carbon nanomaterials with immobilised hydrogenase from the hyperthermophilic bacterium Aquifex aeolicus for H2 detection. The effect of various parameters, including the surface chemistry, dispersion degree and amount of deposited carbon nanotubes, enzyme concentration, temperature and pH on the H2 oxidation are investigated. Although the highest catalytic response is obtained at a temperature around 60 °C, a noticeable current can be obtained at room temperature with a low amount of protein less than 1 μM. An original pulse-strategy to ensure H2 diffusion to the bioelectrode allows to reach H2 sensitivity of 4 μA cm-2 per % H2 and a linear range between 1 and 20%. Sustainable hydrogen was then produced through dark fermentation performed by a synthetic bacterial consortium in an up-flow anaerobic packed-bed bioreactor. Thanks to the outstanding properties of the A. aeolicus hydrogenase, the biosensor was demonstrated to be quite insensitive to CO2 and H2S produced as the main co-products of the bioreactor. Finally, the bioelectrode was used for the in situ measurement of H2 produced in the bioreactor in steady-state.


Change in perceived psychosocial status following a 12-week Tai Chi exercise programme.
This paper reports a study to examine change in psychosocial status following a 12-week Tai Chi exercise intervention among ethnic Chinese people with cardiovascular disease risk factors living in the United States of America. Regular participation in physical activity is associated with protection against cardioavascular disease, and improvements in physical and psychological health. Increasing amounts of scientific evidence suggests that mind-body exercise, such as Tai Chi, are related to improvements in mental health, emotional well-being, and stress reduction. No prior study has examined the effect of a Tai Chi exercise intervention on psychosocial status among people with cardiovascular disease risk factors. This was a quasi-experimental study. Participants attended a 60-minute Tai Chi exercise class three times per week for 12 weeks. Data were collected at baseline, 6 and 12 weeks following the intervention. Psychosocial status was assessed using Chinese versions of Cohen's Perceived Stress Scale, Profile of Mood States, Multidimensional Scale of Perceived Social Support, and Tai Chi exercise self-efficacy. A total of 39 participants, on average 66-year-old (+/-8.3), married (85%), Cantonese-speaking (97%), immigrants participated. The majority were women (69%), with < or =12 years education (87%). Statistically significant improvements in all measures of psychosocial status were found (P < or = 0.05) following the intervention. Improvement in mood state (eta2 = 0.12), and reduction in perceived stress (eta2 = 0.13) were found. In addition, Tai Chi exercise statistically significantly increased self-efficacy to overcome barriers to Tai Chi (eta2 = 0.19), confidence to perform Tai Chi (eta2 = 0.27), and perceived social support (eta2 = 0.12). Tai Chi was a culturally appropriate mind-body exercise for these older adults, with statistically significant psychosocial benefits observed over 12-weeks. Further research examining Tai Chi exercise using a randomized clinical trial design with an attention-control group may reduce potential confounding effects, while exploring potential mechanisms underlying the relaxation response associated with mind-body exercise. In addition, future studies with people with other chronic illnesses in all ethnic groups are recommended to determine if similar benefits can be achieved.


Testosterone-lowering activity of canola and hydrogenated soybean oil in the stroke-prone spontaneously hypertensive rat.
Canola and some other types of oil unusually shorten the survival of stroke-prone spontaneously hypertensive rats (SHRSP), compared with soybean oil, perilla oil and animal fats. Since differential effects of canola and soybean oil on steroid hormone metabolism were suggested by a preliminary DNA microarray analysis as a reason for this, the steroid hormone levels in the serum and tissues of SHRSP fed different oils were investigated. The testosterone levels in the serum and the testes were found to be significantly lower in the canola oil group than in the soybean oil group, while no significant differences were detected in the corticosterone and estradiol levels in tissues. In a second experiment, it was found that hydrogenated soybean oil, with a survival-shortening activity comparable to that of canola oil, also decreased the testosterone level in testes to a similar degree. The testosterone-lowering activity of canola and hydrogenated soybean oil observed in SHRSP was considered in relation to other factors possibly affecting the physiology of SHRSP.


Mechanistic study of carboxylic acid and phosphate ester cleavage by oximate metal complexes surpassing the limiting reactivity of highly basic free oximate anions.
Two tridentate and one tetradentate new ligands containing the terminal oxime group separated from secondary amino and pyridine groups as additional binding sites by two or three methylene groups have been prepared. Their acid-base properties, as well as the composition and stability of their complexes with Zn(ii) and Cd(ii) ions, were determined by potentiometric and spectrophotometric titrations. The X-ray structure of a Cd(ii) complex of a related tridentate oxime ligand previously studied in solution was determined. All oximate complexes show high reactivity in the cleavage of aryl acetates, paraoxon, parathion and 4-nitrophenyl diphenyl phosphate, with rate constants significantly surpassing the limiting rate constants observed for highly basic free oximate anions. The second-order rate constants for individual oximate complexes in solution are assigned to each ligand, metal cation and substrate. The results of the cleavage of 4-substituted phenyl acetates were analyzed in terms of Brønsted correlations with the leaving group pKa, which demonstrated a change in the rate determining step from the nucleophilic attack to the leaving group departure upon an increase in the leaving group basicity. The zero slope of the Brønsted correlation for the nucleophilic attack indicates transition state stabilization through electrophilic assistance by the metal ion. This interpretation is supported by metal selectivity in the relative efficiency of the cleavage of paraoxon and parathion. The existence of the alpha-effect in ester cleavage by coordinated oximates is confirmed by an analysis of the Brønsted correlations with the nucleophile basicity for metal bound oximate and alkoxo or hydroxo nucleophiles. The very high reactivity of the oximate complexes of the new ligands is attributed to transition state stabilization and to the removal of the solvational imbalance of oximate anions that impedes the expected increase in the reactivity of highly basic free anions.


A Review: Wolbachia-Based Population Replacement for Mosquito Control Shares Common Points with Genetically Modified Control Approaches.
The growing expansion of mosquito vectors has made mosquito-borne arboviral diseases a global threat to public health, and the lack of licensed vaccines and treatments highlight the urgent need for efficient mosquito vector control. Compared to genetically modified control strategies, the intracellular bacterium Wolbachia, endowing a pathogen-blocking phenotype, is considered an environmentally friendly strategy to replace the target population for controlling arboviral diseases. However, the incomplete knowledge regarding the pathogen-blocking mechanism weakens the reliability of a Wolbachia-based population replacement strategy. Wolbachia infections are also vulnerable to environmental factors, temperature, and host diet, affecting their densities in mosquitoes and thus the virus-blocking phenotype. Here, we review the properties of the Wolbachia strategy as an approach to control mosquito populations in comparison with genetically modified control methods. Both strategies tend to limit arbovirus infections but increase the risk of selecting arbovirus escape mutants, rendering these strategies less reliable.


A miniature bioassay for testing the acute phytotoxicity of photosystem II herbicides on seagrass.
Photosystem II (PSII) herbicides have been detected in nearshore tropical waters such as those of the Great Barrier Reef and may add to the pressure posed by runoff containing sediments and nutrients to threatened seagrass habitats. There is a growing number of studies into the potential effects of herbicides on seagrass, generally using large experimental setups with potted plants. Here we describe the successful development of an acute 12-well plate phytotoxicity assay for the PSII herbicide Diuron using isolated Halophila ovalis leaves. Fluorescence images demonstrated Diuron affected the entire leaf surface evenly and responses were not influenced by isolating leaves from the plant. The optimum exposure duration was 24 h, by which time the inhibition of effective quantum yield of PSII (∆F/F(m)') was highest and no deterioration of photosystems was evident in control leaves. The inhibition of ∆F/F(m)' by Diuron in isolated H. ovalis leaves was identical to both potted and hydroponically grown plants (with leaves remaining attached to rhizomes), indicating similar reductions in photosynthetic activity in these acute well-plate assays. The sensitivity of the assay was not influenced by irradiance (range tested 40 to 400 μmol photons m(-2) s(-1)). High irradiance, however, caused photo-oxidative stress in H. ovalis and this generally impacted in an additive or sub-additive way with Diuron to damage PSII. The bioassay using isolated leaves is more rapid, uses far less biological material and does not rely on specialised aquarium facilities in comparison with assays using potted plants. The development and validation of this sensitive bioassay will be useful to reliably screen and monitor the phytotoxicity of existing and emerging PSII herbicides and contribute to risk assessments and water quality guideline development in the future.


Temporal control of retroviral transgene expression in newborn cells in the adult brain.
Neural stem/progenitor cells (NSPCs) generate new neurons throughout life in distinct areas of the adult mammalian brain. Besides classical transgenesis-based approaches, retrovirus-mediated genetic manipulation is frequently used to study mechanisms that regulate neurogenesis in the nervous system. Here, we show that fusion of a tamoxifen-regulatable estrogen receptor (ER(T2)) motif to transcription factors (i.e., ASCL1 and NEUROD1) enables temporal control of transgene expression in adult mouse NSPCs in vitro and in vivo. Thus, the approach described here represents a versatile strategy for regulating gene expression to study gene function in dividing cells and their progeny.


Pterodactylus scolopaciceps Meyer, 1860 (Pterosauria, Pterodactyloidea) from the Upper Jurassic of Bavaria, Germany: the problem of cryptic pterosaur taxa in early ontogeny.
The taxonomy of the Late Jurassic pterodactyloid pterosaur Pterodactylus scolopaciceps Meyer, 1860 from the Solnhofen Limestone Formation of Bavaria, Germany is reviewed. Its nomenclatural history is long and complex, having been synonymised with both P. kochi (Wagner, 1837), and P. antiquus (Sömmerring, 1812). The majority of pterosaur species from the Solnhofen Limestone, including P. scolopaciceps are represented by juveniles. Consequently, specimens can appear remarkably similar due to juvenile characteristics detracting from taxonomic differences that are exaggerated in later ontogeny. Previous morphological and morphometric analyses have failed to separate species or even genera due to this problem, and as a result many species have been subsumed into a single taxon. A hypodigm for P. scolopaciceps, comprising of the holotype (BSP AS V 29 a/b) and material Broili referred to the taxon is described. P. scolopaciceps is found to be a valid taxon, but placement within Pterodactylus is inappropriate. Consequently, the new genus Aerodactylus is erected to accommodate it. Aerodactylus can be diagnosed on account of a unique suite of characters including jaws containing 16 teeth per-jaw, per-side, which are more sparsely distributed caudally and terminate rostral to the nasoantorbital fenestra; dorsal surface of the skull is subtly depressed rostral of the cranial table; rostrum very elongate (RI = ∼7), terminating in a point; orbits correspondingly low and elongate; elongate cervical vertebrae (approximately three times the length of their width); wing-metacarpal elongate, but still shorter than the ulna and first wing-phalanx; and pteroid approximately 65% of the total length of the ulna, straight and extremely thin (less than one third the width of the ulna). A cladistic analysis demonstrates that Aerodactylus is distinct from Pterodactylus, but close to Cycnorhamphus Seeley, 1870, Ardeadactylus Bennett, 2013a and Aurorazhdarcho Frey, Meyer and Tischlinger, 2011, consequently we erect the inclusive taxon Aurorazhdarchidae for their reception.


Cancer gene prioritization for targeted resequencing using FitSNP scores.
Although the throughput of next generation sequencing is increasing and at the same time the cost is substantially reduced, for the majority of laboratories whole genome sequencing of large cohorts of cancer samples is still not feasible. In addition, the low number of genomes that are being sequenced is often problematic for the downstream interpretation of the significance of the variants. Targeted resequencing can partially circumvent this problem; by focusing on a limited number of candidate cancer genes to sequence, more samples can be included in the screening, hence resulting in substantial improvement of the statistical power. In this study, a successful strategy for prioritizing candidate genes for targeted resequencing of cancer genomes is presented. Four prioritization strategies were evaluated on six different cancer types: genes were ranked using these strategies, and the positive predictive value (PPV) or mutation rate within the top-ranked genes was compared to the baseline mutation rate in each tumor type. Successful strategies generate gene lists in which the top is enriched for known mutated genes, as evidenced by an increase in PPV. A clear example of such an improvement is seen in colon cancer, where the PPV is increased by 2.3 fold compared to the baseline level when 100 top fitSNP genes are sequenced. A gene prioritization strategy based on the fitSNP scores appears to be most successful in identifying mutated cancer genes across different tumor entities, with variance of gene expression levels as a good second best.


Prediction of outcome following a first episode of schizophrenia. A follow-up study of Northwick Park first episode study subjects.
Although previous studies have attempted to identify predictors of outcome in schizophrenia, few have prospectively studied first episode patients for an adequate follow-up period. The psychopathological predictors of outcome were investigated in a subgroup of 51 subjects, originally included in the Northwick Park study of first episode schizophrenia who were followed up 7.3 years (s.d. 1.1, range 5.3-10.3) after first admission in the Harrow study. Forty-four subjects (24 men, 20 women) were traced. Outcome measures were time to first readmission, occupational level and total duration of hospital admission at five years after first admission. A survival analysis of time to first relapse revealed that the presence of subjective feelings of depression (CATEGO syndrome SD) during the first admission was associated with early relapse while the presence of depressive delusions (CATEGO syndrome DD) and higher educational attainment protected against early relapse. Total duration of hospitalisation at five years after first onset was positively associated with the presence of CATEGO syndromes SD and OD (biological features of depression) and negatively associated with female sex. Poor occupational outcome was not significantly associated with any psychopathological predictors. Our findings challenge the conventional view that symptoms of depression are associated with better outcome in schizophrenia.


Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo.
Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far.


Species groups distributed across elevational gradients reveal convergent and continuous genetic adaptation to high elevations.
Although many cases of genetic adaptations to high elevations have been reported, the processes driving these modifications and the pace of their evolution remain unclear. Many high-elevation adaptations (HEAs) are thought to have arisen in situ as populations rose with growing mountains. In contrast, most high-elevation lineages of the Qinghai-Tibetan Plateau appear to have colonized from low-elevation areas. These lineages provide an opportunity for studying recent HEAs and comparing them with ancestral low-elevation alternatives. Herein, we compare four frogs (three species of Nanorana and a close lowland relative) and four lizards (Phrynocephalus) that inhabit a range of elevations on or along the slopes of the Qinghai-Tibetan Plateau. The sequential cladogenesis of these species across an elevational gradient allows us to examine the gradual accumulation of HEA at increasing elevations. Many adaptations to high elevations appear to arise gradually and evolve continuously with increasing elevational distributions. Numerous related functions, especially DNA repair and energy metabolism pathways, exhibit rapid change and continuous positive selection with increasing elevations. Although the two studied genera are distantly related, they exhibit numerous convergent evolutionary changes, especially at the functional level. This functional convergence appears to be more extensive than convergence at the individual gene level, although we found 32 homologous genes undergoing positive selection for change in both high-elevation groups. We argue that species groups distributed along a broad elevational gradient provide a more powerful system for testing adaptations to high-elevation environments compared with studies that compare only pairs of high-elevation versus low-elevation species.


Quantification of microtubule dynamics in living plant cells using fluorescence redistribution after photobleaching.
Microtubule (MT) turnover within the four principal MT arrays, the cortical array, the preprophase band, the mitotic spindle and the phragmoplast, has been measured in living stamen hair cells of Tradescantia that have been injected with fluorescent neurotubulin. Using the combined techniques of confocal laser scanning microscopy and fluorescence redistribution after photobleaching (FRAP), we report that the half-time of turnover in spindle MTs is t 1/2 = 31 +/- 6 seconds, which is in excellent agreement with previous measurements of turnover in animal cell spindles. Tradescantia interphase MTs, however, exhibit turnover rates (t 1/2 = 67 +/- seconds) that are some 3.4-fold faster than those measured in interphase mammalian cells, and thus are revealed as being highly dynamic. Preprophase band and phragmoplast MTs have turnover rates similar to those of interphase MTs in Tradescantia. The spatial and temporal aspects of the fluorescence redistribution after photobleaching in all four MT arrays are more consistent with subunit exchange by the mechanism of dynamic instability than treadmilling. This is the first quantification of MT dynamics in plant cells.


Histomorphometric evaluation of a nanothickness bioceramic deposition on endosseous implants: a study in dogs.
The objective of this study was to evaluate the bone response to a nanothickness bioceramic ion beam-assisted deposition (IBAD) on endosteal implants in a canine model. Alumina-blasted/acid-etched (control) and IBAD-modified (test) implants were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy + ion beam milling, thin-film mode X-ray diffraction, and atomic force microscope. The implants were surgically placed in four dogs' proximal tibiae and remained for 2 and 4 weeks in vivo. Oxytetracycline (10 mg/kg) was administered for bone labeling 48 hours prior to euthanization. Following euthanization, nondecalcified thin sections were prepared for UV and transmitted light microscopy. The amount of bone labeling was evaluated along the length and away from the implant surface by means of a computer software. The % bone-to-implant contact (BIC) was determined for each specimen. One-way analysis of variance at 95% level of significance along with Tukey's post hoc multiple comparisons were utilized for statistical evaluation. The characterization showed Ca- and P-based amorphous coatings with a 20- to 50-nm thickness. In vivo results showed a significant increase in general and site-specific (to 0.5 mm from the implant surface) bone activity for the 4-week test implants compared with the control implants. Bone activity levels decreased as a function of distance from the implant surface for all groups. No significant differences in BIC were observed between groups. This study showed that both surfaces were biocompatible and osteoconductive and that a time-dependent increase in osteoactivity occurred around the test implants.


Hospice care of the intravenous drug user AIDS patient in a skilled nurse facility.
We report on the initial experience in hospice care for a predominantly poor, black and Hispanic intravenous drug user AIDS population in New York City. Hospice care was provided in a skilled nursing facility with a certified hospice program delivering home care and inpatient care. A formal education program preceded patient admission to familiarize the staff and institution with AIDS issues. Between February 1986 and January 1988, 62 of 175 referred patients were accepted for hospice admission. The patients' mean age was 39 years and all had AIDS dementia complex. The mean length of stay was 35 days (range 1-280 days) and a total of 2011 days of hospice care was provided. Ninety-one percent of hospice days were spent on the inpatient unit; only 9% of hospice days were provided at home. Despite the requirement of expensive inpatient hospice care for most patient days, the estimated savings in decreased costs compared to acute hospital inpatient care was $751,488 for these 62 patients. Continuing fear of transmission among hospice staff was not a major problem; however, several unanticipated problems arose including (a) inability to provide home services, (b) continued drug abuse, (c) increased staff stress, (d) difficulty maintaining confidentiality, (e) difficult interactions with funeral directors, and (f) unsupportive and inappropriate funding requirements. Hospice care of AIDS patients is feasible, humane, and cost effective but problems of the intravenous drug using population require special attention and program modifications if hospice care is to be provided for this substantial and growing AIDS population.


Bond Strength to Microtraction and Nanofiltration Using Ethanol Wet Bonding Technique in Fresh Extracted Teeth: An Ex Vivo Study.
The objective of this study was to evaluate the bond strength to microtraction and nanofiltration using ethanol wet bonding technique in fresh extracted teeth. This quasi-experimental ex vivo study evaluated 48 teeth that had an indication of premolar extraction due to orthodontic reasons. The protocol of dental preparation and restorative procedure was carried out to evaluate the adhesion resistance by means of the universal testing machine at a loading speed of 0.5 mm/min and 500MPa. To evaluate the nanofiltration, matches were made that were immersed in ammoniac silver nitrate for 24h, and then the specimens impregnated with silver were washed thoroughly in distilled water and placed in a photo-developer solution for 8h under a fluorescent light. All statistical analyses were statistically evaluated with a level of significance P < 0.05. The ethanol technique without premature failure (PF) group had an average of 31.26 ± 10.26MPa, whereas the lowest value was found in the water technique group with PF, which had 22.59 ± 12.27MPa. When performing inferential statistics, it was evidenced that there were statistically significant differences between both techniques with a value of P < 0.05. According to the results in both cases, the adhesive strength showed superiority in the ethanol wash group. It determines that this technique presents greater tolerance to the residual presence of water. Finally, in relation to nanofiltration we found that there were no significant differences between the groups evaluated.


Household knowledge, attitudes and practices related to pet contact and associated zoonoses in Ontario, Canada.
Many human infections are transmitted through contact with animals (zoonoses), including household pets. Although pet ownership is common in most countries and non-pet owners may have frequent contact with pets, there is limited knowledge of the public's pet contact practices and awareness of zoonotic disease risks from pets. The objective of this study was to characterize the general public's knowledge, attitudes and risks related to pet ownership and animal contact in southern Ontario, Canada. A self-administered questionnaire was distributed to individuals at two multi-physician clinics in Waterloo, Ontario, Canada during 2010. A single adult from each household was invited to participate in the study. Seventy five percent (641/853) of individuals approached completed the questionnaire. Pet ownership and contact were common; 64% of participants had a pet in their household and 37% of non-pet owning households had a member with at least weekly animal contact outside the home. Pet ownership was high (55%) for households with individuals at higher risk for infections (i.e., < 5 yrs, ≥ 65 yrs, immunocompromised). Most respondents (64%) indicated that they had never received information regarding pet-associated disease risks. When given a list of 11 infectious pathogens, respondents were only able to correctly classify just over half on their potential to be transmitted from pets to people (mean 6.4); independently, pet owners and those who recalled receiving information in the past about this topic were able to make significantly more correct identifications. Pet (36%) and non-pet owning households (10%) reported dog or cat bites or scratches during the preceding year. Households with individuals at higher risk for an infection did not differ from the remaining households regarding their perceived disease risk of pets, zoonotic disease knowledge, recall of being asked by their medical provider if they owned any pets, or recall of having received information regarding pet-associated disease risks and preventive measures. These results suggest that there is a need for accessible zoonotic disease information for both pet and non-owning households, with additional efforts made by veterinary, human and public health personnel. Immediate educational efforts directed toward households with individuals at higher risk to infections are especially needed.


Physiological mechanisms contributing to the QTL qDTY3.2 effects on improved performance of rice Moroberekan x Swarna BC2F3:4 lines under drought.
Traditional rice (Oryza sativa) varieties are valuable resources for the improvement of drought resistance. qDTY3.2 is a drought-yield quantitative trait locus that was identified in a population derived from the traditional variety Moroberekan and the drought-susceptible variety Swarna. In this study, our aim was to characterize the physiological mechanisms associated with qDTY3.2. Our approach was to phenotype fifteen BC2F3:4 lines for shoot and root drought resistance-related traits as compared to Swarna in the field under well-watered and drought stress conditions. Four BC2F3:4 lines contrasting for yield under drought were selected for detailed characterization of shoot morphology, water use related traits, flowering time and root system architecture in the field as well as in controlled environments (lysimeters in a greenhouse, and gel imaging platform in a growth chamber). Across five field experiments, grain yield correlated significantly with root growth along the soil profile, flowering time, and canopy temperature under drought conditions. The four selected BC2F3:4 lines showed earlier flowering time, reduced distribution of root growth to shallow soil layers which resulted in lower water uptake (between 0 and 30 cm) and drought-induced increased distribution of root growth to deep soil layers (between 30 and 60 cm) as compared to Swarna in the field. Root system architecture phenotypes were confirmed in whole root systems in lysimeters, and corresponded to higher numbers of root tips in a gel imaging platform, highlighting the potential stability of some root traits across different growth stages and systems. We conclude that earlier flowering time, reduced shallow root growth, and drought-induced increased deep root growth are associated with the presence of qDTY3.2 since these phenotypes were consistently observed in the selected QTL lines with full introgression of qDTY3.2. We hypothesize that the qDTY3.2 associated RSA phenotypes led to better use of water and metabolic resources which, combined with earlier flowering time, improved yield under drought.


The neural basis of perceptual hypothesis generation and testing.
Four-dot masking is a new form of visual masking that does not involve local contour interactions or spatial superimposition of the target stimulus and the mask (as, e.g., in pattern or metacontrast masking). Rather, the effective masking mechanism is based on object substitution. Object substitution masking occurs when low-level visual information representations are altered before target identification through iterative interaction with high-level visual processing stages has been completed. Interestingly, object substitution interacts with attention processes: Strong masking effects are observed when attentional orientation toward the target location is delayed. In contrast, no masking occurs when attention can be rapidly shifted to and engaged onto the target location. We investigated the neural basis of object substitution masking by studying the interaction of spatial attention and masking processes using functional magnetic resonance imaging. Behavioral data indicated a two-way interaction between the factors Spatial Attention (valid vs. invalid cueing) and Masking (four-dot vs. pattern masking). As expected, spatial attention improved performance more strongly during object substitution masking. Functional correlates of this interaction were found in the primary visual cortex, higher visual areas, and left intraparietal sulcus. A region-of-interest analysis in these areas revealed that the largest blood oxygenation level-dependent signal changes occurred during effective four-dot masking. In contrast, the weakest signal changes in these areas were observed when target visibility was highest. The data suggest that these areas represent an object substitution network dedicated to the generation and testing of a perceptual hypotheses as described by the object substitution theory of masking of Di-Lollo et al. [Competition for consciousness among visual events: The psychophysics of reentrant visual processes. Journal of Experimental Psychology: General, 129, 481-507, 2000].


Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial.
The propagation of prions, the causative agents of Creutzfeldt-Jakob disease and other human prion diseases, requires post-translational conversion of normal cellular prion protein to disease-associated forms. The antimalarial drug quinacrine (mepacrine) prevents this conversion in vitro, and was given to patients with various prion diseases to assess its safety and efficacy in changing the course of these invariably fatal and untreatable diseases. Patients with prion disease were recruited via the UK national referral system and were offered a choice between quinacrine (300 mg daily), no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine in an open-label, patient-preference trial. The primary endpoints were death and serious adverse events possibly or probably related to the study drug. This study is registered, ISRCTN 06722585. 107 patients with prion disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) were enrolled, 23 in a pilot study and 84 in the main study. Only two patients chose randomisation; 40 took quinacrine during follow-up (37 who chose it at enrollment). Choice of treatment was associated with disease severity, with those least and most severely affected more likely to choose not to receive quinacrine. 78 (73%) patients died: one randomly assigned to deferred treatment, 26 of 38 who chose immediate quinacrine, and 51 of 68 who chose no quinacrine. Although adjusted mortality was lower in those who chose to take quinacrine than in those who did not, this was due to confounding with disease severity, and there was no difference in mortality between groups after adjustment. Four of 40 patients who took quinacrine had a transient response on neurological rating scales. Only two of 14 reported serious adverse events were judged quinacrine-related. Quinacrine at a dose of 300 mg per day was reasonably tolerated but did not significantly affect the clinical course of prion diseases in this observational study.


A literature review and survey of childhood pneumonia etiology studies: 2000-2010.
The Pneumonia Etiology Research for Child Health (PERCH) project is the largest multicountry etiology study of childhood pneumonia since the Board on Science and Technology in International Development studies of the 1980s. However, it is not the only recent or ongoing pneumonia etiology study, and even with seven sites, it cannot capture all epidemiologic settings in the developing world. Funding providers, researchers and policymakers rely on the best available evidence to strategically plan programs, new research directions and interventions. We aimed to describe the current landscape of recent pneumonia etiology studies in children under 5 years of age in the developed and developing world, as ascertained by a literature review of relevant studies with data since the year 2000 and a survey of researchers in the field of childhood pneumonia. We collected information on the study population, study design, case definitions, laboratory samples and methods and identified pathogens. A literature review identified 88 studies with child pneumonia etiology results. As of June 2010, our survey of researchers identified an additional 65 ongoing and recently completed child pneumonia etiology studies. This demonstrates the broad existing context into which the PERCH study must be placed. However, the landscape analysis also reveals a multiplicity of case definitions, levels of clinician involvement, facility types, specimen collection, and laboratory techniques. It reinforces the need for the standardization of methods and analyses for present and future pneumonia etiology studies in order to optimize their cumulative potential to accurately describe the microbial causes of childhood pneumonia.


Association of a Beverage Tax on Sugar-Sweetened and Artificially Sweetened Beverages With Changes in Beverage Prices and Sales at Chain Retailers in a Large Urban Setting.
Policy makers have implemented beverage taxes to generate revenue and reduce consumption of sweetened drinks. In January 2017, Philadelphia, Pennsylvania, became the second US city to implement a beverage excise tax (1.5 cents per ounce). To compare changes in beverage prices and sales following the implementation of the tax in Philadelphia compared with Baltimore, Maryland (a control city without a tax) and to assess potential cross-border shopping to avoid the tax in neighboring zip codes. This study used a difference-in-differences approach and analyzed sales data to compare changes between January 1, 2016, before the tax, and December 31, 2017, after the tax. Differences by store type, beverage sweetener status, and beverage size were examined. The commercial retailer sales data included large chain store sales in Philadelphia, Baltimore, and the Pennsylvania zip codes bordering Philadelphia. These data reflect approximately 25% of the ounces of taxed beverages sold in Philadelphia. Philadelphia's tax on sugar-sweetened and artificially sweetened beverages. Change in taxed beverage prices and volume sales. A total of 291 stores (54 supermarkets, 20 mass merchandise stores, 217 pharmacies) were analyzed. The mean price per ounce of taxed beverages in Philadelphia increased from 5.43 cents in 2016 to 6.24 cents in 2017 at supermarkets; from 5.28 cents to 6.24 cents at mass merchandise stores, and from 6.60 cents to 8.28 cents at pharmacies. The mean price per ounce in Baltimore increased from 5.33 cents in 2016 to 5.50 cents in 2017 at supermarkets, from 6.34 cents to 6.52 cents at mass merchandise stores, and from 6.76 cents to 6.93 cents at pharmacies. The mean per-ounce difference in price between the 2 cities was 0.65 cents (95% CI, 0.60 cents-0.69 cents; P<.001) at supermarkets; 0.87 cents (95 % CI, 0.72 cents-1.02 cents; P<.001) at mass merchandise stores, and 1.56 cents (95% CI, 1.50 cents-1.62 cents; P<.001) at pharmacies. Total volume sales of taxed beverages in Philadelphia decreased by 1.3 billion ounces (from 2.475 billion to 1.214 billion) or by 51.0% after tax implementation. Volume sales in the Pennsylvania border zip codes, however, increased by 308.2 million ounces (from 713.1 million to 1.021 billion), offsetting the decrease in Philadelphia's volume sales by 24.4%. In Philadelphia, beverage volume sales in ounces per 4-week period between before and after tax periods decreased from 4.85 million to 1.99 million at supermarkets, from 2.98 million to 1.72 million at mass merchandise stores, and from 0.16 million to 0.13 million at pharmacies. In Baltimore, the beverage volume sales in ounces decreased from 2.83 million to 2.81 million at supermarkets, from 1.05 million to 1.00 million at mass merchandise stores, and from 0.14 million to 0.13 million at pharmacies. This was a 58.7% reduction at supermarkets (difference-in-differences, -2.85 million ounces; 95% CI, -4.10 million to -1.60 million ounces; P < .001), 40.4% reduction at mass merchandise stores (difference-in-differences, -1.20 million ounces; 95% CI, -2.04 million to -0.36 million ounces; P = .001), and 12.6% reduction in pharmacies (difference-in-differences, -0.02 million ounces; 95% CI, -0.03 million to -0.01 million ounces; P < .001). In Philadelphia in 2017, the implementation of a beverage excise tax on sugar-sweetened and artificially sweetened beverages was associated with significantly higher beverage prices and a significant and substantial decline in volume of taxed beverages sold. This decrease in taxed beverage sales volume was partially offset by increases in volume of sales in bordering areas.


Sero-diagnosis of Mycobacterium avium complex lung disease using serum immunoglobulin A antibody against glycopeptidolipid antigen in Taiwan.
Lung disease (LD) due to non-tuberculous mycobacteria is an important clinical concern. Mycobacterium avium complex (MAC) is one of the most common causative agents but the diagnosis of MAC-LD remains challenging. Detection of serum IgA antibody against MAC glycopeptidolipid (GPL) has recently been shown to improve the diagnosis of MAC-LD, but has yet to be validated worldwide. This prospective study was conducted in a tertiary referral center in northern Taiwan and enrolled patients with MAC-LD, MAC contamination, other lung diseases, and control subjects. Serum immunoglobulin A (IgA) antibody against MAC-GPL was detected in the participants and its specificity and sensitivity was assessed. There were 56 patients with MAC-LD, 11 with MAC contamination, 13 M. kansasii-LD, 26 LD due to rapidly-growing mycobacteria (RGM), 48 pulmonary tuberculosis, and 42 household contacts of patients with TB. Patients with MAC-LD were older and 32% of them had an underlying co-morbidity. By logistic regression, serum MAC-GPL IgA level was an independent predictor of MAC-LD among the study subjects and those with culture-positive specimens for MAC. By the receiver operating characteristic curve, serum MAC-GPL IgA had a good power to discriminate MAC-LD from MAC contamination. Under the optimal cut-off value of 0.73 U/mL, its sensitivity and specificity were 60% and 91%, respectively. Among MAC-LD patients, presence of co-morbidity was associated with MAC-GPL <0.73 U/ml in logistic regression analysis. Measurement of serum anti-MAC-GPL IgA level is useful for the diagnosis of MAC-LD. However, its implement in clinical practice for immuno-compromised hosts needs careful consideration.


Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.


Fast and robust design of time-optimal k-space trajectories in MRI.
Many applications in MRI such as accelerated receive and transmit sequences require the synthesis of nonuniform 3-D gradient trajectories. Several methods have been proposed to design these gradient trajectories in a time-optimal manner, subject to hardware specific gradient magnitude and slew rate constraints. In this work a novel method is derived that designs time-optimal trajectories, solely based on a set of arbitrarily chosen control points in k-space. In particular, no path constraint is required for the k-space trajectory. It is shown that the above problem can be formulated as a constrained optimization problem. The fact that the objective function is derived in an analytic manner allows for designing time-optimal 3-D gradient trajectories within only few seconds without any significant numerical instabilities. The utilization of the shape of the trajectory--serving as a degree of freedom--results in significantly accelerated trajectories compared to current standard methods. This is proven in an extensive evaluation of the proposed method and in comparison with what can be considered the current Gold Standard method. The proposed Gradient Basis Function method provides significant benefits over current standard methods in terms of the duration of the trajectory (in average 9.2% acceleration), computation time (acceleration by at least 25% up to factors of 100), and robustness (no significant numerical instabilities).